NITROGEN HETEROCYCLIC COMPOUNDS AND METHODS OF USE RELATED APPLICATION [0001] This application claims priority to, and the benefit of, U.S. Application No. 62/950,717, filed December 19, 2019, the entire content of which is incorporated herein by reference. FIELD OF DISCLOSURE [0002] The present disclosure relates to new compounds as inhibitors of receptor tyrosine kinases (RTK), in particular oncogenic mutants of ErbB-receptors. The disclosure also relates to methods of preparation these compounds, compositions comprising these compounds, and methods of using them in the prevention or treatment of abnormal cell growth in mammals, especially humans. BACKGROUND [0003] Mutations affecting either the intracellular catalytic domain or extracellular ligand binding domain of an ErbB receptor can generate oncogenic activity (the ErbB protein family consists of 4 members including ErbB-1, also named epidermal growth factor receptor (EGFR) and Erb-2, also named HER2 in humans). ErbB inhibitors are a known treatment for a number of cancers. However, not every patient is responsive satisfactorily to this treatment. Thus, there is a long-felt need in the art for new therapies that are able to address the variable responsiveness of cancer patients to known therapies. The present disclosure provides compositions and methods for treating cancer in patients with these oncogenic mutations without the variable reponsivenss observed when patients having these ErbB mutants are treated using the existing standard of care. SUMMARY [0004] In some aspects, the present disclosure provides a compound of Formula (I):
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: W is =CH–, =C(-O(C
1-C
6 alkyl))–, =C(C
1-C
6 alkyl)–, =C(halogen)–, or =N–;
Z is 3- to 8-membered heterocycloalkyl optionally substituted with one or more R
Z; each R
Z independently is halogen, C
1-C
6 alkyl, C
3-C
8 cycloalkyl, or 3- to 8-membered heterocycloalkyl, wherein the C
1-C
6 alkyl, C
3-C
8 cycloalkyl, or 3- to 8-membered heterocycloalkyl is optionally substituted with one or more halogen; X
1 is –NH–, –N(C
1-C
6 alkyl)–, or –O–; X
2 is –CH
2–, –NH–, –N(C
1-C
6 alkyl)–, –O–, or –S–; Y is C
6 aryl or 5- to 9-membered heteroaryl, wherein the C
6 aryl or 5- to 9-membered heteroaryl is optionally substituted with one or more R
Y; each R
Y independently: is oxo, halogen, CN, -OH, -NH
2, -O-(C
1-C
6 alkyl), -NH(C
1-C
6 alkyl), -N(C
1-C
6 alkyl)
2, -C(=O)-NH-C
1-C
6 alkyl, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, 3- to 10- membered cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10- membered heteroaryl, -O-(3- to 10-membered cycloalkyl), -O-(3- to 10-membered heterocycloalkyl), -O-(C
6-C
10 aryl), -O-(5- to 10-membered heteroaryl), -(C
1-C
6 alkyl)-(3- to 10-membered cycloalkyl), -(C
1-C
6 alkyl)-(3- to 10-membered heterocycloalkyl), -(C
1- C
6 alkyl)-(C
6-C
10 aryl), -(C
1-C
6 alkyl)-(5- to 10-membered heteroaryl), -O-(C
1-C
6 alkyl)- (3- to 10-membered cycloalkyl), -O-(C
1-C
6 alkyl)-(3- to 10-membered heterocycloalkyl), -O-(C
1-C
6 alkyl)-(C
6-C
10 aryl), -O-(C
1-C
6 alkyl)-(5- to 10-membered heteroaryl), -NH-(C
1- C
6 alkyl)-(3- to 10-membered heterocycloalkyl), -NH-(C
1-C
6 alkyl)-(C
6-C
10 aryl), or -NH- (C1-C6 alkyl)-(5- to 10-membered heteroaryl); wherein the -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C
1-C
6 alkyl)
2, -C(=O)-NH-C
1-C
6 alkyl, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, -O-(3- to 10-membered cycloalkyl), -O-(3- to 10-membered heterocycloalkyl), -O-(C
6-C
10 aryl), -O-(5- to 10-membered heteroaryl), -(C
1-C
6 alkyl)-(3- to 10-membered cycloalkyl), -(C
1-C
6 alkyl)-(3- to 10-membered heterocycloalkyl), -(C
1- C
6 alkyl)-(C
6-C
10 aryl), -(C
1-C
6 alkyl)-(5- to 10-membered heteroaryl), -O-(C
1-C
6 alkyl)- (3- to 10-membered cycloalkyl), -O-(C1-C6 alkyl)-(3- to 10-membered heterocycloalkyl), -O-(C
1-C
6 alkyl)-(C
6-C
10 aryl), -O-(C
1-C
6 alkyl)-(5- to 10-membered heteroaryl), -NH-(C
1- C
6 alkyl)-(3- to 10-membered heterocycloalkyl), -NH-(C
1-C
6 alkyl)-(C
6-C
10 aryl), or -NH- (C
1-C
6 alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more R
Ya; or
together with another R
Y and the intervening atoms attached thereto, form 4- to 10- membered cycloalkyl or 4- to 10-membered hetero cycloalkyl, wherein the 4- to 10- membered cycloalkyl or 4- to 10-membered hetero cycloalkyl is optionally substituted with one or more R
Ya ; each R
Ya independently is halogen, CN, -OH, -NH
2, C
1-C
6 alkyl, -O(C
1-C
6 alkyl), -C(=O)- (C
1-C
6 alkyl), wherein the C
1-C
6 alkyl or -O(C
1-C
6 alkyl) is optionally substituted with one or more halogen; and R
1 is –HC=CH
2 or –C≡C–(C
1-C
6 alkyl). [0005] In some aspects, the present disclosure provides a compound or a pharmaceutically acceptable salt or stereoisomer thereof of formula I
wherein: W is =CH–, =COMe–, =CMe– or =N–; Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C1-4 alkyl, C3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; X
2 is –NH–, –N(C
1-4 alkyl)–, –O– or –S–; Y is a 6 membered aryl or a 5-9 membered heteroaryl, wherein the 6 membered aryl or the 5-9 membered heteroaryl is unsubstituted or substituted with one or more of a group selected from halogen, CF
3, HCF
2, OCF
3, hydroxy, C
1-6 alkyl, C
1-6 alkoxy, C
1-6 alkylhydroxyl, unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryloxy, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted C
1-3 alkoxy-aryl, unsubstituted or substituted C
1-3 alkoxy-heteroaryl, unsubstituted or substituted C
1-3 alkoxy-heterocycloalkyl, unsubstituted or
substituted C
1-3 alkylamino-heterocycloalkyl, unsubstituted or substituted C
1-3 alkylamino-aryl, unsubstituted or substituted C
1-3 alkylamino-heteroaryl; R
1 is –HC=CH
2 or –C≡C–Me. [0006] In some embodiments, Z is of formula i
wherein: R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; and n is 1 or 2. [0007] In some embodiments, the present disclosure provides the compound or the pharmaceutically acceptable salt or stereoisomer thereof of formula I-1 or I-2
wherein: W is =CH–, =COMe–, =CMe– or =N–; X
1 is –NH–, –NMe– or –O–; X
2 is –NH–, –N(C
1-4 alkyl)–, –O– or –S–;
Y is a 6 membered aryl or a 5-9 membered heteroaryl, wherein the 6 membered aryl or the 5-9 membered heteroaryl is unsubstituted or substituted with one or more of a group selected from halogen, CF
3, HCF
2, OCF
3, hydroxy, C
1-6 alkyl, C
1-6 alkoxy, C
1-6 alkylhydroxyl, unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryloxy, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted C
1-3 alkoxy-aryl, unsubstituted or substituted C
1-3 alkoxy-heteroaryl, unsubstituted or substituted C
1-3 alkoxy-heterocycloalkyl, unsubstituted or substituted C
1-3 alkylamino-heterocycloalkyl, unsubstituted or substituted C
1-3 alkylamino-aryl, unsubstituted or substituted C
1-3 alkylamino-heteroaryl; R
1 is –HC=CH
2 or –C≡C–Me; R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form together an unsubstituted oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; m is 1, 2 or 3; n is 1 or 2; and r is 1 or 2. [0008] In some embodiments, Y is of formula ii or iia
wherein: R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5a is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-6 alkyl, C
1-6 alkoxy, C1-6 alkylhydroxyl, unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryloxy, unsubstituted or substituted C
1-3 alkoxy-aryl, unsubstituted or substituted C
1-3 alkoxy-heteroaryl or unsubstituted or substituted C
1-3 alkoxy-heterocycloalkyl; X
3 is –NH– or –NMe–. [0009] In some embodiments, Y is of formula iii or iv
wherein: R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; X
4 is –O–, –NH–, –NMe–; L is a covalent bond or linear or branched C
1-3 alkyl; A is a C
6 aryl, a 6 membered heterocycloalkyl or a 5-6 membered heteroaryl, wherein the C
6 aryl, 6 membered heterocycloalkyl or 5-6 membered heteroaryl is unsubstituted or substituted with one or more of C
1-4 alkyl, OCH
2F, HCF
2, or halogen, e.g., F or Cl. å [0010] In some embodiments, Y is of formula iii, v, vi or vii
wherein: R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3;
R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; X
4 is –O–, –NH–, –NMe–; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; and L is a covalent bond or linear or branched C
1-3 alkyl. [0011] In some embodiments, Y is of formula iii, v-a, e.g., v-a-1 or v-a-2, or vi-a, e.g., vi-a-1, or vii-a, e.g., vii-a-1
wherein: R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF3, HCF2, OCF3, hydroxy, C1-4 alkoxy or C1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl;
X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; and s is 0, 1, 2, 3. [0012] In some embodiments, Y is of formula iii, v-a(i), v-a(ii), e.g., v-a(i)-1, v-a(ii)-1, v-a(i)-2, v-a(ii)-2, or vi-a(i), e.g., vi-a(i)-1, or vii-a(i) or vii-a(ii), e.g., vii-a(i)-1 or vii-a(ii)-1
wherein R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=;
X
8’ is –O–, –S–, –NH– or –NMe–; and s is 0 or 1. [0013] In some embodiments, wherein Y is of formula v-a(i), v-a(ii), v-a(i)-1, v-a(ii)-1, v-a(i)-2 or v-a(ii)-2, (i) X
5, X
5’, X
6, X
6’, X
7 are -CH=, or (ii) X
5 is =N- and X
5’, X
6, X
6’, X
7 are -CH=, or (iii) X
6 is =N- and X
5, X
5’, X
6’, X
7 are -CH=, or (iv) X
7 is =N- and X
5, X
5’, X
6, X
6’ are -CH=, or (v) X
5 and X
6 are –N= and X
5’, X
6’, X
7 are –CH=, or (vi) X
5 and X
5’ are –N= and X
6, X
6’, X
7 are –CH=, or (vii) X
5 and X
6’ are –N= and X
6, X
5’, X
7 are –CH=, or (viii) X
5 and X
7 are –N= and X
5’, X
6, X
6’ are –CH=, or (ix) X
6 and X
6’ are =N- and X
5, X
5’, X
7 are –CH-, or (x) X
6 and X
7 are =N- and X
5, X
5’, X
6’ are –CH–. [0014] In some embodiments, wherein Y is of formula vii-a(i), vii-a(ii), vii-a(i)-1 or vii-a(ii)-1, (i) X
8’ is –O–, X
8 and X
9 are –N= and X
9’ is –CH=, or (ii) X
8’ is –S–, X
8 and X
9 are –N= and X
9’ is – CH=, or (iii) X
8’ is –O–, X
8, X
9 and X
9’ is –CH=, or (iv) X
8’ is –NH–, X
8, X
9 are –CH= and X
9’ is –N=, or (v) X
8’ is –NH–, X
8, X
9’ are –CH= and X
9 is –N=, or (vi) X
8’ is –NMe–, X
8, X
9 are –CH= and X
9’ is –N=, or (vii) X
8’ is –NMe–, X
8, X
9’ are –CH= and X
9 is –N=, or (viii) X
8’ is –NMe–, X
9’ is –N=, X
8 and X
9 are –CH=, or (ix) X
8’ is –NH–, X
9’ is –N=, X
8 and X
9 are –CH=, or (x) X
8’ is –S–, X
8 is –N=, X
9 and X
9’ are –CH=. [0015] In some embodiments, Y is of formula iii, v-a-3, v-a-4 v-a-5, v-a-6, v-a-7, v-a-8, v-a-9, v- a-10, v-b-1, v-b-2, v-b-3, v-b-4, v-b-5, v-b-6, v-b-7, v-b-8, v-b-9, v-b-10, v-b-11, v-b-12, vi-a, vii- a-1, vii-a-2 or vii-a-3
wherein:
R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; s is 0 or 1. [0016] In some embodiments, Y is of formula iii, v-c-1, v-c-2, v-c-3, v-c-4, v-d-1, v-d-2, v-d-3, v- d-4, v-d-5, v-d-6, v-d-7, vi-a, vii-b-1, vii-b-2, vii-b-3 or vii-b-4
wherein: R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF3, HCF2, OCF3, hydroxy, C1-4 alkoxy or C1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; and s is 0 or 1.
[0017] In some embodiments, Y is of formula v-c(i)-1, v-c(ii)-1, v-c(i)-2, v-c(ii)-2, v-c(i)-3, v- c(ii)-3, v-c(i)-4, v-c(ii)-4, v-d(i)-1, v-d(ii)-1, v-d(i)-2, v-d(ii)-2, v-d(i)-3, v-d(ii)-3, v-d(i)-4, v-d(ii)- 4, v-d(i)-5, v-d(ii)-5, v-d(i)-6, v-d(ii)-6, v-d(i)-7, v-d(ii)-7, vi-a(i), vi-a(ii), iii-(i), iii-(ii), iii-(iii), iii-(iv), vii-b(i)-1, vii-b(ii)-1, vii-b(i)-2, vii-b(ii)-2, vii-b(i)-3, vii-b(ii)-3, vii-b(i)-4 or vii-b(ii)-4
wherein R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF3, HCF2, OCF3, hydroxy, C1-4 alkoxy or C1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; and s is 0 or 1. [0018] In some embodiments, the present disclosure provides the compound or pharmaceutical acceptable salts or stereoisomers thereof having formula II or III
wherein: W is =CH–, =COMe–, =CMe– or =N–; Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF2 or C3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; X
2 is –NH–, –N(C
1-4 alkyl)–, –O– or –S–; Y is a group of formula iii, v, vi or vii
wherein: R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; X
4 is –O–, –NH–, –NMe–; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; L is a covalent bond or linear or branched C
1-3 alkyl. [0019] In some embodiments, the present disclosure provides the compound or pharmaceutical acceptable salts or stereoisomers thereof having formula IV-1, IV-2 or IV-3
wherein: W is =CH–, =COMe–, =CMe– or =N–; Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
1 is –CH=CH
2 or -C≡CMe; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF3, HCF2, OCF3, hydroxy, C1-4 alkoxy or C1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; R
8 is H, Me or Et; X
4 is –O–, –NH–, –NMe–; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; L is a covalent bond or linear or branched C
1-3 alkyl.
[0020] In some embodiments, the present disclosure provides the compounds or pharmaceutical acceptable salts or stereoisomers thereof having formula V-1, V-2 or V-3
wherein: W is =CH–, =COMe–, =CMe– or =N–; Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
1 is –CH=CH
2 or -C≡CMe; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; X
4 is –O–, –NH–, –NMe–; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; and
L is a covalent bond or linear or branched C
1-3 alkyl. [0021] In some embodiments, the present disclosure provides the compounds or pharmaceutical acceptable salts or stereoisomers thereof having formula VI-1, VI-2 or VI-3
wherein: W is =CH–, =COMe–, =CMe– or =N–; Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
1 is –CH=CH2 or -C≡CMe; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; X
4 is –O–, –NH–, –NMe–; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=;
X
8’ is –O–, –S–, –NH– or –NMe–; L is a covalent bond or linear or branched C
1-3 alkyl. [0022] In some embodiments, Z is selected from
wherein: R
2 is hydrogen, Me or Et. [0023] In some aspects, the present disclosure provides a composition comprising a compound as described herein or pharmaceutically acceptable salts or stereoisomers thereof. [0024] In some embodiments, the composition further comprises a pharmaceutically acceptable carrier. [0025] In some embodiments, the composition further comprises a second therapeutically active agent. [0026] In some embodiments, the second therapeutically active agent comprises a non-Type I inhibitor. [0027] In some embodiments, the non-Type I inhibitor comprises a small molecule Type II inhibitor. [0028] In some aspects, the present disclosure provides the compound pharmaceutically acceptable salts or stereoisomers thereof or composition, as described herein for use in the treatment of cancer. [0029] In some aspects, the present disclosure provides a method of inhibiting an oncogenic variant of an ErbB receptor (e.g., an oncogenic variant of an EGFR), comprising administering the subject in need thereof a therapeutically effective amount of a compound described herein. [0030] In some aspects, the present disclosure provides a method of inhibiting an oncogenic variant of an ErbB receptor (e.g., an oncogenic variant of an EGFR), comprising administering the subject in need thereof a composition described herein.
[0031] In some aspects, the present disclosure provides a method of preventing or treating cancer, comprising administering the subject in need thereof a therapeutically effective amount of a compound described herein. [0032] In some aspects, the present disclosure provides a method of preventing or treating cancer, comprising administering the subject in need thereof a composition described herein. [0033] In some aspects, the present disclosure provides a method of preventing or treating cancer, comprising: i) identifying a subject candidate as the subject in need of the treatment when that at least one oncogenic variant of an ErbB receptor described herein is present in the subject; and ii) administering the subject in need of the treatment a therapeutically effective amount of a compound described herein. [0034] In some aspects, the present disclosure provides a method of preventing or treating cancer, comprising: i) identifying a subject candidate as the subject in need of the treatment when that at least one oncogenic variant of an ErbB receptor described herein is present in the subject; and ii) administering the subject in need of the treatment a composition described herein. [0035] In some aspects, the present disclosure provides a method of preventing or treating cancer, comprising: i) identifying a subject candidate as the subject in need of the treatment when that at least one oncogenic variant of an ErbB receptor described herein is present in a biological sample from the subject; and ii) administering the subject in need of the treatment a therapeutically effective amount of a compound described herein. [0036] In some aspects, the present disclosure provides a method of preventing or treating cancer, comprising: i) identifying a subject candidate as the subject in need of the treatment when that at least one oncogenic variant of an ErbB receptor described herein is present in a biological sample from the subject; and ii) administering the subject in need of the treatment a composition described herein. [0037] In some aspects, the present disclosure provides a method of preventing or treating cancer, comprising administering the subject in need thereof a therapeutically effective amount of a compound described herein when that at least one oncogenic variant of an ErbB receptor described herein is identified as being present in the subject. [0038] In some aspects, the present disclosure provides a method of preventing or treating cancer, comprising administering the subject in need thereof a compound described herein when that at least one oncogenic variant of an ErbB receptor described herein is identified as being present in
the subject. [0039] In some aspects, the present disclosure provides a method of preventing or treating cancer, comprising administering the subject in need thereof a therapeutically effective amount of a compound described herein when that at least one oncogenic variant of an ErbB receptor described herein is identified as being present in a biological sample from the subject. [0040] In some aspects, the present disclosure provides a method of preventing or treating cancer, comprising administering the subject in need thereof a composition described herein when that at least one oncogenic variant of an ErbB receptor described herein is identified as being present in a biological sample from the subject. [0041] In some aspects, the present disclosure provides a compound described herein for use in the inhibition of an oncogenic variant of an ErbB receptor (e.g., an oncogenic variant of an EGFR). [0042] In some aspects, the present disclosure provides a compound described herein for use in the prevention or treatment of cancer. [0043] In some aspects, the present disclosure provides a composition described herein for use in the inhibition of an oncogenic variant of an ErbB receptor (e.g., an oncogenic variant of an EGFR). [0044] In some aspects, the present disclosure provides a composition described herein for use in the prevention or treatment of cancer. [0045] In some aspects, the present disclosure provides a compound described herein for use in the prevention or treatment of cancer in a subject, wherein at least one oncogenic variant of an ErbB receptor described herein is present in the subject. [0046] In some aspects, the present disclosure provides a composition described herein for use in the prevention or treatment of cancer in a subject, wherein at least one oncogenic variant of an ErbB receptor described herein is present in the subject. [0047] In some aspects, the present disclosure provides a compound described herein for use in the prevention or treatment of cancer in a subject, wherein at least one oncogenic variant of an ErbB receptor described herein is present in a biological sample from the subject. [0048] In some aspects, the present disclosure provides a composition described herein for use in the prevention or treatment of cancer in a subject, wherein at least one oncogenic variant of an ErbB receptor described herein is present in a biological sample from the subject. [0049] In some aspects, the present disclosure provides use of a compound described herein in the manufacture of a medicament for inhibiting an oncogenic variant of an ErbB receptor (e.g., an
oncogenic variant of an EGFR). [0050] In some aspects, the present disclosure provides use of a compound described herein in the manufacture of a medicament for preventing or treating cancer. [0051] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods and examples are illustrative only and are not intended to be limiting. In the case of conflict between the chemical structures and names of the compounds disclosed herein, the chemical structures will control. [0052] Other features and advantages of the disclosure will be apparent from the following detailed description and claims. BRIEF DESCRIPTION OF FIGURES [0053] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. [0054] Fig. 1 is an illustration of the structure of EGFR and a group of 20 genomic mutations affecting the CR1 or CR2 regions of EGFR and which are expressed in GBM tumors. Mutations are highlighted within the crystal structure for the ectodomain of EGFR (1IVO). Mutations are noted as magenta spheres. EGF ligand is shown in green, and the EGFR protomers are shown in grey and orange. See also Table 2. [0055] Fig. 2 is a schematic depiction of an expression pattern for EGFR splicing events and mutations in the CR1 and CR2 regions for a group of 164 GBM tumors. One tumor, TCGA.878, expressing four variants (EGFR-Viii, EGR-A289T, EGFR-A289V, and EGFR-A289D, is noted. More than 65% of GBM tumors express EGFR ectodomain variants affecting the CR1/2 regions. [0056] Fig. 3 is a graph depicting exemplary ectodomain variants of ErbB receptors that are
transforming. The proliferation of BaF3 cells expressing EGFR-Viii, EGFR-Vii, or EGFR-A289V, or vector alone (parental), cultured in the absence of IL-3. The proliferation of parental BaF3 cells cultured in the presence of IL-3 is shown as a control. [0057] Fig. 4 is an illustration of the structure of EGFR and exemplary free cysteines that are formed at the extracellular dimer interface of EGFR as a result of genomic mutations and alternative splicing events in cancer. Arrows note the positions of free cysteines predicted to be generated as a result of the events EGFR-A289V, EGFR-Viii, EGFR-Vii, and EGFR-Vvi. Positions are mapped onto the crystal structure of the ectodomain of EGFR (1IVO). EGF ligand is shown in green, and EGFR protomers are shown in grey and orange. [0058] Fig. 5A is a series of photographs of Western blots depicting the expression of total and phosphorylated monomeric EGFR versus covalent EGFR dimers for EGFR-Viii, EGFR-Vii, EGFR-Vvi, and EGFR-A289V, detected by resolving proteins under non-reducing conditions. The data demonstrate that EGFR-Viii, EGFR-Vii, EGFR-Vvi, and EGFR-A289V exist as covalently activated dimers. [0059] Fig. 5B is a graph depicting the quantitation of results from Fig. 5A, and the quantitation of percentage of receptor that exists as covalent dimer for total versus phosphorylated receptor. [0060] Fig. 6 is a pair of photographs of Western blots depicting the effect of EGF treatment on levels of monomeric and dimeric phosphorylated EGFR for EGFR-Vii and EGFR-Vvi. In contrast to EGFR-Viii, EGF further potentiates the formation of active covalent dimers for EGFR-Vii and EGFR-Vvi. [0061] Fig.7A is a series of photographs of Western blots depicting the effect of 100nM erlotinib treatment on levels of monomeric and dimeric EGFR levels in cells expressing EGFR-Viii, EGFR- Vii, EGFR-Vvi, or EGFR-A289V. Monomeric and dimeric EGFR levels were detected by resolving proteins under non-reducing conditions. The data demonstrate that Type I inhibitors enhance the formation of covalent dimers for all covalently-activated EGFR variants. [0062] Fig. 7B is a pair of photographs of Western blots depicting the effect of varying concentrations of erlotinib on monomeric and dimeric EGFR levels in cells expressing EGFR-Vii. Monomeric and dimeric EGFR levels were detected by resolving proteins under non-reducing conditions. [0063] Fig. 7C is a graph quantifying the data presented in Fig. 7B. The data demonstrate that erlotinib induces a dose dependent increase in covalently dimerized receptor.
[0064] Fig. 8 is a series of photographs of Western blots depicting the effect of a panel of Type I and Type II inhibitors on dimeric and monomeric EGFR levels for cells expressing EGFR-Vii and EGFR-A289V. Monomeric and dimeric EGFR levels were detected by resolving proteins under non-reducing conditions. The data demonstrate that Type I, but not Type II, ErbB inhibitors enhance the formation of covalent dimers for covalently-activated EGFR variants. [0065] Fig. 9 is a series of photographs of Western blots depicting the effect of 100nM erlotinib treatment on monomeric and dimeric EGFR levels for two EGFR variants. Monomeric and dimeric EGFR levels were detected by resolving proteins under non-reducing conditions. The data demonstrate that both EGFR-Δ660 and EGFR-Δ768 can exist as covalent dimers and covalent dimer is potentiated following treatment with erlotinib. [0066] Fig. 10A is a series of photographs of Western blots depicting the effect of varying concentrations of erlotinib on monomeric and dimeric levels of phosphorylated EGFR in cells expressing EGFR-Viii, EGFR-Vii, and EGFR-A289V. Monomeric and dimeric EGFR levels were detected by resolving proteins under non-reducing conditions. The data demonstrate that sub- saturating concentrations of erlotinib stimulate the phosphorylation of covalently dimerized splice- activated EGFR isoforms. [0067] Fig. 10B is a series of photographs of Western blots depicting the effect of varying concentrations of erlotinib treatment, followed by a 30 minute washout, on total and phosphorylated EGFR levels in cells expressing EGFR-Vii or EGFR-Vvi. Proteins were resolved under non-reducing conditions. The data demonstrate that erlotinib paradoxically enhances the phosphorylation of covalent dimers for EGFR-Vii and EGFR-Vvi. [0068] Fig. 11A is a graph depicting the effect of DMSO, 37nM erlotinib, or 100nM erlotinib on the proliferation of BaF3 cells expressing EGFR-Viii. Proliferation data were collected at multiple time points over a three day period. The data demonstrate that sub-saturating concentrations of erlotinib result in paradoxical stimulation of proliferation in cells expressing splice-activated EGFR. [0069] Fig. 11B is a graph depicting the effect of varying concentrations of erlotinib on the proliferation of BaF3 cells expressing EGFR-Viii, EGFR-Vii or EGFR-A289V. Proliferation was assessed at 72 hours after erlotinib dosing. The data demonstrate that sub-saturating concentrations of erlotinib paradoxically stimulate the growth of BaF3 cells driven by EGFR-Viii, EGFR-Vii, and EGFR-A289V.
[0070] Fig. 12 is a series of graphs depicting the effect of 12.5nM or 1uM of WZ8040, WZ3146, or WZ4002 on the proliferation of BaF3 cells expressing EGFR-Viii. Proliferation data were collected at multiple time points over a three day period. The data demonstrate that sub-saturating concentrations of WZ8040, WZ3146 or WZ4002 result in paradoxical stimulation of proliferation in cells expressing EGFR-Viii. [0071] Fig.13A is an illustration of the structure of EGFR and exemplary free cysteines are formed at the extracellular dimer interface of HER2 receptors as a result of genomic mutations and alternative splicing events in cancer. Arrows point to positions of free cysteines generated by the Δ16 splice event or C311R or S310F mutations. [0072] Fig. 13B is a pair of graphs demonstrating that HER2 and HER4 splice variants are transforming. The proliferation of BaF3 cells expressing HER4-WT (JMA), HER4Δ16 (JMC), and HER2Δ16, or vector alone (parental), cultured in the absence of IL-3. The proliferation of parental BaF3 cells cultured in the presence of IL-3 is shown as a control. [0073] Fig.14 is a series of photographs of Western blots depicting the expression of dimeric and monomeric levels of phosphorylated HER2 or HER4 receptors in cells expressing each variant. Monomeric and dimeric EGFR levels were detected by resolving proteins under non-reducing conditions. The data demonstrate that multiple HER2 and HER4 splicing events and mutations in the CR1 and CR2 regions result in covalently active dimers. [0074] Fig.15A is a series of photographs of Western blots depicting the effect of the Type I HER2 inhibitor sapitinib or the Type I HER4 inhibitor afatinib on levels of dimerized receptors for cells expressing HER2-Δ16, HER2-C311R, HER2-S310F, or HER4Δ16. Monomeric and dimeric HER2 and HER4 levels were detected by resolving proteins under non-reducing conditions. The data demonstrate that Type I inhibitors induce the formation of covalent dimers for covalently- activated HER2 and HER4 isoforms. [0075] Fig. 15B a series of photographs of Western blots and corresponding graphs depicting the effect of varying concentrations of sapitinib or afatinib on the levels of dimerized HER2 or HER2 in cells expressing HER2-Δ16 or HER4-Δ16. Monomeric and dimeric HER2 and HRE4 levels were detected by resolving proteins under non-reducing conditions. The data demonstrate that Type I inhibitors induce a dose dependent increase in covalently dimerized receptors for HER2 and HER4 variants. [0076] Fig. 16 is a graph depicting the effect of varying concentrations of sapitinib on the
proliferation of BaF3-HER2-Δ16 cells. The data demonstrate that sub-saturating concentrations of the Type I inhibitor sapitinib paradoxically stimulate the proliferation of BaF3-HER2Δ16 cells. DETAILED DESCRIPTION [0077] The present disclosure relates to new compounds useful as inhibitors of receptor tyrosine kinases (RTK), including oncogenic mutants of ErbB-receptors. In some embodiments, the oncogenic mutants of ErbB-receptors are also allosteric mutants of ErbB-receptors. In some embodiments, the allosteric mutants may comprise or consist of an ErbB receptor variant having a mutation in a sequence outside of an ATP-binding site. In some embodiments, the allosteric mutants may comprise or consist of an ErbB receptor variant having a mutation in a sequence within one or more of exon 19, exon 20 or a C1-C2 extracellular dimerization interface. [0078] Mutations affecting either the intracellular catalytic domain or extracellular ligand binding domain of an ErbB receptor can generate oncogenic activity (the ErbB protein family consists of 4 members including ErbB-1, also named epidermal growth factor receptor (EGFR) and Erb-2, also named HER2 in humans). Extracellular mutants of ErbB receptors in cancer, including EGFR- Viii (also EGFR-V3) and HER2-S310F, are constitutively activated in the absence of ligand, exhibit sustained signaling that is resistant to downregulation, and are both transforming and tumorigenic (Nishikawa, Ji et al. 1994, 2013, Francis, Zhang et al. 2014). Their expression is associated with metastasis and with poor long term overall survival. [0079] In glioblastoma (also glioblastoma multiforma or GBM), EGFR-Viii is expressed by 20% of tumors (Sugawa, Ekstrand et al.1990, Brennan, Verhaak et al.2013). Expression of EGFR-Viii in GBM tends to be mutually exclusive with expression of other RTK oncogenes, which are co- expressed with EGFR variants in only 7% of GBM tumors (Furnari, Cloughesy et al.2015). These data demonstrate how EGFR-Viii in GBM has a dominant and mutually exclusive expression pattern compared with other oncogenic drivers. EGFR-Viii is also expressed by approximately 30% of SCCHN tumors (Sok, Coppelli et al.2006, Keller, Shroyer et al.2010, Wheeler, Suzuki et al. 2010, Tinhofer, Klinghammer et al. 2011, Wheeler, Egloff et al. 2015) and 10% of squamous NSCLC (Ji, Zhao et al. 2006, Sasaki, Kawano et al. 2007), and is associated with resistance to current therapeutics including the anti-EGFR antibody cetuximab (Sok, Coppelli et al. 2006, Tinhofer, Klinghammer et al.2011). Normal tissues do not express this oncogenic receptor variant. [0080] HER2-S310F is the most common mutation of HER2 expressed in human tumors,
expressed by approximately 0.5% of all tumors. HER2-S310F expression is mutually exclusive with expression of HER2 amplification. HER2-S310F is highly oncogenic, transforming BaF3 cells (a murine interleukin-3 (IL-3) dependent pro-B cell line) to IL-3 independence and promoting tumor growth in vivo. [0081] Short insertions of within Exon 20 of EGFR and HER2 are expressed by lung adenocarcinoma tumors and other tumor groups. ErbB Exon 20 insertion mutants are expressed by 4-5% of lung adenocarcinoma tumors. Examples include HER2-YVMA, EGFR-SVD, and EGFR-NPH. These ErbB Exon 20 insertion mutants are highly oncogenic, transforming BaF3 cells to IL-3 independence and promoting tumor growth in vivo. [0082] ErbB inhibitors are a known treatment for a number of cancers. However, not every patient is responsive satisfactorily to this treatment. Thus, there is a long-felt need in the art for new therapies that are able to address the variable responsiveness of cancer patients to known therapies. The present disclosure is able to overcome some of these drawbacks of the standard of care, as it existed prior to the development of the compositions and methods disclosed herein. Definitions [0083] Unless specified otherwise the following general definitions apply to all compounds of the disclosure according to the description. [0084] The term "compound of the disclosure," as used herein, refers to compounds represented by formulae I to VII and any of the specific examples disclosed herein. [0085] It is understood that “independently of each other” means that when a group is occurring more than one time in any compound, its definition on each occurrence is independent from any other occurrence. [0086] It is further understood that a dashed line (or a wave being transverse to a bond) depicts the site of attachment of a residue (i.e. a partial formula). [0087] The term "halogen" or "hal" as used herein may be fluoro (F), chloro (Cl), bromo (Br), or iodo (I), e.g., fluoro (F) or chloro (Cl). [0088] As used herein, “alkyl”, “C
1, C
2, C
3, C
4, C
5 or C
6 alkyl” or “C
1-C
6 alkyl” is intended to include C
1, C
2, C
3, C
4, C
5 or C
6 straight chain (linear) saturated aliphatic hydrocarbon groups and C
3, C
4, C
5 or C
6 branched saturated aliphatic hydrocarbon groups. For example, C
1-C
6 alkyl is intends to include C
1, C
2, C
3, C
4, C
5 and C
6 alkyl groups. Examples of alkyl include, moieties
having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl or n-hexyl. In some embodiments, a straight chain or branched alkyl has six or fewer carbon atoms (e.g., C
1-C
6 for straight chain, C
3-C
6 for branched chain), and in another embodiment, a straight chain or branched alkyl has four or fewer carbon atoms. In some embodiments, the term "alkyl" as used herein refers to a fully saturated branched or unbranched hydrocarbon moiety. The term "C
1-4alkyl" refers to a fully saturated branched or unbranched hydrocarbon moiety having 1, 2, 3 or 4 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso- butyl, tert-butyl. [0089] As used herein, the term “optionally substituted alkyl” refers to unsubstituted alkyl or alkyl having designated substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulphhydryl, alkylthio, arylthio, thiocarboxylate, sulphates, alkylsulphinyl, sulphonato, sulphamoyl, sulphonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. [0090] As used herein, the term “alkenyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond. For example, the term “alkenyl” includes straight chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), and branched alkenyl groups. In certain embodiments, a straight chain or branched alkenyl group has six or fewer carbon atoms in its backbone (e.g., C
2-C
6 for straight chain, C
3-C
6 for branched chain). The term “C
2-C
6” includes alkenyl groups containing two to six carbon atoms. The term “C3-C6” includes alkenyl groups containing three to six carbon atoms. [0091] As used herein, the term “optionally substituted alkenyl” refers to unsubstituted alkenyl or alkenyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl,
alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulphhydryl, alkylthio, arylthio, thiocarboxylate, sulphates, alkylsulphinyl, sulphonato, sulphamoyl, sulphonamido, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. [0092] As used herein, the term “alkynyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond. For example, “alkynyl” includes straight chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), and branched alkynyl groups. In certain embodiments, a straight chain or branched alkynyl group has six or fewer carbon atoms in its backbone (e.g., C
2-C
6 for straight chain, C
3-C
6 for branched chain). The term “C
2-C
6” includes alkynyl groups containing two to six carbon atoms. The term “C
3-C
6” includes alkynyl groups containing three to six carbon atoms. As used herein, “C
2-C
6 alkenylene linker” or “C
2-C
6 alkynylene linker” is intended to include C
2, C
3, C
4, C
5 or C
6 chain (linear or branched) divalent unsaturated aliphatic hydrocarbon groups. For example, C
2-C
6 alkenylene linker is intended to include C
2, C
3, C
4, C
5 and C
6 alkenylene linker groups. [0093] As used herein, the term “optionally substituted alkynyl” refers to unsubstituted alkynyl or alkynyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulphhydryl, alkylthio, arylthio, thiocarboxylate, sulphates, alkylsulphinyl, sulphonato, sulphamoyl, sulphonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. [0094] The term “alkoxy” or “alkoxyl” as used herein includes substituted and unsubstituted alkyl
groups covalently linked to an oxygen atom. Examples of alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy and pentoxy groups. The term C
1-4alkoxy refers to a fully saturated branched or unbranched hydrocarbon moiety having 1, 2, 3 or 4 carbon atoms, bound to an oxygen. Representative examples include, but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, iso-butoxy, tert-butoxy. The tern C
1-3 alkoxy-aryl refers to a C
1-3 alkoxy group which is substituted with an aryl, such as for example –O–(CH
2)
2–aryl, –O–(CH
2)–aryl, –O–(CH
2)
3–aryl. Likewise, the term C
1-3 alkoxy-heteroaryl refers to a C
1-3 alkoxy group which is substituted with a heteroaryl, such as for example –O–(CH
2)
2–heteroaryl, –O–(CH
2)–heteroaryl, –O–(CH
2)
3–heteroaryl. Likewise, the term C
1-3 alkoxy-heterocycloalkyl refers to a C
1-3 alkoxy group which is substituted with a heterocycloalkyl, such as for example –O–(CH
2)
2–heterocycloalkyl, –O–(CH
2)–heterocycloalkyl, –O–(CH2)3–heterocycloalkyl. [0095] The term “alkyamino” as used herein includes substituted and unsubstituted alkyl groups covalently linked to a nitrogen atom. The term C
1-4alkylamino refers to a fully saturated branched or unbranched hydrocarbon moiety having 1, 2, 3 or 4 carbon atoms, bound to a nitrogen. Representative examples include, but are not limited to, methylamino, dimethylamino, ethylamino, n-propylamino, iso-propylamino, n-butylamino, sec-butylamino, iso-butylamino, tert- butylamino. The tern C
1-3 alkylamino-aryl refers to a C
1-3 alkylamino group which is substituted with an aryl, such as for example –NH–(CH
2)
2–aryl, –NH–(CH
2)–aryl, –NH–(CH
2)
3–aryl, –NMe– (CH2)2–aryl, –NMe–(CH2)–aryl, –NMe–(CH2)3–aryl. Likewise, the term C1-3 alkylamino- heteroaryl refers to a C
1-3 alkylamino group which is substituted with a heteroaryl, such as for example –NH–(CH
2)
2–heteroaryl, –NH–(CH
2)–heteroaryl, –NH–(CH
2)
3–heteroaryl, –NMe– (CH
2)
2–heteroaryl, –NMe–(CH
2)–heteroaryl, –NMe–(CH
2)
3–heteroaryl. Likewise, the term C
1-3 alkylamino-heterocycloalkyl refers to a C
1-3 alkylamino group which is substituted with a heterocycloalkyl, such as for example –NH–(CH
2)
2–heterocycloalkyl, –NH–(CH
2)– heterocycloalkyl, –NH–(CH
2)
3–heterocycloalkyl, –NMe–(CH
2)
2–heterocycloalkyl, –NMe– (CH2)–heterocycloalkyl, –NMe–(CH2)3–heterocycloalkyl. [0096] The term “cycloalkyl” as used herein refers to a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spiro rings) system having 3 to 30 carbon atoms (e.g., C3-C12, C3-C10, or C3-C8). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,
cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, adamantly, hexahydroindacenyl. It is understood that for polycyclic (e.g., fused, bridged, or spiro rings) system, only one of the rings therein needs to be non-aromatic. [0097] The terms “heterocycle” or “heterocycloalkyl” as used herein refer to a saturated or partially unsaturated hydrocarbon monocyclic system having 3 to 10, e.g., 3 to 6 ring atoms selected from C, N, O, S. The term "heterobicycle” refers to a saturated or partially unsaturated hydrocarbon bicyclic system (e.g., fused, bridged, or spiro rings) having 3 to 10, e.g., 5 to 8 ring atoms selected from C, N, O, S. Examples include, but are not limited to, epoxy, oxiranyl, thiaranyl, aziradinyl, oxetanyl, thiatanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiopyranyl, dihydropyranyl, tetrahydropyranyl, 1,3-dioxolanyl, 1,4-dioxanyl, 1,4- oxathianyl 1,4-dithianyl, 1,3-dioxane, 1,3-dithianyl, piperazinyl, thiomorpholinyl, piperidinyl, morpholinyl, oxepanyl, thiepanyl, azepanyl, diazepanyl, oxazepanyl3-azabicyclo[3.1.0]hexyl, 3- azabicyclo[3.3.0]octyl, 3,7-diazabicyclo[3.3.0]octyl, 3-aza-7-oxabicyclo[3.3.0]octyl , 2,6- diazabicyclo[3.3.0]octyl, 2,7-diazabicyclo[3.3.0]octyl, 2,8-diazabicyclo[4.3.0]nonyl, 3-oxa-8- azabicyclo[4.3.0]nonyl, 2-oxa-8-azabicyclo[4.3.0]nonyl, 2,8-diaza-5-oxabicyclo[4.3.0]nonyl, 4,9- diazabicyclo[4.3.0]nonyl, 2,9-diazabicyclo[4.3.0]nonyl, 3,8-diazabicyclo[4.3.0]nonyl, 3,7- diazabicyclo[4.3.0]nonyl, 3,9-diazabicyclo[4.3.0]nonyl, 3-oxa-8-azabicyclo[4.3.0]nonyl, 3-thia- 8-azabicyclo[4.3.0]nonyl, and the like. [0098] The term “aryl” as used herein refers to groups with aromaticity, including “conjugated,” or multicyclic systems with one or more aromatic rings and do not contain any heteroatom in the ring structure. The term aryl includes both monovalent species and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like. Conveniently, an aryl is phenyl. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like. In some embodiments, the aryl is phenyl. [0099] In some embodiments, the term “aryl” (which includes aryloxy, alkoxy-aryl, alkylamino- aryl) when used as substituent of the 6 membered aryl or 5-9 membered heteroaryl group of Y in formula I, I-1, I-2 or as part of group R
5a in formula iia is unsubstituted or substituted with one or more of a group selected from C
1-6 alkyl, C
1-6 alkoxy, halogen, CF
3, HCF
2, OCF
3, OCH
2F, hydroxy, C
1-6 alkylhydroxyl, for example C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl. [0100] The term "aryloxy" means a radical of the formula aryl-O-, in which the term aryl has the
significance given above. [0101] As used herein, the term “heteroaryl” is intended to include a stable 5-, 6-, or 7-membered monocyclic or 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic aromatic heterocyclic ring which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g.¸ 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulphur. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or other substituents, as defined). The nitrogen and sulphur heteroatoms may optionally be oxidised (i.e., NoO and S(O)
p, where p = 1 or 2). It is to be noted that total number of S and O atoms in the aromatic heterocycle is not more than 1. In some embodiments, the term “heteroaryl”, refers to a (fully) aromatic ring system having 3, 4, 5, or 6 ring atoms, preferably 6 ring atoms, selected from C, N, O, or S, preferably C, N, or O, more preferably C, N, with the number of N atoms preferably being 0, 1, 2 or 3 and the number of O and S atoms each being 0, 1 or 2. Examples of “heteroaryl” include furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl (pyrazyl), pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, thiazolyl, thienyl, and the like. Preferred examples of “heteroaryl” include pyridinyl. [0102] In some embodimenets, the term “heteroaryl” (which includes heteroaryloxy, alkoxy- heteroaryl, alkylamino-heteroaryl) when used as substituent of the 6 membered aryl or 5-9 membered heteroaryl group of Y in formula I, I-1, I-2 or as part of group R
5a in formula iia is unsubstituted or substituted with one or more of a group selected from C
1-6 alkyl, C
1-6 alkoxy, halogen, CF
3, HCF
2, OCF
3, OCH
2F, hydroxy, C
1-6 alkylhydroxyl, for example C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl. [0103] The term "heteroaryloxy" means a radical of the formula heteroaryl-O-, in which the term heteroaryl has the significance given above. [0104] In some embodiments, the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is substituted at one or more ring positions (e.g., the ring-forming carbon or heteroatom such as N) with such substituents as described above, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including
alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. In some embodiments, the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is substituted with halogen (e.g., F or Cl). [0105] As used herein, the term “substituted,” means that any one or more hydrogen atoms on the designated atom is replaced with a selection from the indicated groups, provided that the designated atom’s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is oxo or keto (i.e., =O), then 2 hydrogen atoms on the atom are replaced. Keto substituents are not present on aromatic moieties. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N or N=N). [0106] According to the methods of the disclosure, the term “mammal” refers to any mammal, including humans, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, cats, cattle, horses, sheep, pigs, goats, rabbits, etc. (e.g. human). [0107] The term "prevention" or “preventing” refers to reducing or eliminating the onset of the symptoms or complications of a disease (e.g., cancer). In some embodiments, such prevention comprises the step of administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition containing a compound of Formula I or a pharmaceutically acceptable salt thereof) to a subject in need thereof (e.g., a mammal (e.g., a human). [0108] The term "treatment" or “treating” is intended to encompass therapy and cure. In some embodiments, such treatment comprises the step of administering a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition containing a compound of Formula I or a pharmaceutically acceptable salt thereof) to a subject in need thereof (e.g., a mammal (e.g., a human). In some embodiments, the term “treating” or “treatment” refers to therapeutic treatment measures; wherein the object is to slow down (lessen) the targeted pathologic condition or disorder. Those in need of treatment include those already with the disorder as well as those prone to have the disorder. For example, when
treating cancer according to a method of the disclosure, a subject or mammal is successfully “treated” for cancer if, after receiving a therapeutic amount of an ErbB inhibitor according to the methods of the present disclosure, the patient shows observable and/or measurable reduction in or absence of one or more of the following: reduction in the number of cancer cells or absence of the cancer cells; reduction in the proliferation or survival of cancer cells; and/or relief to some extent, one or more of the symptoms associated with the specific infection; reduced morbidity and mortality, and improvement in quality of life issues. The above parameters for assessing successful treatment and improvement in the disease are readily measurable by routine procedures familiar to a physician. [0109] According to the methods of the disclosure, subjects having a mutation of the disclosure may be treated for cancer by administering a therapeutically-effective amount of a composition of the disclosure, a Type II ErbB inhibitor, an EGFR-Viii selective agent/inhibitor or the NT-113 Type I inhibitor. The term “therapeutically effective amount” refers to an amount of a composition of the disclosrue, a Type II ErbB inhibitor, an EGFR-Viii selective agent/inhibitor or the NT-113 Type I inhibitor effective to “treat” a disease or disorder (e.g. cancer) in a subject or mammal. See preceding definition of “treating.” [0110] According to the methods of the disclosure, a Type II ErbB inhibitor may include a small molecule. A “small molecule” is defined herein to have a molecular weight below about 1500 Daltons. [0111] According to the methods of the disclosure, mutations may be detected by analyzing either nucleic acid or amino acid sequences from a subject. Nucleic acid and/or amino acid sequences may be isolated prior to sequence analysis. [0112] The terms “nucleic acid” and “polynucleotide” are used interchangeably herein to refer to single- or double-stranded RNA, DNA, or mixed polymers. Polynucleotides may include genomic sequences, extra-genomic and plasmid sequences, and smaller engineered gene segments that express, or may be adapted to express polypeptides. [0113] An “isolated nucleic acid” is a nucleic acid that is substantially separated from other genome DNA sequences as well as proteins or complexes such as ribosomes and polymerases, which naturally accompany a native sequence. The term embraces a nucleic acid sequence that has been removed from its naturally occurring environment, and includes recombinant or cloned DNA isolates and chemically synthesized analogues or analogues biologically synthesized by
heterologous systems. A substantially pure nucleic acid includes isolated forms of the nucleic acid. This refers to the nucleic acid as originally isolated and does not exclude genes or sequences later added to the isolated nucleic acid. [0114] The term “polypeptide” is used in its conventional meaning, i.e., as a sequence of amino acids. The polypeptides are not limited to a specific length of the product. Peptides, oligopeptides, and proteins are included within the definition of polypeptide, and such terms may be used interchangeably herein unless indicated otherwise. This term also does not refer to or exclude post- expression modifications of the polypeptide, for example, glycosylations, acetylations, phosphorylations and the like, as well as other modifications known in the art, both naturally occurring and non-naturally occurring. A polypeptide may be an entire protein, or a subsequence thereof. [0115] An “isolated polypeptide” is one that has been identified and separated and/or recovered from a component of its natural environment. In some embodiments, the isolated polypeptide will be purified (1) to greater than 95% by weight of polypeptide as determined by the Lowry method (e.g. more than 99% by weight), (2) to a degree sufficient to obtain at least 15 residues of N- terminal or internal amino acid sequence by use of a spinning cup sequenator, or (3) to homogeneity by SDS-PAGE under reducing or non-reducing conditions using Coomassie blue or silver stain. Isolated polypeptide includes the polypeptide in situ within recombinant cells since at least one component of the polypeptide's natural environment will not be present. In some embodiments, the isolated polypeptide will be prepared by at least one purification step. [0116] A “native sequence” polynucleotide is one that has the same nucleotide sequence as a polynucleotide derived from nature. A “native sequence” polypeptide is one that has the same amino acid sequence as a polypeptide (e.g. EGFR) derived from nature (e.g., from any species). Such native sequence polynucleotides and polypeptides can be isolated from nature or can be produced by recombinant or synthetic means. [0117] A polynucleotide “variant,” as the term is used herein, is a polynucleotide that differs from a disclosed polynucleotide herein in one or more substitutions, deletions, additions and/or insertions. [0118] A polypeptide “variant,” as the term is used herein, is a polypeptide that differs from a disclosed polypeptide herein in one or more substitutions, deletions, additions and/or insertions, or inversions. Such variants may be naturally occurring, non-naturally occurring, or may be
synthetically generated. [0119] EGFR mutations (or variants) of the disclosure may comprise one or more substitutions, deletions, additions and/or insertions, or inversions of the amino acid sequence that are alter the function of the resultant protein. Mutations may be detected, for example, by comparison or alignment of a nucleic or amino acid sequence with a wild type sequence. [0120] When comparing polynucleotide and polypeptide sequences, two sequences are said to be “identical” if the sequence of nucleotides or amino acids in the two sequences is the same when aligned for maximum correspondence, as described below. Comparisons between two sequences are performed by comparing the sequences over a comparison window to identify and compare local regions of sequence similarity. A “comparison window” as used herein, refers to a segment of at least about 20 contiguous positions, (e.g. 30 to about 75 or 40 to about 50), in which a sequence may be compared to a reference sequence of the same number of contiguous positions after the two sequences are optimally aligned. [0121] Optimal alignment of sequences for comparison may be conducted using the Megalign program in the Lasergene suite of bioinformatics software (DNASTAR, Inc., Madison, WI), using default parameters. This program embodies several alignment schemes described in the following references: Dayhoff, M.O. (1978) A model of evolutionary change in proteins – Matrices for detecting distant relationships. In Dayhoff, M.O. (ed.) Atlas of Protein Sequence and Structure, National Biomedical Research Foundation, Washington DC Vol.5, Suppl.3, pp.345-358; Hein J. (1990) Unified Approach to Alignment and Phylogenes pp.626-645 Methods in Enzymology vol. 183, Academic Press, Inc., San Diego, CA; Higgins, D.G. and Sharp, P.M. (1989) CABIOS 5:151- 153; Myers, E.W. and Muller W. (1988) CABIOS 4:11-17; Robinson, E.D. (1971) Comb. Theor 11:105; Santou, N. Nes, M. (1987) Mol. Biol. Evol. 4:406-425; Sneath, P.H.A. and Sokal, R.R. (1973) Numerical Taxonomy – the Principles and Practice of Numerical Taxonomy, Freeman Press, San Francisco, CA; Wilbur, W.J. and Lipman, D.J. (1983) Proc. Natl. Acad., Sci. USA 80:726-730. [0122] Optimal alignment of sequences for comparison may be conducted by the local identity algorithm of Smith and Waterman (1981) Add. APL. Math 2:482, by the identity alignment algorithm of Needleman and Wunsch (1970) J. Mol. Biol. 48:443, by the search for similarity methods of Pearson and Lipman (1988) Proc. Natl. Acad. Sci. USA 85: 2444, by computerized implementations of these algorithms (GAP, BESTFIT, BLAST, FASTA, and TFASTA in the
Wisconsin Genetics Software Package, Genetics Computer Group (GCG), 575 Science Dr., Madison, WI), or by inspection. [0123] One example of algorithms that are suitable for determining percent sequence identity and sequence similarity are the BLAST and BLAST 2.0 algorithms, which are described in Altschul et al. (1977) Nucl. Acids Res. 25:3389-3402 and Altschul et al. (1990) J. Mol. Biol.215:403-410, respectively. BLAST and BLAST 2.0 can be used, for example, with the parameters described herein, to determine percent sequence identity for the polynucleotides and polypeptides of the present disclosure. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information. [0124] In some embodiments, cumulative scores can be calculated using, for nucleotide sequences, the parameters M (reward score for a pair of matching residues; always >0) and N (penalty score for mismatching residues; always <0). Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T and X determine the sensitivity and speed of the alignment. The BLASTN program (for nucleotide sequences) uses as defaults a wordlength (W) of 11, and expectation (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff and Henikoff (1989) Proc. Natl. Acad. Sci. USA 89:10915) alignments, (B) of 50, expectation (E) of 10, M=5, N=-4 and a comparison of both strands. [0125] For amino acid sequences, a scoring matrix can be used to calculate the cumulative score. Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T and X determine the sensitivity and speed of the alignment. [0126] In one approach, the “percentage of sequence identity” is determined by comparing two optimally aligned sequences over a window of comparison of at least 20 positions, wherein the portion of the polynucleotide or polypeptide sequence in the comparison window may comprise additions or deletions (i.e., gaps) of 20 percent or less (e.g. 5 to 15 percent, or 10 to 12 percent), as compared to the reference sequences (which does not comprise additions or deletions) for
optimal alignment of the two sequences. The percentage is calculated by determining the number of positions at which the identical nucleic acid bases or amino acid residues occur in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the reference sequence (i.e., the window size) and multiplying the results by 100 to yield the percentage of sequence identity. Sequences [0127] A wild type EGFR sequence of the disclosure may comprise or consist of the amino acid sequence of:
[0128] A wild type HER2 Receptor sequence of the disclosure may comprise or consist of the amino acid sequence of:
[0129] A wild type HER2 Receptor sequence of the disclosure may comprise or consist of the amino acid sequence of:
[0130] A wild type HER2 Receptor sequence of the disclosure may comprise or consist of the amino acid sequence of:
[0131] A wild type HER2 Receptor sequence of the disclosure may comprise or consist of the amino acid sequence of:
[0132] A wild type HER2 Receptor sequence of the disclosure may comprise or consist of the amino acid sequence of:
Compounds of the Present Disclosure [0133] In some aspects, the present disclosure provides a compound of Formula (I):
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: W is =CH–, =C(-O(C
1-C
6 alkyl))–, =C(C
1-C
6 alkyl)–, =C(halogen)–, or =N–; Z is 3- to 8-membered heterocycloalkyl optionally substituted with one or more R
Z; each R
Z independently is halogen, C
1-C
6 alkyl, C
3-C
8 cycloalkyl, or 3- to 8-membered heterocycloalkyl, wherein the C
1-C
6 alkyl, C
3-C
8 cycloalkyl, or 3- to 8-membered heterocycloalkyl is optionally substituted with one or more halogen; X
1 is –NH–, –N(C
1-C
6 alkyl)–, or –O–; X
2 is –CH
2–, –NH–, –N(C
1-C
6 alkyl)–, –O–, or –S–; Y is C6 aryl or 5- to 9-membered heteroaryl, wherein the C6 aryl or 5- to 9-membered heteroaryl is optionally substituted with one or more R
Y; each R
Y independently: is oxo, halogen, CN, -OH, -NH
2, -O-(C
1-C
6 alkyl), -NH(C
1-C
6 alkyl), -N(C
1-C
6 alkyl)
2, -C(=O)-NH-C
1-C
6 alkyl, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, 3- to 10- membered cycloalkyl, 3- to 10-membered heterocycloalkyl, C
6-C
10 aryl, 5- to 10- membered heteroaryl, -O-(3- to 10-membered cycloalkyl), -O-(3- to 10-membered heterocycloalkyl), -O-(C
6-C
10 aryl), -O-(5- to 10-membered heteroaryl), -(C
1-C
6 alkyl)-(3- to 10-membered cycloalkyl), -(C1-C6 alkyl)-(3- to 10-membered heterocycloalkyl), -(C1- C
6 alkyl)-(C
6-C
10 aryl), -(C
1-C
6 alkyl)-(5- to 10-membered heteroaryl), -O-(C
1-C
6 alkyl)-
(3- to 10-membered cycloalkyl), -O-(C
1-C
6 alkyl)-(3- to 10-membered heterocycloalkyl), -O-(C
1-C
6 alkyl)-(C
6-C
10 aryl), -O-(C
1-C
6 alkyl)-(5- to 10-membered heteroaryl), -NH-(C
1- C
6 alkyl)-(3- to 10-membered heterocycloalkyl), -NH-(C
1-C
6 alkyl)-(C
6-C
10 aryl), or -NH- (C1-C6 alkyl)-(5- to 10-membered heteroaryl); wherein the -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C
1-C
6 alkyl)
2, -C(=O)-NH-C
1-C
6 alkyl, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, -O-(3- to 10-membered cycloalkyl), -O-(3- to 10-membered heterocycloalkyl), -O-(C
6-C
10 aryl), -O-(5- to 10-membered heteroaryl), -(C
1-C
6 alkyl)-(3- to 10-membered cycloalkyl), -(C
1-C
6 alkyl)-(3- to 10-membered heterocycloalkyl), -(C
1- C
6 alkyl)-(C
6-C
10 aryl), -(C
1-C
6 alkyl)-(5- to 10-membered heteroaryl), -O-(C
1-C
6 alkyl)- (3- to 10-membered cycloalkyl), -O-(C
1-C
6 alkyl)-(3- to 10-membered heterocycloalkyl), -O-(C1-C6 alkyl)-(C6-C10 aryl), -O-(C1-C6 alkyl)-(5- to 10-membered heteroaryl), -NH-(C1- C
6 alkyl)-(3- to 10-membered heterocycloalkyl), -NH-(C
1-C
6 alkyl)-(C
6-C
10 aryl), or -NH- (C
1-C
6 alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more R
Ya; or together with another R
Y and the intervening atoms attached thereto, form 4- to 10- membered cycloalkyl or 4- to 10-membered hetero cycloalkyl, wherein the 4- to 10- membered cycloalkyl or 4- to 10-membered hetero cycloalkyl is optionally substituted with one or more R
Ya ; each R
Ya independently is halogen, CN, -OH, -NH2, C1-C6 alkyl, -O(C1-C6 alkyl), -C(=O)- (C
1-C
6 alkyl), wherein the C
1-C
6 alkyl or -O(C
1-C
6 alkyl) is optionally substituted with one or more halogen; and R
1 is –HC=CH
2 or –C≡C–(C
1-C
6 alkyl). [0134] In some aspects, the present disclosure provides a compound of Formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: W is =CH–, =C(-O(C
1-C
6 alkyl))–, =C(C
1-C
6 alkyl)–, =C(halogen)–, or =N–; Z is 3- to 8-membered heterocycloalkyl optionally substituted with one or more R
Z; each R
Z independently is halogen, C
1-C
6 alkyl, C
3-C
8 cycloalkyl, or 3- to 8-membered heterocycloalkyl, wherein the C
1-C
6 alkyl, C
3-C
8 cycloalkyl, or 3- to 8-membered heterocycloalkyl is optionally substituted with one or more halogen; X
1 is –NH–, –N(C
1-C
6 alkyl)–, or –O–;
X
2 is –CH
2–, –NH–, –N(C
1-C
6 alkyl)–, –O–, or –S–; Y is C
6 aryl or 5- to 9-membered heteroaryl, wherein the C
6 aryl or 5- to 9-membered heteroaryl is optionally substituted with one or more R
Y; each R
Y independently is halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), - N(C
1-C
6 alkyl)
2, -C(=O)-NH-C
1-C
6 alkyl, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, 3- to 10- membered heterocycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, -O-(3- to 10-membered heterocycloalkyl), -O-(C
6-C
10 aryl), -O-(5- to 10-membered heteroaryl), -O-(C
1-C
6 alkyl)-(3- to 10-membered heterocycloalkyl), -O-(C
1-C
6 alkyl)-(C
6-C
10 aryl), -O-(C
1-C
6 alkyl)-(5- to 10- membered heteroaryl), -NH-(C
1-C
6 alkyl)-(3- to 10-membered heterocycloalkyl), -NH-(C
1-C
6 alkyl)-(C
6-C
10 aryl), or -NH-(C
1-C
6 alkyl)-(5- to 10-membered heteroaryl); wherein the -O-(C
1-C
6 alkyl), -NH(C
1-C
6 alkyl), -N(C
1-C
6 alkyl)
2, -C(=O)-NH-C
1-C
6 alkyl, C
1-C
6 alkyl, C
2-C
6 alkenyl, C2-C6 alkynyl, 3- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, - O-(3- to 10-membered heterocycloalkyl), -O-(C
6-C
10 aryl), -O-(5- to 10-membered heteroaryl), - O-(C
1-C
6 alkyl)-(3- to 10-membered heterocycloalkyl), -O-(C
1-C
6 alkyl)-(C
6-C
10 aryl), -O-(C
1-C
6 alkyl)-(5- to 10-membered heteroaryl), -NH-(C
1-C
6 alkyl)-(3- to 10-membered heterocycloalkyl), -NH-(C
1-C
6 alkyl)-(C
6-C
10 aryl), or -NH-(C
1-C
6 alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more R
Ya; each R
Ya independently is halogen, CN, -OH, -NH
2, C
1-C
6 alkyl, or -O(C
1-C
6 alkyl), wherein the C
1-C
6 alkyl or -O(C
1-C
6 alkyl) is optionally substituted with one or more halogen; and R
1 is –HC=CH2 or –C≡C–(C1-C6 alkyl). [0135] In some aspects, the present disclosure provides a compound of Formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: W is =CH–, =C(-O(C
1-C
6 alkyl))–, =C(C
1-C
6 alkyl)–, or =N–; Z is 3- to 8-membered heterocycloalkyl optionally substituted with one or more R
Z; each R
Z independently C
1-C
6 alkyl or C
3-C
8 cycloalkyl, wherein the C
1-C
6 alkyl or C
3-C
8 cycloalkyl is optionally substituted with one or more halogen; X
1 is –NH– or –O–; X
2 is –CH
2–, –NH–, –N(C
1-C
6 alkyl)–, –O–, or –S–; Y is C
6 aryl or 5- to 9-membered heteroaryl, wherein the C
6 aryl or 5- to 9-membered heteroaryl is optionally substituted with one or more R
Y;
each R
Y independently is halogen, -OH, -O-(C
1-C
6 alkyl), -C(=O)-NH-C
1-C
6 alkyl, C
1-C
6 alkyl, C
2-C
6 alkynyl, 3- to 10-membered heterocycloalkyl, -O-(C
6-C
10 aryl), -O-(C
1-C
6 alkyl)-(3- to 10-membered heterocycloalkyl), -O-(C
1-C
6 alkyl)-(C
6-C
10 aryl), or -O-(C
1-C
6 alkyl)-(5- to 10- membered heteroaryl); wherein the -O-(C1-C6 alkyl), -C(=O)-NH-C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkynyl, 3- to 10-membered heterocycloalkyl, -O-(C
6-C
10 aryl), -O-(C
1-C
6 alkyl)-(3- to 10- membered heterocycloalkyl), -O-(C
1-C
6 alkyl)-(C
6-C
10 aryl), or -O-(C
1-C
6 alkyl)-(5- to 10- membered heteroaryl) is optionally substituted with one or more R
Ya; each R
Ya independently is halogen, -OH, C
1-C
6 alkyl, or -O(C
1-C
6 alkyl), wherein the C
1- C
6 alkyl or -O(C
1-C
6 alkyl) is optionally substituted with one or more halogen; and R
1 is –HC=CH
2. [0136] In some aspects, the present disclosure provides a compound of Formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: W is =CH– or =C(halogen)–; Z is 3- to 8-membered heterocycloalkyl; X
1 is –NH–, –N(C
1-C
6 alkyl)–, or –O–; X
2 is –NH–, –N(C
1-C
6 alkyl)– or –O–; Y is C
6 aryl or 5- to 9-membered heteroaryl, wherein the C
6 aryl or 5- to 9-membered heteroaryl is optionally substituted with one or more R
Y; each R
Y independently: is halogen, -O-(C1-C6 alkyl), C1-C6 alkyl, -O-(C6-C10 aryl), -O-(5- to 10-membered heteroaryl), -(C
1-C
6 alkyl)-(3- to 10-membered cycloalkyl), -O-(C
1-C
6 alkyl)-(3- to 10- membered cycloalkyl), -O-(C
1-C
6 alkyl)-(3- to 10-membered heterocycloalkyl), or -O-(C
1- C
6 alkyl)-(5- to 10-membered heteroaryl); wherein the -O-(C
1-C
6 alkyl), C
1-C
6 alkyl, -O- (C
6-C
10 aryl), -O-(5- to 10-membered heteroaryl), -(C
1-C
6 alkyl)-(3- to 10-membered cycloalkyl), -O-(C
1-C
6 alkyl)-(3- to 10-membered cycloalkyl), -O-(C
1-C
6 alkyl)-(3- to 10- membered heterocycloalkyl), or -O-(C
1-C
6 alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more R
Ya; or together with another R
Y and the intervening atoms attached thereto, form 4- to 10- membered hetero cycloalkyl, wherein the 4- to 10-membered hetero cycloalkyl is optionally substituted with one or more R
Ya ; each R
Ya independently is halogen or C
1-C
6 alkyl; and
R
1 is –HC=CH
2 or –C≡C–(C
1-C
6 alkyl). Variable W [0137] In some embodiments, W is =CH–. [0138] In some embodiments, W is =C(-O(C
1-C
6 alkyl))–. [0139] In some embodiments, W is =C(-OCH
3)–. [0140] In some embodiments, W is =C(-OCH
2CH
3)–. [0141] In some embodiments, W is =C(C
1-C
6 alkyl)–. [0142] In some embodiments, W is =C(CH
3)–. [0143] In some embodiments, W is =C(halogen)–. [0144] In some embodiments, W is =C(F)–. [0145] In some embodiments, W is =N–. Variables Z and R
Z [0146] In some embodiments, Z is 3- to 8-membered heterocycloalkyl optionally substituted with one or more R
Z. [0147] In some embodiments, Z is 3- to 8-membered heterocycloalkyl optionally substituted with one or more R
Z; wherein the 3- to 8-membered heterocycloalkyl is attached to R
1-C(=O)- via a heteroatom (e.g., N) of the 3- to 8-membered heterocycloalkyl. [0148] In some embodiments, Z is 3- to 8-membered heterocycloalkyl optionally substituted with one or more R
Z; wherein the 3- to 8-membered heterocycloalkyl is attached to X
2 via a carbon atom of the 3- to 8-membered heterocycloalkyl. [0149] In some embodiments, Z is 3- to 8-membered heterocycloalkyl optionally substituted with one or more R
Z; wherein the 3- to 8-membered heterocycloalkyl is attached to X
2 via a carbon atom of the 3- to 8-membered heterocycloalkyl, and wherein the carbon atom is substituted with R
Z. [0150] In some embodiments,
which # indicates attachment to R
1-C(=O)-, n
z1 is an integer ranging from 0 to 6, n
z2 is an integer ranging from 0 to 6, and the total
of n
z1 and n
z2 ranges from 1 to 6. [0151] In some embodiments, Z is , in which # indicates attachment to
R
1-C(=O)-, n
z1 is an integer ranging from 0 to 6, n
z2 is an integer ranging from 0 to 6, and the total of nz1 and nz2 ranges from 1 to 6. [0152] In some embodiments, Z is 3- to 8-membered heterocycloalkyl optionally substituted with one or more R
Z; wherein the 3- to 8-membered heterocycloalkyl is attached to X
2 via a heteroatom (e.g., N) of the 3- to 8-membered heterocycloalkyl. [0153] In some embodiments, Z is 3- to 8-membered heterocycloalkyl optionally substituted with one or more R
Z; wherein the 3- to 8-membered heterocycloalkyl is attached to R
1-C(=O)- via a heteroatom (e.g., N) of the 3- to 8-membered heterocycloalkyl, and the 3- to 8-membered heterocycloalkyl is attached to X
2 via a heteroatom (e.g., N) of the 3- to 8-membered heterocycloalkyl. [0154] In some embodiments, Z is 3- to 8-membered heterocycloalkyl. [0155] In some embodiments, Z is 3- to 8-membered heterocycloalkyl substituted with one or more R
Z. [0156] In some embodiments, Z is 4- to 7-membered heterocycloalkyl optionally substituted with one or more R
Z. [0157] In some embodiments, Z is 4- to 7-membered heterocycloalkyl. [0158] In some embodiments, Z is 4- to 7-membered heterocycloalkyl substituted with one or more R
Z. [0159] In some embodiments, Z is 4-membered heterocycloalkyl optionally substituted with one or more R
Z. [0160] In some embodiments, Z is 4-membered heterocycloalkyl optionally substituted with one or more halogen, C
1-C
6 alkyl, or C
3-C
8 cycloalkyl, wherein the C
1-C
6 alkyl or C
3-C
8 cycloalkyl is optionally substituted with one or more halogen. [0161] In some embodiments, Z is 4-membered heterocycloalkyl. [0162] In some embodiments, Z is 4-membered heterocycloalkyl substituted with one or more R
Z. [0163] In some embodiments, Z is 4-membered heterocycloalkyl substituted with one or more
halogen, C
1-C
6 alkyl, or C
3-C
8 cycloalkyl, wherein the C
1-C
6 alkyl or C
3-C
8 cycloalkyl is optionally substituted with one or more halogen. [0164] In some embodiments, Z is acetidinyl optionally substituted with one or more R
Z. [0165] In some embodiments, Z is
1
, in which # indicates attachment to R - C(=O)-. [0166] In some embodiments, Z is acetidinyl optionally substituted with one or more halogen, C
1- C
6 alkyl, or C
3-C
8 cycloalkyl, wherein the C
1-C
6 alkyl or C
3-C
8 cycloalkyl is optionally substituted with one or more halogen. [0167] In some embodiments, Z is acetidinyl. [0168] In some embodiments, Z is
, in which # indicates attachment to R
1-C(=O)-. [0169] In some embodiments, Z is
, in which # indicates attachment to R
1-C(=O)-. [0170] In some embodiments, Z is acetidinyl substituted with one or more R
Z. [0171] In some embodiments, Z is
, in which # indicates attachment to R
1- C(=O)-. [0172] In some embodiments, Z is acetidinyl substituted with one or more halogen, C
1-C
6 alkyl, or C
3-C
8 cycloalkyl, wherein the C
1-C
6 alkyl or C
3-C
8 cycloalkyl is optionally substituted with one or more halogen. [0173] In some embodiments, Z is
in which # indicates attachment to R
1-C(=O)-
. [0174] In some embodiments, Z is 5-membered heterocycloalkyl optionally substituted with one or more R
Z. [0175] In some embodiments, Z is 5-membered heterocycloalkyl optionally substituted with one
or more C
1-C
6 alkyl. [0176] In some embodiments, Z is 5-membered heterocycloalkyl. [0177] In some embodiments, Z is 5-membered heterocycloalkyl substituted with one or more R
Z. [0178] In some embodiments, Z is 5-membered heterocycloalkyl substituted with one or more C1- C
6 alkyl. [0179] In some embodiments, Z is pyrrolidinyl optionally substituted with one or more R
Z. [0180] In some embodiments,
which # indicates attachment to R
1-C(=O)- . [0181] In some embodiments, Z is pyrrolidinyl optionally substituted with one or more C
1-C
6 alkyl. [0182] In some embodiments, Z is pyrrolidinyl. [0183] In some embodiments, Z is
, in which # indicates attachment to R
1-C(=O)- . [0184] In some embodiments, Z is pyrrolidinyl substituted with one or more R
Z. [0185] In some embodiments,
which # indicates attachment to R
1-C(=O)- . [0186] In some embodiments, Z is pyrrolidinyl substituted with one or more C
1-C
6 alkyl. [0187] In some embodiments, Z is
in which # indicates attachment to R
1-C(=O)-. [0188] In some embodiments, Z is 6-membered heterocycloalkyl optionally substituted with one or more R
Z. [0189] In some embodiments, Z is 6-membered heterocycloalkyl optionally substituted with one or more halogen (e.g., F). [0190] In some embodiments, Z is 6-membered heterocycloalkyl. [0191] In some embodiments, Z is 6-membered heterocycloalkyl substituted with one or more R
Z.
[0192] In some embodiments, Z is 6-membered heterocycloalkyl substituted with one or more halogen (e.g., F). [0193] In some embodiments, Z is piperidinyl optionally substituted with one or more R
Z. [0194] In some embodiments, Z is in which # indicates 1
attachment to R -C(=O)-. [0195] In some embodiments, Z is piperidinyl optionally substituted with one or more halogen (e.g., F). [0196] In some embodiments, Z is piperidinyl. [0197] In some embodiments, Z is in which # indicates attachment to R
1-C(=O)-.
[0198] In some embodiments, Z is piperidinyl substituted with one or more R
Z. [0199] In some embodiments, Z is , in which # indicates 1
attachment to R -C(=O)-. [0200] In some embodiments, Z is piperidinyl substituted with one or more halogen (e.g., F). [0201] In some embodiments, Z is piperidinyl substituted with one or more F. [0202] In some embodiments, Z is piperidinyl substituted with two or more halogen (e.g., F). [0203] In some embodiments, Z is piperidinyl substituted with two or more F. [0204] In some embodiments, Z is piperidinyl substituted with two halogen (e.g., F). [0205] In some embodiments, Z is piperidinyl substituted with two F. [0206] In some embodiments, Z is in which # indicates attachment to R
1-C(=O)- .
[0207] In some embodiments, Z is 7-membered heterocycloalkyl optionally substituted with one or more R
Z. [0208] In some embodiments, Z is 7-membered heterocycloalkyl. [0209] In some embodiments, Z is 7-membered heterocycloalkyl substituted with one or more R
Z. [0210] In some embodiments, Z is 2-azabicyclo[2.2.1]heptanyl optionally substituted with one or more R
Z. [0211] In some embodiments, Z is in which # indicates attachment to R
1-
C(=O)-. [0212] In some embodiments, Z is 2-azabicyclo[2.2.1]heptanyl. [0213] In some embodiments, Z is in which # indicates attachment to R
1-C(=O)-
. [0214] In some embodiments, Z is 2-azabicyclo[2.2.1]heptanyl substituted with one or more R
Z. [0215] In some embodiments, Z is in which # indicates attachment to R
1-C(=O)-
. [0216] In some embodiments, Z is
in which # indicates attachment to R
1-C(=O)-. [0217] In some embodiments, Z is imidazolidinyl optionally substituted with one or more R
Z.
[0218] In some embodiments,
which # indicates attachment to R
1-C(=O)- . [0219] In some embodiments, Z is imidazolidinyl. [0220] In some embodiments, Z is in which # indicates attachment to R
1-C(=O)-. [0221] In some embodiments, Z is hexahydropyrimidinyl optionally substituted with one or more R
Z. [0222] In some embodiments,
which # indicates attachment to R
1-C(=O)-. [0223] In some embodiments, Z is hexahydropyrimidinyl. [0224] In some embodiments,
which # indicates attachment to R
1-C(=O)-. [0225] In some embodiments, Z is 1,6-diazaspiro[3.3]heptanyl or 2,6-diazaspiro[3.3]heptanyl optionally substituted with one or more R
Z. [0226] In some embodiments,
which # indicates attachment to R
1-C(=O)-. [0227] In some embodiments, Z is 1,6-diazaspiro[3.3]heptanyl or 2,6-diazaspiro[3.3]heptanyl.
[0228] In some embodiments, Z is in which # indicates
attachment to R
1-C(=O)-. [0229] In some embodiments, Z is octahydropyrrolo[3,4-c]pyrrolyl or octahydropyrrolo[3,4- b]pyrrolyl optionally substituted with one or more R
Z. [0230] In some embodiments, Z is in which # indicates attachment to R
1-C(=O)-.
[0231] In some embodiments, Z is octahydropyrrolo[3,4-c]pyrrolyl or octahydropyrrolo[3,4- b]pyrrolyl. [0232] In some embodiments, Z is in which # indicates
attachment to R
1-C(=O)-. [0233] In some embodiments, Z is
in which # indicates
attachment to R
1-C(=O)-. [0234] In some embodiments, at least one R
Z is halogen. [0235] In some embodiments, at least one R
Z is F [0236] In some embodiments, at least one R
Z is C
1-C
6 alkyl optionally substituted with one or more halogen. [0237] In some embodiments, at least one R
Z is C
1-C
6 alkyl.
[0238] In some embodiments, at least one R
Z is methyl. [0239] In some embodiments, at least one R
Z is ethyl. [0240] In some embodiments, at least one R
Z is C
1-C
6 alkyl substituted with one or more halogen. [0241] In some embodiments, at least one R
Z is C1-C6 alkyl substituted with one or more F. [0242] In some embodiments, at least one R
Z is CH
2F, CHF
2, or CF
3. [0243] In some embodiments, at least one R
Z is C
3-C
8 cycloalkyl optionally substituted with one or more halogen. [0244] In some embodiments, at least one R
Z is C
3-C
8 cycloalkyl. [0245] In some embodiments, at least one R
Z is cyclopropyl. [0246] In some embodiments, at least one R
Z is 3- to 8-membered heterocycloalkyl optionally substituted with one or more halogen. Variables X
1 and X
2 [0247] In some embodiments, X
1 is –NH–. [0248] In some embodiments, X
1 is –N(C
1-C
6 alkyl)–. [0249] In some embodiments, X
1 is –N(CH
3)–. [0250] In some embodiments, X
1 is –O–. [0251] In some embodiments, X
2 is –CH
2–. [0252] In some embodiments, X
2 is –NH–, –N(C
1-C
6 alkyl)–, –O–, or –S–. [0253] In some embodiments, X
2 is –NH–. [0254] In some embodiments, X
2 is –N(C
1-C
6 alkyl)–. [0255] In some embodiments, X
2 is –N(CH
3)–. [0256] In some embodiments, X
2 is –O–. [0257] In some embodiments, X
2 is –S–. [0258] In some embodiments, X
1 is –NH–; and X
2 is –CH
2–. [0259] In some embodiments, X
1 is –NH–; and X
2 is –NH–. [0260] In some embodiments, X
1 is –NH–; and X
2 is –S–. [0261] In some embodiments, X
1 is –NH–; and X
2 is –O–. [0262] In some embodiments, X
1 is –O–; and X
2 is –CH
2–. [0263] In some embodiments, X
1 is –O–; and X
2 is –NH–. [0264] In some embodiments, X
1 is –O–; and X
2 is –S–.
[0265] In some embodiments, X
1 is –O–; and X
2 is –O–. Variables Y, R
Y, and R
Ya [0266] In some embodiments, Y is C6 aryl optionally substituted with one or more R
Y. [0267] In some embodiments, Y is C
6 aryl optionally substituted with one or more R
Y; each R
Y independently: is halogen, -O-(C
1-C
6 alkyl), C
1-C
6 alkyl, -O-(C
6-C
10 aryl), -O-(5- to 10-membered heteroaryl), -(C
1-C
6 alkyl)-(3- to 10-membered cycloalkyl), -O-(C
1-C
6 alkyl)-(3- to 10- membered cycloalkyl), -O-(C
1-C
6 alkyl)-(3- to 10-membered heterocycloalkyl), or -O-(C
1- C
6 alkyl)-(5- to 10-membered heteroaryl); wherein the -O-(C
1-C
6 alkyl), C
1-C
6 alkyl, -O- (C
6-C
10 aryl), -O-(5- to 10-membered heteroaryl), -(C
1-C
6 alkyl)-(3- to 10-membered cycloalkyl), -O-(C1-C6 alkyl)-(3- to 10-membered cycloalkyl), -O-(C1-C6 alkyl)-(3- to 10- membered heterocycloalkyl), or -O-(C
1-C
6 alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more R
Ya; or together with another R
Y and the intervening atoms attached thereto, form 4- to 10- membered hetero cycloalkyl, wherein the 4- to 10-membered hetero cycloalkyl is optionally substituted with one or more R
Ya . [0268] In some embodiments, Y is C
6 aryl optionally substituted with one or more R
Y; each R
Y independently is halogen, -O-(C
1-C
6 alkyl), C
1-C
6 alkyl, -O-(C
6-C
10 aryl), -O-(5- to 10-membered heteroaryl), -(C1-C6 alkyl)-(3- to 10-membered cycloalkyl), -O-(C1-C6 alkyl)-(3- to 10-membered cycloalkyl), -O-(C
1-C
6 alkyl)-(3- to 10-membered heterocycloalkyl), or -O-(C
1- C
6 alkyl)-(5- to 10-membered heteroaryl); wherein the -O-(C
1-C
6 alkyl), C
1-C
6 alkyl, -O-(C
6-C
10 aryl), -O-(5- to 10-membered heteroaryl), -(C
1-C
6 alkyl)-(3- to 10-membered cycloalkyl), -O-(C
1- C
6 alkyl)-(3- to 10-membered cycloalkyl), -O-(C
1-C
6 alkyl)-(3- to 10-membered heterocycloalkyl), or -O-(C
1-C
6 alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more R
Ya. [0269] In some embodiments, Y is C
6 aryl optionally substituted with one or more R
Y; each R
Y independently is halogen, -OH, -O-(C1-C6 alkyl), -C(=O)-NH-C1-C6 alkyl, C1-C6 alkyl, C
2-C
6 alkynyl, 3- to 10-membered heterocycloalkyl, -O-(C
6-C
10 aryl), -O-(C
1-C
6 alkyl)-(3- to 10-membered heterocycloalkyl), -O-(C
1-C
6 alkyl)-(C
6-C
10 aryl), or -O-(C
1-C
6 alkyl)-(5- to 10- membered heteroaryl); wherein the -O-(C
1-C
6 alkyl), -C(=O)-NH-C
1-C
6 alkyl, C
1-C
6 alkyl, C
2-C
6 alkynyl, 3- to 10-membered heterocycloalkyl, -O-(C
6-C
10 aryl), -O-(C
1-C
6 alkyl)-(3- to 10-
membered heterocycloalkyl), -O-(C
1-C
6 alkyl)-(C
6-C
10 aryl), or -O-(C
1-C
6 alkyl)-(5- to 10- membered heteroaryl) is optionally substituted with one or more R
Ya; and each R
Ya independently is halogen, -OH, C
1-C
6 alkyl, or -O(C
1-C
6 alkyl), wherein the C
1- C6 alkyl or -O(C1-C6 alkyl) is optionally substituted with one or more halogen. [0270] In some embodiments, Y is 5- to 9-membered heteroaryl is optionally substituted with one or more R
Y. [0271] In some embodiments, Y is 5- to 9-membered heteroaryl optionally substituted with one or more R
Y; each R
Y independently: is halogen, -O-(C
1-C
6 alkyl), C
1-C
6 alkyl, -O-(C
6-C
10 aryl), -O-(5- to 10-membered heteroaryl), -(C
1-C
6 alkyl)-(3- to 10-membered cycloalkyl), -O-(C
1-C
6 alkyl)-(3- to 10- membered cycloalkyl), -O-(C1-C6 alkyl)-(3- to 10-membered heterocycloalkyl), or -O-(C1- C
6 alkyl)-(5- to 10-membered heteroaryl); wherein the -O-(C
1-C
6 alkyl), C
1-C
6 alkyl, -O- (C
6-C
10 aryl), -O-(5- to 10-membered heteroaryl), -(C
1-C
6 alkyl)-(3- to 10-membered cycloalkyl), -O-(C
1-C
6 alkyl)-(3- to 10-membered cycloalkyl), -O-(C
1-C
6 alkyl)-(3- to 10- membered heterocycloalkyl), or -O-(C
1-C
6 alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more R
Ya; or together with another R
Y and the intervening atoms attached thereto, form 4- to 10- membered hetero cycloalkyl, wherein the 4- to 10-membered hetero cycloalkyl is optionally substituted with one or more R
Ya . [0272] In some embodiments, Y is 5- to 9-membered heteroaryl optionally substituted with one or more R
Y; each R
Y independently is halogen, -O-(C
1-C
6 alkyl), C
1-C
6 alkyl, -O-(C
6-C
10 aryl), -O-(5- to 10-membered heteroaryl), -(C
1-C
6 alkyl)-(3- to 10-membered cycloalkyl), -O-(C
1-C
6 alkyl)-(3- to 10-membered cycloalkyl), -O-(C
1-C
6 alkyl)-(3- to 10-membered heterocycloalkyl), or -O-(C
1- C
6 alkyl)-(5- to 10-membered heteroaryl); wherein the -O-(C
1-C
6 alkyl), C
1-C
6 alkyl, -O-(C
6-C
10 aryl), -O-(5- to 10-membered heteroaryl), -(C1-C6 alkyl)-(3- to 10-membered cycloalkyl), -O-(C1- C
6 alkyl)-(3- to 10-membered cycloalkyl), -O-(C
1-C
6 alkyl)-(3- to 10-membered heterocycloalkyl), or -O-(C
1-C
6 alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more R
Ya. [0273] In some embodiments, Y is 5- to 9-membered heteroaryl optionally substituted with one or more R
Y;
each R
Y independently is halogen, -OH, -O-(C
1-C
6 alkyl), -C(=O)-NH-C
1-C
6 alkyl, C
1-C
6 alkyl, C
2-C
6 alkynyl, 3- to 10-membered heterocycloalkyl, -O-(C
6-C
10 aryl), -O-(C
1-C
6 alkyl)-(3- to 10-membered heterocycloalkyl), -O-(C
1-C
6 alkyl)-(C
6-C
10 aryl), or -O-(C
1-C
6 alkyl)-(5- to 10- membered heteroaryl); wherein the -O-(C1-C6 alkyl), -C(=O)-NH-C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkynyl, 3- to 10-membered heterocycloalkyl, -O-(C
6-C
10 aryl), -O-(C
1-C
6 alkyl)-(3- to 10- membered heterocycloalkyl), -O-(C
1-C
6 alkyl)-(C
6-C
10 aryl), or -O-(C
1-C
6 alkyl)-(5- to 10- membered heteroaryl) is optionally substituted with one or more R
Ya; and each R
Ya independently is halogen, -OH, C
1-C
6 alkyl, or -O(C
1-C
6 alkyl), wherein the C
1- C
6 alkyl or -O(C
1-C
6 alkyl) is optionally substituted with one or more halogen. [0274] In some embodiments, at least one R
Y is oxo. [0275] In some embodiments, at least one R
Y is halogen, CN, -OH, or -NH
2. [0276] In some embodiments, at least one R
Y is halogen. [0277] In some embodiments, at least one R
Y is F. [0278] In some embodiments, at least one R
Y is Cl [0279] In some embodiments, at least one R
Y is -O-(C
1-C
6 alkyl), -NH(C
1-C
6 alkyl), -N(C
1-C
6 alkyl)
2, or -C(=O)-NH-(C
1-C
6 alkyl), wherein the -O-(C
1-C
6 alkyl), -NH(C
1-C
6 alkyl), -N(C
1-C
6 alkyl)
2, or -C(=O)-NH-(C
1-C
6 alkyl) is optionally substituted with one or more R
Ya. [0280] In some embodiments, at least one R
Y is -C(=O)-NH-(C
1-C
6 alkyl) optionally substituted with one or more R
Ya. [0281] In some embodiments, at least one R
Y is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the C
1-C
6 alkyl, C
2-C
6 alkenyl, or C
2-C
6 alkynyl is optionally substituted with one or more R
Ya. [0282] In some embodiments, at least one R
Y is 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl, wherein the 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R
Ya. [0283] In some embodiments, at least one R
Y is 3- to 10-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the - to 10-membered heterocycloalkyl, C
6-C
10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R
Ya. [0284] In some embodiments, at least one R
Y is 3- to 10-membered cycloalkyl optionally substituted with one or more R
Ya.
[0285] In some embodiments, at least one R
Y is 3- to 10-membered heterocycloalkyl optionally substituted with one or more R
Ya. [0286] In some embodiments, at least one R
Y is C
6-C
10 aryl optionally substituted with one or more R
Ya. [0287] In some embodiments, at least one R
Y is 5- to 10-membered heteroaryl is optionally substituted with one or more R
Ya. [0288] In some embodiments, at least one R
Y is -O-(3- to 10-membered cycloalkyl), -O-(3- to 10- membered heterocycloalkyl), -O-(C
6-C
10 aryl), -O-(5- to 10-membered heteroaryl), -O-(C
1-C
6 alkyl)-(3- to 10-membered heterocycloalkyl), -O-(C
1-C
6 alkyl)-(C
6-C
10 aryl), -O-(C
1-C
6 alkyl)-(5- to 10-membered heteroaryl), -NH-(C
1-C
6 alkyl)-(3- to 10-membered heterocycloalkyl), -NH-(C
1- C
6 alkyl)-(C
6-C
10 aryl), or -NH-(C
1-C
6 alkyl)-(5- to 10-membered heteroaryl), wherein the -O-(3- to 10-membered cycloalkyl), -O-(3- to 10-membered heterocycloalkyl), -O-(C6-C10 aryl), -O-(5- to 10-membered heteroaryl), -O-(C
1-C
6 alkyl)-(3- to 10-membered heterocycloalkyl), -O-(C
1-C
6 alkyl)-(C
6-C
10 aryl), -O-(C
1-C
6 alkyl)-(5- to 10-membered heteroaryl), -NH-(C
1-C
6 alkyl)-(3- to 10-membered heterocycloalkyl), -NH-(C
1-C
6 alkyl)-(C
6-C
10 aryl), or -NH-(C
1-C
6 alkyl)-(5- to 10- membered heteroaryl) is optionally substituted with one or more R
Ya. [0289] In some embodiments, at least one R
Y is -O-(3- to 10-membered heterocycloalkyl), -O-(C
6- C
10 aryl), -O-(5- to 10-membered heteroaryl), -O-(C
1-C
6 alkyl)-(3- to 10-membered heterocycloalkyl), -O-(C
1-C
6 alkyl)-(C
6-C
10 aryl), -O-(C
1-C
6 alkyl)-(5- to 10-membered heteroaryl), -NH-(C1-C6 alkyl)-(3- to 10-membered heterocycloalkyl), -NH-(C1-C6 alkyl)-(C6-C10 aryl), or -NH-(C
1-C
6 alkyl)-(5- to 10-membered heteroaryl), wherein the -O-(3- to 10-membered heterocycloalkyl), -O-(C
6-C
10 aryl), -O-(5- to 10-membered heteroaryl), -O-(C
1-C
6 alkyl)-(3- to 10-membered heterocycloalkyl), -O-(C
1-C
6 alkyl)-(C
6-C
10 aryl), -O-(C
1-C
6 alkyl)-(5- to 10- membered heteroaryl), -NH-(C
1-C
6 alkyl)-(3- to 10-membered heterocycloalkyl), -NH-(C
1-C
6 alkyl)-(C
6-C
10 aryl), or -NH-(C
1-C
6 alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more R
Ya. [0290] In some embodiments, at least one R
Y is -O-(3- to 10-membered cycloalkyl) optionally substituted with one or more R
Ya. [0291] In some embodiments, at least one R
Y is -O-(3- to 10-membered heterocycloalkyl) optionally substituted with one or more R
Ya. [0292] In some embodiments, at least one R
Y is -O-(C
6-C
10 aryl) optionally substituted with one
or more R
Ya. [0293] In some embodiments, at least one R
Y is -O-(C
6 aryl) optionally substituted with one or more R
Ya. [0294] In some embodiments, at least one R
Y is -O-(5- to 10-membered heteroaryl) optionally substituted with one or more R
Ya. [0295] In some embodiments, at least one R
Y is -O-(pyridinyl) optionally substituted with one or more R
Ya. [0296] In some embodiments, at least one R
Y is -(C
1-C
6 alkyl)-(3- to 10-membered heterocycloalkyl), -(C
1-C
6 alkyl)-(C
6-C
10 aryl), or -(C
1-C
6 alkyl)-(5- to 10-membered heteroaryl), wherein the -(C
1-C
6 alkyl)-(3- to 10-membered heterocycloalkyl), -(C
1-C
6 alkyl)-(C
6-C
10 aryl), or -(C
1-C
6 alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more R
Ya. [0297] In some embodiments, at least one R
Y is -(C1-C6 alkyl)-(3- to 10-membered heterocycloalkyl) optionally substituted with one or more R
Ya. [0298] In some embodiments, at least one R
Y is -O-(C
1-C
6 alkyl)-(3- to 10-membered heterocycloalkyl) optionally substituted with one or more R
Ya. [0299] In some embodiments, at least one R
Y is -O-(C
1-C
6 alkyl)-(C
6-C
10 aryl) optionally substituted with one or more R
Ya. [0300] In some embodiments, at least one R
Y is -O-(CH
2)-(C
6 aryl) optionally substituted with one or more R
Ya. [0301] In some embodiments, at least one R
Y is -O-(C1-C6 alkyl)-(5- to 10-membered heteroaryl) optionally substituted with one or more R
Ya. [0302] In some embodiments, at least one R
Y is -O-(CH
2)-(pyridinyl) optionally substituted with one or more R
Ya. [0303] In some embodiments, at least one R
Y is -NH-(C
1-C
6 alkyl)-(3- to 10-membered heterocycloalkyl), -NH-(C
1-C
6 alkyl)-(C
6-C
10 aryl), or -NH-(C
1-C
6 alkyl)-(5- to 10-membered heteroaryl), wherein the -NH-(C
1-C
6 alkyl)-(3- to 10-membered heterocycloalkyl), -NH-(C
1-C
6 alkyl)-(C6-C10 aryl), or -NH-(C1-C6 alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more R
Ya. [0304] In some embodiments, at least one R
Y is halogen, -OH, C
1-C
6 alkyl, C
2-C
6 alkynyl, -O-(C
6 aryl), -O-(5- to 6-membered heteroaryl),-O-(CH
2)-(6-membered heterocycloalkyl), -O-(CH
2)-(C
6 aryl), -O-(CH
2)-(5- to 6-membered heteroaryl); wherein the C
1-C
6 alkyl, C
2-C
6 alkynyl, -O-(C
6
aryl), -O-(CH
2)-(6-membered heterocycloalkyl), -O-(CH
2)-(C
6 aryl), -O-(CH
2)-(5- to 6-membered heteroaryl) is optionally substituted with one or more R
Ya. [0305] In some embodiments, at least one R
Y is halogen, -OH, C
1-C
6 alkyl, C
2-C
6 alkynyl, -O-(C
6 aryl), -O-(5- to 6-membered heteroaryl),-O-(CH2)-(6-membered heterocycloalkyl), -O-(CH2)-(C6 aryl), -O-(CH
2)-(5- to 6-membered heteroaryl); wherein the C
1-C
6 alkyl, C
2-C
6 alkynyl, -O-(C
6 aryl), -O-(CH
2)-(6-membered heterocycloalkyl), -O-(CH
2)-(C
6 aryl), -O-(CH
2)-(5- to 6-membered heteroaryl) is optionally substituted with one or more halogen, -OH, or C
1-C
6 alkyl. [0306] In some embodiments, at least one R
Y is halogen, -OH, C
1-C
6 alkyl, C
2-C
6 alkynyl, or -O- (C
6 aryl); wherein the C
1-C
6 alkyl, C
2-C
6 alkynyl, or -O-(C
6 aryl) is optionally substituted with one or more halogen, -OH, or C
1-C
6 alkyl. [0307] In some embodiments, at least one R
Y is halogen, -OH, C
1-C
6 alkyl, C
2-C
6 alkynyl, or -O- (5- to 6-membered heteroaryl); wherein the C1-C6 alkyl, C2-C6 alkynyl, or -O-(5- to 6-membered heteroaryl) is optionally substituted with one or more halogen, -OH, or C
1-C
6 alkyl. [0308] In some embodiments, at least one R
Y is halogen, -OH, C
1-C
6 alkyl, C
2-C
6 alkynyl, or -O- (pyridinyl); wherein the C
1-C
6 alkyl, C
2-C
6 alkynyl, or -O-(pyridinyl) is optionally substituted with one or more halogen, -OH, or C
1-C
6 alkyl. [0309] In some embodiments, at least one R
Y is halogen, -OH, C
1-C
6 alkyl, C
2-C
6 alkynyl, or -O- (CH
2)-(6-membered heterocycloalkyl); wherein the C
1-C
6 alkyl, C
2-C
6 alkynyl, or -O-(CH
2)-(6- membered heterocycloalkyl) is optionally substituted with one or more halogen, -OH, or C
1-C
6 alkyl. [0310] In some embodiments, at least one R
Y is halogen, -OH, C
1-C
6 alkyl, C
2-C
6 alkynyl, or -O- (CH
2)-(C
6 aryl); wherein the C
1-C
6 alkyl, C
2-C
6 alkynyl, or -O-(CH
2)-(C
6 aryl) is optionally substituted with one or more halogen, -OH, or C
1-C
6 alkyl. [0311] In some embodiments, at least one R
Y is halogen, -OH, C
1-C
6 alkyl, C
2-C
6 alkynyl, or -O- (CH
2)-(5- to 6-membered heteroaryl); wherein the C
1-C
6 alkyl, C
2-C
6 alkynyl, or -O-(CH
2)-(5- to 6-membered heteroaryl) is optionally substituted with one or more halogen, -OH, or C
1-C
6 alkyl. [0312] In some embodiments, at least one R
Y is halogen, -OH, C1-C6 alkyl, C2-C6 alkynyl, or -O- (CH
2)-(pyridinyl); wherein the C
1-C
6 alkyl, C
2-C
6 alkynyl, or -O-(CH
2)-(pyridinyl) is optionally substituted with one or more halogen, -OH, or C
1-C
6 alkyl. [0313] In some embodiments, at least one R
Y, together with another R
Y and the intervening atoms attached thereto, form 4- to 10-membered cycloalkyl or 4- to 10-membered heterocycloalkyl,
wherein the 4- to 10-membered cycloalkyl or 4- to 10-membered heterocycloalkyl is optionally substituted with one or more R
Ya. [0314] In some embodiments, at least one R
Y, together with another R
Y and the intervening atoms attached thereto, form 4- to 10-membered cycloalkyl, wherein the 4- to 10-membered cycloalkyl is optionally substituted with one or more R
Ya. [0315] In some embodiments, at least one R
Y, together with another R
Y and the intervening atoms attached thereto, form 4- to 10-membered heterocycloalkyl, wherein the 4- to 10-membered heterocycloalkyl is optionally substituted with one or more R
Ya. [0316] In some embodiments, at least one R
Ya is CN. [0317] In some embodiments, at least one R
Ya is -NH
2. [0318] In some embodiments, at least one R
Ya is halogen, -OH, C
1-C
6 alkyl, or -O(C
1-C
6 alkyl), wherein the C1-C6 alkyl or -O(C1-C6 alkyl) is optionally substituted with one or more halogen. [0319] In some embodiments, at least one R
Ya is halogen. [0320] In some embodiments, at least one R
Ya is F. [0321] In some embodiments, at least one R
Ya is Cl. [0322] In some embodiments, at least one R
Ya is –OH. [0323] In some embodiments, at least one R
Ya is C
1-C
6 alky optionally substituted with one or more halogen. [0324] In some embodiments, at least one R
Ya is C
1-C
6 alky. [0325] In some embodiments, at least one R
Ya is -O(C1-C6 alkyl) optionally substituted with one or more halogen. [0326] In some embodiments, at least one R
Ya is -O(C
1-C
6 alkyl). Variable R
1 [0327] In some embodiments, R
1 is –HC=CH
2. [0328] In some embodiments, R
1 is –C≡C–(C
1-C
6 alkyl). [0329] In some embodiments, R
1 is –C≡C–(CH3). [0330] In some embodiments, R
1-C(=O)-Z- is
, ,
, ,
Exemplary Embodiments of the Compounds [0331] In some embodiments, the compound is
,
[0332] In some embodiments, when W is =CH–, Z is 3- to 8-membered heterocycloalkyl, X
1 is – NH–, X
2 is –NH– or –O–, and Y is C
6 aryl one or more halogen; then R
1 is –C≡C–(C
1-C
6 alkyl). [0333] In some embodiments, when W is =CH–, Z is 3- to 8-membered heterocycloalkyl, X
1 is – NH–, and Y is C
6 aryl one or more halogen; then R
1 is –C≡C–(C
1-C
6 alkyl). [0334] In some embodiments, when W is =CH–, X
1 is –NH–, and Y is C
6 aryl one or more halogen; then R
1 is –C≡C–(C
1-C
6 alkyl). [0335] In some embodiments, when W is =CH–, Z is 3- to 8-membered heterocycloalkyl, and X
2 is –NH– or –O–; then R
1 is –C≡C–(C
1-C
6 alkyl). [0336] In some embodiments, when W is =CH–, Z is 3- to 8-membered heterocycloalkyl, X
1 is –
NH–, X
2 is –NH– or –O–, and R
1 is –C=CH; then Y is not
. [0337] In some embodiments, when W is =CH–, X
1 is –NH–, X
2 is –NH– or –O–, and R
1 is – C=CH; then Y is not
. [0338] In some embodiments, when W is =CH–, X
2 is –NH– or –O–, and R
1 is –C=CH; then Y is not
[0339] In some embodiments, when X
2 is –NH– or –O–, and R
1 is –C=CH; then Y is not
[0340] In some embodiments, when W is =CH–, Z is 3- to 8-membered heterocycloalkyl, X
1 is – NH–, X
2 is –NH– or –O–, and R
1 is –C=CH, and Y is C
6 aryl substituted with one or more R
Y; then each R
Y independently: is oxo, CN, -OH, -NH
2, -O-(C
1-C
6 alkyl), -NH(C
1-C
6 alkyl), -N(C
1-C
6 alkyl)
2, -C(=O)-NH- C
1-C
6 alkyl, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, 3- to 10-membered cycloalkyl, 3- to 10- membered heterocycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, -O-(3- to 10-membered cycloalkyl), -O-(3- to 10-membered heterocycloalkyl), -O-(C
6-C
10 aryl), -O-(5- to 10-membered heteroaryl), -(C
1-C
6 alkyl)-(3- to 10-membered cycloalkyl), -(C
1-C
6 alkyl)-(3- to 10-membered heterocycloalkyl), -(C
1-C
6 alkyl)-(C
6-C
10 aryl), -(C
1-C
6 alkyl)-(5- to 10-membered heteroaryl), - O-(C
1-C
6 alkyl)-(3- to 10-membered cycloalkyl), -O-(C
1-C
6 alkyl)-(3- to 10-membered heterocycloalkyl), -O-(C
1-C
6 alkyl)-(C
6-C
10 aryl), -O-(C
1-C
6 alkyl)-(5- to 10-membered heteroaryl), -NH-(C
1-C
6 alkyl)-(3- to 10-membered heterocycloalkyl), -NH-(C
1-C
6 alkyl)-(C
6-C
10 aryl), or -NH-(C
1-C
6 alkyl)-(5- to 10-membered heteroaryl); wherein the -O-(C
1-C
6 alkyl), - NH(C
1-C
6 alkyl), -N(C
1-C
6 alkyl)
2, -C(=O)-NH-C
1-C
6 alkyl, C
1-C
6 alkyl, C
2-C
6 alkenyl, C
2-C
6 alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, C
6-C
10 aryl, 5- to 10-membered heteroaryl, -O-(3- to 10-membered cycloalkyl), -O-(3- to 10-membered heterocycloalkyl), -O-(C
6-C
10 aryl), -O-(5- to 10-membered heteroaryl), -(C
1-C
6 alkyl)-(3- to 10- membered cycloalkyl), -(C
1-C
6 alkyl)-(3- to 10-membered heterocycloalkyl), -(C
1-C
6 alkyl)-(C
6-
C
10 aryl), -(C
1-C
6 alkyl)-(5- to 10-membered heteroaryl), -O-(C
1-C
6 alkyl)-(3- to 10-membered cycloalkyl), -O-(C
1-C
6 alkyl)-(3- to 10-membered heterocycloalkyl), -O-(C
1-C
6 alkyl)-(C
6-C
10 aryl), -O-(C
1-C
6 alkyl)-(5- to 10-membered heteroaryl), -NH-(C
1-C
6 alkyl)-(3- to 10-membered heterocycloalkyl), -NH-(C1-C6 alkyl)-(C6-C10 aryl), or -NH-(C1-C6 alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more R
Ya; or together with another R
Y and the intervening atoms attached thereto, form 4- to 10- membered cycloalkyl or 4- to 10-membered hetero cycloalkyl, wherein the 4- to 10-membered cycloalkyl or 4- to 10-membered hetero cycloalkyl is optionally substituted with one or more R
Ya. [0341] In some embodiments, the compound is of Formula (I-A) or (I-B):
or a pharmaceutically acceptable salt or stereoisomer thereof. [0342] In some embodiments, the compound is of Formula (I-AA), (I-AB), (I-BA), or (I-BB):
or a pharmaceutically acceptable salt or stereoisomer thereof. [0343] In some embodiments, the compound is of Formula (I-AA1), (I-AA2), (I-AA3), (I-AA4):
or a pharmaceutically acceptable salt or stereoisomer thereof. [0344] In some embodiments, the compound is of Formula (I-AB1), (I-AB2), (I-AB3), (I-AB4):
or a pharmaceutically acceptable salt or stereoisomer thereof. [0345] In some embodiments, the compound is of Formula (I-BA1), (I-BA2), (I-BA3), (I-BA4):
or a pharmaceutically acceptable salt or stereoisomer thereof. [0346] In some embodiments, the compound is of Formula (I-BB1), (I-BB2), (I-BB3), (I-BB4):
or a pharmaceutically acceptable salt or stereoisomer thereof. [0347] In some embodiments, the compound is of Formula (I’):
or a pharmaceutically acceptable salt or stereoisomer thereof. [0348] In some embodiments
, the compound is of Formula (I’-A) or (I’-B):
or a pharmaceutically acceptable salt or stereoisomer thereof. [0349] In some embodiments, the compound is of Formula (I’-AA), (I’-AB), (I’-BA), or (I’-BB):
or a pharmaceutically acceptable salt or stereoisomer thereof. [0350] In some embodiments, the compound is of Formula (I’-AA1), (I’-AA2), (I’-AA3), (I’- AA4):
or a pharmaceutically acceptable salt or stereoisomer thereof. [0351] In some embodiments, the compound is of Formula (I’-AB1), (I’-AB2), (I’-AB3), (I’- AB4):
or a pharmaceutically acceptable salt or stereoisomer thereof. [0352] In some embodiments, the compound is of Formula (I’-BA1), (I’-BA2), (I’-BA3), (I’- BA4):
or a pharmaceutically acceptable salt or stereoisomer thereof. [0353] In some embodiments, the compound is of Formula (I’-BB1), (I’-BB2), (I’-BB3), (I’-BB4):
or a pharmaceutically acceptable salt or stereoisomer thereof. [0354] In some aspects, the disclosure provides a compound or a pharmaceutically acceptable salt
or stereoisomer thereof of formula I wherein:
W is =CH–, =COMe–, =CMe– or =N–; Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, -CHF
2, C
3-4 heterocycloalkyl or C3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; X
2 is –NH–, –N(C
1-4 alkyl)–, –O– or –S–; Y is a 6 membered aryl or a 5-9 membered heteroaryl, wherein the 6 membered aryl or the 5-9 membered heteroaryl is unsubstituted or substituted with one or more of a group selected from halogen, CF
3, HCF
2, OCF
3, hydroxy, C
1-6 alkyl, C
1-6 alkoxy, C
1-6 alkylhydroxyl, unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryloxy, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted C
1-3 alkoxy-aryl, unsubstituted or substituted C
1-3 alkoxy-heteroaryl, unsubstituted or substituted C1-3 alkoxy-heterocycloalkyl, unsubstituted or substituted C
1-3 alkylamino-heterocycloalkyl, unsubstituted or substituted C
1-3 alkylamino-aryl, unsubstituted or substituted C
1-3 alkylamino-heteroaryl; and R
1 is –HC=CH
2 or –C≡C–Me. [0355] In some embodiments of a compound of formula I or pharmaceutically acceptable salts or stereoisomers thereof, Y is a 6 membered aryl or a 5-9 membered heteroaryl, wherein the 6 membered aryl or the 5-9 membered heteroaryl is unsubstituted or substituted with one or more of a group selected from halogen, CF
3, HCF
2, OCF
3, hydroxy, C
1-6 alkyl, C
1-6 alkoxy, C
1-6 alkylhydroxyl, unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryloxy, heterocycloalkyl, unsubstituted or substituted C
1-3 alkoxy-aryl, unsubstituted or substituted C
1-3 alkoxy-heteroaryl, C
1-3 alkoxy-heterocycloalkyl, C
1-3 alkylamino-heterocycloalkyl, unsubstituted
or substituted C
1-3 alkylamino-aryl, unsubstituted or substituted C
1-3 alkylamino-heteroaryl. [0356] In some embodiments of a compound of formula I or pharmaceutically acceptable salts or stereoisomers thereof, Y is a 6 membered aryl or a 5-9 membered heteroaryl, wherein the 6 membered aryl or the 5-9 membered heteroaryl is unsubstituted or substituted with one or more of a group selected from halogen, CF
3, HCF
2, OCF
3, hydroxy, C
1-6 alkyl, C
1-6 alkoxy, C
1-6 alkylhydroxyl, unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryloxy, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted C
1-3 alkoxy-aryl, unsubstituted or substituted C
1-3 alkoxy-heteroaryl, unsubstituted or substituted C
1-3 alkoxy- heterocycloalkyl, C
1-3 alkylamino-heterocycloalkyl, unsubstituted or substituted C
1-3 alkylamino- aryl, unsubstituted or substituted C
1-3 alkylamino-heteroaryl; the aryloxy, heteroaryloxy, heterocycloalkyl, C
1-3 alkoxy-aryl, C
1-3 alkoxy-heteroaryl, C
1-3 alkylamino-aryl, C
1-3 alkylamino- heteroaryl is unsubstituted or substituted with one or more of C1-4 alkyl, OCH2F, HCF2, or halogen, e.g., F or Cl [0357] In some embodiments of a compound of formula I or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl or C
3-4 cycloalkyl; [0358] In some embodiments of a compound of formula I or pharmaceutically acceptable salts or stereoisomers thereof, W is =CH–, =CMe– or =COMe–, e.g., =CH– or =COMe–, e.g., =CH–. [0359] In some embodiments of a compound of formula I or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH–. In some embodiments, X
1 is – NH– or –NMe–, particularly –NH– and W is =CH–, =CMe– or =COMe–, e.g., =CH– or =COMe– , e.g., =CH–. [0360] In some embodiments of a compound of formula I or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH2 and W is =CH–, =CMe– or =COMe–, e.g., =CH– or =COMe–, e.g., =CH–. [0361] In some embodiments of a compound of formula I or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me and W is =CH–, =CMe– or =COMe–, e.g., =CH– or =COMe–, e.g., =CH–.
[0362] In some embodiments of a compound of formula I or pharmaceutically acceptable salts or stereoisomers thereof, W is =N–. [0363] In some embodiments of a compound of formula I or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH–. In some embodiments, X
1 is – NH– or –NMe–, particularly –NH– and W is =N–. [0364] In some embodiments of a compound of formula I or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2 and W is =N–. [0365] In some embodiments of a compound of formula I or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me and W is =N–. [0366] In some embodiments of a compound of formula I or pharmaceutically acceptable salts or stereoisomers thereof, X
2 is –NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–. [0367] In some embodiments of a compound of formula I or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH–, and X
2 is –NH–, –NMe–, –NEt– , –NPr–, –NBu–,or –O–, particularly –NH–, –NMe–, –NEt–,or –O–, particularly –NH–, –NMe–, –NEt–,or –O–. [0368] In some embodiments of a compound of formula I or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2 and X
2 is –NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–,or –O–, particularly –NH–, –NMe–, –NEt–, or –O–. [0369] In some embodiments of a compound of formula I or pharmaceutically acceptable salts or stereoisomers thereof, W is =CH–, =CMe– or =COMe–, e.g., =CH– or =COMe–, e.g., =CH–, and X
2 is –NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or – O–, particularly –NH–, –NMe–, –NEt–, or –O–. [0370] In some embodiments of a compound of formula I or pharmaceutically acceptable salts or stereoisomers thereof, W is =N–, and X
2 is –NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–. [0371] In some embodiments of a compound of formula I or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2 and X
1 is –NH– or –NMe–, particularly –NH–, and X
2 is – NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–. [0372] In some embodiments of a compound of formula I or pharmaceutically acceptable salts or
stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [0373] In some embodiments the compound of formula I or pharmaceutically acceptable salts or stereoisomers thereof is represented by formula Ia or Ib wherein:
Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, CHF
2, C
3-4 heterocycloalkyl or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; X
2 is –NH–, –N(C
1-4 alkyl)–, –O– or –S–; Y is a 6 membered aryl or a 5-9 membered heteroaryl, wherein the 6 membered aryl or the 5-9 membered heteroaryl is unsubstituted or substituted with one or more of a group selected from halogen, CF3, HCF2, OCF3, hydroxy, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylhydroxyl, unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryloxy, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted C
1-3 alkoxy-aryl, unsubstituted or substituted C
1-3 alkoxy-heteroaryl, unsubstituted or substituted C
1-3 alkoxy-heterocycloalkyl, unsubstituted or substituted C
1-3 alkylamino-heterocycloalkyl, unsubstituted or substituted C
1-3 alkylamino-aryl, unsubstituted or substituted C
1-3 alkylamino-heteroaryl; and R
1 is –HC=CH
2 or –C≡C–Me. [0374] In some embodiments of a compound of formula Ia, Ib or pharmaceutically acceptable salts or stereoisomers thereof, Y is a 6 membered aryl or a 5-9 membered heteroaryl, wherein the 6 membered aryl or the 5-9 membered heteroaryl is unsubstituted or substituted with one or more of a group selected from halogen, CF
3, HCF
2, OCF
3, hydroxy, C
1-6 alkyl, C
1-6 alkoxy, C
1-6
alkylhydroxyl, unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryloxy, heterocycloalkyl, unsubstituted or substituted C
1-3 alkoxy-aryl, unsubstituted or substituted C
1-3 alkoxy-heteroaryl, C
1-3 alkoxy-heterocycloalkyl, C
1-3 alkylamino-heterocycloalkyl, unsubstituted or substituted C1-3 alkylamino-aryl, unsubstituted or substituted C1-3 alkylamino-heteroaryl. [0375] In some embodiments of a compound of formula Ia, Ib or pharmaceutically acceptable salts or stereoisomers thereof, Y is a 6 membered aryl or a 5-9 membered heteroaryl, wherein the 6 membered aryl or the 5-9 membered heteroaryl is unsubstituted or substituted with one or more of a group selected from halogen, CF
3, HCF
2, OCF
3, hydroxy, C
1-6 alkyl, C
1-6 alkoxy, C
1-6 alkylhydroxyl, unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryloxy, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted C
1-3 alkoxy-aryl, unsubstituted or substituted C
1-3 alkoxy-heteroaryl, unsubstituted or substituted C
1-3 alkoxy- heterocycloalkyl, unsubstituted or substituted C1-3 alkylamino-heterocycloalkyl, unsubstituted or substituted C
1-3 alkylamino-aryl, unsubstituted or substituted C
1-3 alkylamino-heteroaryl; the aryloxy, heteroaryloxy, heterocycloalkyl, C
1-3 alkoxy-aryl, C
1-3 alkoxy-heteroaryl, C
1-3 alkoxy- heterocycloalkyl, C
1-3 alkylamino-heterocycloalkyl, C
1-3 alkylamino-aryl, C
1-3 alkylamino- heteroaryl is unsubstituted or substituted with one or more of C
1-4 alkyl, OCH
2F, HCF
2, or halogen, e.g., F or Cl [0376] In some embodiments of a compound of formula Ia or Ib or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1- C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3- 4 heterocycloalkyl or C
3-4 cycloalkyl. [0377] In some embodiments of a compound of formula Ia or Ib or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH–. [0378] In some embodiments of a compound of formula Ia or Ib or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH2. [0379] In some embodiments of a compound of formula Ia or Ib or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me. [0380] In some embodiments of a compound of formula Ia or Ib or pharmaceutically acceptable salts or stereoisomers thereof, X
2 is –NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly
–NH–, –NMe–, –NEt–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–. [0381] In some embodiments of a compound of formula Ia or Ib or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH–, and X
2 is –NH–, –NMe– , –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–, particularly –NH– , –NMe–, –NEt–, or –O–. [0382] In some embodiments of a compound of formula Ia or Ib or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2 and X
2 is –NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O– . [0383] In some embodiments of a compound of formula Ia or Ib or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2 and X
1 is –NH– or –NMe–, particularly –NH–, and X
2 is –NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or – O–, particularly –NH–, –NMe–, –NEt–, or –O–. [0384] In some embodiments of a compound of formula Ia or Ib or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., a 4 to 6 membered saturated nitrogen heterocycle containing 1 nitrogen atom. In some embodiments of a compound of formula Ia or Ib or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms, e.g. a 5 to 8 membered saturated nitrogen heterobicycle containing 1 nitrogen atom, e.g. a 7 or 8 membered saturated nitrogen heterobicycle containing 1 nitrogen atom. [0385] In some embodiments of a compound of formula I or Ia or Ib or pharmaceutically acceptable salts or stereoisomers thereof Z is of formula i
wherein: R
2 is hydrogen, C1-4 alkyl –CHF2 or C3-4 cycloalkyl;
R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [0386] In some embodiments, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [0387] In some embodiments, R
2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl. [0388] In some embodiments, R
a and R
b are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl or one of R
a and R
b and one of R
c and R
d form together with C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle. In some embodiments, R
a and R
b are each independently selected from hydrogen, methyl. In some embodiments in which m is 2 or 3, only one R
a and one R
b are not hydrogen and/or only one R
a is not hydrogen. [0389] In some embodiments, R
c and R
d are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl or one of R
a and R
b and one of R
c and R
d form together with C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle. In some embodiments, R
c and R
d are each independently selected from hydrogen, methyl. In some embodiments in which n is 2, only one R
c and one R
c are not hydrogen and/or only one R
c is not hydrogen. [0390] In some embodiments, m and n are selected such that a 4, 5 or 6 membered nitrogen containing ring is formed. [0391] In some embodiments of a compound of formula I or Ia or Ib or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH–, Z is of formula i and R
2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl. [0392] In some embodiments of a compound of formula I or Ia or Ib or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH–, Z is of formula i and R
a and R
b are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle. In some embodiments, R
a and R
b are each
independently selected from hydrogen, methyl or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle. In some embodiments in which m is 2 or 3, only one R
a and one R
b are not hydrogen and/or only one R
a is not hydrogen. [0393] In some embodiments of a compound of formula I or Ia or Ib or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH–, Z is of formula i and R
c and R
d are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle. In some embodiments, R
c and R
d are each independently selected from hydrogen, methyl or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle. In some embodiments in which n is 2, only one R
c and one R
c are not hydrogen and/or only one R
c is not hydrogen. [0394] In some embodiments of a compound of formula I or Ia or Ib or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH–, Z is of formula i and m and n are selected such that a 4, 5 or 6 membered nitrogen containing ring is formed. [0395] In some embodiments of a compound of formula I or Ia or Ib or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2, Z is of formula i and R
a and R
b are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle. In some embodiments in which m is 2 or 3, only one R
a and one R
b are not hydrogen and/or only one R
a is not hydrogen. [0396] In some embodiments of a compound of formula I or Ia or Ib or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2, Z is of formula i and R
c and R
d are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle. In some embodiments, R
c and R
d are each independently selected from hydrogen, methyl or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle. In some embodiments in which n is 2, only one R
c and one R
c are not hydrogen and/or only one R
c is not hydrogen.
[0397] In some embodiments of a compound of formula I or Ia or Ib or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2, Z is of formula i and m and n are selected such that a 4, 5 or 6 membered nitrogen containing ring is formed. [0398] In some embodiments of a compound of formula I or Ia or Ib or pharmaceutically acceptable salts or stereoisomers thereof, X
2 is –NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–, Z is of formula i and R
a and R
b are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl or one of R
a and R
b and one of R
c and R
d form together with the . In some embodiments, R
a and R
b are each independently selected from hydrogen, methyl or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle. In some embodiments in which m is 2 or 3, only one R
a and one R
b are not hydrogen and/or only one R
a is not hydrogen. [0399] In some embodiments of a compound of formula I or Ia or Ib or pharmaceutically acceptable salts or stereoisomers thereof, X
2 is –NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–, Z is of formula i and R
c and R
d are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl and or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle. In some embodiments, R
c and R
d are each independently selected from hydrogen, methyl or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle. In some embodiments in which n is 2, only one R
c and one R
c are not hydrogen and/or only one R
c is not hydrogen. [0400] In some embodiments of a compound of formula I or Ia or Ib or pharmaceutically acceptable salts or stereoisomers thereof, X
2 is –NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–, Z is of formula i and m and n are selected such that a 4, 5 or 6 membered nitrogen containing ring is formed. [0401] In some embodiments, the present disclosure provides the compound or the pharmaceutically acceptable salt or stereoisomer thereof of formula I-1 or I-2
wherein: W is =CH–, =COMe–, =CMe– or =N–; X
1 is –NH–, –NMe– or –O–; X
2 is –NH–, –N(C
1-4 alkyl)–, –O– or –S–; Y is a 6 membered aryl or a 5-9 membered heteroaryl, wherein the 6 membered aryl or the 5-9 membered heteroaryl is unsubstituted or substituted with one or more of a group selected from halogen, CF
3, HCF
2, OCF
3, hydroxy, C
1-6 alkyl, C
1-6 alkoxy, C
1-6 alkylhydroxyl, unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryloxy, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted C
1-3 alkoxy-aryl, unsubstituted or substituted C
1-3 alkoxy-heteroaryl, unsubstituted or substituted C
1-3 alkoxy-heterocycloalkyl, unsubstituted or substituted C
1-3 alkylamino-heterocycloalkyl, unsubstituted or substituted C
1-3 alkylamino-aryl, unsubstituted or substituted C
1-3 alkylamino-heteroaryl; R
1 is –HC=CH
2 or –C≡C–Me R
2 is hydrogen, C
1-4 alkyl, -CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form together an unsubstituted oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; m is 1, 2 or 3; n is 1 or 2; and r is 1 or 2, e.g., 1. [0402] In some embodiments of a compound of formula I-1, I-2 or pharmaceutically acceptable salts or stereoisomers thereof, Y is a 6 membered aryl or a 5-9 membered heteroaryl, wherein the 6 membered aryl or the 5-9 membered heteroaryl is unsubstituted or substituted with one or more of a group selected from halogen, CF
3, HCF
2, OCF
3, hydroxy, C
1-6 alkyl, C
1-6 alkoxy, C
1-6 alkylhydroxyl, unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryloxy,
heterocycloalkyl, unsubstituted or substituted C
1-3 alkoxy-aryl, unsubstituted or substituted C
1-3 alkoxy-heteroaryl, C
1-3 alkoxy-heterocycloalkyl, C
1-3 alkylamino-heterocycloalkyl, unsubstituted or substituted C
1-3 alkylamino-aryl, unsubstituted or substituted C
1-3 alkylamino-heteroaryl. [0403] In some embodiments of a compound of formula I-1, I-2 or pharmaceutically acceptable salts or stereoisomers thereof, Y is a 6 membered aryl or a 5-9 membered heteroaryl, wherein the 6 membered aryl or the 5-9 membered heteroaryl is unsubstituted or substituted with one or more of a group selected from halogen, CF
3, HCF
2, OCF
3, hydroxy, C
1-6 alkyl, C
1-6 alkoxy, C
1-6 alkylhydroxyl, unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryloxy, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted C
1-3 alkoxy-aryl, unsubstituted or substituted C
1-3 alkoxy-heteroaryl, unsubstituted or substituted C
1-3 alkoxy- heterocycloalkyl, unsubstituted or substituted C
1-3 alkylamino-heterocycloalkyl, unsubstituted or substituted C1-3 alkylamino-aryl, unsubstituted or substituted C1-3 alkylamino-heteroaryl; the aryloxy, heteroaryloxy, heterocycloalkyl, C
1-3 alkoxy-aryl, C
1-3 alkoxy-heteroaryl, C
1-3 alkoxy- heterocycloalkyl, C
1-3 alkylamino-heterocycloalkyl, C
1-3 alkylamino-aryl, C
1-3 alkylamino- heteroaryl is unsubstituted or substituted with one or more of C
1-4 alkyl, OCH
2F, HCF
2, or halogen, e.g., F or Cl. [0404] In some embodiments, R
2 is hydrogen, C
1-4 alkyl, or C
3-4 cycloalkyl. [0405] In some embodiments of a compound of formula I-1 or I-2 or pharmaceutically acceptable salts or stereoisomers thereof, W is =CH–, =CMe– or =COMe–, e.g., =CH– or =COMe–, e.g., =CH–. [0406] In some embodiments of a compound of formula I-1 or I-2 or pharmaceutically acceptable salts or stereoisomers thereof, W is =N–. [0407] In some embodiments of a compound of formula I-1 or I-2 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2. [0408] In some embodiments of a compound of formula I-1 or I-2 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH–. In some embodiments, X
1 is –NH– or –NMe–, particularly –NH– and W is =CH–, =CMe– or =COMe–, e.g., =CH– or =COMe–, e.g., =CH–. [0409] In some embodiments of a compound of formula I-1 or I-2 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2 and W is =CH–, =CMe– or =COMe–, e.g., =CH– or =COMe–, e.g., =CH–.
[0410] In some embodiments of a compound of formula I-1 or I-2 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me and W is =CH–, =CMe– or =COMe–, e.g., =CH– or =COMe–, e.g., =CH–. [0411] In some embodiments of a compound of formula I-1 or I-2 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2 and W is =N–. [0412] In some embodiments of a compound of formula I-1 or I-2 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me and W is =N–. [0413] In some embodiments of a compound of formula I-1 or I-2 or pharmaceutically acceptable salts or stereoisomers thereof, X
2 is –NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–. [0414] In some embodiments of a compound of formula I-1 or I-2 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH–, and X
2 is –NH–, –NMe– , –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–, particularly –NH– , –NMe–, –NEt–, or –O–. [0415] In some embodiments of a compound of formula I-1 or I-2 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2 and X
2 is –NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O– . [0416] In some embodiments of a compound of formula I-1 or I-2 or pharmaceutically acceptable salts or stereoisomers thereof, W is =CH–, =CMe– or =COMe–, e.g., =CH– or =COMe–, e.g., =CH–, and X
2 is –NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, – NEt–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–. [0417] In some embodiments of a compound of formula I-1 or I-2 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2 and X
1 is –NH– or –NMe–, particularly –NH–, and X
2 is –NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or – O–, particularly –NH–, –NMe–, –NEt–, or –O–. [0418] In some embodiments of a compound of formula I-1 or I-2 or pharmaceutically acceptable salts or stereoisomers thereof, R
2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl. [0419] In some embodiments of a compound of formula I-1 or pharmaceutically acceptable salts or stereoisomers thereof, R
a and R
b are each independently selected from hydrogen, methyl, ethyl,
n-propyl, n-butyl. In some embodiments, R
a and R
b are each independently selected from hydrogen and methyl. In some embodiments in which m is 2 or 3, only one R
a and one R
b are not hydrogen and/or only one R
a is not hydrogen. [0420] In some embodiments of a compound of formula I-1 or pharmaceutically acceptable salts or stereoisomers thereof, R
c and R
d are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R
c and R
d are each independently selected from hydrogen, methyl. In some embodiments in which n is 2, only one R
c and one R
c are not hydrogen and/or only one R
c is not hydrogen. [0421] In some embodiments of a compound of formula I-1 or pharmaceutically acceptable salts or stereoisomers thereof, m and n are selected such that a 4, 5 or 6 membered nitrogen containing ring is formed. [0422] In some embodiments of a compound of formula I-1 or I-2 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH–, and R
2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl. [0423] In some embodiments of a compound of formula I-1 or I-2 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH–, and X
2 is –NH–, –NMe– , –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–. [0424] In some embodiments of a compound of formula I-1 or I-2 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH– and R
1 is –HC=CH
2. [0425] In some embodiments of a compound of formula I-1 or I-2 or pharmaceutically acceptable salts or stereoisomers thereof, X
2 is –NH–, –NMe–, –NEt–, –NPr–, –NBu–, , or –O–, particularly –NH–, –NMe–, –NEt–, or –O–. and R
1 is –HC=CH
2. [0426] In some embodiments the compounds of formula I-1 or I-2 or pharmaceutically acceptable salts or stereoisomers thereof is represented by formula Ia-1 or Ia-2
X
1 is –NH–, –NMe– or –O–; X
2 is –NH–, –N(C
1-4 alkyl)–, –O– or –S–; Y is a 6 membered aryl or a 5-9 membered heteroaryl, wherein the 6 membered aryl or the 5-9 membered heteroaryl is unsubstituted or substituted with one or more of a group selected from halogen, CF
3, HCF
2, OCF
3, hydroxy, C
1-6 alkyl, C
1-6 alkoxy, C
1-6 alkylhydroxyl, unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryloxy, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted C
1-3 alkoxy-aryl, unsubstituted or substituted C
1-3 alkoxy-heteroaryl, unsubstituted or substituted C
1-3 alkoxy-heterocycloalkyl, unsubstituted or substituted C
1-3 alkylamino-heterocycloalkyl, unsubstituted or substituted C
1-3 alkylamino-aryl, unsubstituted or substituted C
1-3 alkylamino-heteroaryl; R
1 is –HC=CH
2 or –C≡C–Me; R
2 is hydrogen, C1-4 alkyl, -CHF2 or C3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form together an unsubstituted oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; m is 1, 2 or 3; n is 1 or 2; and r is 1 or 2. [0427] In some embodiments of a compound of formula Ia-1, Ia-2 or pharmaceutically acceptable salts or stereoisomers thereof, Y is a 6 membered aryl or a 5-9 membered heteroaryl, wherein the 6 membered aryl or the 5-9 membered heteroaryl is unsubstituted or substituted with one or more of a group selected from halogen, CF
3, HCF
2, OCF
3, hydroxy, C
1-6 alkyl, C
1-6 alkoxy, C
1-6 alkylhydroxyl, unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryloxy, heterocycloalkyl, unsubstituted or substituted C
1-3 alkoxy-aryl, unsubstituted or substituted C
1-3 alkoxy-heteroaryl, C
1-3 alkoxy-heterocycloalkyl, C
1-3 alkylamino-heterocycloalkyl, unsubstituted or substituted C
1-3 alkylamino-aryl, unsubstituted or substituted C
1-3 alkylamino-heteroaryl. [0428] In some embodiments of a compound of formula Ia-1, Ia-2 or pharmaceutically acceptable salts or stereoisomers thereof, Y is a 6 membered aryl or a 5-9 membered heteroaryl, wherein the 6 membered aryl or the 5-9 membered heteroaryl is unsubstituted or substituted with one or more of a group selected from halogen, CF
3, HCF
2, OCF
3, hydroxy, C
1-6 alkyl, C
1-6 alkoxy, C
1-6 alkylhydroxyl, unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryloxy,
unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted C
1-3 alkoxy-aryl, unsubstituted or substituted C
1-3 alkoxy-heteroaryl, unsubstituted or substituted C
1-3 alkoxy- heterocycloalkyl, unsubstituted or substituted C
1-3 alkylamino-heterocycloalkyl, unsubstituted or substituted C1-3 alkylamino-aryl, unsubstituted or substituted C1-3 alkylamino-heteroaryl; the aryloxy, heteroaryloxy, heterocycloalkyl, C
1-3 alkoxy-aryl, C
1-3 alkoxy-heteroaryl, C
1-3 alkoxy- heterocycloalkyl, C
1-3 alkylamino-heterocycloalkyl, C
1-3 alkylamino-aryl, C
1-3 alkylamino- heteroaryl is unsubstituted or substituted with one or more of C
1-4 alkyl, OCH
2F, HCF
2, or halogen, e.g., F or Cl. [0429] In some embodiments, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [0430] In some embodiments of a compound of formula Ia-1 or Ia-2 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2. [0431] In some embodiments of a compound of formula Ia-1 or Ia-2 or pharmaceutically acceptable salts or stereoisomers thereof, X
2 is –NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–. [0432] In some embodiments of a compound of formula Ia-1 or Ia-2 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH–, and X
2 is – NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–. [0433] In some embodiments of a compound of formula Ia-1 or Ia-2 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH2 and X
2 is –NH–, –NMe–, –NEt–, –NPr– , –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–, particularly –NH–, –NMe–, –NEt– , or –O–. [0434] In some embodiments of a compound of formula Ia-1 or Ia-2 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2 and X
1 is –NH– or –NMe–, particularly –NH–, and X
2 is –NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, – NEt–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–. [0435] In some embodiments of a compound of formula Ia-1 or Ia-2 or pharmaceutically acceptable salts or stereoisomers thereof, R
2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl. [0436] In some embodiments of a compound of formula Ia-1 or pharmaceutically acceptable salts or stereoisomers thereof, R
a and R
b are each independently selected from hydrogen, methyl, ethyl,
n-propyl, n-butyl. In some embodiments, R
a and R
b are each independently selected from hydrogen, methyl. In some embodiments in which m is 2 or 3, only one R
a and one R
b are not hydrogen and/or only one R
a is not hydrogen. [0437] In some embodiments of a compound of formula Ia-1 or pharmaceutically acceptable salts or stereoisomers thereof, R
c and R
d are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R
c and R
d are each independently selected from hydrogen, methyl. In some embodiments in which n is 2, only one R
c and one R
c are not hydrogen and/or only one R
c is not hydrogen. [0438] In some embodiments of a compound of formula Ia-1 or pharmaceutically acceptable salts or stereoisomers thereof, m and n are selected such that a 4, 5 or 6 membered nitrogen containing ring is formed. [0439] In some embodiments of a compound of formula Ia-1 or Ia-2 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH–, and R
2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl. [0440] In some embodiments of a compound of formula Ia-1 or Ia-2 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH–, and X
2 is – NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–,or –O–. [0441] In some embodiments of a compound of formula Ia-1 or Ia-2 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH– and R
1 is – HC=CH
2. [0442] In some embodiments of a compound of formula Ia-1 or Ia-2 or pharmaceutically acceptable salts or stereoisomers thereof, X
2 is –NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–. and R
1 is –HC=CH
2. [0443] In some embodiments of a compound of formula I, Ia, I-1, Ia-1, I-2 or Ia-2 or pharmaceutically acceptable salts or stereoisomers thereof, Y is of formula ii or iia
wherein: R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5a is hydrogen, halogen, e.g., F or Cl, CF3, HCF2, OCF3, hydroxy, C1-6 alkyl, C1-6 alkoxy, C
1-6 alkylhydroxyl, unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryloxy, unsubstituted or substituted C
1-3 alkoxy-aryl, unsubstituted or substituted C
1-3 alkoxy-heteroaryl or unsubstituted or substituted C
1-3 alkoxy-heterocycloalkyl; and X
3 is –NH– or –NMe–. [0444] In some embodiments of a compound of formula I or pharmaceutically acceptable salts or stereoisomers thereof, R
5a is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-6 alkyl, C
1-6 alkoxy, C
1-6 alkylhydroxyl, unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryloxy, unsubstituted or substituted C1-3 alkoxy-aryl, unsubstituted or substituted C
1-3 alkoxy-heteroaryl or unsubstituted or substituted C
1-3 alkoxy-heterocycloalkyl; the aryloxy, heteroaryloxy, C
1-3 alkoxy-aryl, C
1-3 alkoxy-heteroaryl, C
1-3 alkoxy-heterocycloalkyl is unsubstituted or substituted with one or more of C
1-4 alkyl, OCH
2F, HCF
2, or halogen, e.g., F or Cl. [0445] In some embodiments, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5a are hydrogen, while the remaining are as defined above. [0446] In some embodiments R
5a is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylhydroxyl. In some embodiments, R
5a is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkyl, C
1-4 alkoxy, C
1-4 alkylhydroxyl [0447] In some embodiments R
5a is unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryloxy, unsubstituted or substituted C
1-3 alkoxy-aryl, unsubstituted or substituted C
1-3 alkoxy-heteroaryl or unsubstituted or substituted C
1-3 alkoxy-heterocycloalkyl. In some embodiments, R
5a is unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryloxy, unsubstituted or substituted C
1-2 alkoxy-aryl, unsubstituted or substituted C
1-2 alkoxy-heteroaryl or unsubstituted or substituted C1-2 alkoxy-heterocycloalkyl. [0448] In some embodiments R
5a is unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryloxy, unsubstituted or substituted C
1-3 alkoxy-aryl, unsubstituted or substituted C
1-3 alkoxy-heteroaryl or unsubstituted or substituted C
1-3 alkoxy-heterocycloalkyl. In some embodiments, R
5a is unsubstituted or substituted aryloxy, unsubstituted or substituted
heteroaryloxy, unsubstituted or substituted C
1-2 alkoxy-aryl, unsubstituted or substituted C
1-2 alkoxy-heteroaryl or unsubstituted or substituted C
1-2 alkoxy-heterocycloalkyl; the aryloxy, heteroaryloxy, C
1-2 alkoxy-aryl, C
1-2 alkoxy-heteroaryl, C
1-2 alkoxy-heterocycloalkyl is unsubstituted or substituted with one or more of C1-4 alkyl, OCH2F, HCF2, or halogen, e.g., F or Cl. [0449] In some embodiments, R
5a is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkyl, C
1-4 alkoxy, C
1-4 alkylhydroxyl, unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryloxy, unsubstituted or substituted C
1-2 alkoxy-aryl, unsubstituted or substituted C
1-2 alkoxy-heteroaryl or unsubstituted or substituted C
1-2 alkoxy-heterocycloalkyl. [0450] In some embodiments, R
5a is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkyl, C
1-4 alkoxy, C
1-4 alkylhydroxyl, unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryloxy, unsubstituted or substituted C1-2 alkoxy-aryl, unsubstituted or substituted C
1-2 alkoxy-heteroaryl or unsubstituted or substituted C
1-2 alkoxy-heterocycloalkyl; the aryloxy, heteroaryloxy, C
1-2 alkoxy-aryl, C
1-2 alkoxy-heteroaryl, C
1-2 alkoxy-heterocycloalkyl is unsubstituted or substituted with one or more of C
1-4 alkyl, OCH
2F, HCF
2, or halogen, e.g., F or Cl. [0451] In some embodiments of a compound of formula I, Ia, I-1, Ia-1, I-2 or Ia-2 or pharmaceutically acceptable salts or stereoisomers thereof, Y is of formula iii or iv wherein:
R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; X
4 is –O–, –NH–, –NMe–; L is a covalent bond or linear or branched C
1-3 alkyl; and
A is a C
6 aryl, a 6 membered heterocycloalkyl or a 5-6 membered heteroaryl, wherein the C
6 aryl, 6 membered heterocycloalkyl or 5-6 membered heteroaryl is unsubstituted or substituted with one or more of C
1-4 alkyl, OCH
2F, HCF
2, or halogen, e.g., F or Cl. [0452] In some embodiments, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above for formula iii to iv. [0453] In some embodiments, X
4 is –O–. [0454] In some embodiments, L is a covalent bond, –(CH
2)– or –(CH
2)
2–. In some embodiments, X
4 is –O– and L is a covalent bond, –(CH
2)– or –(CH
2)
2–. [0455] In some embodiments, A is a C
6 aryl, a 6 membered heterocycloalkyl or a 5-6 membered heteroaryl, wherein the C
6 aryl, 6 membered heterocycloalkyl or 5-6 membered heteroaryl is unsubstituted or substituted with one of C
1-4 alkyl, OCH
2F, HCF
2, or halogen, e.g., F or Cl. [0456] In some embodiments, A is a C6 aryl, a 6 membered heterocycloalkyl or a 5-6 membered heteroaryl, wherein the C
6 aryl, 6 membered heterocycloalkyl or 5-6 membered heteroaryl is unsubstituted or substituted with one of methyl, ethyl, n-propyl, s-propyl, n-butyl, s-butyl, t-butyl, OCH
2F, HCF
2, or halogen, e.g., F or Cl. [0457] In some embodiments, A is a C
6 aryl, a 6 membered heterocycloalkyl or a 5-6 membered heteroaryl, wherein the C
6 aryl, 6 membered heterocycloalkyl or 5-6 membered heteroaryl is unsubstituted or substituted with one methyl, OCH
2F, HCF
2, or halogen, e.g., F or Cl. [0458] In some embodiments, A is phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, thiazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl, which is unsubstituted or substituted with one or more of C
1-4 alkyl, OCH
2F, HCF
2, or halogen, e.g., F or Cl. [0459] In some embodiments, A is phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, thiazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl, which is unsubstituted or substituted with one of methyl, ethyl, n-propyl, s-propyl, n-butyl, s-butyl, t-butyl, OCH
2F, HCF
2, or halogen, e.g., F or Cl. [0460] In some embodiments, A is phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, thiazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl, which is unsubstituted or substituted with one methyl, OCH
2F, HCF
2, or halogen, e.g., F or Cl. [0461] In some embodiments of a compound of formula I, Ia, I-1, Ia-1, I-2 or Ia-2 or pharmaceutically acceptable salts or stereoisomers thereof, Y is of formula iii, v, vi or vii
wherein: R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; X
4 is –O–, –NH–, –NMe–; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; and L is a covalent bond or linear or branched C
1-3 alkyl. [0462] In some embodiments, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above for formula iii to vii. [0463] In some embodiments, X
4 is –O–. [0464] In some embodiments, L is a covalent bond, –(CH
2)– or –(CH
2)
2–. In some embodiments, X
4 is –O– and L is a covalent bond, –(CH
2)– or –(CH
2)
2–. [0465] In some embodiments, X
8 is –O–, –NMe– or –S–. [0466] In some embodiments of a compound of formula I, Ia, I-1, Ia-1, I-2 or Ia-2 or pharmaceutically acceptable salts or stereoisomers thereof, Y is of formula iii, v-a, e.g., v-a-1 or v-a-2, or vi-a, e.g., vi-a-1, or vii-a, e.g., vii-a-1
wherein: R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; and s is 0, 1, 2, 3. [0467] In some embodiments, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above for formula iii to vii-a-1. [0468] In some embodiments, X
8 is –O–, –NMe– or –S–. [0469] In some embodiments of a compound of formula I, Ia, I-1, Ia-1, I-2 or Ia-2 or pharmaceutically acceptable salts or stereoisomers thereof, Y is of formula iii, v-a(i), v-a(ii), e.g., v-a(i)-1, v-a(ii)-1, v-a(i)-2, v-a(ii)-2, or vi-a(i), e.g., vi-a(i)-1, or vii-a(i) or vii-a(ii), e.g., vii-a(i)-1
or vii-a(ii)-1
wherein: R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C1-4 alkyl, e.g., methyl, HCF2, OCH2F or halogen, e.g., F, Cl; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; and s is 0 or 1. [0470] In some embodiments, X
8 is –O–, –NMe– or –S–. [0471] In some embodiments, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’,
R
5 in formula iii are hydrogen, while the remaining are as defined above for formula iii to vii-a(ii)- 1. [0472] In some embodiments, wherein Y is of formula v-a(i), v-a(ii), v-a(i)-1, v-a(ii)-1, v-a(i)-2 or v-a(ii)-2, (i) X
5, X
5’, X
6, X
6’, X
7 are -CH=, or (ii) X
5 is =N- and X
5’, X
6, X
6’, X
7 are -CH=, or (iii) X
6 is =N- and X
5, X
5’, X
6’, X
7 are -CH=, or (iv) X
7 is =N- and X
5, X
5’, X
6, X
6’ are -CH=, or (v) X
5 and X
6 are –N= and X
5’, X
6’, X
7 are –CH=, or (vi) X
5 and X
5’ are –N= and X
6, X
6’, X
7 are –CH=, or (vii) X
5 and X
6’ are –N= and X
6, X
5’, X
7 are –CH=, or (viii) X
5 and X
7 are –N= and X
5’, X
6, X
6’ are –CH=, or (ix) X
6 and X
6’ are =N- and X
5, X
5’, X
7 are –CH-, or (x) X
6 and X
7 are =N- and X
5, X
5’, X
6’ are –CH–. [0473] In some embodiments, wherein Y is of formula vii-a(i), vii-a(ii), vii-a(i)-1 or vii-a(ii)-1, (i) X
8’ is –O–, X
8 and X
9 are –N= and X
9’ is –CH=, or (ii) X
8’ is –S–, X
8 and X
9 are –N= and X
9’ is – CH=, or (iii) X
8’ is –O–, X
8, X
9 and X
9’ is –CH=, or (iv) X
8’ is –NH–, X
8, X
9 are –CH= and X
9’ is –N=, or (v) X
8’ is –NH–, X
8, X
9’ are –CH= and X
9 is –N=, or (vi) X
8’ is –NMe–, X
8, X
9 are –CH= and X
9’ is –N=, or (vii) X
8’ is –NMe–, X
8, X
9’ are –CH= and X
9 is –N=, or (viii) X
8’ is –NMe–, X
9’ is –N=, X
8 and X
9 are –CH=, or (ix) X
8’ is –NH–, X
9’ is –N=, X
8 and X
9 are –CH=, or (x) X
8’ is –S–, X
8 is –N=, X
9 and X
9’ are –CH=. [0474] In some embodiments of a compound of formula I, Ia, I-1, Ia-1, I-2 or Ia-2 or pharmaceutically acceptable salts or stereoisomers thereof, Y is of formula iii, v-a-3, v-a-4 v-a-5, v-a-6, v-a-7, v-a-8, v-a-9, v-a-10, v-b-1, v-b-2, v-b-3, v-b-4, v-b-5, v-b-6, v-b-7, v-b-8, v-b-9, v-b- 10, v-b-11, v-b-12, vi-a, vii-a-1, vii-a-2 or vii-a-3
wherein:
R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; and s is 0 or 1. [0475] In some embodiments, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above. [0476] In some embodiments, X
8’ is –O–, –NMe– or –S–. [0477] In some embodiments, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above for formula iii to vii-a-3. [0478] In some particular embodiments of a compound of formula I, Ia, I-1, Ia-1, I-2 or Ia-2 or pharmaceutically acceptable salts or stereoisomers thereof, Y is of formula iii, v-a-3, v-b-1, v-b-2, v-b-3, v-b-4, v-b-5, v-b-6, v-b-7, v-b-8, v-b-9, v-b-10, v-b-11, v-b-12, vi-a, vii-a-1, vii-a-2 or vii- a-3. [0479] In some embodiments, s is 0 or 1 is Y is of formula v-a-3, v-a-4 v-a-5, v-a-6, v-a-7, v-a-8, v-a-9, v-a-10, v-a-11, v-b-1, v-b-2, v-b-3, v-b-4, v-b-5, v-b-6, v-b-7, v-b-8, v-b-9, v-b-10, v-b-11, v-b-12 and s is 1 for vi-a, vii-a-1, vii-a-2 or vii-a-3. [0480] In some embodiments, s is 0 or 1 is Y is of formula v-a-3, v-a-4 v-a-5, v-a-6, v-a-7, v-a-8, v-a-9, v-a-10, v-a-11, and s is 1 for v-b-1, v-b-2, v-b-3, v-b-4, v-b-5, v-b-6, v-b-7, v-b-8, v-b-9, v- b-10, v-b-11, v-b-12, vi-a, vii-a-1, vii-a-2 or vii-a-3. E.g., embodiments, s is 1. [0481] In some embodiments of a compound of formula I, Ia, I-1, Ia-1, I-2 or Ia-2 or pharmaceutically acceptable salts or stereoisomers thereof, Y is of formula iii, v-c-1, v-c-2, v-c-3, v-c-4, v-d-1, v-d-2, v-d-3, v-d-4, v-d-5, v-d-6, v-d-7, vi-a, vii-b-1, vii-b-2, vii-b-3 or vii-b-4
wherein: R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; and s is 0 or 1. [0482] In some embodiments, R
6 is hydrogen for v-d-1, v-d-2, v-d-3, v-d-4, v-d-5 and v-d-7; and
R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl, for v-c-1, v-c-2, v- c-3, v-c-4, v-d-6, vii-b-1, vii-b-2, vii-b-3 and vii-b-4. [0483] In some embodiments of a compound of formula I, Ia, I-1, Ia-1, I-2 or Ia-2 or pharmaceutically acceptable salts or stereoisomers thereof, Y is of formula v-c(i)-1, v-c(ii)-1, v- c(i)-2, v-c(ii)-2, v-c(i)-3, v-c(ii)-3, v-c(i)-4, v-c(ii)-4, v-d(i)-1, v-d(ii)-1, v-d(i)-2, v-d(ii)-2, v-d(i)- 3, v-d(ii)-3, v-d(i)-4, v-d(ii)-4, v-d(i)-5, v-d(ii)-5, v-d(i)-6, v-d(ii)-6, v-d(i)-7, v-d(ii)-7, vi-a(i), vi- a(ii), iii-(i), iii-(ii), iii-(iii), iii-(iv), vii-b(i)-1, vii-b(ii)-1, vii-b(i)-2, vii-b(ii)-2, vii-b(i)-3, vii-b(ii)- 3, vii-b(i)-4 or vii-b(ii)-4
wherein: R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF3, HCF2, OCF3, hydroxy, C1-4 alkoxy or C1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; and s is 0 or 1. [0484] In some embodiments, s is 0 or 1 for formula v-c(i)-1, v-c(ii)-1, and 1 for v-c(i)-2, v-c(ii)- 2, v-c(i)-3, v-c(ii)-3, v-c(i)-4, v-c(ii)-4, v-d(i)-1, v-d(ii)-1, v-d(i)-2, v-d(ii)-2, v-d(i)-3, v-d(ii)-3, v- d(i)-4, v-d(ii)-4, v-d(i)-5, v-d(ii)-5, v-d(i)-6, v-d(ii)-6, v-d(i)-7, v-d(ii)-7, vi-a(i), vi-a(ii), vii-b(i)- 1, vii-b(ii)-1, vii-b(i)-2, vii-b(ii)-2, vii-b(i)-3, vii-b(ii)-3, vii-b(i)-4 or vii-b(ii)-4. [0485] In some embodiments, R
6 is hydrogen for v-d(i)-1, v-d(ii)-1, v-d(i)-3, v-d(ii)-3, v-d(i)-4, v- d(ii)-4, v-d(i)-5, v-d(ii)-5, v-d(i)-6, v-d(ii)-6, v-d(i)-7 and v-d(ii)-7; and R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl, for v-c(i)-1, v-c(ii)-1, v-c(i)-2, v-c(ii)-2, v-c(i)- 3, v-c(ii)-3, v-c(i)-4, v-c(ii)-4, v-d(i)-2, v-d(ii)-2, vii-b(i)-1, vii-b(ii)-1, vii-b(i)-2, vii-b(ii)-2, vii- b(i)-3, vii-b(ii)-3, vii-b(i)-4 and vii-b(ii)-4. [0486] In some embodiments of a compound of formula I, Ia, I-1, Ia-1, I-2 or Ia-2 or pharmaceutically acceptable salts or stereoisomers thereof, Y is of formula iii, v-e-1, v-e-2, v-f-1, v-f-2, v-f-3, v-f-4, v-f-5, v-f-6a, v-f-6b, v-f-7, vi-a, vii-c-1, vii-c-2, vii-c-3 or vii-c-4
wherein: R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF3, HCF2, OCF3, hydroxy, C1-4 alkoxy or C1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; s is 0 or 1. [0487] In some embodiments at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above for formula iii to vii-c-4. [0488] In some embodiments, the present disclosure provides the compound or pharmaceutical acceptable salts or stereoisomers thereof having formula II or III
wherein: W is =CH–, =COMe–, =CMe– or =N–; Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, -CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; X
2 is –NH–, –N(C
1-4 alkyl)–, –O– or –S–; Y is a group of formula iii, v, vi or vii
wherein: R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl;
R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; X
4 is –O–, –NH–, –NMe–; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; and L is a covalent bond or linear or branched C
1-3 alkyl. [0489] In some embodiments of a compound of formula II or III or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1- C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3- 4 heterocycloalkyl or C
3-4 cycloalkyl. [0490] In some embodiments of a compound of formula II or III or pharmaceutically acceptable salts or stereoisomers thereof, W is =CH–, =CMe– or =COMe–, e.g., =CH– or =COMe–, e.g., =CH–. [0491] In some embodiments of a compound of formula II or III or pharmaceutically acceptable salts or stereoisomers thereof, W is =N–. [0492] In some embodiments of a compound of formula II or III or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH–. In some embodiments, X
1 is –NH– or –NMe–, particularly –NH– and W is =CH–, =CMe– or =COMe–, e.g., =CH– or =COMe–, e.g., =CH–. [0493] In some embodiments of a compound of formula II or III or pharmaceutically acceptable salts or stereoisomers thereof, X
2 is –NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–. [0494] In some embodiments of a compound of formula II or III or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH–, and X
2 is –NH–, –NMe– , –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–, particularly –NH– , –NMe–, –NEt–, or –O–. [0495] In some embodiments of a compound of formula II or III or pharmaceutically acceptable salts or stereoisomers thereof, W is =CH–, =CMe– or =COMe–, e.g., =CH– or =COMe–, e.g., =CH–, and X
2 is –NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, – NEt–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–.
[0496] In some embodiments, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above for formula iii to vii. [0497] In some embodiments, X
4 is –O–. [0498] In some embodiments, L is a covalent bond, –(CH2)– or –(CH2)2–. In some embodiments, X
4 is –O– and L is a covalent bond, –(CH
2)– or –(CH
2)
2–. [0499] In some embodiments, X
8 is –O–, –NMe– or –S–. [0500] In some embodiments the compound of formula II or III or pharmaceutically acceptable salts or stereoisomers thereof is represented by formula IIa or IIIa
wherein: Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, -CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; X
2 is –NH–, –N(C1-4 alkyl)–, –O– or –S–; Y is a group of formula iii, v, vi or vii
wherein: R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; X
4 is –O–, –NH–, –NMe–; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; and L is a covalent bond or linear or branched C
1-3 alkyl. [0501] In some embodiments of a compound of formula II, IIa, III, IIIa or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3- 4 heterocycloalkyl or C
3-4 cycloalkyl. [0502] In some embodiments of a compound of formula II, IIa, III, IIIa or pharmaceutically acceptable salts or stereoisomers thereof, Y is of formula iii, v-a, e.g., v-a-1 or v-a-2, or vi-a, e.g., vi-a-1, or vii-a, e.g., vii-a-1
wherein: R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; and s is 0, 1, 2, 3. [0503] In some embodiments, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above for formula iii to vii-a-1. [0504] In some embodiments, X
8 is –O–, –NMe– or –S–. [0505] In some embodiments of a compound of formula II, IIa, III, IIIa or pharmaceutically acceptable salts or stereoisomers thereof, Y is of formula iii, v-a(i), v-a(ii), e.g., v-a(i)-1, v-a(ii)-1, v-a(i)-2, v-a(ii)-2, or vi-a(i), e.g., vi-a(i)-1, or vii-a(i) or vii-a(ii), e.g., vii-a(i)-1 or vii-a(ii)-1
wherein: R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; s is 0 or 1. [0506] In some embodiments, X
8 is –O–, –NMe– or –S–. [0507] In some embodiments, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 in formula iii are hydrogen, while the remaining are as defined above for formula iii to vii-a(ii)-
1. [0508] In some embodiments, wherein Y is of formula v-a(i), v-a(ii), v-a(i)-1, v-a(ii)-1, v-a(i)-2 or v-a(ii)-2, (i) X
5, X
5’, X
6, X
6’, X
7 are -CH=, or (ii) X
5 is =N- and X
5’, X
6, X
6’, X
7 are -CH=, or (iii) X
6 is =N- and X
5, X
5’, X
6’, X
7 are -CH=, or (iv) X
7 is =N- and X
5, X
5’, X
6, X
6’ are -CH=, or (v) X
5 and X
6 are –N= and X
5’, X
6’, X
7 are –CH=, or (vi) X
5 and X
5’ are –N= and X
6, X
6’, X
7 are –CH=, or (vii) X
5 and X
6’ are –N= and X
6, X
5’, X
7 are –CH=, or (viii) X
5 and X
7 are –N= and X
5’, X
6, X
6’ are –CH=, or (ix) X
6 and X
6’ are =N- and X
5, X
5’, X
7 are –CH-, or (x) X
6 and X
7 are =N- and X
5, X
5’, X
6’ are –CH–. [0509] In some embodiments, wherein Y is of formula vii-a(i), vii-a(ii), vii-a(i)-1 or vii-a(ii)-1, (i) X
8’ is –O–, X
8 and X
9 are –N= and X
9’ is –CH=, or (ii) X
8’ is –S–, X
8 and X
9 are –N= and X
9’ is – CH=, or (iii) X
8’ is –O–, X
8, X
9 and X
9’ is –CH=, or (iv) X
8’ is –NH–, X
8, X
9 are –CH= and X
9’ is –N=, or (v) X
8’ is –NH–, X
8, X
9’ are –CH= and X
9 is –N=, or (vi) X
8’ is –NMe–, X
8, X
9 are –CH= and X
9’ is –N=, or (vii) X
8’ is –NMe–, X
8, X
9’ are –CH= and X
9 is –N=, or (viii) X
8’ is –NMe–, X
9’ is –N=, X
8 and X
9 are –CH=, or (ix) X
8’ is –NH–, X
9’ is –N=, X
8 and X
9 are –CH=, or (x) X
8’ is –S–, X
8 is –N=, X
9 and X
9’ are –CH=. [0510] In some embodiments of a compound of formula II, IIa, III, IIIa or pharmaceutically acceptable salts or stereoisomers thereof, Y is of formula iii, v-a-3, v-a-4 v-a-5, v-a-6, v-a-7, v-a- 8, v-a-9, v-a-10, v-b-1, v-b-2, v-b-3, v-b-4, v-b-5, v-b-6, v-b-7, v-b-8, v-b-9, v-b-10, v-b-11, v-b- 12, vi-a, vii-a-1, vii-a-2 or vii-a-3
wherein:
R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; and s is 0 or 1. [0511] In some embodiments, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above for formula iii to vii-a-3. [0512] In some embodiments, X
8’ is –O–, –NMe– or –S–. [0513] In some embodiments, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above for formula iii to vii-a-3. [0514] In some particular embodiments of a compound of formula II, IIa, III, IIIa or pharmaceutically acceptable salts or stereoisomers thereof, Y is of formula iii, v-a-3, v-b-1, v-b-2, v-b-3, v-b-4, v-b-5, v-b-6, v-b-7, v-b-8, v-b-9, v-b-10, v-b-11, v-b-12, vi-a, vii-a-1, vii-a-2 or vii- a-3. [0515] In some embodiments, s is 0 or 1 is Y is of formula v-a-3, v-a-4 v-a-5, v-a-6, v-a-7, v-a-8, v-a-9, v-a-10, v-a-11, v-b-1, v-b-2, v-b-3, v-b-4, v-b-5, v-b-6, v-b-7, v-b-8, v-b-9, v-b-10, v-b-11, v-b-12 and s is 1 for vi-a, vii-a-1, vii-a-2 or vii-a-3. [0516] In some embodiments, s is 0 or 1 is Y is of formula v-a-3, v-a-4 v-a-5, v-a-6, v-a-7, v-a-8, v-a-9, v-a-10, v-a-11, and s is 1 for v-b-1, v-b-2, v-b-3, v-b-4, v-b-5, v-b-6, v-b-7, v-b-8, v-b-9, v- b-10, v-b-11, v-b-12, vi-a, vii-a-1, vii-a-2 or vii-a-3. In some embodiments, s is 1. [0517] In some embodiments of a compound of formula II, IIa, III, IIIa or pharmaceutically acceptable salts or stereoisomers thereof, Y is of formula iii, v-c-1, v-c-2, v-c-3, v-c-4, v-d-1, v-d- 2, v-d-3, v-d-4, v-d-5, v-d-6, v-d-7, vi-a, vii-b-1, vii-b-2, vii-b-3 or vii-b-4
wherein: R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; and s is 0 or 1. [0518] In some embodiments, R
6 is hydrogen for v-d-1, v-d-2, v-d-3, v-d-4, v-d-5 and v-d-7; and
R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl, for v-c-1, v-c-2, v- c-3, v-c-4, v-d-6, vii-b-1, vii-b-2, vii-b-3 and vii-b-4. [0519] In some embodiments of a compound of formula II, IIa, III, IIIa or pharmaceutically acceptable salts or stereoisomers thereof, Y is of formula v-c(i)-1, v-c(ii)-1, v-c(i)-2, v-c(ii)-2, v- c(i)-3, v-c(ii)-3, v-c(i)-4, v-c(ii)-4, v-d(i)-1, v-d(ii)-1, v-d(i)-2, v-d(ii)-2, v-d(i)-3, v-d(ii)-3, v-d(i)- 4, v-d(ii)-4, v-d(i)-5, v-d(ii)-5, v-d(i)-6, v-d(ii)-6, v-d(i)-7, v-d(ii)-7, vi-a(i), vi-a(ii), iii-(i), iii-(ii), iii-(iii), iii-(iv), vii-b(i)-1, vii-b(ii)-1, vii-b(i)-2, vii-b(ii)-2, vii-b(i)-3, vii-b(ii)-3, vii-b(i)-4 or vii- b(ii)-4
wherein: R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF3, HCF2, OCF3, hydroxy, C1-4 alkoxy or C1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; and s is 0 or 1. [0520] In some embodiments, s is 0 or 1 for formula v-c(i)-1, v-c(ii)-1, and 1 for v-c(i)-2, v-c(ii)- 2, v-c(i)-3, v-c(ii)-3, v-c(i)-4, v-c(ii)-4, v-d(i)-1, v-d(ii)-1, v-d(i)-2, v-d(ii)-2, v-d(i)-3, v-d(ii)-3, v- d(i)-4, v-d(ii)-4, v-d(i)-5, v-d(ii)-5, v-d(i)-6, v-d(ii)-6, v-d(i)-7, v-d(ii)-7, vi-a(i), vi-a(ii), vii-b(i)- 1, vii-b(ii)-1, vii-b(i)-2, vii-b(ii)-2, vii-b(i)-3, vii-b(ii)-3, vii-b(i)-4 or vii-b(ii)-4. [0521] In some embodiments, R
6 is hydrogen for v-d(i)-1, v-d(ii)-1, v-d(i)-3, v-d(ii)-3, v-d(i)-4, v- d(ii)-4, v-d(i)-5, v-d(ii)-5, v-d(i)-6, v-d(ii)-6, v-d(i)-7 and v-d(ii)-7; and R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl, for v-c(i)-1, v-c(ii)-1, v-c(i)-2, v-c(ii)-2, v-c(i)- 3, v-c(ii)-3, v-c(i)-4, v-c(ii)-4, v-d(i)-2, v-d(ii)-2, vii-b(i)-1, vii-b(ii)-1, vii-b(i)-2, vii-b(ii)-2, vii- b(i)-3, vii-b(ii)-3, vii-b(i)-4 and vii-b(ii)-4. [0522] In some embodiments the compound of formula I, Ia, II, IIa, III or IIIa or pharmaceutically acceptable salts or stereoisomers thereof is represented by formula IIb or IIIb
wherein: R
2 is hydrogen, C
1-4 alkyl, -CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle;
m is 1, 2 or 3; n is 1 or 2; X
1 is –NH–, –NMe– or –O–; X
2 is –NH–, –N(C1-4 alkyl)–, –O– or –S–; Y is a group of formula iii, v, vi or vii
wherein: R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; X
4 is –O–, –NH–, –NMe–; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; and L is a covalent bond or linear or branched C
1-3 alkyl. [0523] In some embodiments of a compound of formula IIb or IIIb or pharmaceutically acceptable salts or stereoisomers thereof, R
2 is hydrogen, C1-4 alkyl or C3-4 cycloalkyl. [0524] In some embodiments of a compound of formula IIb or IIIb or pharmaceutically acceptable salts or stereoisomers thereof, Y is of formula iii, v-a, e.g., v-a-1 or v-a-2, or vi-a, e.g., vi-a-1, or vii-a, e.g., vii-a-1
wherein: R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; and S is 0, 1, 2, 3. [0525] In some embodiments, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above for formula iii to vii-a-1. [0526] In some embodiments, X
8 is –O–, –NMe– or –S–. [0527] In some embodiments of a compound of formula IIb or IIIb or pharmaceutically acceptable salts or stereoisomers thereof, Y is of formula iii, v-a(i), v-a(ii), e.g., v-a(i)-1, v-a(ii)-1, v-a(i)-2, v- a(ii)-2, or vi-a(i), e.g., vi-a(i)-1, or vii-a(i) or vii-a(ii), e.g., vii-a(i)-1 or vii-a(ii)-1
wherein: R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; and s is 0 or 1. [0528] In some embodiments, X
8 is –O–, –NMe– or –S–. [0529] In some embodiments, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 in formula iii are hydrogen, while the remaining are as defined above for formula iii to vii-a(ii)-
1. [0530] In some embodiments, wherein Y is of formula v-a(i), v-a(ii), v-a(i)-1, v-a(ii)-1, v-a(i)-2 or v-a(ii)-2, (i) X
5, X
5’, X
6, X
6’, X
7 are -CH=, or (ii) X
5 is =N- and X
5’, X
6, X
6’, X
7 are -CH=, or (iii) X
6 is =N- and X
5, X
5’, X
6’, X
7 are -CH=, or (iv) X
7 is =N- and X
5, X
5’, X
6, X
6’ are -CH=, or (v) X
5 and X
6 are –N= and X
5’, X
6’, X
7 are –CH=, or (vi) X
5 and X
5’ are –N= and X
6, X
6’, X
7 are –CH=, or (vii) X
5 and X
6’ are –N= and X
6, X
5’, X
7 are –CH=, or (viii) X
5 and X
7 are –N= and X
5’, X
6, X
6’ are –CH=, or (ix) X
6 and X
6’ are =N- and X
5, X
5’, X
7 are –CH-, or (x) X
6 and X
7 are =N- and X
5, X
5’, X
6’ are –CH–. [0531] In some embodiments, wherein Y is of formula vii-a(i), vii-a(ii), vii-a(i)-1 or vii-a(ii)-1, (i) X
8’ is –O–, X
8 and X
9 are –N= and X
9’ is –CH=, or (ii) X
8’ is –S–, X
8 and X
9 are –N= and X
9’ is – CH=, or (iii) X
8’ is –O–, X
8, X
9 and X
9’ is –CH=, or (iv) X
8’ is –NH–, X
8, X
9 are –CH= and X
9’ is –N=, or (v) X
8’ is –NH–, X
8, X
9’ are –CH= and X
9 is –N=, or (vi) X
8’ is –NMe–, X
8, X
9 are –CH= and X
9’ is –N=, or (vii) X
8’ is –NMe–, X
8, X
9’ are –CH= and X
9 is –N=, or (viii) X
8’ is –NMe–, X
9’ is –N=, X
8 and X
9 are –CH=, or (ix) X
8’ is –NH–, X
9’ is –N=, X
8 and X
9 are –CH=, or (x) X
8’ is –S–, X
8 is –N=, X
9 and X
9’ are –CH=. [0532] In some embodiments of a compound of formula IIb or IIIb or pharmaceutically acceptable salts or stereoisomers thereof, Y is of formula iii, v-a-3, v-a-4 v-a-5, v-a-6, v-a-7, v-a-8, v-a-9, v- a-10, v-b-1, v-b-2, v-b-3, v-b-4, v-b-5, v-b-6, v-b-7, v-b-8, v-b-9, v-b-10, v-b-11, v-b-12, vi-a, vii- a-1, vii-a-2 or vii-a-3
wherein:
R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; and s is 0 or 1. [0533] In some embodiments, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above for formula iii to vii-a-3. [0534] In some embodiments, X
8’ is –O–, –NMe– or –S–. [0535] In some embodiments, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above for formula iii to vii-a-3. [0536] In some particular embodiments of a compound of formula IIb or IIIb or pharmaceutically acceptable salts or stereoisomers thereof, Y is of formula iii, v-a-3, v-b-1, v-b-2, v-b-3, v-b-4, v- b-5, v-b-6, v-b-7, v-b-8, v-b-9, v-b-10, v-b-11, v-b-12, vi-a, vii-a-1, vii-a-2 or vii-a-3. [0537] In some embodiments, s is 0 or 1 is Y is of formula v-a-3, v-a-4 v-a-5, v-a-6, v-a-7, v-a-8, v-a-9, v-a-10, v-a-11, v-b-1, v-b-2, v-b-3, v-b-4, v-b-5, v-b-6, v-b-7, v-b-8, v-b-9, v-b-10, v-b-11, v-b-12 and s is 1 for vi-a, vii-a-1, vii-a-2 or vii-a-3. [0538] In some embodiments, s is 0 or 1 is Y is of formula v-a-3, v-a-4 v-a-5, v-a-6, v-a-7, v-a-8, v-a-9, v-a-10, v-a-11, and s is 1 for v-b-1, v-b-2, v-b-3, v-b-4, v-b-5, v-b-6, v-b-7, v-b-8, v-b-9, v- b-10, v-b-11, v-b-12, vi-a, vii-a-1, vii-a-2 or vii-a-3. In some embodiments, s is 1. [0539] In some embodiments of a compound of formula IIb or IIIb or pharmaceutically acceptable salts or stereoisomers thereof, Y is of formula iii, v-c-1, v-c-2, v-c-3, v-c-4, v-d-1, v-d-2, v-d-3, v- d-4, v-d-5, v-d-6, v-d-7, vi-a, vii-b-1, vii-b-2, vii-b-3 or vii-b-4
wherein: R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; and s is 0 or 1. [0540] In some embodiments, R
6 is hydrogen for v-d-1, v-d-2, v-d-3, v-d-4, v-d-5 and v-d-7; and
R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl, for v-c-1, v-c-2, v- c-3, v-c-4, v-d-6, vii-b-1, vii-b-2, vii-b-3 and vii-b-4. [0541] In some embodiments of a compound of formula IIb or IIIb or pharmaceutically acceptable salts or stereoisomers thereof, Y is of formula v-c(i)-1, v-c(ii)-1, v-c(i)-2, v-c(ii)-2, v-c(i)-3, v- c(ii)-3, v-c(i)-4, v-c(ii)-4, v-d(i)-1, v-d(ii)-1, v-d(i)-2, v-d(ii)-2, v-d(i)-3, v-d(ii)-3, v-d(i)-4, v-d(ii)- 4, v-d(i)-5, v-d(ii)-5, v-d(i)-6, v-d(ii)-6, v-d(i)-7, v-d(ii)-7, vi-a(i), vi-a(ii), iii-(i), iii-(ii), iii-(iii), iii-(iv), vii-b(i)-1, vii-b(ii)-1, vii-b(i)-2, vii-b(ii)-2, vii-b(i)-3, vii-b(ii)-3, vii-b(i)-4 or vii-b(ii)-4
wherein: R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF3, HCF2, OCF3, hydroxy, C1-4 alkoxy or C1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; and s is 0 or 1. [0542] In some embodiments, s is 0 or 1 for formula v-c(i)-1, v-c(ii)-1, and 1 for v-c(i)-2, v-c(ii)- 2, v-c(i)-3, v-c(ii)-3, v-c(i)-4, v-c(ii)-4, v-d(i)-1, v-d(ii)-1, v-d(i)-3, v-d(ii)-3, v-d(i)-4, v-d(ii)-4, v- d(i)-5, v-d(ii)-5, v-d(i)-6, v-d(ii)-6, v-d(i)-7, v-d(ii)-7, vi-a(i), vi-a(ii), vii-b(i)-1, vii-b(ii)-1, vii- b(i)-2, vii-b(ii)-2, vii-b(i)-3, vii-b(ii)-3, vii-b(i)-4 or vii-b(ii)-4. [0543] In some embodiments, R
6 is hydrogen for v-d(i)-1, v-d(ii)-1, v-d(i)-2, v-d(ii)-2, v-d(i)-3, v- d(ii)-3, v-d(i)-4, v-d(ii)-4, v-d(i)-5, v-d(ii)-5, v-d(i)-7 and v-d(ii)-7; and R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl, for v-c(i)-1, v-c(ii)-1, v-c(i)-2, v-c(ii)-2, v-c(i)- 3, v-c(ii)-3, v-c(i)-4, v-c(ii)-4, v-d(i)-2, v-d(ii)-2, vii-b(i)-1, vii-b(ii)-1, vii-b(i)-2, vii-b(ii)-2, vii- b(i)-3, vii-b(ii)-3, vii-b(i)-4 vii-b(ii)-4, v-d(i)-6, v-d(ii)-6. [0544] In some embodiments the compound of formula I, Ia, II, IIa, IIb, III, IIIa or IIIb or pharmaceutically acceptable salts or stereoisomers thereof is represented by formula IIc-1, IIc-2, IIIc-1 or IIIc-2
wherein: X
1 is –NH–, –NMe– or –O–; X
2 is –NH–, –N(C1-4 alkyl)–, –O– or –S–; R
2 is hydrogen, C
1-4 alkyl, -CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form together an unsubstituted oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; m is 1, 2 or 3; n is 1 or 2; r is 1 or 2; and Y is a group of formula iii, v, vi or vii.
wherein: R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; X
4 is –O–, –NH–, –NMe–; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; and L is a covalent bond or linear or branched C
1-3 alkyl. [0545] In some embodiments of a compound of formula IIc-1, IIc-2, IIIc-1 or IIIc-2 or pharmaceutically acceptable salts or stereoisomers thereof, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl; [0546] In some embodiments of a compound of formula IIc-1, IIc-2, IIIc-1 or IIIc-2 or pharmaceutically acceptable salts or stereoisomers thereof, X
2 is –NH–, –NMe–, –NEt–, –NPr–, – NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–. [0547] In some embodiments of a compound of formula IIc-1, IIc-2, IIIc-1 or IIIc-2 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly – NH–, and X
2 is –NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, – NEt–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–.
[0548] In some embodiments of a compound of formula IIc-1, IIc-2, IIIc-1 or IIIc-2 or pharmaceutically acceptable salts or stereoisomers thereof, R
2 is hydrogen, methyl, ethyl, n- propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl. [0549] In some embodiments of a compound of formula IIc-1 or IIIc-1or pharmaceutically acceptable salts or stereoisomers thereof, R
a and R
b are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R
a and R
b are each independently selected from hydrogen and methyl. In some embodiments in which m is 2 or 3, only one R
a and one R
b are not hydrogen and/or only one R
a is not hydrogen. [0550] In some embodiments of a compound of formula IIc-1 or IIIc-1or pharmaceutically acceptable salts or stereoisomers thereof, R
c and R
d are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R
c and R
d are each independently selected from hydrogen, methyl. In some embodiments in which n is 2, only one R
c and one R
c are not hydrogen and/or only one R
c is not hydrogen. [0551] In some embodiments of a compound of formula IIc-1 or IIIc-1or pharmaceutically acceptable salts or stereoisomers thereof, m and n are selected such that a 4, 5 or 6 membered nitrogen containing ring is formed. [0552] In some embodiments of a compound of formula IIc-1, IIc-2, IIIc-1 or IIIc-2 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly – NH–, and R
2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl. [0553] In some embodiments of a compound of formula IIc-1, IIc-2, IIIc-1 or IIIc-2 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly – NH–, and X
2 is –NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, – NEt–, or –O–. [0554] In some embodiments of a compound of formula IIc-1, IIc-2, IIIc-1 or IIIc-2 or pharmaceutically acceptable salts or stereoisomers thereof, Y is of formula iii, v-a, e.g., v-a-1 or v-a-2, or vi-a, e.g., vi-a-1, or vii-a, e.g., vii-a-1
wherein: R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; and s is 0, 1, 2, 3. [0555] In some embodiments, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above for formula iii to vii-a-1. [0556] In some embodiments, X
8 is –O–, –NMe– or –S–. [0557] In some embodiments of a compound of formula IIc-1, IIc-2, IIIc-1 or IIIc-2 or pharmaceutically acceptable salts or stereoisomers thereof, Y is of formula iii, v-a(i), v-a(ii), e.g., v-a(i)-1, v-a(ii)-1, v-a(i)-2, v-a(ii)-2, or vi-a(i), e.g., vi-a(i)-1, or vii-a(i) or vii-a(ii), e.g., vii-a(i)-1
or vii-a(ii)-1
wherein: R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C1-4 alkyl, e.g., methyl, HCF2, OCH2F or halogen, e.g., F, Cl; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; and s is 0 or 1. [0558] In some embodiments, X
8 is –O–, –NMe– or –S–. [0559] In some embodiments, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’,
R
5 in formula iii are hydrogen, while the remaining are as defined above for formula iii to vii-a(ii)- 1. [0560] In some embodiments, wherein Y is of formula v-a(i), v-a(ii), v-a(i)-1, v-a(ii)-1, v-a(i)-2 or v-a(ii)-2, (i) X
5, X
5’, X
6, X
6’, X
7 are -CH=, or (ii) X
5 is =N- and X
5’, X
6, X
6’, X
7 are -CH=, or (iii) X
6 is =N- and X
5, X
5’, X
6’, X
7 are -CH=, or (iv) X
7 is =N- and X
5, X
5’, X
6, X
6’ are -CH=, or (v) X
5 and X
6 are –N= and X
5’, X
6’, X
7 are –CH=, or (vi) X
5 and X
5’ are –N= and X
6, X
6’, X
7 are –CH=, or (vii) X
5 and X
6’ are –N= and X
6, X
5’, X
7 are –CH=, or (viii) X
5 and X
7 are –N= and X
5’, X
6, X
6’ are –CH=, or (ix) X
6 and X
6’ are =N- and X
5, X
5’, X
7 are –CH-, or (x) X
6 and X
7 are =N- and X
5, X
5’, X
6’ are –CH–. [0561] In some embodiments, wherein Y is of formula vii-a(i), vii-a(ii), vii-a(i)-1 or vii-a(ii)-1, (i) X
8’ is –O–, X
8 and X
9 are –N= and X
9’ is –CH=, or (ii) X
8’ is –S–, X
8 and X
9 are –N= and X
9’ is – CH=, or (iii) X
8’ is –O–, X
8, X
9 and X
9’ is –CH=, or (iv) X
8’ is –NH–, X
8, X
9 are –CH= and X
9’ is –N=, or (v) X
8’ is –NH–, X
8, X
9’ are –CH= and X
9 is –N=, or (vi) X
8’ is –NMe–, X
8, X
9 are –CH= and X
9’ is –N=, or (vii) X
8’ is –NMe–, X
8, X
9’ are –CH= and X
9 is –N=, or (viii) X
8’ is –NMe–, X
9’ is –N=, X
8 and X
9 are –CH=, or (ix) X
8’ is –NH–, X
9’ is –N=, X
8 and X
9 are –CH=, or (x) X
8’ is –S–, X
8 is –N=, X
9 and X
9’ are –CH=. [0562] In some embodiments of a compound of formula IIc-1, IIc-2, IIIc-1 or IIIc-2 or pharmaceutically acceptable salts or stereoisomers thereof, Y is of formula iii, v-a-3, v-a-4 v-a-5, v-a-6, v-a-7, v-a-8, v-a-9, v-a-10, v-b-1, v-b-2, v-b-3, v-b-4, v-b-5, v-b-6, v-b-7, v-b-8, v-b-9, v-b- 10, v-b-11, v-b-12, vi-a, vii-a-1, vii-a-2 or vii-a-3
wherein:
R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; and s is 0 or 1. [0563] In some embodiments, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above. [0564] In some embodiments, X
8’ is –O–, –NMe– or –S–. [0565] In some embodiments, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above for formula iii to vii-a-3. In some embodiments, R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkyl, C
1-4 alkoxy, C
1-4 alkylhydroxyl, aryloxy, heteroaryloxy, heterocycloalkyl, C
1-2 alkoxy-aryl, C
1-2 alkoxy-heteroaryl or C
1-2 alkoxy-cycloalkyl. [0566] In some particular embodiments of a compound of formula IIc-1, IIc-2, IIIc-1 or IIIc-2 or pharmaceutically acceptable salts or stereoisomers thereof, Y is of formula iii, v-a-3, v-b-1, v-b-2, v-b-3, v-b-4, v-b-5, v-b-6, v-b-7, v-b-8, v-b-9, v-b-10, v-b-11, v-b-12, vi-a, vii-a-1, vii-a-2 or vii- a-3. [0567] In some embodiments, s is 0 or 1 is Y is of formula v-a-3, v-a-4 v-a-5, v-a-6, v-a-7, v-a-8, v-a-9, v-a-10, v-b-1, v-b-2, v-b-3, v-b-4, v-b-5, v-b-6, v-b-7, v-b-8, v-b-9, v-b-10, v-b-11, v-b-12 and s is 1 for vi-a, vii-a-1, vii-a-2 or vii-a-3. [0568] In some embodiments, s is 0 or 1 is Y is of formula v-a-3, v-a-4 v-a-5, v-a-6, v-a-7, v-a-8, v-a-9, v-a-10 and s is 1 for v-b-1, v-b-2, v-b-3, v-b-4, v-b-5, v-b-6, v-b-7, v-b-8, v-b-9, v-b-10, v- b-11, v-b-12, vi-a, vii-a-1, vii-a-2 or vii-a-3. In some embodiments, s is 1. [0569] In some embodiments of a compound of formula IIc-1, IIc-2, IIIc-1 or IIIc-2 or pharmaceutically acceptable salts or stereoisomers thereof, Y is of formula iii, v-c-1, v-c-2, v-c-3, v-c-4, v-d-1, v-d-2, v-d-3, v-d-4, v-d-5, v-d-6, v-d-7, vi-a, vii-b-1, vii-b-2, vii-b-3 or vii-b-4
wherein: R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; and s is 0 or 1. [0570] In some embodiments, R
6 is hydrogen for v-d-1, v-d-2, v-d-3, v-d-4, v-d-5 and v-d-7; and
R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl, for v-c-1, v-c-2, v- c-3, v-c-4, v-d-6, vii-b-1, vii-b-2, vii-b-3 and vii-b-4. [0571] In some embodiments of a compound of formula IIc-1, IIc-2, IIIc-1 or IIIc-2 or pharmaceutically acceptable salts or stereoisomers thereof, Y is of formula v-c(i)-1, v-c(ii)-1, v- c(i)-2, v-c(ii)-2, v-c(i)-3, v-c(ii)-3, v-c(i)-4, v-c(ii)-4, v-d(i)-1, v-d(ii)-1, v-d(i)-2, v-d(ii)-2, v-d(i)- 3, v-d(ii)-3, v-d(i)-4, v-d(ii)-4, v-d(i)-5, v-d(ii)-5, v-d(i)-6, v-d(ii)-6, v-d(i)-7, v-d(ii)-7, vi-a(i), vi- a(ii), iii-(i), iii-(ii), iii-(iii), iii-(iv), vii-b(i)-1, vii-b(ii)-1, vii-b(i)-2, vii-b(ii)-2, vii-b(i)-3, vii-b(ii)- 3, vii-b(i)-4 or vii-b(ii)-4
wherein: R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF3, HCF2, OCF3, hydroxy, C1-4 alkoxy or C1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; and s is 0 or 1. [0572] In some embodiments, s is 0 or 1 for formula v-c(i)-1, v-c(ii)-1, and 1 for v-c(i)-2, v-c(ii)- 2, v-c(i)-3, v-c(ii)-3, v-c(i)-4, v-c(ii)-4, v-d(i)-1, v-d(ii)-1, v-d(i)-2, v-d(ii)-2, v-d(i)-3, v-d(ii)-3, v- d(i)-4, v-d(ii)-4, v-d(i)-5, v-d(ii)-5, v-d(i)-6, v-d(ii)-6, v-d(i)-7, v-d(ii)-7, vi-a(i), vi-a(ii), vii-b(i)- 1, vii-b(ii)-1, vii-b(i)-2, vii-b(ii)-2, vii-b(i)-3, vii-b(ii)-3, vii-b(i)-4 or vii-b(ii)-4. [0573] In some embodiments, R
6 is hydrogen for v-d(i)-1, v-d(ii)-1, v-d(i)-3, v-d(ii)-3, v-d(i)-4, v- d(ii)-4, v-d(i)-5, v-d(ii)-5, v-d(i)-7 and v-d(ii)-7; and R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl, for v-d(i)-6, v-d(ii)-6, v-c(i)-1, v-c(ii)-1, v-c(i)-2, v-c(ii)-2, v-c(i)- 3, v-c(ii)-3, v-c(i)-4, v-c(ii)-4, v-d(i)-2, v-d(ii)-2, vii-b(i)-1, vii-b(ii)-1, vii-b(i)-2, vii-b(ii)-2, vii- b(i)-3, vii-b(ii)-3, vii-b(i)-4 and vii-b(ii)-4. [0574] In some embodiments of a compound of formula IIc-1, IIc-2, IIIc-1 or IIIc-2 or pharmaceutically acceptable salts or stereoisomers thereof, Y is of formula iii, v-e-1, v-e-2, v-f-1, v-f-2, v-f-3, v-f-4, v-f-5, v-f-6a, v-f-6b, v-f-7, vi-a, vii-c-1, vii-c-2, vii-c-3 or vii-c-4
wherein: R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; and s is 0 or 1. [0575] In some embodiments at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above for formula iii to vii-c-4.
[0576] In some embodiments, the present disclosure provides the compound or pharmaceutical acceptable salts or stereoisomers thereof having formula IV-1, IV-2, IV-3 or IV-4
wherein: W is =CH–, =COMe–, =CMe– or =N–; Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
1 is –CH=CH
2 or -C≡CMe; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; R
8 is H, Me or Et; X
4 is –O–, –NH–, –NMe–; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=;
X
8’ is –O–, –S–, –NH– or –NMe–; and L is a covalent bond or linear or branched C
1-3 alkyl. [0577] In some embodiments, the present disclosure provides the compound or pharmaceutical acceptable salts or stereoisomers thereof having formula IV-2, IV-3 or IV-4. [0578] In some embodiments, the present disclosure provides the compound or pharmaceutical acceptable salts or stereoisomers thereof having formula IV-1. [0579] In some embodiments of a compound of formula IV-1, IV-2, IV-3 or IV-4 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C1-4 alkyl, C3-4 heterocycloalkyl or C3-4 cycloalkyl. [0580] In some embodiments of a compound of formula IV-1, IV-2, IV-3 or IV-4 or pharmaceutically acceptable salts or stereoisomers thereof, W is =CH–, =CMe– or =COMe–, e.g., =CH– or =COMe–, e.g., =CH–. [0581] In some embodiments of a compound of formula IV-1, IV-2, IV-3 or IV-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly – NH–. In some embodiments, X
1 is –NH– or –NMe–, particularly –NH– and W is =CH–, =CMe– or =COMe–, e.g., =CH– or =COMe–, e.g., =CH–. [0582] In some embodiments of a compound of formula IV-1, IV-2, IV-3 or IV-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2 and W is =CH–, =CMe– or =COMe–, e.g., =CH– or =COMe–, e.g., =CH–. [0583] In some embodiments of a compound of formula IV-1, IV-2, IV-3 or IV-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me and W is =CH–, =CMe– or =COMe–, e.g., =CH– or =COMe–, e.g., =CH–. [0584] In some embodiments of a compound of formula IV-1, IV-2, IV-3 or IV-4 or pharmaceutically acceptable salts or stereoisomers thereof, W is =N–. [0585] In some embodiments of a compound of formula IV-1, IV-2, IV-3 or IV-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly – NH–. In some embodiments, X
1 is –NH– or –NMe–, particularly –NH– and W is =N–. [0586] In some embodiments of a compound of formula IV-1, IV-2, IV-3 or IV-4 or
pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2 and W =N–. [0587] In some embodiments of a compound of formula IV-1, IV-2, IV-3 or IV-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me and W is =N–. [0588] In some embodiments of a compound of formula IV-1, IV-2, IV-3 or IV-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2 and X
2 is –NH–, – NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–. [0589] In some embodiments of a compound of formula IV-1, IV-2, IV-3 or IV-4 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [0590] In some embodiments of a compound of formula IV-1, IV-2, IV-3 or IV-4 or pharmaceutically acceptable salts or stereoisomers thereof, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above. [0591] In some embodiments of a compound of formula IV-1, IV-2, IV-3 or IV-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
4 is –O–. [0592] In some embodiments of a compound of formula IV-1, IV-2, IV-3 or IV-4 or pharmaceutically acceptable salts or stereoisomers thereof, L is a covalent bond, –(CH
2)– or – (CH2)2–. In some embodiments, X
4 is –O– and L is a covalent bond, –(CH2)– or –(CH2)2–. [0593] In some embodiments of a compound of formula IV-1, IV-2, IV-3 or IV-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
8 is –O–, –NMe– or –S–. [0594] In some embodiments, Z is of formula i
wherein: R
2 is hydrogen, C1-4 alkyl, -CHF2 or C3-4 cycloalkyl;
R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; and n is 1 or 2. [0595] In some embodiments R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [0596] In some embodiments of formula IV-1, IV-2, IV-3 or IV-4 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein: R
2 is hydrogen, Me or Et. [0597] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula IV-1, IV-2, IV-3 or IV-4 is represented by formula IVa-1, IVa-2, IVa-3 or IVa- 4
wherein: Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, -CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
1 is –CH=CH
2 or -C≡CMe; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; R
8 is H, Me or Et; X
4 is –O–, –NH–, –NMe–; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; and L is a covalent bond or linear or branched C
1-3 alkyl. [0598] In some embodiments of a compound of formula IVa-1, IVa-2, IVa-3 or IVa-4 or
pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl or C
3-4 cycloalkyl. [0599] In some embodiments of a compound of formula IVa-1, IVa-2, IVa-3 or IVa-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly – NH. [0600] In some embodiments of a compound of formula IVa-1, IVa-2, IVa-3 or IVa-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2. [0601] In some embodiments of a compound of formula IVa-1, IVa-2, IVa-3 or IVa-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me. [0602] In some embodiments of a compound of formula IVa-1, IVa-2, IVa-3 or IVa-4 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [0603] In some embodiments of a compound of formula IVa-1, IVa-2, IVa-3 or IVa-4 or pharmaceutically acceptable salts or stereoisomers thereof, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above. [0604] In some embodiments of a compound of formula IVa-1, IVa-2, IVa-3 or IVa-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
4 is –O–. [0605] In some embodiments of a compound of formula IVa-1, IVa-2, IVa-3 or IVa-4 or pharmaceutically acceptable salts or stereoisomers thereof, L is a covalent bond, –(CH
2)– or – (CH
2)
2–. In some embodiments, X
4 is –O– and L is a covalent bond, –(CH
2)– or –(CH
2)
2–. [0606] In some embodiments of a compound of formula IVa-1, IVa-2, IVa-3 or IVa-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
8 is –O–, –NMe– or –S–. [0607] In some embodiments, Z is of formula i
wherein: R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; and n is 1 or 2. [0608] In some embodiments R
2 is hydrogen, C1-4 alkyl or C3-4 cycloalkyl; [0609] In some embodiments of formula IVa-1, IVa-2, IVa-3 or IVa-4 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein: R
2 is hydrogen, Me or Et. [0610] In some embodiments, the present disclosure provides the compound or pharmaceutical acceptable salts or stereoisomers thereof having formula IV-5, IV-6, IV-7, IV-8, IV-9, IV-10, IV- 11 or IV-12
wherein: W is =CH–, =COMe–, =CMe– or =N–; Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, -CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
1 is –CH=CH
2 or -C≡CMe; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF3;
R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; R
8 is H, Me or Et; X
4 is –O–, –NH–, –NMe–; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; and L is a covalent bond or linear or branched C
1-3 alkyl. [0611] In some embodiments of a compound of formula IV-5, IV-6, IV-7, IV-8, IV-9, IV-10, IV- 11 or IV-12 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl or C
3-4 cycloalkyl. [0612] In some embodiments of a compound of formula IV-5, IV-6, IV-7, IV-8, IV-9, IV-10, IV- 11 or IV-12 or pharmaceutically acceptable salts or stereoisomers thereof, W is =CH–, =CMe– or =COMe–, e.g., =CH– or =COMe–, e.g., =CH–. [0613] In some embodiments of a compound of formula IV-5, IV-6, IV-7, IV-8, IV-9, IV-10, IV- 11 or IV-12 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe– , particularly –NH–. In some embodiments, X
1 is –NH– or –NMe–, particularly –NH– and W is =CH–, =CMe– or =COMe–, e.g., =CH– or =COMe–, e.g., =CH–. [0614] In some embodiments of a compound of formula IV-5, IV-6, IV-7, IV-8, IV-9, IV-10, IV- 11 or IV-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2 and W is =CH–, =CMe– or =COMe–, e.g., =CH– or =COMe–, e.g., =CH–. [0615] In some embodiments of a compound of formula IV-5, IV-6, IV-7, IV-8, IV-9, IV-10, IV- 11 or IV-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me and W is =CH–, =CMe– or =COMe–, e.g., =CH– or =COMe–, e.g., =CH–. [0616] In some embodiments of a compound of formula IV-5, IV-6, IV-7, IV-8, IV-9, IV-10, IV- 11 or IV-12 or pharmaceutically acceptable salts or stereoisomers thereof, W is =N–. [0617] In some embodiments of a compound of formula IV-5, IV-6, IV-7, IV-8, IV-9, IV-10, IV- 11 or IV-12 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–
, particularly –NH–. In some embodiments, X
1 is –NH– or –NMe–, particularly –NH– and W is =N–. [0618] In some embodiments of a compound of formula IV-5, IV-6, IV-7, IV-8, IV-9, IV-10, IV- 11 or IV-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH2 and W is =N–. [0619] In some embodiments of a compound of formula IV-5, IV-6, IV-7, IV-8, IV-9, IV-10, IV- 11 or IV-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me and W is =N–. [0620] In some embodiments of a compound of formula IV-5, IV-6, IV-7, IV-8, IV-9, IV-10, IV- 11 or IV-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2 and X
2 is –NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–. [0621] In some embodiments of a compound of formula IV-5, IV-6, IV-7, IV-8, IV-9, IV-10, IV- 11 or IV-12 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [0622] In some embodiments of a compound of formula IV-5, IV-6, IV-7, IV-8, IV-9, IV-10, IV- 11 or IV-12 or pharmaceutically acceptable salts or stereoisomers thereof, X
4 is –O–. [0623] In some embodiments of a compound of formula IV-5, IV-6, IV-7, IV-8, IV-9, IV-10, IV- 11 or IV-12 or pharmaceutically acceptable salts or stereoisomers thereof, L is a covalent bond, – (CH
2)– or –(CH
2)
2–. In some embodiments, X
4 is –O– and L is a covalent bond, –(CH
2)– or – (CH
2)
2–. [0624] In some embodiments of a compound of formula IV-5, IV-6, IV-7, IV-8, IV-9, IV-10, IV- 11 or IV-12 or pharmaceutically acceptable salts or stereoisomers thereof, X
8 is –O–, –NMe– or – S–. [0625] In some embodiments, Z is of formula i
wherein: R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; and n is 1 or 2. [0626] In some embodiments R
2 is hydrogen, C1-4 alkyl or C3-4 cycloalkyl. [0627] In some embodiments of formula IV-5, IV-6, IV-7, IV-8, IV-9, IV-10, IV-11 or IV-12 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein: R
2 is hydrogen, Me or Et. [0628] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula IV-5, IV-6, IV-7, IV-8, IV-9, IV-10, IV-11 or IV-12 is represented by formula IVa-5, IVa-6, IVa-7, IVa-8, IVa-9, IVa-10, IVa-11 or IVa-12
wherein: Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
1 is –CH=CH
2 or -C≡CMe; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3;
R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; R
8 is H, Me or Et; X
4 is –O–, –NH–, –NMe–; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; and L is a covalent bond or linear or branched C
1-3 alkyl. [0629] In some embodiments of a compound of formula IVa-5, IVa-6, IVa-7, IVa-8, IVa-9, IVa- 10, IVa-11 or IVa-12 or pharmaceutically acceptable salts or stereoisomers thereof Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl or C
3-4 cycloalkyl. [0630] In some embodiments of a compound of formula IVa-5, IVa-6, IVa-7, IVa-8, IVa-9, IVa- 10, IVa-11 or IVa-12 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [0631] In some embodiments of a compound of formula IVa-5, IVa-6, IVa-7, IVa-8, IVa-9, IVa- 10, IVa-11 or IVa-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is – HC=CH2. [0632] In some embodiments of a compound of formula IVa-5, IVa-6, IVa-7, IVa-8, IVa-9, IVa- 10, IVa-11 or IVa-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C– Me. [0633] In some embodiments of a compound of formula IVa-5, IVa-6, IVa-7, IVa-8, IVa-9, IVa- 10, IVa-11 or IVa-12 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [0634] In some embodiments of a compound of formula IVa-5, IVa-6, IVa-7, IVa-8, IVa-9, IVa- 10, IVa-11 or IVa-12 or pharmaceutically acceptable salts or stereoisomers thereof, X
4 is –O–. [0635] In some embodiments of a compound of formula IVa-5, IVa-6, IVa-7, IVa-8, IVa-9, IVa-
10, IVa-11 or IVa-12 or pharmaceutically acceptable salts or stereoisomers thereof, L is a covalent bond, –(CH
2)– or –(CH
2)
2–. In some embodiments, X
4 is –O– and L is a covalent bond, –(CH
2)– or –(CH
2)
2–. [0636] In some embodiments of a compound of formula IVa-5, IVa-6, IVa-7, IVa-8, IVa-9, IVa- 10, IVa-11 or IVa-12 or pharmaceutically acceptable salts or stereoisomers thereof, X
8 is –O–, – NMe– or –S–. [0637] In some embodiments, Z is of formula i
wherein: R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; and n is 1 or 2. [0638] In some embodiments R
2 is hydrogen, C1-4 alkyl or C3-4 cycloalkyl. [0639] In some embodiments of formula IVa-5, IVa-6, IVa-7, IVa-8, IVa-9, IVa-10, IVa-11 or IVa-12 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein: R
2 is hydrogen, Me or Et. [0640] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula IV-1, IV-2, IV-3 or IV-4 is represented by formula IVb-1, IVb-2, IVb-3, IVb- 4, IVc-1, IVc-2, IVc-3 or IVc-4
wherein: W is =CH–, =COMe–, =CMe– or =N–; X
1 is –NH–, –NMe– or –O–; X
4 is –O–, –NH–, –NMe–;
X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; L is a covalent bond or linear or branched C
1-3 alkyl R
1 is –HC=CH2 or –C≡C–Me R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; R
8 is H, Me or Et; R
a, R
b are each independently selected from hydrogen, C1-4 alkyl or form together an unsubstituted oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; m is 1, 2 or 3; n is 1 or 2; and r is 1 or 2, e.g., 1. [0641] In some embodiments of a compound of formula IVb-1, IVb-2, IVb-3, IVb-4, IVc-1, IVc- 2, IVc-3 or IVc-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
2 is hydrogen, C1-4 alkyl or C3-4 cycloalkyl. [0642] In some embodiments of a compound of formula IVb-1, IVb-2, IVb-3, IVb-4, IVc-1, IVc- 2, IVc-3 or IVc-4 or pharmaceutically acceptable salts or stereoisomers thereof, W is =CH–, =CMe– or =COMe–, e.g., =CH– or =COMe–, e.g., =CH–. [0643] In some embodiments of a compound of formula IVb-1, IVb-2, IVb-3, IVb-4, IVc-1, IVc- 2, IVc-3 or IVc-4 or pharmaceutically acceptable salts or stereoisomers thereof, W is =N–. [0644] In some embodiments of a compound of formula IVb-1, IVb-2, IVb-3, IVb-4, IVc-1, IVc- 2, IVc-3 or IVc-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or – NMe–, particularly –NH. [0645] In some embodiments of a compound of formula IVb-1, IVb-2, IVb-3, IVb-4, IVc-1, IVc- 2, IVc-3 or IVc-4 or pharmaceutically acceptable salts or stereoisomers thereof, W is =CH–, =CMe– or =COMe–, e.g., =CH– or =COMe–, e.g., =CH–.
[0646] In some embodiments of a compound of formula IVb-1, IVb-2, IVb-3, IVb-4, IVc-1, IVc- 2, IVc-3 or IVc-4 or pharmaceutically acceptable salts or stereoisomers thereof, W is =N-. [0647] In some embodiments of a compound of formula IVb-1, IVb-2, IVb-3, IVb-4, IVc-1, IVc- 2, IVc-3 or IVc-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH2. [0648] In some embodiments of a compound of formula IVb-1, IVb-2, IVb-3, IVb-4, IVc-1, IVc- 2, IVc-3 or IVc-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me. [0649] In some embodiments of a compound of formula IVb-1, IVb-2, IVb-3, IVb-4, IVc-1, IVc- 2, IVc-3 or IVc-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or – NMe–, particularly –NH–, and X
2 is –NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–. [0650] In some embodiments of a compound of formula IVb-1, IVb-2, IVb-3, IVb-4, IVc-1, IVc- 2, IVc-3 or IVc-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl. [0651] In some embodiments of a compound of formula IVb-1, IVb-2, IVb-3 or IVb-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
a and R
b are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R
a and R
b are each independently selected from hydrogen, methyl. In some embodiments in which m is 2 or 3, only one R
a and one R
b are not hydrogen and/or only one R
a is not hydrogen. [0652] In some embodiments of a compound of formula IVb-1, IVb-2, IVb-3 or IVb-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
c and R
d are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R
c and R
d are each independently selected from hydrogen, methyl. In some embodiments in which n is 2, only one R
c and one R
c are not hydrogen and/or only one R
c is not hydrogen. [0653] In some embodiments of a compound of formula IVb-1, IVb-2, IVb-3 or IVb-4 or pharmaceutically acceptable salts or stereoisomers thereof, m and n are selected such that a 4, 5 or 6 membered nitrogen containing ring is formed. [0654] In some embodiments of a compound of formula IVb-1, IVb-2, IVb-3, IVb-4, IVc-1, IVc- 2, IVc-3 or IVc-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or – NMe–, particularly –NH–, and R
2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl. [0655] In some embodiments of a compound of formula IVb-1, IVb-2, IVb-3, IVb-4, IVc-1, IVc-
2, IVc-3 or IVc-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
4 is –O–. [0656] In some embodiments of a compound of formula IVb-1, IVb-2, IVb-3, IVb-4, IVc-1, IVc- 2, IVc-3 or IVc-4 or pharmaceutically acceptable salts or stereoisomers thereof, L is a covalent bond, –(CH2)– or –(CH2)2–. In some embodiments, X
4 is –O– and L is a covalent bond, –(CH2)– or –(CH
2)
2–. [0657] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula IV-1, IV-2, IV-3 or IV-4 is represented by formula IVb-5 to IVb-12, IVc-5 to IVc-12
wherein: W is =CH–, =COMe–, =CMe– or =N–; X
1 is –NH–, –NMe– or –O–; X
4 is –O–, –NH–, –NMe–; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; L is a covalent bond or linear or branched C
1-3 alkyl R
1 is –HC=CH
2 or –C≡C–Me R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF3, HCF2, OCF3, hydroxy, C1-4 alkoxy or C1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; R
8 is H, Me or Et; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form together an unsubstituted oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; m is 1, 2 or 3; n is 1 or 2; and r is 1 or 2, e.g., 1. [0658] In some embodiments of a compound of formula IVb-5 to IVb-12, IVc-5 to IVc-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [0659] In some embodiments of a compound of formula IVb-5 to IVb-12, IVc-5 to IVc-12 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly – NH. [0660] In some embodiments of a compound of formula IVb-5 to IVb-12, IVc-5 to IVc-12 or pharmaceutically acceptable salts or stereoisomers thereof, W is =CH–, =CMe– or =COMe–, e.g., =CH– or =COMe–, e.g., =CH–. [0661] In some embodiments of a compound of formula IVb-5 to IVb-12, IVc-5 to IVc-12 or
pharmaceutically acceptable salts or stereoisomers thereof, W is =N–. [0662] In some embodiments of a compound of formula IVb-5 to IVb-12, IVc-5 to IVc-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2. [0663] In some embodiments of a compound of formula IVb-5 to IVb-12, IVc-5 to IVc-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me. [0664] In some embodiments of a compound of formula IVb-5 to IVb-12, IVc-5 to IVc-12 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly – NH–, and X
2 is –NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, – NEt–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–. [0665] In some embodiments of a compound of formula IVb-5 to IVb-12, IVc-5 to IVc-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
2 is hydrogen, methyl, ethyl, n- propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl. [0666] In some embodiments of a compound of formula IVb-5 to IVb-12, IVc-5 to IVc-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
a and R
b are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R
a and R
b are each independently selected from hydrogen, methyl. In some embodiments in which m is 2 or 3, only one R
a and one R
b are not hydrogen and/or only one R
a is not hydrogen. [0667] In some embodiments of a compound of formula IVb-5 to IVb-12, IVc-5 to IVc-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
c and R
d are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R
c and R
d are each independently selected from hydrogen, methyl. In some embodiments in which n is 2, only one R
c and one R
c are not hydrogen and/or only one R
c is not hydrogen. [0668] In some embodiments of a compound of formula IVb-5 to IVb-12, IVc-5 to IVc-12 or pharmaceutically acceptable salts or stereoisomers thereof, m and n are selected such that a 4, 5 or 6 membered nitrogen containing ring is formed. [0669] In some embodiments of a compound of formula IVb-5 to IVb-12, IVc-5 to IVc-12 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly – NH–, and R
2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl. [0670] In some embodiments of a compound of formula IVb-5 to IVb-12, IVc-5 to IVc-12 or pharmaceutically acceptable salts or stereoisomers thereof, X
4 is –O–.
[0671] In some embodiments of a compound of IVb-5 to IVb-12, IVc-5 to IVc-12 or pharmaceutically acceptable salts or stereoisomers thereof, L is a covalent bond, –(CH
2)– or – (CH
2)
2–. In some embodiments, X
4 is –O– and L is a covalent bond, –(CH
2)– or –(CH
2)
2–. [0672] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula IVb-1, IVb-2, IVb-3, IVb-4, IVc-1, IVc-2, IVc-3 or IVc-4, X
4 is –O–, such that the compound is represented by formula IVd-1, IVd-2, IVd-3, IVd-4, IVe-1, IVe-2, IVe-3 or IVe- 4
X
1 is –NH–, –NMe– or –O–; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; L is a covalent bond or linear or branched C1-3 alkyl R
1 is –HC=CH
2 or –C≡C–Me R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; R
8 is H, Me or Et; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form together an unsubstituted oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; m is 1, 2 or 3; n is 1 or 2; and r is 1 or 2, e.g., 1. [0673] In some embodiments of a compound of formula IVd-1, IVd-2, IVd-3, IVd-4, IVe-1, IVe- 2, IVe-3 or IVe-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [0674] In some embodiments of a compound of formula IVd-1, IVd-2, IVd-3, IVd-4, IVe-1, IVe- 2, IVe-3 or IVe-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or – NMe–, particularly –NH. [0675] In some embodiments of a compound of formula IVd-1, IVd-2, IVd-3, IVd-4, IVe-1, IVe- 2, IVe-3 or IVe-4 or pharmaceutically acceptable salts or stereoisomers thereof, W is =CH–, =CMe– or =COMe–, e.g., =CH– or =COMe–, e.g., =CH–. [0676] In some embodiments of a compound of formula IVd-1, IVd-2, IVd-3, IVd-4, IVe-1, IVe- 2, IVe-3 or IVe-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2. [0677] In some embodiments of a compound of formula IVd-1, IVd-2, IVd-3, IVd-4, IVe-1, IVe- 2, IVe-3 or IVe-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me.
[0678] In some embodiments of a compound of formula IVd-1, IVd-2, IVd-3, IVd-4, IVe-1, IVe- 2, IVe-3 or IVe-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl. [0679] In some embodiments of a compound of formula IVd-1, IVd-2, IVd-3, IVd-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
a and R
b are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R
a and R
b are each independently selected from hydrogen, methyl. In some embodiments in which m is 2 or 3, only one R
a and one R
b are not hydrogen and/or only one R
a is not hydrogen. [0680] In some embodiments of a compound of formula IVd-1, IVd-2, IVd-3, IVd-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
c and R
d are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R
c and R
d are each independently selected from hydrogen, methyl. In some embodiments in which n is 2, only one R
c and one R
c are not hydrogen and/or only one R
c is not hydrogen. [0681] In some embodiments of a compound of formula IVd-1, IVd-2, IVd-3, IVd-4 or pharmaceutically acceptable salts or stereoisomers thereof, m and n are selected such that a 4, 5 or 6 membered nitrogen containing ring is formed. [0682] In some embodiments of a compound of formula IVd-1, IVd-2, IVd-3, IVd-4, IVe-1, IVe- 2, IVe-3 or IVe-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or – NMe–, particularly –NH–, and R
2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl. [0683] In some embodiments of a compound of formula IVd-1, IVd-2, IVd-3, IVd-4, IVe-1, IVe- 2, IVe-3 or IVe-4 or pharmaceutically acceptable salts or stereoisomers thereof, L is a covalent bond, –(CH
2)– or –(CH
2)
2–. [0684] In some embodiments W is =CH– and the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula IV-1, IV-2, IV-3 or IV-4 is represented by formula IVf-1, IVf-2, IVf-3, IVf-4, IVg-1, IVg-2, IVg-3 or IVg-4
wherein: X
1 is –NH–, –NMe– or –O–; X
4 is –O–, –NH–, –NMe–; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; L is a covalent bond or linear or branched C
1-3 alkyl R
1 is –HC=CH
2 or –C≡C–Me; R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl;
R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; R
8 is H, Me or Et; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form together an unsubstituted oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; m is 1, 2 or 3; n is 1 or 2; and r is 1 or 2, e.g., 1. [0685] In some embodiments of a compound of formula IVf-1, IVf-2, IVf-3, IVf-4, IVg-1, IVg- 2, IVg-3 or IVg-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [0686] In some embodiments of a compound of formula IVf-1, IVf-2, IVf-3, IVf-4, IVg-1, IVg- 2, IVg-3 or IVg-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or – NMe–, particularly –NH. [0687] In some embodiments of a compound of IVf-1, IVf-2, IVf-3, IVf-4, IVg-1, IVg-2, IVg-3 or IVg-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH2. [0688] In some embodiments of a compound of IVf-1, IVf-2, IVf-3, IVf-4, IVg-1, IVg-2, IVg-3 or IVg-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me. [0689] In some embodiments of a compound of formula IVf-1, IVf-2, IVf-3, IVf-4, IVg-1, IVg- 2, IVg-3 or IVg-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or – NMe–, particularly –NH–, and X
2 is –NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–. [0690] In some embodiments of a compound of formula IVf-1, IVf-2, IVf-3, IVf-4, IVg-1, IVg- 2, IVg-3 or IVg-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl. [0691] In some embodiments of a compound of formula IVf-1, IVf-2, IVf-3, IVf-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
a and R
b are each independently
selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R
a and R
b are each independently selected from hydrogen, methyl. In some embodiments in which m is 2 or 3, only one R
a and one R
b are not hydrogen and/or only one R
a is not hydrogen. [0692] In some embodiments of a compound of formula IVf-1, IVf-2, IVf-3, IVf-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
c and R
d are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R
c and R
d are each independently selected from hydrogen, methyl. In some embodiments in which n is 2, only one R
c and one R
c are not hydrogen and/or only one R
c is not hydrogen. [0693] In some embodiments of a compound of formula IVf-1, IVf-2, IVf-3, IVf-4 or pharmaceutically acceptable salts or stereoisomers thereof, m and n are selected such that a 4, 5 or 6 membered nitrogen containing ring is formed. [0694] In some embodiments of a compound of formula IVf-1, IVf-2, IVf-3, IVf-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly – NH–, and R
2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl. [0695] In some embodiments of a compound of formula IVf-1, IVf-2, IVf-3, IVf-4, IVg-1, IVg- 2, IVg-3 or IVg-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
4 is –O–. [0696] In some embodiments of a compound of formula IVf-1, IVf-2, IVf-3, IVf-4, IVg-1, IVg- 2, IVg-3 or IVg-4 or pharmaceutically acceptable salts or stereoisomers thereof, L is a covalent bond, –(CH2)– or –(CH2)2–. In some embodiments, X
4 is –O– and L is a covalent bond, –(CH2)– or –(CH
2)
2–. [0697] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula IVb-5 to IVb12, IVc-5 to IVc12, X
4 is –O–, such that the compound is represented by formula IVd-5 to IVd-12, IVe-5 to IVe-12
wherein: W is =CH–, =COMe–, =CMe– or =N–; X
1 is –NH–, –NMe– or –O–; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; L is a covalent bond or linear or branched C
1-3 alkyl R
1 is –HC=CH
2 or –C≡C–Me R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; R
8 is H, Me or Et; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form together an unsubstituted oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; m is 1, 2 or 3; n is 1 or 2; and r is 1 or 2, e.g., 1. [0698] In some embodiments of a compound of formula IVd-5 to IVd-12, IVe-5 to IVe-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [0699] In some embodiments of a compound of formula IVd-5 to IVd-12, IVe-5 to IVe-12 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly – NH. [0700] In some embodiments of a compound of formula IVd-5 to IVd-12, IVe-5 to IVe-12 or pharmaceutically acceptable salts or stereoisomers thereof, W is =CH–, =CMe– or =COMe–, e.g., =CH– or =COMe–, e.g., =CH–. [0701] In some embodiments of a compound of formula IVd-5 to IVd-12, IVe-5 to IVe-12 or pharmaceutically acceptable salts or stereoisomers thereof, W is =N–.
[0702] In some embodiments of a compound of IVd-5 to IVd-12, IVe-5 to IVe-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2. [0703] In some embodiments of a compound of formula IVd-5 to IVd-12, IVe-5 to IVe-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me. [0704] In some embodiments of a compound of formula IVd-5 to IVd-12, IVe-5 to IVe-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
2 is hydrogen, methyl, ethyl, n- propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl. [0705] In some embodiments of a compound of formula IVd-5 to IVd-12, IVe-5 to IVe-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
a and R
b are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R
a and R
b are each independently selected from hydrogen, methyl. In some embodiments in which m is 2 or 3, only one R
a and one R
b are not hydrogen and/or only one R
a is not hydrogen. [0706] In some embodiments of a compound of formula IVd-5 to IVd-12, IVe-5 to IVe-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
c and R
d are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R
c and R
d are each independently selected from hydrogen, methyl. In some embodiments in which n is 2, only one R
c and one R
c are not hydrogen and/or only one R
c is not hydrogen. [0707] In some embodiments of a compound of formula IVd-5 to IVd-12, IVe-5 to IVe-12 or pharmaceutically acceptable salts or stereoisomers thereof, m and n are selected such that a 4, 5 or 6 membered nitrogen containing ring is formed. [0708] In some embodiments of a compound of formula IVd-5 to IVd-12, IVe-5 to IVe-12 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly – NH–, and R
2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl. [0709] In some embodiments of a compound of formula IVd-5 to IVd-12, IVe-5 to IVe-12 or pharmaceutically acceptable salts or stereoisomers thereof, L is a covalent bond, –(CH
2)– or – (CH2)2–. [0710] In some embodiments W is =CH– and the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula IV-1, IV-2, IV-3 or IV-4 is represented by formula IVf-5 to IVf- 12, IVg-5, IVg-12
wherein: X
1 is –NH–, –NMe– or –O–; X
4 is –O–, –NH–, –NMe–; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; L is a covalent bond or linear or branched C
1-3 alkyl R
1 is –HC=CH
2 or –C≡C–Me R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; R
8 is H, Me or Et; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form together an unsubstituted oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; m is 1, 2 or 3; n is 1 or 2; and r is 1 or 2, e.g., 1. [0711] In some embodiments of a compound of formula IVf-5 to IVf-12, IVg-5, IVg-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [0712] In some embodiments of a compound of formula IVf-5 to IVf-12, IVg-5, IVg-12 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly – NH. [0713] In some embodiments of a compound of formula IVf-5 to IVf-12, IVg-5, IVg-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2. [0714] In some embodiments of a compound of formula IVf-5 to IVf-12, IVg-5, IVg-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me. [0715] In some embodiments of a compound of formula IVf-5 to IVf-12, IVg-5, IVg-12 or
pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly – NH–, and X
2 is –NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, – NEt–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–. [0716] In some embodiments of a compound of formula IVf-5 to IVf-12, IVg-5, IVg-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
2 is hydrogen, methyl, ethyl, n- propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl. [0717] In some embodiments of a compound of formula IVf-5 to IVf-12, IVg-5, IVg-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
a and R
b are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R
a and R
b are each independently selected from hydrogen, methyl. In some embodiments in which m is 2 or 3, only one R
a and one R
b are not hydrogen and/or only one R
a is not hydrogen. [0718] In some embodiments of a compound of formula IVf-5 to IVf-12, IVg-5, IVg-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
c and R
d are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R
c and R
d are each independently selected from hydrogen, methyl. In some embodiments in which n is 2, only one R
c and one R
c are not hydrogen and/or only one R
c is not hydrogen. [0719] In some embodiments of a compound of formula IVf-5 to IVf-12, IVg-5, IVg-12 or pharmaceutically acceptable salts or stereoisomers thereof, m and n are selected such that a 4, 5 or 6 membered nitrogen containing ring is formed. [0720] In some embodiments of a compound of formula IVf-5 to IVf-12, IVg-5, IVg-12 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly – NH–, and R
2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl. [0721] In some embodiments of a compound of formula IVf-5 to IVf-12, IVg-5, IVg-12 or pharmaceutically acceptable salts or stereoisomers thereof, X
4 is –O–. [0722] In some embodiments of a compound of formula IVf-5 to IVf-12, IVg-5, IVg-12 or pharmaceutically acceptable salts or stereoisomers thereof, L is a covalent bond, –(CH2)– or – (CH
2)
2–. In some embodiments, X
4 is –O– and L is a covalent bond, –(CH
2)– or –(CH
2)
2–. [0723] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula IV-1, IV-2, IV-3 or IV-4 is represented by formula IVh-1, IVh-2, IVh-3, e.g., IVh-3a or IVh-3b, or IVh-4
wherein: W is =N– or =CH–; Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
1 is –CH=CH
2 or -C≡CMe; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl;
R
8 is H, Me or Et; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; and s is 0 or 1. [0724] In some embodiments of a compound of formula IVh-1, IVh-2, IVh-3, e.g., IVh-3a or IVh- 3b, or IVh-4 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl or C
3-4 cycloalkyl. [0725] In some embodiments of a compound of formula IVh-1, IVh-2, IVh-3, e.g., IVh-3a or IVh- 3b, or IVh-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe– , particularly –NH. [0726] In some embodiments of a compound of formula IVh-1, IVh-2, IVh-3, e.g., IVh-3a or IVh- 3b, or IVh-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2. [0727] In some embodiments of a compound of formula IVh-1, IVh-2, IVh-3, e.g., IVh-3a or IVh- 3b, or IVh-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me. [0728] In some embodiments of a compound of formula IVh-1, IVh-2, IVh-3, e.g., IVh-3a or IVh- 3b, or IVh-4 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [0729] In some embodiments of the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula IVh-1, IVh-2, IVh-3, e.g., IVh-3a or IVh-3b, or IVh-4, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above. [0730] In some embodiments of the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula IVh-1, IVh-2, IVh-3, e.g., IVh-3a or IVh-3b, or IVh-4, X
8 is –O–, –NMe– or – S–. [0731] In some embodiments, Z is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; and n is 1 or 2. [0732] In some embodiments R
2 is hydrogen, C1-4 alkyl or C3-4 cycloalkyl. [0733] In some embodiments of formula IVh-1, IVh-2, IVh-3, e.g., IVh-3a or IVh-3b, or IVh-4 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et. [0734] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula IV-1, IV-2, IV-3 or IV-4 W is =CH– and the compound is represented by formula IVi-1, IVi-2, IVi-3, e.g., IVi-3a or IVi-3b, or IVi-4
wherein Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
1 is –CH=CH
2 or -C≡CMe; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; R
8 is H, Me or Et;
X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; s is 0 or 1. [0735] In some embodiments of a compound of formula IVi-1, IVi-2, IVi-3, e.g., IVi-3a or IVi- 3b, or IVi-4 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl or C
3-4 cycloalkyl. [0736] In some embodiments of a compound of formula IVi-1, IVi-2, IVi-3, e.g., IVi-3a or IVi- 3b, or IVi-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe– , particularly –NH. [0737] In some embodiments of a compound of formula IVi-1, IVi-2, IVi-3, e.g., IVi-3a or IVi- 3b, or IVi-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2. [0738] In some embodiments of a compound of formula IVi-1, IVi-2, IVi-3, e.g., IVi-3a or IVi- 3b, or IVi-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me. [0739] In some embodiments of a compound of formula IVi-1, IVi-2, IVi-3, e.g., IVi-3a or IVi- 3b, or IVi-4 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [0740] In some embodiments of the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula IVi-1, IVi-2, IVi-3, e.g., IVi-3a or IVi-3b, or IVi-4, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above. [0741] In some embodiments, Z is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; and n is 1 or 2. [0742] In some embodiments R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [0743] In some embodiments of formula IVi-1, IVi-2, IVi-3, e.g., IVi-3a or IVi-3b, or IVi-4 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et. [0744] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula IV-1, IV-2, IV-3 or IV-4 is represented by formula IVh-5, IVh-6, IVh-7, IVh- 8, IVh-9, IVh-10 preferably IVh-11, IVh-12, IVh-13 or IVh-14 IVh-15, or IVh-16
wherein W is =N– or =CH–;
Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C1-4 alkyl, C3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
1 is –CH=CH
2 or -C≡CMe; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C1-4 alkyl, e.g., methyl, HCF2, OCH2F or halogen, e.g., F, Cl; R
8 is H, Me or Et; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; s is 0 or 1. [0745] In some embodiments of a compound of formula IVh-5, IVh-6, IVh-7, IVh-8, IVh-9, e.g., IVh-10, IVh-11, IVh-12 or IVh-13 IVh-14, or IVh-15 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl or C
3-4 cycloalkyl. [0746] In some embodiments of a compound of formula IVh-5, IVh-6, IVh-7, IVh-8, IVh-9, e.g., IVh-10, IVh-11, IVh-12 or IVh-13 IVh-14, or IVh-15 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [0747] In some embodiments of a compound of formula IVh-5, IVh-6, IVh-7, IVh-8, IVh-9, e.g., IVh-10, IVh-11, IVh-12 or IVh-13 IVh-14, or IVh-15 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2. [0748] In some embodiments of a compound of formula IVh-5, IVh-6, IVh-7, IVh-8, IVh-9, e.g., IVh-10, IVh-11, IVh-12 or IVh-13 IVh-14, or IVh-15 or pharmaceutically acceptable salts or
stereoisomers thereof, R
1 is –C≡C–Me. [0749] In some embodiments of a compound of formula IVh-5, IVh-6, IVh-7, IVh-8, IVh-9, e.g., IVh-10, IVh-11, IVh-12 or IVh-13 IVh-14, or IVh-15 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [0750] In some embodiments of the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula IVh-5, IVh-6, IVh-7, IVh-8, IVh-9, e.g., IVh-10, IVh-11, IVh-12 or IVh-13 IVh-14, or IVh-15, X
8 is –O–, –NMe– or –S–. [0751] In some embodiments, Z is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [0752] In some embodiments R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [0753] In some embodiments of formula IVh-5, IVh-6, IVh-7, IVh-8, IVh-9, e.g., IVh-10, IVh- 11, IVh-12 or IVh-13 IVh-14, or IVh-15 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et. [0754] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula IV-1, IV-2, IV-3 or IV-4 W is =CH– and the compound is represented by formula IVi-5, IVi-6, IVi-7, IVi-8, IVi-9, IVi-10, e.g., IVi-11 IVi-12, IVi-13, IVi-14 or IVi-15, or IVi-16
wherein Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4
to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
1 is –CH=CH
2 or -C≡CMe; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; R
8 is H, Me or Et; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; and s is 0 or 1. [0755] In some embodiments of a compound of formula IVi-5, IVi-6, IVi-7, IVi-8, IVi-9, IVi-10, e.g., IVi-11 IVi-12, IVi-13, IVi-14 or IVi-15, or IVi-16 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C1-4 alkyl, C3-4 heterocycloalkyl or C
3-4 cycloalkyl. [0756] In some embodiments of a compound of formula IVi-5, IVi-6, IVi-7, IVi-8, IVi-9, IVi-10, e.g., IVi-11 IVi-12, IVi-13, IVi-14 or IVi-15, or IVi-16 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [0757] In some embodiments of a compound of formula IVi-5, IVi-6, IVi-7, IVi-8, IVi-9, IVi-10, e.g., IVi-11 IVi-12, IVi-13, IVi-14 or IVi-15, or IVi-16 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH2. [0758] In some embodiments of a compound of formula IVi-5, IVi-6, IVi-7, IVi-8, IVi-9, IVi-10, e.g., IVi-11 IVi-12, IVi-13, IVi-14 or IVi-15, or IVi-16 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me. [0759] In some embodiments of a compound of formula IVi-5, IVi-6, IVi-7, IVi-8, IVi-9, IVi-10,
e.g., IVi-11 IVi-12, IVi-13, IVi-14 or IVi-15, or IVi-16 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [0760] In some embodiments, Z is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; and n is 1 or 2. [0761] In some embodiments R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [0762] In some embodiments of formula IVi-5, IVi-6, IVi-7, IVi-8, IVi-9, IVi-10, e.g., IVi-11 IVi- 12, IVi-13, IVi-14 or IVi-15, or IVi-16 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein
R
2 is hydrogen, Me or Et. [0763] In some embodiments of the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula IVi-1, IVi-2, IVi-3, e.g., IVi-3a or IVi-3b, or IVi-4, X
8 is –O–, –NMe– or –S–. [0764] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula IV-1, IV-2, IV-3 or IV-4 is represented by formula IVj-1, IVj-2, IVj-3, e.g., IVj-3a or IVj-3b, or IVj-4
wherein W is =N– or =CH–; Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–;
R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; R
8 is H, Me or Et; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; s is 0 or 1. [0765] In some embodiments of a compound of formula IVj-1, IVj-2, IVj-3, e.g., IVj-3a or IVj- 3b, or IVj-4 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalky or C
3-4 cycloalkyl. [0766] In some embodiments of a compound of formula IVj-1, IVj-2, IVj-3, e.g., IVj-3a or IVj- 3b, or IVj-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe– , particularly –NH. [0767] In some embodiments of a compound of formula IVj-1, IVj-2, IVj-3, e.g., IVj-3a or IVj- 3b, or IVj-4 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [0768] In some embodiments of the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula IVj-1, IVj-2, IVj-3, e.g., IVj-3a or IVj-3b, or IVj-4, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above. [0769] In some embodiments of the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula IVj-1, IVj-2, IVj-3, e.g., IVj-3a or IVj-3b, or IVj-4, X
8 is –O–, –NMe– or –S–. In some embodiments, Z is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; and n is 1 or 2. [0770] In some embodiments R
2 is hydrogen, C1-4 alkyl or C3-4 cycloalkyl. [0771] In some embodiments of formula IVj-1, IVj-2, IVj-3, e.g., IVj-3a or IVj-3b, or IVj-4 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et. [0772] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula IVj-1, IVj-2, IVj-3, e.g., IVj-3a or IVj-3b, or IVj-4 W is =CH– and the compound is represented by formula IVk-1, IVk-2, IVk-3, e.g., IVk-3a or IVk-3b, or IVk-4
wherein Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; R
8 is H, Me or Et; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–;
s is 0 or 1. [0773] In some embodiments of a compound of formula IVk-1, IVk-2, IVk-3, e.g., IVk-3a or IVk- 3b, or IVk-4 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl or C
3-4 cycloalkyl. [0774] In some embodiments of a compound of formula IVk-1, IVk-2, IVk-3, e.g., IVk-3a or IVk- 3b, or IVk-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe– , particularly –NH. [0775] In some embodiments of a compound of formula IVk-1, IVk-2, IVk-3, e.g., IVk-3a or IVk- 3b, or IVk-4 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [0776] In some embodiments of the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula IVk-1, IVk-2, IVk-3, e.g., IVk-3a or IVk-3b, or IVk-4 at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above. [0777] In some embodiments of the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula IVk-1, IVk-2, IVk-3, e.g., IVk-3a or IVk-3b, or IVk-4, X
8 is –O–, –NMe– or – S–. [0778] In some embodiments, Z is of formula i
wherein R
2 is hydrogen, C1-4 alkyl, CHF2 or C3-4 cycloalkyl;
R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; and n is 1 or 2. [0779] In some embodiments, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [0780] In some embodiments of formula IVk-1, IVk-2, IVk-3, e.g., IVk-3a or IVk-3b, or IVk-4 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et. [0781] In some embodiments of the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula IVi-1, IVi-2, IVi-3, e.g., IVi-3a or IVi-3b, or IVi-4, X
8 is –O–, –NMe– or –S–. [0782] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula IV-1, IV-2, IV-3 or IV-4 is represented by formula IVj-5, IVj-6, IVj-7, IVj-8, IVj-9, IVj-10, e.g., IVj-11, IVj-12, IVj-13, IVj-14 or IVj-5, or IVj-16
wherein
W is =N– or =CH–; Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C1-4 alkyl, e.g., methyl, HCF2, OCH2F or halogen, e.g., F, Cl; R
8 is H, Me or Et; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; and s is 0 or 1. [0783] In some embodiments of a compound of formula IVj-5, IVj-6, IVj-7, IVj-8, IVj-9, IVj-10, e.g., IVj-11, IVj-12, IVj-13, IVj-14 or IVj-5, or IVj-16 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl or C
3-4 cycloalkyl. [0784] In some embodiments of a compound of formula IVj-5, IVj-6, IVj-7, IVj-8, IVj-9, IVj-10, e.g., IVj-11, IVj-12, IVj-13, IVj-14 or IVj-5, or IVj-16 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [0785] In some embodiments of a compound of formula IVj-5, IVj-6, IVj-7, IVj-8, IVj-9, IVj-10, e.g., IVj-11, IVj-12, IVj-13, IVj-14 or IVj-5, or IVj-16 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
[0786] In some embodiments of the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula IVj-5, IVj-6, IVj-7, IVj-8, IVj-9, IVj-10, e.g., IVj-11, IVj-12, IVj-13, IVj-14 or IVj-5, or IVj-16, X
8 is –O–, –NMe– or –S–. [0787] In some embodiments, Z is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; and n is 1 or 2. [0788] In some embodiments R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [0789] In some embodiments of formula IVj-5, IVj-6, IVj-7, IVj-8, IVj-9, IVj-10, e.g., IVj-11, IVj-12, IVj-13, IVj-14 or IVj-5, or IVj-16 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et.
[0790] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula IVj-5, IVj-6, IVj-7, IVj-8, IVj-9, IVj-10, e.g., IVj-11, IVj-12, IVj-13, IVj-14 or IVj-5, or IVj-16 W is =CH– and the compound is represented by formula IVk-5, IVk-6, IVk-7, IVk-8, IVk-9, IVk-10, e.g., IVk-11, IVk-12, IVk-13, IVk-14 or IVk-5, or IVk-16
wherein
Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C1-4 alkyl, C3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; R
8 is H, Me or Et; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; and s is 0 or 1. [0791] In some embodiments of a compound of formula IVk-5, IVk-6, IVk-7, IVk-8, IVk-9, IVk- 10, e.g., IVk-11, IVk-12, IVk-13, IVk-14 or IVk-5, or IVk-16 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1- C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3- 4 heterocycloalkyl or C
3-4 cycloalkyl. [0792] In some embodiments of a compound of formula IVk-5, IVk-6, IVk-7, IVk-8, IVk-9, IVk- 10, e.g., IVk-11, IVk-12, IVk-13, IVk-14 or IVk-5, or IVk-16 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [0793] In some embodiments of a compound of formula IVk-5, IVk-6, IVk-7, IVk-8, IVk-9, IVk- 10, e.g., IVk-11, IVk-12, IVk-13, IVk-14 or IVk-5, or IVk-16 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [0794] In some embodiments of the compound or pharmaceutical acceptable salts or stereoisomers
thereof of formula IVk-5, IVk-6, IVk-7, IVk-8, IVk-9, IVk-10, e.g., IVk-11, IVk-12, IVk-13, IVk- 14 or IVk-5, or IVk-16, X
8 is –O–, –NMe– or –S–. [0795] In some embodiments, Z is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; and n is 1 or 2. [0796] In some embodiments R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [0797] In some embodiments of formula IVk-5, IVk-6, IVk-7, IVk-8, IVk-9, IVk-10, e.g., IVk- 11, IVk-12, IVk-13, IVk-14 or IVk-5, or IVk-16 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et. [0798] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers
thereof of formula IV-1, IV-2, IV-3 or IV-4 is represented by formula IVl-1 to IVl-25
wherein
D1 is
Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
1 is –CH=CH
2 or -C≡CMe; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; R
8 is H, Me or Et; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; and s is 0 or 1. [0799] In some embodiments of a compound of formula IVl-1 to IVl-25 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3- 4 heterocycloalkyl or C
3-4 cycloalkyl. [0800] In some embodiments of a compound of formula IVl-1 to IVl-25 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [0801] In some embodiments of a compound of formula IVl-1 to IVl-25 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2.
[0802] In some embodiments of a compound of formula IVl-1 to IVl-25 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me. [0803] In some embodiments of a compound of formula IVl-1 to IVl-25 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [0804] In some embodiments of a compound of formula IVl-1 to IVl-25 or pharmaceutically acceptable salts or stereoisomers thereof, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above. [0805] In some embodiments of a compound of formula IVl-1 to IVl-25 or pharmaceutically acceptable salts or stereoisomers thereof, X
8 is –O–, –NMe– or –S–. [0806] In some embodiments, Z in D1 is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; and n is 1 or 2. [0807] In some embodiments R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [0808] In some embodiments of formula IVl-1 to IVl-25 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et. [0809] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula IV-1, IV-2, IV-3 or IV-4 is represented by formula IVm-1 to IVm-25
wherein D2 is
Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; R
8 is H, Me or Et; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; s is 0 or 1. [0810] In some embodiments of a compound of formula IVm-1 to IVm-25 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3- 4 heterocycloalkyl or C
3-4 cycloalkyl. [0811] In some embodiments of a compound of formula IVm-1 to IVm-25 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [0812] In some embodiments of a compound of formula IVm-1 to IVm-25 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
[0813] In some embodiments of a compound of formula IVm-1 to IVm-25 or pharmaceutically acceptable salts or stereoisomers thereof, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above. [0814] In some embodiments of a compound of formula IVm-1 to IVm-25 or pharmaceutically acceptable salts or stereoisomers thereof, X
8 is –O–, –NMe– or –S–. [0815] In some embodiments, Z in D2 is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [0816] In some embodiments, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [0817] In some embodiments of formula IVm-1 to IVm-25 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein
R
2 is hydrogen, Me or Et. [0818] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula IV-1, IV-2, IV-3 or IV-4 is represented by formula IVn-1 – IVn-17
wherein D
1 is
Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
1 is –CH=CH2 or -C≡CMe; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; R
8 is H, Me or Et; s is 0 or 1. [0819] In some embodiments of a compound of formula IVn-1 – IVn-17 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3- 4 heterocycloalkyl or C
3-4 cycloalkyl. [0820] In some embodiments of a compound of formula IVn-1 – IVn-17 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [0821] In some embodiments, R
6 is hydrogen for IVn-5, IVn-7, IVn-8, IVn-9, IVn-11; and R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl, for IVn-1, IVn-2, IVn-3, IVn-4, IVn-6, IVn-10,IVn-14, IVn-15, IVn-16, IVn-17. [0822] In some embodiments of a compound of formula IVn-1 – IVn-17 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2.
[0823] In some embodiments of a compound of formula IVn-1 – IVn-17 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me. [0824] In some embodiments of a compound of formula IVn-1 – IVn-17 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [0825] In some embodiments of a compound of formula IVn-1 – IVn-17 or pharmaceutically acceptable salts or stereoisomers thereof, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above. [0826] In some embodiments, Z in D1 is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [0827] In seom eembodiments, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [0828] In some embodiments of formula IVn-1 – IVn-17 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et. [0829] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula IV-1, IV-2, IV-3 or IV-4 is represented by formula IVo-1 – IVo-17
wherein D
2 is
Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4
to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; R
8 is H, Me or Et; s is 0 or 1. [0830] In some embodiments of a compound of formula IVo-1 – IVo-17 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3- 4 heterocycloalkyl or C
3-4 cycloalkyl. [0831] In some embodiments of a compound of formula IVo-1 – IVo-17 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [0832] In some embodiments, R
6 is hydrogen for IVo-5 IVo-7, IVo-8, IVo-9, IVo-11; and R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl, for IVo-1, IVo-2, IVo-3, IVo-4, IVo-6, IVo-10, IVo-14, IVo-15, IVo-16, IVo-17. [0833] In some embodiments of a compound of formula IVo-1 – IVo-17 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [0834] In some embodiments of a compound of formula IVo-1 – IVo-17 or pharmaceutically acceptable salts or stereoisomers thereof, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above. [0835] In some embodiments of a compound of formula IVo-1 – IVo-17 or pharmaceutically acceptable salts or stereoisomers thereof, X
8 is –O–, –NMe– or –S–.
[0836] In some embodiments, Z in D2 is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [0837] In seome embodiments R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [0838] In some embodiments of formula IVo-1 – IVo-17 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et. [0839] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula IV-1, IV-2, IV-3 or IV-4 is represented by formula IVn-18 – IVn-51
wherein D
1 is
Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF2 or C3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
1 is –CH=CH
2 or -C≡CMe; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; R
8 is H, Me or Et; s is 0 or 1. [0840] In some embodiments of a compound of formula IVn-18 – IVn-51 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3- 4 heterocycloalkyl or C
3-4 cycloalkyl. [0841] In some embodiments of a compound of formula IVn-18 – IVn-51 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [0842] In some embodiments, R
6 is hydrogen for IVn-25 to IVn27, IVn30 to IVn-35, IVn-38, IVn- 39; and R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl, for IVn-28, IVn-29, IVn-36, IVn-37, IVn-18 to IVn-25, IVn-44 to IVn-51.
[0843] In some embodiments of a compound of formula IVn-18 – IVn-51 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2. [0844] In some embodiments of a compound of formula IVn-18 – IVn-51 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me. [0845] In some embodiments of a compound of formula IVn-18 – IVn-51 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [0846] In some embodiments, Z in D1 is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; and n is 1 or 2. [0847] In some embodiments, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [0848] In some embodiments of formula IVn-18 – IVn-51 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et. [0849] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula IV-1, IV-2, IV-3 or IV-4 is represented by formula IVo-18 – IVo-51
wherein D
2 is
Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF2 or C3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; R
8 is H, Me or Et; s is 0 or 1. [0850] In some embodiments of a compound of formula IVo-18 – IVo-51 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3- 4 heterocycloalkyl or C
3-4 cycloalkyl. [0851] In some embodiments of a compound of formula IVo-18 – IVo-51 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [0852] In some embodiments, R
6 is hydrogen for IVo-25 to IVo27, IVo30 to IVo-35, IVo38, IVo- 39; and R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl, for IVo-18 to Ivo-25, IVo28, IVo29, IVo-36, IVo-37, IVo-44 to IVo-51. [0853] In some embodiments of a compound of formula IVo-18 – IVo-51 or pharmaceutically
acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [0854] In some embodiments of a compound of formula IVo-18 – IVo-51 or pharmaceutically acceptable salts or stereoisomers thereof, X
8 is –O–, –NMe– or –S–. [0855] In some embodiments, Z in D2 is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [0856] In some embodiments, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [0857] In some embodiments of formula IVo-18 – IVo-51 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein
R
2 is hydrogen, Me or Et. [0858] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula IV-1, IV-2, IV-3 or IV-4 is represented by formula IVp-1 – IVp-15
wherein D1 is
Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen
heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
1 is –CH=CH2 or -C≡CMe; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; R
8 is H, Me or Et; s is 0 or 1. [0859] In some embodiments of a compound of formula IVp-1 – IVp-15 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3- 4 heterocycloalkyl or C
3-4 cycloalkyl. [0860] In some embodiments of a compound of formula IVp-1 – IVp-15 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [0861] In some embodiments of a compound of formula IVp-1 – IVp-15 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2. [0862] In some embodiments of a compound of formula IVp-1 – IVp-15 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me. [0863] In some embodiments of a compound of formula IVp-1 – IVp-15 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [0864] In some embodiments of a compound of formula IVp-1 – IVp-15 or pharmaceutically acceptable salts or stereoisomers thereof, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above. [0865] In some embodiments, Z in D1 is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [0866] In some embodiments, R
2 is hydrogen, C1-4 alkyl or C3-4 cycloalkyl. [0867] In some embodiments of formula IVp-1 – IVp-15 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et. [0868] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula IV-1, IV-2, IV-3 or IV-4 is represented by formula IVq-1 – IVq-15
wherein D2 is
Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–;
R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; R
8 is H, Me or Et; s is 0 or 1. [0869] In some embodiments of a compound of formula IVq-1 – IVq-15 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C1-4 alkyl, C3-
4 heterocycloalkyl or C
3-4 cycloalkyl. [0870] In some embodiments of a compound of formula IVq-1 – IVq-15 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [0871] In some embodiments of a compound of formula IVq-1 – IVq-15 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [0872] In some embodiments of a compound of formula IVq-1 – IVq-15 or pharmaceutically acceptable salts or stereoisomers thereof, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above. [0873] In some embodiments of a compound of formula IVq-1 – IVq-15 or pharmaceutically acceptable salts or stereoisomers thereof, X
8 is –O–, –NMe– or –S–. [0874] In some embodiments, Z in D2 is of formula i
wherein
R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the CC-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [0875] In some embodiments R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [0876] In some embodiments of formula IVq-1 – IVq-15 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et. [0877] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula IV-1, IV-2, IV-3 or IV-4 is represented by formula IVp-16 – IVp-45
wherein D1 is
Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF2 or C3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
1 is –CH=CH
2 or -C≡CMe; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; R
8 is H, Me or Et; s is 0 or 1. [0878] In some embodiments of a compound of formula IVp-16 – IVp-45 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3- 4 heterocycloalkyl or C
3-4 cycloalkyl. [0879] In some embodiments of a compound of formula IVp-16 – IVp-45 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [0880] In some embodiments of a compound of formula IVp-16 – IVp-45 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2. [0881] In some embodiments of a compound of formula IVp-16 – IVp-45 or pharmaceutically
acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me. [0882] In some embodiments of a compound of formula IVp-16 – IVp-45 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [0883] In some embodiments, Z in D1 is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [0884] In some embodiments R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [0885] In some embodiments of formula IVp-16 – IVp-45 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein
R
2 is hydrogen, Me or Et. [0886] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula IV-1, IV-2, IV-3 or IV-4 is represented by formula IVq-16 – IVq-45
wherein D2 is
Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF2 or C3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; R
8 is H, Me or Et; s is 0 or 1. [0887] In some embodiments of a compound of formula IVq-16 – IVq-45 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3- 4 heterocycloalkyl or C
3-4 cycloalkyl. [0888] In some embodiments of a compound of formula IVq-16 – IVq-45 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [0889] In some embodiments of a compound of formula IVq-16 – IVq-45 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms.
[0890] In some embodiments of a compound of formula IVq-16 – IVq-45 or pharmaceutically acceptable salts or stereoisomers thereof, X
8 is –O–, –NMe– or –S–. [0891] In some embodiments, Z in D2 is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [0892] In some embodiments R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [0893] In some embodiments of formula IVq-16 – IVq-45 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et. [0894] In some embodiments, the present disclosure provides the compound or pharmaceutical acceptable salts or stereoisomers thereof having formula V-1, V-2, V-3 or V-4
wherein W is =CH–, =COMe–, =CMe– or =N–; Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
1 is –CH=CH
2 or -C≡CMe; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF3, HCF2, OCF3, hydroxy, C1-4 alkoxy or C1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; X
4 is –O–, –NH–, –NMe–; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; L is a covalent bond or linear or branched C
1-3 alkyl. [0895] In some embodiments of a compound of formula V-1, V-2, V-3 or V-4 or pharmaceutically
acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C1-4 alkyl, C3-
4 heterocycloalkyl or C
3-4 cycloalkyl. [0896] In some embodiments, the present disclosure provides the compound or pharmaceutical acceptable salts or stereoisomers thereof having formula V-2, V-3 or V-4. [0897] In some embodiments, the present disclosure provides the compound or pharmaceutical acceptable salts or stereoisomers thereof having formula V-1. [0898] In some embodiments of a compound of formula V-1, V-2, V-3 or V-4 or pharmaceutically acceptable salts or stereoisomers thereof, W is =CH–, =CMe– or =COMe–, e.g., =CH– or =COMe–, e.g., =CH–. [0899] In some embodiments of a compound of formula V-1, V-2, V-3 or V-4 or pharmaceutically acceptable salts or stereoisomers thereof, W is =N–. [0900] In some embodiments of a compound of formula V-1, V-2, V-3 or V-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH–. In some embodiments, X
1 is –NH– or –NMe–, particularly –NH– and W is =CH–, =CMe– or =COMe–, e.g., =CH– or =COMe–, e.g., =CH–. [0901] In some embodiments of a compound of formula V-1, V-2, V-3 or V-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH2 and W is =CH–, =CMe– or =COMe–, e.g., =CH– or =COMe–, e.g., =CH–. [0902] In some embodiments of a compound of formula V-1, V-2, V-3 or V-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me and W is =CH–, =CMe– or =COMe–, e.g., =CH– or =COMe–, e.g., =CH–. [0903] In some embodiments of a compound of formula V-1, V-2, V-3 or V-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2 and X
2 is –NH–, –NMe–, –NEt–, –NPr– , –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–, particularly –NH–, –NMe–, –NEt– , or –O–. [0904] In some embodiments of a compound of formula V-1, V-2, V-3 or V-4 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered
saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [0905] In some embodiments of a compound of formula V-1, V-2, V-3 or V-4 or pharmaceutically acceptable salts or stereoisomers thereof, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above. [0906] In some embodiments of a compound of formula V-1, V-2, V-3 or V-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
4 is –O–. [0907] In some embodiments of a compound of formula V-1, V-2, V-3 or V-4 or pharmaceutically acceptable salts or stereoisomers thereof, L is a covalent bond, –(CH
2)– or –(CH
2)
2–. In some embodiments, X
4 is –O– and L is a covalent bond, –(CH
2)– or –(CH
2)
2–. [0908] In some embodiments of a compound of formula V-1, V-2, V-3 or V-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
8 is –O–, –NMe– or –S–. [0909] In some embodiments, Z is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [0910] In some embodiments, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [0911] In some embodiments of formula V-1, V-2, V-3 or V-4 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et. [0912] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula V-1, V-2, V-3 or V-4 is represented by formula Va-1, Va-2, Va-3 or Va-4
wherein Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
1 is –CH=CH
2 or -C≡CMe;
R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; X
4 is –O–, –NH–, –NMe–; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; L is a covalent bond or linear or branched C
1-3 alkyl. [0913] In some embodiments of a compound of formula Va-1, Va-2, Va-3 or Va-4 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl or C
3-4 cycloalkyl. [0914] In some embodiments of a compound of formula Va-1, Va-2, Va-3 or Va-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly – NH. [0915] In some embodiments of a compound of formula Va-1, Va-2, Va-3 or Va-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH2. [0916] In some embodiments of a compound of formula Va-1, Va-2, Va-3 or Va-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me. [0917] In some embodiments of a compound of formula Va-1, Va-2, Va-3 or Va-4 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [0918] In some embodiments of a compound of formula Va-1, Va-2, Va-3 or Va-4 or pharmaceutically acceptable salts or stereoisomers thereof, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above. [0919] In some embodiments of a compound of formula Va-1, Va-2, Va-3 or Va-4 or
pharmaceutically acceptable salts or stereoisomers thereof, X
4 is –O–. [0920] In some embodiments of a compound of formula Va-1, Va-2, Va-3 or Va-4 or pharmaceutically acceptable salts or stereoisomers thereof, L is a covalent bond, –(CH
2)– or – (CH2)2–. In some embodiments, X
4 is –O– and L is a covalent bond, –(CH2)– or –(CH2)2–. [0921] In some embodiments of a compound of formula Va-1, Va-2, Va-3 or Va-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
8 is –O–, –NMe– or –S–. [0922] In some embodiments, Z is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [0923] In some embodiments, R
2 is hydrogen, C1-4 alkyl or C3-4 cycloalkyl. [0924] In some embodiments of formula Va-1, Va-2, Va-3 or Va-4 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et. [0925] In some embodiments, the present disclosure provides the compound or pharmaceutical acceptable salts or stereoisomers thereof having formula V-5, V-6, V-7, V-8, V-9, V-10, V-11 or V-12
wherein W is =CH–, =COMe–, =CMe– or =N–; Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen
heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
1 is –CH=CH2 or -C≡CMe; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; X
4 is –O–, –NH–, –NMe–; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; L is a covalent bond or linear or branched C
1-3 alkyl. [0926] In some embodiments of a compound of formula V-5, V-6, V-7, V-8, V-9, V-10, V-11 or V-12 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl or C
3-4 cycloalkyl. [0927] In some embodiments of a compound of formula V-5, V-6, V-7, V-8, V-9, V-10, V-11 or V-12 or pharmaceutically acceptable salts or stereoisomers thereof, W is =CH–, =CMe– or =COMe–, e.g., =CH– or =COMe–, e.g., =CH–. [0928] In some embodiments of a compound of formula V-5, V-6, V-7, V-8, V-9, V-10, V-11 or V-12 or pharmaceutically acceptable salts or stereoisomers thereof, W is =N–. [0929] In some embodiments of a compound of formula V-5, V-6, V-7, V-8, V-9, V-10, V-11 or V-12 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH–. In some embodiments, X
1 is –NH– or –NMe–, particularly –NH– and W is =CH–, =CMe– or =COMe–, e.g., =CH– or =COMe–, e.g., =CH–. [0930] In some embodiments of a compound of formula V-5, V-6, V-7, V-8, V-9, V-10, V-11 or V-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2 and W is =CH–, =CMe– or =COMe–, e.g., =CH– or =COMe–, e.g., =CH–.
[0931] In some embodiments of a compound of formula V-5, V-6, V-7, V-8, V-9, V-10, V-11 or V-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me and W is =CH–, =CMe– or =COMe–, e.g., =CH– or =COMe–, e.g., =CH–. [0932] In some embodiments of a compound of formula V-5, V-6, V-7, V-8, V-9, V-10, V-11 or V-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2 and X
2 is – NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–. [0933] In some embodiments of a compound of formula V-5, V-6, V-7, V-8, V-9, V-10, V-11 or V-12 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [0934] In some embodiments of a compound of formula V-5, V-6, V-7, V-8, V-9, V-10, V-11 or V-12 or pharmaceutically acceptable salts or stereoisomers thereof, X
4 is –O–. [0935] In some embodiments of a compound of formula V-5, V-6, V-7, V-8, V-9, V-10, V-11 or V-12 or pharmaceutically acceptable salts or stereoisomers thereof, L is a covalent bond, –(CH
2)– or –(CH
2)
2–. In some embodiments, X
4 is –O– and L is a covalent bond, –(CH
2)– or –(CH
2)
2–. [0936] In some embodiments of a compound of formula V-5, V-6, V-7, V-8, V-9, V-10, V-11 or V-12 or pharmaceutically acceptable salts or stereoisomers thereof, X
8 is –O–, –NMe– or –S–. [0937] In some embodiments, Z is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl;
R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [0938] In some embodiments, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [0939] In some embodiments of formula V-5, V-6, V-7, V-8, V-9, V-10, V-11 or V-12 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et. [0940] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula V-5, V-6, V-7, V-8, V-9, V-10, V-11 or V-12 is represented by formula Va-5, Va-6, Va-7, Va-8, Va-9, Va-10, Va-11 or Va-12
wherein Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
1 is –CH=CH
2 or -C≡CMe; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3;
R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; X
4 is –O–, –NH–, –NMe–; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; L is a covalent bond or linear or branched C
1-3 alkyl. [0941] In some embodiments of a compound of formula Va-5, Va-6, Va-7, Va-8, Va-9, Va-10, Va-11 or Va-12 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl or C
3-4 cycloalkyl. [0942] In some embodiments of a compound of formula Va-5, Va-6, Va-7, Va-8, Va-9, Va-10, Va-11 or Va-12 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or – NMe–, particularly –NH. [0943] In some embodiments of a compound of formula Va-5, Va-6, Va-7, Va-8, Va-9, Va-10, Va-11 or Va-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2. [0944] In some embodiments of a compound of formula Va-5, Va-6, Va-7, Va-8, Va-9, Va-10, Va-11 or Va-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me. [0945] In some embodiments of a compound of formula Va-5, Va-6, Va-7, Va-8, Va-9, Va-10, Va-11 or Va-12 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [0946] In some embodiments of a compound of formula Va-5, Va-6, Va-7, Va-8, Va-9, Va-10, Va-11 or Va-12 or pharmaceutically acceptable salts or stereoisomers thereof, X
4 is –O–. [0947] In some embodiments of a compound of formula Va-5, Va-6, Va-7, Va-8, Va-9, Va-10, Va-11 or Va-12 or pharmaceutically acceptable salts or stereoisomers thereof, L is a covalent bond, –(CH
2)– or –(CH
2)
2–. In some embodiments, X
4 is –O– and L is a covalent bond, –(CH
2)– or – (CH
2)
2–.
[0948] In some embodiments of a compound of formula Va-5, Va-6, Va-7, Va-8, Va-9, Va-10, Va-11 or Va-12 or pharmaceutically acceptable salts or stereoisomers thereof, X
8 is –O–, –NMe– or –S–. [0949] In some embodiments, Z is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [0950] In some embodiments R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [0951] In some embodiments of formula Va-5, Va-6, Va-7, Va-8, Va-9, Va-10, Va-11 or Va-12 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et. [0952] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers
thereof of formula V-1, V-2, V-3 or V-4 is represented by formula Vb-1, Vb-2, Vb-3, Vb-4, Vc- 1, Vc-2, Vc-3 or Vc-4
wherein W is =CH–, =COMe–, =CMe– or =N–; X
1 is –NH–, –NMe– or –O–; X
4 is –O–, –NH–, –NMe–; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; L is a covalent bond or linear or branched C
1-3 alkyl
R
1 is –HC=CH
2 or –C≡C–Me R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form together an unsubstituted oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; m is 1, 2 or 3; n is 1 or 2; r is 1 or 2, e.g., 1. [0953] In some embodiments of a compound of formula Vb-1, Vb-2, Vb-3, Vb-4, Vc-1, Vc-2, Vc- 3 or Vc-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [0954] In some embodiments of a compound of formula Vb-1, Vb-2, Vb-3, Vb-4, Vc-1, Vc-2, Vc- 3 or Vc-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [0955] In some embodiments of a compound of formula Vb-1, Vb-2, Vb-3, Vb-4, Vc-1, Vc-2, Vc- 3 or Vc-4 or pharmaceutically acceptable salts or stereoisomers thereof, W is =CH–, =CMe– or =COMe–, e.g., =CH– or =COMe–, e.g., =CH–. [0956] In some embodiments of a compound of formula Vb-1, Vb-2, Vb-3, Vb-4, Vc-1, Vc-2, Vc- 3 or Vc-4 or pharmaceutically acceptable salts or stereoisomers thereof, W is =N–. [0957] In some embodiments of a compound of formula Vb-1, Vb-2, Vb-3, Vb-4, Vc-1, Vc-2, Vc- 3 or Vc-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2. [0958] In some embodiments of a compound of formula Vb-1, Vb-2, Vb-3, Vb-4, Vc-1, Vc-2, Vc- 3 or Vc-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me. [0959] In some embodiments of a compound of formula Vb-1, Vb-2, Vb-3, Vb-4, Vc-1, Vc-2, Vc- 3 or Vc-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH–, and X
2 is –NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–,
–NMe–, –NEt–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–. [0960] In some embodiments of a compound of formula Vb-1, Vb-2, Vb-3, Vb-4, Vc-1, Vc-2, Vc- 3 or Vc-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl. [0961] In some embodiments of a compound of formula Vb-1, Vb-2, Vb-3 or Vb-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
a and R
b are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R
a and R
b are each independently selected from hydrogen, methyl. In some embodiments in which m is 2 or 3, only one R
a and one R
b are not hydrogen and/or only one R
a is not hydrogen. [0962] In some embodiments of a compound of formula Vb-1, Vb-2, Vb-3 or Vb-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
c and R
d are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R
c and R
d are each independently selected from hydrogen, methyl. In some embodiments in which n is 2, only one R
c and one R
c are not hydrogen and/or only one R
c is not hydrogen. [0963] In some embodiments of a compound of formula Vb-1, Vb-2, Vb-3 or Vb-4 or pharmaceutically acceptable salts or stereoisomers thereof, m and n are selected such that a 4, 5 or 6 membered nitrogen containing ring is formed. [0964] In some embodiments of a compound of formula Vb-1, Vb-2, Vb-3, Vb-4, Vc-1, Vc-2, Vc- 3 or Vc-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH–, and R
2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl. [0965] In some embodiments of a compound of formula Vb-1, Vb-2, Vb-3, Vb-4, Vc-1, Vc-2, Vc- 3 or Vc-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
4 is –O–. [0966] In some embodiments of a compound of formula Vb-1, Vb-2, Vb-3, Vb-4, Vc-1, Vc-2, Vc- 3 or Vc-4 or pharmaceutically acceptable salts or stereoisomers thereof, L is a covalent bond, – (CH
2)– or –(CH
2)
2–. In some embodiments, X
4 is –O– and L is a covalent bond, –(CH
2)– or – (CH2)2–. [0967] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula V-1, V-2, V-3 or V-4 is represented by formula Vb-5 to Vb-12, Vc-5 to Vc-12
wherein W is =CH–, =COMe–, =CMe– or =N–; X
1 is –NH–, –NMe– or –O–; X
4 is –O–, –NH–, –NMe–; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; L is a covalent bond or linear or branched C
1-3 alkyl R
1 is –HC=CH
2 or –C≡C–Me R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF3, HCF2, OCF3, hydroxy, C1-4 alkoxy or C1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form together an unsubstituted oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; m is 1, 2 or 3; n is 1 or 2; r is 1 or 2, e.g., 1. [0968] In some embodiments of a compound of formula Vb-5 to Vb-12, Vc-5 to Vc-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [0969] In some embodiments of a compound of formula Vb-5 to Vb-12, Vc-5 to Vc-12 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly – NH. [0970] In some embodiments of a compound of formula Vb-5 to Vb-12, Vc-5 to Vc-12 or pharmaceutically acceptable salts or stereoisomers thereof, W is =CH–, =CMe– or =COMe–, e.g., =CH– or =COMe–, e.g., =CH–. [0971] In some embodiments of a compound of formula Vb-1, Vb-2, Vb-3, Vb-4, Vc-1, Vc-2, Vc-3 or Vc-4 or pharmaceutically acceptable salts or stereoisomers thereof, W is =N–.
[0972] In some embodiments of a compound of formula Vb-5 to Vb-12, Vc-5 to Vc-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2. [0973] In some embodiments of a compound of formula Vb-5 to Vb-12, Vc-5 to Vc-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me. [0974] In some embodiments of a compound of formula Vb-5 to Vb-12, Vc-5 to Vc-12 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly – NH–, and X
2 is –NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, – NEt–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–. [0975] In some embodiments of a compound of formula Vb-5 to Vb-12, Vc-5 to Vc-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
2 is hydrogen, methyl, ethyl, n- propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl. [0976] In some embodiments of a compound of formula Vb-5 to Vb-12, Vc-5 to Vc-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
a and R
b are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R
a and R
b are each independently selected from hydrogen, methyl. In some embodiments in which m is 2 or 3, only one R
a and one R
b are not hydrogen and/or only one R
a is not hydrogen. [0977] In some embodiments of a compound of formula Vb-5 to Vb-12, Vc-5 to Vc-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
c and R
d are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R
c and R
d are each independently selected from hydrogen, methyl. In some embodiments in which n is 2, only one R
c and one R
c are not hydrogen and/or only one R
c is not hydrogen. [0978] In some embodiments of a compound of formula Vb-5 to Vb-12, Vc-5 to Vc-12 or pharmaceutically acceptable salts or stereoisomers thereof, m and n are selected such that a 4, 5 or 6 membered nitrogen containing ring is formed. [0979] In some embodiments of a compound of formula Vb-5 to Vb-12, Vc-5 to Vc-12 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly – NH–, and R
2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl. [0980] In some embodiments of a compound of formula Vb-5 to Vb-12, Vc-5 to Vc-12 or pharmaceutically acceptable salts or stereoisomers thereof, X
4 is –O–. [0981] In some embodiments of a compound of Vb-5 to Vb-12, Vc-5 to Vc-12 or
pharmaceutically acceptable salts or stereoisomers thereof, L is a covalent bond, –(CH
2)– or – (CH
2)
2–. In some embodiments, X
4 is –O– and L is a covalent bond, –(CH
2)– or –(CH
2)
2–. [0982] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula Vb-1, Vb-2, Vb-3, Vb-4, Vc-1, Vc-2, Vc-3 or Vc-4, X
4 is –O–, such that the compound is represented by formula Vd-1, Vd-2, Vd-3, Vd-4, Ve-1, Ve-2, Ve-3 or Ve-4
wherein W is =CH–, =COMe–, =CMe– or =N–; X
1 is –NH–, –NMe– or –O–; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=;
X
8’ is –O–, –S–, –NH– or –NMe–; L is a covalent bond or linear or branched C
1-3 alkyl R
1 is –HC=CH
2 or –C≡C–Me R
2 is hydrogen, C1-4 alkyl, CHF2 or C3-4 cycloalkyl; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form together an unsubstituted oxiranyl; R
c, R
d are each independently selected from hydrogen, C1-4 alkyl; m is 1, 2 or 3; n is 1 or 2; r is 1 or 2, e.g., 1. [0983] In some embodiments of a compound of formula Vd-1, Vd-2, Vd-3, Vd-4, Ve-1, Ve-2, Ve- 3 or Ve-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [0984] In some embodiments of a compound of formula Vd-1, Vd-2, Vd-3, Vd-4, Ve-1, Ve-2, Ve- 3 or Ve-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [0985] In some embodiments of a compound of formula Vd-1, Vd-2, Vd-3, Vd-4, Ve-1, Ve-2, Ve- 3 or Ve-4 or pharmaceutically acceptable salts or stereoisomers thereof, W is =CH–, =CMe– or =COMe–, e.g., =CH– or =COMe–, e.g., =CH–. [0986] In some embodiments of a compound of formula Vd-1, Vd-2, Vd-3, Vd-4, Ve-1, Ve-2, Ve- 3 or Ve-4 or pharmaceutically acceptable salts or stereoisomers thereof, W is =N–. [0987] In some embodiments of a compound of formula Vd-1, Vd-2, Vd-3, Vd-4, Ve-1, Ve-2, Ve- 3 or Ve-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2. [0988] In some embodiments of a compound of formula Vd-1, Vd-2, Vd-3, Vd-4, Ve-1, Ve-2, Ve- 3 or Ve-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me. [0989] In some embodiments of a compound of formula Vd-1, Vd-2, Vd-3, Vd-4, Ve-1, Ve-2, Ve-
3 or Ve-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl. [0990] In some embodiments of a compound of formula Vd-1, Vd-2, Vd-3, Vd-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
a and R
b are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R
a and R
b are each independently selected from hydrogen, methyl. In some embodiments in which m is 2 or 3, only one R
a and one R
b are not hydrogen and/or only one R
a is not hydrogen. [0991] In some embodiments of a compound of formula Vd-1, Vd-2, Vd-3, Vd-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
c and R
d are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R
c and R
d are each independently selected from hydrogen, methyl. In some embodiments in which n is 2, only one R
c and one R
c are not hydrogen and/or only one R
c is not hydrogen. [0992] In some embodiments of a compound of formula Vd-1, Vd-2, Vd-3, Vd-4 or pharmaceutically acceptable salts or stereoisomers thereof, m and n are selected such that a 4, 5 or 6 membered nitrogen containing ring is formed. [0993] In some embodiments of a compound of formula Vd-1, Vd-2, Vd-3, Vd-4, Ve-1, Ve-2, Ve- 3 or Ve-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH–, and R
2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl. [0994] In some embodiments of a compound of formula Vd-1, Vd-2, Vd-3, Vd-4, Ve-1, Ve-2, Ve- 3 or Ve-4 or pharmaceutically acceptable salts or stereoisomers thereof, L is a covalent bond, – (CH
2)– or –(CH
2)
2–. [0995] In some embodiments W is =CH– and the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula V-1, V-2, V-3 or V-4 is represented by formula Vf-1, Vf-2, Vf- 3, Vf-4, Vg-1, Vg-2, Vg-3 or Vg-4
wherein X
1 is –NH–, –NMe– or –O–; X
4 is –O–, –NH–, –NMe–; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; L is a covalent bond or linear or branched C
1-3 alkyl R
1 is –HC=CH
2 or –C≡C–Me R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl;
R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form together an unsubstituted oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; m is 1, 2 or 3; n is 1 or 2; r is 1 or 2, e.g., 1. [0996] In some embodiments of a compound of formula Vf-1, Vf-2, Vf-3, Vf-4, Vg-1, Vg-2, Vg- 3 or Vg-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [0997] In some embodiments of a compound of formula Vf-1, Vf-2, Vf-3, Vf-4, Vg-1, Vg-2, Vg- 3 or Vg-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [0998] In some embodiments of a compound of Vf-1, Vf-2, Vf-3, Vf-4, Vg-1, Vg-2, Vg-3 or Vg- 4 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2. [0999] In some embodiments of a compound of Vf-1, Vf-2, Vf-3, Vf-4, Vg-1, Vg-2, Vg-3 or Vg- 4 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me. [1000] In some embodiments of a compound of formula Vf-1, Vf-2, Vf-3, Vf-4, Vg-1, Vg-2, Vg- 3 or Vg-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH–, and X
2 is –NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–. [1001] In some embodiments of a compound of formula Vf-1, Vf-2, Vf-3, Vf-4, Vg-1, Vg-2, Vg- 3 or Vg-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl. [1002] In some embodiments of a compound of formula Vf-1, Vf-2, Vf-3, Vf-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
a and R
b are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R
a and R
b are
each independently selected from hydrogen, methyl. In some embodiments in which m is 2 or 3, only one R
a and one R
b are not hydrogen and/or only one R
a is not hydrogen. [1003] In some embodiments of a compound of formula Vf-1, Vf-2, Vf-3, Vf-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
c and R
d are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R
c and R
d are each independently selected from hydrogen, methyl. In some embodiments in which n is 2, only one R
c and one R
c are not hydrogen and/or only one R
c is not hydrogen. [1004] In some embodiments of a compound of formula Vf-1, Vf-2, Vf-3, Vf-4 or pharmaceutically acceptable salts or stereoisomers thereof, m and n are selected such that a 4, 5 or 6 membered nitrogen containing ring is formed. [1005] In some embodiments of a compound of formula Vf-1, Vf-2, Vf-3, Vf-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly – NH–, and R
2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl. [1006] In some embodiments of a compound of formula Vf-1, Vf-2, Vf-3, Vf-4, Vg-1, Vg-2, Vg- 3 or Vg-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
4 is –O–. [1007] In some embodiments of a compound of formula Vf-1, Vf-2, Vf-3, Vf-4, Vg-1, Vg-2, Vg- 3 or Vg-4 or pharmaceutically acceptable salts or stereoisomers thereof, L is a covalent bond, – (CH
2)– or –(CH
2)
2–. In some embodiments, X
4 is –O– and L is a covalent bond, –(CH
2)– or – (CH2)2–. [1008] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula Vb-5 to Vb12, Vc-5 to Vc12, X
4 is –O–, such that the compound is represented by formula Vd-5 to Vd-12, Ve-5 to Ve-12
wherein W is =CH–, =COMe–, =CMe– or =N–; X
1 is –NH–, –NMe– or –O–; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; L is a covalent bond or linear or branched C
1-3 alkyl R
1 is –HC=CH
2 or –C≡C–Me R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form together an unsubstituted oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; m is 1, 2 or 3; n is 1 or 2; r is 1 or 2, e.g., 1. [1009] In some embodiments of a compound of formula Vd-5 to Vd-12, Ve-5 to Ve-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [1010] In some embodiments of a compound of formula Vd-5 to Vd-12, Ve-5 to Ve-12 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly – NH. [1011] In some embodiments of a compound of formula Vd-5 to Vd-12, Ve-5 to Ve-12 or pharmaceutically acceptable salts or stereoisomers thereof, W is =CH–, =CMe– or =COMe–, e.g., =CH– or =COMe–, e.g., =CH–. [1012] In some embodiments of a compound of formula Vd-5 to Vd-12, Ve-5 to Ve-12 or pharmaceutically acceptable salts or stereoisomers thereof, W is =N–. [1013] In some embodiments of a compound of Vd-5 to Vd-12, Ve-5 to Ve-12 or pharmaceutically
acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2. [1014] In some embodiments of a compound of formula Vd-5 to Vd-12, Ve-5 to Ve-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me. [1015] In some embodiments of a compound of formula Vd-5 to Vd-12, Ve-5 to Ve-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
2 is hydrogen, methyl, ethyl, n- propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl. [1016] In some embodiments of a compound of formula Vd-5 to Vd-12, Ve-5 to Ve-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
a and R
b are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R
a and R
b are each independently selected from hydrogen, methyl. In some embodiments in which m is 2 or 3, only one R
a and one R
b are not hydrogen and/or only one R
a is not hydrogen. [1017] In some embodiments of a compound of formula Vd-5 to Vd-12, Ve-5 to Ve-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
c and R
d are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R
c and R
d are each independently selected from hydrogen, methyl. In some embodiments in which n is 2, only one R
c and one R
c are not hydrogen and/or only one R
c is not hydrogen. [1018] In some embodiments of a compound of formula Vd-5 to Vd-12, Ve-5 to Ve-12 or pharmaceutically acceptable salts or stereoisomers thereof, m and n are selected such that a 4, 5 or 6 membered nitrogen containing ring is formed. [1019] In some embodiments of a compound of formula Vd-5 to Vd-12, Ve-5 to Ve-12 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly – NH–, and R
2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl. [1020] In some embodiments of a compound of formula Vd-5 to Vd-12, Ve-5 to Ve-12 or pharmaceutically acceptable salts or stereoisomers thereof, L is a covalent bond, –(CH
2)– or – (CH
2)
2–. [1021] In some embodiments W is =CH– and the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula V-1, V-2, V-3 or V-4 is represented by formula Vf-5 to Vf-12, Vg-5, Vg-12
wherein X
1 is –NH–, –NMe– or –O–; X
4 is –O–, –NH–, –NMe–; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; L is a covalent bond or linear or branched C
1-3 alkyl R
1 is –HC=CH
2 or –C≡C–Me R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form together an unsubstituted oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; m is 1, 2 or 3; n is 1 or 2; r is 1 or 2, e.g., 1. [1022] In some embodiments of a compound of formula Vf-5 to Vf-12, Vg-5, Vg-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [1023] In some embodiments of a compound of formula Vf-5 to Vf-12, Vg-5, Vg-12 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly – NH. [1024] In some embodiments of a compound of formula Vf-5 to Vf-12, Vg-5, Vg-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH2. [1025] In some embodiments of a compound of formula Vf-5 to Vf-12, Vg-5, Vg-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me. [1026] In some embodiments of a compound of formula Vf-5 to Vf-12, Vg-5, Vg-12 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –
NH–, and X
2 is –NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, – NEt–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–. [1027] In some embodiments of a compound of formula Vf-5 to Vf-12, Vg-5, Vg-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
2 is hydrogen, methyl, ethyl, n- propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl. [1028] In some embodiments of a compound of formula Vf-5 to Vf-12, Vg-5, Vg-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
a and R
b are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R
a and R
b are each independently selected from hydrogen, methyl. In some embodiments in which m is 2 or 3, only one R
a and one R
b are not hydrogen and/or only one R
a is not hydrogen. [1029] In some embodiments of a compound of formula Vf-5 to Vf-12, Vg-5, Vg-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
c and R
d are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R
c and R
d are each independently selected from hydrogen, methyl. In some embodiments in which n is 2, only one R
c and one R
c are not hydrogen and/or only one R
c is not hydrogen. [1030] In some embodiments of a compound of formula Vf-5 to Vf-12, Vg-5, Vg-12 or pharmaceutically acceptable salts or stereoisomers thereof, m and n are selected such that a 4, 5 or 6 membered nitrogen containing ring is formed. [1031] In some embodiments of a compound of formula Vf-5 to Vf-12, Vg-5, Vg-12 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly – NH–, and R
2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl. [1032] In some embodiments of a compound of formula Vf-5 to Vf-12, Vg-5, Vg-12 or pharmaceutically acceptable salts or stereoisomers thereof, X
4 is –O–. [1033] In some embodiments of a compound of formula Vf-5 to Vf-12, Vg-5, Vg-12 or pharmaceutically acceptable salts or stereoisomers thereof, L is a covalent bond, –(CH
2)– or – (CH2)2–. In some embodiments, X
4 is –O– and L is a covalent bond, –(CH2)– or –(CH2)2–. [1034] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula V-1, V-2, V-3 or V-4 is represented by formula Vh-1, Vh-2, Vh-3, e.g., Vh-3a or Vh-3b, or Vh-4
wherein W is =N– or =CH–; Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
1 is –CH=CH
2 or -C≡CMe; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C1-4 alkyl, e.g., methyl, HCF2, OCH2F or halogen, e.g., F, Cl; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=;
X
8’ is –O–, –S–, –NH– or –NMe–; s is 0 or 1. [1035] In some embodiments of a compound of formula Vh-1, Vh-2, Vh-3, e.g., Vh-3a or Vh-3b, or Vh-4 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl or C
3-4 cycloalkyl. [1036] In some embodiments of a compound of formula Vh-1, Vh-2, Vh-3, e.g., Vh-3a or Vh-3b, or Vh-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [1037] In some embodiments of a compound of formula Vh-1, Vh-2, Vh-3, e.g., Vh-3a or Vh-3b, or Vh-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2. [1038] In some embodiments of a compound of formula Vh-1, Vh-2, Vh-3, e.g., Vh-3a or Vh-3b, or Vh-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me. [1039] In some embodiments of a compound of formula Vh-1, Vh-2, Vh-3, e.g., Vh-3a or Vh-3b, or Vh-4 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [1040] In some embodiments of the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula Vh-1, Vh-2, Vh-3, e.g., Vh-3a or Vh-3b, or Vh-4, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above. [1041] In some embodiments of the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula Vh-1, Vh-2, Vh-3, e.g., Vh-3a or Vh-3b, or Vh-4, X
8 is –O–, –NMe– or –S–. [1042] In some embodiments, Z is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [1043] In some embodiments, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [1044] In some embodiments of formula Vh-1, Vh-2, Vh-3, e.g., Vh-3a or Vh-3b, or Vh-4 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et. [1045] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula V-1, V-2, V-3 or V-4 W is =CH– and the compound is represented by formula Vi-1, Vi-2, Vi-3, e.g., Vi-3a or Vi-3b, or Vi-4
wherein Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
1 is –CH=CH
2 or -C≡CMe; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–;
s is 0 or 1. [1046] In some embodiments of a compound of formula Vi-1, Vi-2, Vi-3, e.g., Vi-3a or Vi-3b, or Vi-4 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl or C
3-4 cycloalkyl. [1047] In some embodiments of a compound of formula Vi-1, Vi-2, Vi-3, e.g., Vi-3a or Vi-3b, or Vi-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [1048] In some embodiments of a compound of formula Vi-1, Vi-2, Vi-3, e.g., Vi-3a or Vi-3b, or Vi-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH2. [1049] In some embodiments of a compound of formula Vi-1, Vi-2, Vi-3, e.g., Vi-3a or Vi-3b, or Vi-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me. [1050] In some embodiments of a compound of formula Vi-1, Vi-2, Vi-3, e.g., Vi-3a or Vi-3b, or Vi-4 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [1051] In some embodiments of the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula Vi-1, Vi-2, Vi-3, e.g., Vi-3a or Vi-3b, or Vi-4, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above. [1052] In some embodiments, Z is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl;
R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [1053] In some embodiments, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [1054] In some embodiments of formula Vi-1, Vi-2, Vi-3, e.g., Vi-3a or Vi-3b, or Vi-4 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et. [1055] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula V-1, V-2, V-3 or V-4 is represented by formula Vh-5, Vh-6, Vh-7, Vh-8, Vh- 9, Vh-10 preferably Vh-11, Vh-12, Vh-13 or Vh-14 Vh-15, or Vh-16
wherein W is =N– or =CH–;
Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C1-4 alkyl, C3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
1 is –CH=CH
2 or -C≡CMe; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C1-4 alkyl, e.g., methyl, HCF2, OCH2F or halogen, e.g., F, Cl; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; s is 0 or 1. [1056] In some embodiments, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1- C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3- 4 heterocycloalkyl or C3-4 cycloalkyl. [1057] In some embodiments of a compound of formula Vh-5, Vh-6, Vh-7, Vh-8, Vh-9, e.g., Vh- 10, Vh-11, Vh-12 or Vh-13 Vh-14, or Vh-15 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [1058] In some embodiments of a compound of formula Vh-5, Vh-6, Vh-7, Vh-8, Vh-9, e.g., Vh- 10, Vh-11, Vh-12 or Vh-13 Vh-14, or Vh-15 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2. [1059] In some embodiments of a compound of formula Vh-5, Vh-6, Vh-7, Vh-8, Vh-9, e.g., Vh- 10, Vh-11, Vh-12 or Vh-13 Vh-14, or Vh-15 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me. [1060] In some embodiments of a compound of formula Vh-5, Vh-6, Vh-7, Vh-8, Vh-9, e.g., Vh- 10, Vh-11, Vh-12 or Vh-13 Vh-14, or Vh-15 or pharmaceutically acceptable salts or stereoisomers
thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [1061] In some embodiments of the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula Vh-5, Vh-6, Vh-7, Vh-8, Vh-9, e.g., Vh-10, Vh-11, Vh-12 or Vh-13 Vh-14, or Vh-15, X
8 is –O–, –NMe– or –S–. [1062] In some embodiments, Z is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [1063] In some embodiments, R
2 is hydrogen, C1-4 alkyl or C3-4 cycloalkyl. [1064] In some embodiments of formula Vh-5, Vh-6, Vh-7, Vh-8, Vh-9, e.g., Vh-10, Vh-11, Vh- 12 or Vh-13 Vh-14, or Vh-15 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et. [1065] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula V-1, V-2, V-3 or V-4 W is =CH– and the compound is represented by formula Vi-5, Vi-6, Vi-7, Vi-8, Vi-9, Vi-10, e.g., Vi-11 Vi-12, Vi-13, Vi-14 or Vi-15, or Vi-16
wherein Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4
to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
1 is –CH=CH
2 or -C≡CMe; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; s is 0 or 1. [1066] In some embodiments of a compound of formula Vi-5, Vi-6, Vi-7, Vi-8, Vi-9, Vi-10, e.g., Vi-11 Vi-12, Vi-13, Vi-14 or Vi-15, or Vi-16 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl or C3-4 cycloalkyl. [1067] In some embodiments of a compound of formula Vi-5, Vi-6, Vi-7, Vi-8, Vi-9, Vi-10, e.g., Vi-11 Vi-12, Vi-13, Vi-14 or Vi-15, or Vi-16 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [1068] In some embodiments of a compound of formula Vi-5, Vi-6, Vi-7, Vi-8, Vi-9, Vi-10, e.g., Vi-11 Vi-12, Vi-13, Vi-14 or Vi-15, or Vi-16 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2. [1069] In some embodiments of a compound of formula Vi-5, Vi-6, Vi-7, Vi-8, Vi-9, Vi-10, e.g., Vi-11 Vi-12, Vi-13, Vi-14 or Vi-15, or Vi-16 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me. [1070] In some embodiments of a compound of formula Vi-5, Vi-6, Vi-7, Vi-8, Vi-9, Vi-10, e.g., Vi-11 Vi-12, Vi-13, Vi-14 or Vi-15, or Vi-16 or pharmaceutically acceptable salts or stereoisomers
thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [1071] In some embodiments, Z is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [1072] In some embodiments, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [1073] In some embodiments of formula Vi-5, Vi-6, Vi-7, Vi-8, Vi-9, Vi-10, e.g., Vi-11 Vi-12, Vi-13, Vi-14 or Vi-15, or Vi-16 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et.
[1074] In some embodiments of the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula Vi-1, Vi-2, Vi-3, e.g., Vi-3a or Vi-3b, or Vi-4, X
8 is –O–, –NMe– or –S–. [1075] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula V-1, V-2, V-3 or V-4 is represented by formula Vj-1, Vj-2, Vj-3, e.g., Vj-3a or Vj-3b, or Vj-4
wherein W is =N– or =CH–; Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF3 and OCF
3;
R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; s is 0 or 1. [1076] In some embodiments of a compound of formula Vj-1, Vj-2, Vj-3, e.g., Vj-3a or Vj-3b, or Vj-4 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C1-4 alkyl, C3-4 heterocycloalkyl or C3-4 cycloalkyl [1077] In some embodiments of a compound of formula Vj-1, Vj-2, Vj-3, e.g., Vj-3a or Vj-3b, or Vj-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [1078] In some embodiments of a compound of formula Vj-1, Vj-2, Vj-3, e.g., Vj-3a or Vj-3b, or Vj-4 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [1079] In some embodiments of the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula Vj-1, Vj-2, Vj-3, e.g., Vj-3a or Vj-3b, or Vj-4, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above. [1080] In some embodiments of the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula Vj-1, Vj-2, Vj-3, e.g., Vj-3a or Vj-3b, or Vj-4, X
8 is –O–, –NMe– or –S–. [1081] In some embodiments, Z is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [1082] In some embodiments, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [1083] In some embodiments of formula Vj-1, Vj-2, Vj-3, e.g., Vj-3a or Vj-3b, or Vj-4 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et. [1084] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula Vj-1, Vj-2, Vj-3, e.g., Vj-3a or Vj-3b, or Vj-4 W is =CH– and the compound is represented by formula Vk-1, Vk-2, Vk-3, e.g., Vk-3a or Vk-3b, or Vk-4
wherein Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; s is 0 or 1.
[1085] In some embodiments of a compound of formula Vk-1, Vk-2, Vk-3, e.g., Vk-3a or Vk- 3b, or Vk-4 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl or C
3-4 cycloalkyl [1086] In some embodiments of a compound of formula Vk-1, Vk-2, Vk-3, e.g., Vk-3a or Vk- 3b, or Vk-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe– , particularly –NH. [1087] In some embodiments of a compound of formula Vk-1, Vk-2, Vk-3, e.g., Vk-3a or Vk- 3b, or Vk-4 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [1088] In some embodiments of the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula Vk-1, Vk-2, Vk-3, e.g., Vk-3a or Vk-3b, or Vk-4 at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above. [1089] In some embodiments of the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula Vk-1, Vk-2, Vk-3, e.g., Vk-3a or Vk-3b, or Vk-4, X
8 is –O–, – NMe– or –S–. [1090] In some embodiments, Z is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C1-4 alkyl or form togehther an oxiranyl;
R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [1091] In some embodiments, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [1092] In some embodiments of formula Vk-1, Vk-2, Vk-3, e.g., Vk-3a or Vk-3b, or Vk-4 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et. [1093] In some embodiments of the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula Vi-1, Vi-2, Vi-3, e.g., Vi-3a or Vi-3b, or Vi-4, X
8 is –O–, –NMe– or –S–. [1094] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula V-1, V-2, V-3 or V-4 is represented by formula Vj-5, Vj-6, Vj-7, Vj-8, Vj-9, Vj-10, e.g., Vj-11, Vj-12, Vj-13, Vj-14 or Vj-5, or Vj-16
wherein
W is =N– or =CH–; Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C1-4 alkyl, e.g., methyl, HCF2, OCH2F or halogen, e.g., F, Cl; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; s is 0 or 1. [1095] In some embodiments of a compound of formula Vj-5, Vj-6, Vj-7, Vj-8, Vj-9, Vj-10, e.g., Vj-11, Vj-12, Vj-13, Vj-14 or Vj-5, or Vj-16 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl or C
3-4 cycloalkyl [1096] In some embodiments of a compound of formula Vj-5, Vj-6, Vj-7, Vj-8, Vj-9, Vj-10, e.g., Vj-11, Vj-12, Vj-13, Vj-14 or Vj-5, or Vj-16 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [1097] In some embodiments of a compound of formula Vj-5, Vj-6, Vj-7, Vj-8, Vj-9, Vj-10, e.g., Vj-11, Vj-12, Vj-13, Vj-14 or Vj-5, or Vj-16 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [1098] In some embodiments of the compound or pharmaceutical acceptable salts or stereoisomers
thereof of formula Vj-5, Vj-6, Vj-7, Vj-8, Vj-9, Vj-10, e.g., Vj-11, Vj-12, Vj-13, Vj-14 or Vj-5, or Vj-16, X
8 is –O–, –NMe– or –S–. [1099] In some embodiments, Z is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [1100] In some embodiments, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [1101] In some embodiments of formula Vj-5, Vj-6, Vj-7, Vj-8, Vj-9, Vj-10, e.g., Vj-11, Vj-12, Vj-13, Vj-14 or Vj-5, or Vj-16 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et. [1102] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers
thereof of formula Vj-5, Vj-6, Vj-7, Vj-8, Vj-9, Vj-10, e.g., Vj-11, Vj-12, Vj-13, Vj-14 or Vj-5, or Vj-16 W is =CH– and the compound is represented by formula Vk-5, Vk-6, Vk-7, Vk-8, Vk-9, Vk-10, e.g., Vk-11, Vk-12, Vk-13, Vk-14 or Vk-5, or Vk-16
wherein
Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C1-4 alkyl, C3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; s is 0 or 1. [1103] In some embodiments of a compound of formula Vk-5, Vk-6, Vk-7, Vk-8, Vk-9, Vk-10, e.g., Vk-11, Vk-12, Vk-13, Vk-14 or Vk-5, or Vk-16 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C1-4 alkyl, C3-4 heterocycloalkyl or C
3-4 cycloalkyl. [1104] In some embodiments of a compound of formula Vk-5, Vk-6, Vk-7, Vk-8, Vk-9, Vk-10, e.g., Vk-11, Vk-12, Vk-13, Vk-14 or Vk-5, or Vk-16 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [1105] In some embodiments of a compound of formula Vk-5, Vk-6, Vk-7, Vk-8, Vk-9, Vk-10, e.g., Vk-11, Vk-12, Vk-13, Vk-14 or Vk-5, or Vk-16 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [1106] In some embodiments of the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula Vk-5, Vk-6, Vk-7, Vk-8, Vk-9, Vk-10, e.g., Vk-11, Vk-12, Vk-13, Vk-14 or
Vk-5, or Vk-16, X
8 is –O–, –NMe– or –S–. [1107] In some embodiments, Z is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [1108] In some embodiments, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [1109] In some embodiments of formula Vk-5, Vk-6, Vk-7, Vk-8, Vk-9, Vk-10, e.g., Vk-11, Vk- 12, Vk-13, Vk-14 or Vk-5, or Vk-16 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et. [1110] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula V-1, V-2, V-3 or V-4 is represented by formula Vl-1 to Vl-25
wherein D1 is
Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
1 is –CH=CH2 or -C≡CMe; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; s is 0 or 1. [1111] In some embodiments of a compound of formula Vl-1 to Vl-25 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3- 4 heterocycloalkyl or C
3-4 cycloalkyl. [1112] In some embodiments of a compound of formula Vl-1 to Vl-25 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [1113] In some embodiments of a compound of formula Vl-1 to Vl-25 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2. [1114] In some embodiments of a compound of formula Vl-1 to Vl-25 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me.
[1115] In some embodiments of a compound of formula Vl-1 to Vl-25 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [1116] In some embodiments of a compound of formula Vl-1 to Vl-25 or pharmaceutically acceptable salts or stereoisomers thereof, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above. [1117] In some embodiments of a compound of formula Vl-1 to Vl-25 or pharmaceutically acceptable salts or stereoisomers thereof, X
8 is –O–, –NMe– or –S–. [1118] In some embodiments, Z in D1 is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle. m is 1, 2 or 3; n is 1 or 2. [1119] In some embodiments, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [1120] In some embodiments of formula Vl-1 to Vl-25 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et. [1121] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula V-1, V-2, V-3 or V-4 is represented by formula Vm-1 to Vm-25
wherein D2 is
Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; s is 0 or 1. [1122] In some embodiments of a compound of formula Vm-1 to Vm-25 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3- 4 heterocycloalkyl or C
3-4 cycloalkyl. [1123] In some embodiments of a compound of formula Vm-1 to Vm-25 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [1124] In some embodiments of a compound of formula Vm-1 to Vm-25 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [1125] In some embodiments of a compound of formula Vm-1 to Vm-25 or pharmaceutically
acceptable salts or stereoisomers thereof, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above. [1126] In some embodiments of a compound of formula Vm-1 to Vm-25 or pharmaceutically acceptable salts or stereoisomers thereof, X
8 is –O–, –NMe– or –S–. [1127] In some embodiments, Z in D2 is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle. m is 1, 2 or 3; n is 1 or 2. [1128] In some embodiments, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [1129] In some embodiments of formula Vm-1 to Vm-25 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et.
[1130] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula V-1, V-2, V-3 or V-4 is represented by formula Vn-1 – Vn-17
wherein D
1 is
Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C1-4 alkyl, C3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
1 is –CH=CH
2 or -C≡CMe; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C1-4 alkyl, e.g., methyl, HCF2, OCH2F or halogen, e.g., F, Cl; s is 0 or 1. [1131] In some embodiments of a compound of formula Vn-1 – Vn-17 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3- 4 heterocycloalkyl or C
3-4 cycloalkyl. [1132] In some embodiments of a compound of formula Vn-1 – Vn-17 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [1133] In some embodiments, R
6 is hydrogen for Vn-5, Vn-7, Vn-8, Vn-9, Vn-11; and R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl, for Vn-1, Vn-2, Vn-3, Vn-4, Vn-6, Vn-10,Vn-14, Vn-15, Vn-16, Vn-17. [1134] In some embodiments of a compound of formula Vn-1 – Vn-17 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2. [1135] In some embodiments of a compound of formula Vn-1 – Vn-17 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me. [1136] In some embodiments of a compound of formula Vn-1 – Vn-17 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered
saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [1137] In some embodiments of a compound of formula Vn-1 – Vn-17 or pharmaceutically acceptable salts or stereoisomers thereof, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above. [1138] In some embodiments, Z in D1 is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle. m is 1, 2 or 3; n is 1 or 2. [1139] In some embodiments, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [1140] In some embodiments of formula Vn-1 – Vn-17 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et.
[1141] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula V-1, V-2, V-3 or V-4 is represented by formula Vo-1 – Vo-17
wherein D
2 is
Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C1-4 alkyl, C3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; s is 0 or 1. [1142] In some embodiments of a compound of formula Vo-1 – Vo-17 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl or C
3-4 cycloalkyl. [1143] In some embodiments of a compound of formula Vo-1 – Vo-17 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [1144] In some embodiments, R
6 is hydrogen for Vo-5, Vo-7, Vo-8, Vo-9, Vo-11; and R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl, for Vo-1, Vo-2, Vo-3, Vo-4, Vo-6, Vo-10, Vo-14, Vo-15, Vo-16, Vo-17. [1145] In some embodiments of a compound of formula Vo-1 – Vo-17 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [1146] In some embodiments of a compound of formula Vo-1 – Vo-17 or pharmaceutically acceptable salts or stereoisomers thereof, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above. [1147] In some embodiments of a compound of formula Vo-1 – Vo-17 or pharmaceutically
acceptable salts or stereoisomers thereof, X
8 is –O–, –NMe– or –S–. [1148] In some embodiments, Z in D2 is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle. m is 1, 2 or 3; n is 1 or 2. [1149] In some embodiments, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [1150] In some embodiments of formula Vo-1 – Vo-17 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et. [1151] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula V-1, V-2, V-3 or V-4 is represented by formula Vn-18 – Vn-51
wherein D
1 is
Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF2 or C3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
1 is –CH=CH
2 or -C≡CMe; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; s is 0 or 1. [1152] In some embodiments of a compound of formula Vn-18 – Vn-51 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1- 4 alkyl, C
3-4 heterocycloalkyl or C
3-4 cycloalkyl. [1153] In some embodiments of a compound of formula Vn-18 – Vn-51 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [1154] In some embodiments, R
6 is hydrogen for Vn-25 to Vn-27, Vn-30 to Vn-35, Vn-38, Vn- 39; and R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl, for Vn-18 to Vn-25, Vn-28, Vn-29, Vn-36, Vn-37, Vn-44 to Vn-51. [1155] In some embodiments of a compound of formula Vn-18 – Vn-51 or pharmaceutically
acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2. [1156] In some embodiments of a compound of formula Vn-18 – Vn-51 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me. [1157] In some embodiments of a compound of formula Vn-18 – Vn-51 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [1158] In some embodiments, Z in D1 is of formula i
wherein R
2 is hydrogen, C1-4 alkyl, CHF2 or C3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle. m is 1, 2 or 3; n is 1 or 2. [1159] In some embodiments, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [1160] In some embodiments of formula Vn-18 – Vn-51 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et. [1161] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula V-1, V-2, V-3 or V-4 is represented by formula Vo-18 – Vo-51
wherein D
2 is
Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF2 or C3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; s is 0 or 1. [1162] In some embodiments of a compound of formula Vo-18 – Vo-51 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3- 4 heterocycloalkyl or C
3-4 cycloalkyl. [1163] In some embodiments of a compound of formula Vo-18 – Vo-51 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [1164] In some embodiments, R
6 is hydrogen for Vo-25 to Vo-27, Vo-30 to Vo-35, Vo-38, Vo- 39; and R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl, for Vo-18 to Vo-25, Vo-28, Vo-29, Vo-36, Vo-37 Vo-44 to Vo-51. [1165] In some embodiments of a compound of formula Vo-18 – Vo-51 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as
described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [1166] In some embodiments of a compound of formula Vo-18 – Vo-51 or pharmaceutically acceptable salts or stereoisomers thereof, X
8 is –O–, –NMe– or –S–. [1167] In some embodiments, Z in D2 is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle. m is 1, 2 or 3; n is 1 or 2. [1168] In some embodiments, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [1169] In some embodiments of formula Vo-18 – Vo-51 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et.
[1170] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula V-1, V-2, V-3 or V-4 is represented by formula Vp-1 – Vp-15
wherein D1 is
Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C1-4 alkyl, C3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl;
X
1 is –NH–, –NMe– or –O–; R
1 is –CH=CH
2 or -C≡CMe; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; s is 0 or 1. [1171] In some embodiments of a compound of formula Vp-1 – Vp-15 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3- 4 heterocycloalkyl or C
3-4 cycloalkyl. [1172] In some embodiments of a compound of formula Vp-1 – Vp-15 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [1173] In some embodiments of a compound of formula Vp-1 – Vp-15 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2. [1174] In some embodiments of a compound of formula Vp-1 – Vp-15 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me. [1175] In some embodiments of a compound of formula Vp-1 – Vp-15 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [1176] In some embodiments of a compound of formula Vp-1 – Vp-15 or pharmaceutically acceptable salts or stereoisomers thereof, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above. [1177] In some embodiments, Z in D1 is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle. m is 1, 2 or 3; n is 1 or 2. [1178] In some embodiments, R
2 is hydrogen, C1-4 alkyl or C3-4 cycloalkyl. [1179] In some embodiments of formula Vp-1 – Vp-15 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et. [1180] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula V-1, V-2, V-3 or V-4 is represented by formula Vq-1 – Vq-15
wherein D2 is
Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–;
R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; s is 0 or 1. [1181] In some embodiments of a compound of formula Vq-1 – Vq-15 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3- 4 heterocycloalkyl or C3-4 cycloalkyl. [1182] In some embodiments of a compound of formula Vq-1 – Vq-15 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [1183] In some embodiments of a compound of formula Vq-1 – Vq-15 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [1184] In some embodiments of a compound of formula Vq-1 – Vq-15 or pharmaceutically acceptable salts or stereoisomers thereof, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above. [1185] In some embodiments of a compound of formula Vq-1 – Vq-15 or pharmaceutically acceptable salts or stereoisomers thereof, X
8 is –O–, –NMe– or –S–. [1186] In some embodiments, Z in D2 is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl;
R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle. m is 1, 2 or 3; n is 1 or 2. [1187] In some embodiments, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [1188] In some embodiments of formula Vq-1 – Vq-15 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et. [1189] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula V-1, V-2, V-3 or V-4 is represented by formula Vp-16 – Vp-45
wherein D1 is
Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF2 or C3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
1 is –CH=CH
2 or -C≡CMe; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; s is 0 or 1. [1190] In some embodiments of a compound of formula Vp-16 – Vp-45 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3- 4 heterocycloalkyl or C
3-4 cycloalkyl. [1191] In some embodiments of a compound of formula Vp-16 – Vp-45 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [1192] In some embodiments of a compound of formula Vp-16 – Vp-45 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2. [1193] In some embodiments of a compound of formula Vp-16 – Vp-45 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me.
[1194] In some embodiments of a compound of formula Vp-16 – Vp-45 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [1195] In some embodiments, Z in D1 is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle. m is 1, 2 or 3; n is 1 or 2. [1196] In some embodiments, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [1197] In some embodiments of formula Vp-16 – Vp-45 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et.
[1198] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula V-1, V-2, V-3 or V-4 is represented by formula Vq-16 – Vq-45
wherein D
2 is
Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF2 or C3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; s is 0 or 1. [1199] In some embodiments of a compound of formula Vq-16 – Vq-45 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3- 4 heterocycloalkyl or C
3-4 cycloalkyl. [1200] In some embodiments of a compound of formula Vq-16 – Vq-45 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [1201] In some embodiments of a compound of formula Vq-16 – Vq-45 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [1202] In some embodiments of a compound of formula Vq-16 – Vq-45 or pharmaceutically
acceptable salts or stereoisomers thereof, X
8 is –O–, –NMe– or –S–. [1203] In some embodiments, Z in D2 is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle. m is 1, 2 or 3; n is 1 or 2. [1204] In some embodiments, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [1205] In some embodiments of formula Vq-16 – Vq-45 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et.
[1206] In some embodiments, the present disclosure provides the compound or pharmaceutical acceptable salts or stereoisomers thereof having formula VI-1, VI-2, VI-3 or VI-4
wherein W is =CH–, =COMe–, =CMe– or =N–; Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
1 is –CH=CH
2 or -C≡CMe; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; X
4 is –O–, –NH–, –NMe–; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–;
L is a covalent bond or linear or branched C
1-3 alkyl. [1207] In some embodiments of a compound of formula VI-1, VI-2, VI-3 or VI-4 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl or C
3-4 cycloalkyl. [1208] In some embodiments, the present disclosure provides the compound or pharmaceutical acceptable salts or stereoisomers thereof having formula VI-2, VI-3 or VI-4. [1209] In some embodiments, the present disclosure provides the compound or pharmaceutical acceptable salts or stereoisomers thereof having formula VI-1. [1210] In some embodiments of a compound of formula VI-1, VI-2, VI-3 or VI-4 or pharmaceutically acceptable salts or stereoisomers thereof, W is =CH–, =CMe– or =COMe–, e.g., =CH– or =COMe–, e.g., =CH–. [1211] In some embodiments of a compound of formula VI-1, VI-2, VI-3 or VI-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly – NH–. In some embodiments, X
1 is –NH– or –NMe–, particularly –NH– and W is =CH–, =CMe– or =COMe–, e.g., =CH– or =COMe–, e.g., =CH–. [1212] In some embodiments of a compound of formula VI-1, VI-2, VI-3 or VI-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH2 and W is =CH–, =CMe– or =COMe–, e.g., =CH– or =COMe–, e.g., =CH–. [1213] In some embodiments of a compound of formula VI-1, VI-2, VI-3 or VI-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me and W is =CH–, =CMe– or =COMe–, e.g., =CH– or =COMe–, e.g., =CH–. [1214] In some embodiments of a compound of formula VI-1, VI-2, VI-3 or VI-4 or pharmaceutically acceptable salts or stereoisomers thereof, W is =N–. [1215] In some embodiments of a compound of formula VI-1, VI-2, VI-3 or VI-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly – NH–. In some embodiments, X
1 is –NH– or –NMe–, particularly –NH– and W is =N–. [1216] In some embodiments of a compound of formula VI-1, VI-2, VI-3 or VI-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2 and W is =N–.
[1217] In some embodiments of a compound of formula VI-1, VI-2, VI-3 or VI-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me and W is =N–. [1218] In some embodiments of a compound of formula VI-1, VI-2, VI-3 or VI-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH2 and X
2 is –NH–, – NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–. [1219] In some embodiments of a compound of formula VI-1, VI-2, VI-3 or VI-4 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [1220] In some embodiments of a compound of formula VI-1, VI-2, VI-3 or VI-4 or pharmaceutically acceptable salts or stereoisomers thereof, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above. [1221] In some embodiments of a compound of formula VI-1, VI-2, VI-3 or VI-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
4 is –O–. [1222] In some embodiments of a compound of formula VI-1, VI-2, VI-3 or VI-4 or pharmaceutically acceptable salts or stereoisomers thereof, L is a covalent bond, –(CH
2)– or – (CH
2)
2–. In some embodiments, X
4 is –O– and L is a covalent bond, –(CH
2)– or –(CH
2)
2–. [1223] In some embodiments of a compound of formula VI-1, VI-2, VI-3 or VI-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
8 is –O–, –NMe– or –S–. [1224] In some embodiments, Z is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C1-4 alkyl or form togehther an oxiranyl;
R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [1225] In some embodiments, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [1226] In some embodiments of formula VI-1, VI-2, VI-3 or VI-4 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et. [1227] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula VI-1, VI-2, VI-3 or VI-4 is represented by formula VIa-1, VIa-2, VIa-3 or VIa- 4
wherein Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
1 is –CH=CH
2 or -C≡CMe; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; X
4 is –O–, –NH–, –NMe–; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; L is a covalent bond or linear or branched C
1-3 alkyl. [1228] In some embodiments of a compound of formula VIa-1, VIa-2, VIa-3 or VIa-4 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated
nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C1-4 alkyl, C3-4 heterocycloalkyl or C3-4 cycloalkyl. [1229] In some embodiments of a compound of formula VIa-1, VIa-2, VIa-3 or VIa-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly – NH. [1230] In some embodiments of a compound of formula VIa-1, VIa-2, VIa-3 or VIa-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2. [1231] In some embodiments of a compound of formula VIa-1, VIa-2, VIa-3 or VIa-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me. [1232] In some embodiments of a compound of formula VIa-1, VIa-2, VIa-3 or VIa-4 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [1233] In some embodiments of a compound of formula VIa-1, VIa-2, VIa-3 or VIa-4 or pharmaceutically acceptable salts or stereoisomers thereof, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above. [1234] In some embodiments of a compound of formula VIa-1, VIa-2, VIa-3 or VIa-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
4 is –O–. [1235] In some embodiments of a compound of formula VIa-1, VIa-2, VIa-3 or VIa-4 or pharmaceutically acceptable salts or stereoisomers thereof, L is a covalent bond, –(CH
2)– or – (CH
2)
2–. In some embodiments, X
4 is –O– and L is a covalent bond, –(CH
2)– or –(CH
2)
2–. [1236] In some embodiments of a compound of formula VIa-1, VIa-2, VIa-3 or VIa-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
8 is –O–, –NMe– or –S–. [1237] In some embodiments, Z is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [1238] In some embdiments, R
2 is hydrogen, C1-4 alkyl or C3-4 cycloalkyl. [1239] In some embodiments of formula VIa-1, VIa-2, VIa-3 or VIa-4 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et. [1240] In some embodiments, the present disclosure provides the compound or pharmaceutical acceptable salts or stereoisomers thereof having formula VI-5, VI-6, VI-7, VI-8, VI-9, VI-10, VI- 11 or VI-12
wherein W is =CH–, =COMe–, =CMe– or =N–; Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
1 is –CH=CH
2 or -C≡CMe; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF3;
R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; X
4 is –O–, –NH–, –NMe–; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; L is a covalent bond or linear or branched C
1-3 alkyl. [1241] In some embodiments of a compound of formula VI-5, VI-6, VI-7, VI-8, VI-9, VI-10, VI- 11 or VI-12 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl or C
3-4 cycloalkyl. [1242] In some embodiments of a compound of formula VI-5, VI-6, VI-7, VI-8, VI-9, VI-10, VI- 11 or VI-12 or pharmaceutically acceptable salts or stereoisomers thereof, W is =CH–, =CMe– or =COMe–, e.g., =CH– or =COMe–, e.g., =CH–. [1243] In some embodiments of a compound of formula VI-5, VI-6, VI-7, VI-8, VI-9, VI-10, VI- 11 or VI-12 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe– , particularly –NH–. In some embodiments, X
1 is –NH– or –NMe–, particularly –NH– and W is =CH–, =CMe– or =COMe–, e.g., =CH– or =COMe–, e.g., =CH–. [1244] In some embodiments of a compound of formula VI-5, VI-6, VI-7, VI-8, VI-9, VI-10, VI- 11 or VI-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2 and W is =CH–. [1245] In some embodiments of a compound of formula VI-5, VI-6, VI-7, VI-8, VI-9, VI-10, VI- 11 or VI-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me and W is =CH–, =CMe– or =COMe–, e.g., =CH– or =COMe–, e.g., =CH–. [1246] In some embodiments of a compound of formula VI-5, VI-6, VI-7, VI-8, VI-9, VI-10, VI- 11 or VI-12 or pharmaceutically acceptable salts or stereoisomers thereof, W is =N–. [1247] In some embodiments of a compound of formula VI-5, VI-6, VI-7, VI-8, VI-9, VI-10, VI- 11 or VI-12 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe– , particularly –NH–. In some embodiments, X
1 is –NH– or –NMe–, particularly –NH– and W is
=N–. [1248] In some embodiments of a compound of formula VI-5, VI-6, VI-7, VI-8, VI-9, VI-10, VI- 11 or VI-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2 and W is =N–. [1249] In some embodiments of a compound of formula VI-5, VI-6, VI-7, VI-8, VI-9, VI-10, VI- 11 or VI-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me and W is =N–. [1250] In some embodiments of a compound of formula VI-5, VI-6, VI-7, VI-8, VI-9, VI-10, VI- 11 or VI-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2 and X
2 is –NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–. [1251] In some embodiments of a compound of formula VI-5, VI-6, VI-7, VI-8, VI-9, VI-10, VI- 11 or VI-12 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [1252] In some embodiments of a compound of formula VI-5, VI-6, VI-7, VI-8, VI-9, VI-10, VI- 11 or VI-12 or pharmaceutically acceptable salts or stereoisomers thereof, X
4 is –O–. [1253] In some embodiments of a compound of formula VI-5, VI-6, VI-7, VI-8, VI-9, VI-10, VI- 11 or VI-12 or pharmaceutically acceptable salts or stereoisomers thereof, L is a covalent bond, – (CH
2)– or –(CH
2)
2–. In some embodiments, X
4 is –O– and L is a covalent bond, –(CH
2)– or – (CH
2)
2–. [1254] In some embodiments of a compound of formula VI-5, VI-6, VI-7, VI-8, VI-9, VI-10, VI- 11 or VI-12 or pharmaceutically acceptable salts or stereoisomers thereof, X
8 is –O–, –NMe– or – S–. [1255] In some embodiments, Z is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [1256] In some embodiments, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [1257] In some embodiments of formula VI-5, VI-6, VI-7, VI-8, VI-9, VI-10, VI-11 or VI-12 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et. [1258] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula VI-5, VI-6, VI-7, VI-8, VI-9, VI-10, VI-11 or VI-12 is represented by formula VIa-5, VIa-6, VIa-7, VIa-8, VIa-9, VIa-10, VIa-11 or VIa-12
wherein Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
1 is –CH=CH
2 or -C≡CMe; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3;
R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; X
4 is –O–, –NH–, –NMe–; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; L is a covalent bond or linear or branched C
1-3 alkyl. [1259] In some embodiments of a compound of formula VIa-5, VIa-6, VIa-7, VIa-8, VIa-9, VIa- 10, VIa-11 or VIa-12 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl or C
3-4 cycloalkyl. [1260] In some embodiments of a compound of formula VIa-5, VIa-6, VIa-7, VIa-8, VIa-9, VIa- 10, VIa-11 or VIa-12 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [1261] In some embodiments of a compound of formula VIa-5, VIa-6, VIa-7, VIa-8, VIa-9, VIa- 10, VIa-11 or VIa-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is – HC=CH
2. [1262] In some embodiments of a compound of formula VIa-5, VIa-6, VIa-7, VIa-8, VIa-9, VIa- 10, VIa-11 or VIa-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C– Me. [1263] In some embodiments of a compound of formula VIa-5, VIa-6, VIa-7, VIa-8, VIa-9, VIa- 10, VIa-11 or VIa-12 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [1264] In some embodiments of a compound of formula VIa-5, VIa-6, VIa-7, VIa-8, VIa-9, VIa- 10, VIa-11 or VIa-12 or pharmaceutically acceptable salts or stereoisomers thereof, X
4 is –O–. [1265] In some embodiments of a compound of formula VIa-5, VIa-6, VIa-7, VIa-8, VIa-9, VIa- 10, VIa-11 or VIa-12 or pharmaceutically acceptable salts or stereoisomers thereof, L is a covalent
bond, –(CH
2)– or –(CH
2)
2–. In some embodiments, X
4 is –O– and L is a covalent bond, –(CH
2)– or –(CH
2)
2–. [1266] In some embodiments of a compound of formula VIa-5, VIa-6, VIa-7, VIa-8, VIa-9, VIa- 10, VIa-11 or VIa-12 or pharmaceutically acceptable salts or stereoisomers thereof, X
8 is –O–, – NMe– or –S–. [1267] In some embodiments, Z is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [1268] In some embodiments, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [1269] In some embodiments of formula VIa-5, VIa-6, VIa-7, VIa-8, VIa-9, VIa-10, VIa-11 or VIa-12 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein
R
2 is hydrogen, Me or Et. [1270] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula VI-1, VI-2, VI-3 or VI-4 is represented by formula VIb-1, VIb-2, VIb-3, VIb- 4, VIc-1, VIc-2, VIc-3 or VIc-4
wherein W is =CH–, =COMe–, =CMe– or =N–; X
1 is –NH–, –NMe– or –O–; X
4 is –O–, –NH–, –NMe–; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=;
X
8’ is –O–, –S–, –NH– or –NMe–; L is a covalent bond or linear or branched C
1-3 alkyl R
1 is –HC=CH
2 or –C≡C–Me R
2 is hydrogen, C1-4 alkyl, CHF2 or C3-4 cycloalkyl; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form together an unsubstituted oxiranyl; R
c, R
d are each independently selected from hydrogen, C1-4 alkyl; m is 1, 2 or 3; n is 1 or 2; r is 1 or 2, e.g., 1. [1271] In some embodiments of a compound of formula VIb-1, VIb-2, VIb-3, VIb-4, VIc-1, VIc- 2, VIc-3 or VIc-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [1272] In some embodiments of a compound of formula VIb-1, VIb-2, VIb-3, VIb-4, VIc-1, VIc- 2, VIc-3 or VIc-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or – NMe–, particularly –NH. [1273] In some embodiments of a compound of formula VIb-1, VIb-2, VIb-3, VIb-4, VIc-1, VIc- 2, VIc-3 or VIc-4 or pharmaceutically acceptable salts or stereoisomers thereof, W is =CH–, =CMe– or =COMe–, e.g., =CH– or =COMe–, e.g., =CH–. [1274] In some embodiments of a compound of formula VIb-1, VIb-2, VIb-3, VIb-4, VIc-1, VIc- 2, VIc-3 or VIc-4 or pharmaceutically acceptable salts or stereoisomers thereof, W is =N–. [1275] In some embodiments of a compound of formula VIb-1, VIb-2, VIb-3, VIb-4, VIc-1, VIc- 2, VIc-3 or VIc-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2. [1276] In some embodiments of a compound of formula VIb-1, VIb-2, VIb-3, VIb-4, VIc-1, VIc- 2, VIc-3 or VIc-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me. [1277] In some embodiments of a compound of formula VIb-1, VIb-2, VIb-3, VIb-4, VIc-1, VIc-
2, VIc-3 or VIc-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or – NMe–, particularly –NH–, and X
2 is –NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–. [1278] In some embodiments of a compound of formula VIb-1, VIb-2, VIb-3, VIb-4, VIc-1, VIc- 2, VIc-3 or VIc-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl. [1279] In some embodiments of a compound of formula VIb-1, VIb-2, VIb-3 or VIb-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
a and R
b are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R
a and R
b are each independently selected from hydrogen, methyl. In some embodiments in which m is 2 or 3, only one R
a and one R
b are not hydrogen and/or only one R
a is not hydrogen. [1280] In some embodiments of a compound of formula VIb-1, VIb-2, VIb-3 or VIb-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
c and R
d are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R
c and R
d are each independently selected from hydrogen, methyl. In some embodiments in which n is 2, only one R
c and one R
c are not hydrogen and/or only one R
c is not hydrogen. [1281] In some embodiments of a compound of formula VIb-1, VIb-2, VIb-3 or VIb-4 or pharmaceutically acceptable salts or stereoisomers thereof, m and n are selected such that a 4, 5 or 6 membered nitrogen containing ring is formed. [1282] In some embodiments of a compound of formula VIb-1, VIb-2, VIb-3, VIb-4, VIc-1, VIc- 2, VIc-3 or VIc-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or – NMe–, particularly –NH–, and R
2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl. [1283] In some embodiments of a compound of formula VIb-1, VIb-2, VIb-3, VIb-4, VIc-1, VIc- 2, VIc-3 or VIc-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
4 is –O–. [1284] In some embodiments of a compound of formula VIb-1, VIb-2, VIb-3, VIb-4, VIc-1, VIc- 2, VIc-3 or VIc-4 or pharmaceutically acceptable salts or stereoisomers thereof, L is a covalent bond, –(CH
2)– or –(CH
2)
2–. In some embodiments, X
4 is –O– and L is a covalent bond, –(CH
2)– or –(CH
2)
2–. [1285] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula VI-1, VI-2, VI-3 or VI-4 is represented by formula VIb-5 to VIb-12, VIc-5 to
VIc-12
wherein W is =CH–, =COMe–, =CMe– or =N–; X
1 is –NH–, –NMe– or –O–; X
4 is –O–, –NH–, –NMe–; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; L is a covalent bond or linear or branched C
1-3 alkyl R
1 is –HC=CH
2 or –C≡C–Me R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF3, HCF2, OCF3, hydroxy, C1-4 alkoxy or C1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form together an unsubstituted oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; m is 1, 2 or 3; n is 1 or 2; r is 1 or 2, e.g., 1. [1286] In some embodiments of a compound of formula VIb-5 to VIb-12, VIc-5 to VIc-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [1287] In some embodiments of a compound of formula VIb-5 to VIb-12, VIc-5 to VIc-12 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly – NH. [1288] In some embodiments of a compound of formula VIb-5 to VIb-12, VIc-5 to VIc-12 or pharmaceutically acceptable salts or stereoisomers thereof, W is =N–. [1289] In some embodiments of a compound of formula VIb-5 to VIb-12, VIc-5 to VIc-12 or pharmaceutically acceptable salts or stereoisomers thereof, W is =CH–, =CMe– or =COMe–, e.g., =CH– or =COMe–, e.g., =CH–.
[1290] In some embodiments of a compound of formula VIb-5 to VIb-12, VIc-5 to VIc-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2. [1291] In some embodiments of a compound of formula VIb-5 to VIb-12, VIc-5 to VIc-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me. [1292] In some embodiments of a compound of formula VIb-5 to VIb-12, VIc-5 to VIc-12 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly – NH–, and X
2 is –NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, – NEt–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–. [1293] In some embodiments of a compound of formula VIb-5 to VIb-12, VIc-5 to VIc-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
2 is hydrogen, methyl, ethyl, n- propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl. [1294] In some embodiments of a compound of formula VIb-5 to VIb-12, VIc-5 to VIc-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
a and R
b are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R
a and R
b are each independently selected from hydrogen, methyl. In some embodiments in which m is 2 or 3, only one R
a and one R
b are not hydrogen and/or only one R
a is not hydrogen. [1295] In some embodiments of a compound of formula VIb-5 to VIb-12, VIc-5 to VIc-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
c and R
d are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R
c and R
d are each independently selected from hydrogen, methyl. In some embodiments in which n is 2, only one R
c and one R
c are not hydrogen and/or only one R
c is not hydrogen. [1296] In some embodiments of a compound of formula VIb-5 to VIb-12, VIc-5 to VIc-12 or pharmaceutically acceptable salts or stereoisomers thereof, m and n are selected such that a 4, 5 or 6 membered nitrogen containing ring is formed. [1297] In some embodiments of a compound of formula VIb-5 to VIb-12, VIc-5 to VIc-12 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly – NH–, and R
2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl. [1298] In some embodiments of a compound of formula VIb-5 to VIb-12, VIc-5 to VIc-12 or pharmaceutically acceptable salts or stereoisomers thereof, X
4 is –O–. [1299] In some embodiments of a compound of VIb-5 to VIb-12, VIc-5 to VIc-12 or
pharmaceutically acceptable salts or stereoisomers thereof, L is a covalent bond, –(CH
2)– or – (CH
2)
2–. In some embodiments, X
4 is –O– and L is a covalent bond, –(CH
2)– or –(CH
2)
2–. [1300] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula VIb-1, VIb-2, VIb-3, VIb-4, VIc-1, VIc-2, VIc-3 or VIc-4, X
4 is –O–, such that the compound is represented by formula VId-1, VId-2, VId-3, VId-4, VIe-1, VIe-2, VIe-3 or VIe- 4
wherein W is =CH–, =COMe–, =CMe– or =N–; X
1 is –NH–, –NMe– or –O–;
X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; L is a covalent bond or linear or branched C
1-3 alkyl R
1 is –HC=CH2 or –C≡C–Me R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form together an unsubstituted oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; m is 1, 2 or 3; n is 1 or 2; r is 1 or 2, e.g., 1. [1301] In some embodiments of a compound of formula VId-1, VId-2, VId-3, VId-4, VIe-1, VIe- 2, VIe-3 or VIe-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [1302] In some embodiments of a compound of formula VId-1, VId-2, VId-3, VId-4, VIe-1, VIe- 2, VIe-3 or VIe-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or – NMe–, particularly –NH. [1303] In some embodiments of a compound of formula VId-1, VId-2, VId-3, VId-4, VIe-1, VIe- 2, VIe-3 or VIe-4 or pharmaceutically acceptable salts or stereoisomers thereof, W is =CH–, =CMe– or =COMe–, e.g., =CH– or =COMe–, e.g., =CH–. [1304] In some embodiments of a compound of formula VId-1, VId-2, VId-3, VId-4, VIe-1, VIe- 2, VIe-3 or VIe-4 or pharmaceutically acceptable salts or stereoisomers thereof, W is =N–. [1305] In some embodiments of a compound of formula VId-1, VId-2, VId-3, VId-4, VIe-1, VIe- 2, VIe-3 or VIe-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2. [1306] In some embodiments of a compound of formula VId-1, VId-2, VId-3, VId-4, VIe-1, VIe- 2, VIe-3 or VIe-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me.
[1307] In some embodiments of a compound of formula VId-1, VId-2, VId-3, VId-4, VIe-1, VIe- 2, VIe-3 or VIe-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl. [1308] In some embodiments of a compound of formula VId-1, VId-2, VId-3, VId-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
a and R
b are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R
a and R
b are each independently selected from hydrogen, methyl. In some embodiments in which m is 2 or 3, only one R
a and one R
b are not hydrogen and/or only one R
a is not hydrogen. [1309] In some embodiments of a compound of formula VId-1, VId-2, VId-3, VId-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
c and R
d are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R
c and R
d are each independently selected from hydrogen, methyl. In some embodiments in which n is 2, only one R
c and one R
c are not hydrogen and/or only one R
c is not hydrogen. [1310] In some embodiments of a compound of formula VId-1, VId-2, VId-3, VId-4 or pharmaceutically acceptable salts or stereoisomers thereof, m and n are selected such that a 4, 5 or 6 membered nitrogen containing ring is formed. [1311] In some embodiments of a compound of formula VId-1, VId-2, VId-3, VId-4, VIe-1, VIe- 2, VIe-3 or VIe-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or – NMe–, particularly –NH–, and R
2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl. [1312] In some embodiments of a compound of formula VId-1, VId-2, VId-3, VId-4, VIe-1, VIe- 2, VIe-3 or VIe-4 or pharmaceutically acceptable salts or stereoisomers thereof, L is a covalent bond, –(CH
2)– or –(CH
2)
2–. [1313] In some embodiments W is =CH– and the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula VI-1, VI-2, VI-3 or VI-4 is represented by formula VIf-1, VIf-2, VIf-3, VIf-4, VIg-1, VIg-2, VIg-3 or VIg-4
wherein X
1 is –NH–, –NMe– or –O–; X
4 is –O–, –NH–, –NMe–; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; L is a covalent bond or linear or branched C
1-3 alkyl R
1 is –HC=CH
2 or –C≡C–Me R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl;
R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form together an unsubstituted oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; m is 1, 2 or 3; n is 1 or 2; r is 1 or 2, e.g., 1. [1314] In some embodiments of a compound of formula VIf-1, VIf-2, VIf-3, VIf-4, VIg-1, VIg-2, VIg-3 or VIg-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
2 is hydrogen, C
1- 4 alkyl or C
3-4 cycloalkyl. [1315] In some embodiments of a compound of formula VIf-1, VIf-2, VIf-3, VIf-4, VIg-1, VIg-2, VIg-3 or VIg-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or – NMe–, particularly –NH. [1316] In some embodiments of a compound of VIf-1, VIf-2, VIf-3, VIf-4, VIg-1, VIg-2, VIg-3 or VIg-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2. [1317] In some embodiments of a compound of VIf-1, VIf-2, VIf-3, VIf-4, VIg-1, VIg-2, VIg-3 or VIg-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me. [1318] In some embodiments of a compound of formula VIf-1, VIf-2, VIf-3, VIf-4, VIg-1, VIg-2, VIg-3 or VIg-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or – NMe–, particularly –NH–, and X
2 is –NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–. [1319] In some embodiments of a compound of formula VIf-1, VIf-2, VIf-3, VIf-4, VIg-1, VIg-2, VIg-3 or VIg-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl. [1320] In some embodiments of a compound of formula VIf-1, VIf-2, VIf-3, VIf-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
a and R
b are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R
a and R
b are
each independently selected from hydrogen, methyl. In some embodiments in which m is 2 or 3, only one R
a and one R
b are not hydrogen and/or only one R
a is not hydrogen. [1321] In some embodiments of a compound of formula VIf-1, VIf-2, VIf-3, VIf-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
c and R
d are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R
c and R
d are each independently selected from hydrogen, methyl. In some embodiments in which n is 2, only one R
c and one R
c are not hydrogen and/or only one R
c is not hydrogen. [1322] In some embodiments of a compound of formula VIf-1, VIf-2, VIf-3, VIf-4 or pharmaceutically acceptable salts or stereoisomers thereof, m and n are selected such that a 4, 5 or 6 membered nitrogen containing ring is formed. [1323] In some embodiments of a compound of formula VIf-1, VIf-2, VIf-3, VIf-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly – NH–, and R
2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl. [1324] In some embodiments of a compound of formula VIf-1, VIf-2, VIf-3, VIf-4, VIg-1, VIg-2, VIg-3 or VIg-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
4 is –O–. [1325] In some embodiments of a compound of formula VIf-1, VIf-2, VIf-3, VIf-4, VIg-1, VIg-2, VIg-3 or VIg-4 or pharmaceutically acceptable salts or stereoisomers thereof, L is a covalent bond, –(CH
2)– or –(CH
2)
2–. In some embodiments, X
4 is –O– and L is a covalent bond, –(CH
2)– or – (CH2)2–. [1326] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula VIb-5 to Vb12, VIc-5 to Vc12, X
4 is –O–, such that the compound is represented by formula VId-5 to VId-12, VIe-5 to VIe-12
wherein W is =CH–, =COMe–, =CMe– or =N–; X
1 is –NH–, –NMe– or –O–; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; L is a covalent bond or linear or branched C
1-3 alkyl R
1 is –HC=CH
2 or –C≡C–Me R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form together an unsubstituted oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; m is 1, 2 or 3; n is 1 or 2; r is 1 or 2, e.g., 1. [1327] In some embodiments of a compound of formula VId-5 to VId-12, VIe-5 to VIe-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [1328] In some embodiments of a compound of formula VId-5 to VId-12, VIe-5 to VIe-12 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly – NH. [1329] In some embodiments of a compound of formula VId-5 to VId-12, VIe-5 to VIe-12 or pharmaceutically acceptable salts or stereoisomers thereof, W is =CH–, =CMe– or =COMe–, e.g., =CH– or =COMe–, e.g., =CH–. [1330] In some embodiments of a compound of formula VId-5 to VId-12, VIe-5 to VIe-12 or pharmaceutically acceptable salts or stereoisomers thereof, W is =N–. [1331] In some embodiments of a compound of VId-5 to VId-12, VIe-5 to VIe-12 or
pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2. [1332] In some embodiments of a compound of formula VId-5 to VId-12, VIe-5 to VIe-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me. [1333] In some embodiments of a compound of formula VId-5 to VId-12, VIe-5 to VIe-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
2 is hydrogen, methyl, ethyl, n- propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl. [1334] In some embodiments of a compound of formula VId-5 to VId-12, VIe-5 to VIe-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
a and R
b are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R
a and R
b are each independently selected from hydrogen, methyl. In some embodiments in which m is 2 or 3, only one R
a and one R
b are not hydrogen and/or only one R
a is not hydrogen. [1335] In some embodiments of a compound of formula VId-5 to VId-12, VIe-5 to VIe-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
c and R
d are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R
c and R
d are each independently selected from hydrogen, methyl. In some embodiments in which n is 2, only one R
c and one R
c are not hydrogen and/or only one R
c is not hydrogen. [1336] In some embodiments of a compound of formula VId-5 to VId-12, VIe-5 to VIe-12 or pharmaceutically acceptable salts or stereoisomers thereof, m and n are selected such that a 4, 5 or 6 membered nitrogen containing ring is formed. [1337] In some embodiments of a compound of formula VId-5 to VId-12, VIe-5 to VIe-12 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly – NH–, and R
2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl. [1338] In some embodiments of a compound of formula VId-5 to VId-12, VIe-5 to VIe-12 or pharmaceutically acceptable salts or stereoisomers thereof, L is a covalent bond, –(CH
2)– or – (CH
2)
2–. [1339] In some embodiments W is =CH– and the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula VI-1, VI-2, VI-3 or VI-4 is represented by formula VIf-5 to VIf- 12, VIg-5, VIg-12
wherein X
1 is –NH–, –NMe– or –O–; X
4 is –O–, –NH–, –NMe–; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; L is a covalent bond or linear or branched C
1-3 alkyl R
1 is –HC=CH
2 or –C≡C–Me R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form together an unsubstituted oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; m is 1, 2 or 3; n is 1 or 2; r is 1 or 2, e.g., 1. [1340] In some embodiments of a compound of formula VIf-5 to VIf-12, VIg-5, VIg-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [1341] In some embodiments of a compound of formula VIf-5 to VIf-12, VIg-5, VIg-12 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly – NH. [1342] In some embodiments of a compound of formula VIf-5 to VIf-12, VIg-5, VIg-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH2. [1343] In some embodiments of a compound of formula VIf-5 to VIf-12, VIg-5, VIg-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me. [1344] In some embodiments of a compound of formula VIf-5 to VIf-12, VIg-5, VIg-12 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –
NH–, and X
2 is –NH–, –NMe–, –NEt–, –NPr–, –NBu–, or –O–, particularly –NH–, –NMe–, – NEt–, or –O–, particularly –NH–, –NMe–, –NEt–, or –O–. [1345] In some embodiments of a compound of formula VIf-5 to VIf-12, VIg-5, VIg-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
2 is hydrogen, methyl, ethyl, n- propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl. [1346] In some embodiments of a compound of formula VIf-5 to VIf-12, VIg-5, VIg-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
a and R
b are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R
a and R
b are each independently selected from hydrogen, methyl. In some embodiments in which m is 2 or 3, only one R
a and one R
b are not hydrogen and/or only one R
a is not hydrogen. [1347] In some embodiments of a compound of formula VIf-5 to VIf-12, VIg-5, VIg-12 or pharmaceutically acceptable salts or stereoisomers thereof, R
c and R
d are each independently selected from hydrogen, methyl, ethyl, n-propyl, n-butyl. In some embodiments, R
c and R
d are each independently selected from hydrogen, methyl. In some embodiments in which n is 2, only one R
c and one R
c are not hydrogen and/or only one R
c is not hydrogen. [1348] In some embodiments of a compound of formula VIf-5 to VIf-12, VIg-5, VIg-12 or pharmaceutically acceptable salts or stereoisomers thereof, m and n are selected such that a 4, 5 or 6 membered nitrogen containing ring is formed. [1349] In some embodiments of a compound of formula VIf-5 to VIf-12, VIg-5, VIg-12 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly – NH–, and R
2 is hydrogen, methyl, ethyl, n-propyl, n-butyl or cyclopropyl, e.g., hydrogen, methyl, ethyl or cyclopropyl. [1350] In some embodiments of a compound of formula VIf-5 to VIf-12, VIg-5, VIg-12 or pharmaceutically acceptable salts or stereoisomers thereof, X
4 is –O–. [1351] In some embodiments of a compound of formula VIf-5 to VIf-12, VIg-5, VIg-12 or pharmaceutically acceptable salts or stereoisomers thereof, L is a covalent bond, –(CH
2)– or – (CH2)2–. In some embodiments, X
4 is –O– and L is a covalent bond, –(CH2)– or –(CH2)2–. [1352] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula VI-1, VI-2, VI-3 or VI-4 is represented by formula Vh-1, Vh-2, Vh-3, e.g., Vh- 3a or Vh-3b, or Vh-4
wherein W is =N– or =CH–; Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
1 is –CH=CH
2 or -C≡CMe; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl;
X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; s is 0 or 1. [1353] In some embodiments of a compound of formula Vh-1, Vh-2, Vh-3, e.g., Vh-3a or Vh-3b, or Vh-4 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl or C
3-4 cycloalkyl. [1354] In some embodiments of a compound of formula Vh-1, Vh-2, Vh-3, e.g., Vh-3a or Vh-3b, or Vh-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [1355] In some embodiments of a compound of formula Vh-1, Vh-2, Vh-3, e.g., Vh-3a or Vh-3b, or Vh-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2. [1356] In some embodiments of a compound of formula Vh-1, Vh-2, Vh-3, e.g., Vh-3a or Vh-3b, or Vh-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me. [1357] In some embodiments of a compound of formula Vh-1, Vh-2, Vh-3, e.g., Vh-3a or Vh-3b, or Vh-4 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [1358] In some embodiments of the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula Vh-1, Vh-2, Vh-3, e.g., Vh-3a or Vh-3b, or Vh-4, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above. [1359] In some embodiments of the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula Vh-1, Vh-2, Vh-3, e.g., Vh-3a or Vh-3b, or Vh-4, X
8 is –O–, –NMe– or –S–. [1360] In some embodiments, Z is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [1361] In some embodiments, R
2 is hydrogen, C1-4 alkyl or C3-4 cycloalkyl. [1362] In some embodiments of formula Vh-1, Vh-2, Vh-3, e.g., Vh-3a or Vh-3b, or Vh-4 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et. [1363] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula VI-1, VI-2, VI-3 or VI-4 W is =CH– and the compound is represented by formula VI-1, VI-2, VI-3, e.g., VI-3a or VI-3b, or VI-4
wherein Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
1 is –CH=CH
2 or -C≡CMe; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=;
X
8’ is –O–, –S–, –NH– or –NMe–; s is 0 or 1. [1364] In some embodiments of a compound of formula VI-1, VI-2, VI-3, e.g., VI-3a or VI-3b, or VI-4 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl or C
3-4 cycloalkyl. [1365] In some embodiments of a compound of formula VI-1, VI-2, VI-3, e.g., VI-3a or VI-3b, or VI-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [1366] In some embodiments of a compound of formula VI-1, VI-2, VI-3, e.g., VI-3a or VI-3b, or VI-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2. [1367] In some embodiments of a compound of formula VI-1, VI-2, VI-3, e.g., VI-3a or VI-3b, or VI-4 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me. [1368] In some embodiments of a compound of formula VI-1, VI-2, VI-3, e.g., VI-3a or VI-3b, or VI-4 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [1369] In some embodiments of the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula VI-1, VI-2, VI-3, e.g., VI-3a or VI-3b, or VI-4, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above. [1370] In some embodiments, Z is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl;
R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [1371] In some embodiments, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [1372] In some embodiments of formula VI-1, VI-2, VI-3, e.g., VI-3a or VI-3b, or VI-4 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et. [1373] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula VI-1, VI-2, VI-3 or VI-4 is represented by formula Vh-5, Vh-6, Vh-7, Vh-8, Vh-9, Vh-10 preferably Vh-11, Vh-12, Vh-13 or Vh-14 Vh-15, or Vh-16
wherein W is =N– or =CH–;
Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C1-4 alkyl, C3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
1 is –CH=CH
2 or -C≡CMe; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C1-4 alkyl, e.g., methyl, HCF2, OCH2F or halogen, e.g., F, Cl; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; s is 0 or 1. [1374] In some embodiments of a compound of formula Vh-5, Vh-6, Vh-7, Vh-8, Vh-9, e.g., Vh- 10, Vh-11, Vh-12 or Vh-13 Vh-14, or Vh-15 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl or C
3-4 cycloalkyl. [1375] In some embodiments of a compound of formula Vh-5, Vh-6, Vh-7, Vh-8, Vh-9, e.g., Vh- 10, Vh-11, Vh-12 or Vh-13 Vh-14, or Vh-15 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [1376] In some embodiments of a compound of formula Vh-5, Vh-6, Vh-7, Vh-8, Vh-9, e.g., Vh- 10, Vh-11, Vh-12 or Vh-13 Vh-14, or Vh-15 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2. [1377] In some embodiments of a compound of formula Vh-5, Vh-6, Vh-7, Vh-8, Vh-9, e.g., Vh- 10, Vh-11, Vh-12 or Vh-13 Vh-14, or Vh-15 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me.
[1378] In some embodiments of a compound of formula Vh-5, Vh-6, Vh-7, Vh-8, Vh-9, e.g., Vh- 10, Vh-11, Vh-12 or Vh-13 Vh-14, or Vh-15 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [1379] In some embodiments of the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula Vh-5, Vh-6, Vh-7, Vh-8, Vh-9, e.g., Vh-10, Vh-11, Vh-12 or Vh-13 Vh-14, or Vh-15, X
8 is –O–, –NMe– or –S–. [1380] In some embodiments, Z is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl. CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [1381] In some emebodiments, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [1382] In some embodiments of formula Vh-5, Vh-6, Vh-7, Vh-8, Vh-9, e.g., Vh-10, Vh-11, Vh- 12 or Vh-13 Vh-14, or Vh-15 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et. [1383] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula VI-1, VI-2, VI-3 or VI-4 W is =CH– and the compound is represented by formula VI-5, VI-6, VI-7, VI-8, VI-9, VI-10, e.g., VI-11 VI-12, VI-13, VI-14 or VI-15, or VI-16
wherein Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4
to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
1 is –CH=CH
2 or -C≡CMe; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; s is 0 or 1. [1384] In some embodiments of a compound of formula VI-5, VI-6, VI-7, VI-8, VI-9, VI-10, e.g., VI-11 VI-12, VI-13, VI-14 or VI-15, or VI-16 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl or C3-4 cycloalkyl. [1385] In some embodiments of a compound of formula VI-5, VI-6, VI-7, VI-8, VI-9, VI-10, e.g., VI-11 VI-12, VI-13, VI-14 or VI-15, or VI-16 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [1386] In some embodiments of a compound of formula VI-5, VI-6, VI-7, VI-8, VI-9, VI-10, e.g., VI-11 VI-12, VI-13, VI-14 or VI-15, or VI-16 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2. [1387] In some embodiments of a compound of formula VI-5, VI-6, VI-7, VI-8, VI-9, VI-10, e.g., VI-11 VI-12, VI-13, VI-14 or VI-15, or VI-16 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me. [1388] In some embodiments of a compound of formula VI-5, VI-6, VI-7, VI-8, VI-9, VI-10, e.g., VI-11 VI-12, VI-13, VI-14 or VI-15, or VI-16 or pharmaceutically acceptable salts or
stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [1389] In some embodiments, Z is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [1390] In some embodiments, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [1391] In some embodiments of formula VI-5, VI-6, VI-7, VI-8, VI-9, VI-10, e.g., VI-11 VI-12, VI-13, VI-14 or VI-15, or VI-16 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et.
[1392] In some embodiments of the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula VI-1, VI-2, VI-3, e.g., VI-3a or VI-3b, or VI-4, X
8 is –O–, –NMe– or –S–. [1393] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula VI-1, VI-2, VI-3 or VI-4 is represented by formula VIj-1, VIj-2, VIj-3, e.g., VIj-3a or VIj-3b, or VIj-4
wherein W is =N– or =CH–; Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF3 and OCF
3;
R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; s is 0 or 1. [1394] In some embodiments of a compound of formula VIj-1, VIj-2, VIj-3, e.g., VIj-3a or VIj- 3b, or VIj-4 or pharmaceutically acceptable salts or stereoisomers thereof , Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C1-4 alkyl, C3-4 heterocycloalkyl or C3-4 cycloalkyl. [1395] In some embodiments of a compound of formula VIj-1, VIj-2, VIj-3, e.g., VIj-3a or VIj- 3b, or VIj-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe– , particularly –NH. [1396] In some embodiments of a compound of formula VIj-1, VIj-2, VIj-3, e.g., VIj-3a or VIj- 3b, or VIj-4 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [1397] In some embodiments of the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula VIj-1, VIj-2, VIj-3, e.g., VIj-3a or VIj-3b, or VIj-4, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above. [1398] In some embodiments of the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula VIj-1, VIj-2, VIj-3, e.g., VIj-3a or VIj-3b, or VIj-4, X
8 is –O–, –NMe– or –S–. [1399] In some embodiments, Z is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [1400] In some embodiments, R
2 is hydrogen, C1-4 alkyl or C3-4 cycloalkyl. [1401] In some embodiments of formula VIj-1, VIj-2, VIj-3, e.g., VIj-3a or VIj-3b, or VIj-4 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et. [1402] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula VIj-1, VIj-2, VIj-3, e.g., VIj-3a or VIj-3b, or VIj-4 W is =CH– and the compound is represented by formula VIk-1, VIk-2, VIk-3, e.g., VIk-3a or VIk-3b, or VIk-4
wherein Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF3, HCF2, OCF3, hydroxy, C1-4 alkoxy or C1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–;
s is 0 or 1. [1403] In some embodiments of a compound of formula VIk-1, VIk-2, VIk-3, e.g., VIk-3a or VIk- 3b, or VIk-4 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl or C
3-4 cycloalkyl. [1404] In some embodiments of a compound of formula VIk-1, VIk-2, VIk-3, e.g., VIk-3a or VIk- 3b, or VIk-4 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe– , particularly –NH. [1405] In some embodiments of a compound of formula VIk-1, VIk-2, VIk-3, e.g., VIk-3a or VIk- 3b, or VIk-4 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [1406] In some embodiments of the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula VIk-1, VIk-2, VIk-3, e.g., VIk-3a or VIk-3b, or VIk-4 at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above. [1407] In some embodiments of the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula VIk-1, VIk-2, VIk-3, e.g., VIk-3a or VIk-3b, or VIk-4, X
8 is –O–, –NMe– or – S–. [1408] In some embodiments, Z is of formula i
wherein R
2 is hydrogen, C1-4 alkyl. CHF2 or C3-4 cycloalkyl;
R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [1409] In some embodiments, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [1410] In some embodiments of formula VIk-1, VIk-2, VIk-3, e.g., VIk-3a or VIk-3b, or VIk-4 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et. [1411] In some embodiments of the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula VI-1, VI-2, VI-3, e.g., VI-3a or VI-3b, or VI-4, X
8 is –O–, –NMe– or –S–. [1412] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula VI-1, VI-2, VI-3 or VI-4 is represented by formula VIj-5, VIj-6, VIj-7, VIj-8, VIj-9, VIj-10, e.g., VIj-11, VIj-12, VIj-13, VIj-14 or VIj-5, or VIj-16
wherein
W is =N– or =CH–; Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C1-4 alkyl, e.g., methyl, HCF2, OCH2F or halogen, e.g., F, Cl; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; s is 0 or 1. [1413] In some embodiments of a compound of formula VIj-5, VIj-6, VIj-7, VIj-8, VIj-9, VIj-10, e.g., VIj-11, VIj-12, VIj-13, VIj-14 or VIj-5, or VIj-16 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl or C
3-4 cycloalkyl. [1414] In some embodiments of a compound of formula VIj-5, VIj-6, VIj-7, VIj-8, VIj-9, VIj-10, e.g., VIj-11, VIj-12, VIj-13, VIj-14 or VIj-5, or VIj-16 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [1415] In some embodiments of a compound of formula VIj-5, VIj-6, VIj-7, VIj-8, VIj-9, VIj-10, e.g., VIj-11, VIj-12, VIj-13, VIj-14 or VIj-5, or VIj-16 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [1416] In some embodiments of the compound or pharmaceutical acceptable salts or stereoisomers
thereof of formula VIj-5, VIj-6, VIj-7, VIj-8, VIj-9, VIj-10, e.g., VIj-11, VIj-12, VIj-13, VIj-14 or VIj-5, or VIj-16, X
8 is –O–, –NMe– or –S–. [1417] In some embodiments, Z is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [1418] In some embodiments, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [1419] In some embodiments of formula VIj-5, VIj-6, VIj-7, VIj-8, VIj-9, VIj-10, e.g., VIj-11, VIj-12, VIj-13, VIj-14 or VIj-5, or VIj-16 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et. [1420] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers
thereof of formula VIj-5, VIj-6, VIj-7, VIj-8, VIj-9, VIj-10, e.g., VIj-11, VIj-12, VIj-13, VIj-14 or VIj-5, or VIj-16 W is =CH– and the compound is represented by formula VIk-5, VIk-6, VIk-7, VIk-8, VIk-9, VIk-10, e.g., VIk-11, VIk-12, VIk-13, VIk-14 or VIk-5, or VIk-16
wherein
Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C1-4 alkyl, C3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; s is 0 or 1. [1421] In some embodiments of a compound of formula VIk-5, VIk-6, VIk-7, VIk-8, VIk-9, VIk- 10, e.g., VIk-11, VIk-12, VIk-13, VIk-14 or VIk-5, or VIk-16 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1- C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C1-4 alkyl, C3-
4 heterocycloalkyl or C
3-4 cycloalkyl. [1422] In some embodiments of a compound of formula VIk-5, VIk-6, VIk-7, VIk-8, VIk-9, VIk- 10, e.g., VIk-11, VIk-12, VIk-13, VIk-14 or VIk-5, or VIk-16 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [1423] In some embodiments of a compound of formula VIk-5, VIk-6, VIk-7, VIk-8, VIk-9, VIk- 10, e.g., VIk-11, VIk-12, VIk-13, VIk-14 or VIk-5, or VIk-16 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [1424] In some embodiments of the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula VIk-5, VIk-6, VIk-7, VIk-8, VIk-9, VIk-10, e.g., VIk-11, VIk-12, VIk-13, VIk-
14 or VIk-5, or VIk-16, X
8 is –O–, –NMe– or –S–. [1425] In some embodiments, Z is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; n is 1 or 2. [1426] In some embodiments, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [1427] In some embodiments of formula VIk-5, VIk-6, VIk-7, VIk-8, VIk-9, VIk-10, e.g., VIk- 11, VIk-12, VIk-13, VIk-14 or VIk-5, or VIk-16 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et. [1428] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula VI-1, VI-2, VI-3 or VI-4 is represented by formula VIl-1 to VIl-25
wherein D1 is
Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
1 is –CH=CH2 or -C≡CMe; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; s is 0 or 1. [1429] In some embodiments of a compound of formula VIl-1 to VIl-25 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3- 4 heterocycloalkyl or C
3-4 cycloalkyl. [1430] In some embodiments of a compound of formula VIl-1 to VIl-25 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [1431] In some embodiments of a compound of formula VIl-1 to VIl-25 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2. [1432] In some embodiments of a compound of formula VIl-1 to VIl-25 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me.
[1433] In some embodiments of a compound of formula VIl-1 to VIl-25 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [1434] In some embodiments of a compound of formula VIl-1 to VIl-25 or pharmaceutically acceptable salts or stereoisomers thereof, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above. [1435] In some embodiments of a compound of formula VIl-1 to VIl-25 or pharmaceutically acceptable salts or stereoisomers thereof, X
8 is –O–, –NMe– or –S–. [1436] In some embodiments, Z in D1 is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle. m is 1, 2 or 3; n is 1 or 2. [1437] In some embodiments, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [1438] In some embodiments of formula VIl-1 to VIl-25 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et. [1439] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula VI-1, VI-2, VI-3 or VI-4 is represented by formula VIm-1 to VIm-25
wherein D2 is
Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; X
5, X
5’, X
6, X
6’, X
7, X
8, X
9, X
9’ are independently of each other –N= or –CH=; X
8’ is –O–, –S–, –NH– or –NMe–; s is 0 or 1. [1440] In some embodiments of a compound of formula VIm-1 to VIm-25 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3- 4 heterocycloalkyl or C
3-4 cycloalkyl. [1441] In some embodiments of a compound of formula VIm-1 to VIm-25 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [1442] In some embodiments of a compound of formula VIm-1 to VIm-25 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [1443] In some embodiments of a compound of formula VIm-1 to VIm-25 or pharmaceutically
acceptable salts or stereoisomers thereof, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above. [1444] In some embodiments of a compound of formula VIm-1 to VIm-25 or pharmaceutically acceptable salts or stereoisomers thereof, X
8 is –O–, –NMe– or –S–. [1445] In some embodiments, Z in D2 is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle. m is 1, 2 or 3; n is 1 or 2. [1446] In some embodiments, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [1447] In some embodiments of formula VIm-1 to VIm-25 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et.
[1448] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula VI-1, VI-2, VI-3 or VI-4 is represented by formula VIn-1 – VIn-17
wherein D
1 is
Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C1-4 alkyl, C3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
1 is –CH=CH
2 or -C≡CMe; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C1-4 alkyl, e.g., methyl, HCF2, OCH2F or halogen, e.g., F, Cl; s is 0 or 1. [1449] In some embodiments of a compound of formula VIn-1 – VIn-17 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3- 4 heterocycloalkyl or C
3-4 cycloalkyl. [1450] In some embodiments of a compound of formula VIn-1 – VIn-17 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [1451] In some embodiments, R
6 is hydrogen for VIn-5, VIn-7, VIn-8, VIn-9, VIn-11; and R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl, for VIn-1, VIn-2, VIn-3, VIn-4, VIn-6, VIn-10,VIn-14, VIn-15, VIn-16, VIn-17. [1452] In some embodiments of a compound of formula VIn-1 – VIn-17 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2. [1453] In some embodiments of a compound of formula VIn-1 – VIn-17 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me. [1454] In some embodiments of a compound of formula VIn-1 – VIn-17 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered
saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [1455] In some embodiments of a compound of formula VIn-1 – VIn-17 or pharmaceutically acceptable salts or stereoisomers thereof, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above. [1456] In some embodiments, Z in D1 is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle. m is 1, 2 or 3; n is 1 or 2. [1457] In some embodiments, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [1458] In some embodiments of formula VIn-1 – VIn-17 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et.
[1459] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula VI-1, VI-2, VI-3 or VI-4 is represented by formula VIo-1 – VIo-17
wherein D
2 is
Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C1-4 alkyl, C3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; s is 0 or 1. [1460] In some embodiments of a compound of formula VIo-1 – VIo-17 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3- 4 heterocycloalkyl or C
3-4 cycloalkyl. [1461] In some embodiments of a compound of formula VIo-1 – VIo-17 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [1462] In some embodiments, R
6 is hydrogen for VIo-5, VIo-7, VIo-8, VIo-9, VIo-11; and R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl, for VIo-1, VIo-2, VIo-3, VIo-4, VIo-6, VIo-10, VIo-14, VIo-15, VIo-16, VIo-17. [1463] In some embodiments of a compound of formula VIo-1 – VIo-17 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [1464] In some embodiments of a compound of formula VIo-1 – VIo-17 or pharmaceutically acceptable salts or stereoisomers thereof, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above. [1465] In some embodiments of a compound of formula VIo-1 – VIo-17 or pharmaceutically
acceptable salts or stereoisomers thereof, X
8 is –O–, –NMe– or –S–. [1466] In some embodiments, Z in D2 is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle. m is 1, 2 or 3; n is 1 or 2. [1467] In som emebodiments, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [1468] In some embodiments of formula VIo-1 – VIo-17 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et. [1469] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula VI-1, VI-2, VI-3 or VI-4 is represented by formula VIn-18 – VIn-51
wherein D
1 is
Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF2 or C3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
1 is –CH=CH
2 or -C≡CMe; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; s is 0 or 1. [1470] In some embodiments of a compound of formula VIn-18 – VIn-51 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3- 4 heterocycloalkyl or C
3-4 cycloalkyl. [1471] In some embodiments of a compound of formula VIn-18 – VIn-51 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [1472] In some embodiments, R
6 is hydrogen for VIn-25 to VIn-27, VIn-30 to VIn-35, VIn-38, VIn-39; and R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl, for VIn- 18 to VIn-25, VIn-28, VIn-29, VIn-36, VIn-37, VIn-44 to VIn-51. [1473] In some embodiments of a compound of formula VIn-18 – VIn-51 or pharmaceutically
acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2. [1474] In some embodiments of a compound of formula VIn-18 – VIn-51 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me. [1475] In some embodiments of a compound of formula VIn-18 – VIn-51 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [1476] In some embodiments, Z in D1 is of formula i
wherein R
2 is hydrogen, C1-4 alkyl, CHF2 or C3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle. m is 1, 2 or 3; n is 1 or 2. [1477] In some embodiments, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [1478] In some embodiments of formula VIn-18 – VIn-51 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et. [1479] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula VI-1, VI-2, VI-3 or VI-4 is represented by formula VIo-18 – VIo-51
wherein D
2 is
Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF2 or C3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; s is 0 or 1. [1480] In some embodiments of a compound of formula VIo-18 – VIo-51 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3- 4 heterocycloalkyl or C
3-4 cycloalkyl. [1481] In some embodiments of a compound of formula VIo-18 – VIo-51 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [1482] In some embodiments, R
6 is hydrogen for VIo-25 to VIo-27, VIo-30 to VIo-35, VIo-38, VIo-39; and R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl, for VIo- 18 to VIo-25, VIo-28, VIo-29, VIo-36, VIo-37, VIo-44 to VIo-51. [1483] In some embodiments of a compound of formula VIo-18 – VIo-51 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as
described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [1484] In some embodiments of a compound of formula VIo-18 – VIo-51 or pharmaceutically acceptable salts or stereoisomers thereof, X
8 is –O–, –NMe– or –S–. [1485] In some embodiments, Z in D2 is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle. m is 1, 2 or 3; n is 1 or 2. [1486] In some embodiments of formula VIo-18 – VIo-51 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et. [1487] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers
thereof of formula VI-1, VI-2, VI-3 or VI-4 is represented by formula VIp-1 – VIp-15
wherein D1 is
Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–;
R
1 is –CH=CH
2 or -C≡CMe; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF3, HCF2, OCF3, hydroxy, C1-4 alkoxy or C1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; s is 0 or 1. [1488] In some embodiments of a compound of formula VIp-1 – VIp-15 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C1-4 alkyl, C3-
4 heterocycloalkyl or C
3-4 cycloalkyl. [1489] In some embodiments of a compound of formula VIp-1 – VIp-15 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [1490] In some embodiments of a compound of formula VIp-1 – VIp-15 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2. [1491] In some embodiments of a compound of formula VIp-1 – VIp-15 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me. [1492] In some embodiments of a compound of formula VIp-1 – VIp-15 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [1493] In some embodiments of a compound of formula VIp-1 – VIp-15 or pharmaceutically acceptable salts or stereoisomers thereof, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above. [1494] In some embodiments, Z in D1 is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle. m is 1, 2 or 3; n is 1 or 2. [1495] In some embodiments, R
2 is hydrogen, C1-4 alkyl or C3-4 cycloalkyl. [1496] In some embodiments of formula VIp-1 – VIp-15 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et. [1497] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula VI-1, VI-2, VI-3 or VI-4 is represented by formula VIq-1 – VIq-15
wherein D2 is
Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF
2 or C
3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–;
R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; s is 0 or 1. [1498] In some embodiments of a compound of formula VIq-1 – VIq-15 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3- 4 heterocycloalkyl or C3-4 cycloalkyl. [1499] In some embodiments of a compound of formula VIq-1 – VIq-15 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [1500] In some embodiments of a compound of formula VIq-1 – VIq-15 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [1501] In some embodiments of a compound of formula VIq-1 – VIq-15 or pharmaceutically acceptable salts or stereoisomers thereof, at least one, at least two, e.g., two, substituents of R
3, R
4, R
3’, R
4’, R
5 are hydrogen, while the remaining are as defined above. [1502] In some embodiments of a compound of formula VIq-1 – VIq-15 or pharmaceutically acceptable salts or stereoisomers thereof, X
8 is –O–, –NMe– or –S–. [1503] In some embodiments, Z in D2 is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl;
R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle. m is 1, 2 or 3; n is 1 or 2. [1504] In some embodiments, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [1505] In some embodiments of formula VIq-1 – VIq-15 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et. [1506] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula VI-1, VI-2, VI-3 or VI-4 is represented by formula VIp-16 – VIp-45
wherein D1 is
Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF2 or C3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
1 is –CH=CH
2 or -C≡CMe; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; s is 0 or 1. [1507] In some embodiments of a compound of formula VIp-16 – VIp-45 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3- 4 heterocycloalkyl or C
3-4 cycloalkyl. [1508] In some embodiments of a compound of formula VIp-16 – VIp-45 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [1509] In some embodiments of a compound of formula VIp-16 – VIp-45 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –HC=CH
2. [1510] In some embodiments of a compound of formula VIp-16 – VIp-45 or pharmaceutically acceptable salts or stereoisomers thereof, R
1 is –C≡C–Me.
[1511] In some embodiments of a compound of formula VIp-16 – VIp-45 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [1512] In some embodiments, Z in D1 is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle. m is 1, 2 or 3; n is 1 or 2. [1513] In some embodiments, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [1514] In some embodiments of formula VIp-16 – VIp-45 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et.
[1515] In some embodiments, the compound or pharmaceutical acceptable salts or stereoisomers thereof of formula VI-1, VI-2, VI-3 or VI-4 is represented by formula VIq-16 – VIq-45
wherein D2 is
Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3-4 heterocycloalkyl, CHF2 or C3-4 cycloalkyl; X
1 is –NH–, –NMe– or –O–; R
3, R
4, R
3’, R
4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF
3 and OCF
3; R
5 is hydrogen, halogen, e.g., F or Cl, CF
3, HCF
2, OCF
3, hydroxy, C
1-4 alkoxy or C
1-4 alkylhydroxyl; R
6 is hydrogen, C
1-4 alkyl, e.g., methyl, HCF
2, OCH
2F or halogen, e.g., F, Cl; s is 0 or 1. [1516] In some embodiments of a compound of formula VIq-16 – VIq-45 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R
1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C
1-4 alkyl, C
3- 4 heterocycloalkyl or C
3-4 cycloalkyl. [1517] In some embodiments of a compound of formula VIq-16 – VIq-45 or pharmaceutically acceptable salts or stereoisomers thereof, X
1 is –NH– or –NMe–, particularly –NH. [1518] In some embodiments of a compound of formula VIq-16 – VIq-45 or pharmaceutically acceptable salts or stereoisomers thereof, Z is a 4 to 6 membered saturated nitrogen heterocycle as described above containing 1 or 2 nitrogen atoms, e.g., 1 nitrogen atom or Z is a 5 to 8 membered saturated nitrogen heterobicycle as described above containing 1 or 2 nitrogen atoms. [1519] In some embodiments of a compound of formula VIq-16 – VIq-45 or pharmaceutically
acceptable salts or stereoisomers thereof, X
8 is –O–, –NMe– or –S–. [1520] In some embodiments, Z in D2 is of formula i
wherein R
2 is hydrogen, C
1-4 alkyl, CHF
2 or C
3-4 cycloalkyl; R
a, R
b are each independently selected from hydrogen, C
1-4 alkyl or form togehther an oxiranyl; R
c, R
d are each independently selected from hydrogen, C
1-4 alkyl; or one of R
a and R
b and one of R
c and R
d form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle. m is 1, 2 or 3; n is 1 or 2. [1521] In some embodiments, R
2 is hydrogen, C
1-4 alkyl or C
3-4 cycloalkyl. [1522] In some embodiments of formula VIq-16 – VIq-45 or pharmaceutically acceptable salts or stereoisomers thereof Z is selected from
wherein R
2 is hydrogen, Me or Et. [1523] In some embodiments, the compound is selected from the compounds described in Tables I and II, pharmaceutically acceptable salts thereof, and stereoisomers thereof. [1524] In some embodiments, the compound is selected from the compounds described in Tables
I and II and pharmaceutically acceptable salts thereof. [1525] In some embodiments, the compound is selected from the compounds described in Tables I and II. [1526] In some embodiments, the compound is selected from the compounds described in Table I, pharmaceutically acceptable salts thereof, and stereoisomers thereof. [1527] In some embodiments, the compound is selected from the compounds described in Table I and pharmaceutically acceptable salts thereof. [1528] In some embodiments, the compound is selected from the compounds described in Table I. [1529] In some embodiments, the compound is selected from the compounds described in Table II, pharmaceutically acceptable salts thereof, and stereoisomers thereof. [1530] In some embodiments, the compound is selected from the compounds described in Table II and pharmaceutically acceptable salts thereof. [1531] In some embodiments, the compound is selected from the compounds described in Table II. Table I
[1532] The compounds of the present disclosure can contain one or more asymmetric centers in the molecule. A compound without designation of the stereochemistry is to be understood to include all the optical isomers (e.g., diastereomers, enantiomers, etc) in pure or substantially pure form, as well as mixtures thereof (e.g. a racemic mixture, or an enantiomerically enriched mixture). It is well known in the art how to prepare such optically active forms (e.g. by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, by chromatographic separation using a chiral stationary phase, and other methods). [1533] The compounds can be isotopically-labeled compounds, for example, compounds including various isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, iodine, or chlorine. The disclosed compounds may exist in tautomeric forms and mixtures and separate individual tautomers are contemplated. In addition, some compounds may exhibit polymorphism. [1534] The compounds of the present disclosure include the free form as well as the
pharmaceutically acceptable salts and stereoisomers thereof. The pharmaceutically acceptable salts include all the typical pharmaceutically acceptable salts. The pharmaceutically acceptable salts of the present compounds can be synthesized from the compounds of this invention which contain a basic or acidic moiety by conventional chemical methods, see e.g. Berge et al, "Pharmaceutical Salts," J. Pharm. ScL, 1977:66:1-19. [1535] For example, conventional pharmaceutically acceptable salts for a basic compound include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like, as well as salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like. Conventional pharmaceutically acceptable salts for an acidic compound include those derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine caffeine, choline, N
,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine tripropylamine, tromethamine and the like. [1536] The compounds of the present disclosure may exist in solid, i.e. crystalline or noncrystalline form (optionally as solvates) or liquid form. In the solid state, it may exist in, or as a mixture thereof. In crystalline solvates, solvent molecules are incorporated into the crystalline lattice during crystallization. The formation of solvates may include non-aqueous solvents such as, but not limited to, ethanol, isopropanol, DMSO, acetic acid, ethanolamine, or ethyl acetate, or aqueous solvents such as water (also called “hydrates”). It is common knowledge that crystalline forms (and solvates thereof) may exhibit polymorphism, i.e. exist in different crystalline structures known as "polymorphs”, that have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state.
Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties, and may display different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. Such different polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, during preparation of the compound of the present disclosure. Syntheses of Compounds [1537] In some aspects, the present disclosure provides methods of preparation of the compounds of the present disclosure. Typically, they are prepared according to the syntheses shown in schemes A to D in the experimental section. [1538] In some embodiments, the present disclosure provides a method of preparing a compound of the present disclosure. [1539] In some embodiments, the present disclosure provides a method of a compound, comprising one or more steps as described herein. [1540] In some embodiments, the present disclosure provides a compound obtainable by, or obtained by, or directly obtained by a method for preparing a compound as described herein. [1541] In some embodiments, the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein. [1542] The compounds of the present disclosure can be prepared by any suitable technique known in the art. Processes for the preparation of these compounds are described in the accompanying examples. [1543] In the description of the synthetic methods described herein and in any referenced synthetic methods that are used to prepare the starting materials, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be selected by a person skilled in the art. [1544] It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions utilized. [1545] It will be appreciated that during the synthesis of the compounds of the disclosure in the processes defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituent groups to prevent their undesired reaction. The skilled chemist will
appreciate when such protection is required, and how such protecting groups may be put in place, and later removed. For examples of protecting groups see one of the many general texts on the subject, for example, ‘Protective Groups in Organic Synthesis’ by Theodora Green (publisher: John Wiley & Sons). Protecting groups may be removed by any convenient method described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with the minimum disturbance of groups elsewhere in the molecule. Thus, if reactants include, for example, groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein. [1546] As will be understood by the person skilled in the art of organic synthesis, compounds of the present disclosure are readily accessible by various synthetic routes, some of which are exemplified in the accompanying examples. The skilled person will easily recognize which kind of reagents and reactions conditions are to be used and how they are to be applied and adapted in any particular instance – wherever necessary or useful – in order to obtain the compounds of the present disclosure. In some embodiments, some of the compounds of the present disclosure can readily be synthesised by reacting other compounds of the present disclosure under suitable conditions, for instance, by converting one particular functional group being present in a compound of the present disclosure, or a suitable precursor molecule thereof, into another one by applying standard synthetic methods, like reduction, oxidation, addition or substitution reactions; those methods are well known to the skilled person. Likewise, the skilled person will apply – whenever necessary or useful – synthetic protecting (or protective) groups; suitable protecting groups as well as methods for introducing and removing them are well-known to the person skilled in the art of chemical synthesis and are described, in more detail, in, e.g., P.G.M. Wuts, T.W. Greene, “Greene’s Protective Groups in Organic Synthesis”, 4th edition (2006) (John Wiley & Sons). [1547] General routes for the preparation of a compound of the application are described in the general procedures A-C: General Procedure A
[1548] Step A.1: To a solution of XIII (1.00 eq) in isopropyl alcohol was added H
2X
1-Y (1.00 eq) dropwise. The mixture was stirred at 90 °C for 1 h. The mixture was concentrated to give crude product. The crude product was washed with ethyl acetate and filtered. The filter cake was dried to give XIV. [1549] Step A.2: [1550] Variant i: To a solution of XIV (1.00 eq), BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H (1.20 -1.50 eq) and cesium carbonate (2.00 eq) in dioxane was added (2-dicyclohexylphosphino-3,6-dimethoxy- 2,4,6-triisopropyl-1,1-biphenyl)-2-(2-amino-1,1-biphenyl)palladium(II) methanesulfonate (0.100 eq) in one portion under nitrogen. The mixture was stirred at 90 °C for 12 h. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine and dried over sodium sulfate, filtered and concentrated to give crude product. The residue was purified by silica gel chromatography to give the Boc-protected derivative of XV, which was dissolved in EtOAc/HCl (4M). The mixture was stirred at 20 °C for 1 h. The mixture was concentrated to give crude product. The residue was purified by reverse-phase chromatography and concentrated to give XV. [1551] Variant ii: To a solution of XIV (1.00 eq), BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H (1.20 -1.50 eq) and cesium carbonate (2.00 eq) in dioxane was added (2-dicyclohexylphosphino-3,6-dimethoxy- 2,4,6-triisopropyl-1,1-biphenyl)-2-(2-amino-1,1-biphenyl)palladium(II) methanesulfonate (0.100 eq) in one portion under nitrogen. The mixture was stirred at 90 °C for 12 h. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with
brine and dried over sodium sulfate, filtered and concentrated to give crude product. The residue was purified by silica gel chromatography to give the Boc-protected derivative of XV, which was dissolved in dichloromethane and a trifluoroacetic acid (excess) was added. The mixture was stirred at 20 °C for 1 h and concentrated to give XV. [1552] Variant iii: NaH (2.6 eq) was added to a solution of BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H in DMF at 0 °C. After 0,5 h, XIV (1 eq) was added at rt and the mixture was stirred for 25 h. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine and dried over sodium sulfate, filtered and concentrated to give crude product. The residue was purified by silica gel chromatography to give the Boc-protected derivative of XV, which was dissolved in dichloromethane and a trifluoroacetic acid (excess) was added. The mixture was stirred at 20 °C for 1 h and concentrated to give XV. [1553] Step A.3: To a solution of XV (1.00 eq) and triethylamine (3.00 eq) in dimethyformamide was added R
1COCl (1.20 eq) dropwise. The mixture was stirred at 20 °C for 2 h. The mixture was filtered and the filtrate was purified by prep-HPLC and lyophilized to give XVI. General Procedure B
[1554] Step B.1: A mixture of VIII (1.00 eq) and H
2NX
1 (1.00 eq) in isopropanol or MeCN was stirred at 90 °C for 2 h. After the reaction was completed, the mixture was filtered and the filter cake was dried to give XVI. [1555] Step B.2:
[1556] Variant i: A mixture of XVI (1.00 eq), BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, brettphos-Pd-G3 (0.100 eq) and sodium tert-butoxide (2.00 eq) in dioxane was stirred at 90 °C under nitrogen atmosphere for 10 hours. After the reaction was completed, the mixture was filtered and the filtrate was purified by prep-HPLC to give Boc-protected derivative of XVII, which was dissolved in ethyl acetate and a solution of hydrochloric acid in ethyl acetate (4 M, excess of up to 200 eq). The mixture was stirred at 10 °C for 0.5 h and concentrated to XVII (hydrochloride). [1557] Variant ii: A mixture of XVI (1.00 eq), BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, brettphos-Pd-G3 (0.100 eq) and sodium tert-butoxide (2.00 eq) in dioxane was stirred at 90 °C under nitrogen atmosphere for 10 hours. After the reaction was completed, the mixture was filtered and the filtrate was purified by prep-HPLC to give Boc-protected derivative of XVII, which was dissolved in dichloromethane and a trifluoroacetic acid (excess) was added. The mixture was stirred at 20 °C for 1 h and concentrated to afford XVII (TFA). [1558] Variant iii: A mixture of XVI (1.00 eq), and N,N-diisopropylethylamine ( 3 eq) in isopropyl alcohol (8.00 mL) was added BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H. The mixture was stirred at 90 °C for 12 h. The mixture was concentrated to give Boc-protected derivative of XVII, which was dissolved in ethyl acetate and a solution of hydrochloric acid in ethyl acetate (4 M, excess of up to 200 eq). The mixture was stirred at 10 °C for 0.5 h and concentrated to XVII (hydrochloride). [1559] Variant iv: A mixture of XVI (1.00 eq), and N,N-diisopropylethylamine ( 3 eq) in isopropyl alcohol (8.00 mL) was added BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H. The mixture was stirred at 90 °C for 12 h. The mixture was concentrated to give Boc-protected derivative of XVII, which was dissolved in dichloromethane and a trifluoroacetic acid (excess) was added. The mixture was stirred at 20 °C for 1 h and concentrated to XVII (TFA). [1560] Variant v: To a solution of XVI (1.00 eq), in THF was added NaH (2.5 eq) at 0°C. After 0.5 h, BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H was added The mixture was stirred at 0 °C for 2.5 h. The mixture was quenched with water and exacted with ethyl acetate. The organic layer was separated and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under vacuum to give a residue which was purified by column chromatography to give Boc-protected derivative of XVII, which was dissolved in dichloromethane and a trifluoroacetic acid (excess) was added. The mixture was stirred at 20 °C for 1 h and concentrated to XVII (TFA). [1561] Variant vi: A mixture of XVI (1.00 eq), and N,N-diisopropylethylamine ( 3 eq) in isopropyl alcohol (8.00 mL) was added BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H. The mixture was stirred at 90 °C for
12 h. The mixture was concentrated to give Boc-protected derivative of XVII, which was dissolved in dichloromethane and TBSOTf and 2,6 lutidine was added. After 1 h the mixture was concentrated to give XVII. [1562] Step B.3: [1563] Variant i: A mixture of XVII (hydrochloride/TFA, 1.00 eq), pyridine (6.00 eq), acrylic acid (1.50 eq) and carbodiimide hydrochloride (2.00 eq) in dimethyformamide was stirred at 10 °C for 9 h. After the reaction was completed, the mixture was filtered and the filtrate was purified by prep-HPLC and lyophilized to give XVIII. [1564] Vairiant ii: To a solution of XVII (1.00 eq) and triethylamine (3.00 eq) in dimethyl formamide was added acrylic anhydride (1.50 eq) dropwise at 20 °C. The mixture was stirred at 20 °C for 0.5 h. The mixture was filtered and the filtrate was purified by prep-HPLC and lyophilized to give XVIII. [1565] Variant iii: To a solution of XVII (1 eq, HCl), acrylic acid (1.2 eq) and pyridine (5 eq) in dimethyl formamide was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (3 eq) at 25 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was filtered. The filtrate was purified by prep-HPLC and lyophilized to give XVIII. [1566] Step B.4: To a solution of XVI (1.00 eq) and R
1C(O- N[(CR
aR
b)
m(CR
cR
d)
n]-X
2H in isopropyl alcohol (3.00 mL) was added N,N-diisopropylethylamine (4.00 eq) dropwise. The mixture was stirred at 90 °C for 12 h. The mixture was concentrated to give crude product. The crude product was purified by prep-HPLC and lyophilized to give XVIII. General Procedure C
[1567] Step C.1: [1568] Variant i: To a solution of 6-chloro-3-nitropicolinamide IX in tetrahydrofuran, DMSO or DMF was added BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H and a base (3.0 eq) (trimethylamine, DIPEA, tBuOK, CsCO
3 or K
2CO
3). The mixture was stirred at 25 °C - 100 °C for 1-12 h. The mixture was concentrated. The residue was purified by silica gel chromatography to give XIX. [1569] Variant ii: A solution of BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H in tetrahydrofuran (10 mL) and NaH (1.3 eq) was stirred at 15 °C for 30 min, before 6-chloro-3-nitropicolinamide IX in THF was added and stirred at 15 °C for 4 h. The mixture was stirred at 15 °C for 30 h. The mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatographyto give XIX. [1570] Step C.2: [1571] Variant i: A solution of XIX (1.00 eq) in methanolwas added Pd/C. The mixture was stirred at 20 °C under hydrogen (15 Psi) for 12 h. The mixture was filtered. The filtrate was concentrated to give XX. [1572] Variant ii: A mixture of XIX (1.00 eq), iron powder (3.00 eq), ammonium chloride (5.00 eq) in methanol and water was stirred at 80 °C for 1 h. The reaction mixture was poured into
methanol and stirred for 10 min, filtered and the filtrate was concentrate to give a residue. The residue was poured into water and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give XX. [1573] Step C.3: A solution of XX (1.00 eq) in triethoxymethane was stirred at 150 °C for 2 h. The mixture was concentrated. The residue was purified by reversed phase column to give XXI. [1574] Step C.4: To a solution of XXI (1.00 eq) in toluene was added Phosphorus(V) oxychloride (1.50 eq) and N,N-diisopropylethylamine (2.00 eq). The mixture was stirred at 100 °C for 2 h. The mixture was quenched with saturated sodium bicarbonate, extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give XXII. [1575] Step C.5: To a solution of XXII (1.00 eq) in 2-propanol or MeCN was added H2X
2-Y. Optionally, 0.01 to 0.5 eq of HCl or TFA was added. The mixture was stirred at 24 °C - 90 °C for 2 h. The mixture was concentrated to give a residue. The residue was purified by silica gel chromatography to give XXIII. [1576] Step C.6: [1577] Variant i: A solution of XXII (1.00 eq) in hydrochloric acid/ethyl acetate (4 M, excess) or HCl/MeOH (4 M, excess) was stirred at 20 °C for 1 h. The mixture was concentrated to give XXIV. [1578] Variant ii: To a solution of XXII (1.00 eq) in DCM, TFA (excess) was added and the mixture was stirred at 20 °C for 1 h. The mixture was concentrated to give XXIV. [1579] Step C.7: To a solution of XXIV (1.00 eq) in dimethyl formamide was added triethylamine (2.00 eq) and acrylic acid (1.00 eq). The mixture was stirred at 20 °C for 0.5 h. The mixture was filtered. The filtrate was purified by Prep-HPLC to give XXV. [1580] In some aspects, the disclosure also provides methods of preparation of the compounds of the disclosure. Typically, they are prepared according to the syntheses shown in the experimental section, particularly according to general procedure A, B and/or C. [1581] It is to be understood that the synthetic processes of the disclosure can tolerate a wide variety of functional groups, therefore various substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a
pharmaceutically acceptable salt thereof. [1582] It is to be understood that compounds of the present disclosure can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or which will be apparent to the skilled artisan in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as Smith, M. B., March, J., March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5
th edition, John Wiley & Sons: New York, 2001; Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3
rd edition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), incorporated by reference herein, are useful and recognised reference textbooks of organic synthesis known to those in the art Pharmaceutical Compositions [1583] In some aspects, the present disclosure provides a pharmaceutical composition comprising a therapeutically-effective amount of one or more of the compounds of the present disclosure or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers and/or excipients (also referred to as diluents). The excipients are acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof (i.e., the patient). The term "therapeutically-effective amount" as used herein refers to the amount of a compound (as such or in form of a pharmaceutical composition) of the present invention which is effective for producing some desired therapeutic effect. [1584] Pharmaceutical compositions may be in unit dose form containing a predetermined amount of a compound of the present disclosure per unit dose. Such a unit may contain a therapeutically effective dose of a compound of the present disclosure or salt thereof or a fraction of a therapeutically effective dose such that multiple unit dosage forms might be administered at a given time to achieve the desired therapeutically effective dose. Preferred unit dosage formulations
are those containing a daily dose or sub-dose, or an appropriate fraction thereof, of a compound of the present disclosure or salt thereof. [1585] The compounds of the present disclosure may be administered by any aceptable means in solid or liquid form, including (1) oral administration, for example, drenches (aqueous or non- aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; (8) nasally; (9) pulmonary; or (10) intrathecally. [1586] The phrase "pharmaceutically-acceptable carrier" as used herein means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters, polycarbonates and/or polyanhydrides; and (22) other non-toxic compatible substances employed in pharmaceutical compositions. [1587] Such compositions may contain further components conventional in pharmaceutical preparations, e.g. wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and
magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants, pH modifiers, bulking agents, and further active agents. Examples of pharmaceutically-acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha- tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like. [1588] Such compositions may be prepared by any method known in the art, for example, by bringing into association the active ingredient with one or more carriers and/or excipients. Different compositions and examples of carriers and/or excipients are well known to the skilled person and are described in detail in, e.g., Remington: The Science and Practice of Pharmacy. Pharmaceutical Press, 2013; Rowe, Sheskey, Quinn: Handbook of Pharmaceutical Excipients.Pharmaceutical Press, 2009. Excipients that may be used in the preparation of the pharmaceutical compositions may include one or more of buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide a composition suitable for an administration of choice. [1589] As indicated above, the compounds of the present invention may be in solid or liquid form and administered by various routes in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. [1590] In solid dosage forms of the present disclosure for oral administration (capsules, tablets, pills, dragees, powders, granules, trouches and the like), a compound is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators,
such as quaternary ammonium compounds and surfactants, such as poloxamer and sodium lauryl sulfate; (7) wetting agents, such as, for example, cetyl alcohol, glycerol monostearate, and non- ionic surfactants; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof; (10) coloring agents; and (11) controlled release agents such as crospovidone or ethyl cellulose. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like. A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be formulated for rapid release, e.g., freeze-dried. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above- described excipients. [1591] Liquid dosage forms for oral administration of the compounds of the present disclosure
include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. An oral composition can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents. [1592] In form of suspensions, a compound may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof. [1593] Dosage forms for rectal or vaginal administration of a compound of the present disclosure include a suppository, which may be prepared by mixing one or more compounds of the present disclosure with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound. Other suitable forms include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate. [1594] Dosage forms for the topical or transdermal administration of a compound of the present disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically- acceptable carrier, and with any preservatives, buffers, or propellants which may be required. Such ointments, pastes, creams and gels may contain, in addition to a compound of the present disclosure, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. [1595] Dosage forms such as powders and sprays for administration of a compound of the present disclosure, may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain
customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane. [1596] Dosage forms such as transdermal patches for administration of a compound of the present disclosure may include absorption enhancers or retarders to increase or decrease the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel. Other dosage forms contemplated include ophthalmic formulations, eye ointments, powders, solutions and the like. It is understood that all contemplated compositions must be stable under the conditions of manufacture and storage, and preserved against the contaminating action of microorganisms, such as bacteria and fungi. [1597] The dosage levels of a compound of the present disclosure in the pharmaceutical compositions of the present disclosure may be adjusted in order to obtain an amount of a compound of the present disclosure which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being deleterious to the patient. The dosage of choice will depend upon a variety of factors including the nature of the particular compound of the present invention used, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound used, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts. A medical practitioner having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. [1598] Typically, a suitable daily dose of a compound of the present disclosure will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, oral, intravenous, intracerebroventricular and subcutaneous doses of the compounds of this invention for a patient, when used for the indicated analgesic effects, will range from about 0.0001 to about 100 mg, more usual 0.1 to 100 mg/kg per kilogram of body weight of recipient (patient, mammal) per day. Acceptable daily dosages may be from about 1 to about 1000 mg/day, and for example, from about 1 to about 100 mg/day. [1599] The effective dose of a compound of the present disclosure may be administered as two,
three, four, five, six or more sub-doses administered separately at appropriate intervals throughout a specified period (per day or per week or per month), optionally, in unit dosage forms. Preferred dosing also depends on factors as indicated above, e.g. on the administration, and can be readily arrived at by one skilled in medicine or the pharmacy art. Biological Assays [1600] Compounds designed, selected and/or optimised by methods described herein, once produced, can be characterised using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity. For example, the molecules can be characterised by conventional assays, including but not limited to those assays described below, to determine whether they have a predicted activity, binding activity and/or binding specificity. [1601] Furthermore, high-throughput screening can be used to speed up analysis using such assays. As a result, it can be possible to rapidly screen the molecules described herein for activity, using techniques known in the art. General methodologies for performing high-throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. High-throughput assays can use one or more different assay techniques including, but not limited to, those described below. [1602] Various in vitro or in vivo biological assays are may be suitable for detecting the effect of the compounds of the present disclosure. These in vitro or in vivo biological assays can include, but are not limited to, enzymatic activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and the assays described herein. Exemplary Biological Assays [1603] Retroviral Production: EGFR mutants are subcloned into pMXs-IRES-Blasticidin (RTV- 016, Cell Biolabs, San Diego, CA). Retroviral expression vector retrovirus is produced by transient transfection of HEK 293T cells with the retroviral EGFR mutant expression vector pMXs-IRES- Blasticidin (RTV-016, Cell Biolabs), pCMV-Gag-Pol vector and pCMV-VSV-G-Envelope vector. Briefly, HEK 293T/17 cells are plated in 100mm collagen coated plate (354450, Corning Life Sciences, Tewksbury, MA) (4 10
5 per plate) and incubated overnight. The next day, retroviral plasmids (3 Pg of EGFR mutant, 1.0 Pg of pCMV-Gag-Pol and 0.5 Pg pCMV-VSV-G) are mixed in 500 Pl of Optimem (31985, Life Technologies). The mixture is incubated at room temperature
for 5 min and then added to Optimem containing transfection reagent Lipofectamine (11668, Invitrogen) and incubated for 20 minutes. Mixture is then added dropwise to HEK 293T cells. The next day the medium is replaced with fresh culture medium and retrovirus is harvested @ 24 and 48 hrs. [1604] Generation of EGFR mutant stable cell lines: BaF3 cells (1.5E5 cells) are infected with 1 ml of viral supernatant supplemented with 8 Pg/ml polybrene by centrifuging for 30 min at 1000 rpm. Cells are placed in a 37°C incubator overnight. Cells are then spun for 5 minutes to pellet the cells. Supernatant is removed and cells re-infected a fresh 1 ml of viral supernatant supplemented with 8 Pg/ml polybrene by centrifuging for 30 min at 1000 rpm. Cells are placed in 37°C incubator overnight. Cells are then maintained in RPMI containing 10% Heat Inactivated FBS, 2% L- glutamine containing 10 ng/ml IL-3. After 48 hours cells are selected for retroviral infection in 10 Pg/ml Blasticidin for one week. Blasticidin resistant populations are ished twice in phosphate buffered saline before plating in media lacking IL-3 to select for IL-3 independent growth. [1605] Assay for cell proliferation: BaF3 cell lines are resuspended at 1.3E5 c/ml in RPMI containing 10% Heat Inactivated FBS, 2% L-glutamine and 1% Pen/Strep and dispensed in triplicate (17.5E4 c/well) into 96 well plates. To determine the effect of drug on cell proliferation, cells incubated for 3 days in the presence of vehicle control or test drug at varying concentrations. Inhibition of cell growth is determined by luminescent quantification of intracellular ATP content using CellTiterGlo (Promega), according to the protocol provided by the manufacturer. Comparison of cell number on day 0 versus 72 hours post drug treatment is used to plot dose- response curves. The number of viable cells is determined and normalized to vehicle-treated controls. Inhibition of proliferation, relative to vehicle-treated controls is expressed as a fraction of 1 and graphed using PRISM
® software (Graphpad Software, San Diego, CA). EC
50 values are determined with the same application. [1606] Cellular protein analysis: Cell extracts are prepared by detergent lysis (RIPA, R0278, Sigma, St Louis, MO) containing 10 mM Iodoacetamide (786-228, G-Biosciences, St, Louis, MO), protease inhibitor (P8340, Sigma, St. Louis, MO) and phosphatase inhibitors (P5726, P0044, Sigma, St. Louis, MO) cocktails. The soluble protein concentration is determined by micro-BSA assay (Pierce, Rockford IL). Protein immunodetection is performed by electrophoretic transfer of SDS-PAGE separated proteins to nitrocellulose, incubation with antibody, and chemiluminescent second step detection. Nitrocellulose membranes are blocked with 5% nonfat dry milk in TBS and
incubated overnight with primary antibody in 5% bovine serum albumin. The following primary antibodies from Cell Signaling Technology are used at 1:1000 dilution: phospho-EGFR[Y1173] and total EGFR. β-Actin antibody, used as a control for protein loading, is purchased from Sigma Chemicals. Horseradish peroxidase-conjugated secondary antibodies are obtained from Cell Signaling Technology and used at 1:5000 dilution. Horseradish peroxidase-conjugated secondary antibodies are incubated in nonfat dry milk for 1 hour. SuperSignal chemiluminescent reagent (Pierce Biotechnology) is used according to the manufacturer's directions and blots are imaged using the Alpha Innotech image analyzer and AlphaEaseFC software (Alpha Innotech, San Leandro CA). Potent Inhibition [1607] Compounds and compositions of the disclosure are potent inhibitors of one or more oncogenic variants of an EGFR. In some embodiments, compounds and compositions of the disclosure are potent inhibitors of one or more of a wild type HER-2 receptor or an oncogenic variant of a HER-2 receptor. In some embodiments, the oncogenic variant of a HER-2 receptor is an allosteric variant of a HER-2 receptor. [1608] In some embodiments, the compound is capable of inhibiting a mutant EGFR (e.g., EGFR- Viii, EGFR-NPH, or EGFR-SVD). [1609] Inhibition activities of exemplary compounds of the present disclosure are shown in Tables A and B at Example 2. [1610] In some embodiments, the compound exhibits an IC
50 value of 1000 nM or less, 500 nM or less, 100 nM or less, 50 nM or less, or 10 nM or less for inhibiting a mutant EGFR (e.g., EGFR- Viii, EGFR-NPH, or EGFR-SVD). [1611] In some embodiments, the compound exhibits an IC
50 value of 1000 nM or less for inhibiting EGFR-Viii. [1612] In some embodiments, the compound exhibits an IC
50 value of 500 nM or less for inhibiting EGFR-Viii. [1613] In some embodiments, the compound exhibits an IC
50 value of 100 nM or less for inhibiting EGFR-Viii. [1614] In some embodiments, the compound exhibits an IC
50 value of 50 nM or less for inhibiting EGFR-Viii.
[1615] In some embodiments, the compound exhibits an IC
50 value of 10 nM or less for inhibiting EGFR-Viii. [1616] In some embodiments, the compound exhibits greater inhibition of a mutant EGFR (e.g., EGFR-Viii, EGFR-NPH, or EGFR-SVD) relative to wild-type EGFR. [1617] In some embodiments, the compound exhibits at least 2-fold, 3-fold, 5-fold, 10-fold, 20- fold, 30-fold, 50-fold, or 100-fold greater inhibition of a mutant EGFR (e.g., EGFR-Viii, EGFR- NPH, or EGFR-SVD) relative to wild-type EGFR. [1618] In some embodiments, the compound exhibits at least 5-fold greater inhibition of EGFR- Viii relative to wild-type EGFR. [1619] In some embodiments, the compound exhibits at least 10-fold greater inhibition of EGFR- Viii relative to wild-type EGFR. [1620] In some embodiments, the compound exhibits at least 20-fold greater inhibition of EGFR- Viii relative to wild-type EGFR. [1621] In some embodiments, the compound exhibits at least 30-fold greater inhibition of EGFR- Viii relative to wild-type EGFR. [1622] In some embodiments, the compound is capable of inhibiting wild-type HER2 or a mutant HER2 (e.g., HER2-S310F or HER2-YVMA). [1623] In some embodiments, the compound exhibits an IC
50 value of 1000 nM or less, 500 nM or less, 100 nM or less, 50 nM or less, or 10 nM or less for inhibiting wild-type HER2 or a mutant HER2 (e.g., HER2-S310F or HER2-YVMA). [1624] In some embodiments, the compound exhibits an IC
50 value of 1000 nM or less, 500 nM or less, 100 nM or less, 50 nM or less, or 10 nM or less for inhibiting wild-type HER2. [1625] In some embodiments, the compound exhibits an IC
50 value of 1000 nM or less for inhibiting wild-type HER2. [1626] In some embodiments, the compound exhibits an IC
50 value of 500 nM or less for inhibiting wild-type HER2. [1627] In some embodiments, the compound exhibits an IC50 value of 100 nM or less for inhibiting wild-type HER2. [1628] In some embodiments, the compound exhibits an IC
50 value of 50 nM or less for inhibiting wild-type HER2. [1629] In some embodiments, the compound exhibits an IC
50 value of 10 nM or less for inhibiting
wild-type HER2. [1630] In some embodiments, the compound exhibits an IC
50 value of 5 nM or less for inhibiting wild-type HER2. [1631] In some embodiments, the compound exhibits an IC50 value of 1000 nM or less, 500 nM or less, 100 nM or less, 50 nM or less, or 10 nM or less for inhibiting a mutant HER2 (e.g., HER2- S310F or HER2-YVMA). [1632] In some embodiments, the compound exhibits an IC
50 value of 1000 nM or less for inhibiting HER2-S310F. [1633] In some embodiments, the compound exhibits an IC
50 value of 500 nM or less for inhibiting HER2-S310F. [1634] In some embodiments, the compound exhibits an IC
50 value of 100 nM or less for inhibiting HER2-S310F. [1635] In some embodiments, the compound exhibits an IC
50 value of 50 nM or less for inhibiting HER2-S310F. [1636] In some embodiments, the compound exhibits an IC
50 value of 10 nM or less for inhibiting HER2-S310F. [1637] In some embodiments, the compound exhibits an IC
50 value of 1000 nM or less for inhibiting HER2-YVMA. [1638] In some embodiments, the compound exhibits an IC
50 value of 500 nM or less for inhibiting HER2-YVMA. [1639] In some embodiments, the compound exhibits an IC
50 value of 100 nM or less for inhibiting HER2-YVMA. [1640] In some embodiments, the compound exhibits an IC
50 value of 50 nM or less for inhibiting HER2-YVMA. [1641] In some embodiments, the compound exhibits an IC
50 value of 10 nM or less for inhibiting HER2-YVMA. Paradoxic ErbB Receptor Activation [1642] Although the mechanisms described herein apply to any form of cancer in which these EGFR variants of the disclosure are expressed, the prevalence of these variants in glioblastoma (GBM) are provided by way of example. Other cancers expressing the EGFR variants of the
disclosure include, but are not limited to, solid cancers, epithelial cancers and/or cancers of epithelial origin, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, glioblastoma (GBM), head and neck cancer, lung cancer, and non-small cell lung cancer (NSCLC). [1643] In GBM tumors EGFR is frequently the target of genomic mutations and alternative splicing events that result in alteration of the extracellular dimer interface. Many tumors express more than one aberrant isoform. The disclosure provides the mechanism of activation for the most commonly occurring variants, EGFR-Viii, EGFR-Vii, EGFR-Vvi, and EGFR-A289V. Although each isoform is the result of a distinct ectodomain alteration, all are activated by a common mechanism involving covalent ligand-independent dimerization. [1644] AMG-595 (Amgen) is an EGFR-Viii isoform selective antibody that has no activity against wild type EGFR or other splice-activated variants. Rindopepimut (Celldex) is a vaccine the produces an immunological response selectively against tumor cells expressing EGFR-Viii but not wild type EGFR or other splice-activated isoforms. Other EGFR isoforms expressed in GBM tumors (EGFR-Vii and EGFR-Vvi) are constitutively active covalent receptors and their expression may limit the breadth and duration of treatment benefit for an ErbB inhibitor that is selective only for EGFR-Viii. Therefore, it may be useful to exclude patients whose tumors express EGFR-Vii, EGFR-Vvi, or EGFR ectodomain point mutants from treatment with an EGFR-Viii selective therapy. [1645] The heterogenenic expression pattern for multiple ectodomain variants of ErbB receptors in tumors indicates that a small molecule inhibitor that inhibits all variants is preferred. The family of covalently-activated EGFR isoforms responds very differently to small molecule ErbB inhibitors compared to EGFR catalytic domain mutations observed in NSCLC. Importantly, Type I inhibitors, including erlotinib, all induce the formation of covalent EGFR dimers and increase EGFR phosphorylation at sub-saturating concentrations, an activity that is further enhanced when ErbB inhibitor is washed away. This manifests in paradoxical activation of proliferation at sub- saturating concentrations. [1646] The discovery of paradoxical activation of proliferation at sub-saturating concentrations of Type I ErbB inhibitors is further demonstrated for a series of extracellular variants of HER2, prevalent in a number of cancers including breast and bladder. All variants existed as covalently activated receptors, and levels of covalent dimers increased following treatment with Type I
inhibitors including sapitinib and afatinib. As with covalently-activated EGFR variants, sub- saturating doses of Type I inhibitors increased phosphorylation of HER2 variants, increasing the proliferation of cells expressing them. [1647] In contrast to Type I inhibitors, the disclosure demonstrates that Non-Type I (e.g. Type II) inhibitors, including neratinib, are devoid of paradoxical activation for cells expressing ErbB ectodomain variants. Neratinib is found to exemplify a molecule that is both potent and selective for each member of the covalently-activated EGFR family versus wild type EGFR. [1648] In some embodiments, the disclosure provides a structure/functional relationship for predicting how structural variations affecting receptor regions distal to the active site can confer different responses to small molecule active site inhibitors. The disclosure described herein of paradoxical activation of covalently-activated ErbB receptor variants by Type I inhibitors has important clinical implications. The data of the disclosure provide a mechanistic explanation for the failed clinical studies for Type I inhibitors in tumor types where expression of covalently- activated ErbB receptors is prevalent. This includes erlotinib and gefitinib in GBM tumors, erlotinib in SCCHN tumors, and sapitinib in breast tumors. Thus, the disclosure provides methods of using tumor expression levels for covalently-activated ErbB receptors as exclusion criteria for treating patients with a Type I ErbB receptor inhibitor therapeutic. Glioblastoma [1649] Glioblastoma (GBM), grade IV astrocytoma, is the most common form of brain cancer. The outcome for this disease is dismal. Surgery followed by a therapeutic regimen of radiation and temozolomide is standard of care, however this produces a median overall survival (OS) of only 14.6 months and few patients survive for five years. There has been little progress made in extending survival for GBM patients over the past decade. Although bevacizumab showed an improved progression free survival benefit in the recurrent setting, the addition of bevacizumab to standard of care therapy in the front-line setting did not result in an OS benefit. [1650] EGFR is the most frequently altered oncogene in GBM. In addition to EGFR gene amplification, many tumors express variants generated by aberrant splicing or genomic mutation. The first recognized variant is EGFR-Viii, resulting from truncation of exons 2-7 and expressed by approximately 30% of GBM tumors. EGFR-Viii is oncogenic. EGFR-Viii is constitutively activated in the absence of EGF ligand, exhibiting sustained signaling that is resistant to
downregulation. Therefore, EGFR-Viii is both transforming and tumorigenic. Expression of EGFR-Viii is associated with poor long term overall survival in GBM. [1651] RNA sequencing data has revealed that EGFR-Viii is just one of several aberrantly spliced variants of EGFR expressed in GBM tumors. Two others result in truncation of exons 12-13 and 14-15 (EGFR-Vii). Like EGFR-Viii, EGFR-Vii is both transforming and tumorigenic. In addition to splice variants, GBM tumors also express a collection of EGFR point mutations including C620Y and A289V, which are transforming and tumorigenic. The complex landscape of EGFR alterations in GBM is further compounded by the observation that many tumors express more than one receptor variant. [1652] Because the expression of multiple EGFR variants in GBM gives rise to transforming and tumorigenic activity and because EGFR is the most frequently altered oncogene present in GBM tumors, EGFR is an especially attractive target for small molecule ErbB inhibitors. Following the success for small molecule EGFR therapeutics against NSCLC tumors harboring activating mutations in EGFR (erlotinib, gefitinib, and afatinib), these drugs were tested in GBM. Despite intense clinical investigation of this group of ErbB inhibitors in GBM, involving >30 clinical trials and >1500 patients, all failed to produce any benefit, even for those tumors that expressed EGFR- Viii. Some evidence suggests that erlotinib promoted disease progression. A phase II study evaluating erlotinib in combination with radiation and temozolomide showed median PFS (mPFS) and median OS (mOS) of 2.8 months and 8.6 months, as compared to 6.9 months and 14.6 months for patients receiving radiation and temozolomide alone. Another randomized phase II trial with erlotinib showed that patients who received erlotinib, including those whose tumors expressed EGFR-Viii, performed worse by a number of parameters than those patients who received standard of care therapy. The clinical failures for ErbB inhibitors such as erlotinib in GBM tumors has cast doubt on the role of EGFR as a driver of tumor growth in GBM and led to inquiry as to why ErbB inhibitors that were so effective in treating EGFR mutations in lung cancer were so ineffective in treating EGFR variants in GBM. [1653] A feature for the EGFR variants expressed in GBM is their location within the extracellular domain. This is in contrast to activating mutations of EGFR found in lung cancer, which often reside in the intracellular catalytic domain. EGFR is composed of four extracellular domains (two ligand binding domains and two cysteine rich regions), a transmembrane domain, and an intracellular catalytic domain. Ligand binding promotes dimerization of the extracellular cysteine
rich domains (CR1 and CR2), an event that confers dimerization of the intracellular domain and activation of receptor catalytic activity. Nearly all EGFR splicing events and mutations in GBM affect the extracellular region, including two cysteine rich regions (CR1 and CR2) that form the extracellular dimer interface. The CR regions contain >40 cysteine residues, all of which form intramolecular disulfide bonds. In EGFR-Viii, truncation of exons 2-7 results in partial loss of sequence encoding the CR1 region. A consequence is loss of one cysteine from the Cys295- Cys307 pair, leaving Cys307 as a free unpaired cysteine. For EGFR-Viii, this cysteine can form an intermolecular disulfide bond with another EGFR monomer to drive a covalently dimerized and constitutively activated receptor. Mutation of Cysteine 307 to a Serine (C307S) prevents the formation of covalently dimerized EGFR-Viii and is inactive. [1654] Although several recent preclinical studies have suggested that EGFR kinase inhibitors such as erlotinib are ineffective at inhibiting EGFR-Viii, there has been no mechanism proposed for this effect. There is also a lack in current understanding for the mechanism responsible for activation of other ectodomain variants in GBM, including EGFR-Vii and EGFR-A289V. The disclosure provides a mechanism of receptor activation and impact on ErbB inhibitor activity for a group of four of the most common ectodomain variants in GBM, EGFR-Viii, EGFR-Vii, EGFR- delta 12-13, and EGFR-A289V. [1655] The disclosure demonstrates that like EGFR-Viii, an additional group of commonly occurring EGFR variants in GBM (EGFR-Vii, EGFR-Vvi, and EGFR-A289V) all exist as constitutively active covalent dimers and together form a family of EGFR isoforms that are activated by this common mechanism. In some embodiments, the disclosure shows that the propensity of these variants to covalently dimerize is coupled to the conformation of the intracellular catalytic site, conferring distinct activity for classes of small molecules inhibitors binding to this distal site. Inhibitors that stabilize the active conformation of the kinase (Type I inhibitors, including erlotinib) induce the formation of covalent dimers for all covalently-activated EGFR isoforms. This is associated with the propensity of Type I inhibitors to increase EGFR phosphorylation at sub-saturating concentrations and to paradoxically stimulate the proliferation of cells expressing covalently-activated EGFR isoforms. [1656] Neither enhanced dimerization nor paradoxical activation of EGFR is seen with small molecule inhibitors that stabilize the inactive kinase conformation (Type II inhibitors, including lapatinib and neratinib). Examples of Type II inhibitors were identified that were potent inhibitors
of covalently-activated EGFR isoforms and which were selective for this family compared to WT- EGFR. [1657] Similar to the mutations identified for EGFR, the disclosure identifies a group of splice events and mutations affecting the CR domains of HER2 and HER4. The disclosure demonstrates that this group of splice events and mutations affecting the CR domains of HER2 and HER4 exists as covalent dimers and are paradoxically activated by agents with a Type I binding mode. These data provide a mechanistic explanation for the failure of multiple clinical trials involving Type I inhibitors, including >30 clinical trials of Type I ErbB inhibitors in GBM. Collectively these data indicate that tumors expressing covalently-activated EGFR isoforms should be excluded from treatment with Type I ErbB inhibitors such as erlotinib because of paradoxical activation. These data further demonstrate the utility for optimizing Type II ErbB inhibitors against the covalently- activated ErbB family. Clinical Trials using Type I ErbB Inhibitors [1658] Methods of the disclosure identify subjects expressing ErbB family receptor variants in one or more cancer cells or cancer cell types of the subject. Identification of a subject as having a variant of the disclosure may be used as either inclusion or exclusion criteria for either a clinical trial to assess the efficacy of an existing or novel cancer treatment or for an approved treatment protocol. [1659] In some embodiments, the methods of the disclosure may be used to exclude patients expressing one or more of the ErbB variants of the disclosure from a clinical trial assessing the safety and/or efficacy of a Type I inhibitor of the disclosure. The ErbB variants of the disclosure are paradoxically activated upon contact with a Type I inhibitor, leading to increased proliferation of the cancer cell. In past and ongoing clinical trials, the patient populations used for these studies had not been screened for expression of an ErbB variant of the disclosure. Consequently, a Type I inhibitor of the disclosure that “failed” a clinical trial by failing to show increased efficacy over a standard treatment or placebo for the treatment of cancer may, in fact, be effective but the results may have been confounded by the inclusion of patients who express an ErbB variant of the disclosure. Because patients who express an ErbB variant of the disclosure may demonstrate increased proliferation of cancer cells when treated with a Type I inhibitor, and, therefore, demonstrate a lack of improvement or even a further progression of the cancer, these patients may
prevent approval of cancer therapeutics that could be life-saving for those patients who do not express an ErbB receptor variant of the disclosure. Thus, the methods of the disclosure include identifying a subject as expressing an ErbB receptor variant of the disclosure and excluding this patient from treatment with a Type I inhibitor. In some embodiments, a patient who expresses an ErbB receptor variant of the disclosure may be treated with a Non-Type I inhibitor, including a Type II inhibitor. [1660] In some embodiments, when a patient who expresses an ErbB receptor variant of the disclosure is identified as expressing only the EGFR-Viii splice variant, the patient may be treated with an EGFR-Viii selective inhibitor or may be included in a clinical trial for an EGFR-Viii selective inhibitor. In some embodiment of the methods of the disclosure, the patient should express only the EGFR-Viii splice variant to be treated with an EGFR-Viii selective inhibitor. If the patient expresses multiple variants, including the EGFR-Viii variant, resulting in a combination of expressed variants, the patient should be excluded from treatment with an EGFR-Viii selective inhibitor, however, this patient may be successfully treated with a Non-Type I selective inhibitor (e.g. a Type II inhibitor). [1661] By extension, should a selective inhibitor target any one or more of the ErbB receptor variants of the disclosure, the identification of expression of the splice variant in a patient may be used as an inclusion criterion for a clinical study or treatment regimen providing that selective inhibitor. [1662] Table 1 provides a listing of exemplary clinical trials for Type I inhibitors that “failed” when in tumor types that express covalently activated ErbB receptors were included in the study. The disclosure provides a method of screening or re-screening participants in a clinical trial for expression of one or more covalently activated ErbB receptor variants of the disclosure. As a further step, the methods of the disclosure include treating those patients who do not express one or more covalently activated ErbB receptor variants of the disclosure for a first or subsequent attempt with a Type I inhibitor to determine efficacy of the Type I inhibitor in a tumor type or patient that does not express one or more covalently activated ErbB receptor variants of the disclosure. In some embodiments, those patients who are excluded from a first or subsequent treatment with a Type I inhibitor may be treated with a Non-Type I inhibitor of the disclosure, including a Type II inhibitor.
Table 1: Listing of clinical trials for Type I inhibitors that failed in tumor types where expression levels of covalently activated ErbB receptors is prevalent.
[1663] Table 2 provides a listing of exemplary ErbB inhibitors of the disclosure. Methods of the disclosure may include the identification or determination of expression of an ErbB receptor of the disclosure as either an exclusion criteria for treatment or a clinical trial administering a Type I inhibitor or as inclusion criteria for treatment or a clinical trial administering a Non-Type I (e.g. Type II) inhibitor or the NT-113 Type I inhibitor. Table 2: Exemplary ErbB inhibitors
* Type I inhibitors of the disclosure are characterized by their mode of kinase inhibition which is described by their ability to target the ATP-binding site in an active conformation to competitively inhibit ATP-binding. Key structural elements have been described including an alignment of specific hydrophobic residues. ** Inhibitors of inactive kinases bind to target in such a manner as to disrupt key structural elements of the active conformation, including specific hydrophobic residues. These non-Type I inhibitors are differentiated from Type I inhibitors by their interaction with target in such a way as to prevent the target adopting an active ATP-binding conformation. Non-Type I inhibitors of the disclosure include, but are not limited to Type II inhibitors. Inhibitors that are not Type I inhibitors in this table are Type II inhibitors. Paradoxical Stimulation of Proliferation by Type 1 Inhibitors in Cells Driven by Covalently- Activated ErbB Oncoproteins [1664] Although illustrated through the example of EGFR variants in the diagnosis and treatment of glioblastoma, the methods of the disclosure include ErbB receptor variants (e.g. EGFR, and HER2 variants) in any cancer in which these variants are expressed. An exemplary collection of these variants is provided in Table 3. Table 3: Exemplary Covalent ErbB Oncoproteins
[1665] With respect to EGFR and glioblastoma, RNA sequencing of 164 GBM tumors reveals heterogenous expression of multiple ectodomain variants of EGFR. Aberrant splicing, alone or coincident with genomic rearrangement, produces EGFR-Viii (loss of exons 2-7), EGFR-Vii (loss of exons 14-15), and EGFR-Vvi (loss of exons 12-13), Table 4. Table 4
Prevalence is based on expression levels >1% as reported by TCGA data sets (Brennan et al. (2013) Cell 155(2): 462-477). [1666] All three ectodomain variants affect the CR1 or CR2 regions and result in loss of exons coding for sequence at the extracellular dimer interface. There is also a series of greater than 20 genomic mutations found in GBM tumors, which also map to the CR1 and CR2 regions at the
dimer interface (see, for example, Fig.1 and Table 5). Table 5
[1667] The most common of these affect A289, with A289V being most prevalent. EGFR-Viii is expressed by 20%, Vii by 3% and Vvi by 32% of tumors. Mutations within the extracellular region are observed in 40% of tumors, and at position A289 by 16% of tumors. Expression of at least one variant is observed in 65% of GBM tumors (Fig.2). Many tumors express multiple variants. This is exemplified by TCGA.878, a GBM tumor expressing EGFR-Viii, A289T, A289V, and A289D (Fig. 2). 69% of tumors expressing EGFR-Viii also co-express at least one other ectodomain variant of EGFR, and several tumors co-expressed all three ectodomain variants. Only 6% of GBM tumors express EGFR-Viii in isolation. Expression of EGFR in GBM may be mutually exclusive with expression of other RTK oncogenes, which are co-expressed with EGFR variants in only 7% of GBM tumors. These data demonstrate how EGFR alterations in GBM have a dominant and mutually exclusive expression pattern compared with other oncogenic drivers. [1668] Splicing events and mutations affecting the extracellular ligand binding domain have been shown to be both transforming and tumorigenic. The data of the disclosure confirmed the transforming properties for EGFR-Viii, EGFR-Vii, and EGFR-A289V. When expressed in BaF3 cells all transformed cells to proliferate in the absence of IL-3 (Fig.3). [1669] The x-ray structure for the ectodomain of wild type EGFR reveals 21 intramolecular
disulfide bonds lining the dimer interface at the CR1 and CR2 regions. Exemplary disulfide bonds lining the dimer interface at the CR1 and CR2 regions may occcur at one or more regions of C190- C199, C194-C207, C215-C223, C219-C231, C232-C240, C236-C248, C251-C260, C264-C291, C295-C307, C311-C326, C329-C333, C506-C515, C510-C523, C526-C535, C539-C555, C558- C571, C562-C579, C582-C591, C595-C617, C620-C628 and C624-C636 according to SEQ ID NO: 1. Similarly, exemplary disulfide bonds lining the dimer interface at the CR1 and CR2 regions of a HER-2 receptor may occcur at one or more regions of C199-C212, C220-C227, C224-C235, C236-C244, C240-C252, C255-C264, C268-C295, C299-C311, C315-C331, C334-C338, C342- C367, C511-C520, C531-C540, C544-C560, C563-C576, C567-C584, C587-C596, C600-C623, C626-C634 and C630-C642. [1670] This is a common feature for all ErbB receptors. One of the 11 intramolecular disulfide bonds in the CR1 region of EGFR is formed by Cys295-Cys307, which is disrupted in EGFR-Viii. Loss of sequence coding for part of the CR1 region eliminates Cys295, leaving Cys307 free to form an intermolecular disulfide bond with another EGFR-Viii monomer (Fig. 4). The mutation Cys307-Ser prevents formation of covalent EGFR-Viii dimers and exhibits reduced tumorigenicity in vivo. [1671] Inspection of sequences losses produced by truncations for both EGFR-Vvi and EGFR-Vii reveals that intramolecular disulfide bonds at the CR2 ectodomain dimer interface will be disrupted. Loss of exons 14-15 in EGFR-Vvi will result in disruption of the Cys539-Cys555 bond, leaving Cys555 as a free cysteine, and loss of exons 14-15 in EGFR-Vii will result in disruption of the Cys539-Cys555, Cys620-Cys628 and Cys624-Cys636 bonds, leaving Cys555, Cys628 and Cys636 as free cysteines. Cys555, Cys628, and Cys636 all reside in the CR2 region of the dimerization interface, Fig.4. Free cysteines generated at these sites could confer the potential for receptors to form covalent dimers, as has been demonstrated for EGFR-Viii. [1672] Point mutations may reside in cysteine rich regions CR1 and CR2 and could also affect disulfide bonds at the ectodomain dimer interface (Fig. 1). Some point mutations may introduce new cysteines into the CR1 region (e.g. R252C). Other mutations may directly affect cysteines that form intramolecular disulfide bonds in the CR2 region of wild type EGFR (e.g. C624F), and some of these have been shown to promote covalently dimerized receptors in the presence of EGF ligand. Many other mutations do not directly affect cysteine composition within the ectodomain but are situated in close proximity to native intramolecular disulfide bonds at the dimer interface,
and offer the potential to disrupt these structures. Indeed mutations that are adjacent to a disulfide bond in the third Ig-like domain of FGFR2 have been shown to disrupt this bond and confer a covalently dimerized and activated receptor. A289, the most common site for mutation in GBM, is less than 10 angstroms from the Cys-295-Cys307 bond, and alterations at this site might disrupt this disulfide, resulting in presentation of free cysteines at the CR1 dimer interface region. [1673] The occurrence of free cysteines at the ectodomain dimer interface for EGFR-Vvi, EGFR- Vii, and EGFR-A289V could give rise to covalent and constitutively active dimers as has been demonstrated for EGFR-Viii. To test this hypothesis, each receptor isoform was expressed in U87- MG tumor cells, which endogenously express only a very low level of wild type EGFR, and evaluated for the phosphorylation of EGFR under non-reducing conditions to allow detection of covalently dimerized versus monomeric receptor. EGFR-Viii, EGFR-Vii, EGFR-Vvi, and EGFR- A289V were all present as covalent and active receptors (Fig. 5). Although covalent dimer represented only a minor fraction of total receptor levels, the majority of phosphorylated and activated receptors were present as covalent dimers. Therefore, distinct rearrangements within the ectodomain generated by genomic alterations and aberrant splicing all produce receptors activated by a common mechanism involving ligand independent covalent dimerization. [1674] The ability of EGF ligand to modulate the activity for each member of the splice-activated EGFR family was assessed. In EGFR-Viii the ligand binding domain has been mostly truncated because of loss of sequence encoded by exons 2-7. The addition of EGF has no effect on the phosphorylation of monomeric or covalently dimerized EGFR-Viii expressed in U87-MG cells (Fig. 6). The ectodomain truncations for both EGFR-Vii and EGFR-Vvi occur downstream and affect sequence within the CR2 region more proximal to the transmembrane domain. The EGF binding site is intact for both of these variants. In contrast to EGFR-Viii, both EGFR–Vii and EGFR–Vvi have constitutive basal activity for covalent dimers, which can be further enhanced by EGF (Fig.6). [1675] The ability of multiple aberrations of EGFR in GBM to drive constitutive activation indicates that EGFR is an important therapeutic target. However, none of the ErbB inhibitors approved for treatment of EGFR catalytic site mutations in NSCLC proved effective in treating GBM. The experiments of the disclosure sought to establish whether small molecule ErbB inhibitors that have demonstrated clinical activity against oncogenic catalytic mutations expressed in NSCLC might have differential activity against each of the covalently-activated EGFR
isoforms. Herein, the data demonstrate that erlotinib enhances the formation of covalent dimers for all three splice-activated EGFR isoforms and EGFR-A289V (Fig. 7A). These effects were dose-dependent (Fig. 7B). This ability of erlotinib to induce covalent dimers for covalently- activated EGFR variants was observed for all Type I ErbB inhibitors, but not Type II inhibitors, and includes molecules with either reversible or covalent binding modes (Fig.8 and Table 6). Table 6
[1676] This discovery was extended to two other splice variants that were identified in glioblastoma and head and neck cancers, EGFR-Δ768 and EGFR-Δ660 (Fig.9 and Table 7). Both receptor isoforms could exist as covalently activated receptors, and erlotinib induced covalent dimerization for both. Table 7
[1677] Treatment with sub-saturating concentrations of the Type I ErbB inhibitor erlotinib also results in enhanced phosphorylation of covalently-activated EGFR variants, shown for EGFR-Vii, EGFR-Viii, and EGFR-A289V (Fig. 10A). Further, when cells expressing either EGFR-Vii or EGFR-Vvi are treated with erlotinib, and then washed prior to collection of lysates, all show enhanced phosphorylation compared to untreated control cells, consistent with increased dimer formation in response to the Type I inhibitor (Fig. 10B). [1678] To assess the impact of enhanced EGFR activity evoked by sub-saturating concentrations of erlotinib on cell proliferation, EGFR-Viii, EGFR-Vii, and EGFR-A289V were expressed in BaF3 cells to transform them to IL-3 independence. While high saturating concentrations of erlotinib (1uM) inhibited proliferation of BaF3-EGFR-Viii cells, lower sub-saturating concentrations (37nM) stimulated proliferation (Fig.11A). The biphasic effect of erlotinib on the proliferation of cells expressing covalently-activated EGFR was similarly seen in BaF3 cells expressing EGFR-Vii or EGFR-A2989V, but was not seen in isogenic BaF3 cells expressing the oncogenic EGFR catalytic domain mutation E746-A750 (Fig. 11B), thus demonstrating that paradoxical activation is specific to covalently-activated EGFR isoforms. The biphasic effect on proliferation for cells expressing EGFR-Viii was also seen with the covalent inhibitors WZ8040, WZ4002, and WZ3146, indicating that this behavior exists for small molecules with both reversible and covalent binding modes (Fig. 12). The ability of Type I inhibitors to paradoxically enhance cell proliferation at sub-saturating drug concentrations is fully consistent with the ability of molecules with this type of mechanism to promote the formation of covalently activated dimers. [1679] Mutations and splicing events affecting the CR1 and CR2 regions of the HER2 and HER4 ectodomains are also observed cancer (Table 8). The most common of these is HER2Δ16, expressed in approximately 50% of breast cancers, but not detected in any normal tissue. HER2Δ16 results from alternative splicing and loss of exon 16, encoding the extracellular juxtamembrane region, producing two free cysteine residues situated at the dimer interface in the CR2 region, Cys626 and Cys630 (Table 8). Compared to HER2-WT, HER2Δ16 is highly
tumorigenic. In breast cancer patients, expression of HER2Δ16 is associated with greater incidence of lymph node involvement and metastatic disease. Table 8
[1680] As observed with EGFR, point mutations also occur at the dimer interface of the HER2 CR1 region (Table 8 and Fig. 13). Some mutations introduce novel cysteines or remove one member of a pair of cysteines coordinating an intramolecular disulfide bond. Other mutations, including HER2-S310F/Y, are situated proximal to disulfide bonds and may allosterically disrupt them, as discovered for EGFR-A289V. HER2-S310F/Y mutations are the most frequently occurring HER2 mutations in cancer, expressed by >15% of bladder cancers. [1681] Select extracellular variants of HER2, including HER2-C311R and HER2Δ16, exist as covalently activated dimers. The data of the disclosure demonstrate that other commonly occurring extracellular variants including HER2-S310F also exist as covalently activated receptors (Fig.14). [1682] Similar to observations for covalently-activated EGFR variants, Type I inhibitors (sapitinib and afatinib) induce the expression of covalent dimers for HER2 extracellular variants (Fig.15A). These effects were dose dependent (Fig. 15B). Finally, sapitinib can paradoxically stimulate the proliferation of BaF3 cells driven by HER2-Δ16 (Fig. 16). Collectively, these data provide instructive guidelines for the treatment of tumors expressing covalently activated ErbB receptors, including exclusion criteria for Type I inhibitors and preferred method of treatment for Type II pharmacophores in tumors expressing these variant receptors. Uses of the Compounds and Compositions [1683] In some aspects, the present disclosure provides a method of inhibiting an oncogenic
variant of an ErbB receptor (e.g., an oncogenic variant of an EGFR), comprising administering the subject in need thereof a therapeutically effective amount of a compound described herein. [1684] In some aspects, the present disclosure provides a method of inhibiting an oncogenic variant of an ErbB receptor (e.g., an oncogenic variant of an EGFR), comprising administering the subject in need thereof a composition described herein. [1685] In some aspects, the present disclosure provides a method of preventing or treating cancer, comprising administering the subject in need thereof a therapeutically effective amount of a compound described herein. [1686] In some aspects, the present disclosure provides a method of preventing or treating cancer, comprising administering the subject in need thereof a composition described herein. [1687] In some aspects, the present disclosure provides a method of preventing or treating cancer, comprising: i) identifying a subject candidate as the subject in need of the treatment when that at least one oncogenic variant of an ErbB receptor described herein is present in the subject; and ii) administering the subject in need of the treatment a therapeutically effective amount of a compound described herein. [1688] In some aspects, the present disclosure provides a method of preventing or treating cancer, comprising: i) identifying a subject candidate as the subject in need of the treatment when that at least one oncogenic variant of an ErbB receptor described herein is present in the subject; and ii) administering the subject in need of the treatment a composition described herein. [1689] In some aspects, the present disclosure provides a method of preventing or treating cancer, comprising: i) identifying a subject candidate as the subject in need of the treatment when that at least one oncogenic variant of an ErbB receptor described herein is present in a biological sample from the subject; and ii) administering the subject in need of the treatment a therapeutically effective amount of a compound described herein. [1690] In some aspects, the present disclosure provides a method of preventing or treating cancer, comprising: i) identifying a subject candidate as the subject in need of the treatment when that at least one oncogenic variant of an ErbB receptor described herein is present in a biological sample from the subject; and ii) administering the subject in need of the treatment a composition described herein. [1691] In some aspects, the present disclosure provides a method of preventing or treating cancer, comprising administering the subject in need thereof a therapeutically effective amount of a
compound described herein when that at least one oncogenic variant of an ErbB receptor described herein is identified as being present in the subject. [1692] In some aspects, the present disclosure provides a method of preventing or treating cancer, comprising administering the subject in need thereof a compound described herein when that at least one oncogenic variant of an ErbB receptor described herein is identified as being present in the subject. [1693] In some aspects, the present disclosure provides a method of preventing or treating cancer, comprising administering the subject in need thereof a therapeutically effective amount of a compound described herein when that at least one oncogenic variant of an ErbB receptor described herein is identified as being present in a biological sample from the subject. [1694] In some aspects, the present disclosure provides a method of preventing or treating cancer, comprising administering the subject in need thereof a composition described herein when that at least one oncogenic variant of an ErbB receptor described herein is identified as being present in a biological sample from the subject. [1695] In some aspects, the present disclosure provides a compound described herein for use in the inhibition of an oncogenic variant of an ErbB receptor (e.g., an oncogenic variant of an EGFR). [1696] In some aspects, the present disclosure provides a compound described herein for use in the prevention or treatment of cancer. [1697] In some aspects, the present disclosure provides a composition described herein for use in the inhibition of an oncogenic variant of an ErbB receptor (e.g., an oncogenic variant of an EGFR). [1698] In some aspects, the present disclosure provides a composition described herein for use in the prevention or treatment of cancer. [1699] In some aspects, the present disclosure provides a compound described herein for use in the prevention or treatment of cancer in a subject, wherein at least one oncogenic variant of an ErbB receptor described herein is present in the subject. [1700] In some aspects, the present disclosure provides a composition described herein for use in the prevention or treatment of cancer in a subject, wherein at least one oncogenic variant of an ErbB receptor described herein is present in the subject. [1701] In some aspects, the present disclosure provides a compound described herein for use in the prevention or treatment of cancer in a subject, wherein at least one oncogenic variant of an ErbB receptor described herein is present in a biological sample from the subject.
[1702] In some aspects, the present disclosure provides a composition described herein for use in the prevention or treatment of cancer in a subject, wherein at least one oncogenic variant of an ErbB receptor described herein is present in a biological sample from the subject. [1703] In some aspects, the present disclosure provides use of a compound described herein in the manufacture of a medicament for inhibiting an oncogenic variant of an ErbB receptor (e.g., an oncogenic variant of an EGFR). [1704] In some aspects, the present disclosure provides use of a compound described herein in the manufacture of a medicament for preventing or treating cancer. [1705] In some embodiments, the compound is selected from the compounds described in Table 1, pharmaceutically acceptable salts thereof, and stereoisomers thereof. [1706] In some embodiments, the compound is selected from the compounds described in Table 1 and pharmaceutically acceptable salts thereof. [1707] In some embodiments, the compound is selected from the compounds described in Table 1. [1708] In some embodiments, cancer is a solid tumor. [1709] In some embodiments, the cancer is a bladder cancer, a breast cancer, a cervical cancer, a colorectal cancer, an endometrial cancer, a gastric cancer, a glioblastoma (GBM), a head and neck cancer, a lung cancer, a non-small cell lung cancer (NSCLC), or any subtype thereof. [1710] In some embodiments, the cancer is glioblastoma (GBM) or any subtype thereof. [1711] In some embodiments, the cancer is glioblastoma. [1712] The disclosure provides a composition comprising a compound of the disclosure or pharmaceutically acceptable salts or stereoisomers thereof. In some embodiments, the composition comprises a pharmaceutically acceptable carrier. In some embodiments, the composition composition comprises a second therapeutically active agent. In some embodiments, the second therapeutically active agent comprises a second compound of the disclosure. In some embodiments, the second therapeutically active agent comprises a non-Type I inhibitor. In some embodiments, the non-Type I inhibitor comprises a Type II inhibitor. In some embodiments, the Type II inhibitor comprises a small molecule inhibitor. [1713] The disclosure provides a composition of the disclosure for use in the treatment of cancer, wherein the cancer or a tumor or a cell thereof expresses an oncogenic variant of an epidermal growth factor receptor (EGFR).
[1714] In some embodiments of the compositions for use in the treatment of cancer of the disclosure, including those wherein the cancer or a tumor or a cell thereof expresses an oncogenic variant of an epidermal growth factor receptor (EGFR), the oncogenic variant of an EGFR is an allosteric variant of EGFR. [1715] In some embodiments of the compositions for use in the treatment of cancer of the disclosure, cancer or a tumor or a cell thereof expresses an oncogenic variant of an epidermal growth factor receptor (EGFR) and wherein the oncogenic variant of an EGFR is an allosteric variant of EGFR, the oncogenic variant of an EGFR comprises an EGFR variant III (EGFR-Viii) mutation. [1716] In some embodiments of the compositions for use in the treatment of cancer of the disclosure, cancer or a tumor or a cell thereof expresses an oncogenic variant of an epidermal growth factor receptor (EGFR) and wherein the oncogenic variant of an EGFR is an allosteric variant of EGFR, the oncogenic variant of an EGFR comprises a substitution of a valine (V) for an alanine (A) at position 289 of SEQ ID NO: 1. [1717] In some embodiments of the compositions for use in the treatment of cancer of the disclosure, cancer or a tumor or a cell thereof expresses an oncogenic variant of an epidermal growth factor receptor (EGFR) and wherein the oncogenic variant of an EGFR is an allosteric variant of EGFR, the oncogenic variant of an EGFR comprises a modification of a structure of the EGFR, wherein the oncogenic variant of an EGFR is a capable of forming a covalently linked dimer, wherein the covalently linked dimer is constitutively active and wherein the covalently linked dimer enhances an activity of EGFR when contacted to a Type I ErbB inhibitor. In some embodiments, the modification of the structure of the EGFR comprises a modification of one or more of a nucleic acid sequence, an amino acid sequence, a secondary structure, a tertiary structure, and a quaternary structure. In some embodiments, the oncogenic variant comprises a mutation, a splicing event, a post-translational process, a conformational change or any combination thereof. In some embodiments, the modification of the structure of the EGFR occurs within a first cysteine rich (CR1) and/or second cysteine rich (CR2) region of EGFR. In some embodiments, the first cysteine rich (CR1) and/or second cysteine rich (CR2) region of EGFR comprises amino acid residues T211-R334 and/or C526-S645 of SEQ ID NO: 1, respectively. In some embodiments, the oncogenic variant of an EGFR generates a physical barrier to formation of a disulfide bond within the CR1 and/or the CR2 region. In some embodiments, the oncogenic variant of an EGFR removes
a physical barrier to formation of a disulfide bond within the CR1 and/or the CR2 region. In some embodiments, the oncogenic variant of an EGFR comprises one or more free or unpaired Cysteine (C) residues located at a dimer interface of the EGFR. In some embodiments, the oncogenic variant of an EGFR comprises one or more free or unpaired Cysteine (C) residues at a site selected from the group consisting of C190-C199, C194-C207, C215-C223, C219-C231, C232-C240, C236- C248, C251-C260, C264-C291, C295-C307, C311-C326, C329-C333, C506-C515, C510-C523, C526-C535, C539-C555, C558-C571, C562-C579, C582-C591, C595-C617, C620-C628 and C624-C636 according to SEQ ID NO: 1. In some embodiments, the modification occurs within 10 angstroms or less of an intramolecular disulfide bond at a site selected from the group consisting of C190-C199, C194-C207, C215-C223, C219-C231, C232-C240, C236-C248, C251-C260, C264-C291, C295-C307, C311-C326, C329-C333, C506-C515, C510-C523, C526-C535, C539- C555, C558-C571, C562-C579, C582-C591, C595-C617, C620-C628 and C624-C636 according to SEQ ID NO: 1. [1718] In some embodiments of the compositions for use in the treatment of cancer of the disclosure, cancer or a tumor or a cell thereof expresses oncogenic variant of EGFR and the oncogenic variant of EGFR is a mutation of EGFR, a nucleotide sequence encoding the oncogenic variant of an EGFR comprises a deletion or a substitution of a sequence encoding exon 19 or a portion thereof. In some embodiments, the deletion or the substitution comprises one or more amino acids that encode an adenosine triphosphate (ATP) binding site. In some embodiments, the ATP binding site comprises amino acids E746 to A750 of SEQ ID NO: 1. In some embodiments, the ATP binding site or the deletion or substitution thereof comprises K858 of SEQ ID NO: 1. In some embodiments, the deletion comprises K858 of SEQ ID NO: 1. In some embodiments, an arginine (R) is substituted for the lysine (K) at position 858 (K858R) of SEQ ID NO: 1. In some embodiments, an arginine (R) is substituted for the leucine (L) at position 858 (L858R) of SEQ ID NO: 1. [1719] In some embodiments of the compositions for use in the treatment of cancer of the disclosure, cancer or a tumor or a cell thereof expresses an oncogenic variant of an epidermal growth factor receptor (EGFR) and wherein the oncogenic variant of an EGFR is an allosteric variant of EGFR, a nucleotide sequence encoding the oncogenic variant of an EGFR comprises an insertion within a sequence encoding exon 20 or a portion thereof. In some embodiments, the sequence encoding exon 20 or a portion thereof comprises a sequence encoding
KEILDEAYVMASVDNPHVCAR (SEQ ID NO: 7). In some embodiments, the sequence encoding exon 20 or a portion thereof comprises a sequence encoding a C-helix, a terminal end of the C-helix or a loop following the C-helix. In some embodiments, the insertion comprises the amino acid sequence of ASV, SVD, NPH, or FQEA. In some embodiments, the sequence encoding exon 20 or a portion thereof comprises one or more of: (a) an insertion of the amino acid sequence ASV between positions V769 and D770 of SEQ ID NO: 1; (b) an insertion of the amino acid sequence SVD between positions D770 and N771 of SEQ ID NO: 1; (c) an insertion of the amino acid sequence NPH between positions H773 and V774 of SEQ ID NO: 1; (d) an insertion of the amino acid sequence FQEA between positions A763 and Y764 of SEQ ID NO: 1; (e) an insertion of the amino acid sequence PH between positions H773 and V774 of SEQ ID NO: 1; (f) an insertion of the amino acid G between positions D770 and N771 of SEQ ID NO: 1; (g) an insertion of the amino acid H between positions H773 and V774 of SEQ ID NO: 1; (h) an insertion of the amino acid sequence HV between positions V774 and C775 of SEQ ID NO: 1; (i) an insertion of the amino acid sequence AH between positions H773 and V774 of SEQ ID NO: 1; (j) an insertion of the amino acid sequence SVA between positions A767 and S768 of SEQ ID NO: 1; (k) a substitution of the amino acid sequence GYN for the DN between positions 770 and 771 of SEQ ID NO: 1; (l) an insertion of the amino acid H between positions N771 and P772 of SEQ ID NO: 1; (m) an insertion of the amino acid Y between positions H773 and V774 of SEQ ID NO: 1; (n) an insertion of the amino acid sequence PHVC between positions C775 and R776 of SEQ ID NO: 1; (o) a substitution of the amino acid sequence YNPY for the H at position 773 of SEQ ID NO: 1; (p) an insertion of the amino acid sequence DNP between positions P772 and H773 of SEQ ID NO: 1; (q) an insertion of the amino acid sequence VDS between positions S768 and V769 of SEQ ID NO: 1; (r) an insertion of the amino acid H between positions D770 and N771 of SEQ ID NO: 1; (s) an insertion of the amino acid N between positions N771 and P772 of SEQ ID NO: 1; (t) an insertion of the amino acid sequence PNP between positions P772 and H773 of SEQ ID NO: 1; (u) a substitution of the amino acid sequence GSVDN for the DN between positions 770 and 771 of SEQ ID NO: 1; (v) a substitution of the amino acid sequence GYP for the NP between positions 771 and 772 of SEQ ID NO: 1; (w) an insertion of the amino acid G between positions N771 and P772 of SEQ ID NO: 1; (x) an insertion of the amino acid sequence GNP between positions P772 and H773 of SEQ ID NO: 1; (y) an insertion of the amino acid sequence GSV between positions V769 and D770 of SEQ ID NO: 1; (z) a substitution of the amino acid sequence GNPHVC for the
VC between positions 774 and 775 of SEQ ID NO: 1; (aa) an insertion of the amino acid sequence LQEA between positions A763 and Y764 of SEQ ID NO: 1; (bb) an insertion of the amino acid sequence GL between positions D770 and N771 of SEQ ID NO: 1; (cc) an insertion of the amino acid Y between positions D770 and N771 of SEQ ID NO: 1; (dd) an insertion of the amino acid sequence NPY between positions H773 and V774 of SEQ ID NO: 1; (ee) an insertion of the amino acid sequence TH between positions H773 and V774 of SEQ ID NO: 1; (ff) a substitution of the amino acid sequence KGP for the NP between positions 771 and 772 of SEQ ID NO: 1; (gg) a substitution of the amino acid sequence SVDNP for the NP between positions 771 and 772 of SEQ ID NO: 1; (hh) an insertion of the amino acid sequence NN between positions N771 and P772 of SEQ ID NO: 1; (ii) an insertion of the amino acid T between positions N771 and P772 of SEQ ID NO: 1; and (jj) a substitution of the amino acid sequence STLASV for the SV between positions 768 and 769 of SEQ ID NO: 1. [1720] In some embodiments of the compositions for use in the treatment of cancer of the disclosure, cancer or a tumor or a cell thereof expresses an oncogenic variant of an epidermal growth factor receptor (EGFR) and wherein the oncogenic variant of an EGFR is an allosteric variant of EGFR, the oncogenic variant of an EGFR comprises EGFR-Vii, EGFR-Vvi, EGFR- R222C, EGFR-R252C, EGFR-R252P, EGFR-R256Y, EGFR-T263P, EGFR-Y270C, EGFR- A289T, EGFR-A289V, EGFR-A289D, EGFR-H304Y, EGFR-G331R, EGFR-P596S, EGFR- P596L, EGFR-P596R, EGFR-G598V, EGFR-G598A, EGFR-G614D, EGFR-C620Y, EGFR- C614W, EGFR-C628F, EGFR-C628Y, EGFR-C636Y, EGFR-G645C, EGFR-'660, EGFR-'768 or any combination thereof. [1721] The disclosure provides a composition of the disclosure for use in the treatment of cancer, wherein the cancer, a tumor or a cell thereof expresses one or more of: (a) a wild type human epidermal growth factor receptor 2 (HER2) receptor or (b) an oncogenic variant of a HER-2 receptor. [1722] In some embodiments of the compositions for use in the treatment of cancer of the disclosure, including those wherein the cancer or a tumor or a cell thereof expresses a wild type HER-2 receptor, the wild type HER2 receptor comprises the amino acid sequence of SEQ ID NO: 2, 3, 4, 5, or 6. [1723] In some embodiments of the compositions for use in the treatment of cancer of the disclosure, including those wherein the cancer or a tumor or a cell thereof expresses an oncogenic
variant of a HER-2 receptor, the oncogenic variant of a HER2 receptor is an allosteric variant of the HER2 receptor. [1724] In some embodiments of the compositions for use in the treatment of cancer of the disclosure, including those wherein the cancer or a tumor or a cell thereof expresses an oncogenic variant of a HER-2 receptor and wherein the oncogenic variant of the HER-2 receptor is an allosteric variant of the HER-2 receptor, the oncogenic variant of a HER2 receptor comprises a substitution of a phenylalanine (F) for a serine (S) at position 310 of SEQ ID NO: 2 or 5. [1725] In some embodiments of the compositions for use in the treatment of cancer of the disclosure, including those wherein the cancer or a tumor or a cell thereof expresses an oncogenic variant of a HER-2 receptor and wherein the oncogenic variant of the HER-2 receptor is an allosteric variant of the HER-2 receptor, the oncogenic variant of a HER2 receptor comprises a substitution of a tyrosine (Y) for a serine (S) at position 310 of SEQ ID NO: 2 or 5. [1726] In some embodiments of the compositions for use in the treatment of cancer of the disclosure, including those wherein the cancer or a tumor or a cell thereof expresses an oncogenic variant of a HER-2 receptor and wherein the oncogenic variant of the HER-2 receptor is an allosteric variant of the HER-2 receptor, the oncogenic variant of a HER2 receptor comprises a substitution of a glutamine (Q) for an arginine (R) at position 678 of SEQ ID NO: 2 or 5. [1727] In some embodiments of the compositions for use in the treatment of cancer of the disclosure, including those wherein the cancer or a tumor or a cell thereof expresses an oncogenic variant of a HER-2 receptor and wherein the oncogenic variant of the HER-2 receptor is an allosteric variant of the HER-2 receptor, the oncogenic variant of a HER2 receptor comprises a substitution of a leucine (L) for a valine (V) at position 777 of SEQ ID NO: 2 or 5. [1728] In some embodiments of the compositions for use in the treatment of cancer of the disclosure, including those wherein the cancer or a tumor or a cell thereof expresses an oncogenic variant of a HER-2 receptor and wherein the oncogenic variant of the HER-2 receptor is an allosteric variant of the HER-2 receptor, the oncogenic variant of a HER2 receptor comprises a substitution of a methionine (M) for a valine (V) at position 777 of SEQ ID NO: 2 or 5. [1729] In some embodiments of the compositions for use in the treatment of cancer of the disclosure, including those wherein the cancer or a tumor or a cell thereof expresses an oncogenic variant of a HER-2 receptor and wherein the oncogenic variant of the HER-2 receptor is an allosteric variant of the HER-2 receptor, the oncogenic variant of a HER2 receptor comprises a
substitution of an isoleucine (I) for a valine (V) at position 842 of SEQ ID NO: 2 or 5. [1730] In some embodiments of the compositions for use in the treatment of cancer of the disclosure, including those wherein the cancer or a tumor or a cell thereof expresses an oncogenic variant of a HER-2 receptor and wherein the oncogenic variant of the HER-2 receptor is an allosteric variant of the HER-2 receptor, the oncogenic variant of a HER2 receptor comprises a substitution of an alanine (A) for a leucine (L) at position 755 of SEQ ID NO: 2 or 5. [1731] In some embodiments of the compositions for use in the treatment of cancer of the disclosure, including those wherein the cancer or a tumor or a cell thereof expresses an oncogenic variant of a HER-2 receptor and wherein the oncogenic variant of the HER-2 receptor is an allosteric variant of the HER-2 receptor, the oncogenic variant of a HER2 receptor comprises a substitution of a proline (P) for a leucine (L) at position 755 of SEQ ID NO: 2 or 5. [1732] In some embodiments of the compositions for use in the treatment of cancer of the disclosure, including those wherein the cancer or a tumor or a cell thereof expresses an oncogenic variant of a HER-2 receptor and wherein the oncogenic variant of the HER-2 receptor is an allosteric variant of the HER-2 receptor, the oncogenic variant of a HER2 receptor comprises a substitution of a serine (S) for a leucine (L) at position 755 of SEQ ID NO: 2 or 5. [1733] In some embodiments of the compositions for use in the treatment of cancer of the disclosure, including those wherein the cancer or a tumor or a cell thereof expresses an oncogenic variant of a HER-2 receptor and wherein the oncogenic variant of the HER-2 receptor is an allosteric variant of the HER-2 receptor, a nucleotide sequence encoding the oncogenic variant of a HER2 receptor comprises an insertion within a sequence encoding exon 20 or a portion thereof. In some embodiments, the sequence encoding exon 20 or a portion thereof comprises a sequence encoding KEILDEAYVMAGVGSPYVSR(SEQ ID NO: 8). In some embodiments, the sequence encoding exon 20 or a portion thereof comprises a sequence encoding a C-helix, a terminal end of the C-helix or a loop following the C-helix. In some embodiments, the insertion comprises the amino acid sequence of GSP or YVMA. In some embodiments, the sequence encoding exon 20 or a portion thereof comprises one or more of: (a) an insertion of the amino acid sequence YVMA between positions A775 and G776 of SEQ ID NO: 2; (b) an insertion of the amino acid sequence GSP between positions P780 and Y781 of SEQ ID NO: 2; (c) an insertion of the amino acid sequence YVMA between positions A771 and Y772 of SEQ ID NO: 2; (d) an insertion of the amino acid sequence YVMA between positions A775 and G776 of SEQ ID NO: 2; (e) an insertion
of the amino acid V between positions V777 and G778 of SEQ ID NO: 2; (f) an insertion of the amino acid V between positions V777 and G778 of SEQ ID NO: 2; (g) a substitution of the amino acid sequence AVGCV for the GV between positions 776 and 777 of SEQ ID NO: 2; (h) a substitution of the amino acid sequence LC for the G between position 776 of SEQ ID NO: 2; (i) a substitution of the amino acid sequence LCV for the G between position 776 of SEQ ID NO: 2; (j) an insertion of the amino acid sequence GSP between positions V777 and G778 of SEQ ID NO: 2; (k) a substitution of the amino acid sequence PS for the LRE between positions 755 and 757 of SEQ ID NO: 2; (l) a substitution of the amino acid sequence CPGSP for the SP between positions 779 and 780 of SEQ ID NO: 2; (m) an insertion of the amino acid C between positions V777 and G778 of SEQ ID NO: 2; (n) a substitution of the amino acid sequence VVMA for the AG between positions 775 and 776 of SEQ ID NO: 2; (o) a substitution of the amino acid sequence VV for the G at position 776 of SEQ ID NO: 2; (p) a substitution of the amino acid sequence AVCV for the GV between positions 776 and 777 of SEQ ID NO: 2; (q) a substitution of the amino acid sequence VCV for the GV between positions 776 and 777 of SEQ ID NO: 2; (r) an insertion of the amino acid G between positions G778 and S779 of SEQ ID NO: 2; (s) a substitution of the amino acid sequence PK for the LRE between positions 755 and 757 of SEQ ID NO: 2; (t) an insertion of the amino acid V between positions A775 and G776 of SEQ ID NO: 2; (u) an insertion of the amino acid sequenceYAMA between positions A775 and G776 of SEQ ID NO: 2; (v) a substitution of the amino acid sequence CV for the G at position 776 of SEQ ID NO: 2; (w) a substitution of the amino acid sequence AVCGG for the GVG between positions 776 and 778 of SEQ ID NO: 2; (x) a substitution of the amino acid sequence CVCG for the GVG between positions 776 and 778 of SEQ ID NO: 2; (y) a substitution of the amino acid sequence VVVG for the GVG between positions 776 and 778 of SEQ ID NO: 2; (z) a substitution of the amino acid sequence SVGG for the GVGS between positions 776 and 779 of SEQ ID NO: 2; (aa) a substitution of the amino acid sequence VVGES for the GVGS between positions 776 and 779 of SEQ ID NO: 2; (bb) a substitution of the amino acid sequence AVGSGV for the GV between positions 776 and 777 of SEQ ID NO: 2; (cc) a substitution of the amino acid sequence CVC for the GV between positions 776 and 777 of SEQ ID NO: 2; (dd) a substitution of the amino acid sequence HVC for the GV between positions 776 and 777 of SEQ ID NO: 2; (ee) a substitution of the amino acid sequence VAAGV for the GV between positions 776 and 777 of SEQ ID NO: 2; (ff) a substitution of the amino acid sequence VAGV for the GV between positions 776 and 777
of SEQ ID NO: 2; (gg) a substitution of the amino acid sequence VVV for the GV between positions 776 and 777 of SEQ ID NO: 2; (hh) an insertion of the amino acid sequence FPG between positions G778 and S779 of SEQ ID NO: 2; (ii) an insertion of the amino acid sequence GS between positions S779 and P780 of SEQ ID NO: 2; (jj) a substitution of the amino acid sequence VPS for the VLRE between positions 754 and 757 of SEQ ID NO: 2; (kk) an insertion of the amino acid E between positions V777 and G778 of SEQ ID NO: 2; (ll) an insertion of the amino acid sequence MAGV between positions V777 and G778 of SEQ ID NO: 2; (mm) an insertion of the amino acid S between positions V777 and G778 of SEQ ID NO: 2; (nn) an insertion of the amino acid sequence SCV between positions V777 and G778 of SEQ ID NO: 2; and (oo) an insertion of the amino acid sequence LMAY between positions Y772 and V773 of SEQ ID NO: 2. [1734] In some embodiments of the compositions for use in the treatment of cancer of the disclosure, including those wherein the cancer or a tumor or a cell thereof expresses an oncogenic variant of a HER-2 receptor and wherein the oncogenic variant of the HER-2 receptor is an allosteric variant of the HER-2 receptor, the oncogenic variant of a HER2 receptor comprises HER2-'16, HER2-C311R, HER2-S310F, p95-HER2-M611 or any combination thereof. [1735] The disclosure provides a use of the composition of the disclosure for treating cancer, comprising administering to a subject a therapeutically-effective amount of the composition, wherein the cancer, a tumor or a cell thereof expresses an oncogenic variant of an epidermal growth factor receptor (EGFR). [1736] In some embodiments of the uses of the compositions of the disclosure for the treatment of cancer, including those wherein the cancer or a tumor or a cell thereof expresses an oncogenic variant of an EGFR, the oncogenic variant of EGFR is an allosteric variant of EGFR. [1737] In some embodiments of the uses of the compositions of the disclosure for the treatment of cancer, including those wherein the cancer or a tumor or a cell thereof expresses an oncogenic variant of an EGFR and wherein the oncogenic variant of EGFR is an allosteric variant of EGFR, the oncogenic variant of an EGFR comprises an EGFR variant III (EGFR-Viii) mutation. [1738] In some embodiments of the uses of the compositions of the disclosure for the treatment of cancer, including those wherein the cancer or a tumor or a cell thereof expresses an oncogenic variant of an EGFR and wherein the oncogenic variant of EGFR is an allosteric variant of EGFR, the oncogenic variant of an EGFR comprises a substitution of a valine (V) for an alanine (A) at position 289 of SEQ ID NO: 1.
[1739] In some embodiments of the uses of the compositions of the disclosure for the treatment of cancer, including those wherein the cancer or a tumor or a cell thereof expresses an oncogenic variant of an EGFR and wherein the oncogenic variant of EGFR is an allosteric variant of EGFR, the oncogenic variant of an EGFR comprises a modification of a structure of the EGFR, wherein the oncogenic variant of an EGFR is a capable of forming a covalently linked dimer, wherein the covalently linked dimer is constitutively active and wherein the covalently linked dimer enhances an activity of EGFR when contacted to a Type I ErbB inhibitor. In some embodiments, the modification of the structure of the EGFR comprises a modification of one or more of a nucleic acid sequence, an amino acid sequence, a secondary structure, a tertiary structure, and a quaternary structure. In some embodiments, the oncogenic variant comprises a mutation, a splicing event, a post-translational process, a conformational change or any combination thereof. In some embodiments, the modification of the structure of the EGFR occurs within a first cysteine rich (CR1) and/or second cysteine rich (CR2) region of EGFR. In some embodiments, the first cysteine rich (CR1) and/or second cysteine rich (CR2) region of EGFR comprises amino acid residues T211-R334 and/or C526-S645 of SEQ ID NO: 1, respectively. In some embodiments, the oncogenic variant of an EGFR generates a physical barrier to formation of a disulfide bond within the CR1 and/or the CR2 region. In some embodiments, the oncogenic variant of an EGFR removes a physical barrier to formation of a disulfide bond within the CR1 and/or the CR2 region. In some embodiments, the oncogenic variant of an EGFR comprises one or more free or unpaired Cysteine (C) residues located at a dimer interface of the EGFR. In some embodiments, the oncogenic variant of an EGFR comprises one or more free or unpaired Cysteine (C) residues at a site selected from the group consisting of C190-C199, C194-C207, C215-C223, C219-C231, C232-C240, C236- C248, C251-C260, C264-C291, C295-C307, C311-C326, C329-C333, C506-C515, C510-C523, C526-C535, C539-C555, C558-C571, C562-C579, C582-C591, C595-C617, C620-C628 and C624-C636 according to SEQ ID NO: 1. In some embodiments, the modification occurs within 10 angstroms or less of an intramolecular disulfide bond at a site selected from the group consisting of C190-C199, C194-C207, C215-C223, C219-C231, C232-C240, C236-C248, C251-C260, C264-C291, C295-C307, C311-C326, C329-C333, C506-C515, C510-C523, C526-C535, C539- C555, C558-C571, C562-C579, C582-C591, C595-C617, C620-C628 and C624-C636 according to SEQ ID NO: 1. [1740] In some embodiments of the uses of the compositions of the disclosure for the treatment of
cancer, including those wherein the cancer or a tumor or a cell thereof expresses an oncogenic variant of EGFR and the oncogenic variant of EGFR is a mutation of EGFR, a nucleotide sequence encoding the oncogenic variant of an EGFR comprises a deletion or the substitution comprises one or more amino acids that encode an adenosine triphosphate (ATP) binding site. In some embodiments, the ATP binding site comprises amino acids E746 to A750 of SEQ ID NO: 1. In some embodiments, the ATP binding site or the deletion or substitution thereof comprises K858 of SEQ ID NO: 1. In some embodiments, the deletion comprises K858 of SEQ ID NO: 1. In some embodiments, an arginine (R) is substituted for the lysine (K) at position 858 (K858R) of SEQ ID NO: 1. In some embodiments, an arginine (R) is substituted for the leucine (L) at position 858 (L858R) of SEQ ID NO: 1. [1741] In some embodiments of the uses of the compositions of the disclosure for the treatment of cancer, including those wherein the cancer or a tumor or a cell thereof expresses an oncogenic variant of an EGFR and wherein the oncogenic variant of EGFR is an allosteric variant of EGFR, a nucleotide sequence encoding the oncogenic variant of an EGFR comprises an insertion within a sequence encoding exon 20 or a portion thereof. In some embodiments, the sequence encoding exon 20 or a portion thereof comprises a sequence encoding KEILDEAYVMASVDNPHVCAR (SEQ ID NO: 7). In some embodiments, the sequence encoding exon 20 or a portion thereof comprises a sequence encoding a C-helix, a terminal end of the C-helix or a loop following the C- helix. In some embodiments, the insertion comprises the amino acid sequence of ASV, SVD, NPH, or FQEA. In some embodiments, the sequence encoding exon 20 or a portion thereof comprises one or more of: (a) an insertion of the amino acid sequence ASV between positions V769 and D770 of SEQ ID NO: 1; (b) an insertion of the amino acid sequence SVD between positions D770 and N771 of SEQ ID NO: 1; (c) an insertion of the amino acid sequence NPH between positions H773 and V774 of SEQ ID NO: 1; (d) an insertion of the amino acid sequence FQEA between positions A763 and Y764 of SEQ ID NO: 1; (e) an insertion of the amino acid sequence PH between positions H773 and V774 of SEQ ID NO: 1; (f) an insertion of the amino acid G between positions D770 and N771 of SEQ ID NO: 1; (g) an insertion of the amino acid H between positions H773 and V774 of SEQ ID NO: 1; (h) an insertion of the amino acid sequence HV between positions V774 and C775 of SEQ ID NO: 1; (i) an insertion of the amino acid sequence AH between positions H773 and V774 of SEQ ID NO: 1; (j) an insertion of the amino acid sequence SVA between positions A767 and S768 of SEQ ID NO: 1; (k) a substitution of the amino acid
sequence GYN for the DN between positions 770 and 771 of SEQ ID NO: 1; (l) an insertion of the amino acid H between positions N771 and P772 of SEQ ID NO: 1; (m) an insertion of the amino acid Y between positions H773 and V774 of SEQ ID NO: 1; (n) an insertion of the amino acid sequence PHVC between positions C775 and R776 of SEQ ID NO: 1; (o) a substitution of the amino acid sequence YNPY for the H at position 773 of SEQ ID NO: 1; (p) an insertion of the amino acid sequence DNP between positions P772 and H773 of SEQ ID NO: 1; (q) an insertion of the amino acid sequence VDS between positions S768 and V769 of SEQ ID NO: 1; (r) an insertion of the amino acid H between positions D770 and N771 of SEQ ID NO: 1; (s) an insertion of the amino acid N between positions N771 and P772 of SEQ ID NO: 1; (t) an insertion of the amino acid sequence PNP between positions P772 and H773 of SEQ ID NO: 1; (u) a substitution of the amino acid sequence GSVDN for the DN between positions 770 and 771 of SEQ ID NO: 1; (v) a substitution of the amino acid sequence GYP for the NP between positions 771 and 772 of SEQ ID NO: 1; (w) an insertion of the amino acid G between positions N771 and P772 of SEQ ID NO: 1; (x) an insertion of the amino acid sequence GNP between positions P772 and H773 of SEQ ID NO: 1; (y) an insertion of the amino acid sequence GSV between positions V769 and D770 of SEQ ID NO: 1; (z) a substitution of the amino acid sequence GNPHVC for the VC between positions 774 and 775 of SEQ ID NO: 1; (aa) an insertion of the amino acid sequence LQEA between positions A763 and Y764 of SEQ ID NO: 1; (bb) an insertion of the amino acid sequence GL between positions D770 and N771 of SEQ ID NO: 1; (cc) an insertion of the amino acid Y between positions D770 and N771 of SEQ ID NO: 1; (dd) an insertion of the amino acid sequence NPY between positions H773 and V774 of SEQ ID NO: 1; (ee) an insertion of the amino acid sequence TH between positions H773 and V774 of SEQ ID NO: 1; (ff) a substitution of the amino acid sequence KGP for the NP between positions 771 and 772 of SEQ ID NO: 1; (gg) a substitution of the amino acid sequence SVDNP for the NP between positions 771 and 772 of SEQ ID NO: 1; (hh) an insertion of the amino acid sequence NN between positions N771 and P772 of SEQ ID NO: 1; (ii) an insertion of the amino acid T between positions N771 and P772 of SEQ ID NO: 1; and (jj) a substitution of the amino acid sequence STLASV for the SV between positions 768 and 769 of SEQ ID NO: 1. [1742] In some embodiments of the uses of the compositions of the disclosure for the treatment of cancer, including those wherein the cancer or a tumor or a cell thereof expresses an oncogenic variant of an EGFR and wherein the oncogenic variant of EGFR is an allosteric variant of EGFR,
the oncogenic variant of an EGFR comprises EGFR-Vii, EGFR-Vvi, EGFR-R222C, EGFR- R252C, EGFR-R252P, EGFR-R256Y, EGFR-T263P, EGFR-Y270C, EGFR-A289T, EGFR- A289V, EGFR-A289D, EGFR-H304Y, EGFR-G331R, EGFR-P596S, EGFR-P596L, EGFR- P596R, EGFR-G598V, EGFR-G598A, EGFR-G614D, EGFR-C620Y, EGFR-C614W, EGFR- C628F, EGFR-C628Y, EGFR-C636Y, EGFR-G645C, EGFR-'660, EGFR-'768 or any combination thereof. [1743] The disclosure provides a use of a compsosition of the disclosure for treating cancer, comprising administering to a subject a therapeutically-effective amount of the composition, wherein the cancer, a tumor or a cell thereof expresses one or more of: (a) a wild type human epidermal growth factor receptor 2 (HER2) receptor or an oncogenic variant of a HER-2 receptor. [1744] In some embodiments of the uses of the compositions of the disclosure for the treatment of cancer, including those wherein the cancer, a tumor or a cell thereof expresses a wild type HER-2 receptor, the wild type HER2 receptor comprises the amino acid sequence of SEQ ID NO: 2, 3, 4, 5, or 6. [1745] In some embodiments of the uses of the compositions of the disclosure for the treatment of cancer, including those wherein the cancer, a tumor or a cell thereof expresses an oncogenic variant of a HER-2 receptor, the oncogenic variant of a HER2 receptor is an allosteric variant of the HER2 receptor. [1746] In some embodiments of the uses of the compositions of the disclosure for the treatment of cancer, including those wherein the cancer, a tumor or a cell thereof expresses an oncogenic variant of a HER-2 receptor and wherein the oncogenic variant of a HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of a HER2 receptor comprises a substitution of a phenylalanine (F) for a serine (S) at position 310 of SEQ ID NO: 2 or 5. [1747] In some embodiments of the uses of the compositions of the disclosure for the treatment of cancer, including those wherein the cancer, a tumor or a cell thereof expresses an oncogenic variant of a HER-2 receptor and wherein the oncogenic variant of a HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of a HER2 receptor comprises a substitution of a tyrosine (Y) for a serine (S) at position 310 of SEQ ID NO: 2 or 5. [1748] In some embodiments of the uses of the compositions of the disclosure for the treatment of cancer, including those wherein the cancer, a tumor or a cell thereof expresses an oncogenic variant of a HER-2 receptor and wherein the oncogenic variant of a HER2 receptor is an allosteric variant
of the HER2 receptor, the oncogenic variant of a HER2 receptor comprises a substitution of a glutamine (Q) for an arginine (R) at position 678 of SEQ ID NO: 2 or 5. [1749] In some embodiments of the uses of the compositions of the disclosure for the treatment of cancer, including those wherein the cancer, a tumor or a cell thereof expresses an oncogenic variant of a HER-2 receptor and wherein the oncogenic variant of a HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of a HER2 receptor comprises a substitution of a leucine (L) for a valine (V) at position 777 of SEQ ID NO: 2 or 5. [1750] In some embodiments of the uses of the compositions of the disclosure for the treatment of cancer, including those wherein the cancer, a tumor or a cell thereof expresses an oncogenic variant of a HER-2 receptor and wherein the oncogenic variant of a HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of a HER2 receptor comprises a substitution of a methionine (M) for a valine (V) at position 777 of SEQ ID NO: 2 or 5. [1751] In some embodiments of the uses of the compositions of the disclosure for the treatment of cancer, including those wherein the cancer, a tumor or a cell thereof expresses an oncogenic variant of a HER-2 receptor and wherein the oncogenic variant of a HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of a HER2 receptor comprises a substitution of an isoleucine (I) for a valine (V) at position 842 of SEQ ID NO: 2 or 5. [1752] In some embodiments of the uses of the compositions of the disclosure for the treatment of cancer, including those wherein the cancer, a tumor or a cell thereof expresses an oncogenic variant of a HER-2 receptor and wherein the oncogenic variant of a HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of a HER2 receptor comprises a substitution of an alanine (A) for a leucine (L) at position 755 of SEQ ID NO: 2 or 5. [1753] In some embodiments of the uses of the compositions of the disclosure for the treatment of cancer, including those wherein the cancer, a tumor or a cell thereof expresses an oncogenic variant of a HER-2 receptor and wherein the oncogenic variant of a HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of a HER2 receptor comprises a substitution of a proline (P) for a leucine (L) at position 755 of SEQ ID NO: 2 or 5. [1754] In some embodiments of the uses of the compositions of the disclosure for the treatment of cancer, including those wherein the cancer, a tumor or a cell thereof expresses an oncogenic variant of a HER-2 receptor and wherein the oncogenic variant of a HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of a HER2 receptor comprises a substitution of a
serine (S) for a leucine (L) at position 755 of SEQ ID NO: 2 or 5. [1755] In some embodiments of the uses of the compositions of the disclosure for the treatment of cancer, including those wherein the cancer, a tumor or a cell thereof expresses an oncogenic variant of a HER-2 receptor and wherein the oncogenic variant of a HER2 receptor is an allosteric variant of the HER2 receptor, a nucleotide sequence encoding the oncogenic variant of a HER2 receptor comprises an insertion within a sequence encoding exon 20 or a portion thereof. In some embodiments, the sequence encoding exon 20 or a portion thereof comprises a sequence encoding KEILDEAYVMAGVGSPYVSR(SEQ ID NO: 8). In some embodiments, the sequence encoding exon 20 or a portion thereof comprises a sequence encoding a C-helix, a terminal end of the C- helix or a loop following the C-helix. In some embodiments, the insertion comprises the amino acid sequence of GSP or YVMA. In some embodiments, the sequence encoding exon 20 or a portion thereof comprises one or more of: (a) an insertion of the amino acid sequence YVMA between positions A775 and G776 of SEQ ID NO: 2; (b) an insertion of the amino acid sequence GSP between positions P780 and Y781 of SEQ ID NO: 2; (c) an insertion of the amino acid sequence YVMA between positions A771 and Y772 of SEQ ID NO: 2; (d) an insertion of the amino acid sequence YVMA between positions A775 and G776 of SEQ ID NO: 2; (e) an insertion of the amino acid V between positions V777 and G778 of SEQ ID NO: 2; (f) an insertion of the amino acid V between positions V777 and G778 of SEQ ID NO: 2; (g) a substitution of the amino acid sequence AVGCV for the GV between positions 776 and 777 of SEQ ID NO: 2; (h) a substitution of the amino acid sequence LC for the G between position 776 of SEQ ID NO: 2; (i) a substitution of the amino acid sequence LCV for the G between position 776 of SEQ ID NO: 2; (j) an insertion of the amino acid sequence GSP between positions V777 and G778 of SEQ ID NO: 2; (k) a substitution of the amino acid sequence PS for the LRE between positions 755 and 757 of SEQ ID NO: 2; (l) a substitution of the amino acid sequence CPGSP for the SP between positions 779 and 780 of SEQ ID NO: 2; (m) an insertion of the amino acid C between positions V777 and G778 of SEQ ID NO: 2; (n) a substitution of the amino acid sequence VVMA for the AG between positions 775 and 776 of SEQ ID NO: 2; (o) a substitution of the amino acid sequence VV for the G at position 776 of SEQ ID NO: 2; (p) a substitution of the amino acid sequence AVCV for the GV between positions 776 and 777 of SEQ ID NO: 2; (q) a substitution of the amino acid sequence VCV for the GV between positions 776 and 777 of SEQ ID NO: 2; (r) an insertion of the amino acid G between positions G778 and S779 of SEQ ID NO: 2; (s) a substitution of the
amino acid sequence PK for the LRE between positions 755 and 757 of SEQ ID NO: 2; (t) an insertion of the amino acid V between positions A775 and G776 of SEQ ID NO: 2; (u) an insertion of the amino acid sequenceYAMA between positions A775 and G776 of SEQ ID NO: 2; (v) a substitution of the amino acid sequence CV for the G at position 776 of SEQ ID NO: 2; (w) a substitution of the amino acid sequence AVCGG for the GVG between positions 776 and 778 of SEQ ID NO: 2; (x) a substitution of the amino acid sequence CVCG for the GVG between positions 776 and 778 of SEQ ID NO: 2; (y) a substitution of the amino acid sequence VVVG for the GVG between positions 776 and 778 of SEQ ID NO: 2; (z) a substitution of the amino acid sequence SVGG for the GVGS between positions 776 and 779 of SEQ ID NO: 2; (aa) a substitution of the amino acid sequence VVGES for the GVGS between positions 776 and 779 of SEQ ID NO: 2; (bb) a substitution of the amino acid sequence AVGSGV for the GV between positions 776 and 777 of SEQ ID NO: 2; (cc) a substitution of the amino acid sequence CVC for the GV between positions 776 and 777 of SEQ ID NO: 2; (dd) a substitution of the amino acid sequence HVC for the GV between positions 776 and 777 of SEQ ID NO: 2; (ee) a substitution of the amino acid sequence VAAGV for the GV between positions 776 and 777 of SEQ ID NO: 2; (ff) a substitution of the amino acid sequence VAGV for the GV between positions 776 and 777 of SEQ ID NO: 2; (gg) a substitution of the amino acid sequence VVV for the GV between positions 776 and 777 of SEQ ID NO: 2; (hh) an insertion of the amino acid sequence FPG between positions G778 and S779 of SEQ ID NO: 2; (ii) an insertion of the amino acid sequence GS between positions S779 and P780 of SEQ ID NO: 2; (jj) a substitution of the amino acid sequence VPS for the VLRE between positions 754 and 757 of SEQ ID NO: 2; (kk) an insertion of the amino acid E between positions V777 and G778 of SEQ ID NO: 2; (ll) an insertion of the amino acid sequence MAGV between positions V777 and G778 of SEQ ID NO: 2; (mm) an insertion of the amino acid S between positions V777 and G778 of SEQ ID NO: 2; (nn) an insertion of the amino acid sequence SCV between positions V777 and G778 of SEQ ID NO: 2; and (oo) an insertion of the amino acid sequence LMAY between positions Y772 and V773 of SEQ ID NO: 2. [1756] In some embodiments of the uses of the compositions of the disclosure for the treatment of cancer, including those wherein the cancer, a tumor or a cell thereof expresses an oncogenic variant of a HER-2 receptor and wherein the oncogenic variant of a HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of a HER2 receptor comprises HER2-'16, HER2- C311R, HER2-S310F, p95-HER2-M611 or any combination thereof.
[1757] The disclosure provides a use of a composition of the disclosure the treatment of cancer, including those wherein the cancer, a tumor or a cell thereof expresses an oncogenic variant of a HER-4 receptor. In some embodiments, the oncogenic variant of the HER-4 receptor is an allosteric variant of the HER4 receptor. In some embodiments, the oncogenic variant of a HER4 receptor comprises deletion of exon 16 (HER4-Δ16). [1758] In some embodiments of the uses of the compositions of the disclosure for the treatment of cancer, the composition is suitable for systemic administration. In some embodiments, the composition is suitable for oral administration. In some embodiments, the composition is suitable for intravenous administration [1759] In some embodiments of the uses of the compositions of the disclosure for the treatment of cancer, the composition is suitable for local administration. In some embodiments, the composition is suitable for intratumoral, intraocular, intraosseus, intraspinal or intracerebroventricular administration. [1760] In some embodiments of the uses of the compositions of the disclosure for the treatment of cancer, the subject or the cancer is insensitive or resistant to treatment with one or more of gefinitinib, erlotinib, afatinib, osimertinib, and necitunumab. In some embodiments, the subject or the cancer is insensitive or resistant to treatment with one or more of crixotinib, alectinib, and ceritinib. In some embodiments, the subject or the cancer is insensitive or resistant to treatment with one or more of dabrafenib and trametinib. In some embodiments, the subject or the cancer is insensitive or resistant to treatment with crizotinib. [1761] In some embodiments of the uses of the compositions of the disclosure for the treatment of cancer, the cancer, tumor or cell thereof expresses an oncogenic variant of an EGFR, wherein the sequence encoding the oncogenic variant of the EGFR comprises a deletion of exon 20 or a portion thereof and wherein the cancer, tumor or cell thereof does not comprise an oncogenic variation in a sequence encoding one or more of an EGFR kinase domain (KD), BRAF, NTRK, and KRAS. [1762] In some embodiments of the uses of the compositions of the disclosure for the treatment of cancer, the cancer, tumor or cell thereof comprises an oncogenic variant of an EGFR, wherein the sequence encoding the oncogenic variant of the EGFR comprises a deletion of exon 20 or a portion thereof and wherein the cancer, tumor or cell thereof does not comprise a marker indicating responsiveness to immunotherapy. [1763] In some embodiments, the oncogenic variant (e.g., allosteric variant) or the oncogenic
mutation (e.g., allosteric mutation) is detected by a Food and Drug Aministration (FDA)-approved diagnosis. [1764] In some embodiments, the subject has an adverse reaction to treatment with a therapeutic agent different from the compound of the present disclosure. In some embodiments, the subject has an adverse reaction to treatment with a Type I inhibitor. In some embodiments, the subject has an adverse reaction to treatment with one or more of gefinitinib, erlotinib, afatinib, osimertinib, necitunumab, crizotinib, alectinib, ceritinib, dabrafenib, trametinib, afatinib, sapitinib, dacomitinib, canertinib, pelitinib, WZ4002, WZ8040, WZ3146, CO-1686 and AZD9291. In some embodiments, the adverse reaction is an activation of the oncogenic variant of an EGFR and wherein the oncogenic variant comprises a mutation in an extracellular domain of the receptor. In some embodiments, the adverse reaction is an activation of the oncogenic variant of a HER-2 Receptor and wherein the oncogenic variant comprises a mutation in an extracellular domain of the receptor. [1765] In some embodiments, the method comprises administering to the subject in need thereof a therapeutically effective amount of a non-Type I inhibitor. In some embodiments, the non-Type I inhibitor comprises a small molecule Type II inhibitor. [1766] In some embodiments, the method comprises administering to the subject in need thereof a therapeutically effective amount of a non-Type I inhibitor. In some embodiments, the non-Type I inhibitor comprises a small molecule Type II inhibitor. [1767] In some embodiments, the compound is used in combination with a therapeutically effective amount of a non-Type I inhibitor. In some embodiments, the non-Type I inhibitor comprises a small molecule Type II inhibitor. [1768] In some embodiments, the composition comprises a non-Type I inhibitor. In some embodiments, the non-Type I inhibitor comprises a small molecule Type II inhibitor. [1769] In some embodiments of the uses of the compositions of the disclosure for the treatment of cancer, the cancer comprises a solid tumor. In some embodiments, the cancer comprises a bladder cancer, a breast cancer, a cervical cancer, a colorectal cancer, an endometrial cancer, a gastric cancer, a glioblastoma (GBM), a head and neck cancer, a lung cancer, a non-small cell lung cancer (NSCLC) or any subtype thereof. In some embodiments, the cancer comrprises a glioblastoma (GBM). In some embodiments, the cancer comprises a breast cancer. In some embodiments, the cancer comprises a lung cancer.
[1770] In some embodiments of the uses of the compositions of the disclosure for the treatment of cancer, the therapeutically effective amount reduces a severity of a sign or symptom of the cancer. In some embodiments, the sign of the cancer comprises a tumor grade and wherein a reduction of the severity of the sign comprises a decrease of the tumor grade. In some embodiments, the sign of the cancer comprises a tumor metastasis and wherein a reduction of the severity of the sign comprises an elimination of the metastasis or a reduction in the rate or extent the metastasis. In some embodiments, the sign of the cancer comprises a tumor volume and wherein a reduction of the severity of the sign comprises an elimination of the tumor or a reduction in the volume. In some embodiments, the symptom of the cancer comprises pain and wherein a reduction of the severity of the sign comprises an elimination or a reduction in the pain. [1771] In some embodiments of the uses of the compositions of the disclosure for the treatment of cancer, the therapeutically effective amount induces a period of remission. [1772] In some embodiments of the uses of the compositions of the disclosure for the treatment of cancer, the therapeutically effective amount improves a prognosis of the subject. [1773] In some embodiments of the uses of the compositions of the disclosure for the treatment of cancer, the subject is a participant or a candidate for participation in in a clinical trial or protocol thereof. In some embodiments, the subject is excluded from treatment with a Type I inhibitor. In some embodiments, the Type I inhibitor comprises gefinitinib, erlotinib, afatinib, osimertinib, necitunumab, crizotinib, alectinib, ceritinib, dabrafenib, trametinib, afatinib, sapitinib, dacomitinib, canertinib, pelitinib, WZ4002, WZ8040, WZ3146, CO-1686 or AZD9291. [1774] In some embodiments of the uses of the compositions of the disclosure for the treatment of cancer, the use comprises treating the subject with a Non-Type I inhibitor. [1775] In some embodiments of the uses of the compositions of the disclosure for the treatment of cancer, the composition comprises a Non-Type I inhibitor. [1776] In some embodiments of the uses of the compositions of the disclosure for the treatment of cancer, the Non-Type I inhibitor comprises a Type II small molecule inhibitor. In some embodiments, the Type II small molecule inhibitor comprises neratinib, AST-1306, HKI-357, or lapatinib. [1777] In some embodiments, the oncogenic variant is an oncogenic variant in an ErbB receptor. [1778] In some embodiments, the oncogenic variant in the ErbB receptor is an allosteric variant. [1779] In some embodiments, the ErbB receptor is an epidermal growth factor receptor (EGFR)
or a human epidermal growth factor receptor 2 (HER2) receptor. [1780] In some embodiments, the ErbB receptor is an epidermal growth factor receptor (EGFR). [1781] In some embodiments, the ErbB receptor is a HER2 receptor. [1782] In some embodiments, the oncogenic variant is an oncogenic variant in an epidermal growth factor receptor (EGFR). [1783] In some embodiments, the oncogenic variant in the EGFR is an allosteric variant. [1784] In some embodiments, the oncogenic variant is an oncogenic variant of a HER2 receptor. [1785] In some embodiments, the oncogenic variant in the HER2 receptor is an allosteric variant. [1786] In some embodiments, the oncogenic variant in the EGFR is an EGFR variant III (EGFR- Viii) variant. [1787] In some embodiments, the oncogenic variant in the EGFR is a substitution of a valine (V) for an alanine (A) at position 289 of SEQ ID NO: 1. [1788] In some embodiments, the oncogenic variant is an oncogenic variant in an EGFR and wherein the oncogenic variant in the EGFR is an allosteric variant in the EGFR, the oncogenic variant in the EGFR is a modification of a structure of the EGFR, wherein the oncogenic variant in the EGFR is capable of forming a covalently linked dimer, wherein the covalently linked dimer is constitutively active and wherein the covalently linked dimer enhances an activity of EGFR when contacted to a Type I ErbB inhibitor. In some embodiments, the modification of the structure of the EGFR comprises a modification of one or more of a nucleic acid sequence, an amino acid sequence, a secondary structure, a tertiary structure, and a quaternary structure. In some embodiments, the modification of the structure of the EGFR occurs within a first cysteine rich (CR1) and/or second cysteine rich (CR2) region of EGFR. In some embodiments, the first cysteine rich (CR1) and/or second cysteine rich (CR2) region of EGFR comprises amino acid residues T211-R334 and/or C526-S645 of SEQ ID NO: 1, respectively. In some embodiments, the oncogenic variant in the EGFR generates a physical barrier to formation of a disulfide bond within the CR1 and/or the CR2 region. In some embodiments, the oncogenic variant in the EGFR removes a physical barrier to formation of a disulfide bond within the CR1 and/or the CR2 region. In some embodiments, the oncogenic variant in the EGFR results into one or more free or unpaired Cysteine (C) residues located at a dimer interface of the EGFR. In some embodiments, the oncogenic variant in the EGFR results into one or more free or unpaired Cysteine (C) residues at a site selected from the group consisting of C190-C199, C194-C207, C215-C223, C219-C231, C232-C240, C236-
C248, C251-C260, C264-C291, C295-C307, C311-C326, C329-C333, C506-C515, C510-C523, C526-C535, C539-C555, C558-C571, C562-C579, C582-C591, C595-C617, C620-C628 and C624-C636 according to SEQ ID NO: 1. In some embodiments, the modification occurs within 10 angstroms or less of an intramolecular disulfide bond at a site selected from the group consisting of C190-C199, C194-C207, C215-C223, C219-C231, C232-C240, C236-C248, C251-C260, C264-C291, C295-C307, C311-C326, C329-C333, C506-C515, C510-C523, C526-C535, C539- C555, C558-C571, C562-C579, C582-C591, C595-C617, C620-C628 and C624-C636 according to SEQ ID NO: 1. [1789] In some embodiments, the oncogenic variant is an oncogenic variant in an EGFR and wherein the oncogenic variant in the EGFR is an allosteric variant in the EGFR, wherein a nucleotide sequence encoding the EGFR having the oncogenic variant comprises a deletion or the substitution comprises one or more amino acids that encode an adenosine triphosphate (ATP) binding site. In some embodiments, the ATP binding site comprises amino acids E746 to A750 of SEQ ID NO: 1. In some embodiments, the ATP binding site or the deletion or substitution thereof comprises K858 of SEQ ID NO: 1. In some embodiments, the deletion comprises K858 of SEQ ID NO: 1. In some embodiments, an arginine (R) is substituted for the lysine (K) at position 858 (K858R) of SEQ ID NO: 1. In some embodiments, an arginine (R) is substituted for the leucine (L) at position 858 (L858R) of SEQ ID NO: 1. [1790] In some embodiments, the oncogenic variant is an oncogenic variant in an EGFR and wherein the oncogenic variant in the EGFR is an allosteric variant in the EGFR, wherein a nucleotide sequence encoding the EGFR having the oncogenic variant comprises an insertion within a sequence encoding exon 20 or a portion thereof. In some embodiments, the sequence encoding exon 20 or a portion thereof comprises a sequence encoding KEILDEAYVMASVDNPHVCAR (SEQ ID NO: 7). In some embodiments, the sequence encoding exon 20 or a portion thereof comprises a sequence encoding a C-helix, a terminal end of the C-helix or a loop following the C-helix. In some embodiments, the insertion comprises the amino acid sequence of ASV, SVD, NPH, or FQEA. In some embodiments, the sequence encoding exon 20 or a portion thereof comprises one or more of: (a) an insertion of the amino acid sequence ASV between positions V769 and D770 of SEQ ID NO: 1; (b) an insertion of the amino acid sequence SVD between positions D770 and N771 of SEQ ID NO: 1; (c) an insertion of the amino acid sequence NPH between positions H773 and V774 of SEQ ID NO: 1; (d) an insertion of the
amino acid sequence FQEA between positions A763 and Y764 of SEQ ID NO: 1; (e) an insertion of the amino acid sequence PH between positions H773 and V774 of SEQ ID NO: 1; (f) an insertion of the amino acid G between positions D770 and N771 of SEQ ID NO: 1; (g) an insertion of the amino acid H between positions H773 and V774 of SEQ ID NO: 1; (h) an insertion of the amino acid sequence HV between positions V774 and C775 of SEQ ID NO: 1; (i) an insertion of the amino acid sequence AH between positions H773 and V774 of SEQ ID NO: 1; (j) an insertion of the amino acid sequence SVA between positions A767 and S768 of SEQ ID NO: 1; (k) a substitution of the amino acid sequence GYN for the DN between positions 770 and 771 of SEQ ID NO: 1; (l) an insertion of the amino acid H between positions N771 and P772 of SEQ ID NO: 1; (m) an insertion of the amino acid Y between positions H773 and V774 of SEQ ID NO: 1; (n) an insertion of the amino acid sequence PHVC between positions C775 and R776 of SEQ ID NO: 1; (o) a substitution of the amino acid sequence YNPY for the H at position 773 of SEQ ID NO: 1; (p) an insertion of the amino acid sequence DNP between positions P772 and H773 of SEQ ID NO: 1; (q) an insertion of the amino acid sequence VDS between positions S768 and V769 of SEQ ID NO: 1; (r) an insertion of the amino acid H between positions D770 and N771 of SEQ ID NO: 1; (s) an insertion of the amino acid N between positions N771 and P772 of SEQ ID NO: 1; (t) an insertion of the amino acid sequence PNP between positions P772 and H773 of SEQ ID NO: 1; (u) a substitution of the amino acid sequence GSVDN for the DN between positions 770 and 771 of SEQ ID NO: 1; (v) a substitution of the amino acid sequence GYP for the NP between positions 771 and 772 of SEQ ID NO: 1; (w) an insertion of the amino acid G between positions N771 and P772 of SEQ ID NO: 1; (x) an insertion of the amino acid sequence GNP between positions P772 and H773 of SEQ ID NO: 1; (y) an insertion of the amino acid sequence GSV between positions V769 and D770 of SEQ ID NO: 1; (z) a substitution of the amino acid sequence GNPHVC for the VC between positions 774 and 775 of SEQ ID NO: 1; (aa) an insertion of the amino acid sequence LQEA between positions A763 and Y764 of SEQ ID NO: 1; (bb) an insertion of the amino acid sequence GL between positions D770 and N771 of SEQ ID NO: 1; (cc) an insertion of the amino acid Y between positions D770 and N771 of SEQ ID NO: 1; (dd) an insertion of the amino acid sequence NPY between positions H773 and V774 of SEQ ID NO: 1; (ee) an insertion of the amino acid sequence TH between positions H773 and V774 of SEQ ID NO: 1; (ff) a substitution of the amino acid sequence KGP for the NP between positions 771 and 772 of SEQ ID NO: 1; (gg) a substitution of the amino acid sequence SVDNP for the NP between positions 771 and 772 of SEQ
ID NO: 1; (hh) an insertion of the amino acid sequence NN between positions N771 and P772 of SEQ ID NO: 1; (ii) an insertion of the amino acid T between positions N771 and P772 of SEQ ID NO: 1; and (jj) a substitution of the amino acid sequence STLASV for the SV between positions 768 and 769 of SEQ ID NO: 1. [1791] In some embodiments, the oncogenic variant is an oncogenic variant in an EGFR and wherein the oncogenic variant in the EGFR is an allosteric variant in the EGFR, the EGFR having the oncogenic variant comprises EGFR-Vii, EGFR-Vvi, EGFR-R222C, EGFR-R252C, EGFR- R252P, EGFR-R256Y, EGFR-T263P, EGFR-Y270C, EGFR-A289T, EGFR-A289V, EGFR- A289D, EGFR-H304Y, EGFR-G331R, EGFR-P596S, EGFR-P596L, EGFR-P596R, EGFR- G598V, EGFR-G598A, EGFR-G614D, EGFR-C620Y, EGFR-C614W, EGFR-C628F, EGFR- C628Y, EGFR-C636Y, EGFR-G645C, EGFR-'660, EGFR-'768 or any combination thereof. [1792] In some embodiments, the oncogenic variant is an oncogenic variant in a HER-2 receptor. [1793] In some embodiments, the oncogenic variant is an oncogenic variant in a HER-2 receptor, the oncogenic variant in the HER2 receptor is an allosteric variant in the HER2 receptor. [1794] In some embodiments, the oncogenic variant is an oncogenic variant in a HER-2 receptor and wherein the oncogenic variant in the HER2 receptor is an allosteric variant in the HER2 receptor, the oncogenic mutatin in the HER2 receptor comprises a substitution of a phenylalanine (F) for a serine (S) at position 310 of SEQ ID NO: 2 or 5. [1795] In some embodiments, the oncogenic variant is an oncogenic variant in a HER-2 receptor and wherein the oncogenic variant in the HER2 receptor is an allosteric variant in the HER2 receptor, the oncogenic mutatin in the HER2 receptor comprises a substitution of a tyrosine (Y) for a serine (S) at position 310 of SEQ ID NO: 2 or 5. [1796] In some embodiments, the oncogenic variant is an oncogenic variant in a HER-2 receptor and wherein the oncogenic variant in the HER2 receptor is an allosteric variant in the HER2 receptor, the oncogenic mutatin in the HER2 receptor comprises a substitution of a glutamine (Q) for an arginine (R) at position 678 of SEQ ID NO: 2 or 5. [1797] In some embodiments, the oncogenic variant is an oncogenic variant in a HER-2 receptor and wherein the oncogenic variant in the HER2 receptor is an allosteric variant in the HER2 receptor, the oncogenic mutatin in the HER2 receptor comprises a substitution of a leucine (L) for a valine (V) at position 777 of SEQ ID NO: 2 or 5. [1798] In some embodiments, the oncogenic variant is an oncogenic variant in a HER-2 receptor
and wherein the oncogenic variant in the HER2 receptor is an allosteric variant in the HER2 receptor, the oncogenic mutatin in the HER2 receptor comprises a substitution of a methionine (M) for a valine (V) at position 777 of SEQ ID NO: 2 or 5. [1799] In some embodiments, the oncogenic variant is an oncogenic variant in a HER-2 receptor and wherein the oncogenic variant in the HER2 receptor is an allosteric variant in the HER2 receptor, the oncogenic mutatin in the HER2 receptor comprises a substitution of an isoleucine (I) for a valine (V) at position 842 of SEQ ID NO: 2 or 5. [1800] In some embodiments, the oncogenic variant is an oncogenic variant in a HER-2 receptor and wherein the oncogenic variant in the HER2 receptor is an allosteric variant in the HER2 receptor, the oncogenic mutatin in the HER2 receptor comprises a substitution of an alanine (A) for a leucine (L) at position 755 of SEQ ID NO: 2 or 5. [1801] In some embodiments, the oncogenic variant is an oncogenic variant in a HER-2 receptor and wherein the oncogenic variant in the HER2 receptor is an allosteric variant in the HER2 receptor, the oncogenic mutatin in the HER2 receptor comprises a substitution of a proline (P) for a leucine (L) at position 755 of SEQ ID NO: 2 or 5. [1802] In some embodiments, the oncogenic variant is an oncogenic variant in a HER-2 receptor and wherein the oncogenic variant in the HER2 receptor is an allosteric variant in the HER2 receptor, the oncogenic mutatin in the HER2 receptor comprises a substitution of a serine (S) for a leucine (L) at position 755 of SEQ ID NO: 2 or 5. [1803] In some embodiments, the oncogenic variant is an oncogenic variant in a HER-2 receptor and wherein the oncogenic variant in the HER2 receptor is an allosteric variant in the HER2 receptor, wherein a nucleotide sequence encoding the HER2 receptor having the oncogenic variant comprises an insertion within a sequence encoding exon 20 or a portion thereof. In some embodiments, the sequence encoding exon 20 or a portion thereof comprises a sequence encoding KEILDEAYVMAGVGSPYVSR(SEQ ID NO: 8). In some embodiments, the sequence encoding exon 20 or a portion thereof comprises a sequence encoding a C-helix, a terminal end of the C- helix or a loop following the C-helix. In some embodiments, the insertion comprises the amino acid sequence of GSP or YVMA. In some embodiments, the sequence encoding exon 20 or a portion thereof comprises one or more of: (a) an insertion of the amino acid sequence YVMA between positions A775 and G776 of SEQ ID NO: 2; (b) an insertion of the amino acid sequence GSP between positions P780 and Y781 of SEQ ID NO: 2; (c) an insertion of the amino acid
sequence YVMA between positions A771 and Y772 of SEQ ID NO: 2; (d) an insertion of the amino acid sequence YVMA between positions A775 and G776 of SEQ ID NO: 2; (e) an insertion of the amino acid V between positions V777 and G778 of SEQ ID NO: 2; (f) an insertion of the amino acid V between positions V777 and G778 of SEQ ID NO: 2; (g) a substitution of the amino acid sequence AVGCV for the GV between positions 776 and 777 of SEQ ID NO: 2; (h) a substitution of the amino acid sequence LC for the G between position 776 of SEQ ID NO: 2; (i) a substitution of the amino acid sequence LCV for the G between position 776 of SEQ ID NO: 2; (j) an insertion of the amino acid sequence GSP between positions V777 and G778 of SEQ ID NO: 2; (k) a substitution of the amino acid sequence PS for the LRE between positions 755 and 757 of SEQ ID NO: 2; (l) a substitution of the amino acid sequence CPGSP for the SP between positions 779 and 780 of SEQ ID NO: 2; (m) an insertion of the amino acid C between positions V777 and G778 of SEQ ID NO: 2; (n) a substitution of the amino acid sequence VVMA for the AG between positions 775 and 776 of SEQ ID NO: 2; (o) a substitution of the amino acid sequence VV for the G at position 776 of SEQ ID NO: 2; (p) a substitution of the amino acid sequence AVCV for the GV between positions 776 and 777 of SEQ ID NO: 2; (q) a substitution of the amino acid sequence VCV for the GV between positions 776 and 777 of SEQ ID NO: 2; (r) an insertion of the amino acid G between positions G778 and S779 of SEQ ID NO: 2; (s) a substitution of the amino acid sequence PK for the LRE between positions 755 and 757 of SEQ ID NO: 2; (t) an insertion of the amino acid V between positions A775 and G776 of SEQ ID NO: 2; (u) an insertion of the amino acid sequenceYAMA between positions A775 and G776 of SEQ ID NO: 2; (v) a substitution of the amino acid sequence CV for the G at position 776 of SEQ ID NO: 2; (w) a substitution of the amino acid sequence AVCGG for the GVG between positions 776 and 778 of SEQ ID NO: 2; (x) a substitution of the amino acid sequence CVCG for the GVG between positions 776 and 778 of SEQ ID NO: 2; (y) a substitution of the amino acid sequence VVVG for the GVG between positions 776 and 778 of SEQ ID NO: 2; (z) a substitution of the amino acid sequence SVGG for the GVGS between positions 776 and 779 of SEQ ID NO: 2; (aa) a substitution of the amino acid sequence VVGES for the GVGS between positions 776 and 779 of SEQ ID NO: 2; (bb) a substitution of the amino acid sequence AVGSGV for the GV between positions 776 and 777 of SEQ ID NO: 2; (cc) a substitution of the amino acid sequence CVC for the GV between positions 776 and 777 of SEQ ID NO: 2; (dd) a substitution of the amino acid sequence HVC for the GV between positions 776 and 777 of SEQ ID NO: 2; (ee) a substitution of
the amino acid sequence VAAGV for the GV between positions 776 and 777 of SEQ ID NO: 2; (ff) a substitution of the amino acid sequence VAGV for the GV between positions 776 and 777 of SEQ ID NO: 2; (gg) a substitution of the amino acid sequence VVV for the GV between positions 776 and 777 of SEQ ID NO: 2; (hh) an insertion of the amino acid sequence FPG between positions G778 and S779 of SEQ ID NO: 2; (ii) an insertion of the amino acid sequence GS between positions S779 and P780 of SEQ ID NO: 2; (jj) a substitution of the amino acid sequence VPS for the VLRE between positions 754 and 757 of SEQ ID NO: 2; (kk) an insertion of the amino acid E between positions V777 and G778 of SEQ ID NO: 2; (ll) an insertion of the amino acid sequence MAGV between positions V777 and G778 of SEQ ID NO: 2; (mm) an insertion of the amino acid S between positions V777 and G778 of SEQ ID NO: 2; (nn) an insertion of the amino acid sequence SCV between positions V777 and G778 of SEQ ID NO: 2; and (oo) an insertion of the amino acid sequence LMAY between positions Y772 and V773 of SEQ ID NO: 2. [1804] In some embodiments, the oncogenic variant is an oncogenic variant in a HER-2 receptor and wherein the oncogenic variant in the HER2 receptor is an allosteric variant in the HER2 receptor, the HER2 receptor having the oncogenic variant comprises HER2-'16, HER2-C311R, HER2-S310F, p95-HER2-M611 or any combination thereof. [1805] In some embodiments, the oncogenic variant is an oncogenic variant in a HER-4 receptor. In some embodiments, the oncogenic variant in the HER-4 receptor is an allosteric variant in the HER4 receptor. In some embodiments, the oncogenic variant in the HER4 receptor results into the deletion of exon 16 (HER4-Δ16). [1806] In some embodiments, the oncogenic variant is an oncogenic variant in an EGFR, wherein the sequence encoding the EGFR having the oncogenic variant comprises a deletion of exon 20 or a portion thereof and wherein the cancer, the tumor or the cell thereof does not comprise a second oncogenic variant in a sequence other than exon 20 of EGFR. In some embodiments, the second oncogenic variation comprises a sequence encoding one or more of an EGFR kinase domain (KD), BRAF, NTRK, and KRAS. [1807] In some embodiments, the oncogenic variant is an oncogenic variant in an EGFR, wherein the sequence encoding the EGFR having the oncogenic variant comprises a deletion of exon 20 or a portion thereof and wherein the cancer, the tumor or the cell thereof does not comprise a marker indicating responsiveness to immunotherapy.
EXAMPLES Example 1. Synthesis of Exemplary Compounds of the Present Disclosure Synthesis of IV (2,8-dichloropyrimido(5,4-d)pyrimidine)
[1808] Sulfuric acid (21.0 mL) was added to nitric acid (8.45 mL) slowly to keep the temperature below 50°C. Then 2, 6-dioxo-1,2,3,6- tetrahydropyrimidine-4-carboxylic acid I (10.0 g, 64.1 mmol, 1.00 eq) was added by portions. The reaction mixture was heated to 50-55 °C for 3 h. The reaction mixture was cooled down to about 10-15 °C. The mixture was poured into water (40 mL) and kept the temperature below 30 °C. The resulting mixture was cooled to about 0-10 °C and stirred slowly. The precipitated product was filtered and the filter cake was dried in vacuo to afford 5-nitro-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid II (10.0 g, 49.7 mmol, 78% yield) as a white solid.
13C NMR (D
2O) δ = 162.4, 158.2, 150.8, 150.1, 122.9. [1809] To a solution of 5-nitro-2, 6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid II (5.00 g, 24.9 mmol, 1.00 eq) in ethanol (50.0 mL) was added sulfuric acid (7.50 mL). The reaction was
stirred at 80 °C for 8 h. The reaction mixture was filtered. The filter cake was dried in vacuo to afford ethyl 5-nitro-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylate III (3.90 g, 17.0 mmol, 68% yield) as a yellow solid.
1H NMR (400 MHz, DMSO) δ = 12.13 - 11.90 (m, 1H), 4.42 - 4.31 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H). [1810] To a solution of ethyl 5-nitro-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylate III (3.00 g, 13.1 mmol, 1.00 eq) in N,N-diethylaniline (4.00 mL) was added phosphorus oxychloride (30.0 mL). The reaction was stirred at 110 °C for 3 h. The reaction mixture was concentrated in vacuo. The residue was poured into water (50.0 mL) and extracted with ethyl acetate (3 × 50.0 mL). The organic layer was washed with 2 M hydrochloric acid (50.0 mL), saturated sodium bicarbonate (50.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate =1:0 to 10:1) to afford mono-chloride (2.70 g, 10.9 mmol, 83% yield) as a yellow solid. A solution of mono-chloride (2.70 g, 10.9 mmol, 1.00 eq) in phosphorus oxychloride (30.0 mL) was stirred at 110 °C for 12 h. The reaction mixture was concentrated in vacuo. The residue was added to water (50.0 mL) and extracted with ethyl acetate (3 × 50.0 mL). The organic layer was washed with 2 M hydrochloric acid (50.0 mL), saturated sodium bicarbonate (50.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate =1:1~10:1) to afford ethyl 2,6- dichloro-5-nitropyrimidine-4-carboxylate IV (1.90 g, 6.93 mmol, 64% yield) as yellow oil.
1H NMR (400 MHz, DMSO-d6) δ = 12.08 (br s, 1H), 4.38 - 4.34 (m, 2H), 4.36 (d, J = 7.1 Hz, 2H), 1.28 (t, J = 7.1 Hz, 3H). [1811] To a solution of ethyl 2, 6-dichloro-5-nitropyrimidine-4-carboxylate V (1.30 g, 4.89 mmol, 1.00 eq) in dioxane (10.0 mL) was added magnesium oxide (985 mg, 24.4 mmol, 5.00 eq) and palladium on carbon (460 mg, 489 umol, 5% purity, 0.100 eq). The reaction was stirred at 20°C for 4 h under hydrogen atmosphere (50 psi). The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate =1:0 to 3:1) to afford ethyl 5-amino-2-chloropyrimidine-4-carboxylate VI (260 mg, 1.29 mmol, 26% yield) as a yellow solid.
1H NMR (400 MHz, DMSO-d
6) δ = 8.49 (s, 1H), 6.90 (br s, 2H), 4.34 (q, J = 7.1 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H). [1812] To a solution of ammonia (0.100 M, 100 mL, 4.03 eq) in anhydrous ethanol (10.0 mL) was added ethyl 5-amino-2-chloro-pyrimidine-4-carboxylate V (500 mg, 2.48 mmol, 1.00 eq). The
reaction mixture in the sealed-tube was heated to 100 °C for 15 h. After the reaction was completed, the mixture was concentrated to give 5-amino-2-chloro-pyrimidine-4-carboxamide VI (380 mg, 2.20 mmol, 88% yield) as a yellow solid.
1H NMR (400 MHz, DMSO-d
6) δ = 8.37 (s, 1H), 8.00 (br s, 1H), 7.74 (br s, 1H), 6.97 (br s, 2H). [1813] A mixture of 5-amino-2-chloro-pyrimidine-4-carboxamide VI (320 mg, 1.85 mmol, 1.00 eq) and diethoxymethyl acetate (2.41 g, 14.8 mmol, 2.41 mL, 8.00 eq) was stirred at 100 °C for 12 h. After the reaction was completed, the suspension was filtered. The filter cake was washed with ethyl acetate (2.00 mL) and dried to give 6-chloropyrimido(5,4-d)pyrimidin-4-ol VII (0.314 g, 1.72 mmol, 92% yield) as a gray solid.
1H NMR (400 MHz, DMSO-d6) δ = 13.00 (br s, 1H), 9.32 (s, 1H), 8.30 (s, 1H). [1814] To a mixture of 6-chloropyrimido(5,4-d)pyrimidin-4-ol VII (0.260 g, 1.42 mmol, 1.00 eq) in thionyl chloride (8.53 g, 71.7 mmol, 5.20 mL, 50.33 eq) was added dimethyl formamide (0.1 mL). The mixture was stirred at 90 °C for 11 h. After the reaction was completed, the mixture was concentrated to give 2,8-dichloropyrimido(5,4-d)pyrimidine VIII (0.291 g, crude) as a yellow solid.1H NMR (400 MHz, CDCl3) δ = 9.61 (s, 1H), 9.27 (s, 1H). Synthesis of IX (6-chloropyrido[3,2-d]pyrimidin-4-ol)
[1815] 6-chloro-3-nitropicolinonitrile IX (8.80 g, 47.9 mmol, 1.00 eq) was dissolved in sulfuric acid (90.0 mL, 90% purity) and the mixture was stirred at 75 °C for 2 h. The mixture was poured into ice water (500 mL) and filtered. The filter cake was dried in vacuum to give 6-chloro-3- nitropicolinamide X (7.80 g, crude) as a white solid.1H NMR (400 MHz, DMSO-d6) δ = 8.53 (d,
J = 8.5 Hz, 1H), 8.32 - 8.24 (m, 1H), 8.06 - 7.97 (m, 1H), 7.92 (d, J = 8.6 Hz, 1H). [1816] To a solution of 6-chloro-3-nitropicolinamide X (7.80 g, 38.7 mmol, 1.00 eq) and nickel ( ^) chloride hexahydrate (9.20 g, 38.7 mmol, 1.00 eq) in dichloromethane (40.0 mL) and methanol (40.0 mL) was added sodium borohydride (2.93 g, 77.4 mmol, 2.00 eq) in portions at 0 °C. The mixture was stirred at 20 °C for 1 h. The mixture was filtered and the filtrate was concentrated in vacuum. The residue was diluted with water (300 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give 3-amino-6-chloropicolinamide XI (3.80 g, crude) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 7.69 (br s, 1H), 7.39 (br s, 1H), 7.31 - 7.26 (m, 1H), 7.25 - 7.20 (m, 1H), 6.99 (br s, 2H). [1817] 3-amino-6-chloropicolinamide XI (3.80 g, 22.2 mmol, 1.00 eq) was dissolved in triethoxymethane (44.6 g, 301 mmol, 50.0 mL, 13.6 eq) and the mixture was stirred at 150 °C for 2 h. The mixture was filtered and the filter cake was washed with petroleum ether (30 mL) and dried to give 6-chloropyrido[3,2-d]pyrimidin-4-ol XII (3.50 g, 19.3 mmol, 87% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 12.73 (br s, 1H), 8.20 (s, 1H), 8.14 (dd, J = 1.1, 8.6 Hz, 1H), 7.88 (dd, J = 1.0, 8.6 Hz, 1H). [1818] To a solution of 6-chloropyrido[3,2-d]pyrimidin-4-ol XII (3.50 g, 19.3 mmol, 1.00 eq) in thionyl chloride (57.4 g, 482 mmol, 35.0 mL, 25.0 eq) was added dimethyformamide (141 mg, 1.93 mmol, 148 uL, 0.100 eq) dropwise. The mixture was stirred at 90 °C for 4 h. The mixture was concentrated to give 4,6-dichloropyrido[3,2-d]pyrimidine XIII (3.80 g, crude) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 8.38 - 8.25 (m, 1H), 8.16 (dd, J = 2.8, 8.7 Hz, 1H), 7.89 (d, J = 8.6 Hz, 1H). Synthesis of 4,6-dichloro-7-methoxypyrido[3,2-d]pyrimidine
[1819] To a solution of 2-bromo-5-fluoropyridin-3-amine IXa (50.0 g, 262 mmol, 1.00 eq) in methanol (500 mL) and dimethylsulfoxide (50.0 mL) was added [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (19.2 g, 26.2 mmol, 0.100 eq) and triethylamine (79.5 g, 785 mmol, 109 mL, 3.00 eq). The mixture was stirred at 80 °C for 24 h under carbon monoxide (50 Psi). The mixture was concentrated under reduce pressure to get a residue. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 100/1 to 0/1) to give methyl 3-amino-5-fluoropicolinate Xa (17.5 g, crude) as a yellow solid. [1820] To a solution of methyl 3-amino-5-fluoropicolinate Xa (35.0 g, 206 mmol, 1.00 eq) in acetonitrile (200 mL) was added N-bromosuccinimide (40.3 g, 226 mmol, 1.1 eq). Then the mixture was stirred at 25 °C for 12 h. The mixture was concentrated under reduced pressure to give a residue which was purified by chromatography on silica gel (petroleum ether / ethyl acetate = 15/1 to pure ethyl acetate) to give methyl 3-amino-6-bromo-5-fluoro-pyridine-2-carboxylate XIa (12.0 g, 48.2 mmol, 23% yield) as a yellow solid.
1H NMR (400 MHz, DMSO-d
6) δ = 7.18 (d, J = 6.0 Hz, 1H), 7.07 (br s, 1H), 3.81 (s, 3H). [1821] To a solution of methyl methyl 3-amino-6-bromo-5-fluoro-pyridine-2-carboxylate XIa (6.00 g, 24.1 mmol, 1.00 eq) in ethanol (100 mL) was added formamidine acetate (12.0 g, 115 mmol, 4.78 eq). The mixture was stirred at 120 °C for 40 h. After being cooled to room temperature, the mixture was concentrated under reduced pressure to give a residue. The residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate = 15/1 to 0/1) to give 6-bromo-7-fluoropyrido[3,2-d]pyrimidin-4-ol XIIa (2.50 g, 9.87 mmol, 40% yield) as a yellow solid.
1H NMR (400 MHz, DMSO-d
6) δ = 12.80 (s, 1H), 8.17 (s, 1H), 8.16 (d, J = 1.2 Hz, 1H).
[1822] To a solution of methanol (15.8 g, 494 mmol, 20.0 mL, 30.1 eq) in dimethylsulfoxide (15.0 mL) was added potassium tert-butoxide (6.00 g, 53.5 mmol, 3.26 eq). The mixture was stirred at 25 °C for 1 h. Then 6-bromo-7-fluoropyrido[3,2-d]pyrimidin-4-ol XIIa (4.00 g, 16.4 mmol, 1.00 eq) was added. Then the mixture was stirred at 25 °C for another 2 h. The mixture was dissolved in water (100 mL). The solution was adjusted to pH = 7 with hydrochloric acid (1M). Yellow solid was precipitated from the mixture which was collected by filtration and dried in vacuo to give 6- bromo-7-methoxypyrido[3,2-d]pyrimidin-4-ol XIIIa (4.00 g, 15.6 mmol, 95% yield) as a yellow solid. MS (ESI) m/z 255.9 [M+H]
+. [1823] To a suspension of 6-bromo-7-methoxypyrido[3,2-d]pyrimidin-4-ol XIIIa (3.70 g, 14.4 mmol, 1.00 eq) in thionyl chloride (50.0 mL) was added dimethyl formamide (1.90 g, 26.0 mmol, 2.00 mL, 1.80 eq). The mixture was stirred at 100 °C for 1 h. The mixture was concentrated under reduced pressure to give 4,6-dichloro-7-methoxypyrido[3,2-d]pyrimidine XIVa (3.50 g, crude) as a yellow solid. General Procedure A
[1824] Step A.1: To a solution of XIII (1.00 eq) in isopropyl alcohol was added H
2X
1-Y (1.00 eq) dropwise. The mixture was stirred at 90 °C for 1 h. The mixture was concentrated to give crude product. The crude product was washed with ethyl acetate and filtered. The filter cake was dried to give XIV. [1825] Step A.2:
[1826] Variant i: To a solution of XIV (1.00 eq), BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H (1.20 -1.50 eq) and cesium carbonate (2.00 eq) in dioxane was added (2-dicyclohexylphosphino-3,6-dimethoxy- 2,4,6-triisopropyl-1,1-biphenyl)-2-(2-amino-1,1-biphenyl)palladium(II) methanesulfonate (0.100 eq) in one portion under nitrogen. The mixture was stirred at 90 °C for 12 h. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine and dried over sodium sulfate, filtered and concentrated to give crude product. The residue was purified by silica gel chromatography to give the Boc-protected derivative of XV, which was dissolved in EtOAc/HCl (4M). The mixture was stirred at 20 °C for 1 h. The mixture was concentrated to give crude product. The residue was purified by reverse-phase chromatography and concentrated to give XV. [1827] Variant ii: To a solution of XIV (1.00 eq), BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H (1.20 -1.50 eq) and cesium carbonate (2.00 eq) in dioxane was added (2-dicyclohexylphosphino-3,6-dimethoxy- 2,4,6-triisopropyl-1,1-biphenyl)-2-(2-amino-1,1-biphenyl)palladium(II) methanesulfonate (0.100 eq) in one portion under nitrogen. The mixture was stirred at 90 °C for 12 h. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine and dried over sodium sulfate, filtered and concentrated to give crude product. The residue was purified by silica gel chromatography to give the Boc-protected derivative of XV, which was dissolved in dichloromethane and a trifluoroacetic acid (excess) was added. The mixture was stirred at 20 °C for 1 h and concentrated to give XV. [1828] Variant iii: NaH (2.6 eq) was added to a solution of BocN[(CR
aR
b)m(CR
cR
d)n]-X
2H in DMF at 0 °C. After 0,5 h, XIV (1 eq) was added at rt and the mixture was stirred for 25 h. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine and dried over sodium sulfate, filtered and concentrated to give crude product. The residue was purified by silica gel chromatography to give the Boc-protected derivative of XV, which was dissolved in dichloromethane and a trifluoroacetic acid (excess) was added. The mixture was stirred at 20 °C for 1 h and concentrated to give XV. [1829] Step A.3: Variant i: To a solution of XV (1.00 eq) and triethylamine (3.00 eq) in dimethyformamide was added R
1COCl (1.20 eq) dropwise. The mixture was stirred at 20 °C for 2 h. The mixture was filtered and the filtrate was purified by prep-HPLC and lyophilized to give XVI.
General Procedure B
[1830] Step B.1: A mixture of VIII (1.00 eq) and H
2NX
1 (1.00 eq) in isopropanol or MeCN was stirred at 90 °C for 2 h. After the reaction was completed, the mixture was filtered and the filter cake was dried to give XVI. [1831] Step B.2: [1832] Variant i: A mixture of XVI (1.00 eq), BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, brettphos-Pd-G3 (0.100 eq) and sodium tert-butoxide (2.00 eq) in dioxane was stirred at 90 °C under nitrogen atmosphere for 10 hours. After the reaction was completed, the mixture was filtered and the filtrate was purified by prep-HPLC to give Boc-protected derivative of XVII, which was dissolved in ethyl acetate and a solution of hydrochloric acid in ethyl acetate (4 M, excess of up to 200 eq). The mixture was stirred at 10 °C for 0.5 h and concentrated to XVII (hydrochloride). [1833] Variant ii: A mixture of XVI (1.00 eq), BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, brettphos-Pd-G3 (0.100 eq) and sodium tert-butoxide (2.00 eq) in dioxane was stirred at 90 °C under nitrogen atmosphere for 10 hours. After the reaction was completed, the mixture was filtered and the filtrate was purified by prep-HPLC to give Boc-protected derivative of XVII, which was dissolved in dichloromethane and a trifluoroacetic acid (excess) was added. The mixture was stirred at 20 °C for 1 h and concentrated to afford XVII (TFA). [1834] Variant iii: A mixture of XVI (1.00 eq), and N,N-diisopropylethylamine ( 3 eq) in isopropyl alcohol (8.00 mL) was added BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H. The mixture was stirred at 90 °C for 12 h. The mixture was concentrated to give Boc-protected derivative of XVII, which was dissolved
in ethyl acetate and a solution of hydrochloric acid in ethyl acetate (4 M, excess of up to 200 eq). The mixture was stirred at 10 °C for 0.5 h and concentrated to XVII (hydrochloride). [1835] Variant iv: A mixture of XVI (1.00 eq), and N,N-diisopropylethylamine ( 3 eq) in isopropyl alcohol (8.00 mL) was added BocN[(CR
aR
b)m(CR
cR
d)n]-X
2H. The mixture was stirred at 90 °C for 12 h. The mixture was concentrated to give Boc-protected derivative of XVII, which was dissolved in dichloromethane and a trifluoroacetic acid (excess) was added. The mixture was stirred at 20 °C for 1 h and concentrated to XVII (TFA). [1836] Variant v: To a solution of XVI (1.00 eq), in THF was added NaH (2.5 eq) at 0°C. After 0.5 h, BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H was added The mixture was stirred at 0 °C for 2.5 h. The mixture was quenched with water and exacted with ethyl acetate. The organic layer was separated and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under vacuum to give a residue which was purified by column chromatography to give Boc-protected derivative of XVII, which was dissolved in dichloromethane and a trifluoroacetic acid (excess) was added. The mixture was stirred at 20 °C for 1 h and concentrated to XVII (TFA). [1837] Variant vi: A mixture of XVI (1.00 eq), and N,N-diisopropylethylamine ( 3 eq) in isopropyl alcohol (8.00 mL) was added BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H. The mixture was stirred at 90 °C for 12 h. The mixture was concentrated to give Boc-protected derivative of XVII, which was dissolved in dichloromethane and TBSOTf and 2,6 lutidine was added. After 1 h the mixture was concentrated to give XVII. [1838] Step B.3: [1839] Variant i: A mixture of XVII (hydrochloride/TFA, 1.00 eq), pyridine (6.00 eq), acrylic acid (1.50 eq) and carbodiimide hydrochloride (2.00 eq) in dimethyformamide was stirred at 10 °C for 9 h. After the reaction was completed, the mixture was filtered and the filtrate was purified by prep-HPLC and lyophilized to give XVIII. [1840] Vairiant ii: To a solution of XVII (1.00 eq) and triethylamine (3.00 eq) in dimethyl formamide was added acrylic anhydride (1.50 eq) dropwise at 20 °C. The mixture was stirred at 20 °C for 0.5 h. The mixture was filtered and the filtrate was purified by prep-HPLC and lyophilized to give XVIII. [1841] Variant iii: To a solution of XVII (1 eq, HCl), acrylic acid (1.2 eq) and pyridine (5 eq) in dimethyl formamide was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (3 eq) at 25 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was filtered. The filtrate was
purified by prep-HPLC and lyophilized to give XVIII. [1842] Step B.4: To a solution of XVI (1.00 eq) and R
1C(O- N[(CR
aR
b)
m(CR
cR
d)
n]-X
2H in isopropyl alcohol (3.00 mL) was added N,N-diisopropylethylamine (4.00 eq) dropwise. The mixture was stirred at 90 °C for 12 h. The mixture was concentrated to give crude product. The crude product was purified by prep-HPLC and lyophilized to give XVIII. General Procedure C
[1843] Step C.1: [1844] Variant i: To a solution of 6-chloro-3-nitropicolinamide IX in tetrahydrofuran, DMSO or DMF was added BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H and a base (3.0 eq) (trimethylamine, DIPEA, tBuOK, CsCO
3 or K
2CO
3). The mixture was stirred at 25 °C - 100 °C for 1-12 h. The mixture was concentrated. The residue was purified by silica gel chromatography to give XIX. [1845] Variant ii: A solution of BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H in tetrahydrofuran (10 mL) and NaH (1.3 eq) was stirred at 15 °C for 30 min, before 6-chloro-3-nitropicolinamide IX in THF was added and stirred at 15 °C for 4 h. The mixture was stirred at 15 °C for 30 h. The mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The
residue was purified by column chromatographyto give XIX. [1846] Step C.2: [1847] Variant i: A solution of XIX (1.00 eq) in methanolwas added Pd/C. The mixture was stirred at 20 °C under hydrogen (15 Psi) for 12 h. The mixture was filtered. The filtrate was concentrated to give XX. [1848] Variant ii: A mixture of XIX (1.00 eq), iron powder (3.00 eq), ammonium chloride (5.00 eq) in methanol and water was stirred at 80 °C for 1 h. The reaction mixture was poured into methanol and stirred for 10 min, filtered and the filtrate was concentrate to give a residue. The residue was poured into water and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give XX. [1849] Step C.3: A solution of XX (1.00 eq) in triethoxymethane was stirred at 150 °C for 2 h. The mixture was concentrated. The residue was purified by reversed phase column to give XXI. [1850] Step C.4: To a solution of XXI (1.00 eq) in toluene was added Phosphorus(V) oxychloride (1.50 eq) and N,N-diisopropylethylamine (2.00 eq). The mixture was stirred at 100 °C for 2 h. The mixture was quenched with saturated sodium bicarbonate, extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give XXII. [1851] Step C.5: To a solution of XXII (1.00 eq) in 2-propanol or MeCN was added H
2X
2-Y. Optionally, 0.01 to 0.5 eq of HCl or TFA was added. The mixture was stirred at 24 °C - 90 °C for 2 h. The mixture was concentrated to give a residue. The residue was purified by silica gel chromatography to give XXIII. [1852] Step C.6: [1853] Variant i: A solution of XXII (1.00 eq) in hydrochloric acid/ethyl acetate (4 M, excess) or HCl/MeOH (4 M, excess) was stirred at 20 °C for 1 h. The mixture was concentrated to give XXIV. [1854] Variant ii: To a solution of XXII (1.00 eq) in DCM, TFA (excess) was added and the mixture was stirred at 20 °C for 1 h. The mixture was concentrated to give XXIV. [1855] Step C.7: To a solution of XXIV (1.00 eq) in dimethyl formamide was added triethylamine (2.00 eq) and acrylic acid (1.00 eq). The mixture was stirred at 20 °C for 0.5 h. The mixture was filtered. The filtrate was purified by Prep-HPLC to give XXV.
[1856] Synthesis of Compound No.1: Synthesized according to general procedure B, wherein in step B.13-chloro-4-(2-pyridylmethoxy)aniline (327 mg, 1.39 mmol, 1.00 eq) as H
2NX
1, in step B.2 variant i and tert-butyl 3-aminoazetidine-1-carboxylate (181 mg, 1.05 mmol, 1.20 eq) as BocN[(CR
aR
b)m(CR
cR
d)n]-X2H was used and in step B.3 variant i was employed to give 1-(3-((8- ((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)pyrimido(5,4-d)pyrimidin-2- yl)amino)azetidin-1-yl)prop-2-en-1-one 1 (6.07 mg, 12.29 umol) in 1% overall yield. 1H NMR (400 MHz, CDCl3) δ = 9.08 (s, 1H), 8.64 - 8.58(m, 2H), 8.39 (br s, 1H), 8.05 (d, J = 2.8 Hz, 1H), 7.80 - 7.73 (m, 1H), 7.70 - 7.63 (m, 2H), 7.26 - 7.23 (m, 1H), 7.05 (d, J = 9.2 Hz, 1H), 6.43 - 6.35 (m, 1H), 6.30 - 6.20 (m, 1H), 5.88 (br s, 1H), 5.73 (dd, J = 1.6, 10.0 Hz, 1H), 5.32 (s, 2H), 4.91- 4.79 (m, 1H), 4.71 - 4.51 (m, 2H), 4.29 (br s, 2H); MS (ESI) m/z 489.1 [M+H]
+ [1857] Synthesis of Compound No.2: Synthesized according to general procedure B, wherein in step B.13-chloro-4-(2-pyridylmethoxy)aniline (327 mg, 1.39 mmol, 1.00 eq) was used as H2NX
1, in step B.2 variant i and tert-butyl 3-hydroxyazetidine-1-carboxylate (390 mg, 2.25 mmol, 1.50 eq) as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H was used and in step B.3 variant ii was employed to give 1- (3-((8-((3-chloro-4-(pyridin- 2-ylmethoxy)phenyl)amino)pyrimido[5,4-d]pyrimidin-2- yl)oxy)azetidin-1-yl)prop-2-en-1-one 2 in 5% overall yield from intermediate XVI.
1H NMR (400MHz, DMSO-d
6) δ = 9.87 (br s, 1 H), 9.36 (s, 1 H), 8.63 (s, 1 H), 8.60 (d, J = 4.0 Hz, 1 H), 8.11 (d, J = 2.6 Hz, 1 H), 7.89 (td, J = 7.6, 1.8 Hz, 1 H), 7.84 (dd, J = 9.0, 2.6 Hz, 1 H), 7.59 (d, J = 7.8 Hz, 1 H), 7.38 (dd, J = 7.2, 5.2 Hz, 1 H), 7.31 (d, J = 9.0 Hz, 1 H), 6.37 (dd, J = 17.0, 10.4 Hz, 1 H), 6.15 (dd, J = 17.0, 2.0 Hz, 1 H), 5.79 - 5.73 (m, 1 H), 5.72 - 5.68 (m, 1 H), 5.31 (s, 2 H), 4.84 (br dd, J = 9.4, 7.0 Hz, 1 H), 4.55 (br dd, J = 11.0, 6.6 Hz, 1 H), 4.32 (br dd, J = 10.0, 3.4 Hz, 1 H), 4.03 (br dd, J = 11.4, 3.8 Hz, 1 H). MS (ESI) m/z 490.2 [M+H]
+. [1858] Synthesis of Compound No.3: Synthesized according to general procedure B, wherein in step B.1 5-chloro-2-fluoroaniline (1.42 g, 9.77 mmol, 1.05 eq) was used as H
2NX
1, in step B.2 variant i and tert-butyl 3-aminoazetidine-1-carboxylate (333 mg, 1.93 mmol, 1.2 eq) as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H was used and in step B.3 variant iii was employed to give 1-(3- ((8-((5-chloro-2- fluorophenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)amino)azetidin-1-yl)prop- 2-en-1-one 3 in 11% overall yield.
1H NMR (400MHz, DMSO- d
6) δ = 9.36 (br s, 1H), 9.42 - 9.29 (m, 1H), 9.14 (s, 1H), 8.69 (br s, 1H), 8.51 (s, 1H), 8.28 (br s, 1H), 8.24 (s, 1H), 7.45 (dd, J=8.9, 10.5 Hz, 1H), 7.33 (br s, 1H), 6.36 (dd, J=10.3, 16.9 Hz, 1H), 6.13 (dd, J=2.3, 17.0 Hz, 1H), 5.69 (dd, J=2.2, 10.3 Hz, 1H), 4.95 - 4.85 (m, 1H), 4.66 (br t, J=7.9 Hz, 1H), 4.35 (br d, J=8.4 Hz, 1H),
4.19 (dd, J=5.7, 9.1 Hz, 1H), 3.98 (dd, J=5.8, 10.1 Hz, 1H). MS (ESI) m/z 400.2 [M+H]
+ [1859] Synthesis of Compound No.4: Synthesized according to general procedure B, wherein in step B.14-phenoxyaniline (737 mg, 3.98 mmol, 1.00 eq) was used as H
2NX
1, in step B.2 variant ii and tert-butyl 3-aminoazetidine-1-carboxylate (684 mg, 3.97 mmol, 1.00 eq) as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H was used and in step B.3 variant i was employed to give 1-(3-((8- ((4-phenoxyphenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)amino)azetidin-1-yl)prop-2-en-1-one 4 in 4% overall yield.
1H NMR (400 MHz, DMSO-d
6) δ = 9.42 (s, 1H), 9.06 (s, 1H), 8.54 (br s, 1H), 8.42 (s, 1H), 7.94 (d, J = 9.0 Hz, 2H), 7.45 - 7.35 (m, 2H), 7.18 - 7.08 (m, 3H), 7.05 - 6.97 (m, 2H), 6.37 (dd, J = 10.3, 17.0 Hz, 1H), 6.13 (dd, J = 2.3, 17.0 Hz, 1H), 5.68 (dd, J = 2.3, 10.3 Hz, 1H), 5.13 (br s, 1H), 4.69 (br t, J = 8.3 Hz, 1H), 4.37 (br t, J = 9.1 Hz, 1H), 4.17 (dd, J = 5.9, 8.7 Hz, 1H), 3.99 (dd, J = 5.8, 10.2 Hz, 1H). MS (ESI) m/z 440.2 [M+H]
+ [1860] Synthesis of Compound No.5: Synthesized according to general procedure B, wherein in step B.1 5-chloro-2-fluoroaniline (1.42 g, 9.77 mmol, 1.05 eq) was used as H
2NX
1, in step B.2 variant i tert-butyl 3-hydroxyazetidine-1-carboxylate (754 mg, 4.35 mmol, 1.50 eq) as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H was used and in step B.3 variant iii was employed to give 1-(3- ((8-((5-chloro-2-fluorophenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)oxy)azetidin- 1-yl)prop-2- en-1-one 5 in 23% overall yield.
1H NMR (400MHz, DMSO-d
6) δ = 9.78 (br s, 1 H), 9.44 (s, 1 H), 8.66 (s, 1 H), 8.03 (dd, J = 6.6, 2.6 Hz, 1 H), 7.52 - 7.43 (m, 1 H), 7.43 - 7.36 (m, 1 H), 6.37 (dd, J = 17.0, 10.2 Hz, 1 H), 6.15 (dd, J = 17.0, 2.2 Hz, 1 H), 5.71 (dd, J = 10.4, 2.2 Hz, 1 H), 5.65 (tt, J = 6.6, 4.2 Hz, 1 H), 4.91 - 4.77 (m, 1 H), 4.56 (br dd, J = 11.2, 6.6 Hz, 1 H), 4.37 (br dd, J = 10.0, 3.8 Hz, 1 H), 4.05 (br dd, J = 11.2, 3.6 Hz, 1 H). MS (ESI) m/z 401.1 [M+H]
+ [1861] Synthesis of Compound No.6: Synthesized according to general procedure A, wherein in step A.1 3-chloro-4-(pyridin-2-ylmethoxy)aniline (1.06 g, 4.50 mmol, 1.00 eq) was used as H
2NX
1, in step A.2 variant i and tert-butyl 3-aminoazetidine-1-carboxylate (584 mg, 3.39 mmol, 1.50 eq) as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H was used and in step A.3 variant iii was employed to give 1-(3-((4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)pyrido [3,2-d]pyrimidin-6- yl)amino)azetidin-1-yl)prop-2-en-1-one 6 in 34% overall yield.
1H NMR (400MHz, DMSO-d6) δ = 9.13 (s, 1 H), 8.60 (d, J = 4.2 Hz, 1 H), 8.41 (s, 1 H), 8.17 (d, J = 2.6 Hz, 1 H), 8.14 (d, J = 7.0 Hz, 1 H), 7.91 - 7.78 (m, 3 H), 7.59 (d, J = 7.8 Hz, 1 H), 7.37 (dd, J = 7.0, 5.2 Hz, 1 H), 7.28 (d, J = 9.0 Hz, 1 H), 7.11 (d, J = 9.0 Hz, 1 H), 6.40 (dd, J = 16.8, 10.2 Hz, 1 H), 6.14 (dd, J = 16.8, 2.2 Hz, 1 H), 5.69 (dd, J = 10.2, 2.2 Hz, 1 H), 5.30 (s, 2 H), 5.21 - 5.09 (m, 1 H), 4.73 (t, J = 8.2 Hz,
1 H), 4.41 (br t, J = 9.2 Hz, 1 H), 4.09 (dd, J = 8.8, 5.4 Hz, 1 H), 3.91 (br dd, J = 10.4, 5.4 Hz, 1 H). MS (ESI) m/z 488.2 [M+H]
+ [1862] Synthesis of Compound No.7: Synthesized according to general procedure B, wherein in step B.14-methoxyaniline (142 mg, 1.15 mmol, 1.00 eq) was used as H2NX
1, in step B.2 variant iv tert-butyl 3-aminoazetidine-1-carboxylate (114 mg, 660 umol, 1.00 eq) as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H was used and in step B.3 variant i was employed to give 1-(3-((8- ((4-methoxyphenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)amino)azetidin-1- yl)prop-2-en-1-one 7 in 18% overall yield.
1H NMR (400 MHz, DMSO-d
6) δ = 9.33 (s, 1H), 9.04 (s, 1H), 8.51 (br s, 1H), 8.42 (br s, 0.6 H), 8.38 (s, 1H), 7.80 (d, J = 9.0 Hz, 2H), 7.07 - 6.94 (m, 2H), 6.38 (dd, J = 10.3, 17.0 Hz, 1H), 6.13 (dd, J = 2.2, 17.0 Hz, 1H), 5.69 (dd, J = 2.3, 10.3 Hz, 1H), 5.12 (br s, 1H), 4.69 (br t, J = 7.9 Hz, 1H), 4.36 (br t, J = 9.1 Hz, 1H), 4.17 (br dd, J = 5.7, 8.7 Hz, 1H), 3.99 (br dd, J = 5.8, 9.8 Hz, 1H), 3.78 (s, 3H). MS (ESI) m/z 378.2 [M+H]
+. [1863] Synthesis of Compound No.8: Synthesized according to general procedure B, wherein in step B.1 3-chloro-4-(pyridin-2-ylmethoxy)aniline (630 mg, 2.69 mmol, 0.900 eq) was used as H
2NX
1, in step B.2 variant iii tert-butyl 4-aminopiperidine-1-carboxylate (331 mg, 1.65 mmol, 1.20 eq) as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H was used and in step B.3 variant i was employed to give 1-(4-((8-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)pyrimido[5,4-d]pyrimidin-2- yl)amino)piperidin-1-yl)prop-2-en-1-one 8 in 16% overall yield.
1H NMR (400 MHz, DMSO-d
6) δ = 9.38 (s, 1 H), 9.01 (br s, 1 H), 8.66 - 8.57 (m, 1 H), 8.41 (s, 1 H), 8.16 (br s, 1 H), 7.89 (td, J = 7.6, 1.8 Hz, 2 H), 7.82 (br d, J = 8.0 Hz, 1 H), 7.59 (d, J = 7.8 Hz, 1 H), 7.37 (dd, J = 6.6, 4.8 Hz, 1 H), 7.30 (d, J = 9.0 Hz, 1 H), 6.86 (dd, J = 16.6, 10.6 Hz, 1 H), 6.12 (dd, J = 16.8, 2.4 Hz, 1 H), 5.73 - 5.66 (m, 1 H), 5.31 (s, 2 H), 4.53 - 4.33 (m, 2 H), 4.09 (br d, J = 13.4 Hz, 1 H), 3.30 (br s, 1 H), 2.97 (br s, 1 H), 2.00 (br s, 2 H), 1.52 - 1.37 (m, 2 H). MS (ESI) m/z 517.2 [M+H]
+ [1864] Synthesis of Compound No.9: Synthesized according to general procedure B, wherein in step B.13-chloro-2-fluoroaniline (290 mg, 1.99 mmol, 0.800 eq) was used as H
2NX
1, in step B.2 variant iv tert-butyl 3-aminoazetidine-1-carboxylate (322 mg, 1.87 mmol, 1.00 eq) as BocN[(CR
aR
b)m(CR
cR
d)n]-X2H was used and in step B.3 variant ii was employed to give 1-(3-((8- ((3-chloro-2-fluorophenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)amino)azetidin-1-yl)prop-2-en- 1-one 9 in 8% overall yield.
1H NMR (400MHz, DMSO-d
6) δ = 9.48 (br s, 1H), 9.11 (s, 1H), 8.63 (br s, 1H), 8.73 - 8.53 (m, 1H), 8.43 (s, 1H), 7.97 (br s, 1H), 7.53 - 7.39 (m, 1H), 7.32 (dt, J = 1.5, 8.2 Hz, 1H), 7.26 - 7.23 (m, 1H), 6.36 (dd, J = 10.3, 17.0 Hz, 1H), 6.12 (dd, J = 2.3, 16.9 Hz, 1H),
5.75 - 5.62 (m, 1H), 4.95 (br d, J = 6.5 Hz, 1H), 4.67 (br t, J = 8.2 Hz, 1H), 4.37 (br t, J = 8.7 Hz, 1H), 4.43 - 4.30 (m, 1H), 4.18 (dd, J = 5.9, 8.7 Hz, 1H), 3.96 (dd, J = 5.7, 10.1 Hz, 1H), 4.03 - 3.90 (m, 1H). MS (ESI) m/z 400.1 [M+H]
+ [1865] Synthesis of Compound No. 10: Synthesized according to general procedure B, wherein in step B.14-amino-2-chlorophenol (286 mg, 1.99 mmol, 0.800 eq) was used as H
2NX
1, in step B.2 variant iv tert-butyl 3-aminoazetidine-1-carboxylate (279 mg, 1.62 mmol, 1.00 eq) as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H was used and in step B.3 variant ii was employed to give 1-(3-((8- ((3-chloro-4-hydroxyphenyl)amino) pyrimido[5,4-d] pyrimidin-2-yl)amino) azetidin-1-yl)prop-2- en-1-one 10 in 1% overall yield.
1H NMR (400MHz, DMSO-d
6) δ = 9.32 (br s, 1H), 9.03 (br s, 1H), 8.51 (br s, 1H), 8.40 (br s, 1H), 7.97 (br s, 1H), 7.66 (br s, 1H), 7.02 (br s, 1H), 6.35 (br d, J = 9.3 Hz, 1H), 6.13 (br d, J = 16.6 Hz, 1H), 5.69 (br d, J = 8.7 Hz, 1H), 5.10 (br s, 2H), 4.68 (br s, 2H), 4.36 (br s, 1H), 4.16 (br s, 1H), 3.98 (br s, 1H). MS (ESI) m/z 398.1 [M+H]
+ [1866] Synthesis of Compound No. 11: Synthesized according to general procedure B, wherein in step B.13-chloro-4-(pyridin-2-ylmethoxy)aniline (630 mg, 2.69 mmol, 0.900 eq) was used as H
2NX
1, in step B.41-(3-(methylamino)azetidin-1-yl)prop-2-en-1-one (127 mg, 501 umol, 2.00 eq, TFA) was used as R
1C(O- N[(CR
aR
b)
m(CR
cR
d)
n]-X
2H to give 1-(3-((8-((3-chloro-4- (pyridin-2- ylmethoxy)phenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)(methyl)amino)azetidin-1-yl)prop-2- en-1-one 11 in 19% yield from XVI.
1H NMR (400MHz, DMSO-d
6) δ = 9.56 (s, 1 H), 9.13 (s, 1 H), 8.60 (br d, J = 4.2 Hz, 1 H), 8.44 (s, 1 H), 8.12 (d, J = 2.4 Hz, 1 H), 7.96 - 7.82 (m, 2 H), 7.59 (d, J = 7.8 Hz, 1 H), 7.42 - 7.34 (m, 1 H), 7.31 (d, J = 9.0 Hz, 1 H), 6.40 (dd, J = 17.0, 10.2 Hz, 1 H), 6.15 (dd, J = 17.0, 2.2 Hz, 1 H), 5.91 (br s, 1 H), 5.71 (dd, J = 10.2, 2.0 Hz, 1 H), 5.31 (s, 2 H), 4.64 - 4.54 (m, 1 H), 4.50 - 4.41 (m, 1 H), 4.34 - 4.27 (m, 1 H), 4.19 (br dd, J = 10.6, 6.0 Hz, 1 H), 3.42 (s, 3 H). MS (ESI) m/z 503.2 [M+H]
+ Synthesis of 1-(3-(methylamino) azetidin-1-yl)prop-2-en-1-one [1867] To a solution of tert-butyl azetidin-3-yl(methyl)carbamate (500 mg, 2.25 mmol, 1.00 eq, HCl) and sodium hydrogencarbonate (566 mg, 6.74 mmol, 262 uL, 3.00 eq) in tetrahydrofuran (10.0 mL) was added acryloyl chloride (406 mg, 4.49 mmol, 366 uL, 2.00 eq) dropwise at 0 °C. The mixture was stirred at 25 °C for 1 h. The mixture was diluted with water (30.0 mL) and extracted with ethyl acetate (3 × 30.0 mL). The combined organic layer was washed with brine (10.0 mL) and dried over sodium sulfate, filtered and concentrated to give tert-butyl (1-
acryloylazetidin-3-yl)(methyl)carbamate (540 mg, crude) as colorless oil. To a solution of tert- butyl (1-acryloylazetidin-3-yl)(methyl)carbamate (540 mg, 2.25 mmol, 1.00 eq) in dichloromethane (5.00 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol, 1.00 mL, 6.01 eq) dropwise. The mixture was stirred at 25 °C for 0.5 h. The mixture was concentrated to give 1-(3- (methylamino) azetidin-1-yl)prop-2-en-1-one (580 mg, crude, TFA) as colorless oil.
1H NMR (400MHz, DMSO-d
6) δ = 6.36 - 6.27 (m, 1 H), 6.18 - 6.09 (m, 1 H), 5.72 (dd, J = 10.2, 2.0 Hz, 1 H), 4.48 (dd, J = 9.8, 7.0 Hz, 1 H), 4.23 (br dd, J = 9.6, 4.2 Hz, 1 H), 4.15 (br dd, J = 10.2, 7.0 Hz, 1 H), 4.08 - 3.99 (m, 2 H), 2.57 (br s, 3 H). [1868] Synthesis of Compound No. 12: Synthesized according to general procedure B, wherein in step B.1 tert-butyl 5-amino-1H-indole-1-carboxylate (462 mg, 1.99 mmol, 0.800 eq) was used as H
2NX
1, in step B.4 1-(3-aminoazetidin-1-yl)prop-2-en-1-one (260 mg, 1.51 mmol, 3.00 eq, TFA) was used as R
1C(O- N[(CR
aR
b)m(CR
cR
d)n]-X
2H to give tert-butyl 5-((6-((1- acryloylazetidin-3-yl)amino)pyrimido[5,4-d]pyrimidin-4-yl)amino)-1H-indole-1-carboxylate 12 in 27% overall yield.
1H NMR (400 MHz, DMSO-d
6) δ = 11.10 (br s, 1H), 9.35 (br s, 1H), 9.03 (s, 1H), 8.48 (br s, 1H), 8.39 (s, 1H), 8.13 (s, 1H), 7.51 (br d, J = 8.9 Hz, 1H), 7.45 - 7.41 (m, 1H), 7.37 (t, J = 2.7 Hz, 1H), 6.46 (br s, 1H), 6.43 - 6.34 (m, 1H), 6.14 (dd, J = 2.3, 16.9 Hz, 1H), 5.69 (dd, J = 2.3, 10.3 Hz, 1H), 5.13 (br s, 1H), 4.81 - 4.58 (m, 1H), 4.38 (br t, J = 9.0 Hz, 1H), 4.24 - 4.14 (m, 1H), 4.10 - 3.90 (m, 1H). MS (ESI) m/z 387.2 [M+H]
+ Synthesis of Synthesis of 1-(3-aminoazetidin-1-yl)prop-2-en-1-one [1869] To a solution of tert-butyl azetidin-3-ylcarbamate (1.00 g, 4.79 mmol, 1.00 eq, HCl) and sodium hydrogencarbonate (1.21 g, 14.4 mmol, 3.00 eq) in tetrahydrofuran (10.0 mL) was added prop-2-enoyl chloride (477 mg, 5.27 mmol, 1.10 eq) at 0 °C. The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was diluted with water (20.0 mL) and extracted with ethyl acetate (3 × 50.0 mL). The combined organic layers were washed with brine (3 × 20.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl (1-acryloylazetidin-3- yl)carbamate (1.00 g, 4.42 mmol, 92% yield) as a white solid. A mixture of tert-butyl (1- acryloylazetidin-3-yl)carbamate (1.00 g, 4.42 mmol, 1.00 eq) and trifluoroacetic acid (3.08 g, 27.0 mmol, 2.00 mL) in dichloromethane (10.0 mL) was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated to give 1-(3-aminoazetidin-1-yl)prop-2-en-1-one (1.20 g, crude, TFA) as a yellow oil.
1H NMR (400 MHz, DMSO-d
6) δ = 6.34 (dd, J = 10.3, 16.9 Hz, 1H), 6.13 (dd, J = 2.1,
17.0 Hz, 1H), 5.71 (dd, J = 2.2, 10.3 Hz, 1H), 4.56 - 4.41 (m, 1H), 4.15 (td, J = 4.8, 9.2 Hz, 2H), 4.08 - 4.03 (m, 1H), 3.89 (dd, J = 4.2, 11.0 Hz, 1H). [1870] Synthesis of Compound No. 13: Synthesized according to general procedure A, wherein in step A.13-chloro-2-fluoroaniline (2.77 g, 19.0 mmol, 1.00 eq) was used as H2NX
1, in step A.2 variant ii tert-butyl 3-hydroxyazetidine-1-carboxylate (4.87 g, 28.1 mmol, 1.50 eq) as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H was used and in step A.3 variant i was employed to give 1-(3-((4- ((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)azetidin-1-yl) prop-2-en-1- one 13 in 7% overall yield.
1H NMR (400 MHz, DMSO-d
6) δ = 9.47 (s, 1 H), 8.58 (s, 1 H), 8.21 (d, J = 9.1 Hz, 1 H), 8.09 - 7.92 (m, 1 H), 7.59 - 7.43 (m, 2 H), 7.34 (td, J = 8.2, 1.4 Hz, 1 H), 6.38 (dd, J = 17.0, 10.4 Hz, 1 H), 6.14 (dd, J = 17.1, 2.1 Hz, 1 H), 5.76 (tt, J = 6.7, 4.4 Hz, 1 H), 5.71 (dd, J = 10.2, 2.2 Hz, 1 H), 4.85 (br dd, J = 9.1, 7.4 Hz, 1 H), 4.58 (br dd, J = 10.6, 7.0 Hz, 1 H), 4.32 (br dd, J = 9.8, 4.1 Hz, 1 H), 4.02 (br dd, J = 11.2, 4.1 Hz, 1 H). MS (ESI) m/z 400.2 [M+H]
+ [1871] Synthesis of Compound No. 14: Synthesized according to general procedure A, wherein in step A.13-chloro-2-fluoroaniline (2.77 g, 19.0 mmol, 1.00 eq) was used as H
2NX
1, in step A.2 variant ii tert-butyl 3-aminoazetidine-1-carboxylate (501 mg, 2.91 mmol, 1.50 eq) as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H was used and in step A.3 variant i was employed to give 1-(3-((4- ((3-chloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)amino) azetidin-1-yl)prop-2-en-1- one 14 in 1% overall yield.
1H NMR (400 MHz, DMSO-d
6) δ = 9.24 (s, 1H), 8.43 (s, 1H), 8.38 - 8.20 (m, 2H), 7.88 (d, J = 9.0 Hz, 1H), 7.39 - 7.24 (m, 2H), 7.16 (d, J = 9.0 Hz, 1H), 6.38 (dd, J = 10.3, 17.0 Hz, 1H), 6.17 - 6.09 (m, 1H), 5.76 - 5.65 (m, 1H), 4.90 (br d, J = 5.1 Hz, 1H), 4.70 (br t, J = 8.1 Hz, 1H), 4.40 (br t, J = 8.8 Hz, 1H), 4.20 - 4.05 (m, 1H), 3.88 (br dd, J = 5.1, 10.0 Hz, 1H). MS (ESI) m/z 399.3 [M+H]
+ [1872] Synthesis of Compound No. 15: Synthesized according to general procedure A, wherein in step A.13-chloro-2-fluoroaniline (2.77 g, 19.0 mmol, 1.00 eq) was used as H
2NX
1, in step A.2 variant ii tert-butyl 3-(methylamino)azetidine-1-carboxylate (343 mg, 1.84 mmol, 1.50 eq) as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H was used and in step A.3 variant i was employed to give 1-(3-((4- ((3-chloro-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)(methyl)amino)azetidin-1- yl)prop-2-en-1-one 15 in 4% yield from XIV.
1H NMR (400 MHz, DMSO-d
6) δ = 9.37 (s, 1H), 8.43 (s, 1H), 8.19 - 8.09 (m, 1H), 8.01 (d, J = 9.4 Hz, 1H), 7.52 (d, J = 9.3 Hz, 1H), 7.47 - 7.38 (m, 1H), 7.36 - 7.24 (m, 1H), 6.40 (dd, J = 10.3, 17.0 Hz, 1H), 6.15 (dd, J = 2.2, 17.0 Hz, 1H), 5.71 (dd, J = 2.2, 10.3 Hz, 2H), 4.62 (br t, J = 8.6 Hz, 1H), 4.46 - 4.37 (m, 1H), 4.33 (br t, J = 9.5
Hz, 1H), 4.12 (br dd, J = 6.1, 10.7 Hz, 1H), 3.23 (s, 3H). MS (ESI) m/z 413.3 [M+H]
+ [1873] Synthesis of Compound No. 16: Synthesized according to general procedure C, wherein in step C.1, variant i and (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (4.44 g, 23.8 mmol, 1.20 eq) was used as BocN[(CR
aR
b)m(CR
cR
d)n]-X
2H, in step C.2 variant i was used. in step C.53,4- dichloro-2-fluoroaniline (515 mg, 2.86 mmol, 1.00 eq) was used as HX
1-Y and in step C.6, variant i was used to give (S)-1-(3-((4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6- yl)amino)pyrrolidin-1-yl)prop-2-en-1-one 16 in 5% overall yield.
1H NMR (400 MHz, DMSO-d
6) δ = 9.27 (br d, J = 7.1 Hz, 1H), 8.52 - 8.30 (m, 2H), 7.90 (br dd, J = 6.2, 12.0 Hz, 1H), 7.83 (dd, J = 1.0, 9.2 Hz, 1H), 7.57 (d, J = 9.0 Hz, 1H), 7.14 (dd, J = 2.3, 9.2 Hz, 1H), 6.72 - 6.52 (m, 1H), 6.15 (ddd, J = 2.4, 6.1, 16.8 Hz, 1H), 5.67 (ddd, J = 2.4, 10.3, 17.6 Hz, 1H), 4.80 - 4.57 (m, 1H), 4.12 - 3.77 (m, 1H), 3.76 - 3.70 (m, 1H), 3.64 - 3.44 (m, 2H), 2.37 - 2.21 (m, 1H), 2.12 - 1.91 (m, 1H). LC-MS (ESI) m/z 447.2 [M+1]
+ [1874] Synthesis of Compound No. 17: Synthesized according to general procedure C, wherein in step C.1 variant ii and (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (4.44 g, 23.8 mmol, 1.20 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.53,4- dichloro-2-fluoroaniline (154 mg, 855 umol, 0.75 eq) was used as HX
1-Y and in step C.6, variant i was used to give (S)-1-(3-((4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,2-d] pyrimidin-6- yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one 17 in 3% overall yield.
1H NMR (400 MHz, DMSO-d
6) δ = 9.65 (br s, 1H), 8.56 (s, 1H), 8.16 (dd, J = 1.0, 9.0 Hz, 1H), 8.03 (dt, J = 3.5, 8.4 Hz, 1H), 7.69 - 7.60 (m, 1H), 7.42 (dd, J = 4.4, 9.0 Hz, 1H), 6.75 - 6.50 (m, 1H), 6.17 (ddd, J = 2.3, 6.1, 16.8 Hz, 1H), 6.09 - 5.91 (m, 1H), 5.69 (ddd, J = 2.3, 10.3, 19.0 Hz, 1H), 4.11 - 3.80 (m, 2H), 3.78 - 3.49 (m, 2H), 2.42 - 2.17 (m, 2H). MS (ESI) m/z 448.2 [M+H]
+. [1875] Synthesis of Compound No. 18: Synthesized according to general procedure C, wherein in step C.1 variant i and tert-butyl 3-amino-3-methylazetidine-1-carboxylate (1.11 g, 5.95 mmol, 1.20 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant ii was used and in step C.54-phenoxyaniline (29.1 mg, 157 umol, 1.10 eq) was used as HX
1-Y and in step C.6, variant ii was used to give 1-(3-methyl-3-((4-((4-phenoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6- yl)amino)azetidin-1-yl)prop-2-en-1-one 18 in 8% overall yield.
1H NMR (400 MHz, CDCl
3) δ = 8.62 - 8.60 (m, 1H), 8.53 (s, 1H), 7.93 (d, J = 9.0 Hz, 1H), 7.84 - 7.79 (m, 2H), 7.38 - 7.32 (m, 2H), 7.14 - 7.10 (m, 1H), 7.10 - 7.06 (m, 2H), 7.06 - 7.01 (m, 2H), 6.93 (d, J = 9.0 Hz, 1H), 6.39 - 6.33 (m, 1H), 6.31 - 6.23 (m, 1H), 5.72 - 5.66 (m, 1H), 5.01 (s, 1H), 4.90 (d, J = 8.0 Hz, 1H), 4.83
(d, J = 10.4 Hz, 1H), 4.17 (d, J = 8.4 Hz, 1H), 4.12 (d, J = 10.0 Hz, 1H), 1.83 (s, 3H). MS (ESI) m/z 453.0 [M+H]. [1876] Synthesis of Compound No. 19: Synthesized according to general procedure C, wherein in step C.1 variant i and (S)-tert-butyl 3-(methylamino)pyrrolidine-1-carboxylate (1.50 g, 7.49 mmol, 1.01 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.53,4-dichloro-2-fluoro-aniline (400 mg, 2.22 mmol, 1.01 eq) was used as HX
1-Y and in step C.6, variant i was used to give (S)-1-(3-((4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)(methyl)amino) pyrrolidin-1- yl)prop-2-en-1-one 19 in 3% overall yield.
1H NMR (400 MHz, DMSO-d
6) δ = 9.39 (br d, J = 6.5 Hz, 1H), 8.42 (s, 1H), 8.20 (td, J = 8.6, 10.9 Hz, 1H), 7.98 (d, J = 9.4 Hz, 1H), 7.59 (d, J = 8.9 Hz, 1H), 7.54 (dd, J = 5.5, 9.3 Hz, 1H), 6.65 (dt, J = 10.4, 16.9 Hz, 1H), 6.18 (ddd, J = 2.4, 5.3, 16.8 Hz, 1H), 5.69 (ddd, J = 2.4, 10.4, 14.7 Hz, 1H), 5.63 - 5.43 (m, 1H), 3.99 - 3.82 (m, 1H), 3.81 - 3.68 (m, 1H), 3.67 - 3.52 (m, 1H), 3.47 - 3.40 (m, 1H), 3.10 (d, J = 5.3 Hz, 3H), 2.26 - 2.09 (m, 2H). MS (ESI) m/z 460.9 [M+H]
+ [1877] Synthesis of Compound No. 20: Synthesized according to general procedure C, wherein in step C.1 variant i and tert-butyl 3-hydroxyazetidine-1-carboxylate (2.60 g, 15.0 mmol, 1.21 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.5 3- chloro-4-((3-fluorobenzyl)oxy)aniline (396 mg, 1.57 mmol, 1.00 eq) was used as HX
1-Y and in step C.6, variant ii was used to give 1-(3-((4-((3-chloro-4-((3- fluorobenzyl)oxy)phenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)oxy)azetidin-1-yl)prop-2-en-1-one 20 in 3% overall yield.
1H NMR (400 MHz, DMSO-d6) δ = 9.36 (s, 1H), 8.57 (s, 1H), 8.15 (d, J = 9.0 Hz, 1H), 8.09 (d, J = 2.5 Hz, 1H), 7.83 (dd, J = 2.6, 8.9 Hz, 1H), 7.50 - 7.43 (m, 2H), 7.35 - 7.28 (m, 3H), 7.18 (dt, J = 2.1, 8.6 Hz, 1H), 6.38 (dd, J = 10.3, 17.0 Hz, 1H), 6.14 (dd, J = 2.1, 17.0 Hz, 1H), 5.88 (tt, J = 4.3, 6.7 Hz, 1H), 5.72 - 5.67 (m, 1H), 5.27 (s, 2H), 4.87 (dd, J = 7.3, 9.3 Hz, 1H), 4.56 (dd, J = 7.0, 11.0 Hz, 1H), 4.26 (dd, J = 3.9, 9.8 Hz, 1H), 4.00 (dd, J = 3.9, 11.2 Hz, 1H). MS (ESI) m/z 506.1 [M+H]
+ [1878] Synthesis of Compound No. 21: Synthesized according to general procedure C, wherein in step C.1 variant i and tert-butyl 3-amino-3-methylazetidine-1-carboxylate (1.11 g, 5.95 mmol, 1.20 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant ii was used and in step C.53-chloro-4-[(3-fluorophenyl)methoxy]aniline (68.0 mg, 270 umol, 0.900 eq) was used as HX
1- Y and in step C.6, variant i was used to give 1-(3-((4-((3-chloro-4-((3-fluorobenzyl)oxy) phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)amino)-3-methylazetidin-1-yl)prop-2-en-1-one 21 in
4% yield from XXII.
1H NMR (400 MHz, CDCl
3) δ = 8.51 (s, 1H), 8.31 (s, 1H), 7.94 (d, J = 2.6 Hz, 1H), 7.83 (d, J = 9.0 Hz, 1H), 7.54 (dd, J = 2.8, 8.8 Hz, 1H), 7.33 - 7.25 (m, 1H), 7.18 - 7.12 (m, 2H), 6.95 (dt, J = 2.4, 8.4 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 6.83 (d, J = 9.0 Hz, 1H), 6.32 - 6.25 (m, 1H), 6.22 - 6.13 (m, 1H), 5.60 (dd, J = 2.0, 10.2 Hz, 1H), 5.08 (s, 2H), 4.89 (s, 1H), 4.85 - 4.77 (m, 2H), 4.09 - 3.95 (m, 2H), 1.72 (s, 3H). MS (ESI) m/z 519.1 [M+H] [1879] Synthesis of Compound No. 22: Synthesized according to general procedure C, wherein in step C.1 variant i and tert-butyl 3-hydroxy-3-methyl-azetidine-1-carboxylate (1.34 g, 7.14 mmol, 1.20 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant ii was used and in step C.5 4-phenoxyaniline (23.8 mg, 128 umol, 0.900 eq) was used as HX
1-Y and in step C.6, variant ii was used to give 1-(3-methyl-3-((4-((4-phenoxyphenyl)amino)pyrido[3,2-d] pyrimidin- 6-yl)oxy)azetidin-1-yl)prop-2-en-1-one 22 in 3% overall yield.
1H NMR (400 MHz, CDCl
3) δ = 8.72 (s, 1H), 8.37 (s, 1H), 8.13 (d, J = 8.8 Hz, 1H), 7.86 - 7.77 (m, 2H), 7.40 - 7.33 (m, 2H), 7.28 (s, 1H), 7.24 (d, J = 9.0 Hz, 1H), 7.16 - 7.10 (m, 3H), 7.08 - 7.03 (m, 2H), 6.46 - 6.35 (m, 1H), 6.32 - 6.21 (m, 1H), 5.74 (dd, J = 1.8, 10.4 Hz, 1H), 4.67 (br d, J = 9.2 Hz, 1H), 4.58 (br d, J = 10.8 Hz, 1H), 4.42 - 4.28 (m, 2H), 1.99 (s, 3H). MS (ESI) m/z 454.4 [M+H] [1880] Synthesis of Compound No. 23: Synthesized according to general procedure C, wherein in step C.1 variant i and tert-butyl 3-hydroxy-3-methyl-azetidine-1-carboxylate (1.34 g, 7.14 mmol, 1.20 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant ii was used and in step C.53-chloro-4-((3-fluorobenzyl)oxy)aniline (32.3 mg, 128 umol, 0.900 eq) was used as HX
1- Y and in step C.6, variant ii was used to give 1-(3-((4-((3-chloro-4-((3- fluorobenzyl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)-3-methylazetidin-1-yl)prop-2- en-1-one 23 in 13% yield frim XXII.
1H NMR (400 MHz, CDCl
3) δ = 8.72 (s, 1H), 8.26 (s, 1H), 8.13 (d, J = 9.0 Hz, 1H), 8.02 (d, J = 2.8 Hz, 1H), 7.62 (dd, J = 2.6, 8.8 Hz, 1H), 7.43 - 7.35 (m, 1H), 7.28 - 7.22 (m, 3H), 7.08 - 7.00 (m, 2H), 6.44 - 6.38 (m, 1H), 6.30 - 6.22 (m, 1H), 5.75 (dd, J = 1.6, 10.2 Hz, 1H), 5.20 (s, 2H), 4.70 - 4.57 (m, 2H), 4.39 - 4.30 (m, 2H), 1.98 (s, 3H). MS (ESI) m/z 520.3 [M+H] [1881] Synthesis of Compound No. 24: Synthesized according to general procedure C, wherein in step C.1 no base was added and the mixture was heated to 130 °C for 16 h with tert-butyl (3S)- 3-(ethylamino)pyrrolidine-1-carboxylate (700 mg, 3.27 mmol, 1.09 eq) as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.5 3,4-dichloro-2- fluoro-aniline (30.0 mg, 167 umol, 1.05 eq) was used as HX
1-Y in the presence of 0.13 eq HCl
and in step C.6, variant ii was used to give (S)-1-(3-((4-((3,4-dichloro-2- fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)(ethyl)amino)pyrrolidin-1-yl)prop-2-en-1-one 24 in 2% overall yield.
1H NMR (400 MHz, DMSO-d
6) δ = 9.36 (br d, J = 10.4 Hz, 1H), 8.42 (d, J = 1.9 Hz, 1H), 8.25 (td, J = 8.4, 12.6 Hz, 1H), 7.97 (d, J = 9.4 Hz, 1H), 7.60 (dd, J = 1.6, 9.0 Hz, 1H), 7.50 (dd, J = 3.4, 9.4 Hz, 1H), 6.65 (dt, J = 10.3, 16.5 Hz, 1H), 6.17 (ddd, J = 2.4, 7.0, 16.7 Hz, 1H), 5.69 (ddd, J = 2.4, 10.3, 19.7 Hz, 1H), 5.56 - 5.30 (m, 1H), 3.71 (br d, J = 8.4 Hz, 2H), 3.64 - 3.58 (m, 2H), 3.49 - 3.43 (m, 1H), 3.35 - 3.28 (m, 1H), 2.29 - 2.09 (m, 2H), 1.25 - 1.18 (m, 3H). MS (ESI) m/z 475.1 [M+H]
+ Synthesis of tert-butyl (3S)-3-(ethylamino)pyrrolidine-1-carboxylate [1882] To a solution of tert-butyl (3S)-3-aminopyrrolidine-1-carboxylate (2.00 g, 10.7 mmol, 1.00 eq), acetaldehyde (946 mg, 21.4 mmol, 1.21 mL, 2.00 eq) in methanol (50.0 mL) was added sodium triacetoxy borohydride (1.35 g, 21.4 mmol, 2.00 eq) and acetic acid (4.97 g, 82.7 mmol, 4.73 mL, 7.70 eq) at 25 °C. The mixture was stirred for 48 h at 40 °C. The mixture was adjusted to pH = 8 with saturated sodium bicarbonate and extracted with dichloromethane (3 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/methanol=10/1 to 5/1) to give tert-butyl (3S)-3-(ethylamino)pyrrolidine-1- carboxylate (200 mg, 933 umol, 8.69% yield) as colorless oil. To a solution of 6-chloro-3-nitropicolinamide (600 mg, 2.98 mmol, 1.00 eq) in dimethyl formamide / toluene (20.0 mL / 20.0 mL) was added tert-butyl (3S)-3-(ethylamino)pyrrolidine-1-carboxylate (700 mg, 3.27 mmol, 1.09 eq). The mixture was stirred at 130 °C for 16 h. After being cooled to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (0.1% formic acid) to give (S)-tert-butyl3-((6-carbamoyl-5-nitropyridin-2-yl)(ethyl)amino)pyrrolidine- 1- carboxylate (350 mg, 673 umol, 42% yield, 73% purity) as a brown oil. MS (ESI) m/z 280.0 [M+H-56]
+ [1883] Synthesis of Compound No. 25: Synthesized according to general procedure C, wherein in step C.1 variant i and tert-butyl 3-hydroxyazetidine-1-carboxylate (2.60 g, 15.0 mmol, 1.21 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.5 4- phenoxyaniline (182 mg, 983 umol, 1.04 eq) was used as HX
1-Y and in step C.6, variant ii was used to give 1-(3-((4-((4-phenoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)azetidin-1-
yl)prop-2-en-1-one 25 in 8% yield from XXII.
1H NMR (400 MHz, DMSO-d
6) δ = 9.41 (s, 1H), 8.56 (s, 1H), 8.17 (d, J = 9.0 Hz, 1H), 7.96 - 7.88 (m, 2H), 7.47 (d, J = 9.0 Hz, 1H), 7.43 - 7.37 (m, 2H), 7.15 - 7.09 (m, 3H), 7.05 - 6.99 (m, 2H), 6.38 (dd, J = 10.3, 16.9 Hz, 1H), 6.14 (dd, J = 2.1, 16.9 Hz, 1H), 5.90 (tt, J = 4.3, 6.7 Hz, 1H), 5.69 (dd, J = 2.1, 10.3 Hz, 1H), 4.88 (br dd, J = 7.3, 9.3 Hz, 1H), 4.56 (dd, J = 7.1, 10.7 Hz, 1H), 4.28 (br dd, J = 4.2, 10.0 Hz, 1H), 4.01 (br dd, J = 3.9, 11.2 Hz, 1H). MS (ESI) m/z 440.3 [M+H]
+ [1884] Synthesis of Compound No. 26: Synthesized according to general procedure C, wherein in step C.1 variant ii and (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (3.62 g, 19.3 mmol, 1.30 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.5 3-chloro-4-((3-fluorobenzyl)oxy)aniline (215 mg, 855 umol, 1.00 eq) was used as HX
1-Y and in step C.6, variant i was used to give (S)-1-(3-((4-((3-chloro-4- ((3- fluorobenzyl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1- one 26 in 1% overall yield.
1H NMR (400MHz, DMSO-d
6) δ = 9.53 (br d, J = 1.8 Hz, 1H), 8.55 (s, 1H), 8.18 - 8.02 (m, 2H), 7.83 (dd, J = 2.6, 8.9 Hz, 1H), 7.53 - 7.44 (m, 1H), 7.39 - 7.25 (m, 4H), 7.23 - 7.11 (m, 1H), 6.73 - 6.50 (m, 1H), 6.26 - 6.06 (m, 2H), 5.76 - 5.55 (m, 1H), 5.27 (s, 2H), 4.07 - 3.50 (m, 4H), 2.41 - 2.09 (m, 2H). MS (ESI) m/z 520.2 [M+H]
+ [1885] Synthesis of Compound No. 27: Synthesized according to general procedure C, wherein in step C.1 variant i and (S)-tert-butyl 3-aminopiperidine-1-carboxylate (1.79 g, 8.93 mmol, 1.20 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.53,4- dichloro-2-fluoroaniline (296 mg, 1.65 mmol, 1.00 eq) was used as HX
1-Y and in step C.6, variant i was used to give (S)-1-(3-((4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6- yl)amino) piperidin-1-yl)prop-2-en-1-one 27 in 5% overall yield.
1H NMR (400 MHz, DMSO-d
6) δ = 9.32 - 9.15 (m, 1H), 8.43 (s, 1H), 8.36 (br d, J = 6.8 Hz, 1H), 7.82 (d, J = 9.0 Hz, 1H), 7.54 (dd, J = 1.9, 9.0 Hz, 1H), 7.43 (br d, J = 6.2 Hz, 1H), 7.19 (d, J = 9.2 Hz, 1H), 6.76 - 6.60 (m, 1H), 6.02 (br d, J = 16.9 Hz, 1H), 5.64 - 5.45 (m, 1H), 4.16 - 3.99 (m, 1H), 3.96 - 3.85 (m, 1H), 3.31 - 3.22 (m, 1H), 2.49 - 2.43 (m, 2H), 2.18 - 2.04 (m, 1H), 1.93 - 1.82 (m, 1H), 1.75 - 1.63 (m, 1H), 1.61 - 1.47 (m, 1H). MS (ESI) m/z 461.1 [M+H]
+ [1886] Synthesis of Compound No. 28: Synthesized according to general procedure C, wherein in step C.1 variant ii and (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (3.62 g, 19.3 mmol, 1.30 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.5 4-phenoxyaniline (158 mg, 855 umol, 1.00 eq) was used as HX
1-Y and in step C.6, variant i was
used to give (S)-1-(3-((4-((4-phenoxyphenyl)amino)pyrido[3,2-d] pyrimidin-6-yl)oxy)pyrrolidin- 1-yl)prop-2-en-1-one 28 in 21% from XXII.
1H NMR (400MHz, DMSO-d
6) δ = 9.57 (br d, J = 1.7 Hz, 1H), 8.54 (s, 1H), 8.11 (d, J = 8.9 Hz, 1H), 7.91 (br d, J = 8.6 Hz, 2H), 7.48 - 7.31 (m, 3H), 7.19 - 7.07 (m, 3H), 7.03 (br d, J = 8.3 Hz, 2H), 6.71 - 6.52 (m, 1H), 6.27 - 6.07 (m, 2H), 5.75 - 5.58 (m, 1H), 4.07 (dd, J = 4.7, 11.9 Hz, 1H), 3.92 - 3.64 (m, 3H), 3.60 - 3.49 (m, 1H), 2.40 - 2.14 (m, 2H). MS (ESI) m/z 454.3 [M+H]
+ [1887] Synthesis of Compound No. 29: Synthesized according to general procedure A, wherein in step A.13-chloro-4-((6-fluoropyridin-2-yl)methoxy)aniline (1.40 g, 5.54 mmol, 1.11 eq) was used as H
2NX
1, in step A.2 variant ii tert-butyl 4-aminopiperidine-1-carboxylate (160 mg, 799 umol, 1.66 eq) as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H was used and in step A.3 variant i was employed to give 1-(4-((4-((3-chloro-4-((6-fluoropyridin-2-yl)methoxy)phenyl)amino)-pyrido[3,2- d]pyrimidin-6-yl)amino)piperidin-1-yl)prop-2-en-1-one 29 in 3% overall yield.
1H NMR (400 MHz, DMSO-d
6) δ = 9.13 (s, 1H), 8.38 (s, 1H), 8.23 (d, J = 2.5 Hz, 1H), 8.09 (q, J = 8.2 Hz, 1H), 7.74-7.84 (m, 2H), 7.54 (dd, J = 7.4, 2.4 Hz, 1H), 7.45 (br d, J = 7.4 Hz, 1H), 7.28 (d, J = 9.0 Hz, 1H), 7.17 (dd, J = 8.0, 2.4 Hz, 1H), 7.08 (d, J = 9.2 Hz, 1H), 6.87 (dd, J = 16.7, 10.4 Hz, 1H), 6.12 (dd, J = 16.7, 2.4 Hz, 1H), 5.69 (dd, J = 10.4, 2.5 Hz, 1H), 5.26 (s, 2H), 4.43-4.61 (m, 1H), 4.26- 4.40 (m, 1H), 3.99-4.12 (m, 1H), 3.42 (br s, 1H), 3.03-3.14 (m, 1H), 2.00-2.11 (m, 2H), 1.33-1.45 (m, 2H). MS (ESI) m/z 534.1 [M+H]
+. [1888] Synthesis of Compound No. 30: Synthesized according to general procedure B, wherein in step B.13,4-dichloro-2-fluoroaniline (120 mg, 697 umol, 1.20 eq) was used as H2NX
1, in step B.2 variant iv and tert-butyl 3-aminoazetidine-1-carboxylate (114 mg, 660 umol, 1.00 eq) as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H was used and in step B.3 variant i was employed to give 1-(3-((8- ((3,4-dichloro-2-fluorophenyl)amino)pyrimido[5,4-d]pyrimidin-2- yl)amino)azetidin-1-yl)prop- 2-en -1-one 30 in 0.5% overall yield from XVI.
1H NMR (400 MHz, CDCl
3) δ = 9.13 (s, 1H), 8.90 (br d, J = 1.8 Hz, 1H), 8.80 (t, J = 8.6 Hz, 1H), 8.68 (s, 1H), 7.37 (dd, J = 2.0, 9.0 Hz, 1H), 6.45 - 6.36 (m, 1H), 6.30 - 6.19 (m, 1H), 5.97 (br dd, J = 2.8, 5.6 Hz, 1H), 5.74 (dd, J = 1.7, 10.3 Hz, 1H), 4.92 - 4.80 (m, 1H), 4.77 - 4.67 (m, 1H), 4.65 - 4.55 (m, 1H), 4.26 - 4.18 (m, 1H), 4.16 - 4.06 (m, 1H), 1.26 (s, 1H). MS (ESI) m/z 434.0 [M+H]
+ [1889] Synthesis of Compound No. 31: Synthesized according to general procedure C, wherein in step C.1 variant i and (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (1.52 g, 8.19 mmol, 1.10 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.53,4-
dichloro-2-fluorophenol (330 mg, 1.82 mmol, 1.10 eq) was used as HX
1-Y and in step C.6, variant ii was used to give (S)-1-(3-((4-(3,4-dichloro-2-fluorophenoxy)pyrido[3,2-d] pyrimidin-6- yl)amino)pyrrolidin-1-yl)prop-2-en-1-one 31 in 4% overall yield.
1H NMR (400 MHz, DMSO-d
6) δ = 8.45 (d, J = 2.9 Hz, 1H), 8.06 - 7.93 (m, 2H), 7.68 - 7.62 (m, 1H), 7.61 - 7.53 (m, 1H), 7.26 (dd, J = 2.3, 9.2 Hz, 1H), 6.68 - 6.46 (m, 1H), 6.14 (ddd, J = 2.3, 5.7, 16.8 Hz, 1H), 5.66 (ddd, J = 2.4, 10.3, 14.2 Hz, 1H), 4.75 - 4.50 (m, 1H), 3.95 (dd, J = 6.2, 10.6 Hz, 1H), 3.82 - 3.69 (m, 1H), 3.79 - 3.69 (m, 1H), 3.59 - 3.47 (m, 2H), 3.42 - 3.38 (m, 1H), 2.30 - 2.16 (m, 1H), 2.09 - 1.88 (m, 1H). MS (ESI) m/z 448.2 [M+H]
+ [1890] Synthesis of Compound No. 32: Synthesized according to general procedure B, wherein in step B.13,4-dichloro-2-fluoro-aniline (810 mg, 4.50 mmol, 1.01 eq) was used as H
2NX
1, in step B.2 variant iv and (S)-tert-butyl 3-(ethylamino)pyrrolidine-1-carboxylate (150 mg, 700 umol, 1.55 eq) as BocN[(CR
aR
b)m(CR
cR
d)n]-X2H was used and in step B.3 variant i was employed to give (S)- 1-(3-((8-((3,4-dichloro-2-fluorophenyl)amino)pyrimido[5,4-d] pyrimidin-2- yl)(ethyl)amino)pyrrolidin-1-yl)prop-2-en-1-one 32 in 1% overall yield.
1H NMR (400 MHz, DMSO-d
6) δ = 9.75 - 9.54 (m, 1H), 9.19 (d, J = 2.6 Hz, 1H), 8.42 (s, 1H), 8.14 - 7.88 (m, 1H), 7.62 (dd, J = 1.6, 8.9 Hz, 1H), 6.74 - 6.53 (m, 1H), 6.17 (ddd, J = 2.4, 5.8, 16.7 Hz, 1H), 5.69 (ddd, J = 2.3, 10.3, 16.6 Hz, 1H), 5.59 - 5.38 (m, 1H), 4.03 - 3.85 (m, 1H), 3.80 (br d, J = 7.8 Hz, 3H), 3.67 - 3.40 (m, 2H), 2.31 - 2.15 (m, 2H), 1.22 (br t, J = 6.7 Hz, 3H). MS (ESI) m/z 476.0 [M+H]
+. [1891] Synthesis of Compound No. 33: Synthesized according to general procedure B, wherein in step B.13,4-dichloro-2-fluoroaniline (120 mg, 697 umol, 1.20 eq) was used as H2NX
1, in step B.2 variant iv and (S)-tert-butyl 3-(methylamino)pyrrolidine-1-carboxylate (192 mg, 961 umol, 1.10 eq) as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H was used and in step B.3 variant i was employed to give (S)-1-(3-((8-((3,4-dichloro-2-fluorophenyl)amino)pyrimido[5,4-d] pyrimidin-2- yl)(methyl)amino)pyrrolidin-1-yl)prop-2-en-1-one 33 in 17% yield from XVI.
1H NMR (400 MHz, DMSO-d
6) δ = 9.71 (br d, J = 10.8 Hz, 1H), 9.18 (d, J = 2.8 Hz, 1H), 8.34-8.45 (m, 1H), 7.88-8.01 (m, 1H), 7.62 (dd, J = 8.8, 1.4 Hz, 1H), 6.59-6.70 (m, 1H), 6.16-6.27 (m, 1H), 5.64-5.65 (m, 1H), 5.57-5.68 (m, 1H), 3.83-3.95 (m, 1H), 3.71-3.80 (m, 1H) , 3.68 (s, 1H), 3.39-3.46 (m, 1H), 3.22 (d, J = 4.9 Hz, 3H), 2.13-2.29 ppm (m, 2H). MS (ESI) m/z 462.0 [M+H]
+ [1892] Synthesis of Compound No. 34: Synthesized according to general procedure B, wherein in step B.13,4-dichloro-2-fluoroaniline (120 mg, 697 umol, 1.20 eq) was used as H
2NX
1, in step B.2 variant v and (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (210 mg, 1.12 mmol, 1.29 eq)
as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H was used and in step B.3 variant i was employed to give (S)-1- (3-((8-((3,4-dichloro-2-fluorophenyl)amino)pyrimido[5,4-d] pyrimidin-2-yl)oxy)pyrrolidin-1- yl)prop-2-en-1-one 34 in 4% yield from XVI.
1H NMR (400 MHz, DMSO-d
6) δ = 10.16 (br s, 1H), 9.40 (d, J = 2.2 Hz, 1H), 8.60 (d, J = 0.7 Hz, 1H), 7.80 (dt, J = 5.3, 8.3 Hz, 1H), 7.63 (dd, J = 1.7, 8.9 Hz, 1H), 6.70 - 6.52 (m, 1H), 6.16 (ddd, J = 2.4, 6.8, 16.8 Hz, 1H), 5.96 - 5.83 (m, 1H), 5.68 (ddd, J = 2.4, 10.3, 19.1 Hz, 1H), 4.06 - 3.87 (m, 1H), 3.85 - 3.71 (m, 2H), 3.70 - 3.48 (m, 1H), 2.41 - 2.21 (m, 2H). MS (ESI) m/z 449.1 [M+H]
+. [1893] Synthesis of Compound No. 35: Synthesized according to general procedure C, wherein in step C.1 variant i and tert-butyl 3-amino-3-methylazetidine-1-carboxylate (1.11 g, 5.95 mmol, 1.20 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant ii was used and in step C.5 3,4-dichloro-2-fluoro-aniline (77.0 mg, 428 umol, 1.00 eq) was used as HX
1-Y and in step C.6, variant ii was used to give 1-(3-((4-((3,4-dichloro-2-fluorophenyl) amino)pyrido[3,2- d]pyrimidin-6-yl)amino)-3-methylazetidin-1-yl)prop-2-en-1-one 35 in 7% yield from XXII.
1H NMR (400 MHz, CDCl
3) δ = 8.93 (br d, J = 3.2 Hz, 1H), 8.78 (t, J = 8.8 Hz, 1H), 8.58 (s, 1H), 7.85 (d, J = 9.0 Hz, 1H), 7.28 (dd, J = 2.0, 9.0 Hz, 1H), 6.90 (d, J = 9.0 Hz, 1H), 6.36 - 6.26 (m, 1H), 6.23 - 6.12 (m, 1H), 5.65 (dd, J = 1.8, 10.2 Hz, 1H), 5.31 (s, 1H), 4.50 (d, J = 8.8 Hz, 1H), 4.30 (d, J = 8.8 Hz, 1H), 4.25 - 4.18 (m, 1H), 4.14 - 4.03 (m, 1H), 1.81 (s, 3H). MS (ESI) m/z 447.0 [M+H]. [1894] Synthesis of Compound No. 36: Synthesized according to general procedure C, wherein in step C.1 variant i and (2S,3R)-tert-butyl 3-hydroxy-2-methylazetidine-1-carboxylate (240 mg, 1.28 mmol, 1.29 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.53,4-dichloro-2-fluoro-aniline (65.0 mg, 361 umol, 1.06 eq) was used as HX
1-Y and in step C.6, variant ii was used to give 1-((2S,3R)-3-((4-((3,4-dichloro-2-fluorophenyl) amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)-2-methylazetidin-1-yl)prop-2-en-1-one 36 in 5% overall yield.
1H NMR (400 MHz, DMSO-d
6) δ = 9.19 (br s, 1H), 8.63 (s, 1H), 8.28 (t, J = 8.5 Hz, 1H), 8.21 (d, J = 9.0 Hz, 1H), 7.59 (dd, J = 2.1, 8.9 Hz, 1H), 7.48 (d, J = 9.0 Hz, 1H), 6.38 - 6.28 (m, 1H), 6.19 - 6.11 (m, 1H), 5.68 (dd, J = 2.3, 10.3 Hz, 1H), 5.42 (td, J = 3.8, 6.5 Hz, 1H), 4.76 - 4.63 (m, 1H), 4.57 (br dd, J = 1.5, 3.9 Hz, 1H), 4.09 - 3.99 (m, 1H), 1.65 (d, J = 6.5 Hz, 3H). MS (ESI) m/z 448.0 [M+H]
+ [1895] Synthesis of Compound No. 37: Synthesized according to general procedure C, wherein in step C.1 variant i and tert-butyl 3-hydroxy-3-methyl-azetidine-1-carboxylate (1.34 g, 7.14
mmol, 1.20 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant ii was used and in step C.53,4-dichloro-2-fluoroaniline (77.0 mg, 427 umol, 1.00 eq) was used as HX
1-Y and in step C.6, variant ii was used to give 1-(3-((4-((3,4-dichloro-2-fluorophenyl)amino)pyrido [3,2- d]pyrimidin-6-yl)oxy)-3-methylazetidin-1-yl)prop-2-en-1-one 37 in 19% yield from XXII.
1H NMR (400 MHz, CDCl
3) δ = 8.94 - 8.88 (m, 2H), 8.80 (s, 1H), 8.18 (d, J = 9.0 Hz, 1H), 7.39 (dd, J = 2.0, 9.0 Hz, 1H), 7.30 (s, 1H), 6.45 - 6.36 (m, 1H), 6.31 - 6.20 (m, 1H), 5.75 (dd, J = 1.6, 10.4 Hz, 1H), 4.65 (br d, J = 9.4 Hz, 1H), 4.52 - 4.44 (m, 2H), 4.33 (br d, J = 10.8 Hz, 1H), 2.02 (s, 3H). MS (ESI) m/z 448.0 [M+H]. [1896] Synthesis of Compound No. 38: Synthesized according to general procedure C, wherein in step C.1 variant i and tert-butyl 3-hydroxy-3-methyl-azetidine-1-carboxylate (1.34 g, 7.14 mmol, 1.20 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant ii was used and in step C.53-chloro-4-((6-fluoropyridin-2-yl)methoxy)aniline (36.0 mg, 142 umol, 1.00 eq) was used as HX
1-Y and in step C.6, variant ii was used to give 1-(3-((4-((3,4-dichloro-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)-3-methylazetidin-1-yl)prop-2-en-1-one 38 in 19% yield from XXII.
1H NMR (400 MHz,CDCl
3) δ = 8.76 - 8.68 (m, 1H), 8.27 (s, 1H), 8.13 (d, J = 9.0 Hz, 1H), 8.06 (d, J = 2.6 Hz, 1H), 7.88 (q, J = 7.8 Hz, 1H), 7.62 (dd, J = 2.8, 8.8 Hz, 1H), 7.61 - 7.57 (m, 1H), 7.24 (d, J = 9.0 Hz, 1H), 7.03 (d, J = 8.8 Hz, 1H), 6.91 (dd, J = 2.4, 8.2 Hz, 1H), 6.44 - 6.37 (m, 1H), 6.31 - 6.22 (m, 1H), 5.75 (dd, J = 1.6, 10.2 Hz, 1H), 5.25 (s, 2H), 4.72 - 4.56 (m, 2H), 4.42 - 4.27 (m, 2H), 1.98 (s, 3H). MS (ESI) m/z 521.0 [M+H]. [1897] Synthesis of Compound No. 39: Synthesized according to general procedure C, wherein in step C.1 variant i (2R,3S)-tert-butyl 3-hydroxy-2-methylazetidine-1-carboxylate (390 mg, 2.08 mmol, 1.05 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.53,4-dichloro-2-fluoroaniline (205 mg, 1.14 mmol, 1.00 eq) was used as HX
1-Y and in step C.6, variant ii was used to give 1-((2R,3S)-3-((4-((3,4-dichloro-2-fluorophenyl)amino)pyrido [3,2- d]pyrimidin-6-yl)oxy)-2-methylazetidin-1-yl)prop-2-en-1-one 39 in 22% overall yield.
1H NMR (400 MHz, DMSO-d
6) δ = 9.56 - 9.28 (m, 1H), 8.61 (s, 1H), 8.26 - 8.21 (m, 1H), 8.20 - 8.07 (m, 1H), 7.64 (dd, J = 1.8, 9.0 Hz, 1H), 7.52 (d, J = 9.0 Hz, 1H), 6.47 - 6.25 (m, 1H), 6.22 - 6.08 (m, 1H), 5.70 (br d, J = 10.3 Hz, 1H), 5.48 - 5.35 (m, 1H), 4.92 - 4.63 (m, 1H), 4.59 - 4.42 (m, 1H), 4.18 - 3.80 (m, 1H), 1.70 - 1.51 (m, 3H). MS (ESI) m/z 448.0 [M+H]
+. [1898] Synthesis of Compound No. 40: Synthesized according to general procedure C, wherein in step C.1 variant ii and (S)-tert-butyl 3-hydroxypiperidine-1-carboxylate (2.60 g, 12.9 mmol,
1.30 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.5 3,4-dichloro-2-fluoroaniline (177 mg, 986 umol, 1.20 eq) was used as HX
1-Y and in step C.6, variant i was used to give (S)-1-(3-((4-((3,4-dichloro-2-fluorophenyl)amino) pyrido[3,2- d]pyrimidin-6-yl)oxy)piperidin-1-yl)prop-2-en-1-one 40 in 7% overall yield.
1H NMR (400MHz, DMSO-d
6) δ = 9.70 - 9.59 (s, 1H), 8.55 (br d, J = 5.7 Hz, 1H), 8.14 (br t, J = 8.3 Hz, 1H), 8.06 - 7.95 (m, 1H), 7.62 (br d, J = 8.9 Hz, 1H), 7.43 - 7.27 (m, 1H), 6.86 -6.57 (br dd, J = 10.5, 16.6 Hz, 1H), 6.15 - 5.94 (m, 1H), 5.70 - 5.57 (br d, J = 10.5 Hz, 1H), 5.43 -5.24 (br d, J = 10.8 Hz, 1H), 4.46, 3.41 - 3.37 (m, 1H), 3.91 - 3.72 (m, 2H), 3.45 (br d, J = 8.9 Hz, 1H), 2.18 - 2.05 (m, 1H), 1.94 - 1.75 (m, 2H), 1.60 (br s, 1H). MS (ESI) m/z 462.1 [M+H]
+ [1899] Synthesis of Compound No. 41: Synthesized according to general procedure C, wherein in step C.1 variant i and (S)-tert-butyl 3-(methylamino)pyrrolidine-1-carboxylate (1.50 g, 7.49 mmol, 1.01 eq) was used as BocN[(CR
aR
b)m(CR
cR
d)n]-X
2H, in step C.2 variant i was used and in step C.53,4-dichloro-2-fluorophenol (290 mg, 1.60 mmol, 1.10 eq) was used as HX
1-Y and in step C.6, variant i was used to give (S)-1-(3-((4-(3,4-dichloro-2-fluorophenoxy) pyrido[3,2- d]pyrimidin-6-yl)(methyl)amino)pyrrolidin-1-yl)prop-2-en-1-one 41 in 6% yield from XXII.
1H NMR (400 MHz, DMSO-d
6) δ = 8.49 (d, J = 2.6 Hz, 1H), 8.12 (dd, J = 2.1, 9.4 Hz, 1H), 7.73 - 7.62 (m, 2H), 7.61 - 7.54 (m, 1H), 6.61 (ddd, J = 10.3, 12.1, 16.8 Hz, 1H), 6.20 - 6.11 (m, 1H), 5.67 (dt, J = 2.3, 10.5 Hz, 1H), 5.42 - 5.26 (m, 1H), 3.92 (dd, J = 7.8, 10.1 Hz, 1H), 3.86 - 3.79 (m, 1H), 3.78 - 3.65 (m, 1H), 3.64 - 3.53 (m, 1H), 3.39 (dd, J = 7.8, 12.2 Hz, 1H), 3.11 (d, J = 4.9 Hz, 3H), 2.25 - 2.17 (m, 1H), 2.16 - 2.08 (m, 1H). MS (ESI) m/z 462.2[M+H]
+. [1900] Synthesis of Compound No. 42: Synthesized according to general procedure B, wherein in step B.13,4-dichloro-2-fluoroaniline (120 mg, 697 umol, 1.20 eq) was used as H
2NX
1, in step B.2 variant v and tert-butyl 3-hydroxyazetidine-1-carboxylate (190 mg, 1.10 mmol, 1.26 eq) as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H was used and in step B.3 variant i was employed to give 1-(3-((8- ((3,4-dichloro-2-fluorophenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)oxy)azetidin-1-yl)prop-2- en-1-one 42 in 2 % yield from XXII.
1H NMR (400 MHz, DMSO-d
6) δ = 10.15 - 9.89 (m, 1H), 9.43 (s, 1H), 8.62 (s, 1H), 7.83 (dd, J = 8.0, 8.7 Hz, 1H), 7.64 (dd, J = 1.8, 8.9 Hz, 1H), 6.45 - 6.29 (m, 1H), 6.14 (dd, J = 2.1, 17.1 Hz, 1H), 5.75 - 5.60 (m, 2H), 4.82 (dd, J = 7.5, 9.3 Hz, 1H), 4.56 (dd, J = 7.2, 11.0 Hz, 1H), 4.35 (dd, J = 4.0, 10.0 Hz, 1H), 4.04 (dd, J = 4.0, 11.5 Hz, 1H). MS (ESI) m/z 434.9 [M+H]
+ [1901] Synthesis of Compound No. 43: Synthesized according to general procedure B, wherein
in step B.13,4-dichloro-2-fluoroaniline (120 mg, 697 umol, 1.20 eq) was used as H
2NX
1, in step B.2 variant vi and tert-butyl 3-(methylamino)azetidine-1-carboxylate (215 mg, 1.15 mmol, 1.21 eq) as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H was used and in step B.3 variant i was employed to give 1- (3-((8-((3,4-dichloro-2-fluorophenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)(methyl)- amino)azetidin-1-yl) prop- 2-en-1-one 43 in 3% overall yield from XVI.
1H NMR (400 MHz, DMSO-d
6) δ = 9.70 (br s, 1H), 9.19 (s, 1H), 8.43 (s, 1H), 7.94 (t, J = 8.4 Hz, 1H), 7.62 (dd, J = 1.9, 8.9 Hz, 1H), 6.38 (dd, J = 10.4, 17.0 Hz, 1H), 6.14 (dd, J = 2.3, 16.9 Hz, 1H), 5.86 - 5.75 (m, 1H), 5.74 - 5.67 (m, 1H), 4.58 (t, J = 8.9 Hz, 1H), 4.45 (br dd, J = 6.2, 8.6 Hz, 1H), 4.35 - 4.25 (m, 1H), 4.17 (dd, J = 6.0, 10.1 Hz, 1H), 3.35 (s, 3H). MS (ESI) m/z 448.0 [M+H]
+. [1902] Synthesis of Compound No. 44: Synthesized according to general procedure C, wherein in step C.1 variant i and tert-butyl 4-(methylamino)piperidine-1-carboxylate (1.38 g, 6.45 mmol, 1.30 eq) was used as BocN[(CR
aR
b)m(CR
cR
d)n]-X
2H, in step C.2 variant i was used and in step C.5 3-chloro-4-((3-fluorobenzyl)oxy)aniline (150 mg, 595 umol, 1.13 eq) was used as HX
1-Y and in step C.6, variant ii was used to give 1-(4-((4-((3-chloro-4-((3- fluorobenzyl)oxy)phenyl)amino)pyrido[3,2-d] pyrimidin-6-yl)(methyl)amino)piperidin-1- yl)prop-2-en-1-one 44 in 9% yield from XXII.
1H NMR (400 MHz, CDCl
3) δ = 9.20 (s, 1H), 8.41 (s, 1H), 8.22 (d, J = 2.5 Hz, 1H), 7.91 (d, J = 9.4 Hz, 1H), 7.81 (dd, J = 2.6, 9.0 Hz, 1H), 7.53 - 7.44 (m, 2H), 7.36 - 7.25 (m, 3H), 7.18 (dt, J = 2.4, 8.5 Hz, 1H), 6.87 (dd, J = 10.5, 16.6 Hz, 1H), 6.13 (dd, J = 2.4, 16.7 Hz, 1H), 5.74 - 5.64 (m, 1H), 5.26 (s, 2H), 4.99 - 4.82 (m, 1H), 4.67 - 4.55 (m, 1H), 4.26 - 4.13 (m, 1H), 3.05 (s, 3H), 2.94 - 2.85 (m, 1H), 1.81 - 1.66 (m, 4H). MS (ESI) m/z 547.1 [M+H]
+ [1903] Synthesis of Compound No. 45: Synthesized according to general procedure C, wherein in step C.1 variant i and (S)-tert-butyl 3-(methylamino)pyrrolidine-1-carboxylate (1.50 g, 7.49 mmol, 1.01 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.5 3-chloro-4-((6-fluoropyridin-2-yl)methoxy)aniline (292 mg, 1.15 mmol, 1.00 eq) was used as HX
1-Y and in step C.6, variant i was used to give (S)-1-(3-((4-((3-chloro-4-((6- fluoropyridin-2-yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)(methyl)amino)- pyrrolidin-1-yl)prop-2-en-1-one 45 in 26% yield from XXII.
1H NMR (400 MHz, DMSO-d
6) δ = 9.30 (d, J = 7.8 Hz, 1H), 8.39 (s, 1H), 8.15 - 8.04 (m, 2H), 7.93 (d, J = 9.3 Hz, 1H), 7.81 (ddd, J = 2.6, 6.7, 9.0 Hz, 1H), 7.53 (dd, J = 2.3, 7.3 Hz, 1H), 7.47 (dd, J = 5.7, 9.4 Hz, 1H), 7.27 (d, J = 9.0 Hz, 1H), 7.16 (dd, J = 2.4, 8.3 Hz, 1H), 6.65 (ddd, J = 10.3, 15.2, 16.6 Hz, 1H), 6.17 (ddd, J = 2.3,
6.5, 16.7 Hz, 1H), 5.79 - 5.62 (m, 2H), 5.26 (s, 2H), 3.95 (s, 1H), 3.99 - 3.89 (m, 1H), 3.94 - 3.79 (m, 1H), 3.77 - 3.49 (m, 2H), 3.46 - 3.37 (m, 1H), 3.09 (d, J = 5.0 Hz, 3H), 2.23 - 2.15 (m, 1H), 2.14 - 2.04 (m, 1H). MS (ESI) m/z 534.0 [M+H]
+ [1904] Synthesis of Compound No. 46: Synthesized according to general procedure C, wherein in step C.1 variant i and tert-butyl 4-(methylamino)piperidine-1-carboxylate (1.38 g, 6.45 mmol, 1.30 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.5 added 3-chloro-4-((6-fluoropyridin-2-yl)methoxy) aniline (150 mg, 594 umol, 1.12 eq) was used as HX
1-Y and in step C.6, variant ii was used to give 1-(4-((4-((3-chloro-4-((6-fluoropyridin-2- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)(methyl)amino)-piperidin-1-yl)prop-2- en-1-one 46 in 1% overall yield.
1H NMR (400 MHz, CDCl
3) δ = 8.57 (br d, J = 3.0 Hz, 2H), 8.07 (d, J = 2.5 Hz, 1H), 7.97 (d, J = 9.3 Hz, 1H), 7.86 (q, J = 7.9 Hz, 1H), 7.63 - 7.55 (m, 2H), 7.19 (d, J = 9.4 Hz, 1H), 7.00 (d, J = 8.9 Hz, 1H), 6.89 (dd, J = 2.1, 8.1 Hz, 1H), 6.65 (dd, J = 10.5, 16.8 Hz, 1H), 6.35 (dd, J = 1.6, 16.8 Hz, 1H), 5.76 (dd, J = 1.6, 10.5 Hz, 1H), 5.21 (s, 2H), 4.94 (br d, J = 11.3 Hz, 1H), 4.75 - 4.66 (m, 1H), 4.23 (br d, J = 11.4 Hz, 1H), 3.35 - 3.22 (m, 1H), 3.05 (s, 3H), 2.88 - 2.75 (m, 1H), 1.91 (br s, 2H), 1.83 (br d, J = 13.1 Hz, 2H). MS (ESI) m/z 548.1 [M+H]
+ [1905] Synthesis of Compound No. 47: Synthesized according to general procedure C, wherein in step C.1 variant i and tert-butyl 3-amino-3-methylazetidine-1-carboxylate (1.11 g, 5.95 mmol, 1.20 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant ii was used and in step C.53-chloro-4-((6-fluoropyridin-2-yl)methoxy)aniline (130 mg, 514 umol, 0.900 eq) was used as HX
1-Y and in step C.6, variant ii was used to give 1-(3-((4-((3,4-dichloro-2-fluoro phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)-3-methylazetidin-1-yl)prop-2-en-1-one 47 in 11% yield from XXII.
1H NMR (400 MHz, DMSO-d
6) δ = 8.58 - 8.54 (m, 1H), 8.44 (s, 1H), 8.13 (d, J = 2.6 Hz, 1H), 8.10 - 8.03 (m, 1H), 7.89 (s, 1H), 7.87 - 7.81 (m, 1H), 7.76 - 7.68 (m, 1H), 7.56 - 7.48 (m, 1H), 7.25 (d, J = 8.8 Hz, 1H), 7.18 - 7.16 (m, 1H), 7.16 - 7.13 (m, 1H), 6.42 (dd, J = 10.4, 17.0 Hz, 1H), 6.18 - 6.12 (m, 1H), 5.66 (dd, J = 2.0, 10.2 Hz, 1H), 5.26 (s, 2H), 4.65 (d, J = 8.8 Hz, 1H), 4.48 (d, J = 10.0 Hz, 1H), 4.30 (d, J = 8.8 Hz, 1H), 3.98 (d, J = 10.0 Hz, 1H), 1.71 (s, 3H). MS (ESI) m/z 520.1 [M+H]. [1906] Synthesis of Compound No. 48: Synthesized according to general procedure C, wherein in step C.1 no base was added and the mixture was heated to 130 °C for 16 h with tert-butyl (3S)- 3-(ethylamino)pyrrolidine-1-carboxylate (700 mg, 3.27 mmol, 1.09 eq) as
BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.5 3-chloro-4-((6- fluoropyridin-2-yl)methoxy)aniline (299 mg, 1.18 mmol, 0.900 eq) was used as HX
1-Y in the presence of 0.13 eq HCl and in step C.6, variant i was used to give (S)-1-(3-((4-((3-chloro-4-((6- fluoropyridin-2-yl)methoxy)phenyl) amino)pyrido[3,2-d]pyrimidin-6-yl)amino)pyrrolidin-1- yl)prop-2-en-1-one 48 in 17% yield from XXII.
1H NMR (400 MHz, DMSO-d
6) δ = 9.22 (d, J = 7.8 Hz, 1H), 8.38 (d, J = 1.0 Hz, 1H), 8.16 (dd, J = 2.6, 10.2 Hz, 1H), 8.08 (q, J = 8.1 Hz, 1H), 7.84 (td, J = 2.4, 9.0 Hz, 1H), 7.78 (d, J = 9.0 Hz, 1H), 7.73 (dd, J = 7.0, 10.9 Hz, 1H), 7.53 (dd, J = 2.1, 7.4 Hz, 1H), 7.27 (d, J = 9.2 Hz, 1H), 7.16 (dd, J = 2.3, 8.1 Hz, 1H), 7.09 (dd, J = 3.1, 9.1 Hz, 1H), 6.63 (ddd, J = 10.4, 16.8, 18.9 Hz, 1H), 6.15 (ddd, J = 2.5, 9.0, 16.8 Hz, 1H), 5.73 - 5.61 (m, 1H), 5.25 (s, 2H), 5.09 - 4.90 (m, 1H), 4.08 (dd, J = 6.1, 10.4 Hz, 0.5H), 3.81 (dd, J = 6.2, 12.4 Hz, 0.5H), 3.78 - 3.66 (m, 1H), 3.65 - 3.49 (m, 1H), 3.43 - 3.39 (m, 1H), 2.31 - 2.16 (m, 1H), 2.02 - 1.86 (m, 1H). MS (ESI) m/z 520.3 [M+H]
+. [1907] Synthesis of 3-chloro-4-((6-fluoropyridin-2-yl)methoxy)aniline. To a solution of 2- fluoro-6-methylpyridine (8.00 g, 72.0 mmol, 7.41 mL, 1.00 eq) in acetonitrile (200 mL) was added 1-chloropyrrolidine-2,5-dione (24.0 g, 180 mmol, 2.50. eq), benzoic peroxyanhydride (2.09 g, 8.64 mmol, 0.120 eq) and acetic acid (0.400 mL). The mixture was stirred at 85 °C for 12 h. The mixture was concentrated to afford a residue. The residue was diluted with water (50.0 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to afford a residue. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 1/0 – 10/1) to afford 2-(chloromethyl)-6- fluoropyridine (4.50 g, 30.9 mmol, 43% yield) as a colorless oil. MS (ESI) m/z 145.9 [M+H]
+. To a solution of 2-(chloromethyl)-6-fluoropyridine (2.00 g, 13.7 mmol, 0.750 eq) in acetonitrile (40.0 mL) was added potassium carbonate (2.53 g, 18.3 mmol, 1.00 eq), followed by the addition of 4- amino-2-chlorophenol (2.63 g, 18.3 mmol, 1.00 eq), potassium iodide (304mg, 1.83 mmol, 0.100 eq) and potassium hydroxide (1.03 g, 18.3 mmol, 1.00 eq). The mixture was stirred at 90 °C for 12 h. The mixture was concentrated to afford a residue. The residue was diluted with water (100 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to afford a residue. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 1/1) to afford 3-chloro-4-((6- fluoropyridin-2-yl)methoxy)aniline (1.10 g, 4.35 mmol, 24% yield) as a yellow solid.
1H NMR (400 MHz, CDCl
3) δ = 7.83 (q, J = 7.9 Hz, 1H), 7.60 - 7.50 (m, 1H), 6.86 (dd, J = 2.1, 8.2 Hz,
1H), 6.81 - 6.75 (m, 2H), 6.52 (dd, J = 2.8, 8.6 Hz, 1H), 5.10 (s, 2H), 3.54 (br s, 2H). [1908] Synthesis of Compound No. 49: Synthesized according to general procedure C, wherein in step C.1 variant ii was used with tert-butyl 3-ethyl-3-hydroxy-azetidine-1-carboxylate (3.30 g, 16.4 mmol, 1.10 eq) as BocN[(CR
aR
b)m(CR
cR
d)n]-X
2H, in step C.2 variant ii was used and in step C.5 3,4-dichloro-2-fluoro-aniline (44.4 mg, 246 umol, 0.900 eq) was used as HX
1-Y in the presence of 0.13 eq HCl and in step C.6, variant ii was used to give 1-(3-((4-((3,4-dichloro-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)-3-ethylazetidin-1-yl)prop-2-en-1-one 49 in 0.5% overall yield.
1H NMR (400 MHz, DMSO-d
6) δ = 9.04 - 8.98 (m, 1H), 8.64 (s, 1H), 8.33 (t, J = 8.4 Hz, 1H), 8.23 (d, J = 9.0 Hz, 1H), 7.65 (dd, J = 1.8, 9.0 Hz, 1H), 7.49 (d, J = 9.0 Hz, 1H), 6.37 (dd, J = 10.2, 17.2 Hz, 1H), 6.14 (dd, J = 2.0, 17.2 Hz, 1H), 5.71 (dd, J = 2.0, 10.2 Hz, 1H), 4.66 - 4.59 (m, 1H), 4.57 - 4.51 (m, 1H), 4.35 (d, J = 11.2 Hz, 1H), 4.26 - 4.18 (m, 1H), 2.44 - 2.37 (m, 2H), 0.89 (t, J = 7.2 Hz, 3H). MS (ESI) m/z 462.0 [M+H]. [1909] Synthesis of tert-butyl 3-ethyl-3-hydroxyazetidine-1-carboxylate. To a solution of tert- butyl 3-oxoazetidine-1-carboxylate (10.0 g, 58.4 mmol, 1.00 eq) in tetrahydrofuran (150 mL) was added bromo(ethyl)magnesium (3.00 M, 23.4 mL, 1.20 eq) dropwise at -78 °C under nitrogen. Then the mixture was stirred at 20 °C for 1 h. The mixture was quenched with saturated ammonium chloride (500 mL) and extracted with ethyl acetate (2 × 200 mL). The organic layer was washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated to afford tert- butyl 3-ethyl-3-hydroxyazetidine-1-carboxylate (11 g, 54.7 mmol, 93% yield) as light yellow oil.
1H NMR (400 MHz, CDCl3) δ = 3.83 (q, J = 9.2 Hz, 4H), 2.23 (s, 1H), 1.78 (q, J = 7.4 Hz, 2H), 1.46 (s, 9H), 0.99 (t, J = 7.4 Hz, 3H). [1910] Synthesis of Compound No. 50: Synthesized according to general procedure C, wherein in step C.1 variant i was used with diethylamine instead of triethylamine with tert-butyl 3-amino- 3-methylpyrrolidine-1-carboxylate (400 mg, 2.00 mmol, 1.00 eq) as BocN[(CR
aR
b)
m(CR
cR
d)
n]- X
2H, in step C.2 variant i was used and in step C.5 3,4-dichloro-2-fluoroaniline (80.2 mg, 445 umol, 0.900 eq) was used as HX
1-Y in the presence of 0.13 eq HCl and in step C.6, variant i was used to give 1-(3-((4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,2-d] pyrimidin-6-yl)amino)- 3-methylpyrrolidin-1-yl)prop-2-en-1-one 50 in 8% overall yield.
1H NMR (400 MHz, DMSO-d
6) δ = 9.10 (d, J = 2.4 Hz, 1H), 8.75 - 8.62 (m, 1H), 8.50 (d, J = 1.5 Hz, 1H), 7.84 (dd, J = 2.8, 9.1 Hz, 1H), 7.73 (d, J = 16.8 Hz, 1H), 7.60 (d, J = 9.0 Hz, 1H), 7.18 (dd, J = 2.9, 9.1 Hz, 1H), 6.60 (dt, J = 10.3, 16.7 Hz, 1H), 6.13 (br d, J = 16.8 Hz, 1H), 5.66 (ddd, J = 2.3, 10.3, 15.8 Hz, 1H),
4.22 - 4.06 (m, 1H), 3.83 (d, J = 10.8 Hz, 0.5H), 3.78 - 3.63 (m, 1H), 3.54 (br t, J = 7.1 Hz, 1H), 3.47 (br d, J = 12.5 Hz, 0.5H), 2.68 (br s, 1H), 2.17 - 1.95 (m, 1H), 1.68 (d, J = 10.1 Hz, 3H). MS (ESI) m/z 461.2 [M+H]
+. [1911] Synthesis of Compound No. 51: Synthesized according to general procedure C, wherein in step C.1 variant ii and (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (3.62 g, 19.3 mmol, 1.30 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.5 3-chloro-4-((6-fluoropyridin-2-yl)methoxy)aniline (149 mg, 590 umol, 0.900 eq) was used as HX
1-Y and in step C.6, variant i was used to give (S)-1-(3-((4-((3-chloro-4-((6-fluoropyridin-2- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one 51 in 24% yield from XXII.
1H NMR (400 MHz, DMSO-d
6) δ = 9.54 (br s, 1H), 8.56 (s, 1H), 8.14 - 8.04 (m, 3H), 7.84 (dd, J = 2.5, 9.0 Hz, 1H), 7.54 (dd, J = 2.0, 7.5 Hz, 1H), 7.41 - 7.34 (m, 1H), 7.31 (br d, J = 9.0 Hz, 1H), 7.17 (dd, J = 2.0, 7.9 Hz, 1H), 6.71 - 6.54 (m, 1H), 6.25 - 6.09 (m, 2H), 5.74 - 5.61 (m, 1H), 5.27 (s, 2H), 4.06 (dd, J = 4.5, 12.0 Hz, 0.5H), 3.85 - 3.79 (m, 1H), 3.76 - 3.63 (m, 2H), 3.55 - 3.50 (m, 0.5H), 2.30 - 2.23 (m, 1H), 2.23 - 2.07 (m, 1H). MS (ESI) m/z 521.2 [M+H]
+. [1912] Synthesis of Compound No. 52: Synthesized according to general procedure C, wherein in step C.1 variant ii was used with tert-butyl 4-hydroxypiperidine-1-carboxylate (2.50 g, 12.4 mmol, 1.25 eq) as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.5 added 3-chloro-4-((6-fluoropyridin-2-yl)methoxy)aniline (90.0 mg, 356 umol, 1.08 eq) was used as HX
1-Y in the presence of 0.13 eq HCl and in step C.6, variant ii was used to give 1-(4-((4-((3- chloro-4-((6-fluoropyridin-2-yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy) piperidin-1-yl)prop-2-en-1-one 52 in 1% overall yield.
1H NMR (400 MHz, DMSO-d
6) δ = 9.48 (s, 1H), 8.56 (s, 1H), 8.15 - 8.06 (m, 3H), 7.82 (dd, J = 2.5, 9.0 Hz, 1H), 7.54 (dd, J = 2.3, 7.7 Hz, 1H), 7.37 (d, J = 9.0 Hz, 1H), 7.31 (d, J = 9.0 Hz, 1H), 7.18 (dd, J = 2.2, 8.3 Hz, 1H), 6.87 (dd, J = 10.5, 16.6 Hz, 1H), 6.13 (dd, J = 2.4, 16.8 Hz, 1H), 5.91 - 5.84 (m, 1H), 5.70 (dd, J = 2.5, 10.4 Hz, 1H), 5.28 (s, 2H), 3.97 - 3.86 (m, 2H), 3.59 (br s, 2H), 2.14 - 2.03 (m, 2H), 1.75 - 1.65 (m, 2H). MS (ESI) m/z 535.1 [M+H]
+ [1913] Synthesis of Compound No. 53: Synthesized according to general procedure C, wherein in step C.1 variant ii was used with tert-butyl 4-hydroxypiperidine-1-carboxylate (2.50 g, 12.4 mmol, 1.25 eq) as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.5 added 3-chloro-4-((3-fluorobenzyl)oxy)aniline (85.0 mg, 338umol, 1.03 eq) was used as HX
1-Y
in the presence of 0.13 eq HCl and in step C.6, variant ii was used to give 1-(4-((4-((3-chloro- 4- ((3-fluorobenzyl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)piperidin-1-yl)prop-2-en- 1-one 53 in 10% yield from XXII.
1H NMR (400 MHz, DMSO-d
6) δ = 9.46 (s, 1H), 8.55 (s, 1H), 8.13 - 8.09 (m, 2H), 7.81 (dd, J = 2.6, 8.9 Hz, 1H), 7.48 (dt, J = 6.1, 8.0 Hz, 1H), 7.31 (s, 4H), 7.19 (dt, J = 1.9, 8.7 Hz, 1H), 6.87 (dd, J = 10.5, 16.6 Hz, 1H), 6.13 (dd, J = 2.4, 16.7 Hz, 1H), 5.90 - 5.83 (m, 1H), 5.72 - 5.67 (m, 1H), 5.28 (s, 2H), 4.01 - 3.86 (m, 2H), 3.63 - 3.46 (m, 2H), 2.08 (br s, 2H), 1.76 - 1.64 (m, 2H). MS (ESI) m/z 534.0 [M+H]
+ [1914] Synthesis of Compound No. 54: Synthesized according to general procedure C, wherein in step C.1 variant i was used with diethylamine instead of trimethylamine with tert-butyl 5- (methylamino)-2-azabicyclo[2.2.1]heptane-2-carboxylate (600 mg, 2.65 mmol, 1.07 eq) as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.5 added 3,4-dichloro- 2-fluoroaniline (150 mg, 833 umol, 1.20 eq) was used as HX
1-Y in the presence of 0.13 eq HCl and in step C.6, variant ii was used to give 1-(5-((4-((3,4-dichloro-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin -6-yl)(methyl) amino)-2-azabicyclo[2.2.1]heptan-2- yl)prop-2-en-1-one 54 in 3% overall yield.
1H NMR (400 MHz, MeOD) δ = 8.71 (dt, J = 2.1, 8.7 Hz, 1H), 8.48 (s, 1H), 7.94 (d, J = 9.4 Hz, 1H), 7.50 (d, J = 9.4 Hz, 1H), 7.41 (d, J = 8.7 Hz, 1H), 6.76 (dd, J = 10.5, 16.8 Hz, 1H), 6.60 - 6.51 (m, 1H), 6.34 (ddd, J = 2.0, 4.4, 16.8 Hz, 1H), 5.79 (dd, J = 1.8, 10.5 Hz, 1H), 5.03 - 4.97 (m, 1H), 4.74 - 4.65 (m, 1H), 3.65 - 3.52 (m, 1H), 3.51 - 3.35 (m, 1H), 3.23 (br s, 1H), 3.15 (d, J = 4.8 Hz, 3H), 2.39 - 2.22 (m, 1H), 2.17 - 2.01 (m, 1H), 2.00 - 1.82 (m, 2H). MS (ESI) m/z 487.0 [M+H]
+. [1915] Synthesis of tert-butyl 5-(methylamino)-2-azabicyclo[2.2.1]heptane-2-carboxylate. To a solution of tert-butyl 5-oxo-2-azabicyclo[2.2.1]heptane-2-carboxylate (2.00 g, 9.47 mmol, 1.00 eq) in dichloromethane (20.0 mL) was added phenylmethanamine (1.05 g, 9.80 mmol, 1.07 mL, 1.04 eq), sodium triacetoxy borohydride (4.00 g, 18.9 mmol, 1.99 eq) and acetic acid (600 mg, 9.99 mmol, 571 uL, 1.06 eq). The mixture was stirred at 25 °C for 16 h. Then formaldehyde (2.80 g, 93.3 mmol, 2.57 mL, 9.85 eq) was added to the mixture. The mixture was stirred at 25 °C for another 12 h. The mixture was concentrated under reduced pressure to give a residue which was purified by reverse phase (0.1% formic acid). The desired fraction was concentrated under reduced pressure to give tert-butyl 5-(benzyl(methyl)amino)-2- azabicyclo[2.2.1]heptane-2-carboxylate (1.80 g, 5.69 mmol, 60% yield) as a yellow solid. To a solution of tert-butyl 5- (benzyl(methyl)amino)-2-azabicyclo[2.2.1]heptane-2-carboxylate (1.20 g, 3.79 mmol, 1.00 eq) in
methanol (50.0 mL) was added wet palladium on carbon (200 mg, 10% purity). The mixture was stirred at 25 °C for 1 h under hydrogen (15 Psi). After filtration, the filtrate was concentrated under reduced pressure to give tert-butyl 5-(methylamino)-2-azabicyclo[2.2.1]heptane-2-carboxylate (680 mg, crude) as a colorless oil.
1H NMR (400 MHz, DMSO-d6) δ = 3.94 (br d, J = 13.1 Hz, 1H), 3.41 (t, J = 8.9 Hz, 1H), 3.01 - 2.88 (m, 2H), 2.21 (s, 3H), 1.90 - 1.78 (m, 1H), 1.65 - 1.52 (m, 1H), 1.46 (br d, J = 8.5 Hz, 1H), 1.40 - 1.35 (m, 9H), 1.05 - 0.93 (m, 1H). [1916] Synthesis of Compound No. 55: Synthesized according to general procedure C, wherein in step C.1 variant i was with tert-butyl 5-amino-2- azabicyclo[2.2.1]heptane-2-carboxylate (700 mg, 3.30 mmol, 1.11 eq) as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.5 added 3,4-dichloro-2-fluoro-aniline (210 mg, 1.17 mmol, 1.04 eq) was used as HX
1-Y in the presence of 0.13 eq HCl and in step C.6, variant ii was used to give 1-(5-((4-((3,4-dichloro-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)amino)-2-azabicyclo[2.2.1]-heptan-2-yl)prop- 2-en-1-one 55 in 7% overall yield.
1H NMR (400 MHz, MeOD) δ = 8.67 (dt, J = 5.7, 8.7 Hz, 1H), 8.41 (d, J = 1.6 Hz, 1H), 7.72 (dd, J = 2.7, 9.2 Hz, 1H), 7.33 (td, J = 2.4, 9.2 Hz, 1H), 7.12 (d, J = 9.0 Hz, 1H), 6.72 (dd, J = 10.5, 16.8 Hz, 1H), 6.56 (dd, J = 10.4, 16.8 Hz, 1H), 6.31 (ddd, J = 2.0, 4.9, 16.8 Hz, 1H), 5.84 - 5.71 (m, 1H), 4.69 - 4.59 (m, 1H), 4.50 - 4.35 (m, 1H), 3.76 - 3.61 (m, 1H), 3.52 (dd, J = 2.8, 10.1 Hz, 1H), 3.37 (br dd, J = 1.6, 13.6 Hz, 1H), 3.31 - 3.22 (m, 1H), 2.56 - 2.34 (m, 1H), 2.04 - 1.84 (m, 2H), 1.63 - 1.49 (m, 1H). MS (ESI) m/z 472.9 [M+H]
+ [1917] Synthesis of tert-butyl 5-amino-2- azabicyclo[2.2.1]heptane-2-carboxylate. To a solution of tert-butyl 5-oxo-2-azabicyclo[2.2.1]heptane-2-carboxylate (1.50 g, 7.10 mmol, 1.00 eq) in dichloromethane (20.0 mL) was added phenylmethanamine (790 mg, 7.37 mmol, 1.04 eq), sodium triacetoxy borohydride (3.00 g, 14.2 mmol, 1.99 eq) and acetic acid (450 mg, 7.49 mmol, 428 uL, 1.06 eq). The mixture was stirred at 25 °C for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (0.1% FA). The desired fraction was concentrated under reduced pressure to give tert-butyl 5-(benzylamino)-2- azabicyclo[2.2.1]heptane-2-carboxylate (2.10 g, 6.94 mmol, 98% yield) as a white solid. To a solution of tert-butyl 5-(benzylamino)-2-azabicyclo[2.2.1]heptane-2-carboxylate (2.10 g, 6.94 mmol, 1.00 eq) in methanol (50.0 mL) was added wet palladium on carbon (200 mg, 10% purity). The mixture was stirred at 25 °C for 1 h under hydrogen atmosphere (15 Psi). After filtration, the filtrate was concentrated under reduced pressure to give tert-butyl 5-amino-2- azabicyclo[2.2.1]heptane-2-carboxylate (1.20 g, crude) as a colorless oil which was used directly
in the next step.
1H NMR (400 MHz, DMSO-d
6) δ = 3.94 (br d, J = 7.0 Hz, 1H), 3.56 - 3.53 (m, 1H), 3.40 - 3.33 (m, 1H), 3.04 - 2.94 (m, 1H), 2.36 (br s, 1H), 1.99 - 1.88 (m, 1H), 1.62 - 1.53 (m, 1H), 1.48 (br d, J = 9.8 Hz, 1H), 1.04 - 0.95 (m, 1H). [1918] Synthesis of Compound No. 56: Synthesized according to general procedure C, wherein in step C.1 variant i and tert-butyl 3-hydroxy-3-methyl-azetidine-1-carboxylate (1.34 g, 7.14 mmol, 1.20 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant ii was used and in step C.5 3,4-dichloro-2-fluoro-phenol (103 mg, 570 umol, 1.00 eq) was used as HX
1-Y in the presence of DIPEA at 90 °C and in step C.6, variant ii was used to give 1-(3-((4-(3,4-dichloro-2- fluorophenoxy)pyrido [3,2-d]pyrimidin-6-yl)oxy)-3-methylazetidin-1-yl)prop-2-en-1-one 56 in 1% yield from XXII.
1H NMR (400 MHz,CDCl
3) δ = 8.70 (s, 1H), 8.24 (d, J = 9.0 Hz, 1H), 7.42 (dd, J = 2.0, 8.9 Hz, 1H), 7.36 (d, J = 9.2 Hz, 1H), 7.32 - 7.29 (m, 1H), 6.41 - 6.34 (m, 1H), 6.29 - 6.21 (m, 1H), 5.70 (dd, J = 1.8, 10.2 Hz, 1H), 4.62 (d, J = 9.6 Hz, 1H), 4.48 - 4.40 (m, 2H), 4.32 - 4.26 (m, 1H), 1.97 (s, 3H). MS (ESI) m/z 448.9 [M+H]. [1919] Synthesis of Compound No. 58: Synthesized according to general procedure C, wherein in step C.1 variant ii and (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (3.62 g, 19.3 mmol, 1.30 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.5 4-((tert-butyldimethylsilyl)oxy)-3-chloroaniline (161 mg, 627 umol, 1.10 eq) was used as HX
1-Y and in step C.6, variant i was used to give TBS protected derivative of 58, which was dissolved in THF and tetrabutylammonium fluoride 1 M tetrahydrofuran (1 M, 532 uL, 2.00 eq) was added at 0 °C under nitrogen. The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 200*40mm*10um;mobilephase:[water(0.2%FA)- ACN];B%:20%-60%,10min) to give (S)-1-(3-((4-((3- chloro-4-hydroxyphenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one 58 in 66% yield from XXII.
1H NMR (400MHz, DMSO-d
6) δ = 10.06 (br s, 1H), 9.46 (s, 1H), 8.52 (s, 1H), 8.09 (d, J = 9.0 Hz, 1H), 7.92 (br s, 1H), 7.65 (br d, J = 8.6 Hz, 1H), 7.36 (dd, J = 3.8, 8.9 Hz, 1H), 7.02 (d, J = 8.7 Hz, 1H), 6.75 - 6.48 (m, 1H), 6.31 - 6.03 (m, 2H), 5.83 - 5.54 (m, 1H), 4.07 - 3.51 (m, 4H), 2.39 - 2.10 (m, 2H). MS (ESI) m/z 412.2 [M+H]
+ [1920] Synthesis of 4-((tert-butyldimethylsilyl)oxy)-3-chloroaniline. To a solution of 4-amino- 2-chlorophenol (1.50 g, 10.4 mmol, 1.00 eq) in dichloromethane (20.0 mL) was added imidazole (853 mg, 12.5 mmol, 1.20 eq) and tert-butylchlorodimethylsilane (1.73 g, 11.4 mmol, 1.41 mL,
1.10 eq) in dichloromethane (10.0 mL) at 0 °C. The mixture was stirred at 25 °C for 3 h. The reaction mixture was quenched with water (20.0 mL), and extracted with dichloromethane (50.0 mL). The organic layer was concentrated under reduced pressure to give a residue. The residue was washed with water (3× 10.0 mL), the organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 4-((tert-butyldimethylsilyl)oxy)-3- chloroaniline (2.60 g, 10.0 mmol, 96% yield) as a brown oil.
1H NMR (400MHz, CDCl
3) δ = 6.58 - 6.42 (m, 2H), 6.28 (dd, J = 2.6, 8.6 Hz, 1H), 3.26 (br s, 2H), 0.83 (s, 9H), 0.00 (s, 6H). [1921] Synthesis of Compound No. 59: To a mixture of 4,6-dichloropyrido[3,2-d]pyrimidine (1.00 g, 5.00 mmol, 1.00 eq) and 3,4-dichloro-2-fluoro-aniline (899 mg, 5.00 mmol, 1.00 eq) in propan-2-ol (10.0 mL) was added trifluoroacetic acid (114 mg, 999 umol, 74.0 uL, 0.200 eq) in one portion at 25 °C. The mixture was stirred at 80 °C for 0.5 h. Petroleum ether (20.0 mL) was added with stirring and the mixture was filtered. The solid was washed with petroleum ether (3.00 mL), dried to give 6-chloro-N-(3,4-dichloro -2-fluorophenyl)pyrido[3,2-d]pyrimidin-4-amine (1.60 g, 4.66 mmol, 93% yield) as a yellow solid. To a mixture of 6-chloro-N-(3,4-dichloro -2- fluorophenyl)pyrido[3,2-d]pyrimidin-4-amine (1.00 g, 2.91 mmol, 1.00 eq) and methyl 3- mercaptopropanoate (524 mg, 4.37 mmol, 472 uL, 1.50 eq) in dioxane (10.0 mL) was added tris(dibenzylideneacetone)dipalladium(0) (106 mg, 116 umol, 0.0400 eq), Xantphos (101 mg, 174 umol, 0.0600 eq), diisopropylethylamine (752 mg, 5.82 mmol, 1.01 mL, 2.00 eq) in one portion at 25 °C under nitrogen. The mixture was stirred at 110 °C for 18 h. The mixture was concentrated to give residue. The crude product was purified by re-crystallization from acetonitrile (30.0 mL) at 25 °C to give methyl 3-((4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6- yl)thio)propanoate (1.14 g, 2.67 mmol, 91% yield) as an off-white solid. To a mixture of methyl 3-((4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)thio) propanoate (0.300 g, 702 umol, 1.00 eq) in ethanol (18.0 mL) was added dropwise sodium ethoxide (1.00 M, 1.40 mL, 2.00 eq) at 0 °C under nitrogen
, then heated to 80 °C and stirred for 2 h. The reaction mixture was concentrated under reduced pressure to give sodium 4-((3,4-dichloro-2- fluorophenyl)amino)pyrido[3,2-d] pyrimidine-6-thiolate (0.254 g, crude) as a brown solid. To a mixture of sodium 4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidine-6-thiolate (0.254 g, 699 umol, 1.00 eq) and (R)-tert-butyl 3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (556 mg, 2.10 mmol, 3.00 eq) in ethanol (12.0 mL) was added potassium carbonate (144 mg, 1.05 mmol, 1.50 eq) in one portion at 20 °C under nitrogen. Then the mixture was heated to 60 °C and
stirred for 12 h. The reaction mixture was diluted with water (20.0 mL) and extracted with ethyl acetate (3 × 20.0 mL). The combined organic layers were washed with brine (20.0 mL), dried over sodium sulfate, filtered and concentrated to give (S)-tert-butyl3-((4-((3,4-dichloro-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)thio)pyrrolidine-1-carboxylate (0.626 g, crude) as a yellow solid. A mixture of (S)-tert-butyl3-((4-((3,4-dichloro-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)thio) pyrrolidine-1-carboxylate (0.736 g, 1.44 mmol, 1.00 eq) in hydrochloric acid/ ethyl acetate (50.0 mL) was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Phenomenex luna C18 250*50mm*10 um;mobile phase: [water(0.225%FA)-ACN];B%: 20%-50%,10min) to give (S)-N-(3,4-dichloro-2-fluorophenyl)-6- (pyrrolidin -3-ylthio)pyrido[3,2-d]pyrimidin-4-amine (0.184 g, 448 umol, 31% yield) as a white solid. To a mixture of (S)-N-(3,4-dichloro-2-fluorophenyl)-6-(pyrrolidin -3-ylthio)pyrido[3,2- d]pyrimidin-4-amine (0.130 g, 316 umol, 1.00 eq) and triethylamine (96.1 mg, 950 umol, 132 uL, 3.00 eq) in dimethyl formamide (0.600 mL) was added dropwise acryloyl chloride (57.3 mg, 633 umol, 51.6 uL, 2.00 eq) at 0 °C under nitrogen
, then stirred at 0 °C for 1 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep- HPLC (column: Phenomenex Luna C18 200*40mm*10um;mobile phase: [water(0.2%FA)- ACN];B%: 50%-80%,10min) to give (S)-1-(3-((4-((3,4- dichloro-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)thio)pyrrolidin-1-yl)prop-2-en-1-one 59 (58.92 mg, 126 umol, 40% yield, 100% purity) as a white solid.
1H NMR (400 MHz, DMSO-d6) δ = 9.67 (s, 1H), 8.60 (s, 1H), 8.13 (t, J = 8.3 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.81 (dd, J = 2.9, 8.8 Hz, 1H), 7.63 (br d, J = 8.7 Hz, 1H), 6.68 - 6.52 (m, 1H), 6.15 (ddd, J = 2.1, 8.2, 16.7 Hz, 1H), 5.74 - 5.60 (m, 1H), 4.87 - 4.78 (m, 1H), 4.28 -4.01 (m, 1H), 3.76 (br t, J = 6.9 Hz, 1H), 3.68 - 3.50 (m, 2H), 2.65 - 2.56 (m, 1H), 2.16 - 1.97 (m, 1H). MS (ESI) m/z 464.1 [M+H]
+. [1922] Synthesis of (R)-tert-butyl 3-((methylsulfonyl)oxy)pyrrolidine -1-carboxylate. To a mixture of (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1.00 g, 5.34 mmol, 1.00 eq) and triethylamine (1.62 g, 16.0 mmol, 2.23 mL, 3.00 eq) in dichloromethane (15.0 mL) was added methanesulfonyl chloride (917 mg, 8.01 mmol, 620 uL, 1.50 eq) dropwise at 0 °C under nitrogen. The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (40.0 mL) and extracted with ethyl acetate (3 × 20.0 mL). The combined organic layers were washed with saturated sodium bicarbonate (20.0 mL),
dried over sodium sulfate, filtered and concentrated under reduced pressure to give (R)-tert-butyl 3-((methylsulfonyl)oxy)pyrrolidine -1-carboxylate (1.40 g, 5.28 mmol, 98% yield) as a yellow oil.
1H NMR (400 MHz, CDCl
3) δ = 5.27 (br s, 1H), 3.74 - 3.42 (m, 4H), 3.09 - 3.02 (m, 3H), 2.36 - 2.21 (m, 1H), 2.14 (br d, J = 3.5 Hz, 1H), 2.20 - 2.07 (m, 1H), 1.47 (s, 9H). [1923] Synthesis of Compound No. 60: Synthesized according to general procedure C, wherein in step C.1 variant i and tert-butyl 3-hydroxyazetidine-1-carboxylate (2.60 g, 15.0 mmol, 1.21 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.5 4- amino-2,3-difluorophenol (103 mg, 712 umol, 1.20 eq) was used as HX
1-Y in the presence of 0.1 eq HCl and in step C.6, variant ii was used to give 1-(3-((4-((2,3-difluoro-4-hydroxyphenyl)amino) pyrido[3,2-d]pyrimidin-6-yl)oxy)azetidin-1-yl)prop-2-en-1-one 60 in 9% yield from XXII.
1H NMR (400 MHz, DMSO-d
6) δ = 10.96 - 10.20 (m, 1H), 9.36 (s, 1H), 8.45 (s, 1H), 8.16 (d, J = 9.0 Hz, 1H), 7.46 (d, J = 9.0 Hz, 1H), 7.28 (dt, J = 2.0, 8.6 Hz, 1H), 6.86 (dt, J = 1.9, 9.0 Hz, 1H), 6.36 (dd, J = 10.3, 17.0 Hz, 1H), 6.13 (dd, J = 2.1, 16.9 Hz, 1H), 5.83 - 5.72 (m, 1H), 5.69 (dd, J = 2.1, 10.3 Hz, 1H), 4.94 - 4.80 (m, 1H), 4.57 (br dd, J = 7.3, 11.2 Hz, 1H), 4.28 (br dd, J = 4.1, 10.0 Hz, 1H), 3.99 (br dd, J = 3.4, 11.4 Hz, 1H). MS (ESI) m/z 399.9 [M+H]
+ [1924] Synthesis of Compound No. 61: Synthesized according to general procedure C, wherein in step C.1 variant i and tert-butyl 3-amino-3-ethyl-azetidine-1-carboxylate (491 mg, 2.46 mmol, 1.10 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant ii was used and in step C.53,4-dichloro-2-fluoro-aniline (86.6 mg, 480 umol, 0.700 eq) was used as HX
1-Y and in step C.6, variant ii was used to give 1-(3-((4-((3,4-dichloro-2-fluorophenyl) amino)pyrido[3,2- d]pyrimidin-6-yl)amino)-3-ethylazetidin-1-yl)prop-2-en-1-one 61 in 2% overall yield.
1H NMR (400 MHz, DMSO-d
6) δ = 8.97 (d, J = 2.4 Hz, 1H), 8.66 (t, J = 8.8 Hz, 1H), 8.51 (s, 1H), 8.18 (s, 1H), 7.90 (d, J = 9.2 Hz, 1H), 7.61 (dd, J = 1.6, 9.2 Hz, 1H), 7.20 (d, J = 9.0 Hz, 1H), 6.38 (dd, J = 10.2, 16.8 Hz, 1H), 6.12 (dd, J = 2.0, 17.0 Hz, 1H), 5.75 - 5.62 (m, 1H), 4.36 (s, 2H), 4.12 - 4.02 (m, 2H), 2.29 - 2.16 (m, 2H), 0.87 (t, J = 7.2 Hz, 3H). MS (ESI) m/z 461.1 [M+H]. [1925] Synthesis of Compound No. 62: Synthesized according to general procedure C, wherein in step C.1 variant i and tert-butyl 4-aminopiperidine-1-carboxylate (1.00 g, 4.99 mmol, 1.01 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.5 3- chloro-4-((3-fluorophenyl)methoxy)aniline (380 mg, 1.51 mmol, 1.14 eq) was used in the presence of 0.1 eq HCl as HX
1-Y and in step C.6, variant ii was used to give 1-(4-((4-((3-chloro-4-((3- fluorobenzyl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)amino)piperidin- 1-yl)prop-2-en-1-
one 62 in %5 overall yield.
1H NMR (400 MHz, DMSO-d
6) δ = 9.44 - 9.31 (m, 1H), 8.45 (s, 1H), 8.15 (d, J = 2.5 Hz, 1H), 7.80 - 7.76 (m, 2H), 7.56 (br d, J = 7.4 Hz, 1H), 7.50 - 7.45 (m, 1H), 7.35 - 7.31 (m, 2H), 7.29 (d, J = 9.0 Hz, 1H), 7.19 (dt, J = 2.3, 8.5 Hz, 1H), 7.11 (d, J = 9.2 Hz, 1H), 6.87 (dd, J = 10.4, 16.7 Hz, 1H), 6.12 (dd, J = 2.4, 16.6 Hz, 1H), 5.71 - 5.67 (m, 1H), 5.27 (s, 2H), 4.60 - 4.50 (m, 1H), 4.35 - 4.28 (m, 1H), 4.10 - 4.01 (m, 1H), 3.44 - 3.40 (m, 1H), 3.11 - 3.03 (m, 1H), 2.09 - 2.00 (m, 2H), 1.38 (br s, 2H). MS (ESI) m/z 533.1 [M+H]
+. [1926] Synthesis of Compound No. 63: To a solution of 6-chloropyrimido[5,4-d]pyrimidin-4-ol (500 mg, 2.74 mmol, 1.00 eq) in dimethyl formamide (8.00 mL) was added diisopropylethylamine (1.11 g, 8.61 mmol, 1.50 mL, 3.14 eq) and tert-butyl (3S)-3-(methylamino)pyrrolidine-1- carboxylate (800 mg, 3.99 mmol, 1.46 eq). The mixture was stirred at 130 °C for 2 h. After being cooled to 25 °C, the mixture was concentrated under vacuum to give a residue which was purified by column chromatography on silica gel with petroleum ether / ethyl acetate = 1/1 to 0/1 to give (S)-tert-butyl 3-((8-hydroxypyrimido[5,4-d]pyrimidin-2-yl)(methyl)amino)pyrrolidine-1- carboxylate (610 mg, 1.76 mmol, 64% yield) as a yellow solid. To a solution of (S)-tert-butyl 3- ((8-hydroxypyrimido[5,4-d]pyrimidin-2-yl)(methyl)amino)pyrrolidine-1- carboxylate (300 mg, 866 umol, 1.00 eq) in toluene (20.0 mL) was added diisopropylethylamine (559 mg, 4.33 mmol, 754 uL, 5.00 eq) and phosphoryl trichloride (399 mg, 2.60 mmol, 242 uL, 3.01 eq) under nitrogen. The mixture was stirred at 100 °C for 2 h. After being cooled to 25 °C, the reaction mixture was quenched with saturated sodium bicarbonate solution (100 mL) and exacted with ethyl acetate (3 × 80.0 mL). The organic layer was separated and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under vacuum to give (S)-tert-butyl 3-((8- chloropyrimido[5,4-d]pyrimidin-2-yl) (methyl)amino)pyrrolidine-1-carboxylate (315 mg, crude) as a brown oil. To a solution of (S)-tert-butyl 3-((8-chloropyrimido[5,4-d]pyrimidin-2- yl)(methyl)amino)pyrrolidine- 1-carboxylate (315 mg, 863 umol, 1.00 eq) in isopropanol (15.0 mL) was added diisopropylethylamine (335 mg, 2.59 mmol, 451 uL, 3.00 eq) and 3,4-dichloro-2- fluorophenol (187 mg, 1.03 mmol, 1.20 eq). The mixture was stirred at 90 °C for 2 h. After being cooled to 25 °C, the mixture was concentrated under vacuum to give a residue which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 3/1 to 0/1) to give (S)- tert-butyl 3-((8-(3,4-dichloro-2-fluorophenoxy) pyrimido[5,4-d]pyrimidin -2- yl)(methyl)amino)pyrrolidine-1-carboxylate (240 mg, 471 umol, 54% yield) as a yellow solid. To a solution of (S)-tert-butyl 3-((8-(3,4-dichloro-2-fluorophenoxy)pyrimido[5,4-d]pyrimidin-2-
yl)(methyl) amino)pyrrolidine-1-carboxylate (200 mg, 393 umol, 1.00 eq) in dichloromethane (10.0 mL) was added trifluoroacetic acid (2.31 g, 20.3 mmol, 1.50 mL, 51.6 eq). The mixture was stirred at 25 °C for 2 h. The mixture was concentrated under vacuum to give (S)-8-(3,4-dichloro- 2-fluorophenoxy)-N-methyl-N- (pyrrolidin-3-yl)pyrimido[5,4-d]pyrimidin-2-amine (100 mg, crude, trifluoroacetic acid) as a yellow solid. To a solution of (S)-8-(3,4-dichloro-2- fluorophenoxy)-N-methyl-N-(pyrrolidin-3-yl)pyrimido[5,4-d] pyrimidin-2-amine (40.0 mg, 76.4 umol, 1.00 eq) in dimethyl formamide (2.00 mL) was added diisopropylethylamine (30.0 mg, 229 umol, 40.0 uL, 3.00 eq) and acryloyl chloride (11.1 mg, 123 umol, 10.0 uL, 1.60 eq). The mixture was stirred at 25 °C for 10 min. The mixture was filtered and the filtrate was purified by prep- HPLC (column: Phenomenex Synergi C18 150*25*10um; mobile phase: [water(0.225%FA)- ACN];B%: 53%-83%, 10 min) and lyophilized to give (S)-1-(3-((8-(3,4-dichloro-2- fluorophenoxy)pyrimido[5,4-d]pyrimidin-2-yl)(methyl)amino)pyrrolidin-1-yl)prop-2-en-1-one 63 (3.83 mg, 8.10 umol, 11% yield, 98% purity, formate) as a yellow solid.
1H NMR (400 MHz, DMSO-d
6) δ = 9.37 (d, J = 3.8 Hz, 1H), 8.56 (d, J = 3.1 Hz, 1H), 7.74 - 7.54 (m, 2H), 6.61 (ddd, J = 10.4, 14.2, 16.8 Hz, 1H), 6.16 (td, J = 2.9, 16.7 Hz, 1H), 5.68 (dt, J = 2.3, 10.4 Hz, 1H), 5.60 - 5.35 (m, 1H), 3.95 - 3.80 (m, 1H), 3.79 - 3.59 (m, 2H), 3.47 - 3.38 (m, 1H), 3.20 (d, J = 2.9 Hz, 3H), 2.30 - 2.19 (m, 1H), 2.19 - 2.09 (m, 1H). MS (ESI) m/z 463.1 [M+H]
+. [1927] Synthesis of Compound No. 64: Synthesized according to general procedure C, wherein in step C.1 variant ii and (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (3.62 g, 19.3 mmol, 1.30 eq) was used as BocN[(CR
aR
b)m(CR
cR
d)n]-X
2H, in step C.2 variant i was used and in step C.5 4-((tert-butyldimethylsilyl)oxy)-2,3-difluoroaniline (184 mg, 712 umol, 1.00 eq) was used as HX
1- Y and in step C.6, variant i was used, which also fleaved the TBS group to give (S)-1-(3-((4-((2,3- difluoro-4-hydroxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl) prop-2-en-1- one 64 in 25% yield from XXII.
1H NMR (400MHz, DMSO-d
6) δ = 10.41 (br d, J = 5.3 Hz, 1H), 9.54 (s, 1H), 8.41 (s, 1H), 8.08 (d, J = 9.0 Hz, 1H), 7.35 (dd, J = 4.2, 9.0 Hz, 1H), 7.29 - 7.14 (m, 1H), 6.84 (br t, J = 8.4 Hz, 1H), 6.68 - 6.45 (m, 1H), 6.23 - 5.97 (m, 2H), 5.66 (ddd, J = 2.3, 10.3, 18.5 Hz, 1H), 4.05 - 3.43 (m, 4H), 2.39 - 2.08 (m, 2H). MS (ESI) m/z 414.0 [M+H]
+. [1928] Synthesis of 4-((tert-butyldimethylsilyl)oxy)-2,3-difluoroaniline. To a mixture of 4- amino-2,3-difluorophenol (300 mg, 2.07 mmol, 1.00 eq) and imidazole (422 mg, 6.20 mmol, 3.00 eq) in acetonitrile (10.0 mL) was added tert-butylchlorodimethylsilane (373 mg, 2.48 mmol, 304
uL, 1.20 eq) at 0 °C, and the mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure to remove acetonitrile. The residue was diluted with water (10.0 mL) and extracted with ethyl actate (3× 10.0 mL). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO
2, petroleum ether/ethyl acetate = 1/1) to give 4-((tert-butyldimethylsilyl)oxy)-2,3- difluoroaniline (360 mg, 1.39 mmol, 67% yield) as a white oil.
1H NMR (400 MHz, CDCl
3) δ = 6.51 (dt, J = 2.1, 8.5 Hz, 1H), 6.39 (dt, J = 2.2, 9.0 Hz, 1H), 3.52 (br s, 2H), 1.00 (s, 9H), 0.17 (s, 6H). [1929] Synthesis of Compound No. 65: Synthesized according to general procedure C, wherein in step C.1 variant i and tert-butyl 3-hydroxyazetidine-1-carboxylate (2.60 g, 15.0 mmol, 1.21 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.5 4- amino-2-chlorophenol (102 mg, 712 umol, 1.2 eq) was used as HX
1-Y in the presence of 0.1 eq HCl and in step C.6, variant ii was used to give 1-(3-((4-((3- chloro-4- hydroxyphenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)azetidin-1-yl)prop-2-en-1-one 65 in 8% yield from XXII.
1H NMR (400 MHz, DMSO-d
6) δ = 10.07 (s, 1H), 9.30 (s, 1H), 8.54 (s, 1H), 8.14 (d, J = 9.0 Hz, 1H), 7.93 (d, J = 2.4 Hz, 1H), 7.65 (dd, J = 2.4, 8.8 Hz, 1H), 7.45 (d, J = 8.9 Hz, 1H), 7.02 (d, J = 8.8 Hz, 1H), 6.38 (dd, J = 10.3, 16.9 Hz, 1H), 6.14 (dd, J = 2.1, 17.0 Hz, 1H), 5.93 - 5.80 (m, 1H), 5.69 (dd, J = 2.1, 10.3 Hz, 1H), 4.87 (br dd, J = 7.2, 9.0 Hz, 1H), 4.56 (br dd, J = 7.0, 10.9 Hz, 1H), 4.26 (br dd, J = 3.9, 9.8 Hz, 1H), 3.99 (br dd, J = 3.9, 11.2 Hz, 1H). MS (ESI) m/z 398.0 [M+H]
+. [1930] Synthesis of Compound No. 66: To a mixture of 6-chloropyrimido[5,4-d]pyrimidin-4-ol VII (400 mg, 2.19 mmol, 1.00 eq) in dimethyl formamide (5.00 mL) was added diisopropylethylamine (850 mg, 6.58 mmol, 1.15 mL, 3.00 eq) and (S)-tert-butyl 3- aminopyrrolidine-1-carboxylate (530 mg, 2.85 mmol, 1.30 eq). The mixture was stirred at 130 °C for 12 h. After being cooled to 25 °C, the mixture was concentrated under reduced pressure to give a residue which was purified by reversed phase HPLC (0.1% FA condition). The desired fraction was collected and concentrated to remove acetonitrile. The residue was extracted with ethyl acetate (80.0 mL). The organic layer was separated and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give (S)-tert-butyl 3-((8- hydroxypyrimido[5,4-d]pyrimidin-2- yl)amino) pyrrolidine-1-carboxylate (380 mg, 1.14 mmol, 52% yield) as a yellow solid. To a solution of (S)-tert-butyl 3-((8-hydroxypyrimido[5,4-
d]pyrimidin-2-yl)amino)pyrrolidine-1-carboxylate (380 mg, 1.14 mmol, 1.00 eq) in toluene (5.00 mL) was added diisopropylethylamine (742 mg, 5.74 mmol, 1.00 mL, 5.02 eq) and phosphoryl trichloride (527 mg, 3.44 mmol, 319 uL, 3.01 eq) under nitrogen. The mixture was stirred at 100 °C for 2 h. After being cooled to room temperature, the reaction mixture was quenched with saturated sodium bicarbonate solution (100 mL) and exacted with ethyl acetate (3 × 80 mL). The organic layer was separated and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give (S)-tert-butyl 3-((8-chloropyrimido[5,4- d]pyrimidin- 2-yl)amino)pyrrolidine-1-carboxylate (400 mg, crude) as brown oil. To a solution of (S)-tert-butyl 3-((8-chloropyrimido[5,4-d]pyrimidin-2-yl)amino)pyrrolidine-1-carboxylate (400 mg, 1.14 mmol, 1.00 eq) in isopropanol (8.00 mL) was added diisopropylethylamine (440 mg, 3.40 mmol, 593 uL, 2.99 eq) and 3,4-dichloro-2-fluorophenol (245 mg, 1.35 mmol, 1.19 eq). The mixture was stirred at 90 °C for 2 h. After being cooled to room temperature, the mixture was concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 5/1 to 0/1) to give (S)-tert-butyl 3- ((8-(3,4-dichloro-2-fluorophenoxy)pyrimido[5,4-d]pyrimidin-2-yl)amino)pyrrolidine-1- carboxylate (300 mg, 606 umol, 53% yield) as a yellow solid. To a solution of (S)-tert-butyl 3-((8- (3,4-dichloro-2-fluorophenoxy)pyrimido[5,4-d]pyrimidin-2-yl)amino) pyrrolidine-1-carboxylate (100 mg, 202 umol, 1.00 eq) in dichloromethane (5.00 mL) was added trifluoroacetic acid (308 mg, 2.70 mmol, 200 uL, 13.4 eq). The mixture was stirred at 25 °C for 2 h. The mixture was concentrated under vacuum to give (S)-8-(3,4-dichloro-2-fluorophenoxy)-N-(pyrrolidin-3-yl) pyrimido[5,4-d]pyrimidin-2-amine (100 mg, crude) as a yellow solid. To a solution of (S)-8-(3,4- dichloro-2-fluorophenoxy)-N-(pyrrolidin-3-yl)pyrimido[5,4-d]pyrimidin-2-amine (100 mg, 196 umol, 1.00 eq) in dimethyl formamide (2.00 mL) was added diisopropylethylamine (76.4 mg, 591 umol, 103 uL, 3.01 eq) and acryloyl chloride (22.2 mg, 245 umol, 20.0 uL, 1.25 eq). The mixture was stirred at 25 °C for 10 min. The suspension was dissolved in dimethyl formamide (2.00 mL) and purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10um; mobile phase: [water (0.225%FA)-ACN]; B%: 38%-68%, 10 min). The desired fraction was collected and lyophilized to give (S)-1-(3-((8-(3,4- dichloro-2-fluorophenoxy)pyrimido[5,4-d]pyrimidin-2- yl)amino)pyrrolidin-1-yl)prop-2-en-1-one 66 (14.83 mg, 29.3 umol, 15% yield, 98% purity) as a yellow solid.
1H NMR (400 MHz, DMSO-d
6) δ = 9.46 - 9.20 (m, 1H), 8.70 - 8.41 (m, 2H), 7.71 - 7.65 (m, 1H), 7.65 - 7.55 (m, 1H), 6.65 - 6.49 (m, 1H), 6.13 (ddd, J = 2.4, 5.2, 16.8 Hz, 1H), 5.66
(ddd, J = 2.4, 10.6, 13.5 Hz, 1H), 4.68 - 4.46 (m, 1H), 3.92 (br d, J = 5.1 Hz, 1H), 3.81 - 3.70 (m, 1H), 3.69 - 3.44 (m, 3H), 2.31 - 2.13 (m, 1H), 2.12 - 1.93 (m, 1H). MS (ESI) m/z 449.0 [M+H]
+ [1931] Synthesis of Compound No. 67: Synthesized according to general procedure C, wherein in step C.1 variant i and tert-butyl 3-amino-3-ethyl-azetidine-1-carboxylate (491 mg, 2.46 mmol, 1.10 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant ii was used and in step C.53,4-dichloro-2-fluorophenol (134 mg, 742 umol, 0.900 eq) was used as HX
1-Y and in step C.6, variant ii was used to give 1-(3-((4-(3,4-dichloro-2-fluorophenoxy) pyrido[3,2-d]pyrimidin-6- yl)amino)-3-ethylazetidin-1-yl)prop-2-en-1-one 67 in 2% yield from XXII.
1H NMR (400 MHz, CDCl
3) δ = 8.55 (s, 1H), 8.02 (d, J = 9.2 Hz, 1H), 7.39 (dd, J = 2.0, 8.8 Hz, 1H), 7.28 - 7.25 (m, 1H), 7.06 (d, J = 9.2 Hz, 1H), 6.27 - 6.22 (m, 2H), 5.64 - 5.58 (m, 1H), 5.30 (s, 1H), 4.67 (d, J = 8.8 Hz, 1H), 4.31 (d, J = 10.4 Hz, 1H), 4.25 (d, J = 8.8 Hz, 1H), 4.10 (d, J = 10.4 Hz, 1H), 2.38 (qd, J = 7.2, 14.2 Hz, 1H), 2.10 (dd, J = 7.2, 14.4 Hz, 1H), 0.99 (t, J = 7.2 Hz, 3H). MS (ESI) m/z 462.1 [M+H]. [1932] Synthesis of Compound No. 68: Synthesized according to general procedure A, wherein in step A.13,4-dichloro-2-fluoroaniline (340 mg, 1.89 mmol, 0.988 eq) was used as H
2NX
1, in step A.2 variant iii (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (150 mg, 801 umol, 1.50 eq) as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H was used and in step A.3 variant i was employed to give (S)-1- (3-((4-((3,4-dichloro-2-fluorophenyl)amino)- 7-methoxypyrido[3,2-d]pyrimidin-6- yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one 68 in 5% overall yield.
1H NMR (400 MHz, DMSO-d
6) δ = 9.17 (br s, 1H), 8.54 (s, 1H), 8.19 (t, J = 8.6 Hz, 1H), 7.57 (br d, J = 8.9 Hz, 1H), 7.52 (s, 1H), 6.67 - 6.54 (m, 1H), 6.16 (br d, J = 16.8 Hz, 1H), 5.97 (br d, J = 6.7 Hz, 1H), 5.71 - 5.62 (m, 1H), 4.00 (s, 3H), 3.93 - 3.54 (m, 4H), 2.39 - 2.21 (m, 2H). MS (ESI) m/z 478.0 [M+H]
+. [1933] Synthesis of Compound No. 69: Synthesized according to general procedure C, wherein in step C.1 variant i and tert-butyl 3-cyclopropyl-3-hydroxyazetidine-1-carboxylate (530 mg, 2.49 mmol, 1.00 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.53,4-dichloro-2-fluoroaniline (55.0mg, 305 umol, 1.00 eq) in the presence of 0.1 eq HCl was used as HX
1-Y and in step C.6, variant ii was used to give 1-(3-cyclopropyl-3-((4-((3,4- dichloro-2-fluorophenyl) amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)azetidin-1-yl)prop-2-en-1-one 69 in 5% overall yield.
1H NMR (400 MHz, DMSO-d
6) δ = 9.04 (s, 1H), 8.65 (s, 1H), 8.36 (t, J = 8.6 Hz, 1H), 8.24 (d, J = 9.0 Hz, 1H), 7.65 (dd, J = 1.9, 9.0 Hz, 1H), 7.49 (d, J = 9.0 Hz, 1H), 6.36 (dd, J = 10.4, 17.0 Hz, 1H), 6.13 (dd, J = 2.1, 17.1 Hz, 1H), 5.72 - 5.68 (m, 1H), 4.53 - 4.45 (m,
2H), 4.16 (s, 2H), 2.14 - 2.08 (m, 1H), 0.62 (s, 2H), 0.61 - 0.51 (m, 2H). MS (ESI) m/z 474.0 [M+H]
+. [1934] Synthesis of Compound No. 70: Synthesized according to general procedure C, wherein in step C.1 variant i and (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (2.09 g, 11.2 mmol, 1.50 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant ii was used and in step C.53,4-dichloro-2-fluorophenol (232 mg, 1.28 mmol, 1.50 eq) in the presence of 0.1 eq HCl was used as HX
1-Y and in step C.6, variant ii was used to give (S)-1-(3-((4-(3,4-dichloro-2- fluorophenoxy) pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one 70 in 3% overall yield.
1H NMR (400 MHz, CDCl
3) δ = 8.60 (d, J = 4.0 Hz, 1H), 8.12 (dd, J = 8.1, 9.0 Hz, 1H), 7.38 - 7.29 (m, 1H), 7.25 (dd, J = 7.9, 9.1 Hz, 1H), 7.21 - 7.16 (m, 2H), 6.49 - 6.30 (m, 2H), 5.86 (qdd, J = 2.2, 4.6, 11.5 Hz, 1H), 5.71 - 5.56 (m, 1H), 4.01 - 3.65 (m, 5H), 2.42 - 2.15 (m, 2H). MS (ESI) m/z 449.1 [M+H]
+. [1935] Synthesis of Compound No. 71: Synthesized according to general procedure C, wherein in step C.1 variant i and (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (2.09 g, 11.2 mmol, 1.50 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant ii was used and in step C.53-chloro-4-(pyrazin-2-ylmethoxy)aniline (202 mg, 857 umol, 1.00 eq) in the presence of 0.1 eq HCl was used as HX
1-Y and in step C.6, variant ii was used to give 1-(3-((4-((3-chloro-4- (pyrazin-2- ylmethoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)amino)-3-methylazetidin-1- yl)prop-2-en-1-one 71 in 32% yield from XXII.
1H NMR (400MHz, CDCl
3) δ = 8.91 (s, 1H), 8.52 (s, 1H), 8.50 (s, 2H), 8.34 (s, 1H), 7.97 (d, J = 2.8 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.60 (dd, J = 2.4, 8.8 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 6.84 (d, J = 9.0 Hz, 1H), 6.35 - 6.26 (m, 1H), 6.24 - 6.15 (m, 1H), 5.61 (dd, J = 2.0, 10.2 Hz, 1H), 5.24 (s, 2H), 4.90 (s, 1H), 4.86 - 4.79 (m, 2H), 4.09 - 3.98 (m, 2H), 1.73 (s, 3H). MS (ESI) m/z 503.1 [M+H] [1936] Synthesis of 53-chloro-4-(pyrazin-2-ylmethoxy)aniline. A mixture of 2-chloro-1-fluoro- 4-nitrobenzene (956 mg, 5.45 mmol, 1.20 eq), pyrazin-2-ylmethanol (500 mg, 4.54 mmol, 1.00 eq) and potassium carbonate (1.88 g, 13.6 mmol, 3.00 eq) in dimethyl formamide (12.0 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 60 °C for 18 h under nitrogen atmosphere. To the reaction mixture was added water (70.0 mL), and stirred at 25 °C for 10 min. The mixture was filtered, and the filter cake was concentrated under reduced pressure to give 2-((2-chloro-4-nitrophenoxy)methyl)pyrazine (1.00 g, 3.76 mmol, 82% yield) as a yellow solid. To a solution of 2-((2-chloro-4-nitrophenoxy)methyl)pyrazine (900 mg, 3.39 mmol,
1.00 eq) and ammonium chloride (543 mg, 10.1 mmol, 3.00 eq) in a mixture solvent of methanol (50.0 mL), tetrahydrofuran (10.0 mL) and water (15.0 mL) was added iron (756 mg, 13.5 mmol, 4.00 eq) in portions. The mixture was stirred at 90 °C for 1 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to remove the organic solvent. The mixture was extracted with dichloromethane (2 × 60.0 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give 3-chloro-4- (pyrazin-2-ylmethoxy)aniline (810 mg, crude) as a yellow solid.
1H NMR (400MHz, DMSO-d
6) δ = 8.80 (br s, 1H), 8.65 (br s, 2H), 6.96 (br s, 1H), 6.66 (br s, 1H), 6.47 (br s, 1H), 5.16 (br s, 2H), 4.99 (br s, 2H). [1937] Synthesis of Compound No. 72: Synthesized according to general procedure C, wherein in step C.1 variant i and tert-butyl 3-hydroxyazetidine-1-carboxylate (1.55 g, 8.93 mmol, 1.20 eq) was used as BocN[(CR
aR
b)m(CR
cR
d)n]-X
2H, in step C.2 variant i was used and in step C.5 3- chloro-4-(pyrazin-2-ylmethoxy)aniline (139 mg, 593 umol, 1.00 eq) in the presence of 0.3 eq TFA was used as HX
1-Y and in step C.6, variant ii was used to give 1-(3-((4-((3-chloro-4-(pyrazin-2- ylmethoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)azetidin-1-yl)prop-2-en-1-one 72 in 54% overall yield.
1H NMR (400MHz, DMSO-d
6) δ = 9.37 (s, 1H), 8.87 (d, J = 1.3 Hz, 1H), 8.70 (dd, J = 1.5, 2.5 Hz, 1H), 8.66 (d, J = 2.6 Hz, 1H), 8.58 (s, 1H), 8.16 (d, J = 9.0 Hz, 1H), 8.11 (d, J = 2.6 Hz, 1H), 7.86 (dd, J = 2.6, 9.0 Hz, 1H), 7.46 (d, J = 9.0 Hz, 1H), 7.37 (d, J = 9.0 Hz, 1H), 6.38 (dd, J = 10.3, 17.0 Hz, 1H), 6.14 (dd, J = 2.2, 17.0 Hz, 1H), 5.89 (tt, J = 4.3, 6.7 Hz, 1H), 5.72 - 5.67 (m, 1H), 5.39 (s, 2H), 4.88 (dd, J = 7.3, 9.2 Hz, 1H), 4.56 (dd, J = 7.1, 10.9 Hz, 1H), 4.26 (dd, J = 4.0, 9.9 Hz, 1H), 4.00 (dd, J = 4.2, 11.1 Hz, 1H). MS (ESI) m/z 490.2 [M+H]
+. [1938] Synthesis of Compound No. 73: Synthesized according to general procedure C, wherein in step C.1 variant ii and (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (3.62 g, 19.3 mmol, 1.30 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.5 3-chloro-4-(pyrazin-2-ylmethoxy)aniline (154 mg, 655 umol, 1.00 eq) was used as HX
1-Y in the presence of 0.3 eq TFA and in step C.6, variant i was used to give (S)-1-(3-((4-((3-chloro-4- (pyrazin-2-ylmethoxy) phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2- en-1-one 73 in 46% from XXII.
1H NMR (400MHz, DMSO-d
6) δ = 9.54 (br s, 1H), 8.88 (s, 1H), 8.77 - 8.63 (m, 2H), 8.57 (s, 1H), 8.19 - 8.06 (m, 2H), 7.87 (dd, J = 2.3, 9.0 Hz, 1H), 7.44 - 7.30 (m, 2H), 6.75 - 6.52 (m, 1H), 6.29 - 6.10 (m, 2H), 5.77 - 5.59 (m, 1H), 5.40 (s, 2H), 4.08 - 3.50 (m, 4H), 2.39 - 2.12 (m, 2H). MS (ESI) m/z 504.2 [M+H]
+.
[1939] Synthesis of Compound No. 74: Synthesized according to general procedure C, wherein in step C.1 variant i and tert-butyl 3-aminoazetidine-1-carboxylate (1.03 g, 5.95 mmol, 1.20 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.5 3- chloro-4-(pyrazin-2-ylmethoxy)aniline (105 mg, 446 umol, 1.00 eq) was used as HX
1-Y and in step C.6, variant ii was used to give 1-(3-((4-((3-chloro-4-(pyrazin-2- ylmethoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)amino)azetidin-1-yl)prop-2-en-1-one 74 in 14% overall yield.
1H NMR (400 MHz, DMSO-d
6) δ = 9.15 (s, 1H), 8.86 (s, 1H), 8.73 - 8.62 (m, 2H), 8.41 (s, 1H), 8.18 (d, J = 2.3 Hz, 1H), 8.15 (br d, J = 6.7 Hz, 1H), 7.89 (dd, J = 2.3, 8.9 Hz, 1H), 7.83 (d, J = 9.0 Hz, 1H), 7.34 (d, J = 9.0 Hz, 1H), 7.10 (d, J = 9.0 Hz, 1H), 6.39 (dd, J = 10.3, 16.9 Hz, 1H), 6.14 (dd, J = 2.0, 16.9 Hz, 1H), 5.69 (dd, J = 1.9, 10.3 Hz, 1H), 5.38 (s, 2H), 5.15 (br d, J = 6.5 Hz, 1H), 4.73 (br t, J = 8.2 Hz, 1H), 4.41 (br t, J = 9.0 Hz, 1H), 4.08 (br dd, J = 5.5, 8.6 Hz, 1H), 3.90 (br dd, J = 5.6, 10.1 Hz, 1H). MS (ESI) m/z 489.2 [M+H]
+. [1940] Synthesis of Compound No. 75: Synthesized according to general procedure A, wherein in step A.13,4-dichloro-2-fluoroaniline (340 mg, 1.89 mmol, 0.988 eq) was used as H
2NX
1, in step A.2 variant iii tert-butyl 4-hydroxypiperidine-1-carboxylate (150 mg, 745 umol, 1.74 eq) as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H was used and in step A.3 variant i was employed to give 1-(4-((4- ((3,4-dichloro-2-fluorophenyl)amino)-7-methoxypyrido[3,2-d]pyrimidin-6-yl)oxy)piperidin-1- yl)prop-2-en-1-one 75 in 8% yield from XIV.
1H NMR (400 MHz, DMSO-d
6) δ = 9.32 (s, 1H), 8.52 (s, 1H), 8.11 (t, J = 8.5 Hz, 1H), 7.62 (dd, J = 1.8, 9.0 Hz, 1H), 7.54 (s, 1H), 6.87 (dd, J = 10.5, 16.7 Hz, 1H), 6.13 (dd, J = 2.4, 16.7 Hz, 1H), 5.74 - 5.66 (m, 2H), 4.09 - 4.01 (m, 1H), 3.99 (s, 3H), 3.97 - 3.88 (m, 1H), 3.57 - 3.47 (m, 1H), 3.43 - 3.37 (m, 1H), 2.17 - 2.09 (m, 2H), 1.78 - 1.65 (m, 2H). MS (ESI) m/z 492.1 [M+H]
+. [1941] Synthesis of Compound No. 76: Synthesized according to general procedure C, wherein in step C.1 variant i and tert-butyl 3-hydroxy-3-methyl-azetidine-1-carboxylate (1.34 g, 7.14 mmol, 1.20 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant ii was used and in step C.53-chloro-4-(pyrazin-2-ylmethoxy)aniline (202 mg, 855 umol, 1.00 eq) was used as HX
1- Y and in step C.6, variant ii was used to give 1-(3-((4-((3-chloro-4-(pyrazin-2-ylmethoxy) phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)-3-methylazetidin-1-yl)prop-2-en-1-one 76 in 6% yield from XXII.
1H NMR (400 MHz, CDCl
3) δ = 9.01 (s, 1H), 8.76 - 8.71 (m, 1H), 8.60 (s, 2H), 8.31 - 8.26 (m, 1H), 8.14 (d, J = 8.8 Hz, 1H), 8.09 - 8.02 (m, 1H), 7.70 - 7.65 (m, 1H), 7.25 (d, J = 9.2 Hz, 1H), 7.11 (s, 1H), 6.39 (d, J = 1.6 Hz, 1H), 6.27 (s, 1H), 5.79 - 5.72 (m, 1H), 5.36 (s,
2H), 4.71 - 4.58 (m, 2H), 4.40 - 4.30 (m, 2H), 1.99 (s, 3H). MS (ESI) m/z 504.4 [M+H]. [1942] Synthesis of Compound No. 77: Synthesized according to general procedure A, wherein in step A.1 3-chloro-4-(pyrazin-2-ylmethoxy)aniline (1.54 g, 6.52 mmol, 1.50 eq) was used as H2NX
1, in step A.2 variant iii tert-butyl 3-hydroxyazetidine-1-carboxylate (180 mg, 1.05 mmol, 1.50 eq) as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H was used and in step A.3 variant i was employed to give 1-(3-((4-((3-chloro-4- (pyrazin-2-ylmethoxy)phenyl)amino)-7-methoxypyrido[3,2- d]pyrimidin-6-yl)oxy)azetidin-1-yl)prop-2-en-1-one 77 in 0.4% overall yield.
1H NMR (400 MHz, DMSO-d
6) δ = 9.20 (s, 1H), 8.87 (d, J = 1.3 Hz, 1H), 8.72 - 8.70 (m, 1H), 8.67 (d, J = 2.5 Hz, 1H), 8.54 (s, 1H), 8.10 (d, J = 2.5 Hz, 1H), 7.84 (dd, J = 2.6, 9.0 Hz, 1H), 7.56 (s, 1H), 7.37 (d, J = 9.0 Hz, 1H), 6.39 (dd, J = 10.3, 16.9 Hz, 1H), 6.15 (dd, J = 2.1, 16.9 Hz, 1H), 5.95 - 5.86 (m, 1H), 5.76 - 5.66 (m, 1H), 5.40 (s, 2H), 4.88 (dd, J = 7.7, 9.4 Hz, 1H), 4.57 (dd, J = 7.2, 11.0 Hz, 1H), 4.28 (dd, J = 3.8, 10.0 Hz, 1H), 4.03 - 3.98 (m, 4H). MS (ESI) m/z 520.1 [M+H]
+. [1943] Synthesis of Compound No. 78: Synthesized according to general procedure C, wherein in step C.1 variant i and (S)-tert-butyl 3-(methylamino)pyrrolidine-1-carboxylate (1.64 g, 8.18 mmol, 1.10 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.53-chloro-4-(pyrazin-2-ylmethoxy)aniline (583 mg, 2.47 mmol, 1.00 eq) was used as HX
1- Y and in step C.6, variant ii was used to give (S)-1-(3-((4-((3-chloro-4-(pyrazin-2- ylmethoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)(methyl)amino)pyrrolidin-1-yl)prop-2-en- 1-one 78 in 11%.
1H NMR (400 MHz, CDCl
3) δ = 8.99 (s, 1H), 8.61 - 8.57 (m, 3H), 8.54 (d, J = 7.5 Hz, 1H), 8.07 - 7.95 (m, 2H), 7.77 - 7.66 (m, 1H), 7.23 (dd, J = 3.5, 9.4 Hz, 1H), 7.07 (d, J = 8.9 Hz, 1H), 6.59 - 6.42 (m, 2H), 5.81 - 5.70 (m, 1H), 5.49 - 5.34 (m, 1H), 5.34 (s, 2H), 4.00 (dd, J = 7.7, 11.7 Hz, 1H), 3.97 - 3.83 (m, 1H), 3.78 - 3.57 (m, 2H), 3.14 (d, J = 7.8 Hz, 3H), 2.41 - 2.18 (m, 2H). MS (ESI) m/z 517.4 [M+H]
+. [1944] Synthesis of Compound No. 79: Synthesized according to general procedure C, wherein in step C.1 variant i and (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (1.52 g, 8.19 mmol, 1.10 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.53- chloro-4-(pyrazin-2-ylmethoxy)aniline (229 mg, 972 umol, 1.00 eq) was used as HX
1-Y and in step C.6, variant ii was used to give (S)-1-(3-((4-((3-chloro-4-(pyrazin-2-ylmethoxy)phenyl) amino)pyrido[3,2-d]pyrimidin-6-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one 79 in 10% overall yield.
1H NMR (400 MHz, CDCl
3) δ = 9.00 (s, 1H), 8.63 - 8.54 (m, 4H), 8.00 (d, J = 2.5 Hz, 1H), 7.87 (dd, J = 7.5, 8.9 Hz, 1H), 7.75 (td, J = 1.2, 8.9 Hz, 1H), 7.07 (dd, J = 2.8, 8.9 Hz, 1H), 7.01
(dd, J = 7.8, 8.9 Hz, 1H), 6.59 - 6.38 (m, 2H), 5.79 - 5.75 (m, 1H), 5.74 - 5.56 (m, 1H), 5.34 (d, J = 1.5 Hz, 2H), 4.86 - 4.69 (m, 1H), 4.09 - 3.91 (m, 1H), 3.80 - 3.59 (m, 3H), 2.46 - 2.08 (m, 2H). MS (ESI) m/z 503.2 [M+H]
+. [1945] Synthesis of Compound No. 80: Synthesized according to general procedure C, wherein in step C.1 variant i and tert-butyl 3-(methylamino)azetidine-1-carboxylate (1.02 g, 5.46 mmol, 1.10 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.5 3-chloro-4-(pyrazin-2-ylmethoxy)aniline (101 mg, 428 umol, 1.00 eq) was used as HX
1-Y and in step C.6, variant ii was used to give 1-(3-((4-((3-chloro-4-(pyrazin-2-ylmethoxy) phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)(methyl)amino)azetidin-1-yl)prop-2-en-1-one 80 in 14% overall yield.
1H NMR (400 MHz, DMSO-d
6) δ = 9.28 (s, 1H), 8.86 (s, 1H), 8.68 (br d, J = 13.0 Hz, 2H), 8.42 (s, 1H), 8.14 (d, J = 2.1 Hz, 1H), 7.96 (br d, J = 9.3 Hz, 1H), 7.90 - 7.83 (m, 1H), 7.45 (br d, J = 9.3 Hz, 1H), 7.35 (br d, J = 9.0 Hz, 1H), 6.40 (br dd, J = 10.3, 17.0 Hz, 1H), 6.15 (br d, J = 16.9 Hz, 1H), 5.98 - 5.88 (m, 1H), 5.70 (br d, J = 10.3 Hz, 1H), 5.38 (s, 2H), 4.60 (br t, J = 8.6 Hz, 1H), 4.44 - 4.36 (m, 1H), 4.31 (br t, J = 9.5 Hz, 1H), 4.17 - 4.09 (m, 1H), 3.22 (s, 3H). MS (ESI) m/z 503.2 [M+H]
+. [1946] Synthesis of Compound No. 82: Synthesized according to general procedure A, wherein in step A.13,4-dichloro-2-fluoroaniline (340 mg, 1.89 mmol, 0.988 eq) was used as H
2NX
1, in step A.2 variant iii tert-butyl 3-hydroxyazetidine-1-carboxylate (180 mg, 1.04 mmol, 1.29 eq) as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H was used and in step A.3 variant i was employed to give 1-(3-((4- ((3,4-dichloro-2-fluorophenyl)amino)-7-methoxypyrido[3,2-d]pyrimidin-6-yl)oxy)azetidin-1- yl) prop-2-en-1-one 82 in 4% yield from XIV.
1H NMR (400 MHz, DMSO-d
6) δ = 9.44 - 9.11 (m, 1H), 8.50 (s, 1H), 8.01 (t, J = 8.5 Hz, 1H), 7.59 (dd, J = 1.8, 9.0 Hz, 1H), 7.57 (s, 1H), 6.41 - 6.30 (m, 1H), 6.13 (dd, J = 2.2, 17.0 Hz, 1H), 5.77 - 5.72 (m, 1H), 5.72 - 5.68 (m, 1H), 4.88 - 4.77 (m, 1H), 4.56 (dd, J = 7.1, 11.1 Hz, 1H), 4.32 (br dd, J = 4.1, 10.1 Hz, 1H), 4.00 (s, 4H). MS (ESI) m/z 464.1 [M+H]
+. [1947] 83: To a solution of (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (292 mg, 1.56 mmol, 2.00 eq) in dimethyl formamide (8.00 mL) was added sodium hydride (187 mg, 4.69 mmol, 60% purity, 6.00 eq) in portions at 25 °C, and then 6-bromo-7-methoxypyrido[3,2-d]pyrimidin-4- ol (200 mg, 781 umol, 1.00 eq) was added and the reaction mixture was stirred at 90 °C for 12 h. The mixture was quenched with saturated sodium bicarbonate (2.00 mL). The reaction mixture was purified by reversed-phase HPLC (0.1% FA condition) to get (S)-tert-butyl 3-((4-hydroxy-7-
methoxypyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidine-1-carboxylate (100 mg, 220 umol, 28% yield, 80% purity) as a yellow solid. To a solution of (S)-tert-butyl 3-((4-hydroxy-7- methoxypyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidine-1- carboxylate (90.0 mg, 248 umol, 1.00 eq) in toluene (2.00 mL) was added diisopropylethylamine (96.3 mg, 745 umol, 130 uL, 3.00 eq) and phosphoryl trichloride (190 mg, 1.24 mmol, 115 uL, 5.00 eq). Then the mixture was stirred at 100 °C for 2 h. The mixture was quenched with saturated sodium bicarbonate (30.0 mL) and extracted with ethyl acetate (2 × 50.0 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to get (S)-tert-butyl 3-((4-chloro-7- methoxypyrido [3,2-d]pyrimidin-6-yl)oxy)pyrrolidine-1-carboxylate (80.0 mg, crude) as a yellow solid. To a solution of (S)-tert-butyl 3-((4-chloro-7-methoxypyrido[3,2-d]pyrimidin-6- yl)oxy)pyrrolidine-1- carboxylate (70.0 mg, 184 umol, 1.00 eq) in acetonitrile (2.00 mL) was added hydrochloric acid / ethyl acetate (4 M, 10.0 uL) and 3-chloro-4-(pyrazin-2- ylmethoxy)aniline (65.0 mg, 276 umol, 1.50 eq). Then the mixture was stirred at 25 °C for 2 h. The mixture was concentrated under reduce pressure to get a residue. The residue was purified by reversed-phase HPLC (0.1% FA condition) to get (S)-tert-butyl 3-((4-((3-chloro-4-(pyrazin-2- ylmethoxy)phenyl)amino)-7-methoxypyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidine-1-carboxylate (30 mg, 51.7 umol, 28% yield) as a yellow solid. To a solution of (S)-tert-butyl 3-((4-((3-chloro- 4-(pyrazin-2-ylmethoxy)phenyl)amino)-7-methoxypyrido [3,2-d]pyrimidin-6-yl)oxy)pyrrolidine- 1-carboxylate (30.0 mg, 51.7 umol, 1.00 eq) in dichloromethane (2.00 mL) was added trifluoroacetic acid (154 mg, 1.35 mmol, 0.10 mL). Then the mixture was stirred at 25 °C for 2 h. The mixture was concentrated under reduce pressure to get (S)-N-(3-chloro-4-(pyrazin-2-yl methoxy)phenyl)-7-methoxy-6-(pyrrolidin-3-yloxy)pyrido[3,2-d]pyrimidin-4-amine (25 mg, 37.1 umol, 72% yield, 88% purity, TFA) as a brown oil. To a solution of (S)-N-(3-chloro-4-(pyrazin-2- ylmethoxy)phenyl)-7-methoxy-6-(pyrrolidin-3-yloxy)pyrido [3,2-d]pyrimidin-4-amine (20.0 mg, 41.7 umol, 1.00 eq) in dimethyl formamide (2.00 mL) was added diisopropylethylamine (16.2 mg, 125 umol, 21.8 uL, 3.00 eq) and a solution of acryloyl chloride (5.66 mg, 62.5 umol, 5.10 uL, 1.50 eq) in dimethyl formamide (0.50 mL). Then the mixture was stirred at 25 °C for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10um;mobile phase: [water(0.225%FA)-ACN];B%: 21%-54%,10min) to get (S)-1-(3-((4-((3-chloro-4-(pyrazin-2- ylmethoxy) phenyl)amino)-7-methoxypyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-
en-1-one 83 (12 mg, 21.8 umol, 52% yield, 97% purity) as an off-white solid.
1H NMR (400 MHz, DMSO-d
6) δ = 9.35 (d, J = 2.4 Hz, 1H), 8.87 (s, 1H), 8.70 (dd, J = 1.5, 2.4 Hz, 1H), 8.67 (d, J = 2.6 Hz, 1H), 8.52 (s, 1H), 8.47 (s, 1H), 8.08 (t, J = 2.3 Hz, 1H), 7.84 (dd, J = 2.6, 8.9 Hz, 1H), 7.50 (s, 1H), 7.36 (d, J = 9.0 Hz, 1H), 6.74 - 6.52 (m, 1H), 6.29 - 6.12 (m, 2H), 5.78 - 5.59 (m, 1H), 5.39 (s, 2H), 4.08 (br d, J = 5.0 Hz, 1H), 3.96 (s, 3H), 3.83 (br d, J = 2.2 Hz, 1H), 3.69 (br d, J = 2.8 Hz, 3H), 2.32 - 2.13 (m, 2H). MS (ESI) m/z 534.5 [M+H]
+. [1948] Synthesis of Compound No. 84: Synthesized according to general procedure C, wherein in step C.1 variant ii and (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (3.62 g, 19.3 mmol, 1.30 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.5 4-amino-2-chloro-3-fluorophenol (92.1 mg, 570 umol, 1.00 eq) was used as HX
1-Y and in step C.6, variant i was used to give (S)-1-(3-((4-((3-chloro-2-fluoro-4- hydroxyphenyl)amino)pyrido[3,2-d]pyrimidin -6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one 84 in 33% from XXII.
1H NMR (400 MHz, DMSO-d
6) δ = 9.53 (s, 1H), 8.43 (s, 1H), 8.10 (d, J = 9.0 Hz, 1H), 7.45 (br d, J = 3.5 Hz, 1H), 7.37 (dd, J = 4.2, 9.0 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 6.70 - 6.54 (m, 1H), 6.16 (ddd, J = 2.3, 6.7, 16.8 Hz, 1H), 6.02 (br s, 1H), 5.68 (ddd, J = 2.3, 10.3, 18.1 Hz, 1H), 3.87 - 3.65 (m, 3H), 3.56 (br d, J = 8.4 Hz, 1H), 2.28 (td, J = 4.3, 8.7 Hz, 1H), 2.20 - 2.12 (m, 1H). MS (ESI) m/z 430.2 [M+H]
+. [1949] Synthesis of Compound No. 85: Synthesized according to general procedure C, wherein in step C.1 variant ii and (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (3.62 g, 19.3 mmol, 1.30 eq) was used as BocN[(CR
aR
b)m(CR
cR
d)n]-X
2H, in step C.2 variant i was used and in step C.5 4-amino-2-chloro-6-fluorophenol (101 mg, 627 umol, 1.00 eq) was used as HX
1-Y and in step C.6, variant i was used to give (S)-1-(3-((4-((3-chloro-5-fluoro-4-hydroxyphenyl)amino) pyrido[3,2- d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one 85 in 19% from XXII.
1H NMR (400 MHz, DMSO-d
6) δ = 9.48 (d, J = 2.4 Hz, 1H), 8.60 (d, J = 0.9 Hz, 1H), 8.12 (dd, J = 0.7, 9.0 Hz, 1H), 7.93 (dd, J = 2.3, 12.7 Hz, 1H), 7.84 (q, J = 2.2 Hz, 1H), 7.38 (dd, J = 3.8, 9.0 Hz, 1H), 6.74 - 6.52 (m, 1H), 6.17 (dt, J = 2.3, 8.4 Hz, 2H), 5.74 - 5.62 (m, 1H), 4.07 (dd, J = 4.7, 12.0 Hz, 1H), 3.87 - 3.66 (m, 3H), 2.32 - 2.22 (m, 1H), 2.21 - 2.12 (m, 1H). MS (ESI) m/z 430.0 [M+H]
+. [1950] Synthesis of Compound No. 86: Synthesized according to general procedure C, wherein in step C.1 variant ii and (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (3.62 g, 19.3 mmol, 1.30 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.5 2-(4-amino-2-chloro-3-fluorophenyl)propan-2-ol (174 mg, 855 umol, 1.00 eq) was used as HX
1-
Y and in step C.6, variant i was used to give (S)-1-(3-((4-((3-chloro-2-fluoro-4-(2-hydroxypropan- 2-yl)phenyl)amino)pyrido [3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one 86 in 14% yield from XXII.
1H NMR (400 MHz, DMSO-d
6) δ = 9.59 (s, 1H), 8.53 (d, J = 0.8 Hz, 1H), 8.15 (dd, J = 1.0, 9.0 Hz, 1H), 7.91 - 7.82 (m, 1H), 7.74 - 7.70 (m, 1H), 7.41 (dd, J = 4.4, 9.0 Hz, 1H), 6.78 - 6.45 (m, 1H), 6.16 (ddd, J = 2.4, 6.4, 16.8 Hz, 1H), 6.08 - 5.94 (m, 1H), 5.69 (ddd, J = 2.4, 10.4, 19.0 Hz, 1H), 5.46 (s, 1H), 4.08 (dd, J = 4.8, 11.8 Hz, 1H), 3.87 - 3.77 (m, 2H), 3.76 - 3.62 (m, 2H), 3.54 (ddd, J = 7.6, 9.2, 12.0 Hz, 1H), 2.53 (d, J = 2.0 Hz, 1H), 2.39 (br dd, J = 4.8, 9.4 Hz, 1H), 2.35 - 2.29 (m, 1H), 2.25 - 2.16 (m, 1H), 1.64 (s, 6H). MS (ESI) m/z 472.3[M+H]
+. [1951] Synthesis of 2-(4-amino-2-chloro-3-fluorophenyl)propan-2-ol. To a mixture of 4- bromo-3-chloro-2-fluoroaniline (5.00 g, 22.3 mmol, 1.00 eq) and triethylamine (6.76 g, 66.8 mmol, 9.30 mL, 3.00 eq) in methanol (40.0 mL) was added (1,1'- bis(diphenylphosphino)ferrocene) dichloropalladium(II) (1.63 g, 2.23 mmol, 0.100 eq) at 25 °C. The mixture was stirred at 80 °C under carbonic oxide atmosphere (45 psi) for 12 h. The mixture was concentrated to give a residue. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 5/1) to afford methyl 4-amino-2-chloro-3-fluoro-benzoate (2.50 g, 12.3 mmol, 55% yield) as a yellow solid. To a solution of methyl 4-amino-2-chloro-3- fluorobenzoate (300 mg, 1.47 mmol, 1.00 eq) in tetrahydrofuran (10.0 mL) was added methylmagnesium bromide (3.00 M, 3.93 mL, 8.00 eq) dropwise at 0 °C under nitrogen. The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated in vacuum to give a residue. The residue was purified silica gel chromatography (petroleum ether/ethyl acetate = 2/1) to afford 2-(4-amino-2-chloro-3-fluorophenyl)propan-2-ol (106 mg, 521 umol, 35% yield) as a yellow oil.
1H NMR (400 MHz, CDCl
3) δ = 7.14 (dd, J = 1.8, 8.6 Hz, 1H), 6.58 (t, J = 8.6 Hz, 1H), 3.77 - 3.64 (m, 2H), 2.47 - 2.41 (m, 1H), 1.62 (s, 6H). [1952] Synthesis of Compound No. 87: Synthesized according to general procedure C, wherein in step C.1 variant ii was used with tert-butyl 3-ethyl-3-hydroxy-azetidine-1-carboxylate (3.30 g, 16.4 mmol, 1.10 eq) as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant ii was used and in step C.54-phenoxyaniline (60.9 mg, 329 umol, 1.00 eq) was used as HX
1-Y and in step C.6, variant ii was used to give 1-(3-ethyl-3- ((4-((4-phenoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6- yl)oxy)azetidin-1-yl)prop-2-en-1-one 87 in 31% yield from XXII.
1H NMR (400 MHz, CDCl
3) δ = 8.71 (s, 1H), 8.36 (s, 1H), 8.14 (d, J = 8.8 Hz, 1H), 7.84 - 7.79 (m, 2H), 7.40 - 7.34 (m, 2H), 7.26 (d, J = 9.0 Hz, 1H), 7.16 - 7.10 (m, 3H), 7.06 (dd, J = 1.0, 8.8 Hz, 2H), 6.43 - 6.36 (m, 1H), 6.32
- 6.22 (m, 1H), 5.74 (dd, J = 1.8, 10.4 Hz, 1H), 4.65 - 4.55 (m, 2H), 4.40 - 4.31 (m, 2H), 2.47 - 2.34 (m, 2H), 1.02 (t, J = 7.4 Hz, 3H). MS (ESI) m/z 462.0 [M+H]. [1953] Synthesis of Compound No. 88: Synthesized according to general procedure C, wherein in step C.1, variant i and (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (4.44 g, 23.8 mmol, 1.20 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used. in step C.53,4- dichloro-2-fluoroaniline (515 mg, 2.86 mmol, 1.00 eq) was used as HX
1-Y and in step C.6, variant ii was used to give (S)-1-(3-((4-((3-chloro-4-((3-fluorobenzyl) oxy)phenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one 88 in 4% yield from XXII.
1H NMR (400 MHz, DMSO-d
6) δ = 9.20 (d, J = 7.6 Hz, 1H), 8.38 (d, J = 1.0 Hz, 1H), 8.14 (dd, J = 2.6, 9.2 Hz, 1H), 7.86 - 7.67 (m, 3H), 7.47 (dt, J = 6.1, 8.0 Hz, 1H), 7.35 - 7.29 (m, 2H), 7.27 (d, J = 9.0 Hz, 1H), 7.17 (dt, J = 2.5, 8.6 Hz, 1H), 7.09 (dd, J = 3.0, 9.1 Hz, 1H), 6.62 (ddd, J = 10.3, 16.8, 19.4 Hz, 1H), 6.15 (ddd, J = 2.4, 9.1, 16.8 Hz, 1H), 5.75 - 5.57 (m, 1H), 5.25 (s, 2H), 5.04 - 4.89 (m, 1H), 4.12 - 3.69 (m, 2H), 3.66 - 3.39 (m, 2H), 2.32 - 2.17 (m, 1H), 2.03 - 1.86 (m, 1H). MS (ESI) m/z 519.1 [M+H]. [1954] Synthesis of Compound No. 89: Synthesized according to general procedure C, wherein in step C.1, variant i and (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (4.44 g, 23.8 mmol, 1.20 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used. in step C.5 4- phenoxyaniline (132 mg, 713 umol, 0.804 eq) was used as HX
1-Y and in step C.6, variant ii was used to give (S)-1-(3-((4-((4-phenoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6- yl)amino)pyrrolidin-1-yl)prop-2-en-1-one 89 in 13% yield from XXII.
1H NMR (400 MHz, CDCl
3) δ = 8.67 (br d, J = 13.7 Hz, 1H), 8.58 (d, J = 5.3 Hz, 1H), 7.91 (dd, J = 6.0, 9.0 Hz, 1H), 7.86 - 7.78 (m, 2H), 7.39 - 7.31 (m, 2H), 7.13 - 7.07 (m, 3H), 7.03 (d, J = 8.4 Hz, 2H), 6.99 (dd, J = 6.5, 9.0 Hz, 1H), 6.55 - 6.38 (m, 2H), 5.80 - 5.66 (m, 1H), 5.59 - 5.33 (m, 1H), 4.88 - 4.65 (m, 1H), 4.11 - 3.89 (m, 1H), 3.83 - 3.59 (m, 3H), 2.41 - 2.35 (m, 1H), 2.40 - 2.33 (m, 1H), 2.13 - 2.07 (m, 1H). MS (ESI) m/z 453.2 [M+H]
+. [1955] Synthesis of Compound No. 90: Synthesized according to general procedure C, wherein in step C.1, variant i and (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (4.44 g, 23.8 mmol, 1.20 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used. in step C.54-((1,3- dioxan-2-yl)methoxy)-3-chloroaniline (261 mg, 857 umol, 1.00 eq) was used as HX
1-Y and in step C.6, variant i was used to give (S)-1-(3-((4-((4-((1,3-dioxan-2-yl) methoxy)-3- chlorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one 90 in
5% yield from XXII.
1H NMR (400 MHz, DMSO-d
6) δ = 9.21 (d, J = 8.0 Hz, 1H), 8.38 (d, J = 1.0 Hz, 1H), 8.10 (dd, J = 2.6, 10.2 Hz, 1H), 7.88 - 7.68 (m, 3H), 7.21 (d, J = 9.0 Hz, 1H), 7.09 (dd, J = 3.0, 9.2 Hz, 1H), 6.63 (ddd, J = 10.3, 16.8, 18.9 Hz, 1H), 6.16 (ddd, J = 2.4, 9.0, 16.8 Hz, 1H), 5.77 - 5.58 (m, 1H), 5.08 - 4.85 (m, 2H), 4.11 (s, 3H), 4.03 (d, J = 4.4 Hz, 2H), 3.77 (br s, 3H), 3.75 - 3.70 (m, 1H), 3.66 - 3.48 (m, 1H), 3.46 - 3.38 (m, 1H), 2.36 - 2.22 (m, 1H), 2.05 - 1.86 (m, 2H), 1.41 (br d, J = 13.3 Hz, 1H). MS (ESI) m/z 511.4 [M+H]
+ [1956] Synthesis of 4-((1,3-dioxan-2-yl)methoxy)-3-chloroaniline. To s solution of 2- (benzyloxy)acetaldehyde (1.07 g, 7.13 mmol, 1.00 mL, 1.00 eq) and propane-1,3-diol (1.63 g, 21.3 mmol, 1.55 mL, 3.00 eq) in diethoxymethoxyethane (1.78 g, 12.0 mmol, 2.00 mL, 1.69 eq) was added 4-methylbenzenesulfonic acid (125 mg, 725 umol, 0.01 eq) and the mixture was stirred at 15 °C for 12 h. The reaction mixture was diluted with water (50.0 mL), extracted with ethyl acetate (2 × 50.0 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give 2-((benzyloxy)methyl)-1,3-dioxane (1.30 g, 6.24 mmol, 87% yield) as a colorless oil. To a solution of 2-(benzyloxymethyl)-1,3-dioxane (1.00 g, 4.80 mmol, 1.00 eq) in methanol (20.0 mL) was added Pd/C (100 mg, 4.80 mmol, 10% purity, 1.00 eq) and the mixture was stirred at 15°C for 12 h under H
2 (15 psi). The reaction mixture was filtered and the filtrate was consentrated to give 1,3-dioxan-2- ylmethanol (700 mg, crude) as a yellow liquid. To a solution of 2-chloro-1-fluoro-4-nitro-benzene (900 mg, 5.13 mmol, 1.00 eq) and 1,3-dioxan-2- ylmethanol (700 mg, 5.93 mmol, 1.16 eq) in dimethyl formamide (10.0 mL) was added potassium carbonate (1.33 g, 9.64 mmol, 1.88 eq) and the mixture wa stirred at 60 °C for 12 h. The reaction mixture was quenched with water (20.0 mL) at 15°C, filtered and the filter cake was concentrated under reduced pressure to give a residue. The crude product was triturated with methanol (2.00 mL) at 15 °C for 0.1 h. The filter cake was dried to give 2-((2-chloro-4- nitrophenoxy)methyl)-1,3- dioxane (600 mg, 2.19 mmol, 42% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 8.32 (d, J = 2.8 Hz, 1H), 8.21 (dd, J = 2.8, 9.2 Hz, 1H), 7.41 (d, J = 9.3 Hz, 1H), 4.98 (t, J = 4.3 Hz, 1H), 4.22 (d, J = 4.4 Hz, 2H), 4.10 - 4.03 (m, 2H), 3.82 (dt, J = 2.4, 12.1 Hz, 2H), 2.01 - 1.85 (m, 1H), 1.41 (td, J = 1.2, 13.4 Hz, 1H). [1957] To a solution of 2-((2-chloro-4-nitrophenoxy)methyl)-1,3-dioxane (500 mg, 1.83 mmol, 1.00 eq) in methanol (10.0 mL) and water (2.00 mL) was added iron powder (1.00 g, 17.9 mmol, 9.80 eq) and saturated ammonium chloride (1.00 g, 18.6 mmol, 10.2 eq), then the mixture was stirred at 80 °C for 1 h. The reaction mixture was diluted with water (20.0 mL) and extracted with
ethyl acetate (50.0 mL). The combined organic layers were washed with brine (20.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% FA condition) to give 3-chloro-4-(1,3- dioxan-2-ylmethoxy)aniline (250 mg, 1.03 mmol, 56% yield) as a white gum. MS (ESI) m/z 244.0 [M+H]
+ [1958] Synthesis of Compound No. 91: Synthesized according to general procedure C, wherein in step C.1 variant i and (S)-tert-butyl 3-(methylamino)pyrrolidine-1-carboxylate (1.50 g, 7.49 mmol, 1.01 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.5 3-chloro-4-(1,3-dioxan-2-ylmethoxy)aniline (240 mg, 985 umol, 1.19 eq) was used as HX
1-Y and in step C.6, variant i was used to give (S)-1-(3-((4-((4-((1,3-dioxan-2-yl)methoxy) -3- chlorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)(methyl)amino)pyrrolidin-1-yl)prop-2-en-1- one 91 in 10% from XXII.
1H NMR (400 MHz, DMSO-d6) δ = 9.29 (d, J = 7.9 Hz, 1H), 8.39 (s, 1H), 8.06 (dd, J = 2.5, 9.2 Hz, 1H), 7.93 (d, J = 9.3 Hz, 1H), 7.81 (ddd, J = 2.6, 6.7, 9.0 Hz, 1H), 7.47 (dd, J = 5.6, 9.4 Hz, 1H), 7.22 (d, J = 9.0 Hz, 1H), 6.66 (ddd, J = 10.3, 15.3, 16.6 Hz, 1H), 6.18 (ddd, J = 2.4, 6.5, 16.8 Hz, 1H), 5.82 - 5.61 (m, 2H), 4.95 (t, J = 4.4 Hz, 1H), 4.13 - 3.99 (m, 4H), 3.93 (dd, J = 8.5, 9.7 Hz, 1H), 3.88 - 3.64 (m, 4H), 3.59 - 3.50 (m, 1H), 3.48 - 3.38 (m, 1H), 3.09 (d, J = 5.0 Hz, 3H), 2.25 - 2.06 (m, 2H), 2.02 - 1.85 (m, 1H), 1.41 (br d, J = 13.4 Hz, 1H). MS (ESI) m/z 525.4 [M+H]
+ [1959] Synthesis of Compound No. 92: Synthesized according to general procedure C, wherein in step C.1 variant ii and (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (3.62 g, 19.3 mmol, 1.30 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.5 3-chloro-4-(pyridazin-3-ylmethoxy)aniline (134 mg, 570 umol, 1.00 eq) was used as HX
1-Y and in step C.6, variant ii was used to give (S)-1-(3-((4-((3-chloro-4-(pyridazin -3- ylmethoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one 92 in 10% from XXII.
1H NMR (400 MHz, DMSO-d
6) δ = 9.55 (d, J = 3.0 Hz, 1H), 9.25 (dd, J = 1.6, 4.8 Hz, 1H), 8.57 (d, J = 0.8 Hz, 1H), 8.14 - 8.09 (m, 2H), 7.87 (ddd, J = 2.1, 6.3, 8.6 Hz, 2H), 7.84 - 7.79 (m, 1H), 7.42 - 7.36 (m, 2H), 6.71 - 6.55 (m, 1H), 6.27 - 6.12 (m, 2H), 5.74 - 5.62 (m, 1H), 5.55 (s, 2H), 4.07 (dd, J = 4.8, 12.1 Hz, 1H), 3.88 - 3.66 (m, 3H), 3.58 - 3.47 (m, 1H), 2.44 - 2.35 (m, 1H), 2.28 (dt, J = 4.5, 9.0 Hz, 1H). MS (ESI) m/z 504.4[M+H]
+. [1960] Synthesis of 3-chloro-4-(pyridazin-3-ylmethoxy)aniline. To a solution of pyridazin-3- ylmethanol (1.00 g, 9.08 mmol, 1.00 eq) and 2-chloro-1-fluoro-4-nitro-benzene (1.59 g, 9.08
mmol, 1.00 eq) in dimethyl formamide (10.0 mL) was added potassium carbonate (2.51 g, 18.2 mmol, 2.00 eq). The mixture was stirred at 60 °C for 12 h. The mixture was concentrated to dryness to give a residue. The residue was triturated with water (100 mL), filtered and the filter cake was wash with water (30.0 mL). The filter cake was dried to give 3-((2-chloro-4- nitrophenoxy)methyl)pyridazine (2.30 g, 8.66 mmol, 95% yield) as a brown solid.
1H NMR (400 MHz, CDCl
3) δ = 9.25 - 9.23 (m, 1H), 8.36 (d, J = 2.8 Hz, 1H), 8.22 - 8.18 (m, 1H), 7.89 - 7.85 (m, 1H), 7.65 - 7.60 (m, 1H), 7.21 (d, J = 9.2 Hz, 1H), 5.64 (s, 2H). MS (ESI) m/z 266.0 [M+H] [1961] A mixture of 3-((2-chloro-4-nitrophenoxy)methyl)pyridazine (2.30 g, 8.66 mmol, 1.00 eq), iron powder (2.42 g, 43.3 mmol, 5.00 eq) and ammonium chloride (2.32 g, 43.3 mmol, 5.00 eq) in methanol (20.0 mL) and water (5.00 mL) was stirred at 80 °C for 1 h. To the mixture was added methanol (100 ml) and filtered, the filtrate was concentrated to give a residue. The residue was poured into water (30.0 mL) and stirred for 10 min. The aqueous phase was extracted with ethyl acetate (3 × 20.0 mL). The combined organic phase was washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give 3-chloro-4-(pyridazin-3- ylmethoxy)aniline (1.77 g, 7.51 mmol, 87% yield) as a brown solid. [1962] Synthesis of Compound No. 93: Synthesized according to general procedure C, wherein in step C.1 variant i and (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (1.52 g, 8.19 mmol, 1.10 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.53- chloro-4-(pyridin-2-ylmethoxy)aniline (201 mg, 857 umol, 1.00 eq) was used as HX
1-Y and in step C.6, variant ii was used to give (S)-1-(3-((4-((3-chloro-4-(pyridin-2- ylmethoxy)phenyl)amino)pyrido[3,2-d] pyrimidin-6-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one 93 in 1% from XXII.
1H NMR (400 MHz, CDCl
3) δ ppm 2.08 - 2.31 (m, 1 H) 2.34 - 2.48 (m, 1 H) 3.58 - 3.75 (m, 1 H) 3.75 - 3.84 (m, 2 H) 3.93 - 4.13 (m, 1 H) 4.64 - 4.86 (m, 1 H) 5.14 (dd, J = 17.6, 6.4 Hz, 1 H) 5.31 (s, 2 H) 5.69 - 5.80 (m, 1 H) 6.41 - 6.44 (m, 1 H) 6.45 - 6.55 (m, 1 H) 6.95 (d, J = 9.0 Hz, 1 H) 7.04 (dd, J = 9.0, 3.2 Hz, 1 H) 7.24 - 7.27 (m, 1 H) 7.63 - 7.72 (m, 2 H) 7.73 - 7.81 (m, 1 H) 7.91 (dd, J = 9.0, 5.6 Hz, 1 H) 8.01 (dd, J = 5.8, 2.8 Hz, 1 H) 8.55 (br d, J = 13.6 Hz, 1 H) 8.59 (d, J = 3.8 Hz, 1 H) 8.61 (br d, J = 4.8 Hz, 1 H). MS (ESI) m/z 502.3 [M+H]
+. [1963] Synthesis of Compound No. 94: Synthesized according to general procedure C, wherein in step C.1 variant i and (S)-tert-butyl 3-(methylamino)pyrrolidine-1-carboxylate (1.50 g, 7.49 mmol, 1.01 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.54-phenoxyaniline (105 mg, 567 umol, 1.01 eq) was used as HX
1-Y and in step C.6, variant
i was used to give (S)-1-(3-(methyl(4-((4-phenoxyphenyl)amino)pyrido[3,2-d]pyrimidin-6- yl)amino)pyrrolidin-1-yl)prop-2-en-1-one 94 in 23% yield from XXII.
1H NMR (400 MHz, DMSO-d
6) δ = 9.34 (d, J = 7.9 Hz, 1H), 8.37 (d, J = 1.8 Hz, 1H), 7.93 (d, J = 5.4 Hz, 1H), 7.92 - 7.88 (m, 2H), 7.46 (dd, J = 5.3, 9.4 Hz, 1H), 7.42 - 7.35 (m, 2H), 7.14 - 7.06 (m, 3H), 7.03 - 6.97 (m, 2H), 6.65 (ddd, J = 10.3, 13.3, 16.7 Hz, 1H), 6.17 (ddd, J = 2.4, 6.2, 16.8 Hz, 1H), 5.84 - 5.71 (m, 1H), 5.70 - 5.63 (m, 1H), 3.96 - 3.80 (m, 1H), 3.79 - 3.67 (m, 1H), 3.67 - 3.50 (m, 1H), 3.47 - 3.37 (m, 1H), 3.09 (d, J = 4.8 Hz, 3H), 2.24 - 2.15 (m, 1H), 2.14 - 2.06 (m, 1H). MS (ESI) m/z 467.3 [M+H]
+. [1964] Synthesis of Compound No. 95: Synthesized according to general procedure C, wherein in step C.1 variant i and (S)-tert-butyl 3-(methylamino)pyrrolidine-1-carboxylate (1.50 g, 7.49 mmol, 1.01 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.53-chloro-4-((3-fluorobenzyl) oxy)aniline (200 mg, 795 umol, 0.904 eq) was used as HX
1- Y and in step C.6, variant ii was used to give (S)-1-(3-((4-((3-chloro-4-((3- fluorobenzyl)oxy)phenyl)amino) pyrido[3,2-d]pyrimidin-6-yl)(methyl)amino)pyrrolidin-1- yl)prop-2-en-1-one 95 in 4% yield from XXII.
1H NMR (400 MHz, DMSO-d
6) δ = 9.31 (d, J = 8.2 Hz, 1H), 8.39 (s, 1H), 8.14 - 8.09 (m, 1H), 7.93 (d, J = 9.3 Hz, 1H), 7.80 (dt, J = 2.5, 8.7 Hz, 1H), 7.51 - 7.43 (m, 2H), 7.37 - 7.30 (m, 2H), 7.28 (d, J = 9.0 Hz, 1H), 7.23 - 7.15 (m, 1H), 6.66 (dt, J = 10.3, 16.0 Hz, 1H), 6.18 (ddd, J = 2.4, 6.5, 16.8 Hz, 1H), 5.82 - 5.63 (m, 2H), 5.26 (s, 2H), 4.01 - 3.82 (m, 1H), 3.53 (br t, J = 9.2 Hz, 2H), 3.47 - 3.39 (m, 1H), 3.09 (d, J = 5.0 Hz, 3H), 2.24 - 2.15 (m, 1H), 2.15 - 2.07 (m, 1H). MS (ESI) m/z 533.2 [M+H] [1965] Synthesis of Compound No. 96: Synthesized according to general procedure C, wherein in step C.1 variant i and (S)-tert-butyl 3-(methylamino)pyrrolidine-1-carboxylate (1.50 g, 7.49 mmol, 1.01 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.53-chloro-4-(pyridin-2-ylmethoxy)aniline (174 mg, 742 umol, 0.90 eq) was used as HX
1- Y and in step C.6, variant ii was used to give (S)-1-(3-((4-((3-chloro-4-(pyridin-2-ylmethoxy) phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)(methyl)amino)pyrrolidin-1-yl)prop-2-en-1-one 96 in 16% yield from XXII.
1H NMR (400 MHz, CDCl3) δ = 9.18 (s, 1H), 8.72 (s, 1H), 8.38 - 8.30 (m, 2H), 7.94 (s, 1H), 7.78 (br s, 1H), 7.23 - 7.12 (m, 2H), 6.55 - 6.46 (m, 1H), 6.38 - 6.23 (m, 1H), 5.92 (d, J = 10.4 Hz, 1H), 3.28 (br d, J = 8.8 Hz, 1H), 3.08 (br d, J = 9.0 Hz, 1H), 2.59 (br d, J = 8.4 Hz, 2H), 2.39 (s, 3H), 1.96 (td, J = 4.2, 8.2 Hz, 1H), 1.25 (s, 1H), 1.09 (br dd, J = 4.2, 8.2 Hz, 1H). MS (ESI) m/z 516.3 [M+H].
[1966] Synthesis of Compound No. 97: Synthesized according to general procedure C, wherein in step C.1 variant ii and (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (3.62 g, 19.3 mmol, 1.30 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.5 3-chloro-4-(pyridin-2-ylmethoxy)aniline (134 mg, 570 umol, 1.00 eq) was used as HX
1-Y and in step C.6, variant ii was used to give (S)-1-(3-((4-((3-chloro-4-(pyridine-2- ylmethoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one 97 in 40% from XXII.
1H NMR (400 MHz, DMSO-d
6) δ = 9.53 (d, J = 2.4 Hz, 1H), 8.63 - 8.59 (m, 1H), 8.56 (d, J = 1.2 Hz, 1H), 8.13 - 8.08 (m, 2H), 7.89 (dt, J = 1.7, 7.7 Hz, 1H), 7.83 (dd, J = 2.6, 9.0 Hz, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.39 - 7.35 (m, 2H), 7.31 (d, J = 9.0 Hz, 1H), 6.71 - 6.55 (m, 1H), 6.25 - 6.13 (m, 2H), 5.73 - 5.62 (m, 1H), 5.32 (s, 2H), 4.07 (dd, J = 4.6, 12.0 Hz, 1H), 3.86 - 3.66 (m, 3H), 3.58 - 3.48 (m, 1H), 2.42 - 2.36 (m, 1H), 2.31 - 2.22 (m, 1H), 2.22 - 2.12 (m, 1H). MS (ESI) m/z 503.3[M+H]
+ [1967] Synthesis of Compound No. 98: Synthesized according to general procedure C, wherein in step C.1, variant i and (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (4.44 g, 23.8 mmol, 1.20 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used. in step C.5 3- chloro-4-(pyridazin-3-ylmethoxy)aniline (251 mg, 1.07 mmol, 1.20 eq) was used as HX
1-Y and in step C.6, variant ii was used to give (S)-1-(3-((4-((3-chloro-4-(pyridazin-3- ylmethoxy)phenyl)amino) pyrido[3,2-d]pyrimidin-6-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one 98 in 18% from XXII.
1H NMR (400 MHz, DMSO-d
6) δ = 9.27 - 9.20 (m, 2H), 8.38 (d, J = 1.1 Hz, 1H), 8.20 - 8.12 (m, 1H), 7.86 (tt, J = 2.1, 6.6 Hz, 2H), 7.83 - 7.77 (m, 2H), 7.74 (br dd, J = 7.2, 10.9 Hz, 1H), 7.35 (d, J = 9.0 Hz, 1H), 7.09 (dd, J = 3.1, 9.1 Hz, 1H), 6.63 (ddd, J = 10.3, 16.8, 18.8 Hz, 1H), 6.15 (ddd, J = 2.4, 8.9, 16.7 Hz, 1H), 5.72 - 5.61 (m, 1H), 5.52 (s, 2H), 5.06 - 4.88 (m, 1H), 4.08 (dd, J = 6.2, 10.5 Hz, 1H), 3.86 - 3.68 (m, 2H), 3.66 - 3.42 (m, 2H), 2.33 - 2.13 (m, 1H), 2.05 - 1.81 (m, 1H). MS (ESI) m/z 503.1 [M+H]
+. [1968] Synthesis of Compound No. 99: Synthesized according to general procedure C, wherein in step C.1 variant ii and (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (3.62 g, 19.3 mmol, 1.30 eq) was used as BocN[(CR
aR
b)m(CR
cR
d)n]-X
2H, in step C.2 variant i was used and in step C.5 4-((1,3-dioxan-2-yl)methoxy)-3-chloroaniline (176 mg, 722 umol, 1.20 eq) was used as HX
1-Y and in step C.6, variant ii was used to give (S)-1-(3-((4-((4-((1,3-dioxan-2-yl) methoxy)-3- chlorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one 99 in 21% from XXII.
1H NMR (400 MHz, DMSO-d
6) δ = 9.52 (br s, 1H), 8.56 (d, J = 1.0 Hz, 1H), 8.10 (dd,
J = 0.9, 9.0 Hz, 1H), 8.05 - 8.02 (m, 1H), 7.84 (dd, J = 2.4, 8.9 Hz, 1H), 7.41 - 7.33 (m, 1H), 7.28 - 7.21 (m, 1H), 6.72 - 6.54 (m, 1H), 6.27 - 6.10 (m, 2H), 5.75 - 5.60 (m, 1H), 4.96 (t, J = 4.4 Hz, 1H), 4.11 - 4.03 (m, 5H), 3.90 - 3.76 (m, 4H), 3.75 - 3.66 (m, 2H), 3.58 - 3.48 (m, 1H), 3.32 (br s, 1H), 2.38 - 2.12 (m, 2H), 2.00 - 1.88 (m, 1H), 1.41 (br d, J = 13.4 Hz, 1H). MS (ESI) m/z 512.1 [M+H]
+. [1969] Synthesis of Compound No.100: Synthesized according to general procedure A, wherein in step A.13,4-dichloro-2-fluoroaniline (340 mg, 1.89 mmol, 0.988 eq) was used as H
2NX
1, in step A.2 variant iii tert-butyl 3-hydroxy-3-methylazetidine-1-carboxylate (230 mg, 1.23 mmol, 1.53 eq) as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H was used and in step A.3 variant i was employed to give 1-(3-((4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxypyrido[3,2-d]pyrimidin-6-yl)oxy)- 3-methylazetidin-1-yl)prop-2-en-1-one 100 in 1% yield from XIV.
1H NMR (400MHz, DMSO- d6) δ = 8.84 (s, 1H), 8.62 - 8.53 (m, 1H), 8.32 (br t, J = 8.6 Hz, 1H), 7.63 (dd, J = 1.6, 9.0 Hz, 1H), 7.60 (s, 1H), 6.36 (dd, J = 10.3, 17.1 Hz, 1H), 6.13 (dd, J = 2.0, 17.0 Hz, 1H), 5.73 - 5.67 (m, 1H), 4.59 (s, 2H), 4.34 - 4.22 (m, 2H), 4.00 (s, 3H), 1.91 (s, 3H). MS (ESI) m/z 478.0 [M+H]
+ [1970] Synthesis of Compound No.101: Synthesized according to general procedure C, wherein in step C.1, variant i and (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (4.44 g, 23.8 mmol, 1.20 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used. in step C.5 3- chloro-4-((5-methylpyrazin-2-yl)methoxy)aniline (150 mg, 600 umol, 1.00 eq) was used as HX
1- Y and in step C.6, variant ii was used to give (S)-1-(3-((4-((3-chloro-4-((5-methylpyrazin-2-yl) methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one 101 in 11% from XXII.
1H NMR (400 MHz, CDCl
3) δ = 8.82 (s, 1H), 8.60 - 8.53 (m, 2H), 8.45 (s, 1H), 8.00 - 7.96 (m, 1H), 7.88 (dd, J = 6.6, 9.0 Hz, 1H), 7.73 (dd, J = 2.6, 8.9 Hz, 1H), 7.07 (dd, J = 1.8, 8.9 Hz, 1H), 6.97 (dd, J = 4.2, 9.0 Hz, 1H), 6.56 - 6.38 (m, 2H), 5.79 - 5.67 (m, 1H), 5.39 (br d, J = 6.0 Hz, 1H), 5.29 (s, 3H), 4.75 - 4.66 (m, 1H), 4.86 - 4.66 (m, 1H), 4.11 - 3.93 (m, 1H), 3.82 - 3.70 (m, 3H), 3.61 (dd, J = 3.9, 10.7 Hz, 1H), 2.61 (s, 3H), 2.50 - 2.25 (m, 2H), 2.10 (qd, J = 6.3, 12.3 Hz, 1H), 1.97 (s, 1H). MS (ESI) m/z 517.5 [M+H]
+. [1971] Synthesis of 3-chloro-4-((5-methylpyrazin-2-yl)methoxy)aniline. To a solution of 2- chloro-1-fluoro-4-nitrobenzene (2.40 g, 13.7 mmol, 1.00 eq) and (5-methylpyrazin-2-yl) methanol (1.70 g, 13.7 mmol, 1.00 eq) in dimethyl formamide (25.0 mL) was added potassium carbonate (3.79 g, 27.4 mmol, 2.00 eq) in one portion. The mixture was stirred at 60 °C for 12 h. The mixture was triturated with water (200 mL) for 20 min and filtered. The filter cake was dried to give 2-((2-
chloro-4- nitrophenoxy)methyl)-5-methylpyrazine (3.30 g, 11.8 mmol, 86% yield) as a yellow solid. To a solution of 2-((2-chloro-4-nitrophenoxy)methyl)-5-methylpyrazine (3.80 g, 13.6 mmol, 1.00 eq) and ammonium chloride (3.63 g, 67.9 mmol, 5.00 eq) in methanol (80.0 mL) and water (20.0 mL) was added iron powder (3.79 g, 67.9 mmol, 5.00 eq) in portions. The mixture was stirred at 80 °C for 2 h. The mixture was filtered and the filtrate was concentrated to give crude product. The crude product was diluted with saturated sodium hydrogencarbonate solution (80.0 mL) and extracted with ethyl acetate (3 × 40.0 mL). The combined organic layer was washed with brine (20.0 mL) and dried over sodium sulfate, filtered and concentrated to give 3-chloro-4-((5- methylpyrazin-2-yl)methoxy)aniline (3.40 g, crude) as a brown solid.
1H NMR (400 MHz, DMSO- d
6) δ = 8.65 (s, 1H), 8.54 (s, 1H), 6.96 (d, J = 8.7 Hz, 1H), 6.65 (d, J = 2.6 Hz, 1H), 6.47 (dd, J = 2.7, 8.7 Hz, 1H), 5.11 (s, 2H), 4.98 (s, 2H), 2.50 (br s, 3H). [1972] Synthesis of Compound No.102: Synthesized according to general procedure C, wherein in step C.1 variant i and (S)-tert-butyl 3-(methylamino)pyrrolidine-1-carboxylate (1.50 g, 7.49 mmol, 1.01 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.55-chloro-2-fluoro-4-((3-fluorobenzyl)oxy)aniline (140 mg, 520 umol, 0.899 eq) was used as HX
1-Y and in step C.6, variant ii was used to give (S)-1-(3-((4-((5-chloro-2-fluoro-4-((3- fluorobenzyl)oxy) phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)(methyl)amino)pyrrolidin-1- yl)prop-2-en-1-one 102 in 10% yield from XXII.
1H NMR (400 MHz, DMSO-d
6) δ = 9.23 (d, J = 8.4 Hz, 1H), 8.34 (s, 1H), 8.07 (dd, J = 8.4, 9.8 Hz, 1H), 7.95 (d, J = 9.4 Hz, 1H), 7.55 - 7.49 (m, 1H), 7.48 - 7.46 (m, 1H), 7.39 (d, J = 12.2 Hz, 1H), 7.34 (s, 1H), 7.30 (br s, 1H), 7.20 (dt, J = 2.2, 8.6 Hz, 1H), 6.71 - 6.57 (m, 1H), 6.21 - 6.13 (m, 1H), 5.30 (s, 2H), 3.96 - 3.81 (m, 1H), 3.81 - 3.69 (m, 1H), 3.62 - 3.49 (m, 1H), 3.47 - 3.39 (m, 1H), 3.08 (d, J = 5.0 Hz, 3H), 2.22 - 2.16 (m, 1H), 2.13 - 2.07 (m, 1H). MS (ESI) m/z 551.1 [M+H]. [1973] Synthesis of 5-chloro-2-fluoro-4-((3-fluorobenzyl)oxy)aniline. To a solution of 1- chloro-2,4-difluoro-5-nitro-benzene (100 g, 517 mmol, 1.00 eq) and potassium carbonate (140 g, 1.01 mol, 1.96 eq) in dimethyl formamide (500 mL) was added (3-fluorophenyl)methanol (65.0 g, 515 mmol, 56.0 mL, 0.997 eq). The mixture was stirred at 25 °C for 40 h. The mixture was diluted with ethyl acetate (2.00 L) and water (2.00 L). The organic layer was separated and concentrated under reduced pressure. The residue was triturated with methanol (100 mL) for 1 h at 10 °C. The filter cake was collected by filtration and washed with methanol (5.00 mL), dried in vacuum to give 1-chloro-4-fluoro-2-((3-fluorobenzyl)oxy)-5-nitrobenzene (80.0 g, 259 mmol, 50% yield) as
a white solid.
1H NMR (400 MHz, CDCl
3) δ = 8.25 (d, J = 7.8 Hz, 1H), 7.43 (dt, J = 5.9, 7.9 Hz, 1H), 7.28 (s, 1H), 7.22 (dd, J = 8.4, 17.1 Hz, 2H), 7.10 (dt, J = 2.4, 8.4 Hz, 1H), 6.84 (d, J = 12.1 Hz, 1H), 5.25 (s, 2H). To a solution of 1-chloro-4-fluoro-2-[(3-fluorophenyl)methoxy]-5-nitro- benzene (35.0 g, 117 mmol, 1.00 eq) in methanol (300 mL) was added water (100 mL), iron power (30.0 g, 537 mmol, 4.60 eq) and ammonium chloride (50.0 g, 934.73 mmol, 8.00 eq) at 25 °C. The mixture was stirred at 80 °C for 1 h. The mixture was cooled to room temperature. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (2.00 L) and water (1.00 L). The organic layer was separated and concentrated under reduced pressure to give 5-chloro-2-fluoro-4-((3-fluorobenzyl)oxy)aniline (30.0 g, 334 mmol, 95% yield as a yellow solid which was used directly in the next step.
1H NMR (400 MHz, CDCl
3) δ = 7.27 (dt, J = 6.1, 8.0 Hz, 1H), 7.15 - 7.08 (m, 2H), 6.99 - 6.91 (m, 1H), 6.77 (d, J = 9.2 Hz, 1H), 6.61 (d, J = 11.9 Hz, 1H), 4.95 (s, 2H). [1974] Synthesis of Compound No.103: Synthesized according to general procedure C, wherein in step C.1 variant ii and (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (3.62 g, 19.3 mmol, 1.30 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.5 3-chloro-4-((5-methylpyrazin-2-yl)methoxy)aniline (149 mg, 599 umol, 1.00 eq) was used as HX
1-Y and in step C.6, variant i was used to give (S)-1-(3-((4-((3-chloro-4- ((5-methylpyrazin-2- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one 103 in 38% yield from XXII.
1H NMR (400 MHz, DMSO-d
6) δ = 9.54 (d, J = 2.7 Hz, 1H), 8.72 (s, 1H), 8.59 (d, J = 0.9 Hz, 1H), 8.57 (d, J = 1.2 Hz, 1H), 8.11 (dd, J = 0.8, 9.0 Hz, 1H), 8.09 (dd, J = 1.5, 2.4 Hz, 1H), 7.86 (dd, J = 2.6, 9.0 Hz, 1H), 7.40 - 7.38 (m, 1H), 7.38 - 7.35 (m, 1H), 6.72 - 6.55 (m, 1H), 6.26 - 6.17 (m, 1H), 6.17 - 6.12 (m, 1H), 5.74 - 5.63 (m, 1H), 5.34 (s, 2H), 4.07 (dd, J = 4.7, 12.0 Hz, 1H), 3.86 - 3.66 (m, 3H), 3.58 - 3.48 (m, 1H), 2.53 (s, 3H), 2.43 - 2.36 (m, 1H), 2.31 - 2.12 (m, 2H). MS (ESI) m/z 518.1[M+H]
+. [1975] Synthesis of Compound No.104: Synthesized according to general procedure C, wherein in step C.1 variant i and (S)-tert-butyl 3-(methylamino)pyrrolidine-1-carboxylate (1.50 g, 7.49 mmol, 1.01 eq) was used as BocN[(CR
aR
b)m(CR
cR
d)n]-X
2H, in step C.2 variant i was used and in step C.53-chloro-4-(pyridazin-3- ylmethoxy)aniline (110 mg, 467 umol, 0.849 eq) was used as HX
1-Y and in step C.6, variant ii was used to give (S)-1-(3-((4-((3-chloro-4-(pyridazin-3- ylmethoxy) phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)(methyl)amino)pyrrolidin-1-yl)prop-2- en-1-one 104 in 45% from XXII.
1H NMR (400 MHz, DMSO-d
6) δ = 9.36 (br s, 1H), 9.25 (dd, J
= 1.6, 4.8 Hz, 1H), 8.41 (d, J = 1.5 Hz, 1H), 8.13 (dd, J = 2.4, 9.6 Hz, 1H), 7.94 (d, J = 9.4 Hz, 1H), 7.90 - 7.85 (m, 1H), 7.85 - 7.76 (m, 2H), 7.48 (dd, J = 5.4, 9.4 Hz, 1H), 7.36 (d, J = 8.9 Hz, 1H), 6.72 - 6.59 (m, 1H), 6.18 (ddd, J = 2.4, 6.4, 16.7 Hz, 1H), 5.82 - 5.62 (m, 2H), 5.53 (s, 2H), 3.97 - 3.82 (m, 1H), 3.76 - 3.51 (m, 2H), 3.49 - 3.41 (m, 1H), 3.10 (d, J = 5.0 Hz, 3H), 2.24 - 2.16 (m, 1H), 2.15 - 2.08 (m, 1H). MS (ESI) m/z 517.5 [M+H]. [1976] Synthesis of Compound No.105: Synthesized according to general procedure C, wherein in step C.1 variant i and (S)-tert-butyl 3-(methylamino)pyrrolidine-1-carboxylate (1.50 g, 7.49 mmol, 1.01 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.5 3-chloro-4-((5-methylpyrazin-2-yl)methoxy)aniline (139 mg, 557 umol, 0.900 eq) was used as HX
1-Y and in step C.6, variant ii was used to give (S)-1-(3-((4-((3-chloro-4-((5- methylpyrazin-2-yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6- yl)(methyl)amino)pyrrolidin-1-yl)prop-2-en-1-one 105 in 16% yield from XXII.
1H NMR (400 MHz, DMSO-d) δ ppm 2.23 - 2.41 (m, 2 H) 2.62 (s, 3 H) 3.15 (d, J = 7.4 Hz, 3 H) 3.57 - 3.77 (m, 2 H) 3.85 - 4.07 (m, 2 H) 5.30 - 5.32 (m, 2 H) 5.32 - 5.47 (m, 1 H) 5.73 - 5.81 (m, 1 H) 6.44 - 6.48 (m, 1 H) 6.49 - 6.58 (m, 1 H) 7.08 (d, J = 8.8 Hz, 1 H) 7.24 (dd, J = 9.4, 3.0 Hz, 1 H) 7.65 - 7.77 (m, 1 H) 7.98 - 8.01 (m, 1 H) 8.01 - 8.05 (m, 1 H) 8.47 (s, 1 H) 8.54 (br d, J = 9.6 Hz, 1 H) 8.60 (d, J = 3.6 Hz, 1 H) 8.84 (s, 1 H). MS (ESI) m/z 531.3 [M+H]
+. [1977] Synthesis of Compound No.106: Synthesized according to general procedure C, wherein in step C.1 variant ii and (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (3.62 g, 19.3 mmol, 1.30 eq) was used as BocN[(CR
aR
b)m(CR
cR
d)n]-X
2H, in step C.2 variant i was used and in step C.5 3-chloro-4-(pyrimidin-4-ylmethoxy)aniline (141 mg, 599 umol, 1.00 eq) (215 mg, 855 umol, 1.00 eq) was used as HX
1-Y and in step C.6, variant ii was used to give (S)-1-(3-((4-((3-chloro-4- (pyrimidin-4-ylmethoxy)phenyl) amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2- en-1-one 106 in 20% yield from XXII.
1H NMR (400 MHz, DMSO-d
6) δ = 9.55 (d, J = 2.6 Hz, 1H), 9.21 (d, J = 1.3 Hz, 1H), 8.90 (d, J = 5.1 Hz, 1H), 8.57 (d, J = 1.1 Hz, 1H), 8.35 (s, 1H), 8.13 (s, 1H), 8.12 - 8.10 (m, 1H), 7.85 (dd, J = 2.6, 9.0 Hz, 1H), 7.69 (d, J = 4.8 Hz, 1H), 7.38 (dd, J = 4.0, 9.0 Hz, 1H), 7.31 (d, J = 9.0 Hz, 1H), 6.70 - 6.56 (m, 1H), 6.26 - 6.18 (m, 1H), 6.17 - 6.13 (m, 1H), 5.73 - 5.63 (m, 1H), 5.36 (s, 2H), 4.07 (dd, J = 4.6, 12.0 Hz, 1H), 3.86 - 3.69 (m, 3H), 3.55 - 3.51 (m, 1H), 2.40 (br dd, J = 4.8, 9.5 Hz, 1H), 2.28 (dt, J = 4.5, 9.2 Hz, 1H), 2.21 - 2.16 (m, 1H). MS (ESI) m/z 504.3[M+H]
+. [1978] Synthesis of 3-chloro-4-(pyrimidin-4-ylmethoxy)aniline. To a solution of 2-chloro-1-
fluoro-4-nitrobenzene (1.59 g, 9.08 mmol, 1.00 eq) and pyrimidin-4-ylmethanol (1.00 g, 9.08 mmol, 1.00 eq) in dimethyl formamide (10.0 mL) was added potassium carbonate (2.51 g, 18.2 mmol, 2.00 eq). The mixture was stirred at 60 °C for 12 h. The crude product was triturated with water at 25
oC for 5 min and filtered to give a filter cake. The filter cake was concentrated to give 4-((2-chloro-4-nitrophenoxy)methyl)pyrimidine (1.40 g, 5.27 mmol, 58.0% yield) as a yellow solid. To a solution of 4-((2-chloro-4-nitrophenoxy)methyl)pyrimidine (1.40 g, 5.27 mmol, 1.00 eq) in methanol (10.0 mL) and water (4.00 mL) was added iron (1.47 g, 26.4 mmol, 5.00 eq) and ammonium chloride (1.41 g, 26.4 mmol, 5.00 eq). The mixture was stirred at 80°C for 1 h. The reaction mixture was added methanol (50.0ml) and filtered, the filtrate was concentrated on a rotary evaporator. Ethyl acetate (40.0 mL) and saturated sodium bicarbonate solution (40.0 mL) were added and the organic layers were separated. The aqueous phase was extracted with ethyl acetate (3 × 20.0 mL). Combined organic phase was washed with brine (2 × 20.0 mL), dried over sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by reversed- phase HPLC ( 0.100% FA condition) to give 3-chloro-4- (pyrimidin-4-ylmethoxy) aniline (0.77 g, 3.27 mmol, 62.0% yield) as a brown solid. MS (ESI) m/z 236.0 [M+H]
+ [1979] Synthesis of Compound No.110: Synthesized according to general procedure C, wherein in step C.1 variant i and tert-butyl 3-amino- 2,2-dimethyl-azetidine-1-carboxylate (600 mg, 3.00 mmol, 1.10 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.53,4-dichloro-2-fluoro-aniline (53.4 mg, 296 umol, 0.900 eq) was used as HX
1-Y and in step C.6, variant ii was used to give 1-(3-((4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl) amino)-2,2-dimethylaz etidin-1-yl)prop-2-en-1-one 110 in 6% yield from XXII.
1H NMR (400 MHz, CDCl
3) δ = 9.03 (br dd, J = 3.0, 12.7 Hz, 1H), 8.93 (td, J = 8.8, 11.6 Hz, 1H), 8.68 (s, 1H), 7.96 (dd, J = 2.0, 9.0 Hz, 1H), 7.36 (dd, J = 1.7, 9.1 Hz, 1H), 7.17 - 7.03 (m, 1H), 6.42 (dt, J = 1.8, 17.3 Hz, 1H), 6.32 - 6.13 (m, 1H), 5.83 (br d, J = 7.3 Hz, 0.5H), 5.76 - 5.68 (m, 1H), 5.36 (br d, J = 7.1 Hz, 0.5H), 4.85 - 4.73 (m, 1H), 4.70 - 4.60 (m, 1H), 4.48 (dd, J = 8.8, 11.4 Hz, 1H), 4.01 (dd, J = 5.9, 9.1 Hz, 0.5H), 3.86 (dd, J = 6.0, 11.4 Hz, 0.5H), 1.92 (d, J = 9.0 Hz, 3H), 1.55 (s, 1.5H), 1.43 (s, 1.5H). MS (ESI) m/z 461.3 [M+H]. [1980] Synthesis of tert-butyl 3-amino- 2,2-dimethyl-azetidine-1-carboxylate. To a solution of tert-butyl 3-hydroxy-2,2-dimethyl-azetidine-1-carboxylate (650 mg, 3.23 mmol, 1.00 eq) in dichloromethane (5.00 mL) was added dess-martin periodinane (2.05 g, 4.84 mmol, 1.50 mL, 1.50 eq) at 0 °C. The mixture was stirred at 25 °C for 2 h. The mixture was concentrated to dryness to
give a residue. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate = 10/1) to afford tert-butyl 2,2-dimethyl-3-oxoazetidine-1-carboxylate (800 mg, crude) as a white solid. The mixture of tert-butyl 2,2-dimethyl-3-oxoazetidine-1-carboxylate (800 mg, 4.02 mmol, 1.00 eq) and hydroxylamine (837 mg, 12.0 mmol, 3.00 eq, HCl) in pyridine (10.0 mL) was stirred at 25 °C for 12 h. The mixture was poured into water (100 mL) and extracted with ethyl acetate (3 × 30.0 mL). The combined organic phase was washed with brine (50.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give tert-butyl 3- (hydroxyimino)-2,2-dimethylazetidine-1-carboxylate (0.900 g, crude) as yellow oil.
1H NMR (400 MHz, CDCl
3) δ = 4.57 (s, 2H), 1.53 (br s, 3H), 1.47 (br s, 12H). [1981] A mixture of tert-butyl 3-(hydroxyimino)-2,2-dimethylazetidine-1-carboxylate (800 mg, 3.73 mmol, 1.00 eq) and palladium/carbon (100 mg, 10% purity) in methanol (15.0 mL) was stirred at 45 °C under hydrogen atmosphere for 96 h. The mixture was filtered and the filtrate was concentrated to dryness to give tert-butyl 3-amino-2,2-dimethylazetidine-1-carboxylate (0.750 g, crude ) as colorless oil. [1982] Synthesis of Compound No.111: Synthesized according to general procedure C, wherein in step C.1 variant i and (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (1.52 g, 8.19 mmol, 1.10 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.53- chloro-4-(pyrimidin-4-ylmethoxy)aniline (202 mg, 857 umol, 1.00 eq) was used as HX
1-Y and in step C.6, variant ii was used to give (S)-1-(3-((4-((3- chloro-4-(pyrimidin-4- ylmethoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one 111 in 4% yield from XXII.
1H NMR (400 MHz, CDCl
3) δ ppm 2.09 - 2.32 (m, 1 H) 2.37 - 2.49 (m, 1 H) 3.60 - 3.76 (m, 1 H) 3.78 - 3.85 (m, 2 H) 3.98 - 4.12 (m, 1 H) 4.66 - 4.88 (m, 1 H) 5.19 - 5.29 (m, 3 H) 5.72 - 5.80 (m, 1 H) 6.43 - 6.52 (m, 2 H) 6.98 (dd, J = 9.0, 2.4 Hz, 1 H) 7.02 (dd, J = 8.8, 3.6 Hz, 1 H) 7.73 (ddd, J = 8.8, 4.4, 2.8 Hz, 1 H) 7.78 (d, J = 5.4 Hz, 1 H) 7.91 (dd, J = 9.0, 6.4 Hz, 1 H) 8.06 (dd, J = 6.2, 2.6 Hz, 1 H) 8.55 - 8.63 (m, 2 H) 8.83 (d, J = 5.2 Hz, 1 H) 9.23 (d, J = 1.2 Hz, 1 H). MS (ESI) m/z 503.1 [M+H]
+. [1983] Synthesis of Compound No. 112: To a solution of 1-benzhydryl-3- (difluoromethyl)azetidin-3-ol (330 mg, 1.14 mmol, 1.00 eq) in dimethylsulfoxide (5.00 mL) was added potassium tert-butoxide (256 mg, 2.28 mmol, 2.00 eq) in portions, then 6-chloro-3- nitropicolinamide IX (230 mg, 1.14 mmol, 1.00 eq) was added. The mixture was stirred at 25 °C for 2 h. The mixture was diluted with water (50.0 mL) and extracted with ethyl acetate (3 × 30.0
mL). The combined organic layer was washed with brine (20.0 mL) and dried over sodium sulfate, filtered and concentrated to give crude product. The crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate = 20/1 to 3/1) to give 6-((1-benzhydryl-3- (difluoromethyl)azetidin-3-yl)oxy) -3-nitropicolinamide (110 mg, 242 umol, 21% yield) as a white solid.
1H NMR (400 MHz, CDCl
3) δ = 8.07 (d, J = 8.9 Hz, 1H), 7.44 - 7.39 (m, 4H), 7.33 - 7.28 (m, 5H), 7.26 - 7.21 (m, 2H), 7.08 (d, J = 8.8 Hz, 1H), 6.85 (br s, 1H), 6.53 - 6.15 (m, 1H), 5.86 (br s, 1H), 4.51 (s, 1H), 3.78 (d, J = 10.5 Hz, 2H), 3.49 (br d, J = 10.5 Hz, 2H). MS (ESI) m/z 455.1 [M+H]
+ [1984] To a solution of 6-((1-benzhydryl-3-(difluoromethyl)azetidin-3-yl)oxy)-3- nitropicolinamide (100 mg, 220 umol, 1.00 eq) in methanol (5.00 mL) was added di-tert- butyldicarbonate (72.0 mg, 330 umol, 75.8 uL, 1.50 eq) dropwise, then palladium/carbon (40.0 mg, 10% purity) was added. The mixture was stirred under hydrogen (15 psi) at 25 °C for 12 h. The mixture was filtered and the filtrate was concentrated to give crude product. The crude product was purified by reversed-phase HPLC (0.1% FA condition) to give tert-butyl 3-((5-amino-6- carbamoylpyridin-2-yl)oxy)-3-(difluoromethyl)azetidine-1-carboxylate (80.0 mg, crude) as a yellow solid.
1H NMR (400 MHz, CDCl
3) δ = 7.04 (d, J = 8.9 Hz, 1H), 6.99 (br s, 1H), 6.78 (d, J = 8.9 Hz, 1H), 6.48 - 6.12 (m, 1H), 5.98 - 5.45 (m, 2H), 5.34 (br s, 1H), 4.28 (d, J = 10.3 Hz, 2H), 4.13 (br d, J = 10.1 Hz, 2H), 1.38 (s, 9H). MS (ESI) m/z 359.2 [M+H]
+ [1985] A mixture of tert-butyl 3-((5-amino-6-carbamoylpyridin-2-yl)oxy)-3-(difluoro- methyl)azetidine-1- carboxylate (410 mg, 1.14 mmol, 1.00 eq) in triethoxymethane (8.91 g, 60.1 mmol, 10.0 mL, 52.6 eq) was stirred at 150 °C for 2 h. The mixture was concentrated to give crude product. The crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate = 5/1 to 0/1) to give tert-butyl 3-(difluoromethyl)-3-((4-hydroxypyrido[3,2-d]pyrimidin-6- yl)oxy)azetidine-1-carboxylate (330 mg, 896 umol, 78% yield) as a yellow solid.
1H NMR (400 MHz, DMSO-d
6) δ = 12.64 (br s, 1H), 8.21 - 8.05 (m, 2H), 7.43 (d, J = 8.8 Hz, 1H), 6.97 - 6.67 (m, 1H), 4.28 (br d, J = 10.1 Hz, 2H), 4.16 (br s, 2H), 1.40 (s, 9H). MS (ESI) m/z 369.2 [M+H]
+ [1986] To a solution of tert-butyl 3-(difluoromethyl)-3-((4-hydroxypyrido[3,2-d]pyrimidin-6- yl)oxy)azetidine -1-carboxylate (100 mg, 271 umol, 1.00 eq) and N,N-diisopropylethylamine (175 mg, 1.36 mmol, 236 uL, 5.00 eq) in toluene (5.00 mL) was added phosphorus oxychloride (125 mg, 814 umol, 75.7 uL, 3.00 eq) dropwise. The mixture was stirred under nitrogen at 100 °C for 2 h. The mixture was diluted with saturated sodium hydrogencarbonate solution (50.0 mL) and
extracted with ethyl acetate (3 × 30.0 mL). The combined organic layer was washed with brine (20.0 mL) and dried over sodium sulfate, filtered and concentrated to give tert-butyl 3-((4- chloropyrido[3,2-d]pyrimidin-6-yl)oxy)-3-(difluoromethyl) azetidine-1-carboxylate (100 mg, crude) as yellow oil. MS (ESI) m/z 387.0 [M+H]
+ [1987] To a mixture of tert-butyl 3-((4-chloropyrido[3,2-d]pyrimidin-6-yl)oxy)-3- (difluoromethyl) azetidine-1-carboxylate (100 mg, 259 umol, 1.00 eq) and 3,4-dichloro-2- fluoroaniline (46.5 mg, 258 umol, 1.00 eq) in acetonitrile (3.00 mL) was added hydrochloric acid/ethyl acetate (4.00 M, 6.46 uL, 0.100 eq) dropwise. The mixture was stirred at 25 °C for 12 h. The mixture was concentrated to give crude product. The crude product was triturated with ethyl acetate (30.0 mL) for 20 min and filtered. The filter cake was dried to give tert-butyl 3-((4-((3,4- dichloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)-3 -(difluoromethyl)azetidine- 1-carboxylate (60.0 mg, 113 umol, 44% yield) as a yellow solid.
1H NMR (400 MHz, DMSO-d6) δ = 10.04 - 9.87 (m, 1H), 8.81 (s, 1H), 8.38 (d, J = 9.2 Hz, 1H), 7.98 (t, J = 8.4 Hz, 1H), 7.73 - 7.69 (m, 1H), 7.69 - 7.66 (m, 1H), 7.30 - 6.92 (m, 1H), 4.56 (br d, J = 10.4 Hz, 2H), 4.23 (br d, J = 5.1 Hz, 2H), 1.40 (s, 9H). MS (ESI) m/z 530.1 [M+H]
+ [1988] A mixture of tert-butyl 3-((4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)oxy)-3- (difluoromethyl)azetidine-1-carboxylate (60.0 mg, 113 umol, 1.00 eq) in hydrochloric acid/ethyl acetate (4.00 M, 5.00 mL, 177 eq) was stirred at 25 °C for 1h. The mixture was concentrated to give N-(3,4-dichloro-2-fluorophenyl)-6-((3-(difluoromethyl)azetidin- 3-yl)oxy)pyrido[3,2-d]pyrimidin-4-amine (50 mg, crude) as yellow oil. MS (ESI) m/z 430.1 [M+H]
+ [1989] To a solution of N-(3,4-dichloro-2-fluorophenyl)-6-((3-(difluoromethyl)azetidin-3- yl)oxy)pyrido[3,2-d] pyrimidin-4-amine (50.0 mg, 116 umol, 1.00 eq) and triethylamine (58.8 mg, 581 umol, 80.9 uL, 5.00 eq) in dimethyl formamide (1.00 mL) was added acryloyl chloride (13.7 mg, 151 umol, 12.3 uL, 1.30 eq) dropwise. The mixture was stirred at 25 °C for 0.5 h. The mixture was filtered and the filtrate was purified by prep-HPLC (column: Waters Xbridge C18 150*50mm* 10um; mobile phase: [water(10mM NH4HCO3)-ACN]; B%: 50%-70%,10min) and lyophilized to give 1-(3-((4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6- yl)oxy)-3-(difluoromethyl)azetidin-1-yl)prop-2-en-1-one 112 (8.15 mg, 17.0 umol, 14% yield, 99% purity) as a white solid.
1H NMR (400 MHz, CDCl
3) δ = 8.86 (d, J = 8.4 Hz, 1H), 8.84 - 8.82 (m, 1H), 8.66 (br d, J = 3.5 Hz, 1H), 8.26 (d, J = 9.0 Hz, 1H), 7.43 - 7.36 (m, 2H), 6.82 - 6.54 (m,
1H), 6.46 - 6.39 (m, 1H), 6.30 - 6.21 (m, 1H), 5.79 (dd, J = 1.6, 10.4 Hz, 1H), 4.85 (br d, J = 10.0 Hz, 1H), 4.72 (br d, J = 11.8 Hz, 1H), 4.58 (br d, J = 9.5 Hz, 1H), 4.45 (br d, J = 11.9 Hz, 1H). MS (ESI) m/z 484.1 [M+H]
+. [1990] Synthesis of 1-benzhydryl-3-(difluoromethyl)azetidin-3-ol. To a solution of 1- benzhydrylazetidin-3-one (500 mg, 2.11 mmol, 1.00 eq) and hexamethylphosphoric triamide (1.89 g, 10.5 mmol, 1.85 mL, 5.00 eq) in tetrahydrofuran (15.0 mL) was added cesium fluoride (96.0 mg, 632 umol, 23.3 uL, 0.30 eq) in portions under nitrogen, then (difluoromethyl)trimethylsilane (523 mg, 4.21 mmol, 2.00 eq) was added. The mixture was stirred at 60 °C for 12 h. The mixture was diluted with water (50.0 mL) and extracted with ethyl acetate (3 × 30.0 mL). The combined organic layer was washed with brine (20.0 mL) and dried over sodium sulfate, filtered and concentrated to give crude product. The crude product was purified by reversed-phase HPLC (0.1% FA condition) to give 1-benzhydryl-3-(difluoromethyl)azetidin-3-ol (20.0 mg, 69.1 umol, 3% yield) as yellow oil.
1H NMR (400 MHz, CDCl
3) δ = 7.32 (d, J = 7.3 Hz, 4H), 7.20 (t, J = 7.5 Hz, 4H), 7.13 (d, J = 7.3 Hz, 2H), 6.10 - 5.70 (m, 1H), 4.34 (s, 1H), 3.38 - 3.34 (m, 2H), 3.03 - 2.98 (m, 2H). [1991] Synthesis of Compound No.113: Synthesized according to general procedure C, wherein in step C.1 variant i and (S)-tert-butyl 3-(methylamino)pyrrolidine-1-carboxylate (1.50 g, 7.49 mmol, 1.01 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.5 3-chloro-4-((1-methyl-1H-pyrazol-5-yl)methoxy)aniline (137 mg, 577 umol, 1.00 eq) was used as HX
1-Y and in step C.6, variant ii was used to give (S)-1-(3-((4-((3-chloro-4-((1- methyl-1H-pyrazol-5-yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6- yl)(methyl)amino)pyrrolidin-1-yl)prop-2-en-1-one 113 in 29% yield from XXII.
1H NMR (400 MHz, DMSO-d
6) δ = 9.49 (s, 1H), 8.45 (d, J = 2.9 Hz, 1H), 8.11 - 8.04 (m, 1H), 7.94 (d, J = 9.4 Hz, 1H), 7.85 - 7.78 (m, 1H), 7.50 (dd, J = 4.6, 9.4 Hz, 1H), 7.39 (dd, J = 3.6, 5.4 Hz, 2H), 6.72 - 6.58 (m, 1H), 6.41 (d, J = 1.7 Hz, 1H), 6.18 (ddd, J = 2.4, 5.9, 16.8 Hz, 1H), 5.83 - 5.71 (m, 1H), 5.71 - 5.65 (m, 1H), 5.31 (s, 2H), 3.97 - 3.92 (m, 0.5H), 3.90 (s, 3H), 3.85 - 3.64 (m, 2H), 3.58 - 3.44 (m, 1.5H), 3.10 (d, J = 4.8 Hz, 3H), 2.23 - 2.16 (m, 1H), 2.15 - 2.08 (m, 1H). MS (ESI) m/z 519.4[M+H]
+. [1992] Synthesis of 3-chloro-4-((1-methyl-1H-pyrazol-5-yl)methoxy)aniline. To a solution of 2-chloro-1-fluoro-4-nitrobenzene (800 mg, 7.13 mmol, 1.00 eq) and (1-methyl-1H-pyrazol -5- yl)methanol (1.25 g, 7.13 mmol, 1.00 eq) in dimethyl formamide (10.0 mL) was added potassium
carbonate (1.97 g, 14.3 mmol, 2.00 eq) in portions. The mixture was stirred at 60 °C for 12 h. The mixture was concentrated to give crude product. The crude product was triturated with water (80.0 mL) for 20 min and filtered. The filter cake was dried to give 5-((2-chloro-4- nitrophenoxy)methyl)-1-methyl-1H- pyrazole (1.90 g, 7.10 mmol, 99% yield) as an off-white solid. [1993] To a solution of 5-((2-chloro-4-nitrophenoxy)methyl)-1-methyl-1H-pyrazole (800 mg, 2.99 mmol, 1.00 eq) and ammonium chloride (799 mg, 14.9 mmol, 5.00 eq) in methanol (40.0 mL) and water (10.0 mL) was added iron powder (835 mg, 14.9 mmol, 5.00 eq) dropwise. The mixture was stirred at 80 °C for 2 h. The mixture was filtered and the filtrate was concentrated to give crude product. The crude product was diluted with saturated sodium hydrogencarbonate solution (50.0 mL) and extracted with ethyl acetate (3 × 30.0 mL). The combined organic layer was washed with brine (20.0 mL) and dried over sodium sulfate, filtered and concentrated to give 3-chloro-4- ((1-methyl-1H-pyrazol-5-yl)methoxy)aniline (640 mg, 2.69 mmol, 90% yield) as a yellow solid.
1H NMR (400 MHz, DMSO-d
6) δ = 7.40 (d, J = 1.7 Hz, 1H), 7.02 (d, J = 8.7 Hz, 1H), 6.68 (d, J = 2.7 Hz, 1H), 6.53 (dd, J = 2.6, 8.7 Hz, 1H), 6.36 (d, J = 1.7 Hz, 1H), 5.10 (s, 2H), 5.07 - 4.98 (m, 2H), 3.91 (s, 3H). MS (ESI) m/z 238.0 [M+H]
+ [1994] Synthesis of Compound No.114: Synthesized according to general procedure C, wherein in step C.1 variant i and (S)-tert-butyl 3-(methylamino)pyrrolidine-1-carboxylate (1.50 g, 7.49 mmol, 1.01 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.5 3-chloro-4-((5- methylthiazol-2-yl)methoxy)aniline (140 mg, 550 umol, 1.00 eq) was used as HX
1-Y and in step C.6, variant ii was used to give (S)-1-(3-((4-((3-chloro-4-((5- methylthiazol-2-yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)(methyl)amino)- pyrrolidin-1-yl)prop-2-en-1-one 114 in 19% yield from XXII.
1H NMR (400 MHz, DMSO-d
6) δ = 9.41 (br s, 1H), 8.48 - 8.35 (m, 1H), 8.17 - 8.04 (m, 1H), 7.93 (d, J = 9.4 Hz, 1H), 7.85 - 7.74 (m, 1H), 7.53 - 7.46 (m, 2H), 7.34 (d, J = 9.0 Hz, 1H), 6.74 - 6.57 (m, 1H), 6.17 (ddd, J = 2.4, 6.2, 16.8 Hz, 1H), 5.78 - 5.65 (m, 2H), 5.46 (s, 2H), 3.95 - 3.81 (m, 1H), 3.78 - 3.64 (m, 2H), 3.54 (br d, J = 9.3 Hz, 1H), 3.45 - 3.38 (m, 1H), 3.09 (d, J = 4.9 Hz, 3H), 2.45 (d, J = 0.9 Hz, 3H), 2.24 - 2.15 (m, 1H), 2.13 - 2.07 (m, 1H). MS (ESI) m/z 536.4 [M+H]
+. [1995] Synthesis of 3-chloro-4-((5- methylthiazol-2-yl)methoxy)aniline. To a solution of 2- chloro-1-fluoro-4-nitrobenzene (815 mg, 4.64 mmol, 1.00 eq) and (5-methylthiazol-2-yl) methanol (600 mg, 4.64 mmol, 1.00 eq) in dimethyformamide (10.0 mL) was added potassium
carbonate (1.28 g, 9.29 mmol, 2.00 eq) in portions. The mixture was stirred at 60 °C for 12 h. The mixture was added water (100 mL) and filtered. The filter cake was concentrated in vacuum to give 2-((2-chloro-4- nitrophenoxy)methyl)-5-methylthiazole (1.10 g, crude) as a yellow solid. [1996] To a solution of 2-((2-chloro-4-nitrophenoxy)methyl)-5-methylthiazole (1.00 g, 3.51 mmol, 1.00 eq) and ammonium chloride (1.32 g, 24.6 mmol, 7.00 eq) in methanol (20.0 mL) and water (5.00 mL) was added iron powder (981 mg, 17.6 mmol, 5.00 eq) in portions. The mixture was stirred at 80 °C for 2 h. The mixture was filtered. The filtrate was concentrated in vacuum. The residue was diluted with saturated sodium bicarbonate solution (100 mL) and extracted with ethyl acetate (3 × 80.0 mL). The combined organic layer was washed with brine (60.0 mL), dried over sodium sulfate, filtered and concentrated in vacuum to give 3-chloro-4-((5-methylthiazol-2- yl)methoxy)aniline (900 mg, crude) as a yellow solid.
1H NMR (400 MHz, DMSO-d
6) δ = 7.47 (d, J = 1.1 Hz, 1H), 6.95 (d, J = 8.7 Hz, 1H), 6.65 (d, J = 2.7 Hz, 1H), 6.46 (dd, J = 2.6, 8.7 Hz, 1H), 5.21 (s, 2H), 5.00 (s, 2H), 2.43 (d, J = 0.7 Hz, 3H). MS (ESI) m/z 255.1 [M+H]
+. [1997] Synthesis of Compound No.115: Synthesized according to general procedure C, wherein in step C.1 variant i and (S)-tert-butyl 3-(methylamino)pyrrolidine-1-carboxylate (1.50 g, 7.49 mmol, 1.01 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.53-chloro-4-((5-methyl- 1,3,4-thiadiazol-2-yl)methoxy)aniline (75.0 mg, 294 umol, 0.97 eq) was used as HX
1-Y and in step C.6, variant ii was used to give (S)-1-(3-((4-((3-chloro-4-((5- methyl-1,3,4-thiadiazol-2-yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)(methyl)- amino)pyrrolidin-1-yl)prop-2-en-1-one 115 in 18% yield from XXII.
1H NMR (400 MHz, DMSO- d
6) δ = 9.32 (d, J = 7.6 Hz, 1H), 8.45 - 8.36 (m, 1H), 8.19 (s, 1H), 8.18 - 8.09 (m, 1H), 7.94 (d, J = 9.4 Hz, 1H), 7.89 - 7.82 (m, 1H), 7.48 (dd, J = 5.8, 9.4 Hz, 1H), 7.38 (d, J = 9.0 Hz, 1H), 6.72 - 6.58 (m, 1H), 6.18 (ddd, J = 2.5, 6.5, 16.8 Hz, 1H), 5.81 - 5.71 (m, 1H), 5.70 (dd, J = 2.4, 6.9 Hz, 1H), 5.66 (s, 2H), 3.97 - 3.81 (m, 1H), 3.80 - 3.51 (m, 2H), 3.51 - 3.41 (m, 1H), 3.10 (d, J = 5.1 Hz, 3H), 2.75 (s, 3H), 2.24 - 2.07 (m, 2H). MS (ESI) m/z 537.2 [M+H]. [1998] Synthesis of 3-chloro-4-((5-methyl-1,3,4-thiadiazol-2-yl)methoxy)aniline. To a solution of 2-chloro-1-fluoro-4-nitrobenzene (100 mg, 569 umol, 1.00 eq) in dimethyl formamide (5.00 mL) was added (5-methyl-1,3,4-thiadiazol-2-yl)methanol (70.0 mg, 538 umol, 0.944 eq) and potassium carbonate (250 mg, 1.81 mmol, 3.18 eq). The mixture was stirred at 25 °C for 12 h. The mixture was diluted with ethyl acetate (50.0 mL) and water (20.0 mL). The organic layer was separated and concentrated under reduced pressure to give 2-((2-chloro-4-nitrophenoxy)methyl)-
5-methyl-1,3,4-thiadiazole (150 mg, crude) as a yellow solid. [1999] To a solution of 2-((2-chloro-4-nitrophenoxy)methyl)-5-methyl-1,3,4-thiadiazole (300 mg, 1.05 mmol, 1.00 eq) in methanol (20.0 mL) and water (5.00 mL) was added iron powder (300 mg, 5.37 mmol, 5.12 eq) and ammonium chloride (450 mg, 8.41 mmol, 8.01 eq). The mixture was stirred at 80 °C for 1 h. After filtration, the filtrate was concentrated under reduced pressure. The residue was triturated with water (10.0 mL) for 0.5 h. Then the mixture was filtered and the filter cake was collected and dried under vacuum to give 3-chloro-4-((5-methyl-1,3,4-thiadiazol-2- yl)methoxy)aniline (210 mg, 821 umol, 78% yield) as a white solid.
1H NMR (400 MHz, DMSO- d
6) δ = 6.99 (d, J = 8.8 Hz, 1H), 6.65 (d, J = 2.6 Hz, 1H), 6.48 (dd, J = 2.8, 8.8 Hz, 1H), 5.41 (s, 2H), 5.07 - 5.00 (m, 1H), 2.73 (s, 3H). MS (ESI) m/z 256.0 [M+H]
+. [2000] Synthesis of Compound No.116: Synthesized according to general procedure C, wherein in step C.1 variant i and (S)-tert-butyl 3-(methylamino)pyrrolidine-1-carboxylate (1.50 g, 7.49 mmol, 1.01 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.53-chloro-4-((5-methyl-1,3,4-oxadiazol-2-yl)methoxy)aniline (75.0 mg, 312.95 umol, 1.14 eq) was used as HX
1-Y and in step C.6, variant ii was used to give (S)-1-(3-((4-((3-chloro-4-((5- methyl-1,3,4- oxadiazol-2-yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6- yl)(methyl)amino)pyrrolidin-1-yl)prop-2-en-1-one 116 in 11% yield from XXII.
1H NMR (400 MHz, DMSO-d
6) δ = 9.32 (d, J = 7.5 Hz, 1H), 8.40 (s, 1H), 8.20 - 8.09 (m, 1H), 7.93 (d, J = 9.4 Hz, 1H), 7.84 (ddd, J = 2.5, 6.5, 8.9 Hz, 1H), 7.47 (dd, J = 5.8, 9.3 Hz, 1H), 7.36 (d, J = 9.0 Hz, 1H), 6.65 (ddd, J = 10.3, 15.2, 16.6 Hz, 1H), 6.17 (ddd, J = 2.5, 6.4, 16.8 Hz, 1H), 5.78 - 5.64 (m, 2H), 5.46 (s, 2H), 3.99 - 3.81 (m, 1H), 3.79 - 3.50 (m, 2H), 3.48 - 3.37 (m, 1H), 3.09 (d, J = 5.1 Hz, 3H), 2.54 (s, 3H), 2.23 - 2.14 (m, 1H), 2.14 - 2.06 (m, 1H). MS (ESI) m/z 521.2 [M+H]
+. [2001] Synthesis of Compound No. 117: A mixture of 2-bromo-5-methyl-3-nitropyridine (20.0 g, 92.1 mmol, 1.00 eq), [1,1'-bis(diphenylphosphino) ferrocene]dichloropalladium(II) (3.37 g, 4.61 mmol, 0.0500 eq), triethylamine (27.9 g, 276 mmol, 38.4 mL, 3.00 eq) in methanol (100 mL) and acetonitrile (400 mL) was heated to 80 °C for 36 h under carbon monoxide (50 psi) atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 10/1 to 3/1) to give methyl 5-methyl-3- nitropicolinate (10.0 g, 50.9 mmol, 55% yield) as a yellow solid and methyl 3-amino-5- methyl-
picolinate (2.50 g, 15.0 mmol, 16% yield) as a light yellow solid. [2002] A mixture of methyl 5-methyl-3-nitropicolinate (10.0 g, 50.9 mmol, 1.00 eq), palladium/carbon (4.00 g, 50.9 mmol, 10% purity, 1.00 eq) in tetrahydrofuran (100 mL) was stirred at 25 °C for 16 h under hydrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give methyl 3-amino-5-methylpicolinate (8.00 g, 48.1 mmol, 94% yield) as a light yellow solid. [2003] To a solution of methyl 3-amino-5-methylpicolinate (10.5 g, 63.1 mmol, 1.00 eq) in acetonitrile (100 mL) was added N-bromosuccinimide (13.5 g, 75.5 mmol, 1.20 eq) at 0 °C. The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 × 50.0 mL). The combined organic layers were washed with brine (10.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 10/1 to 5/1) to give methyl 3-amino-6- bromo-5-methylpicolinate (9.40 g, 38.3 mmol, 60% yield) as a yellow solid. [2004] To a solution of methyl 3-amino-6-bromo-5-methylpicolinate (9.40 g, 38.3 mmol, 1.00 eq) in methanol (100 mL) was added sodium hydroxide (2 M, 57.5 mL, 3.00 eq). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in water (20.0 mL) and then acidified by the addition of 2 M hydrochloric acid. The mixture was extracted with ethyl acetate (3 × 50.0 mL), the combined organic layers were washed with water (10.0 mL), brine (10.0 mL), dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give 3-amino-6-bromo-5- methylpicolinic acid (5.40 g, 23.3 mmol, 60% yield) as a light yellow solid. [2005] A mixture of 3-amino-6-bromo-5-methylpicolinic acid (5.40 g, 23.3 mmol, 1.00 eq), formimidamide acetate (4.87 g, 46.7 mmol, 2.00 eq) in ethyl alcohol (10.0 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 100 °C for 12 h under nitrogen atmosphere. The reaction mixture was filtered, the filter cake was washed with ethyl acetate (50.0 mL), and dried to give 6-bromo-7-methylpyrido [3,2-d]pyrimidin-4-ol (2.40 g, 10.0 mmol, 42% yield) as a white solid.
1H NMR (400 MHz, DMSO-d
6) δ = 12.72 - 12.54 (m, 1H), 8.18 (s, 1H), 8.07 (d, J = 0.6 Hz, 1H), 2.47 (s, 3H). [2006] To a solution of 6-bromo-7-methylpyrido[3,2-d]pyrimidin-4-ol (1.00 g, 4.17 mmol, 1.00 eq) in thionyl chloride (10.0 mL) was added dimethyl formamide (30.4 mg, 416 umol, 32.0 uL,
0.100 eq). The mixture was stirred at 90 °C for 3 h. The reaction mixture was concentrated under reduced pressure to give 4,6-dichloro-7-methylpyrido[3,2-d]pyrimidine (900 mg, crude) as a yellow solid. [2007] A mixture of 4,6-dichloro-7-methylpyrido[3,2-d]pyrimidine (800 mg, 3.74 mmol, 1.00 eq), 3,4-dichloro-2-fluoroaniline (807 mg, 4.48 mmol, 1.20 eq) in isopropanol (10.0 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 80 °C for 1 h under nitrogen atmosphere. The reaction mixture was filtered, washed with isopropanol (10.0 mL), and the filter cake was dried to give 6-chloro-N-(3,4-dichloro-2-fluorophenyl)-7-methylpyrido[3,2-d] pyrimidin-4-amine (840 mg, 2.35 mmol, 62% yield) as a yellow solid. [2008] A mixture of 6-chloro-N-(3,4-dichloro-2-fluorophenyl)-7-methylpyrido[3,2-d]pyrimidin- 4-amine (100 mg, 279 umol, 1.00 eq), methylsulfinyloxysodium (57.1 mg, 559 umol, 2.00 eq), L- proline (9.66 mg, 83.8 umol, 0.300 eq), copper iodide (15.9 mg, 83.8 umol, 0.300 eq) and cesium carbonate (27.3 mg, 83.8 umol, 0.300 eq) in dimethyl sulfoxide (1.00 mL) was stirred at 140 °C for 4 h under nitrogen. The mixture was poured into water (10.0 mL) to give a suspension. The solid was filtered, washed with water (5.00 mL), the filter cake was triturated in methanol (5.00 mL), filtered and the filter cake was dried to give N-(3,4-dichloro-2-fluorophenyl)-7-methyl-6- (methylsulfonyl)pyrido[3,2-d]pyrimidin-4-amine (45.0 mg, 112 umol, 40% yield) as a white solid. [2009] A solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (97.1 mg, 560 umol, 3.00 eq) and potassium tert-butoxide (62.9 mg, 560 umol, 3.00 eq) in dimethyl sulfoxide (1.00 mL) was stirred at 20 °C for 0.5 h. Then the mixture was added N-(3,4-dichloro-2-fluorophenyl)-7-methyl- 6-(methylsulfonyl)pyrido[3,2-d] pyrimidin-4-amine (75.0 mg, 186 umol, 1.00 eq) and stirred at 20 °C for 12 h. The reaction mixture was diluted with saturated ammonium chloride (10.0 mL) and extracted with ethyl acetate (2 × 20.0 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (petroleum ether/ethyl acetate = 1/1, R
f = 0.62) to give tert-butyl 3-((4-((3,4- dichloro-2-fluorophenyl)amino)-7-methylpyrido[3,2-d]pyrimidin-6-yl)oxy) azetidine-1- carboxylate (120 mg, crude) as a yellow solid. [2010] To a solution of tert-butyl 3-((4-((3,4-dichloro-2-fluorophenyl)amino)-7- methylpyrido[3,2-d]pyrimidin -6-yl)oxy)azetidine-1-carboxylate (110 mg, 222 umol, 1.00 eq) in dichloromethane (2.00 mL) was added trifluoroacetic acid (1.69 g, 14.8 mmol, 1.10 mL, 66.7 eq). The mixture was stirred at 20 °C for 1 h. The mixture was concentrated to give 6-(azetidin-3-
yloxy)-N-(3,4-dichloro-2-fluorophenyl)-7-methylpyrido [3,2-d]pyrimidin-4-amine (110 mg, 216 umol, 97% yield, trifluoroacetic acid) as yellow oil. [2011] To a solution of 6-(azetidin-3-yloxy)-N-(3,4-dichloro-2-fluorophenyl)-7- methylpyrido[3,2-d]pyrimidin-4- amine (100 mg, 196 umol, 1.00 eq, trifluoroacetic acid) in dichloromethane (2.00 mL) was added triethylamine (59.7 mg, 590 umol, 82.1 uL, 3.00 eq). Then the mixture was added prop-2-enoyl chloride (17.8 mg, 196 umol, 16.0 uL, 1.00 eq) at 0 °C and stirred at 0 °C for 0.5 h. The reaction mixture was diluted with water (5.00mL) and extracted with dichloromethane (2 × 15.0 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*25mm*5um;mobile phase: [water(10mM ammonium bicarbonate)-acetonitrile];B%: 40%-75%,10min) to give 1-(3-((4-((3,4-dichloro-2- fluorophenyl)amino)-7-methylpyrido[3,2-d]pyrimidin-6-yl)oxy)azetidin-1-yl)prop-2-en-1-one 117 (8.31 mg, 17.9 umol, 9% yield, 97% purity) as a white solid.
1H NMR (400 MHz, DMSO-d
6) δ = 9.34 (s, 1H), 8.55 (s, 1H), 8.16 - 8.02 (m, 2H), 7.61 (dd, J = 1.7, 8.9 Hz, 1H), 6.37 (dd, J = 10.4, 17.0 Hz, 1H), 6.14 (dd, J = 2.0, 17.0 Hz, 1H), 5.79 - 5.67 (m, 2H), 4.91 - 4.79 (m, 1H), 4.58 (br dd, J = 6.8, 11.0 Hz, 1H), 4.32 (br dd, J = 4.0, 9.7 Hz, 1H), 4.03 (br dd, J = 4.0, 11.0 Hz, 1H), 2.40 (s, 3H). MS (ESI) m/z 448.1 [M+H]
+. [2012] Synthesis of Compound No.118: Synthesized according to general procedure C, wherein in step C.1 variant ii and (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (3.62 g, 19.3 mmol, 1.30 eq) was used as BocN[(CR
aR
b)m(CR
cR
d)n]-X
2H, in step C.2 variant i was used and in step C.5 3-chloro-4-((1-methyl-1H-pyrazol-5-yl)methoxy)aniline was used as HX
1-Y and in step C.6, variant ii was used to give (S)-1-(3-((4-((3-chloro-4-((1-methyl-1H-pyrazol-5- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one 118 in 34% overall yield from XXII.
1H NMR (400 MHz, DMSO-d
6) δ = 9.54 (d, J = 2.1 Hz, 1H), 8.56 (d, J = 1.1 Hz, 1H), 8.11 (dd, J = 1.0, 9.0 Hz, 1H), 8.09 - 8.06 (m, 1H), 7.87 (dd, J = 2.6, 8.9 Hz, 1H), 7.42 - 7.36 (m, 3H), 6.71 - 6.56 (m, 1H), 6.42 (d, J = 1.7 Hz, 1H), 6.26 - 6.18 (m, 1H), 6.17 - 6.12 (m, 1H), 5.73 - 5.63 (m, 1H), 5.32 (s, 2H), 4.11 - 4.04 (m, 1H), 3.90 (s, 3H), 3.85 - 3.81 (m, 1H), 3.78 (s, 2H), 3.58 - 3.48 (m, 1H), 2.42 - 2.37 (m, 1H), 2.32 - 2.24 (m, 1H), 2.22 - 2.13 (m, 1H). MS (ESI) m/z 506.4[M+H]
+. [2013] Synthesis of Compound No.119: Synthesized according to general procedure C, wherein in step C.1 variant i and (S)-tert-butyl 3-(methylamino)pyrrolidine-1-carboxylate (1.50 g, 7.49
mmol, 1.01 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.5 3-chloro-4-(pyrimidin-4-ylmethoxy)aniline (161 mg, 687 umol, 1.00 eq) was used as HX
1-Y and in step C.6, variant ii was used to give (S)-1-(3-((4-((3-chloro-4- (pyrimidin-4- ylmethoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)(methyl)amino)pyrrolidin-1-yl)prop-2-en- 1-one 119 in 23% overall yield from XXII.
1H NMR (400 MHz, CDCl
3) δ = 2.33 - 2.20 (m, 2 H), 3.15 (d, J = 7.2 Hz, 3 H), 3.77 - 3.60 (m, 2 H), 4.05 - 3.87 (m, 2 H), 5.26 (s, 2 H), 5.49 - 5.33 (m, 1 H), 5.81 - 5.73 (m, 1 H), 6.57 - 6.45 (m, 2 H), 7.02 (d, J = 8.8 Hz, 1 H), 7.26 (dd, J = 9.4, 1.4 Hz, 1 H), 7.78 - 7.66 (m, 2 H), 8.13 - 8.04 (m, 2 H), 8.60 (d, J = 3.6 Hz, 1 H), 8.67 (br d, J = 10.8 Hz, 1 H), 8.83 (d, J = 5.2 Hz, 1 H), 9.22 (d, J = 1.4 Hz, 1 H). MS (ESI) m/z 517.4 [M+H]
+ [2014] Synthesis of Compound No.120: Synthesized according to general procedure C, wherein in step C.1 variant i and (S)-tert-butyl 3-(methylamino)pyrrolidine-1-carboxylate (1.50 g, 7.49 mmol, 1.01 eq) was used as BocN[(CR
aR
b)m(CR
cR
d)n]-X
2H, in step C.2 variant i was used and in step C.53-chloro-4-((2-methylthiazol-5-yl)methoxy)aniline (182 mg, 714 umol, 1.00 eq) was used as HX
1-Y and in step C.6, variant ii was used to give (S)-1-(3-((4-((3-chloro-4- ((2-methylthiazol- 5-yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)(methyl)amino)pyrrolidin-1-yl)prop-2- en-1-one 120 in 34% overall yield from XXII.
1H NMR (400 MHz, CDCl
3) δ = 2.15 - 2.35 (m, 2 H) 2.73 (s, 3 H) 3.15 (d, J = 7.6 Hz, 3 H) 3.57 - 3.79 (m, 2 H) 3.83 - 4.05 (m, 2 H) 5.30 (s, 2 H) 5.33 - 5.51 (m, 1 H) 5.71 - 5.82 (m, 1 H) 6.41 - 6.59 (m, 2 H) 7.07 (dd, J = 8.8, 1.2 Hz, 1 H) 7.26 (dd, J = 9.4, 1.0 Hz, 1 H) 7.60 - 7.74 (m, 2 H) 7.99 (dd, J = 15.4, 2.6 Hz, 1 H) 8.11 - 8.19 (m, 1 H) 8.60 (d, J = 3.8 Hz, 1 H) 8.73 (br d, J = 10.2 Hz, 1 H)^ MS (ESI) m/z 536.4 [M+H]
+. [2015] Synthesis of 3-chloro-4-((2-methylthiazol-5-yl)methoxy)aniline: To a solution of 2- chloro-1-fluoro-4-nitrobenzene (1.22 g, 6.97 mmol, 1.00 eq) and (2-methylthiazol-5-yl) methanol (900 mg, 6.97 mmol, 1.00 eq) in dimethyl formamide (10.0 mL) was added potassium carbonate (1.93 g, 13.9 mmol, 2.00 eq). The mixture was stirred at 60 °C for 12 h. The crude product was triturated with water (100.0 mL) and filtered. The filter cake was washed with water (30.0 mL) and dried to give 5-((2-chloro-4-nitrophenoxy)methyl)-2-methylthiazole (1.88 g, 6.60 mmol, 94% yield) as a yellow soild. To a solution of 5-((2-chloro-4-nitrophenoxy)methyl)-2-methylthiazole (1.88 g, 6.60 mmol, 1.00 eq) in methanol (10.0 mL) and water (4.00 mL) was added saturated ammonium chloride (1.77 g, 33.0 mmol, 5.00 eq) and iron powder (1.84 g, 33.0 mmol, 5.00 eq). The mixture was stirred at 80 C for 1 h. The reaction mixture was added methanol (50.0 ml) and filtered, the filtrate was concentrated on a rotary evaporator. Ethyl acetate (40.0 mL) and saturated
sodium bicarbonate solution (40.0 mL) were added and layers were separated. The aqueous phase was extracted with ethyl acetate (3 × 20.0 mL). Combined organic phase was washed with brine (2 × 20.0 mL), dried over sodium sulfate, filtered, and concentrated to give 3-chloro-4-((2- methylthiazol-5-yl)methoxy)aniline (1.41 g, 5.54 mmol, 83% yield) as a brown solid.
1H NMR (400 MHz, DMSO-d
6) δ = 2.63 (s, 3 H) 4.93 - 5.02 (m, 2 H) 5.17 (s, 2 H) 6.47 (dd, J = 8.8, 2.6 Hz, 1 H) 6.62 (d, J = 2.6 Hz, 1 H) 6.95 (d, J = 8.8 Hz, 1 H) 7.62 (s, 1 H). MS (ESI) m/z 254.9 [M+H]
+. [2016] Synthesis of Compound No.121: Synthesized according to general procedure C, wherein in step C.1, variant i and (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (4.44 g, 23.8 mmol, 1.20 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used. in step C.5 5- chloro-2-fluoro-4-((3-fluorobenzyl)oxy)aniline (260 mg, 964 umol, 0.803 eq) was used as HX
1-Y and in step C.6, variant ii was used to give (S)-1-(3-((4-((5-chloro-2-fluoro-4-((3- fluorobenzyl)oxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl) amino)pyrrolidin-1-yl)prop-2-en- 1-one 121 in 19% overall yield from XXII.
1H NMR (400 MHz, DMSO-d
6) δ = 9.11 (d, J = 8.8 Hz, 1H), 8.36 (d, J = 4.0 Hz, 1H), 8.31 - 8.21 (m, 1H), 7.85 - 7.76 (m, 2H), 7.48 (dt, J = 6.1, 8.0 Hz, 1H), 7.40 (dd, J = 1.7, 12.4 Hz, 1H), 7.35 - 7.28 (m, 2H), 7.19 (dt, J = 2.1, 8.6 Hz, 1H), 7.11 (dd, J = 1.5, 9.2 Hz, 1H), 6.71 - 6.50 (m, 1H), 6.15 (ddd, J = 2.4, 6.9, 16.7 Hz, 1H), 5.67 (ddd, J = 2.4, 10.3, 17.6 Hz, 1H), 5.28 (s, 2H), 4.84 - 4.60 (m, 1H), 4.09 - 3.71 (m, 2H), 3.63 - 3.57 (m, 1H), 3.45 (br d, J = 5.9 Hz, 1H), 2.35 - 2.16 (m, 1H), 2.10 - 1.87 (m, 1H). MS (ESI) m/z 537.3 [M+H]
+. [2017] Synthesis of 5-chloro-2-fluoro-4-((3-fluorobenzyl)oxy)aniline: To a solution of 1- chloro-2,4-difluoro-5-nitrobenzene (5.00 g, 25.8 mmol, 1.00 eq) in dimethyl formamide (20.0 mL) was added potassium carbonate (7.14 g, 51.7 mmol, 2.00 eq) and (3-fluorophenyl)methanol (5.00 g, 39.6 mmol, 4.31 mL, 1.53 eq). The mixture was stirred at 25 °C for 16 h. The mixture was diluted with water (100 mL) and ethyl acetate (100 mL). The organic layer was separated and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated reduced pressure to give a residue which was triturated with methanol (50.0 mL) at 25
oC for 30 min. The suspension was filtered through a pad of filter paper and the filter cake was washed with methanol (3 × 10.0 mL). The filter cake was concentrated to dryness to give 1-chloro-4-fluoro-2-((3- fluorobenzyl)oxy)-5-nitrobenzene (4.00 g, 13.3 mmol, 52% yield) as a white solid. To a solution of 1-chloro-4-fluoro-2-((3-fluorobenzyl)oxy)-5-nitrobenzene (1.60 g, 5.34 mmol, 1.00 eq) in methanol (100 mL) and water (20.0 mL) was added ammonium chloride (2.00 g, 37.4 mmol, 7.00
eq) and iron powder (1.49 g, 26.7 mmol, 5.00 eq). The mixture was stirred at 80 °C for 2 h. After being cooled to 25 °C, the suspension was filtered through a pad of diatomite and filter cake was washed with methanol (3 × 50.0 mL). The combined filtrates were concentrated to give 5-chloro- 2-fluoro-4-((3-fluorobenzyl)oxy) aniline (1.40 g, 5.19 mmol, 97% yield) as a red solid.
1H NMR (400 MHz, CDCl
3) δ = 7.35 (dt, J = 6.2, 7.8 Hz, 1H), 7.23 - 7.15 (m, 2H), 7.06 - 6.99 (m, 1H), 6.92 - 6.82 (m, 1H), 6.75 - 6.63 (m, 1H), 5.05 - 5.01 (m, 2H). MS (ESI) m/z 270.1 [M+H]
+. [2018] Synthesis of Compound No.122: Synthesized according to general procedure A, wherein in step A.1 3-chloro-4-(pyrazin-2-ylmethoxy)aniline (166 mg, 704 umol, 0.90 eq) was used as H
2NX
1, in step A.2 variant ii and (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (91 mg, 489 umol, 1.50 eq) as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H was used and in step A.3 variant i was employed to give (S)-1-(3-((4-((3-chloro-4-(pyrazin-2-ylmethoxy)phenyl)amino)-7- methoxypyrido[3,2- d]pyrimidin-6-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one 122 in 5% overall yield.
1H NMR (400 MHz, DMSO-d
6) δ = 9.09 (d, J = 8.3 Hz, 1H), 8.86 (s, 1H), 8.70 - 8.68 (m, 1H), 8.66 (d, J = 2.5 Hz, 1H), 8.38 (s, 1H), 8.38 (s, 1H), 8.14 (dd, J = 2.6, 9.5 Hz, 1H), 7.83 (ddd, J = 2.6, 4.5, 8.9 Hz, 1H), 7.32 (d, J = 9.0 Hz, 1H), 7.23 - 7.18 (m, 2H), 6.73 - 6.52 (m, 1H), 6.14 (ddd, J = 2.4, 5.8, 16.7 Hz, 1H), 5.66 (ddd, J = 2.4, 10.3, 19.1 Hz, 1H), 5.37 (s, 2H), 5.19 - 5.05 (m, 1H), 4.09 (dd, J = 7.0, 10.2 Hz, 1H), 3.99 (s, 3H), 3.89 - 3.79 (m, 1H), 3.69 - 3.59 (m, 2H), 3.51 - 3.48 (m, 1H), 2.30 - 2.16 (m, 1H), 2.13 - 2.03 (m, 1H). MS (ESI) m/z 533.3 [M+H]
+. [2019] Synthesis of 3-chloro-4-(pyrazin-2-ylmethoxy)aniline: To a solution of 2-chloro-1- fluoro-4-nitrobenzene (2.00 g, 11.4 mmol, 1.00 eq) and pyrazin-2-ylmethanol (1.25 g, 11.4 mmol, 1.00 eq) in dimethyl formamide (20.0 mL) was added potassium carbonate (4.72 g, 34.2 mmol, 3.00 eq). The mixture was stirred at 60 °C for 12 h. After being cooled to room temperature, the mixture was diluted with water (50.0 mL), then the suspension was filtered through a filter paper. The filter cake was washed with water (30.0 mL) and concentrated to dryness to give 2-((2-chloro- 4-nitrophenoxy) methyl)pyrazine (2.50 g, 9.41 mmol, 82% yield) as a gray solid. To a solution of 2-((2-chloro-4-nitrophenoxy)methyl)pyrazine (2.50 g, 9.41 mmol, 1.00 eq) in methanol (60.0 mL) and water (20.0 mL) was added iron powder (2.63 g, 47.1 mmol, 5.00 eq), ammonium chloride (4.03 g, 75.3 mmol, 8.00 eq). The mixture was stirred at 80 °C for 2 h. After being cooled to 25 °C, the suspension was filtered through a filter paper and the filter cake was washed with methanol (3 × 10.0 mL). The combined filtrates were concentrated to dryness to give a residue, then was diluted with water (100 mL) and exacted with ethyl acetate (3 × 80 mL). The organic layer was
separated and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give 3-chloro-4-(pyrazin-2-ylmethoxy)aniline (2.2 g, crude) as a yellow solid.
1H NMR (400 MHz, DMSO-d
6) δ = 8.80 (s, 1H), 8.66 - 8.64 (m, 1H), 8.62 (d, J = 2.4 Hz, 1H), 6.96 (d, J = 8.7 Hz, 1H), 6.66 (d, J = 2.7 Hz, 1H), 6.48 (dd, J = 2.7, 8.7 Hz, 1H), 5.16 (s, 2H), 4.98 (br s, 2H). [2020] Synthesis of Compound No.123: Synthesized according to general procedure C, wherein in step C.1 variant ii and (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (3.62 g, 19.3 mmol, 1.30 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.5 3-chloro-4-((5-methylthiazol-2-yl)methoxy)aniline (131 mg, 513 umol, 1.00 eq) was used as HX
1- Y and in step C.6, variant ii was used to give (S)-1-(3-((4-((3-chloro-4-((5- methylthiazol-2- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one 123 in 15% overall yield from XXII.
1H NMR (400 MHz, DMSO-d6) δ = 9.54 (d, J = 3.1 Hz, 1H), 8.57 (d, J = 1.3 Hz, 1H), 8.12 (dd, J = 1.0, 9.0 Hz, 1H), 8.09 (dd, J = 1.2, 2.6 Hz, 1H), 7.85 (dd, J = 2.6, 9.0 Hz, 1H), 7.53 (d, J = 1.3 Hz, 1H), 7.40 - 7.38 (m, 1H), 7.38 - 7.35 (m, 1H), 6.71 - 6.56 (m, 1H), 6.26 - 6.17 (m, 1H), 6.17 - 6.12 (m, 1H), 5.73 - 5.63 (m, 1H), 5.48 (s, 2H), 4.07 (dd, J = 4.8, 12.0 Hz, 1H), 3.87 - 3.66 (m, 3H), 3.53 (ddd, J = 7.6, 9.8, 12.0 Hz, 1H), 2.46 (d, J = 1.0 Hz, 3H), 2.39 (dt, J = 4.6, 9.4 Hz, 1H), 2.34 - 2.26 (m, 1H), 2.22 - 2.14 (m, 1H). MS (ESI) m/z 523.2[M+H]
+. [2021] Synthesis of Compound No.124: Synthesized according to general procedure C, wherein in step C.1 variant ii and (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (3.62 g, 19.3 mmol, 1.30 eq) was used as BocN[(CR
aR
b)m(CR
cR
d)n]-X
2H, in step C.2 variant i was used and in step C.5 3-chloro-4-[(2-methylthiazol-5-yl)methoxy]aniline (217 mg, 855 umol, 1.00 eq) was used as HX
1- Y and in step C.6, variant ii was used to give (S)-1-(3-((4-((3-chloro-4-((2-methylthiazol -5- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one 124 in 19% overall yield from XXII.
1H NMR (400 MHz, CDCl
3) δ = 2.30 - 2.51 (m, 2 H) 2.74 (s, 3 H) 3.77 - 3.92 (m, 2 H) 3.92 - 4.08 (m, 2 H) 5.31 (s, 2 H) 5.70 - 5.90 (m, 2 H) 6.40 - 6.58 (m, 2 H) 7.08 (dd, J = 8.8, 1.6 Hz, 1 H) 7.21 - 7.27 (m, 1 H) 7.60 - 7.76 (m, 2 H) 7.92 - 8.01 (m, 1 H) 8.15 (d, J = 8.8 Hz, 1 H) 8.44 - 8.54 (m, 1 H) 8.69 - 8.75 (m, 1 H). MS (ESI) m/z 523.3 [M+H]
+. [2022] Synthesis of Compound No.125: Synthesized according to general procedure C, wherein in step C.1, variant i and (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (4.44 g, 23.8 mmol, 1.20 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used. in step C.5 3- chloro-4-((2-methylthiazol-5-yl)methoxy)aniline (218 mg, 857 umol, 1.00 eq) was used as HX
1-
Y and in step C.6, variant ii was used to give (S)-1-(3-((4-((3-chloro-4-((2- methylthiazol-5- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one 125 in 13% overall yield from XXII.
1H NMR (400 MHz, CDCl
3) δ = 2.07 - 2.34 (m, 1 H) 2.35 - 2.50 (m, 1 H) 2.73 (s, 3 H) 3.56 - 3.75 (m, 1 H) 3.76 - 3.83 (m, 2 H) 3.91 - 4.10 (m, 1 H) 4.68 - 4.88 (m, 1 H) 5.29 (d, J = 1.6 Hz, 2 H) 5.47 - 5.71 (m, 1 H) 5.71 - 5.82 (m, 1 H) 6.38 - 6.56 (m, 2 H) 6.96 - 7.10 (m, 2 H) 7.63 (s, 1 H) 7.73 (dt, J = 8.8, 2.2 Hz, 1 H) 7.88 (dd, J = 8.8, 7.2 Hz, 1 H) 7.97 - 8.02 (m, 1 H) 8.56 - 8.63 (m, 2 H). MS (ESI) m/z 522.3 [M+H]
+. [2023] Synthesis of Compound No.126: Synthesized according to general procedure C, wherein in step C.1 variant ii and (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (3.62 g, 19.3 mmol, 1.30 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.5 3-chloro-4-((5-methyl-1,3,4-thiadiazol-2-yl) methoxy)aniline (70.0 mg, 274 umol, 0.915 eq) was used as HX
1-Y and in step C.6, variant ii was used to give (S)-1-(3-((4-((3-chloro-4-((5-methyl- 1,3,4-thiadiazol-2-yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin- 6-yl)oxy)pyrrolidin-1- yl)prop-2-en-1-one 126 in 18% overall yield from XXII.
1H NMR (400 MHz, DMSO-d
6) δ = 9.54 (br s, 1H), 8.56 (s, 1H), 8.10 (br s, 2H), 7.87 (dd, J = 2.3, 9.0 Hz, 1H), 7.45 - 7.28 (m, 2H), 6.73 - 6.51 (m, 1H), 6.28 - 6.04 (m, 2H), 5.76 - 5.59 (m, 3H), 4.12 - 3.76 (m, 2H), 3.73 - 3.48 (m, 2H), 2.75 (s, 3H), 2.38 - 2.27 (m, 1H), 2.27 - 2.11 (m, 1H). MS (ESI) m/z 524.1 [M+H]
+. [2024] Synthesis of Compound No.127: Synthesized according to general procedure C, wherein in step C.1, variant i and (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (4.44 g, 23.8 mmol, 1.20 eq) was used as BocN[(CR
aR
b)m(CR
cR
d)n]-X
2H, in step C.2 variant i was used. in step C.5 3- chloro-4-((5-methyl-1,3,4-thiadiazol-2-yl) methoxy)aniline (109 mg, 427 umol, 0.950 eq) was used as HX
1-Y and in step C.6, variant ii was used to give (S)-1-(3-((4-((3-chloro-4-((5-methyl- 1,3,4-thiadiazol-2-yl)methoxy)phenyl)amino)pyrido[3,2-d] pyrimidin-6-yl)amino)pyrrolidin-1- yl)prop-2-en-1-one 127 in 21% overall yield from XXII.
1H NMR (400 MHz, DMSO-d
6) δ = 9.23 (d, J = 7.7 Hz, 1H), 8.39 (s, 1H), 8.17 (dd, J = 2.5, 9.8 Hz, 1H), 7.86 (td, J = 2.2, 9.0 Hz, 1H), 7.81 - 7.68 (m, 2H), 7.37 (d, J = 9.0 Hz, 1H), 7.09 (dd, J = 3.1, 9.1 Hz, 1H), 6.63 (ddd, J = 10.3, 16.8, 18.8 Hz, 1H), 6.15 (ddd, J = 2.4, 8.8, 16.8 Hz, 1H), 5.73 - 5.59 (m, 2H), 5.07 - 4.87 (m, 1H), 4.12 - 3.70 (m, 2H), 3.66 - 3.45 (m, 2H), 2.74 (s, 3H), 2.33 - 2.18 (m, 1H), 2.01 - 1.84 (m, 1H). MS (ESI) m/z 523.1 [M+H]
+. [2025] Synthesis of Compound No. 128: : Synthesized according to general procedure C, wherein in step C.1 variant i and (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (1.52 g, 8.19
mmol, 1.10 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.5 3-chloro-4-((1-methyl-1H-pyrazol-5-yl)methoxy)aniline (129 mg, 543 umol, 1.00 eq) was used as HX
1-Y and in step C.6, variant ii was used to give (S)-1-(3-((4-((3-chloro-4-((1- methyl- 1H-pyrazol-5-yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)amino)pyrrolidin- 1-yl)prop-2-en-1-one 128 in 18% overall yield from XXII.
1H NMR (400 MHz, DMSO-d
6) δ = 9.22 (d, J = 8.0 Hz, 1H), 8.39 (d, J = 0.6 Hz, 1H), 8.14 (dd, J = 2.6, 9.0 Hz, 1H), 7.87 (td, J = 2.5, 9.0 Hz, 1H), 7.79 (d, J = 9.1 Hz, 1H), 7.73 (dd, J = 7.1, 11.1 Hz, 1H), 7.40 - 7.35 (m, 2H), 7.10 (dd, J = 3.1, 9.1 Hz, 1H), 6.63 (ddd, J = 10.3, 16.8, 18.8 Hz, 1H), 6.41 (d, J = 1.8 Hz, 1H), 6.16 (ddd, J = 2.4, 8.6, 16.8 Hz, 1H), 5.73 - 5.62 (m, 1H), 5.29 (s, 2H), 5.06 - 4.90 (m, 1H), 4.09 (dd, J = 6.3, 10.4 Hz, 1H), 3.90 (s, 3H), 3.85 - 3.71 (m, 2H), 3.66 - 3.52 (m, 1H), 3.45 - 3.38 (m, 1H), 2.37 - 2.21 (m, 1H), 2.03 - 1.88 (m, 1H). MS (ESI) m/z 505.4[M+H]
+. [2026] Synthesis of Compound No. 129: : Synthesized according to general procedure C, wherein in step C.1 variant i and (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (1.52 g, 8.19 mmol, 1.10 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.53-chloro-4-((5-methylthiazol-2-yl)methoxy)aniline (138 mg, 543 umol, 1.00 eq) was used as HX
1-Y and in step C.6, variant ii was used to give (S)-1-(3-((4-((3-chloro-4-((5- methylthiazol- 2-yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one 129 in 20% overall yield from XXII.
1H NMR (400 MHz, DMSO-d
6) δ = 9.22 (d, J = 7.6 Hz, 1H), 8.39 (s, 1H), 8.16 (dd, J = 2.5, 9.5 Hz, 1H), 7.85 (td, J = 2.3, 9.0 Hz, 1H), 7.79 (d, J = 9.0 Hz, 1H), 7.73 (dd, J = 7.1, 10.9 Hz, 1H), 7.52 (d, J = 1.1 Hz, 1H), 7.33 (d, J = 9.1 Hz, 1H), 7.10 (dd, J = 3.1, 9.1 Hz, 1H), 6.63 (ddd, J = 10.3, 16.7, 18.9 Hz, 1H), 6.16 (ddd, J = 2.4, 9.1, 16.8 Hz, 1H), 5.73 - 5.62 (m, 1H), 5.46 (s, 2H), 5.05 - 4.90 (m, 1H), 4.09 (dd, J = 6.1, 10.4 Hz, 1H), 3.85 - 3.69 (m, 2H), 3.66 - 3.50 (m, 1H), 3.43 (br dd, J = 4.8, 10.6 Hz, 1H), 2.46 (s, 3H), 2.35 - 2.23 (m, 1H), 2.03 - 1.88 (m, 1H). MS (ESI) m/z 522.1[M+H]
+. [2027] Synthesis of Compound No.130: Synthesized according to general procedure C, wherein in step C.1 variant i and (S)-tert-butyl 3-(methylamino)pyrrolidine-1-carboxylate (1.50 g, 7.49 mmol, 1.01 eq) was used as BocN[(CR
aR
b)m(CR
cR
d)n]-X
2H, in step C.2 variant i was used and in step C.53-chloro-4-((2-methyloxazol -5-yl)methoxy)aniline (131 mg, 550 umol, 1.00 eq) was used as HX
1-Y and in step C.6, variant i was used to give (S)-1-(3-((4-((3-chloro-4-((2-methyloxazol- 5-yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)(methyl)amino)pyrrolidin-1-yl)prop-2- en-1-one 130 in 8% overall yield from XXII.
1H NMR (400 MHz, DMSO-d
6) δ = 9.31 (d, J = 8.0
Hz, 1H), 8.39 (s, 1H), 8.09 (dd, J = 2.5, 8.1 Hz, 1H), 7.93 (d, J = 9.4 Hz, 1H), 7.87 - 7.79 (m, 1H), 7.47 (dd, J = 5.6, 9.4 Hz, 1H), 7.35 (d, J = 9.0 Hz, 1H), 7.20 (s, 1H), 6.65 (ddd, J = 10.4, 15.4, 16.7 Hz, 1H), 6.17 (ddd, J = 2.4, 6.4, 16.7 Hz, 1H), 5.80 - 5.61 (m, 2H), 5.20 (s, 2H), 3.97 - 3.81 (m, 1H), 3.77 - 3.65 (m, 1H), 3.57 - 3.36 (m, 2H), 3.09 (d, J = 5.1 Hz, 3H), 2.43 (s, 3H), 2.26 - 2.01 (m, 2H). MS (ESI) m/z 520.2 [M+H]
+. [2028] Synthesis of 3-chloro-4-((2-methyloxazol -5-yl)methoxy)aniline: To a solution of 2- chloro-1-fluoro-4-nitrobenzene (500 mg, 2.85 mmol, 1.00 eq) and (2-methyloxazol-5-yl) methanol (483 mg, 4.27 mmol, 1.50 eq) in dimethyl formamide (10.0 mL) was added potassium carbonate (787 mg, 5.70 mmol, 2.00 eq). The mixture was stirred at 60 °C for 12 h. The reaction mixture was partitioned between water (20.0 mL) and ethyl acetate (3 × 20.0 mL). The organic phase was separated, washed with brine (20.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give 5-((2-chloro-4-nitrophenoxy)methyl)-2-methyloxazole (0.8 g, crude) as a yellow oil. To a solution of 5-((2-chloro-4-nitrophenoxy)methyl)-2-methyloxazole (0.80 g, 2.98 mmol, 1.00 eq) and ammonium chloride (1.59 g, 29.8 mmol, 10.0 eq) in ethyl alcohol (5.00 mL) and water (1.00 mL) was added iron powder (665 mg, 11.9 mmol, 4.00 eq). Then the reaction was stirred at 80 °C for 1 h. Upon completion, the reaction mixture was filtered through a pad of celite. The residue was diluted with water (20.0 mL) and extracted with ethyl acetate (3 × 20.0 mL). The combined organic layers were washed with brine (20.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give 3-chloro-4-((2-methyloxazol-5- yl)methoxy)aniline (800 mg, crude) as a yellow oil.
1H NMR (400 MHz, CDCl3) δ = 6.94 (s, 1H), 6.84 (d, J = 8.8 Hz, 1H), 6.73 (d, J = 2.8 Hz, 1H), 6.54 - 6.50 (m, 1H), 4.95 (s, 2H), 3.56 (br s, 2H), 2.48 (s, 3H). [2029] Synthesis of Compound No.131: Synthesized according to general procedure C, wherein in step C.1 variant i and (S)-tert-butyl 3-(methylamino)pyrrolidine-1-carboxylate (1.50 g, 7.49 mmol, 1.01 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.53-chloro-4-((5-methyl-1,3,4-oxadiazol-2-yl) methoxy)aniline (71.0 mg, 296 umol, 0.990 eq) was used as HX
1-Y and in step C.6, variant ii was used to give (S)-1-(3-((4-((3-chloro-4-((5- methyl-1,3,4-oxadiazol-2-yl)methoxy)phenyl)amino)pyrido [3,2-d]pyrimidin-6- yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one 131 in 11% overall yield from XXII.
1H NMR (400 MHz, DMSO-d
6) δ = 9.55 (d, J = 2.3 Hz, 1H), 8.57 (d, J = 1.3 Hz, 1H), 8.45 (s, 1H), 8.13 - 8.08 (m, 2H), 7.88 (dd, J = 2.6, 9.0 Hz, 1H), 7.42 - 7.33 (m, 2H), 6.71 - 6.53 (m, 1H), 6.18 (br dd, J = 2.4, 8.4
Hz, 1H), 6.16 - 6.12 (m, 1H), 5.74 - 5.60 (m, 1H), 5.48 (s, 2H), 4.07 (dd, J = 4.6, 12.0 Hz, 1H), 3.87 - 3.78 (m, 2H), 3.73 - 3.65 (m, 2H), 3.53 (ddd, J = 7.5, 9.7, 11.9 Hz, 1H), 2.55 (s, 3H), 2.37 - 2.27 (m, 1H), 2.27 - 2.12 (m, 1H). MS (ESI) m/z 508.2 [M+H]
+. [2030] Synthesis of Compound No.132: Synthesized according to general procedure C, wherein in step C.1 variant i and (S)-tert-butyl 3-(methylamino)pyrrolidine-1-carboxylate (1.50 g, 7.49 mmol, 1.01 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.5 3-chloro-4-(difluoromethyl)aniline (25.0 mg, 141 umol, 0.988 eq) was used as HX
1-Y and in step C.6, variant ii was used to give (S)-1-(3-((4-((3-chloro-4- (difluoromethyl)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl) oxy)pyrrolidin-1- yl)prop-2-en-1- one 132 in 15% overall yield from XXII.
1H NMR (400 MHz, DMSO-d
6) δ = 9.75 (br d, J = 2.7 Hz, 1H), 8.71 (s, 1H), 8.49 (s, 1H), 8.39 (br s, 1H), 8.24 - 8.12 (m, 2H), 7.76 (br d, J = 8.4 Hz, 1H), 7.43 (dd, J = 4.0, 9.0 Hz, 1H), 7.21 (t, J = 54.4 Hz, 1H), 6.74 - 6.56 (m, 1H), 6.31 - 6.12 (m, 2H), 5.75 - 5.62 (m, 1H), 4.08 (br dd, J = 4.8, 11.7 Hz, 1H), 3.84 (br dd, J = 4.9, 13.2 Hz, 2H), 3.76 - 3.68 (m, 2H), 3.60 - 3.53 (m, 1H), 2.34 - 2.15 (m, 2H). MS (ESI) m/z 446.0 [M+H]
+. [2031] Synthesis of 3-chloro-4-(difluoromethyl)aniline: A mixture of (2-chloro-4- nitrophenyl)methanol (500 mg, 2.67 mmol, 1.00 eq) in dichloromethane (20.0 mL) was added dess-martin periodinane (2.26 g,5.33 mmol, 1.65 mL, 2.00 eq). The mixture was stirred at 0 °C for 0.5 h. The mixture was stirred at 25 °C for 1.5 h. The residue was diluted with water (20.0 mL) and exacted with dichloromethane (30.0 mL). The organic layer was separated and dried over sodium sulfate. After filtration, the filtrate was concentrated reduced pressure to give a residue. The crude product was purified by column chromatography on silica gel eluted with petroleum ether/ethyl acetate = 1/0 to 30/1 to give 2-chloro-4-nitrobenzaldehyde (470 mg, 2.53 mmol, 95% yield) as a white solid. To a solution of 2-chloro-4-nitrobenzaldehyde (200 mg, 1.08 mmol, 1.00 eq) in dichloromethane (8.00 mL) was added (diethylamino)sulfur trifluoride (869 mg, 5.39mmol, 712 uL, 5.00 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h. The mixture was quenched with saturated sodium bicarbonate at 0 °C and extracted with dichloromethane (2 × 10.0 mL). The organic layer was separated and dried over sodium sulfate. After filtration, the filtrate was concentrated reduced pressure to give a residue. The residue was purified by preparative TLC (petroleum ether/ethyl acetate = 20/1). The desired compositional banding was collected. After dissolved and filtration, the filtrate was concentrated under vacuum to give 2-chloro-1- (difluoromethyl)-4-nitrobenzene (200 mg, 964 umol, 89% yield) as yellow oil. To a solution of 2-
chloro-1-(difluoromethyl)-4-nitrobenzene (50.0 mg, 241 umol, 1.00 eq) in dichloromethane (2.00 mL) and methanol (4.00 mL) was added nickel chloride hexahydrate (102 mg, 430 umol, 1.78 eq) and sodium borohydride (38.0 mg, 1.00 mmol, 4.17 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure to give a residue. The crude product was triturated with dichloromethane (10.0 mL) for 10 min. The suspension was filtered through a pad of filter paper and the filter cake was washed with dichloromethane (3 × 10.0 mL). The combined filtrate was concentrated under reduced pressure to give 3-chloro-4- (difluoromethyl)aniline (40.0 mg, crude) as yellow oil. MS (ESI) m/z 178.0 [M+H]
+. [2032] Synthesis of Compound No.133: Synthesized according to general procedure C, wherein in step C.1 variant ii and (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (3.62 g, 19.3 mmol, 1.30 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.5 3-chloro-4-((1-methyl-1H-tetrazol-5-yl)methoxy)aniline (164 mg, 684 umol, 1.20 eq) was used as HX
1-Y and in step C.6, variant i was used to give (S)-1-(3-((4-((3-chloro-4- ((1-methyl-1H- tetrazol-5-yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en- 1-one 133 in 45% overall yield from XXII.
1H NMR (400 MHz, MeOD) δ = 2.31 - 2.46 (m, 2 H), 3.63 - 3.73 (m, 1 H), 3.78 - 3.86 (m, 1 H), 3.88 - 3.98 (m, 2 H), 4.08 - 4.15 (m, 1 H), 4.26 (s, 3 H), 5.59 (s, 2 H), 5.75 (ddd, J = 19.39, 10.38, 1.75 Hz, 1 H), 6.05 - 6.18 (m, 1 H), 6.25 - 6.34 (m, 1 H), 6.56 - 6.72 (m, 1 H), 7.29 - 7.35 (m, 1 H), 7.29 - 7.34 (m, 1 H), 7.80 (dt, J = 8.88, 2.69 Hz, 1 H), 8.04 (dd, J = 9.01, 3.13 Hz, 1 H), 8.11 (d, J = 2.38 Hz, 1 H), 8.53 (s, 1 H). MS (ESI) m/z 508.3 [M+H]. [2033] Synthesis of Compound No.134: Synthesized according to general procedure C, wherein in step C.1 variant i and (S)-tert-butyl 3-(methylamino)pyrrolidine-1-carboxylate (1.50 g, 7.49 mmol, 1.01 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.5 3-chloro-4-((1-methyl-1H-tetrazol-5-yl)methoxy)aniline (158 mg, 660 umol, 1.20 eq) was used as HX
1-Y and in step C.6, variant i was used to give (S)-1-(3-((4-((3-chloro-4- ((1- methyl-1H-tetrazol-5-yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6- yl)(methyl)amino)pyrrolidin-1-yl)prop-2-en-1-one 134 in 30% overall yield from XXII.
1H NMR (400 MHz, CD
3OD) δ = 2.20 - 2.36 (m, 2 H), 3.14 (d, J = 5.00 Hz, 3 H), 3.49 - 3.81 (m, 2 H), 3.82 - 4.07 (m, 2 H), 4.26 (s, 3 H), 5.58 (s, 2 H), 5.77 (ddd, J = 15.73, 10.47, 2.06 Hz, 2 H), 6.32 (ddd, J = 16.79, 5.91, 1.94 Hz, 1 H), 6.67 (ddd, J = 16.79, 15.04, 10.44 Hz, 1 H), 7.28 (dd, J = 9.01, 1.38 Hz, 1 H), 7.43 (dd, J = 9.44, 3.06 Hz, 1 H), 7.73 (ddd, J = 8.91, 4.22, 2.63 Hz, 1 H), 7.89 (dd, J =
9.38, 2.00 Hz, 1 H), 8.09 (dd, J = 6.38, 2.50 Hz, 1 H), 8.37 (s, 1 H). MS (ESI) m/z 521.3 [M+H]. [2034] Synthesis of 3-chloro-4-((1-methyl-1H-tetrazol-5-yl)methoxy)aniline: To a solution of 2-chloro-1-fluoro-4-nitrobenzene (0.90 g, 5.13 mmol, 1.00 eq) and potassium carbonate (1.42 g, 10.3 mmol, 2.00 eq) in dimethyl formamide (15.0 mL) wsa added (1-methyl-1H-tetrazol-5-yl) methanol (878 mg, 7.69 mmol, 1.50 eq). The mixture was stirred at 60 °C for 4 h. The mixture was quenched by addition of water (30.0 mL), then extracted with ethyl acetate (3 × 50.0 mL). The combined organic phase was washed with brine (3 × 50.0 mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum to give compound 5-((2-chloro-4- nitrophenoxy)methyl)-1-methyl-1H-tetrazole (1.41 g, 4.96 mmol, 97% yield, 95% purity) was obtained as a yellow solid. To a solution of 5-((2-chloro-4-nitrophenoxy)methyl)-1-methyl-1H- tetrazole (700 mg, 2.60 mmol, 1.00 eq) and ammonium chloride (1.39 g, 26.0 mmol, 10.0 eq) in ethyl alcohol (8.00 mL) and water (2.00 mL) was added iron powder (435 mg, 7.79 mmol, 3.00 eq). The mixture was stirred at 80 °C for 1 h. The reaction mixture was added water (20.0 mL), then filtered through a pad of celite. The residue was washed with ethyl acetate (50.0 mL), then quenched by addition of hydrochloric acid (1.00 M, 10.0 mL). The filtrate extracted with ethyl acetate (2 × 20.0 mL). The combined organic phase was washed with brine (50.0 mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum to give 3-chloro-4-((1- methyl-1H- tetrazol-5-yl)methoxy)aniline (650 mg, 2.56 mmol, 99% yield, 94% purity) was obtained as a yellow solid.
1H NMR (400 MHz, CDCl
3) δ = 6.86 (d, J = 8.76 Hz, 1 H), 6.73 (d, J = 2.75 Hz, 1 H), 6.53 (dd, J = 8.63, 2.75 Hz, 1 H), 5.37 (s, 2 H), 4.24 (s, 3 H), 3.59 (br s, 2 H). MS (ESI) m/z 240.2 [M+H]. [2035] Synthesis of Compound No.135: Synthesized according to general procedure C, wherein in step C.1 variant ii and (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (3.62 g, 19.3 mmol, 1.30 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.5 3-chloro-4-((2-methyloxazol-5-yl)methoxy)aniline (168 mg, 705 umol, 1.20 eq) was used as HX
1- Y and in step C.6, variant i was used to give (S)-1-(3-((4-((3-chloro-4-((2-methyloxazol-5- yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one 135 in 11% overall yield from XXII.
1H NMR (400 MHz, CD
3OD) δ = 8.52 (s, 1H), 8.17 - 7.96 (m, 2H), 7.76 (td, J = 2.9, 8.9 Hz, 1H), 7.33 (dd, J = 4.1, 9.0 Hz, 1H), 7.24 (dd, J = 2.1, 8.9 Hz, 1H), 7.12 (s, 1H), 6.76 - 6.52 (m, 1H), 6.36 - 6.23 (m, 1H), 6.19 - 6.03 (m, 1H), 5.76 (ddd, J = 1.9, 10.5, 19.1 Hz, 1H), 5.18 (s, 2H), 3.99 - 3.88 (m, 2H), 3.88 - 3.78 (m, 1H), 3.76 - 3.61 (m, 1H), 2.49 (s,
3H), 2.46 - 2.28 (m, 2H). MS (ESI) m/z 507.2 [M+H]
+. [2036] Synthesis of Compound No. 136: : Synthesized according to general procedure C, wherein in step C.1 variant i and (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (1.52 g, 8.19 mmol, 1.10 eq) was used as BocN[(CR
aR
b)m(CR
cR
d)n]-X
2H, in step C.2 variant i was used and in step C.5 3-chloro-4-((1-methyl-1H-tetrazol-5-yl) methoxy)aniline (164 mg, 686 umol, 1.20 eq) was used as HX
1-Y and in step C.6, variant i was used to give (S)-1-(3-((4-((3- chloro-4-((1- methyl-1H-tetrazol-5-yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)amino)pyrrolidin- 1-yl)prop-2-en-1-one 136 in 12% overall yield from XXII.
1H NMR (400 MHz, MeOD) δ = 8.38 (s, 1H), 8.20 - 8.10 (m, 1H), 7.76 (br d, J = 1.5 Hz, 2H), 7.35 - 7.26 (m, 1H), 7.13 - 7.06 (m, 1H), 6.76 - 6.56 (m, 1H), 6.35 - 6.23 (m, 1H), 5.82 - 5.71 (m, 1H), 5.59 (s, 2H), 5.00 (quin, J = 5.7 Hz, 1H), 4.27 (s, 3H), 4.20 - 3.96 (m, 1H), 3.90 - 3.80 (m, 1H), 3.79 - 3.64 (m, 1H), 3.63 - 3.53 (m, 1H), 2.53 - 1.96 (m, 2H). MS (ESI) m/z 507.1 [M+H]
+. [2037] Synthesis of Compound No.137: Synthesized according to general procedure C, wherein in step C.1 variant i and (S)-tert-butyl 3-(methylamino)pyrrolidine-1-carboxylate (1.50 g, 7.49 mmol, 1.01 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.5 3-chloro-4-((5-(fluoromethoxy)pyrazin-2-yl)methoxy)aniline (156 mg, 550 umol, 1.00 eq) was used as HX
1-Y and in step C.6, variant i was used to give (S)-1-(3-((4-((3-chloro-4-((5- (fluoromethoxy)pyrazin-2-yl)methoxy)phenyl) amino)pyrido[3,2-d]pyrimidin-6- yl)(methyl)amino)pyrrolidin-1-yl)prop-2-en-1-one 137 in 2% overall yield from XXII.
1H NMR (400MHz, MeOD) δ = 8.46 (s, 1H), 8.39 - 8.30 (m, 2H), 8.21 (s, 1H), 8.03 (dd, J = 2.6, 4.8 Hz, 1H), 7.88 (dd, J = 2.0, 9.4 Hz, 1H), 7.67 (ddd, J = 2.6, 5.1, 8.8 Hz, 1H), 7.41 (dd, J = 3.0, 9.4 Hz, 1H), 7.25 - 7.11 (m, 1H), 6.66 (ddd, J = 10.5, 14.5, 16.8 Hz, 1H), 6.31 (ddd, J = 2.0, 6.1, 16.8 Hz, 1H), 6.21 - 5.97 (m, 2H), 5.88 - 5.62 (m, 2H), 5.27 (s, 2H), 4.09 - 3.81 (m, 2H), 3.79 - 3.49 (m, 2H), 3.14 (d, J = 4.6 Hz, 3H), 2.42 - 2.13 (m, 2H). MS (ESI) m/z 565.2 [M+H]. [2038] Synthesis of 3-chloro-4-((5-(fluoromethoxy)pyrazin-2-yl)methoxy)aniline: To a solution of ethyl 5-(fluoromethoxy)pyrazine-2-carboxylate (550 mg, 2.75 mmol, 1.00 eq) in tetrahydrofuran (15.0 mL) was added diisobutylaluminum hydride (1.00 M in toluene, 8.24 mL, 3.00 eq) at 0 °C, then the mixture was stirred at 25 °C for 2 h. The reaction mixture was added aqueous of potassium sodium tartrate tetrahydrate (10.0 mL) and filtered, the filtrate was extracted with dichloromethane (3 × 50.0 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by
silica gel chromatography (petroleum ether/ethyl acetate = 1/0 to 1/1) to afford (5- (fluoromethoxy)pyrazin-2-yl)methanol (240 mg, 1.52 mmol, 55% yield) as light yellow oil. A mixture of (5-(fluoromethoxy)pyrazin-2-yl)methanol (240 mg, 1.52 mmol, 1.00 eq), 2-chloro-1- fluoro-4-nitro-benzene (293 mg, 1.67 mmol, 1.10 eq) and potassium carbonate (419 mg, 3.04 mmol, 2.00 eq) in dimethyl formamide (3.00 mL) was stirred at 60 °C for 3 h. The reaction mixture was added water (20.0 mL), extracted with ethyl acetate (2 × 20.0 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give crude product. The crude product was purified by prep-TLC (petroleum ether/ethyl acetate = 3/1) to give 2-((2-chloro-4-nitrophenoxy) methyl)-5-(fluoromethoxy)pyrazine (410 mg, 1.29 mmol, 85% yield, 99% purity) as a yellow solid. A mixture of 2-((2-chloro-4-nitrophenoxy)methyl)-5- (fluoromethoxy)pyrazine (410 mg, 1.31 mmol, 1.00 eq) in ethyl alcohol (4.00 mL) and water (1.00 mL) was added ammonium chloride (699 mg, 13.1 mmol, 10.0 eq) and iron powder (219 mg, 3.92 mmol, 3.00 eq), then the mixture was stirred at 80 °C for 1 h. The reaction mixture was concentrated to remove solvent and added ethyl acetate (10.0 mL), the mixture was filtered and the filtrate was concentrated under reduced pressure to give 3-chloro-4-((5- (fluoromethoxy)pyrazine -2-yl)methoxy)aniline (330 mg, 1.16 mmol, 89% yield) as a yellow solid.
1H NMR (400 MHz, DMSO-d
6) δ = 8.48 (d, J = 1.25 Hz, 1 H), 8.42 (d, J = 0.75 Hz, 1 H), 6.97 (d, J = 8.76 Hz, 1 H), 6.64 (d, J = 2.63 Hz, 1 H), 6.47 (dd, J = 8.69, 2.69 Hz, 1 H), 6.02 - 6.23 (m, 2 H), 5.10 (s, 2 H), 4.98 (s, 2 H). [2039] Synthesis of Compound No.138: Synthesized according to general procedure C, wherein in step C.1 variant i and (S)-tert-butyl 3-(methylamino)pyrrolidine-1-carboxylate (1.50 g, 7.49 mmol, 1.01 eq) was used as BocN[(CR
aR
b)
m(CR
cR
d)
n]-X
2H, in step C.2 variant i was used and in step C.53-chloro-4-((6-(difluoromethyl) pyrazin-2-yl)methoxy)aniline (105 mg, 367 umol, 0.892 eq) was used as HX
1-Y and in step C.6, variant ii was used to give (S)-1-(3-((4-((3-chloro-4-((6- (difluoromethyl)pyrazin-2-yl)methoxy)phenyl)amino)pyrido[3,2-d]pyrimidin-6- yl)(methyl)amino)pyrrolidin-1-yl)prop-2-en-1-one 138 in 6% overall yield from XXII.
1H NMR (400 MHz, DMSO-d6) δ = 9.32 (d, J = 7.7 Hz, 1H), 9.06 (s, 1H), 8.99 (s, 1H), 8.41 (d, J = 0.9 Hz, 1H), 8.20 - 8.09 (m, 1H), 7.94 (d, J = 9.3 Hz, 1H), 7.90 - 7.81 (m, 1H), 7.48 (dd, J = 5.7, 9.3 Hz, 1H), 7.37 (d, J = 9.0 Hz, 1H), 7.18 (t, J = 54.0 Hz, 1H), 6.66 (ddd, J = 10.3, 15.1, 16.7 Hz, 1H), 6.18 (ddd, J = 2.4, 6.4, 16.8 Hz, 1H), 5.82 - 5.61 (m, 2H), 5.46 (s, 2H), 3.99 - 3.80 (m, 1H), 3.80 - 3.52 (m, 2H), 3.49 - 3.41 (m, 1H), 3.10 (d, J = 5.1 Hz, 3H), 2.23 - 2.07 (m, 2H). MS (ESI) m/z
567.2 [M+H]
+. [2040] Synthesis of 3-chloro-4-((6-(difluoromethyl) pyrazin-2-yl)methoxy)aniline: To a solution of methyl 6-chloropyrazine-2-carboxylate (15.0 g, 86.9 mmol, 1.00 eq) in water (100 mL) was added sodium borohydride (6.58 g, 173 mmol, 2.00 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h. Saturated potassium carbonate aqueous (50.0 mL) and ethanol (10.0 mL) was added to the mixture and then extracted with ethyl acetate (200 mL). The organic layer was separated and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 5/1) to give (6-chloropyrazin-2-yl)methanol (3.80 g, 26.3 mmol, 30% yield) as a white solid. To a solution of (6-chloropyrazin-2-yl)methanol (3.60 g, 24.9 mmol, 1.00 eq) in dichloromethane (100 mL) was added dess-martin periodinane (20.0 g, 47.1 mmol, 1.89 eq). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 10/1) to give 6-chloropyrazine-2- carbaldehyde (2.10 g, 14.7 mmol, 59% yield) as yellow liquid. To a solution of 6-chloropyrazine- 2-carbaldehyde (2.10 g, 14.7 mmol, 1.00 eq) in methanol (50.0 mL) was added triethylamine (1.60 g, 15.8 mmol, 1.07 eq), 1,1’-bis(diphenylphosphino)ferrocene (800 mg, 1.44 mmol, 0.100 eq) and tetrakis(triphenylphosphine)palladium (850 mg, 735 umol, 0.050 eq). The mixture was stirred at 60 °C for 16 h under carbon monoxide (50 Psi). After being cooled to room temperature, the mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 10/1) to give methyl 6-formylpyrazine-2-carboxylate (2.06 g, 12.4 mmol, 84% yield) as a yellow liquid. To a solution of methyl 6-formylpyrazine-2-carboxylate (2.06 g, 12.4 mmol, 1.00 eq) in dichloromethane (50.0 mL) was added diethylaminosulfur trifluoride (4.03 g, 25.0 mmol, 3.30 mL, 2.01 eq). The mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with saturated sodium bicarbonate at 0 °C. The organic layer was separated and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 20/1) to give methyl 6-(difluoromethyl)pyrazine-2- carboxylate (1.50 g, 7.97 mmol, 64% yield) as a white solid. To a solution of methyl 6- (difluoromethyl)pyrazine-2-carboxylate (500 mg, 2.66 mmol, 1.00 eq) in water (20.0 mL) was added sodium borohydride (202 mg, 5.34 mmol, 2.01 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was extracted with ethyl acetate (2 × 50 mL). The organic layer
was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 5/1) to give (6- (difluoromethyl)pyrazin- 2-yl)methanol (360 mg, 2.25 mmol, 85% yield) as a white solid. To a solution of (6-(difluoromethyl)pyrazin-2-yl)methanol (340 mg, 2.12 mmol, 1.00 eq) in dimethyl formamide (2.00 mL) was added potassium carbonate (884 mg, 6.40 mmol, 3.01 eq) and 2-chloro- 1-fluoro -4-nitro-benzene (373 mg, 2.12 mmol, 1.00 eq). The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with ethyl acetate (100 mL) and water (50 mL). The organic layer was separated and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 10/1 to 5/1) to give 2-((2-chloro-4- nitrophenoxy)methyl)-6-(difluoromethyl)pyrazine (400 mg, 1.27 mmol, 60% yield) as a white solid.
1H NMR (400 MHz, CDCl
3) δ = 9.13 (s, 1H), 8.97 (s, 1H), 8.39 (d, J = 2.8 Hz, 1H), 8.22 (dd, J = 2.4 Hz, 9.2 Hz, 1H), 7.14 (d, J = 3.0 Hz, 1H), 6.73 (t, J = 54.4 Hz, 1H). To a solution of 2-((2-chloro-4-nitrophenoxy)methyl)-6-(difluoromethyl)pyrazine (150 mg, 475 umol, 1.00 eq) in dichloromethane (5.00 mL) and methanol (10.0 mL) was added nickel(II) chloride hexahydrate (200 mg, 841 umol, 1.77 eq) and sodium borohydride (70.0 mg, 1.85 mmol, 3.89 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure. The residue was triturated with dichloromethane (50.0 mL). After filtration, the filtrate was concentrated under reduced pressure to give 3-chloro-4-((6-(difluoromethyl)pyrazin- 2-yl)methoxy)aniline (105 mg, crude) as a yellow solid. MS (ESI) m/z 286.0[M+H]
+. Synthesis of Compound No. 139: 4-((6-((1-Acryloylazetidin-3-yl)amino)pyrimido[5,4- d]pyrimidin-4-yl)amino)-N-methylbenzamide
[2041] Step 1. A mixture of 2,8-dichloropyrimido[5,4-d]pyrimidine (300 mg, 1.49 mmol, 1.00 eq)
and 4-amino-N-methylbenzamide (134 mg, 895 μmol, 0.60 eq) in acetonitrile (10 mL) was stirred at 25 °C for 2 h under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to give 4-((6-chloropyrimido[5,4-d]pyrimidin-4-yl)amino)-N-methylbenzamide (380 mg, crude) as a gray solid that was used directly without further purification. MS (ESI) m/z 315.2 [M+H]
+ [2042] Step 2. A mixture of 4-((6-chloropyrimido[5,4-d]pyrimidin-4-yl)amino)-N- methylbenzamide (360 mg, 1.14 mmol, 1.00 eq), tert-butyl 3-aminoazetidine-1-carboxylate (256 mg, 1.49 mmol, 1.30 eq), and N,N-diisopropylethylamine (444 mg, 3.43 mmol, 598 μL, 3.00 eq) in propan-2-ol (10 mL) was stirred at 90 °C for 12 h under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase flash chromatography (0.1% formic acid) to give tert-butyl 3-((8-((4- (methylcarbamoyl)phenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)amino)azetidine-1-carboxylate (41.0 mg, 91.0 μmol, 7%) as a yellow solid.
1H NMR (400 MHz, CDCl
3) δ 9.11 (s, 1H), 8.74 (s, 1H), 8.68 (s, 1H), 8.01 (d, J = 8.8 Hz, 2H), 7.87 (d, J = 8.8 Hz, 2H), 6.15 (br. s, 1H), 6.02 - 5.79 (m, 1H), 4.85- 4.75 (m, 1H), 4.44 (t, J = 8.4 Hz, 2H), 4.07 – 3.97 (m, 2H), 3.07 (d, J = 4.8 Hz, 3H), 1.49 (s, 9H). [2043] Step 3. To a solution of tert-butyl 3-((8-((4-(methylcarbamoyl)phenyl)amino)- pyrimido[5,4-d] pyrimidin-2-yl)amino) azetidine-1-carboxylate (37.0 mg, 82.1 μmol, 1.00 eq) in dichloromethane (1 mL) was added trifluoroacetic acid (308 mg, 2.70 mmol, 0.2 mL) at 0 °C and the mixture was stirred at 25 °C for 2 h. The mixture was concentrated under vacuum to give 4- ((6-(azetidin-3-ylamino)pyrimido[5,4-d]pyrimidin-4-yl)amino)-N-methylbenzamide (40.0 mg, crude, trifluoroacetic acid) as a brown oil, which was used in the next step without further purification. MS (ESI) m/z 351.1 [M+H]
+ [2044] Step 4. To a solution of 4-((6-(azetidin-3-ylamino)pyrimido[5,4-d]pyrimidin-4-yl)amino)- N-methylbenzamide (35.0 mg, 75.4 μmol, 1.00 eq, trifluoroacetic acid salt) in dimethylformamide (0.7 mL) was added triethylamine (30.5 mg, 301 μmol, 42.0 μL, 4.00 eq) at 0 °C, followed by the dropwise addition of acrylic anhydride (8.08 mg, 64.1 μmol, 0.85 eq) in dimethylformamide (0.1 mL) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. The mixture was diluted with acetonitrile (1 mL) to afford a solution. The solution was purified by prep-HPLC (column: Xtimate C18 150*25mm*5um;mobile phase: [water (0.05% ammonia hydroxide v/v)-acetonitrile]; B%: 8%- 38%,10min) to give 4-((6-((1-acetylazetidin-3-yl)amino)pyrimido[5,4-d]pyrimidin-4-yl)amino)-
N-methylbenzamide (13 mg, 32.1 μmol, 42%, 100% purity) as a yellow solid. MS (ESI) m/z 405.3 [M+H]
+;
1H NMR (400 MHz, DMSO-d
6) δ 9.47 (s, 1H), 9.10 (s, 1H), 8.62 (br. s, 1H), 8.52 (s, 1H), 8.44 - 8.32 (m, 1H), 8.09 (d, J = 8.8 Hz, 2H), 7.90 (d, J = 8.8 Hz, 2H), 6.38 (dd, J = 10.0, 16.8 Hz, 1H), 6.14 (dd, J = 2.4, 16.8 Hz, 1H), 5.75 - 5.64 (m, 1H), 5.20 – 5.10 (m, 1H), 4.69 (t, J = 8.4 Hz, 1H), 4.38 (t, J = 8.8 Hz, 1H), 4.19 (dd, J = 5.6, 8.4 Hz, 1H), 4.01 (dd, J = 6.0, 10.0 Hz, 1H), 2.80 (d, J = 4.4 Hz, 3H). Synthesis of Compound No. 140: 1-(3-((8-((3-Chloro-2-fluorophenyl)amino)pyrimido[5,4- d]pyrimidin-2-yl)(methyl)amino)azetidin-1-yl)prop-2-en-1-one
[2045] Step 1. A mixture of 4,6-dichloropyrimido[5,4-d]pyrimidine (730 mg, 3.63 mmol, 1.00 eq) and 3-chloro-2-fluoro-aniline (476 mg, 3.27 mmol, 0.90 eq) in propan-2-ol (15 mL) was stirred at 80 °C for 1 h. The mixture was concentrated under vacuum. The residue was purified by reverse- phase flash chromatography (formic acid condition) to give 6-chloro-N-(3-chloro-2-fluoro- phenyl)pyrimido[5,4-d]pyrimidin-4-amine (180 mg, 15%, 97% purity) as a yellow solid. MS (ESI) m/z 310.1 [M+H]
+. [2046] Step 2. A mixture of 6-chloro-N-(3-chloro-2-fluoro-phenyl)pyrimido[5,4-d]pyrimidin-4- amine (150 mg, 484 μmol, 1.00 eq), tert-butyl 3-(methylamino)azetidine-1-carboxylate (99.1 mg, 532 μmol, 1.10 eq) and diisopropylethylamine (156 mg, 1.21 mmol, 211 μL, 2.50 eq) in propan- 2-ol (2.50 mL) was stirred at 80 °C for 1 h. The mixture was cooled to 25 °C while stirring. The mixture was filtered and the filter cake then dried to give tert-butyl 3-((8-((3-chloro-2- fluorophenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)(methyl)amino)azetidine-1-carboxylate (175
mg, 74%, 94% purity) as a yellow solid. MS (ESI) m/z 460.1 [M+H]
+ [2047] Step 3. To a solution of tert-butyl 3-((8-((3-chloro-2-fluorophenyl)amino)pyrimido[5,4- d]pyrimidin-2-yl)(methyl) amino)azetidine-1-carboxylate (175 mg, 381 μmol, 1.00 eq) in dichloromethane (3.50 mL) was added trifluoroacetic acid (0.7 mL) dropwise at 0 °C. The mixture was stirred at 25 °C for 6 h. The mixture was concentrated to give 3-((8-((3-chloro-2- fluorophenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)(methyl)amino)azetidine-1-carboxylic acid (320 mg, crude, trifluoroacetic acid salt) as a brown solid. MS (ESI) m/z 360.0 [M+H]
+ [2048] Step 4. To a mixture of 3-((8-((3-chloro-2-fluorophenyl)amino)pyrimido[5,4-d]pyrimidin- 2-yl)(methyl)amino)azetidine-1-carboxylic acid (270 mg, 570 μmol, 1.00 eq, trifluoroacetic acid salt) and triethylamine (173 mg, 1.71 mmol, 238 μL, 3.00 eq) in dimethylformamide (5mL) was added prop-2-enoyl chloride (51.6 mg, 570 μmol, 46.5 μL, 1.00 eq). The mixture was then stirred at 25 °C for 0.5 h. The mixture was filtered, and the filtrate concentrated in vacuo then purified firstly by prep-HPLC (formic acid condition) and then by prep-TLC (silica, ethyl acetate/methanol = 10/1) to give 1-(3-((8-((3-chloro-2-fluorophenyl)amino)pyrimido[5,4-d]pyrimidin-2- yl)(methyl)amino)azetidin-1-yl)prop-2-en-1-one (5 mg, 10.7 μmol, 2%, 98% purity, formic acid salt) as a white solid. MS (ESI) m/z 414.0 [M+H]
+;
1H NMR (400 MHz, DMSO-d
6) δ 8.63 - 8.54 (m, 1H), 8.44 - 8.36 (m, 1H), 8.35 – 8.25 (m, 1H), 8.24 (s, 1H), 7.24 (d, J = 6.8 Hz, 2H), 6.59 - 6.51 (m, 1H), 6.33 - 6.23 (m, 1H), 6.17 - 6.10 (m, 1H), 5.65 – 5.05 (m 1H), 3.70 - 3.49 (m, 4H), 3.48 – 3.42 (m, 1H), 3.03 - 2.94 (m, 3H). Synthesis of Compound No. 141: (S)-1-(3-((8-((3,4-Dichloro-2-fluorophenyl)amino)- pyrimido[5,4-d]pyrimidin-2-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one
[2049] Step 1. Liquid ammonia (10.0 g, 587 mmol, 23.9 eq) was dissolved in ethanol (200 mL) at -30 °C to give a solution. Then ethyl 5-amino-2-chloropyrimidine-4-carboxylate (5.00 g, 24.8 mmol, 1.00 eq) was added and the mixture was stirred at 100 °C for 12 h in a sealed tube. After being cooled to room temperature, the mixture was concentrated under reduced pressure to give 5-amino-2- chloropyrimidine-4-carboxamide (4.20 g, crude) as a brown solid which was used directly in the next step. [2050] Step 2. A suspension of 5-amino-2-chloropyrimidine-4-carboxamide (4.20 g, 24.3 mmol, 1.00 eq) in triethoxymethane (44.6 g, 301 mmol, 50 mL, 12.3 eq) was heated to 150 °C and stirred for 24 h. After being cooled to room temperature, the mixture was triturated with petroleum ether (200 mL) and stirred at 25 °C for 1 h. The product was collected by filtration and dried under vacuum to give 6-chloropyrimido[5,4-d]pyrimidin-4-ol (4.10 g, crude) as a brown solid which was used directly in the next step.
1H NMR (400 MHz, DMSO-d
6) δ 9.31 (s, 1H), 8.30 (s, 1H). [2051] Step 3. To a solution of 6-chloropyrimido[5,4-d]pyrimidin-4-ol (4.10 g, 22.4 mmol, 1.00 eq) in thionyl chloride (100 mL) was added dimethylformamide (410 mg, 5.62 mmol, 431 μL, 0.25 eq). The mixture was stirred at 100 °C for 16 h. The mixture was concentrated under reduced pressure to give 2,8-dichloropyrimido[5,4- d]pyrimidine (5.60 g, crude) as a brown solid which was used directly in the next step. [2052] Step 4. To a solution of 2,8-dichloropyrimido[5,4-d]pyrimidine (5.60 g, 27.9 mmol, 1.00 eq) in propan-2-ol (150 mL) was added 3,4-dichloro-2-fluoroaniline (5.1 g, 28.3 mmol, 1.02 eq).
The mixture was stirred at 80 °C for 1 h. The mixture was concentrated under reduced pressure, then the residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 5/1 to 3/1) to give 6-chloro-N-(3,4-dichloro-2-fluorophenyl)pyrimido[5,4-d]pyrimidin-4-amine (3.20 g, 9.29 mmol, 33%) as a brown solid. MS (ESI) m/z 344.0 [M+H]
+;
1H NMR (400 MHz, DMSO-d
6) δ 10.67 (s, 1H), 9.51 (s, 1H), 8.73 (s, 1H), 7.72 - 7.66 (m, 1H), 7.64 - 7.60 (m, 1H). [2053] Step 5. To a solution of 6-chloro-N-(3,4-dichloro-2-fluoro-phenyl)pyrimido[5,4- d]pyrimidin-4-amine (3.20 g, 9.29 mmol, 1.00 eq) in propan-2-ol (100 mL) was added tert-butyl (3S)-3-aminopyrrolidine-1-carboxylate (2.10 g, 11.3 mmol, 1.21 eq) and diisopropylethylamine (3.71 g, 28.7 mmol, 5mL, 3.09 eq). The mixture was stirred at 90 °C for 16 h. After being cooled to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1/1 to 0/1) to give (S)-tert- butyl 3-((8-((3,4-dichloro-2-fluorophenyl)amino)pyrimido[5,4-d] pyrimidin-2-yl)amino)- pyrrolidine-1-carboxylate (4.40 g, 8.90 mmol, 95%) as a brown solid. MS (ESI) m/z 494.1 [M+H]
+ [2054] Step 6. To a solution of (S)-tert-butyl 3-((8-((3,4-dichloro-2- fluorophenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl) amino)pyrrolidine-1-carboxylate (2.40 g, 4.85 mmol, 1.00 eq) in dichloromethane (20 mL) was added trifluoroacetic acid (3.70 g, 32.4 mmol, 2.40 mL). The mixture was stirred at 25 °C for 12 h. The mixture was concentrated under reduced pressure to give (S)-N
8-(3,4-dichloro-2-fluorophenyl)-N
2-(pyrrolidin-3-yl)pyrimido[5,4- d]pyrimidine-2,8-diamine (2.80 g, crude, trifluoroacetic acid salt) as a brown oil, which was used directly in the next step. MS (ESI) m/z 394.0 [M+H]
+ [2055] Step 7. To a solution of (S)-N
8-(3,4-dichloro-2-fluorophenyl)-N
2-(pyrrolidin-3- yl)pyrimido[5,4-d]pyrimidine-2,8-diamine (2.80 g, 5.51 mmol, 1.00 eq, trifluoroacetic acid) in dimethylformamide (10 mL) was added diisopropylethylamine (3.71 g, 28.7 mmol, 5 mL, 5.21 eq) and acryloyl chloride (600 mg, 6.63 mmol, 540 μL, 1.20 eq). The mixture was stirred at 25 °C for 10 min, then it was diluted with ethyl acetate (300 mL) and water (200 mL). The organic layer was separated and concentrated under reduced pressure. The residue was purified by column chromatography (silica, ethyl acetate / methanol = 1/0 to 10/1) to give a the mostly pure product. This was dissolved in methanol (100 mL) and ethyl acetate (30 mL) at 80 °C. The solution was cooled to room temperature, and the solid that precipitated was collected by filtration and dried in vacuo to give (S)-1-(3-((8-((3,4-dichloro-2- fluorophenyl)amino)pyrimido[5,4-d]pyrimidin-2- yl)amino)pyrrolidin-1-yl)prop-2-en-1-one (0.948 g, 2.07 mmol, 44%,98% purity) as a yellow solid.
MS (ESI) m/z 448.0 [M+H]
+;
1H NMR (400 MHz, DMSO-d
6) δ 9.55 (br. dd, J = 2.4, 6.0 Hz, 1H), 9.09 (br. s, 1H), 8.43 (br. s, 1H), 8.38 - 8.22 (m, 1H), 8.06 (br. d, J = 2.4 Hz, 1H), 7.61 (br. d, J = 8.8 Hz, 1H), 6.70 - 6.51 (m, 1H), 6.15 (td, J = 2.0, 16.4 Hz, 1H), 5.79 - 5.56 (m, 1H), 4.81 - 4.60 (m, 1H), 4.14 - 3.99 (m, 0.5H), 3.87 - 3.76 (m, 1H), 3.72 - 3.62 (m, 1H), 3.54 - 3.44 (m, 1.5H), 2.33 - 2.18 (m, 1H), 2.13 - 1.95 (m, 1H). Synthesis of Compound No. 142: 1-(3-((4-(3,4-dichloro-2-fluorophenoxy)pyrido[3,2- d]pyrimidin-6-yl)amino)-3-methylazetidin-1-yl)prop-2-en-1-one
[2056] Step 1. To a solution of tert-butyl 3-((4-chloropyrido[3,2-d]pyrimidin-6-yl)amino)-3- methylazetidine-1-carboxylate (150 mg, 428 μmol, 1.00 eq) and 3,4-dichloro-2-fluoro-phenol (77.6 mg, 428 μmol, 1.00 eq) in propan-2-ol (2 mL) was added N,N-diisopropylethylamine (166 mg, 1.29 mmol, 224 μL, 3.00 eq) at 25 °C. The mixture was stirred at 90 °C for 24 h. The residue was poured into water (80 mL) and stirred for 10 min. Then the aqueous phase was extracted with ethyl acetate (3 × 50 mL). The combined organic phase was washed with brine (90 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give tert-butyl 3-((4-(3,4-dichloro- 2-fluorophenoxy)pyrido[3,2-d]pyrimidin-6-yl)amino)-3-methylazetidine -1-carboxylate (200 mg, crude) as a yellow solid. MS (ESI) m/z 494.0 [M+H]
+ [2057] Step 2. To a solution of tert-butyl 3-((4-(3,4-dichloro-2-fluorophenoxy)pyrido[3,2- d]pyrimidin-6-yl)amino)-3- methylazetidine-1-carboxylate (200 mg, 404 μmol, 1.00 eq) in dichloromethane (2 mL) was added trifluoroacetic acid (616 mg, 5.40 mmol, 0.4 mL) at 25 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated to give a residue. The residue was purified by reverse-phase HPLC (0.1% formic acid condition) to afford 4-(3,4- dichloro-2-fluoro-phenoxy)-N-(3-methylazetidin-3-yl)pyrido[3,2-d]pyrimidin-6-amine (50.0 mg,
28%, formic acid salt) as a yellow solid. MS (ESI) m/z 394.0 [M+H]
+ [2058] Step 3. To a solution of 4-(3,4-dichloro-2-fluoro-phenoxy)-N-(3-methylazetidin-3- yl)pyrido[3,2-d]pyrimidin-6-amine (50.0 mg, 126 μmol, 1.00 eq) and triethylamine (38.5 mg, 380 μmol, 52.9 μL, 3.00 eq) in dimethylformamide (1 mL) was added prop-2-enoyl chloride (12.6 mg, 139 μmol, 11.4 μL, 1.10 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h. Then the reaction mixture was filtered. The filtrate was purified by prep-HPLC (column: Waters Xbridge 150*25mm*5um;mobile phase: [water (0.05% ammonia hydroxide v/v)-acetonitrile];B%: 34%- 54%,10min) to afford 1-(3-((4-(3,4-dichloro-2-fluorophenoxy)pyrido[3,2-d] pyrimidin-6- yl)amino)-3-methylazetidin-1-yl)prop-2-en-1-one (5.2 mg, 11.6 μmol, 9%) as a yellow solid. MS (ESI) m/z 448.1 [M+H]
+;
1H NMR (400 MHz, CDCl
3) δ 8.18 (s, 1H), 7.32 - 7.29 (m, 1H), 7.20 (s, 1H), 7.12 (dd, J = 7.6, 8.8 Hz, 1H), 6.91 - 6.87 (m, 1H), 6.24 - 6.16 (m, 1H), 6.07 - 6.00 (m, 1H), 6.00 - 5.95 (m, 1H), 5.56 (dd, J = 1.2, 10.2 Hz, 1H), 4.28 (d, J = 11.6 Hz, 1H), 4.15 (d, J = 11.6 Hz, 1H), 3.60 (dd, J = 7.2, 13.6 Hz, 1H), 3.36 (dd, J = 7.2, 13.6 Hz, 1H), 1.32 (s, 3H). Synthesis of Compound No. 143: (S)-1-(3-((8-(3,4-Dichloro-2-fluorophenoxy)pyrimido[5,4- d]pyrimidin-2-yl)(methyl)amino)pyrrolidin-1-yl)prop-2-en-1-one
[2059] Step 1. To a solution of 6-chloropyrimido[5,4-d]pyrimidin-4-ol (500 mg, 2.74 mmol, 1.00 eq) in dimethylformamide (8 mL) was added diisopropylethylamine (1.11 g, 8.61 mmol, 1.50 mL, 3.14 eq) and tert-butyl (3S)-3-(methylamino)pyrrolidine-1-carboxylate (800 mg, 3.99 mmol, 1.46 eq). The mixture was stirred at 130 °C for 2 h. After being cooled to 25 °C, the mixture was concentrated under vacuum to give a residue, which was purified by column chromatography (silica, petroleum ether / ethyl acetate = 1/1 to 0/1) to give (S)-tert-butyl 3-((8- hydroxypyrimido[5,4-d]pyrimidin-2-yl)(methyl)amino)pyrrolidine-1-carboxylate (610 mg, 1.76 mmol, 64%) as a yellow solid. MS (ESI) m/z 247.1; [M+H-100]
+;
1H NMR (400 MHz, DMSO-
d
6) δ 12.45 (br. s, 1H), 8.95 (s, 1H), 7.90 (s, 1H), 5.47 - 5.20 (m, 1H), 3.59 - 3.40 (m, 2H), 3.28 (br. d, J = 8.4 Hz, 1H), 3.24 - 3.18 (m, 1H), 3.10 (s, 3H), 2.18 - 2.00 (m, 2H), 1.40 (br. s, 9H). [2060] Step 2. To a solution of (S)-tert-butyl 3-((8-hydroxypyrimido[5,4-d]pyrimidin-2- yl)(methyl)amino)pyrrolidine-1- carboxylate (300 mg, 866 μmol, 1.00 eq) in toluene (20 mL) was added diisopropylethylamine (559 mg, 4.33 mmol, 754 μL, 5.00 eq) and phosphorus trichloride (399 mg, 2.60 mmol, 242 μL, 3.01 eq) under nitrogen. The mixture was stirred at 100 °C for 2 h. After being cooled to 25 °C, the reaction mixture was quenched with saturated sodium bicarbonate solution (100 mL) and extracted with ethyl acetate (3 × 80 mL). The organic layer was separated and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under vacuum to give (S)-tert-butyl 3-((8-chloropyrimido[5,4-d]pyrimidin-2-yl) (methyl)amino)- pyrrolidine-1-carboxylate (315 mg, crude) as a brown oil. This was used directly in the next step without further purification. MS (ESI) m/z 309.0 [M+H-56]
+ [2061] Step 3. To a solution of (S)-tert-butyl 3-((8-chloropyrimido[5,4-d]pyrimidin-2- yl)(methyl)amino)pyrrolidine-1-carboxylate (315 mg, 863 μmol, 1.00 eq) in propan-2-ol (15 mL) was added diisopropylethylamine (335 mg, 2.59 mmol, 451 μL, 3.00 eq) and 3,4-dichloro-2- fluorophenol (187 mg, 1.03 mmol, 1.20 eq). The mixture was stirred at 90 °C for 2 h. After being cooled to 25 °C, the mixture was concentrated under vacuum to give a residue, which was purified by column chromatography (silica, petroleum ether/ethyl acetate = 3/1 to 0/1) to give (S)-tert-butyl 3-((8-(3,4-dichloro-2-fluorophenoxy)pyrimido[5,4-d]pyrimidin-2-yl)(methyl)amino)pyrrolidine- 1-carboxylate (240 mg, 471 μmol, 54%) as a yellow solid. MS (ESI) m/z 453.1 [M+H-56]
+;
1H NMR (400 MHz, DMSO-d
6) δ 9.36 (s, 1H), 8.55 (s, 1H), 7.71 - 7.66 (m, 1H), 7.64 - 7.58 (m, 1H), 5.51 - 5.35 (m, 1H), 3.63 - 3.46 (m, 2H), 3.31 - 3.25 (m, 2H), 3.19 (s, 3H), 2.22 - 2.04 (m, 2H), 1.41 (br. s, 9H). [2062] Step 4. To a solution of (S)-tert-butyl 3-((8-(3,4-dichloro-2-fluorophenoxy)pyrimido[5,4- d]pyrimidin-2-yl)(methyl) amino)pyrrolidine-1-carboxylate (200 mg, 393 μmol, 1.00 eq) in dichloromethane (10 mL) was added trifluoroacetic acid (2.31 g, 20.3 mmol, 1.50 mL). The mixture was stirred at 25 °C for 2 h. The mixture was concentrated under vacuum to give (S)-8- (3,4-dichloro-2-fluorophenoxy)-N-methyl-N-(pyrrolidin-3-yl)pyrimido[5,4-d]pyrimidin-2-amine (100 mg, crude, trifluoroacetate salt) as a yellow solid. MS (ESI) m/z 409.1 [M+H]
+ [2063] Step 5. To a solution of (S)-8-(3,4-dichloro-2-fluorophenoxy)-N-methyl-N-(pyrrolidin-3- yl)pyrimido[5,4-d] pyrimidin-2-amine (40.0 mg, 76.4 μmol, 1.00 eq) in dimethylformamide (2 mL)
was added diisopropylethylamine (30.0 mg, 229 μmol, 40.0 μL, 3.00 eq) and acryloyl chloride (11.1 mg, 123 μmol, 10.0 μL, 1.60 eq). The mixture was stirred at 25 °C for 10 min. The mixture was then filtered and the filtrate was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10um; mobile phase: [water(0.225% formic acid)-acetonitrile];B%: 53%-83%, 10 min) to give (S)-1-(3-((8-(3,4-dichloro-2-fluorophenoxy)pyrimido[5,4-d]pyrimidin-2-yl)(methyl)- amino)pyrrolidin-1-yl)prop-2-en-1-one (3.83 mg, 8.10 μmol, 11%, 98% purity, formate salt) as a yellow solid. MS (ESI) m/z 463.1 [M+H]
+;
1H NMR (400 MHz, DMSO-d
6) δ 9.37 (d, J = 3.6 Hz, 1H), 8.56 (d, J = 3.2 Hz, 1H), 7.74 - 7.54 (m, 2H), 6.61 (ddd, J = 10.4, 14.4, 16.8 Hz, 1H), 6.16 (td, J = 2.8, 16.8 Hz, 1H), 5.68 (dt, J = 2.3, 10.4 Hz, 1H), 5.60 - 5.35 (m, 1H), 3.95 - 3.80 (m, 1H), 3.79 - 3.59 (m, 2H), 3.47 - 3.38 (m, 1H), 3.20 (d, J = 2.8 Hz, 3H), 2.30 - 2.19 (m, 1H), 2.19 - 2.09 (m, 1H). Synthesis of Compound No. 144: (S)-1-(3-((8-(3,4-Dichloro-2-fluorophenoxy)pyrimido[5,4- d]pyrimidin-2-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one
[2064] Step 1. A mixture of 5-amino-2-chloropyrimidine-4-carboxamide (2.00 g, 11.6 mmol, 1.00 eq) in triethoxymethane (17.8 g, 120 mmol, 20 mL, 10.4 eq) was stirred at 150 °C for 8 h. After being cooled to 25 °C, the mixture was concentrated under reduced pressure to give a residue, which was triturated with ethyl acetate (10 mL) for 30 min. The suspension was filtered and the filter cake was washed with ethyl acetate (3 × 10 mL), then dried to give 6-chloropyrimido[5,4- d]pyrimidin-4-ol (1.60 g, 8.76 mmol, 76%) as a brown solid.
1H NMR (400 MHz, DMSO-d
6) δ
13.69 - 11.55 (m, 1H), 9.31 (s, 1H), 8.29 (s, 1H). [2065] Step 2. To a mixture of 6-chloropyrimido[5,4-d]pyrimidin-4-ol (400 mg, 2.19 mmol, 1.00 eq) in dimethylformamide (5 mL) was added diisopropylethylamine (850 mg, 6.58 mmol, 1.15 mL, 3.00 eq) and (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (530 mg, 2.85 mmol, 1.30 eq). The mixture was stirred at 130 °C for 12 h. After being cooled to 25 °C, the mixture was concentrated under reduced pressure to give a residue, which was purified by reverse-phase HPLC (0.1% formic acid condition) to give (S)-tert-butyl 3-((8-hydroxypyrimido[5,4-d]pyrimidin-2- yl)amino) pyrrolidine-1-carboxylate (380 mg, 1.14 mmol, 52%) as a yellow solid. MS (ESI) m/z 333.1 [M+H]
+ [2066] Step 3. To a solution of (S)-tert-butyl 3-((8-hydroxypyrimido[5,4-d]pyrimidin-2- yl)amino)pyrrolidine-1-carboxylate (380 mg, 1.14 mmol, 1.00 eq) in toluene (5mL) was added diisopropylethylamine (742 mg, 5.74 mmol, 1 mL, 5.02 eq) and phosphoryl trichloride (527 mg, 3.44 mmol, 319 μL, 3.01 eq) under nitrogen. The mixture was stirred at 100 °C for 2 h. After being cooled to room temperature, the reaction mixture was quenched with saturated sodium bicarbonate solution (100 mL) and extracted with ethyl acetate (3 × 80 mL). The organic layer was separated and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give (S)-tert-butyl 3-((8-chloropyrimido[5,4-d]pyrimidin- 2- yl)amino)pyrrolidine-1-carboxylate (400 mg, crude) as a brown oil. MS (ESI) m/z 294.8 [M+H- 56]
+ [2067] Step 4. To a solution of (S)-tert-butyl 3-((8-chloropyrimido[5,4-d]pyrimidin-2- yl)amino)pyrrolidine-1-carboxylate (400 mg, 1.14 mmol, 1.00 eq) in propan-2-ol (8 mL) was added diisopropylethylamine (440 mg, 3.40 mmol, 593 μL, 2.99 eq) and 3,4-dichloro-2- fluorophenol (245 mg, 1.35 mmol, 1.19 eq). The mixture was stirred at 90 °C for 2 h. After being cooled to room temperature, the mixture was concentrated under reduced pressure to give a residue, which was purified by column chromatography (silica, petroleum ether/ethyl acetate = 5/1 to 0/1) to give (S)-tert-butyl 3-((8-(3,4-dichloro-2-fluorophenoxy)pyrimido [5,4-d]pyrimidin-2- yl)amino)pyrrolidine-1-carboxylate (300 mg, 606 μmol, 53%) as a yellow solid. MS (ESI) m/z 495.1 [M+H]
+;
1H NMR (400 MHz, DMSO-d
6) δ 9.38 - 9.21 (m, 1H), 8.56 - 8.44 (m, 2H), 7.69 - 7.64 (m, 1H), 7.63 - 7.53 (m, 1H), 4.48 (br. s, 1H), 4.28 - 3.97 (m, 1H), 3.67 (br. s, 1H), 3.59 (br. s, 1H), 3.21 (br. dd, J = 4.8, 10.7 Hz, 1H), 2.16 (br. d, J = 6.2 Hz, 1H), 2.02 - 1.88 (m, 1H), 1.38 (br. d, J = 7.8 Hz, 9H).
[2068] Step 5. To a solution of (S)-tert-butyl 3-((8-(3,4-dichloro-2-fluorophenoxy)pyrimido[5,4- d]pyrimidin-2-yl)amino) pyrrolidine-1-carboxylate (100 mg, 202 μmol, 1.00 eq) in dichloromethane (5 mL) was added trifluoroacetic acid (308 mg, 2.70 mmol, 0.2 mL). The mixture was stirred at 25 °C for 2 h. The mixture was concentrated under vacuum to give (S)-8-(3,4- dichloro-2-fluorophenoxy)-N-(pyrrolidin-3-yl) pyrimido[5,4-d]pyrimidin-2-amine (100 mg, crude) as a yellow solid. MS (ESI) m/z 395.2 [M+H]
+ [2069] Step 6. To a solution of (S)-8-(3,4-dichloro-2-fluorophenoxy)-N-(pyrrolidin-3- yl)pyrimido[5,4-d]pyrimidin-2-amine (100 mg, 196 μmol, 1.00 eq) in dimethylformamide (2 mL) was added diisopropylethylamine (76.4 mg, 591 μmol, 103 μL, 3.01 eq) and acryloyl chloride (22.2 mg, 245 μmol, 20.0 μL, 1.25 eq). The mixture was stirred at 25 °C for 10 min. The suspension was dissolved in dimethylformamide (2 mL) and purified by prep-HPLC (column: Phenomenex Synergi C18150*25*10um; mobile phase: [water (0.225%formic acid)-acetonitrile]; B%: 38%-68%, 10 min) to give (S)-1-(3-((8-(3,4-dichloro-2-fluorophenoxy)pyrimido[5,4- d]pyrimidin-2-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one (14.83 mg, 29.3 μmol, 15%, 98% purity) as a yellow solid. MS (ESI) m/z 449.0 [M+H]
+;
1H NMR (400 MHz, DMSO-d
6) δ 9.46 - 9.20 (m, 1H), 8.70 - 8.41 (m, 2H), 7.71 - 7.65 (m, 1H), 7.65 - 7.55 (m, 1H), 6.65 - 6.49 (m, 1H), 6.13 (ddd, J = 2.4, 5.2, 16.8 Hz, 1H), 5.66 (ddd, J = 2.4, 10.4, 13.6 Hz, 1H), 4.68 - 4.46 (m, 1H), 3.96 – 3.86 (m, 0.5H), 3.81 - 3.70 (m, 1H), 3.69 - 3.44 (m, 2.5H), 2.31 - 2.13 (m, 1H), 2.12 - 1.93 (m, 1H). Synthesis of Compound No. 145: 1-(3-((4-(3,4-dichloro-2-fluorophenoxy)pyrido[3,2- d]pyrimidin-6-yl)oxy)-3-ethylazetidin-1-yl)prop-2-en-1-one
[2070] Step 1. To a solution of tert-butyl 3-oxoazetidine-1-carboxylate (3.00 g, 17.5 mmol, 1.00 eq) in tetrahydrofuran (50 mL) was added ethylmagnesium bromide (3 M, 7.01 mL, 1.20 eq) dropwise at -78 °C under nitrogen. The mixture was stirred at 25 °C for 1 h. The mixture was diluted with saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (3 × 80 mL). The combined organic layer was washed with brine (60 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give tert-butyl 3-ethyl-3-hydroxyazetidine-1-carboxylate (3.40 g, crude) as yellow oil.
1H NMR (400 MHz, CDCl
3) δ 3.79 (d, J = 0.8 Hz, 4H), 1.74 (q, J = 7.2 Hz, 2H), 1.42 (s, 9H), 0.95 (t, J = 7.2 Hz, 3H). [2071] Step 2. To a solution of tert-butyl 3-ethyl-3-hydroxyazetidine-1-carboxylate (2.20 g, 10.9 mmol, 1.10 eq) in dimethylsulfoxide (20 mL) was added potassium tert-butoxide (3.34 g, 29.8 mmol, 3.00 eq) portionwise and the mixture was stirred at 0 °C for 0.5 h. 6-chloro-3- nitropicolinamide (2.00 g, 9.92 mmol, 1.00 eq) in dimethylsulfoxide (5 mL) was added dropwise
and the mixture was stirred at 25 °C for 1 h. The mixture was diluted with water (150 mL) and extracted with ethyl acetate (3 × 80 mL). The combined organic layer was washed with brine (60 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse-phase flash chromatography (0.1% formic acid) to give tert-butyl 3-((6-carbamoyl-5- nitropyridin-2-yl)oxy)-3-ethylazetidine-1-carboxylate (300 mg, 819 μmol, 8%) as a yellow oil.
1H NMR (400 MHz, DMSO-d
6) δ 8.41 (d, J = 8.8 Hz, 1H), 7.95 (br. s, 1H), 7.84 (br. s, 1H), 7.12 (d, J = 8.8 Hz, 1H), 4.13 - 3.95 (m, 4H), 2.27 - 2.09 (m, 2H), 1.38 (s, 9H), 0.88 - 0.81 (m, 3H). Step 3. To a solution of tert-butyl 3-((6-carbamoyl-5-nitropyridin-2-yl)oxy)-3-ethylazetidine-1- carboxylate (450 mg, 1.23 mmol, 1.00 eq) in methanol (10 mL) was added palladium on carbon (200 mg, 628 μmol, 10% loading) in portions. The mixture was degassed and purged with H
2 for 3 times, and then stirred at 25 °C for 1 h under H
2 (15 psi). The mixture was filtered and concentrated in vacuo to give tert-butyl 3-((5-amino-6-carbamoylpyridin-2-yl)oxy)-3- ethylazetidine-1- carboxylate (390 mg, crude) as a colorless oil. MS (ESI) m/z 337.1 [M+H]
+ Step 4. tert-Butyl 3-((5-amino-6-carbamoylpyridin-2-yl)oxy)-3-ethylazetidine-1-carboxylate (390 mg, 1.16 mmol, 1.00 eq) was dissolved in triethoxymethane (5.35 g, 36.1 mmol, 6 mL, 31.1 eq) and the mixture was stirred at 150 °C for 2 h. The mixture was concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 5/1 to 0/1) to give tert- butyl 3-ethyl-3-((4-hydroxypyrido [3,2-d]pyrimidin-6-yl)oxy)azetidine-1-carboxylate (230 mg, 664 μmol, 57%) as a colorless oil. MS (ESI) m/z 347.1 [M+H]
+ Step 5. To a solution of tert-butyl 3-ethyl-3-((4-hydroxypyrido[3,2-d]pyrimidin-6- yl)oxy)azetidine-1-carboxylate (230 mg, 664 μmol, 1.00 eq) and N,N-diisopropylethylamine (429 mg, 3.32 mmol, 578 μL, 5.00 eq) in toluene (5 mL) was added phosphorus oxychloride (305 mg, 1.99 mmol, 185 μL, 3.00 eq) dropwise. The mixture was stirred at 100 °C for 2 h. The mixture was quenched with saturated sodium bicarbonate solution (30 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layer was washed with brine (10 mL) and dried over sodium sulfate, filtered and concentrated to give tert-butyl 3-((4-chloropyrido[3,2-d]pyrimidin-6-yl)oxy)- 3-ethylazetidine-1-carboxylate (240 mg, crude) as a yellow oil. MS (ESI) m/z 365.0 [M+H]
+ Step 6. To a solution of tert-butyl 3-((4-chloropyrido[3,2-d]pyrimidin-6-yl)oxy)-3-ethylazetidine- 1-carboxylate (240 mg, 658 μmol, 1.00 eq) and 3,4-dichloro-2-fluorophenol (131 mg, 724 μmol, 1.10 eq) in propan-2-ol (8 mL) was added N,N-diisopropylethylamine (170 mg, 1.32 mmol, 229 μL, 2.00 eq) dropwise. The mixture was stirred at 90 °C for 12 h. The mixture was concentrated
to give a crude product. The crude product was purified by column chromatography (silica, petroleum ether/ethyl acetate = 10/1 to 1/1) to give tert-butyl 3-((4-(3,4-dichloro-2- fluorophenoxy)pyrido[3,2-d]pyrimidin-6-yl)oxy)-3-ethylazetidine-1-carboxylate (200 mg, 393 μmol, 60%) as a yellow solid. MS (ESI) m/z 509.2 [M+H]
+ Step 7. To a solution of tert-butyl 3-((4-(3,4-dichloro-2-fluorophenoxy)pyrido[3,2-d]pyrimidin-6- yl)oxy)-3-ethylazetidine-1-carboxylate (200 mg, 393 μmol, 1.00 eq) in dichloromethane (3 mL) was added trifluoroacetic acid (770 mg, 6.75 mmol, 0.5 mL) dropwise. The mixture was stirred at 25 °C for 0.5 h. The mixture was concentrated to give 4-(3,4-dichloro-2-fluorophenoxy)-6-((3- ethylazetidin -3-yl)oxy)pyrido[3,2-d]pyrimidine (160 mg, crude) as a yellow oil. MS (ESI) m/z 408.9 [M+H]
+ Step 8. To a solution of 4-(3,4-dichloro-2-fluorophenoxy)-6-((3-ethylazetidin-3- yl)oxy)pyrido[3,2-d]pyrimidine (160 mg, 391 μmol, 1.00 eq) and triethylamine (158 mg, 1.56 mmol, 218 μL, 4.00 eq) in dimethylformamide (3 mL) was added acryloyl chloride (42.5 mg, 469 μmol, 38.3 μL, 1.20 eq) dropwise. The mixture was stirred at 25 °C for 1 h. The mixture was filtered and the filtrate was purified by prep-HPLC (column: Shim-pack C18 150*25*10um;mobile phase: [water(0.225%formic acid)-acetonitrile];B%: 53%-83%,10min) and further purified by prep-HPLC (column: Waters Xbridge C18150*50mm* 10um;mobile phase: [water(10mM NH
4HCO
3)-acetonitrile];B%: 41%-71%,10min) to give 1-(3-((4-(3,4-dichloro-2- fluorophenoxy)pyrido[3,2-d]pyrimidin-6-yl)oxy)-3-ethylazetidin-1-yl)prop-2-en-1-one (2.62 mg, 5.60 μmol,, 1%, 99% purity) as an off-white solid. MS (ESI) m/z 463.0 [M+H]
+;
1H NMR (400 MHz, CDCl
3) δ 8.70 (s, 1H), 8.24 (d, J = 8.8 Hz, 1H), 7.42 (dd, J = 2.0, 8.8 Hz, 1H), 7.38 (d, J = 9.2 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 6.41 - 6.32 (m, 1H), 6.30 - 6.21 (m, 1H), 5.70 (dd, J = 2.0, 10.0 Hz, 1H), 4.61 (d, J = 9.6 Hz, 1H), 4.41 (t, J = 10.8 Hz, 2H), 4.34 - 4.27 (m, 1H), 2.56 - 2.44 (m, 1H), 2.42 - 2.32 (m, 1H), 0.97 (t, J = 7.2 Hz, 3H). Synthesis of Compound No. 146: 1-(3-((4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)prop-2-en-1-one
[2072] Step 1. To a solution of 6-chloro-3-nitropicolinamide (2.50 g, 12.4 mmol, 1.00 eq) and ammonium chloride (3.32 g, 62.0 mmol, 5.00 eq) in methanol (40 mL) and water (10 mL) was added iron powder (3.46 g, 62.0 mmol, 5.00 eq) in portions. The mixture was stirred at 80 °C for 2 h. The mixture was then diluted with methanol (30 mL) and filtered. The filtrate was concentrated to give a crude product. The residue was diluted with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layer was washed with brine (10 mL) and dried over sodium sulfate, filtered and concentrated to give 3-amino-6-chloropicolinamide (2.00 g, 11.7 mmol, 94%) as a white solid.
1H NMR (400 MHz, DMSO-d
6) δ 7.71 (s, 1H), 7.41 (s, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 7.00 (s, 2H). [2073] Step 2. A mixture of 3-amino-6-chloropicolinamide (2.00 g, 11.7 mmol, 1.00 eq) in triethoxymethane (17.8 g, 120 mmol, 20 mL, 10.3 eq) was stirred at 150 °C for 2 h. The mixture was concentrated to give a residue. The residue was washed with ethyl acetate (50 mL) and filtered. The filter cake was dried under vacuum to give 6-chloropyrido[3,2-d]pyrimidin-4-ol (1.80 g, 9.91 mmol, 85%) as a yellow solid. MS (ESI) m/z 182.0 [M+H]
+
[2074] Step 3. To a solution of 6-chloropyrido[3,2-d]pyrimidin-4-ol (500 mg, 2.75 mmol, 1.00 eq), tert-butyl 3-(bromomethyl)pyrrolidine-1-carboxylate (1.09 g, 4.13 mmol, 1.50 eq), dichloronickel:1,2-dimethoxyethane (60.5 mg, 275 μmol, 0.10 eq) and picolinimidamide hydrochloride (86.8 mg, 551 μmol, 0.20 eq) in N,N-dimethylacetamide (4 mL) was added zinc powder (540 mg, 8.26 mmol, 3.00 eq) in portions under nitrogen. The mixture was stirred at 60 °C for 3 h under nitrogen. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated to give a crude product. The residue was purified by reverse- phase flash (formic acid conditions) to give tert-butyl 3-((4-hydroxypyrido[3,2-d] pyrimidin-6- yl)methyl)pyrrolidine-1-carboxylate (150 mg, 454 μmol, 16%) as a yellow oil.
1H NMR (400 MHz, DMSO-d
6) δ 12.49 (br. s, 1H), 8.11 (s, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 3.44 - 3.38 (m, 2H), 3.30 (br. s, 2H), 3.17 (br. d, J = 8.9 Hz, 1H), 3.02 - 2.91 (m, 4H), 1.39 (br. s, 9H). [2075] Step 4. To a solution of tert-butyl 3-((4-hydroxypyrido[3,2-d]pyrimidin-6- yl)methyl)pyrrolidine-1-carboxylate (150 mg, 454 μmol, 1.00 eq) and N,N-diisopropylethylamine (293 mg, 2.27 mmol, 395 μL, 5.00 eq) in toluene (5mL) was added phosphorus oxychloride (209 mg, 1.36 mmol, 127 μL, 3.00 eq) dropwise. The mixture was stirred at 100 °C for 2 h. The mixture was diluted with saturated sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layer was washed with brine (10 mL) and dried over sodium sulfate, filtered and concentrated to give tert-butyl 3-((4-chloropyrido[3,2-d]pyrimidin-6- yl)methyl)pyrrolidine-1-carboxylate (150 mg, crude) as a yellow oil. MS (ESI) m/z 293.1 [M+H- 56]
+ [2076] Step 5. To a solution of tert-butyl 3-((4-chloropyrido[3,2-d]pyrimidin-6- yl)methyl)pyrrolidine-1-carboxylate (150 mg, 430 μmol, 1.00 eq) and 3,4-dichloro-2-fluoroaniline (77.4 mg, 430 μmol, 1.00 eq) in acetonitrile (3 mL) was added HCl/ethyl acetate (4 M, 10.8 μL, 0.10 eq) dropwise. The mixture was stirred at 25 °C for 1 h. The mixture was concentrated to give a crude product. The residue was washed with ethyl acetate (2 × 20 mL) and filtered. The filter cake was dried under vacuum to give tert-butyl 3-((4-((3,4-dichloro-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)methyl)pyrrolidine-1-carboxylate (200 mg, crude) as a yellow solid. MS (ESI) m/z 492.1 [M+H]
+ [2077] Step 6. A mixture of tert-butyl 3-((4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl) methyl)pyrrolidine-1-carboxylate (200 mg, 406 μmol, 1.00 eq) in HCl/ethyl
acetate (4 M, 5mL) was stirred at 25 °C for 0.5 h. The mixture was concentrated to give N-(3,4- dichloro-2-fluorophenyl)-6-(pyrrolidin-3-ylmethyl)pyrido[3,2-d]pyrimidin-4-amine (175 mg, crude, HCl salt) as a yellow solid. MS (ESI) m/z 392.0 [M+H]
+ [2078] Step 7. To a solution of N-(3,4-dichloro-2-fluorophenyl)-6-(pyrrolidin-3- ylmethyl)pyrido[3,2-d]pyrimidin-4-amine (150 mg, 382 μmol, 1.00 eq, HCl salt) and triethylamine (116 mg, 1.15 mmol, 160 μL, 3.00 eq) in dimethylformamide (2 mL) was added acryloyl chloride (45.0 mg, 497 μmol, 40.5 μL, 1.30 eq) dropwise. The mixture was stirred at 25 °C for 0.5 h. The mixture was filtered. The filtrate was purified by prep-HPLC (column: Shim- pack C18 150*25*10um;mobile phase: [water(0.225%formic acid)-acetonitrile];B%: 55%- 80%,11min) to give 1-(3-((4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl) methyl)pyrrolidin-1-yl)prop-2-en-1-one (39 mg, 79.0 μmol, 21%, 99% purity) as a white solid. MS (ESI) m/z 446.0 [M+H]
+;
1H NMR (400 MHz, DMSO-d6) δ 9.90 (br. s, 1H), 8.65 (d, J = 2.4 Hz, 1H), 8.21 (dd, J = 1.6, 8.4 Hz, 1H), 8.12 (q, J = 8.0 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.62 (td, J = 1.6, 8.8 Hz, 1H), 6.63 - 6.50 (m, 1H), 6.12 (td, J = 2.8, 16.8 Hz, 1H), 5.63 (ddd, J = 2.4, 10.4, 15.6 Hz, 1H), 3.86 - 3.70 (m, 1H), 3.65 - 3.48 (m, 2H), 3.24 - 3.07 (m, 3H), 3.02 - 2.80 (m, 1H), 2.14 - 1.95 (m, 1H), 1.82 - 1.60 (m, 1H). Synthesis of Compound No. 147: 1-(3-((4-((3,4-Dichloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl)methyl)-3-methylazetidin-1-yl)prop-2-en-1-one
[2079] Step 1. A mixture of 6-chloropyrido[3,2-d]pyrimidin-4-ol (1.00 g, 5.51 mmol, 1.00 eq) in phosphoryl trichloride (10 mL) was stirred at 110 °C for 2 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give 4,6-dichloropyrido[3,2-d]pyrimidine (2.20 g, crude) as a yellow solid, which was used for next step directly without purification. [2080] Step 2. To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (2.20 g, 11.0 mmol, 1.00 eq) in tetrahydrofuran (20 mL) was added 3,4-dichloro-2-fluoroaniline (3.96 g, 22.0 mmol, 2.00 eq) and diisopropylethylamine (4.26 g, 33.0 mmol, 5.75 mL, 3.00 eq). The mixture was stirred at 60 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by flash column chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~20% Ethyl acetate/Petroleum ether gradient @ 50 mL/min) to give 6-chloro-N-(3,4-dichloro-2-fluorophenyl)pyrido [3,2-d]pyrimidin-4-amine (0.85 g, 2.25 mmol, 20%, 91% purity) as a light yellow solid. [2081] Step 3. To a solution of 6-chloro-N-(3,4-dichloro-2-fluorophenyl)pyrido[3,2-d]pyrimidin- 4-amine (195 mg, 568 μmol, 1.00 eq), picolinimidamide hydrochloride (17.9 mg, 114 μmol, 0.20 eq), nickel chloride ethylene glycol dimethyl ether complex (12.5 mg, 56.8 μmol, 0.10 eq) and tert-butyl 3-(bromomethyl)-3- methylazetidine-1-carboxylate (300 mg, 1.14 mmol, 2.00 eq) in N,N-dimethylacetamide (3 mL) was added zinc powder (112 mg, 1.71 mmol, 3.02 eq). Then the
reaction was stirred at 60 °C for 3 h under nitrogen. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 0/1 to 1/1) to give tert-butyl 3-((4-((3,4-dichloro-2- fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)methyl)-3-methylazetidine-1-carboxylate (112 mg, 203 μmol, 36%, 89% purity) as a yellow solid. MS (ESI) m/z 492.2 [M+H]
+ [2082] Step 4. To a solution of tert-butyl 3-((4-((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,2- d]pyrimidin-6-yl) methyl)-3-methylazetidine-1-carboxylate (80.0 mg, 162 μmol, 1.00 eq) in dichloromethane (1 mL) was added HCl/ethyl acetate (4 M, 1 mL). The mixture was stirred at 25 °C for 30 min. The reaction mixture was concentrated under reduced pressure to give N-(3,4- dichloro-2-fluorophenyl)-6-((3-methylazetidin-3-yl)methyl)pyrido[3,2-d]pyrimidin-4-amine (70.0 mg, crude, HCl salt) as a yellow solid, which was used directly in the next step without purification. MS (ESI) m/z 392.0 [M+H]
+ [2083] Step 5. To a solution of N-(3,4-dichloro-2-fluorophenyl)-6-((3-methylazetidin-3- yl)methyl)pyrido[3,2-d]pyrimidin-4-amine hydrochloride (70.0 mg, 163 μmol, 1.00 eq) and diisopropylethylamine (63.3 mg, 490 μmol, 85.3 μL, 3.00 eq) in dichloromethane (1 mL) was added prop-2-enoyl prop-2-enoate (10.3 mg, 81.6 μmol, 0.500 eq). The mixture was stirred at 25 °C for 10 min. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (petroleum ether/ethyl acetate = 0/1, R
f = 0.2) to give 1-(3-((4- ((3,4-dichloro-2-fluorophenyl)amino)pyrido[3,2-d]pyrimidin-6-yl)methyl)-3-methyl azetidin-1- yl)prop-2-en-1-one (24.80 mg, 53.9 μmol, 33%, 97% purity) as a white solid. MS (ESI) m/z 446.1 [M+H]
+;
1H NMR (400 MHz, CDCl
3) δ 9.36 (br. s, 1H), 8.91 - 8.85 (m, 1H), 8.84 (s, 1H), 8.18 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.38 (dd, J = 2.0, 9.2 Hz, 1H), 6.40 - 6.33 (m, 1H), 6.30 - 6.22 (m, 1H), 5.71 (dd, J = 2.0, 10.0 Hz, 1H), 4.50 (d, J = 8.4 Hz, 1H), 4.15 (d, J = 10.0 Hz, 1H), 4.07 (d, J = 8.4 Hz, 1H), 3.92 (d, J = 10.0 Hz, 1H), 3.42 - 3.26 (m, 2H), 1.42 (s, 3H). Synthesis of Compound No. 148: 1-(3-((4-((3,4-Dichloro-2-fluorophenyl)amino)-7- methoxypyrido[3,2-d]pyrimidin-6-yl)methyl)-3-methylazetidin-1-yl)prop-2-en-1-one
[2084] Step 1. To a solution of potassium tert-butoxide (1.38 g, 12.3 mmol, 1.50 eq) and methanol (788 mg, 24.6 mmol, 995 μL, 3.00 eq) in dimethylsulfoxide (20 mL) was stirred at 25 °C for 0.5 h. Then 6-bromo-7-fluoropyrido[3,2-d]pyrimidin-4-ol (2.00 g, 8.20 mmol, 1.00 eq) was added and the mixture was stirred at 25 °C for 2 h. The mixture was slowly poured into water and adjusted to pH = 7 with aq. HCl solution (1 N). The resulting precipitate was filtered and dried under reduced pressure to give 6-bromo-7-methoxypyrido[3,2-d] pyrimidin-4-ol (1.20 g, crude) as a gray solid. MS (ESI) m/z 256.0 [M+H]
+ [2085] Step 2. A solution of 6-bromo-7-methoxypyrido[3,2-d]pyrimidin-4-ol (1.00 g, 3.91 mmol, 1.00 eq) in phosphoryl trichloride (10 mL) was stirred at 110 °C for 2 h. The mixture was concentrated in vacuo to give 4,6-dichloro-7-methoxypyrido[3,2-d]pyrimidine (0.90 g, crude) as a black brown solid. [2086] Step 3. To a solution of 4,6-dichloro-7-methoxypyrido[3,2-d]pyrimidine (650 mg, 2.83 mmol, 1.00 eq) in tetrahydrofuran (10 mL) was added 3,4-dichloro-2-fluoroaniline (1.02 g, 5.65 mmol, 2.00 eq). Then diisopropylethylamine (1.10 g, 8.48 mmol, 1.48 mL, 3.00 eq) was added and the mixture was stirred at 60 °C for 2 h. On completion, the mixture was concentrated in vacuo. Then the residue was purified by flash column chromatography (Biotage®; 12.0 g Agela Silica Flash Column, Eluent of 0 ~ 30% ethyl acetate/petroleum ether gradient @ 20 mL/min) to give 6- chloro-N-(3,4-dichloro-2-fluorophenyl) -7-methoxypyrido[3,2-d]pyrimidin-4-amine (150 mg, 402 μmol, 14%) as a white solid.
1H NMR (400 MHz, CDCl
3) δ 8.92 (br. s, 1 H), 8.76 (s, 1 H), 8.69 (t, J = 8.4 Hz, 1 H), 7.49 (s, 1 H), 7.34 (dd, J = 9.2, 1.8 Hz, 1 H), 4.08 (s, 3 H).
[2087] Step 4. To a solution of 6-chloro-N-(3,4-dichloro-2-fluorophenyl)-7-methoxypyrido[3,2- d]pyrimidin-4-amine (210 mg, 562 μmol, 1.00 eq), nickel chloride ethylene glycol dimethyl ether complex (12.4 mg, 56.2 μmol, 0.10 eq), picolinimidamide hydrochloride (17.7 mg, 112 μmol, 0.20 eq) and tert-butyl 3-(bromomethyl)-3-methylazetidine-1-carboxylate (297 mg, 1.12 mmol, 2.00 eq) in N,N-dimethylacetamide (3 mL) was added zinc powder (111 mg, 1.70 mmol, 3.02 eq), then the reaction was stirred at 60 °C for 2 h under nitrogen. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 1/0 to 0/1) to give tert-butyl 3-((4-((3,4-dichloro-2- fluorophenyl)amino)-7-methoxypyrido[3,2-d]pyrimidin-6-yl)methyl)-3-methylazetidine-1- carboxylate (150 mg, 241 μmol, 43%, 84% purity) as a yellow solid. MS (ESI) m/z 522.3 [M+H]
+ [2088] Step 5. To a solution of tert-butyl 3-((4-((3,4-dichloro-2-fluorophenyl)amino)-7- methoxypyrido[3,2-d]pyrimidin-6-yl)methyl)-3-methylazetidine-1-carboxylate (120 mg, 230 μmol, 1.00 eq) in dichloromethane (1 mL) was added HCl/ethyl acetate (4.00 M, 2 mL). The mixture was stirred at 25 °C for 30 min. The reaction mixture was concentrated under reduced pressure to give N-(3,4-dichloro-2-fluorophenyl)-7-methoxy-6-((3-methylazetidin-3- yl)methyl)pyrido[3,2-d] pyrimidin-4-amine hydrochloride (110 mg, crude) as a yellow solid, which was directly used to next step without purification. MS (ESI) m/z 422.1 [M+H]+ [2089] Step 6. To a solution of N-(3,4-dichloro-2-fluorophenyl)-7-methoxy-6-((3-methylazetidin- 3-yl)methyl)pyrido[3,2-d] pyrimidin-4-amine hydrochloride (110 mg, 240 μmol, 1.00 eq) and N- ethyl-N-isopropylpropan-2-amine (93.0 mg, 719 μmol, 125 μL, 3.00 eq) in dichloromethane (1 mL) was added prop-2-enoyl prop-2-enoate (15.1 mg, 120 μmol, 0.50 eq). The mixture was stirred at 25 °C for 10 min. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (petroleum ether/ethyl acetate = 0/1, R
f = 0.2) and further purified by prep-HPLC (column: Phenomenex luna C18 100*40mm*3 um;mobile phase: water (0.225% formic acid) - acetonitrile; B%: 40% - 70%, 10 min) to give 1-(3-((4-((3,4-dichloro-2- fluorophenyl)amino)-7-methoxypyrido[3,2-d]pyrimidin-6-yl)methyl)-3-methylazetidin-1- yl)prop-2-en-1-one (24.92 mg, 48.1 μmol, 20%, 92% purity) as a white solid. MS (ESI) m/z 476.1 [M+H]
+;
1H NMR (400 MHz, CDCl
3) δ 9.15 (s, 1H), 8.86 (t, J = 8.8 Hz, 1H), 8.77 (s, 1H), 7.43 (s, 1H), 7.36 (dd, J = 2.0, 9.2 Hz, 1H), 6.39 - 6.32 (m, 1H), 6.29 - 6.20 (m, 1H), 5.69 (dd, J = 2.0, 10.0 Hz, 1H), 4.42 (d, J = 8.4 Hz, 1H), 4.13 (d, J = 4.8 Hz, 1H), 4.11 (d, J = 2.8 Hz, 1H), 4.02 (s, 3H), 3.95 (d, J = 10.0 Hz, 1H), 3.41 - 3.24 (m, 2H), 1.49 (s, 3H).
Synthesis of Compound No. 149: (S)-1-(3-((4-(3,4-Dichlorophenoxy)pyrido[3,2-d]pyrimidin- 6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one
[2090] Step 1. To a mixture of tert-butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6- yl)oxypyrrolidine -1-carboxylate (120 mg, 342 μmol) and 3,4-dichlorophenol (83.6 mg, 513 μmol) in acetonitrile (2 mL) was added potassium carbonate (94.6 mg, 684 μmol) at 16 °C under nitrogen. The mixture was stirred at 60 °C for 2 h. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-TLC [silica, petroleum ether/ethyl acetate = 1/1] to give tert-butyl (3S)-3-[4-(3,4-dichlorophenoxy)pyrido[3,2-d]pyrimidin-6- yl]oxypyrrolidine-1-carboxylate (160 mg, 98%) as a yellow solid. m/z ES + [M+H]
+ 477.0 [2091] Step 2. To a mixture of tert-butyl (3S)-3-[4-(3,4-dichlorophenoxy)pyrido[3,2-d]pyrimidin- 6-yl] oxypyrrolidine-1-carboxylate (140 mg, 293 μmol) in dichloromethane (1.5 mL) was added HCl/ethyl acetate (4 M, 73.32 μL,) at 16 °C under nitrogen. The mixture was stirred at 16 °C for 30 min. On completion, the reaction mixture was concentrated in vacuo to give 4-(3,4- dichlorophenoxy)-6-[(3S)-pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidine (140 mg, crude, HCl salt) as a yellow solid. m/z ES+ [M+H]
+ 377.0 [2092] Step 3. A mixture of 4-(3,4-dichlorophenoxy)-6-[(3S)-pyrrolidin-3-yl]oxy-pyrido[3,2- d]pyrimidine (100 mg, 265 μmol) and solid sodium bicarbonate (77.9 mg, 928 μmol) in tetrahydrofuran (1 mL) and water (1 mL) was cooled to 0 °C. Then acryloyl chloride (24.0 mg, 265 μmol) was slowly added and the mixture was stirred at 0 °C for 30 min. On completion, the reaction mixture was diluted with ethyl acetate (2 mL). The aqueous layer was extracted with ethyl acetate (2 mL x 2). The organic layer was combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC
[column: Phenomenex Synergi C18150*25mm* 10um;mobile phase: [water(0.225%formic acid)- acetonitrile]; B%: 44%-74%,10min] to give 1-[(3S)-3-[4-(3,4-dichlorophenoxy)pyrido[3,2- d]pyrimidin-6-yl] oxypyrrolidin-1-yl] prop -2-en-1-one (32 mg, 72.6 μmol, 27%, formic acid salt) as an off-white solid. m/z ES+ [M+H]
+ 431.0;
1H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J = 3.6 Hz, 1H), 8.32 (dd, J = 1.2, 9.2 Hz, 1H), 7.84 - 7.74 (m, 2H), 7.55 (dd, J = 3.6, 9.2 Hz, 1H), 7.42 (td, J = 2.8, 8.8 Hz, 1H), 6.71 - 6.50 (m, 1H), 6.23 - 6.07 (m, 1H), 5.94 - 5.62 (m, 2H), 4.00 (dd, J = 4.8, 12.0 Hz, 0.5H), 3.86 - 3.65 (m, 3H), 3.54 - 3.46 (m, 0.5H), 2.38 - 2.20 (m, 2H). Synthesis of Compound No. 150: (S)-1-(3-((4-((5,6-Dichloropyridin-3-yl)oxy)pyrido[3,2- d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one
[2093] Step 1. To a solution of tert-butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6-yl) oxypyrrolidine-1-carboxylate (120 mg, 273 μmol) in acetonitrile (2 mL) was added 5,6- dichloropyridin-3-ol (53.8 mg, 328 μmol) and potassium carbonate (75.6 mg, 547 μmol). The mixture was stirred at 40 °C for 12 h. On completion, the reaction mixture was quenched by saturated ammonium chloride (2 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed with brine (15 mL × 3), dried over sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl (3S)-3-[4-[(5,6-dichloro-3- pyridyl)oxy]pyrido [3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (130 mg, 99%) as a yellow solid. m/z ES+ [M+H]
+ 478.0 [2094] Step 2. A solution of tert-butyl (3S)-3-[4-[(5,6-dichloro-3-pyridyl)oxy] pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (110 mg, 230 μmol) in HCl/ethyl acetate (4 M, 3 mL) was stirred at 25 °C for 0.5 h. On completion, the reaction mixture was concentrated under reduced pressure to give 4-[(5,6-dichloro-3-pyridyl)oxy]-6-[(3S)-pyrrolidin-3-yl]oxy-pyrido[3,2-
d]pyrimidine (110 mg, crude) as a white solid. [2095] Step 3. To a solution of 4-[(5,6-dichloro-3-pyridyl)oxy]-6-[(3S)-pyrrolidin-3-yl]oxy- pyrido[3,2-d]pyrimidine (110 mg, 265 μmol) in tetrahydrofuran (2 mL) was added prop-2-enoyl chloride (26.4 mg, 291 μmol) and sodium bicarbonate (89.1 mg, 1.06 mmol) in (2 mL). The mixture was stirred at 25 °C for 30 min. On completion, the reaction mixture was quenched with saturated ammonium chloride (5 mL) and extracted with ethyl acetate (5 mL x 3). The organic layers were washed with brine (5 mL x 3), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25 mm* 5 um; mobile phase: [water (0.05% ammonia hydroxide v/v)-acetonitrile]; B%: 35%-55%, 10min) to give 1-[(3S)-3-[4-[(5,6-dichloro-3-pyridyl)oxy]pyrido[3,2-d] pyrimidin-6-yl]oxypyrrolidin-1-yl]prop-2-en-1-one (10.1 mg, 23.3 μmol, 8.8%) as a white solid. m/z ES+ [M+H]
+ 432.1;
1H NMR (400 MHz, CDCl3) δ 8.70 (d, J = 4.4 Hz, 1H), 8.38 (t, J = 2.0 Hz, 1H), 8.21 (t, J = 8.8 Hz, 1H), 7.86 (d, J = 2.4 Hz, 1H), 7.34 (t, J = 8.8 Hz, 1H), 6.56 - 6.38 (m, 2H), 5.93 (td, J = 2.0, 16.8 Hz, 1H), 5.77 - 5.68 (m, 1H), 4.03 - 3.74 (m, 4H), 2.49 - 2.25 (m, 2H). Synthesis of Compound No. 151: (S)-1-(3-((4-(3-Ethynyl-4-fluorophenoxy)pyrido[3,2- d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one
[2096] Step 1. To a mixture of tert-butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6-
yl)oxypyrrolidine-1- carboxylate (250 mg, 713 μmol) and 3-bromo-4-fluoro-phenol (204 mg, 1.07 mmol) in acetonitrile (4 mL) was added potassium carbonate (197 mg, 1.43 mmol) under nitrogen. The mixture was stirred at 60 °C for 2 h. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-TLC [silica, petroleum ether/ethyl acetate = 1/1] to give tert-butyl (3S)-3-[4-(3-bromo-4-fluoro-phenoxy)pyrido[3,2-d]pyrimidin-6- yl] oxypyrrolidine-1-carboxylate (350 mg, 96%) as a yellow solid. m/z ES+ [M+H]
+ 507.0 [2097] Step 2. To a solution of tert-butyl (3S)-3-[4-(3-bromo-4-fluoro-phenoxy)pyrido[3,2-d] pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (300 mg, 594 μmol) in dimethylformamide (4 mL) was added triethylamine (180 mg, 1.78 mmol), copper(I) iodide (11.31 mg, 59.37 μmol), ethynyl(trimethyl)silane (175 mg, 1.78 mmol) and bis(triphenylphosphine)palladium(II) dichloride (41.7 mg, 59.4 μmol). The mixture was stirred at 80 °C under nitrogen atmosphere for 12 h. On completion, the reaction mixture was quenched by water (5 mL). The aqueous layer was extracted with ethyl acetate (2 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography [silica, petroleum ether/ethyl acetate=2/1 to 0/1] to give tert-butyl (3S)-3-[4-[4-fluoro-3-(2- trimethylsilylethynyl)phenoxy]pyrido[3,2-d]pyrimidin-6- yl]oxypyrrolidine-1-carboxylate (210 mg, 62%) as a black brown solid. m/z ES+ [M+H]
+ 523.2;
1H NMR (400 MHz, DMSO-d
6) δ 8.44 (s, 1H), 8.06 (d, J = 9.2 Hz, 1H), 7.29 (d, J = 9.2 Hz, 2H), 7.24 - 7.15 (m, 2H), 5.59 - 5.41 (m, 1H), 3.55 - 3.39 (m, 1H), 3.33 - 3.17 (m, 3H), 2.06 - 1.86 (m, 2H), 1.16 (d, J = 7.1 Hz, 9H), 0.00 (s, 9H). [2098] Step 3. To a mixture of tert-butyl (3S)-3-[4-[4-fluoro-3-(2-trimethylsilylethynyl)- phenoxy]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (140 mg, 268 μmol) in tetrahydrofuran (3 mL) was added tetrabutylammonium fluoride (1 M in tetrahydrofuran, 482 μL) at 16 °C. The mixture was stirred at 16 °C for 30 min. On completion, the reaction mixture was quenched by water (5 mL). The aqueous layer was extracted with ethyl acetate (3 mL x 2). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl (3S)-3-[4-(3-ethynyl-4-fluoro-phenoxy)pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (120 mg, crude) as a yellow solid. m/z ES+ [M+H]
+ 451.1 [2099] Step 4. To a mixture of tert-butyl (3S)-3-[4-(3-ethynyl-4-fluoro-phenoxy)pyrido[3,2- d]pyrimidin -6-yl]oxypyrrolidine-1-carboxylate (100 mg, 222 μmol) in dichloromethane (1 mL)
was added HCl/ethyl acetate (4 M, 0.5 mL) at 18 °C. The mixture was stirred at 18 °C for 30 min. On completion, the reaction mixture was concentrated in vacuo to give 4-(3-ethynyl-4-fluoro- phenoxy)-6-[(3S)-pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidine (70 mg, crude, HCl salt) as a yellow solid. m/z ES+ [M+H]
+ 351.0 [2100] Step 5. To a mixture of 4-(3-ethynyl-4-fluoro-phenoxy)-6-[(3S)-pyrrolidin-3-yl]oxy- pyrido[3,2-d] pyrimidine (70.0 mg, 200 μmol, HCl salt) in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added sodium bicarbonate (50.4 mg, 599 μmol). Then a solution of prop-2-enoyl chloride (18.1 mg, 200 μmol) in tetrahydrofuran (0.1 mL) was added dropwise at 0 °C over a period of 2 min under nitrogen. The mixture was stirred at 0 °C for 15 min. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by Prep-HPLC [column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(0.225%formic acid)- acetonitrile];B%: 36%-66%,10 min] and further purified by prep-TLC [petroleum ether/ethyl acetate=0/1] to give 1-[(3S)-3-[4-(3-ethynyl-4-fluoro-phenoxy)pyrido[3,2-d]pyrimidin-6-yl] oxypyrrolidin-1-yl]prop-2-en-1-one (11.7 mg, 29.0 μmol, 14.5%) as a yellow solid. m/z ES+ [M+H]
+ 405.0;
1H NMR (400 MHz, DMSO-d
6) δ 8.69 (d, J = 2.8 Hz, 1H), 8.31 (d, J = 9.2 Hz, 1H), 7.69 - 7.39 (m, 4H), 6.73 - 6.48 (m, 1H), 6.22 - 6.10 (m, 1H), 5.94 - 5.60 (m, 2H), 4.60 (d, J = 2.0 Hz, 1H), 4.06 - 3.95 (m, 0.5H), 3.86 - 3.65 (m, 3H), 3.56 - 3.50 (m, 0.5H), 2.40 - 2.16 (m, 2H). Synthesis of Compound No. 152: (S)-1-(3-((4-(4-Chloro-3-ethynylphenoxy)pyrido[3,2- d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one
[2101] Step 1. A solution of tert-butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6-yl) oxypyrrolidine-1-carboxylate (250 mg, 713 μmol), 3-bromo-4-chloro-phenol (177 mg, 855 μmol) and potassium carbonate (295 mg, 2.14 mmol) in acetonitrile (2.5 mL) was stirred at 60 °C for 2 h. On completion, the reaction mixture was diluted with water (8 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (5 mL x 3), dried over sodium sulfate and evaporated. The residue was purified by column chromatography (silica, petroleum ether/ethyl acetate=1/1 to 2/1) to afford tert-butyl (3S)-3-[4-(3-bromo-4-chloro- phenoxy)pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (300 mg, 81%) as a white solid. m/z ES+ [M+H]
+ 523.1 [2102] Step 2. To a solution of tert-butyl (3S)-3-[4-(3-bromo-4-chloro-phenoxy)pyrido[3,2-d] pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (300 mg, 575 μmol), copper(I) iodide (11.0 mg, 57.5 μmol) and triethylamine (175 mg, 1.72 mmol) in dimethylformamide (3 mL) was added ethynyl(trimethyl)silane (169 mg, 1.72 mmol) and bis(triphenylphosphine)palladium(II) dichloride (40.4 mg, 57.5 μmol) under nitrogen. The mixture was stirred at 80 °C for 12 h under nitrogen. On completion, the reaction mixture was concentrated under vacuum. The residue was purified by reverse-phase HPLC (acetonitrile/0.1% ammonium hydroxide:water = 85%) to afford tert-butyl (3S)-3-[4-[4-chloro-3-(2-trimethylsilylethynyl)phenoxy]pyrido[3,2-d]pyrimidin-6- yl]oxypyrrolidine-1-carboxylate (280 mg, 90%) as a yellow oil. m/z ES+ [M+H]
+ 539.3 [2103] Step 3. To a solution of tert-butyl (3S)-3-[4-[4-chloro-3-(2-trimethylsilylethynyl)-
phenoxy]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (220 mg, 408 μmol) in tetrahydrofuran (2 mL) was added tetrabutylammonium fluoride (1 M in tetrahydrofuran, 735 μL). The mixture was stirred at 20 °C for 1 h. On completion, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (8 mL x 3). The combined organic layers were washed with brine (5 mL x 3), dried over sodium sulfate and evaporated. The residue was purified by column chromatography (silica, petroleum ether/ethyl acetate=2/1 to 1/1) to afford tert-butyl (3S)-3-[4-(4-chloro-3-ethynyl-phenoxy)pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1- carboxylate (180 mg, crude) as a colorless oil. m/z ES+ [M+1]
+ 467.1 [2104] Step 4. A solution of tert-butyl (3S)-3-[4-(4-chloro-3-ethynyl-phenoxy)pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (180 mg, 386 μmol) in HCl/ethyl acetate (4 M, 1.80 mL) was stirred at 20 °C for 0.5 h. On completion, the reaction mixture was concentrated in vacuo to afford 4-(4-chloro-3-ethynyl-phenoxy)-6-[(3S)-pyrrolidin-3-yl]oxy-pyrido[3,2- d]pyrimidine (160 mg, crude, HCl) as a white solid. [2105] Step 5. To a solution of 4-(4-chloro-3-ethynyl-phenoxy)-6-[(3S)-pyrrolidin-3-yl]oxy- pyrido[3,2-d]pyrimidine (160 mg, 397 μmol, HCl salt) and sodium bicarbonate (117 mg, 1.39 mmol) in tetrahydrofuran (1.5 mL) and water (1.5 mL) was added prop-2-enoyl chloride (35.9 mg, 397 μmol) at 0 °C and the mixture was stirred at 0 °C for 0.5 h. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25 mm* 5 um; mobile phase: [water(10 mM NH
4HCO
3)-acetonitrile]; B%: 33%-63%, 10 min) to afford 1-[(3S)-3-[4-(4-chloro-3-ethynyl-phenoxy)pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin- 1-yl]prop-2-en-1-one (80.0 mg, 188.3 μmol, 47%, 99% purity) as a white solid. m/z ES+ [M+1]
+ 421.0;
1H NMR (400 MHz, DMSO-d
6) δ 8.69 (d, J = 3.6 Hz, 1H), 8.31 (d, J = 8.8 Hz, 1H), 7.70 - 7.63 (m, 2H), 7.54 (dd, J = 3.6, 8.8 Hz, 1H), 7.47 - 7.43 (m, 1H), 6.69 - 6.51 (m, 1H), 6.19 - 6.11 (m, 1H), 5.90 - 5.76 (m, 1H), 5.72 - 5.63 (m, 1H), 4.68 (d, J = 2.0 Hz, 1H), 3.99 (dd, J = 4.4, 12.4 Hz, 0.5H), 3.85 - 3.79 (m, 1H), 3.77 - 3.64 (m, 2H), 3.56 - 3.46 (m, 0.5H), 2.34 - 2.17 (m, 2H). Synthesis of Compound No. 153: (S)-1-(3-((4-(3-Chloro-4-fluorophenoxy)pyrido[3,2- d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one
[2106] Step 1. To a solution of tert-butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6-yl) oxypyrrolidine-1-carboxylate (150 mg, 428 μmol) in acetonitrile (2 mL) was added potassium carbonate (118 mg, 855 μmol) and 3-chloro-4-fluoro-phenol (68.9 mg, 470 μmol). The mixture was stirred at 60 °C for 2 h. The reaction mixture was concentrated in vacuo. The residue was purified by prep-TLC (silica, petroleum ether/ethyl acetate= 1:1) to give tert-butyl (3S)-3-[4-(3- chloro-4-fluoro-phenoxy)pyrido [3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (150 mg, 76%) as a white solid. m/z ES+ [M+H]
+ 461.2 [2107] Step 2. To a solution of tert-butyl (3S)-3-[4-(3-chloro-4-fluoro-phenoxy)pyrido [3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (140 mg, 303 μmol ) in dichloromethane (3 mL) was added HCl/ethyl acetate (1 mL). The mixture was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated in vacuo to give 4-(3-chloro-4-fluoro-phenoxy)-6-[(3S)-pyrrolidin-3-yl] oxy-pyrido[3,2-d]pyrimidine (120 mg, crude, HCl salt) as a white solid. m/z ES+ [M+H]
+ 361.1 [2108] Step 3. To a solution of 4-(3-chloro-4-fluoro-phenoxy)-6-[(3S)-pyrrolidin-3-yl] oxy- pyrido[3,2-d]pyrimidine (120 mg, 302 μmol, HCl) in tetrahydrofuran (1 mL) was added sodium bicarbonate (63.4 mg, 755 μmol) in water (1.5 mL) and prop-2-enoyl chloride (30.1 mg, 332 μmol ) in tetrahydrofuran (0.5 mL). The mixture was stirred at 0 °C for 1 h. The reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini- NX C1875*30 mm*3 um; mobile phase: [water (0.225% formic acid)-acetonitrile]; B%: 35%- 65%, 9 min) and further purified by prep-TLC (silica, petroleum ether/ethyl acetate = 0/1) to give 1-[(3S)-3-[4-(3-chloro-4-fluoro-phenoxy) pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin-1-yl]prop- 2-en-1-one (2.00 mg, 4.79 μmol, 1.6%) as a white solid. m/z ES+ [M+H]+ 415.2;
1H NMR (400 MHz, CDCl
3) δ 8.70 (d, J = 4.0 Hz, 1H), 8.19 (t, J = 8.8 Hz, 1H), 7.39 (dd, J = 2.4, 6.0 Hz, 1H), 7.34 - 7.28 (m, 1H), 7.25 (d, J = 2.0 Hz, 1H), 7.22 - 7.15 (m, 1H), 6.56 - 6.37 (m, 2H), 5.98 - 5.88
(m, 1H), 5.77 - 5.66 (m, 1H), 4.04 - 3.97 (m, 1H), 3.95 - 3.88 (m, 1H), 3.87 - 3.73 (m, 2H), 2.44 - 2.25 (m, 2H). Synthesis of Compound No. 154: (S)-1-(3-((4-((4-Fluoro-1H-indol-5-yl)oxy)pyrido[3,2- d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one
[2109] Step 1. To a mixture of 4-fluoro-1H-indol-5-ol (92.0 mg, 608 μmol) and tert-butyl (3S)-3- (4-chloropyrido[3,2-d]pyrimidin-6-yl)oxypyrrolidine-1-carboxylate (234 mg, 669 μmol) in acetonitrile (2 mL) was added potassium carbonate (168 mg, 1.22 mmol) in one portion at 20 °C under nitrogen. The mixture was stirred at 20 °C for 4 h. On completion, the mixture was diluted with ethyl acetate (10 mL), then filtered. The filtrate was diluted with water (5 mL) and extracted with ethyl acetate (5 mL x 2). The combined organic phase was washed with brine (5 mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography [petroleum ether/ethyl acetate = 10/1 to 1/1] to give tert-butyl (3S)-3-[4- [(4-fluoro-1H-indol-5-yl)oxy]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (270 mg, 95%) as a white solid.
1H NMR (400 MHz, CDCl
3) δ 8.68 (s, 1H), 8.33 (s, 1H), 8.17 (d, J = 8.8 Hz, 1H), 7.31 (d, J = 9.2 Hz, 1H), 7.25 (s, 1H), 7.19 - 7.10 (m, 1H), 6.71 (t, J = 2.0 Hz, 1H), 5.93 (s, 1H), 3.85 - 3.47 (m, 4H), 2.34 - 2.20 (m, 2H), 1.49 (s, 9H). [2110] Step 2. A mixture of tert-butyl (3S)-3-[4-[(4-fluoro-1H-indol-5-yl)oxy]pyrido[3,2- d]pyrimidin -6-yl]oxypyrrolidine-1-carboxylate (110 mg, 236 μmol) in HCl/ethyl acetate (3 mL, 4 M) was stirred at 20 °C for 1 h. On completion, the mixture was concentrated under vacuum to give a residue. The crude product was triturated with methyl tert-butyl ether (10 mL) at 20
oC for 5 min, and then filtered. The filtered cake was dried under vacuum to give 4-[(4-fluoro-3a,7a- dihydro-1H-indol-5-yl)oxy]-6-[(3S)-pyrrolidin-3-yl]oxy-pyrido[3,2-d]pyrimidine (100 mg, crude,
HCl salt) as a yellow solid. [2111] Step 3. To a mixture of 4-[(4-fluoro-3a,7a-dihydro-1H-indol-5-yl)oxy]-6-[(3S)-pyrrolidin- 3-yl] oxy-pyrido[3,2-d]pyrimidine (50.0 mg, 136 μmol, HCl salt) in tetrahydrofuran (0.3 mL) and water (0.1 mL) was added sodium bicarbonate (45.7 mg, 544 μmol) at 0 °C under nitrogen. Then prop-2-enoyl chloride (11.0 mg, 122 μmol) in tetrahydrofuran (0.1 mL) was slowly added at 0 °C and the mixture was stirred at 0 °C for 0.5 h. On completion, 0.2 mL methanol was added to quench the reaction. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water(10mM NH
4HCO
3)-acetonitrile]; B%: 25%-55%, 6 min) to give 1-[(3S)-3-[4-[(4-fluoro-1H-indol-5-yl)oxy]pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidin-1- yl]prop-2-en-1-one (31.3 mg, 74.6 μmol, 54%) as a white solid. m/z ES+ [M+H]
+ 420.1;
1H NMR (400 MHz, DMSO-d
6) δ 11.52 (br. s, 1H), 8.64 (d, J = 1.6 Hz, 1H), 8.31 (d, J = 9.2 Hz, 1H), 7.54 (dd, J = 3.2, 9.2 Hz, 1H), 7.48 (t, J = 2.8 Hz, 1H), 7.31 (d, J = 8.8 Hz, 1H), 7.11 (dt, J = 3.6, 8.0 Hz, 1H), 6.71 - 6.52 (m, 2H), 6.15 (ddd, J = 2.4, 6.0, 16.8 Hz, 1H), 5.96 - 5.79 (m, 1H), 5.68 (ddd, J = 2.4, 10.0, 16.0 Hz, 1H), 4.05 - 3.97 (m, 0.5H), 3.90 - 3.77 (m, 1.5H), 3.77 - 3.63 (m, 1.5H), 3.57 - 3.46 (m, 0.5H), 2.40 – 2.17 (m, 2H). Synthesis of Compound No.155: (S)-1-(3-((4-((1H-Indazol-5-yl)oxy)pyrido[3,2-d]pyrimidin- 6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one
[2112] Step 1. To a mixture of (S)-tert-butyl 3-((4-chloropyrido[3,2-d]pyrimidin-6- yl)oxy)pyrrolidine-1- carboxylate (100 mg, 285 μmol) and 1H-indazol-5-ol (45.9 mg, 342 μmol) in acetonitrile (1 mL) was added potassium carbonate (78.8 mg, 570 μmol) in one portion at 20 °C under nitrogen. The mixture was stirred at 20 °C for 12 h. On completion, the mixture was filtered and the filtered cake was washed with acetonitrile (2 mL x 3). The filtrate was then concentrated
in vacuo to give a residue. The residue was purified by prep-TLC [silica, petroleum ether/ ethyl acetate = 1/ 1, R
f = 0.15] to give (S)-tert-butyl3-((4-((1H-indazol-5-yl)oxy)pyrido[3,2- d]pyrimidin-6-yl)oxy)pyrrolidine-1-carboxylate (80 mg, 63%) as a white solid.
1H NMR (400 MHz, DMSO-d6) δ 13.21 (s, 1H), 8.62 (s, 1H), 8.29 (d, J = 9.2 Hz, 1H), 8.09 (s, 1H), 7.68 (s, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.53 (d, J = 9.2 Hz, 1H), 7.30 (br. d, J = 8.4 Hz, 1H), 5.78 (br. d, J = 16.4 Hz, 1H), 3.78 - 3.65 (m, 1H), 3.56 - 3.43 (m, 2H), 3.43 - 3.35 (m, 1H), 2.38 - 2.09 (m, 2H), 1.40 (d, J = 6.8 Hz, 9H). [2113] Step 2. To a mixture of (S)-tert-butyl3-((4-((1H-indazol-5-yl)oxy)pyrido[3,2-d]pyrimidin- 6-yl)oxy) pyrrolidine-1-carboxylate (100 mg, 223 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL) in one portion at 20 °C under nitrogen. The mixture was stirred at 20 °C for 1 h. On completion, the mixture was concentrated in vacuo to give (S)-4-((1H-indazol-5- yl)oxy)-6-(pyrrolidin-3- yloxy)pyrido[3,2-d]pyrimidine (100 mg, crude, trifluoroacetic acid salt) as a yellow oil. [2114] Step 3. To a mixture of (S)-4-((1H-indazol-5-yl)oxy)-6-(pyrrolidin-3-yloxy)pyrido[3,2- d]pyrimidine (100 mg, 287 μmol) in tetrahydrofuran (1 mL) and water (0.25 mL) was added sodium bicarbonate (96.5 mg, 1.15 mmol) in one portion at 20 °C under nitrogen. Then the mixture was cooled to 0 °C and a solution of prop-2-enoyl chloride (23.4 mg, 258 μmol, 21 μL) in tetrahydrofuran (1 mL) was added dropwise at 0 °C. The mixture was stirred at 0 °C for 2 h. On completion, the mixture was quenched by methanol (0.5 mL). And the mixture was purified by prep-HPLC ( column: Phenomenex Gemini-NX C1875*30mm*3um;mobile phase: [water(10mM NH
4HCO
3)-acetonitrile];B%: 15%-40%,6min) to give (S)-1-(3-((4-((1H-indazol-5- yl)oxy)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one (16.3 mg, 40.5 μmol, 14%) as a white solid. m/z ES+ [M+H]
+ 403.0;
1H NMR (400 MHz, DMSO-d
6) δ 13.21 (s, 1H), 8.63 (d, J = 2.8 Hz, 1H), 8.30 (d, J = 9.2 Hz, 1H), 8.10 (s, 1H), 7.69 (br. s, 1H), 7.64 (d, J = 9.2 Hz, 1H), 7.53 (dd, J = 9.2, 3.2 Hz, 1H), 7.31 (br. d, J = 8.8 Hz, 1H), 6.69 - 6.52 (m, 1H), 6.15 (ddd, J = 16.8, 5.6, 2.4 Hz, 1H), 5.94 - 5.78 (m, 1H), 5.68 (ddd, J = 16.4, 9.8, 2.4 Hz, 1 H), 4.03 - 3.98 (m, 0.5H), 3.87 - 3.64 (m, 3H), 3.57 - 3.45 (m, 0.5H), 2.42 - 2.20 (m, 2H). Synthesis of Compound No. 156: (S)-1-(3-((4-(Benzo[d]isoxazol-6-yloxy)pyrido[3,2- d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one
[2115] Step 1. To a mixture of 1,2-benzoxazol-6-ol (69.3 mg, 513 μmol) in acetonitrile (1 mL) was added potassium carbonate (118 mg, 855 μmol) and tert-butyl (3S)-3-(4-chloropyrido[3,2- d]pyrimidin-6-yl) oxypyrrolidine-1-carboxylate (150 mg, 428 μmol) in one portion at 20 °C under nitrogen. The mixture was stirred at 20 °C for 12 h. On completion, the mixture was filtered and the filter cake was washed with acetonitrile (2 mL x 3). The filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography [silica, petroleum ether/ ethyl acetate = 1/ 0 to 0/ 1] to give (S)-tert-butyl 3-((4-(benzo[d]isoxazol-6-yloxy)pyrido[3,2- d]pyrimidin-6-yl) oxy)pyrrolidine-1-carboxylate (100 mg, 52%) as a yellow solid.
1H NMR (400 MHz, DMSO-d
6) δ 8.71 - 8.78 (m, 1H), 8.29 - 8.38 (m, 1H), 7.71 - 7.80 (m, 1H), 7.50 - 7.61 (m, 1H), 6.94 (d, J = 2.0 Hz, 1 H), 6.89 (dd, J = 8.8, 2.4 Hz, 1H), 6.28 - 6.42 (m, 1H), 5.71 (br. s, 1H), 3.63 - 3.73 (m, 1H), 3.42 - 3.55 (m, 2H), 3.34 - 3.42 (m, 1H), 2.11 - 2.35 (m, 2H), 1.40 (br. d, J = 10.8 Hz, 9H). [2116] Step 2. To a solution of ((S)-tert-butyl 3-((4-(benzo[d]isoxazol-6-yloxy)pyrido[3,2- d]pyrimidin-6- yl)oxy)pyrrolidine-1-carboxylate (100 mg, 223 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL) in one portion at 20 °C under nitrogen. The mixture was stirred at 20 °C for 1 h. On completion, the mixture was concentrated in vacuo to give (S)-6-((6- (pyrrolidin-3-yloxy)pyrido[3,2-d]pyrimidin-4-yl)oxy)benzo[d]isoxazole (100 mg, crude, TFA salt) as a black oil. m/z ES+ [M+H]+ 350.1 [2117] Step 3. To a mixture of (S)-6-((6-(pyrrolidin-3-yloxy)pyrido[3,2-d]pyrimidin-4- yl)oxy)benzo [d]isoxazole (100 mg, 286 μmol, TFA salt) and sodium bicarbonate (96.2 mg, 1.15 mmol) in tetrahydrofuran (1 mL) and water (0.25 mL) was added prop-2-enoyl chloride (23.3 mg, 258 μmol, 21.0 μL) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 1 h. On completion, The mixture was quenched by methanol (0.5 mL) and the residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um;mobile phase: [water(10mM
NH
4HCO
3)-acetonitrile];B%: 10%-40%, 8 min) to give (S)-1-(3-((4-(benzo[d]isoxazol-6- yloxy)pyrido[3,2-d]pyrimidin-6-yl) oxy)pyrrolidin-1-yl)prop-2-en-1-one (13.9 mg, 34.4 μmol, 12%) as a white solid. m/z ES+ [M+H]
+ 404.0;
1H NMR (400 MHz, DMSO-d
6) δ 8.75 (d, J = 4.8 Hz, 1H), 8.34 (dd, J = 9.2, 1.6 Hz, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.57 (dd, J = 9.2, 3.6 Hz, 1H), 6.95 - 6.92 (m, 1H), 6.87 (dd, J = 8.8, 1.6 Hz, 1H), 6.68 - 6.50 (m, 1H), 6.15 (ddd, J = 16.8, 7.2, 2.4 Hz, 1H), 5.84 - 5.74 (m, 1H), 5.72 - 5.62 (m, 1H), 4.01 (dd, J = 12.0, 4.8 Hz, 0.5H), 3.86 - 3.66 (m, 3H), 3.65 - 3.45 (m, 0.5H), 2.43 – 2.16 (m, 2H). Synthesis of Compound No. 157: (S)-1-(3-((4-(Imidazo[1,2-a]pyridin-7-yloxy)pyrido[3,2- d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one
[2118] Step 1. To a mixture of imidazo[1,2-a]pyridin-7-ol (50.0 mg, 373 μmol) and (S)-4- (imidazo[1,2-a] pyridin-7-yloxy)-6-(pyrrolidin-3-yloxy)pyrido[3,2-d]pyrimidine (131 mg, 373 μmol) in dimethylformamide (1 mL) was added potassium carbonate (103 mg, 746 μmol) at 20 °C under nitrogen. The mixture was stirred at 20 °C for 16 h. The reaction mixture was poured into water (5 mL) and extrated with ethyl acetate (10 mL × 3). The combined organic phase was washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography [dichloromethane: methanol = 40:1 to 20: 1] to give (S)-tert-butyl3-((4-(imidazo[1,2-a]pyridin-7-yloxy)pyrido[3,2-d]pyrimidin-6-yl)oxy)- pyrrolidine-1-carboxylate (100 mg, 60%) as a yellow solid.
1H NMR (400 MHz, DMSO-d
6) δ 8.72 - 8.64 (m, 2H), 8.32 (d, J = 9.2 Hz, 1H), 8.00 (s, 1H), 7.64 - 7.53 (m, 3H), 7.04 - 6.97 (m, 1H), 5.81 - 5.70 (m, 1H), 3.77 - 3.63 (m, 1H), 3.55 - 3.37 (m, 3H), 2.35 - 2.09 (m, 2H), 1.40 (d, J = 7.2 Hz, 9H). [2119] Step 2. A mixture of (S)-tert-butyl 3-((4-(imidazo[1,2-a]pyridin-7-yloxy)pyrido[3,2- d]yrimidin6-yl) xy)rrolidine-1-carboxylate (50.0 mg, 111 μmol) in trifluoroacetic acid (0.10 mL)
and dichloromethane (0.50 mL) was stirred at 20 °C for 0.5 h. The organic solution was removed by nitrogen purge to give (S)-4-(imidazo[1,2-a]pyridin-7-yloxy)-6-(pyrrolidin-3- yloxy)pyrido[3,2-d]pyrimidine (40.0 mg, trifluoroacetic acid salt, crude) as a yellow oil. m/z ES+ [M+H]
+ 349.3 [2120] Step 3. To a mixture of (S)-4-(imidazo[1,2-a]pyridin-7-yloxy)-6-(pyrrolidin-3- yloxy)pyrido[3,2-d] pyrimidine (40.0 mg, 115 μmol, trifluoroacetic acid salt) in tetrahydrofuran (0.40 mL) and water (0.10 mL) was added sodium bicarbonate (48.2 mg, 574 μmol) and prop-2- enoyl chloride (9.35 mg, 103 μmol) at 0
o C under nitrogen. The mixture was stirred at 0 °C for 30 min. The reaction mixture was quenched with methanol (0.5 mL) and the organic solution was removed by nitrogen purge. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875*30 mm*3 um; mobile phase: [water (10 mM NH
4HCO
3)-acetonitrile]; B%: 15%-40%, 6 min) to give (S)-1-(3-((4- (imidazo[1,2-a]pyridin-7-yloxy)pyrido[3,2-d]pyrimidin-6- yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one (4.41 mg, 11.0 μmol, 10%) as a white solid. m/z ES+ [M+H]
+ 403.1;
1H NMR (400 MHz, DMSO-d
6) δ 8.71 (d, J = 4.8 Hz, 1H), 8.66 (d, J = 7.2 Hz, 1H), 8.32 (d, J = 9.2 Hz, 1H), 7.99 (s, 1H), 7.60 (s, 1H), 7.58 - 7.51 (m, 2H), 7.00 (dd, J = 2.0, 7.2 Hz, 1H), 6.72 - 6.49 (m, 1H), 6.15 (ddd, J = 2.4, 6.0, 16.8 Hz, 1H), 5.92 - 5.76 (m, 1H), 5.68 (ddd, J = 2.4, 10.4, 16.0 Hz, 1H), 3.98 (dd, J = 4.4, 12.0 Hz, 0.5H), 3.88 - 3.63 (m, 3H), 3.55 – 3.45 (m, 0.5H), 2.41 - 2.16 (m, 2H). Synthesis of Compound No.158: 1-(3-((4-((4-Phenoxyphenyl)amino)pyrido[3,2-d]pyrimidin- 6-yl)methyl)pyrrolidin-1-yl)prop-2-en-1-one
[2121] Step 1. To a solution of N'-(6-chloro-2-cyano-3-pyridyl)-N,N-dimethyl-formamidine (2.7 g, 12.9 mmol) in toluene (30 mL) and acetic acid (30 mL) was added 4-phenoxyaniline (2.40 g, 12.9 mmol). The mixture was stirred at 110 °C for 3 h. On completion, the mixture was concentrated in vacuo and purified by column chromatography (petroleum ether/ethyl acetate=5/1~3/1) to give compound 6-chloro-N-(4-phenoxyphenyl)pyrido[3,2-d]pyrimidin-4- amine (3 g, 66%) as a yellow solid. m/z ES+ [M+H]
+ 349.2 [2122] Step 2. To an 40 mL vial equipped with a stir bar was added 6-chloro-N-(4- phenoxyphenyl)pyrido[3,2-d]pyrimidin-4-amine (300 mg, 860 μmol), tert-butyl 3- (bromomethyl)pyrrolidine-1-carboxylate (272 mg, 1.03 mmol), [4,4′-bis(1,1-dimethylethyl)-2,2′- bipyridine-N1,N1′]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]Iridium(III) hexafluorophosphate (9.65 mg, 8.60 μmol), [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine] Nickel(II) dichloride (1.71 mg, 4.30 μmol), tris(trimethylsilyl)silane (213 mg, 860 μmol), sodium carbonate (182 mg, 1.72 mmol) in dimethoxyethane (8 mL). The vial was sealed and placed under nitrogen. The reaction was stirred and irradiated with a 34 W blue LED lamp (7 cm away), with cooling fan to keep the reaction temperature at 25 °C for 4 h. On completion, the mixture was concentrated in vacuo and purified by column chromatography (petroleum ether/ethyl acetate=1/1) to give compound tert-butyl 3-[[4-(4-phenoxyanilino)pyrido[3,2-d]pyrimidin-6-yl]methyl]pyrrolidine-1- carboxylate (120 mg, 28%) as a yellow solid. [2123] Step 3. To a solution of tert-butyl 3-[[4-(4-phenoxyanilino)pyrido[3,2-d]pyrimidin-6- yl]methyl]pyrrolidine-1-carboxylate (120 mg, 241 μmol) in dichloromethane (5 mL) was added
trifluoroacetic acid (770 mg, 6.75 mmol). The mixture was stirred at 25 °C for 1 h. On completion, the mixture was concentrated in vacuo to give compound N-(4-phenoxyphenyl)-6-(pyrrolidin-3- ylmethyl)pyrido[3,2-d]pyrimidin-4-amine (120 mg, crude, trifluoroacetic acid salt) as a yellow solid. m/z ES+ [M+H]
+ 398.3 [2124] Step 4. To a solution of N-(4-phenoxyphenyl)-6-(pyrrolidin-3-ylmethyl)pyrido[3,2- d]pyrimidin-4-amine (120 mg, 234 μmol, trifluoroacetic acid salt) in tetrahydrofuran (2 mL) and water (2 mL) was added sodium bicarbonate (98.5 mg, 1.17 mmol) and prop-2-enoyl chloride (25.3 mg, 281 μmol). The mixture was stirred at 25 °C for 0.5 h. On completion, the mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(0.225% formic acid)-acetonitrile]; B%: 34%-64%,10 min) to give 1-[3-[[4-(4-phenoxyanilino)pyrido[3,2-d]pyrimidin-6-yl]methyl]pyrrolidin-1- yl]prop-2-en-1-one (50 mg, 100 μmol, 43%, 100% purity, formic acid salt) as a yellow solid. m/z ES+ [M+H]
+ 452.1;
1H NMR (400 MHz, DMSO-d
6) δ 9.87 (d, J = 4.0 Hz, 1H), 8.61 (s, 1H), 8.14 (dd, J = 2.8, 8.4 Hz, 1H), 8.05 - 7.94 (m, 2H), 7.84 (d, J = 8.4 Hz, 1H), 7.40 (t, J = 8.0 Hz, 2H), 7.15 - 7.07 (m, 3H), 7.02 (d, J = 8.0 Hz, 2H), 6.56 (td, J =10.0, 16.8 Hz, 1H), 6.11 (ddd, J = 2.4, 8.8, 16.8 Hz, 1H), 5.68 - 5.57 (m, 1H), 3.80 - 3.68 (m, 1H), 3.62 - 3.49 (m, 2H), 3.19 (dd, J = 7.6, 12.0 Hz, 1H), 3.15 - 3.05 (m, 2H), 3.03 - 2.83 (m, 1H), 2.11 - 1.93 (m, 1H), 1.81 - 1.60 (m, 1H). Synthesis of Compound No.160: (S)-1-(3-((4-(3-Chloro-2-fluoro-4-methoxyphenoxy)pyrido- [3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one
[2125] Step 1. To a solution of 2-chloro-3-fluoro-phenol (3.00 g, 20.5 mmol) in dimethylformamide (30 mL) was added potassium carbonate (8.49 g, 61.4 mmol) and methyl iodide (14.5 g, 102 mmol). The mixture was stirred at 60 °C for 6 h. On completion, the mixture was poured into ammonium chloride solution (20 mL) and then extracted with ethyl acetate (40 mL x 2). The combined organic phase was washed with brine (60 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography [petroleum ether/ethyl acetate = 50/1 to 0/1] to give 2-chloro-1-fluoro-3- methoxybenzene (2.58 g, 79%) as a yellow oil.
1H NMR (400 MHz, CDCl
3) δ 7.18 (dt, J = 6.4, 8.4 Hz, 1H), 6.79 (dt, J = 1.2, 8.4 Hz, 1H), 6.73 (d, J = 8.8 Hz, 1H), 3.91 (d, J = 0.8 Hz, 3H). [2126] Step 2. To a solution of 2-chloro-1-fluoro-3-methoxy-benzene (611 mg, 3.81 mmol) in dichloromethane (5 mL) was added bromine (608 mg, 3.81 mmol) portionwise at 0 °C. The mixture was stirred at 20 °C for 6 h. On completion, the residue was poured into water (30 mL). The aqueous phase was extracted with dichloromethane (20 mL x 2). The combined organic phase was washed with sodium thiosulfate solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 1-bromo-3-chloro-2-fluoro-4-methoxybenzene (763 mg, 84 %) as a white soild.
1H NMR (400 MHz, CDCl
3) δ 7.40 (dd, J = 7.6, 9.2 Hz, 1H), 6.66 (dd, J = 1.6, 9.2 Hz, 1H), 3.92 (s, 3H).
[2127] Step 3. A mixture of 1-bromo-3-chloro-2-fluoro-4-methoxy-benzene (300 mg, 1.25 mmol), bis(pinacolato)diboron (1.59 g, 6.26 mmol), potassium acetate (984 mg, 10.0 mmol) in dioxane (15 mL) was degassed and purged with nitrogen 3 times. Then [1,1’- bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (205 mg, 251 μmol) was added. The mixture was stirred at 110 °C for 10 h under nitrogen atmosphere. On completion, the reaction mixture was quenched by water (30 mL). The aqueous phase was extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography [petroleum ether/ethyl acetate = 50/1 to 0/1] to give 2-(3- chloro-2-fluoro-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (673 mg, crude) as a white soild.
1H NMR (400 MHz, CDCl
3) δ 7.60 (dd, J = 6.8, 8.4 Hz, 1H), 6.75 - 6.70 (m, 1H), 3.94 (s, 3H), 1.35 (s, 9H). [2128] Step 4. To a solution of 2-(3-chloro-2-fluoro-4-methoxy-phenyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (2.63 g, 9.18 mmol) in tetrahydrofuran (40 mL) and water (20 mL) was added sodium perborate tetrahydrate (14.1 g, 91.8 mmol). The mixture was stirred at 55 °C for 3 h. On completion, the reaction mixture was filtered, and the filtrate was diluted with water (20 mL). The aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with brine (70 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography [petroleum ether/ethyl acetate = 50/1 to 1/1] to give 3-chloro-2-fluoro-4-methoxyphenol (185 mg, 11%) as a light yellow solid.
1H NMR (400 MHz, CDCl
3) δ 6.89 (t, J = 9.2 Hz, 1H), 6.64 (dd, J = 2.4, 9.2 Hz, 1H), 4.82 (d, J = 3.6 Hz, 1H), 3.87 (s, 3H). [2129] Step 5. To a solution of 3-chloro-2-fluoro-4-methoxy-phenol (83.1 mg, 470 μmol) in acetonitrile (5mL) was added tert-butyl (3S)-3-(4-chloropyrido[3,2-d]pyrimidin-6- yl)oxypyrrolidine-1-carboxylate (150 mg, 428 μmol) and potassium carbonate (118 mg, 855 μmol). Then the mixture was stirred at 20 °C for 2 h. On completion, the reaction mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by prep-TLC (silica, petroleum ether: EA = 2:1) to give (S)-tert-butyl 3-((4-(3-chloro-2-fluoro-4- methoxyphenoxy)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidine-1-carboxylate (25 mg, 12%) as a white solid.
1H NMR (400 MHz, CDCl
3) δ 8.68 (s, 1H), 8.17 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 9.2 Hz, 1H), 7.23 (br. d, J = 6.0 Hz, 1H), 6.83 (d, J = 10.8 Hz, 1H), 5.87 (br. s, 1H), 3.98 (s, 3H), 3.85
- 3.69 (m, 2H), 3.64 – 3.50 (m, 2H), 2.30 – 2.20 (m, 2H), 1.49 (s, 9H). [2130] Step 6. A solution of tert-butyl (3S)-3-[4-(3-chloro-2-fluoro-4-methoxy-phenoxy)- pyrido[3,2-d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (20.0 mg, 40.7 μmol) in trifluoroacetic acid (0.1 mL) and dichloromethane (1 mL) was stirred at 20 °C for 2 h. On completion, the reaction was concentrated under vacuum to give (S)-4-(3-chloro-2-fluoro-4-methoxyphenoxy)-6- (pyrrolidin-3-yloxy)pyrido[3,2-d]pyrimidine (20 mg, crude) as a yellow oil. m/z ES+ [M+H]
+ 391.1 [2131] Step 7. To a solution of 4-(3-chloro-2-fluoro-4-methoxy-phenoxy)-6-[(3S)-pyrrolidin-3- yl]oxy-pyrido[3,2-d]pyrimidine (20.0 mg, 51.2 μmol) in tetrahydrofuran (1 mL) and water (0.25 mL) was added sodium bicarbonate (21.5 mg, 256 ummol) and prop-2-enoyl chloride (4.17 mg, 46.1 μmol). The mixture was stirred at -10 - 0 °C for 2 h. On completion, the reaction mixture was diluted with methanol (1 mL) and stirred for 2 min. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18100*25mm*5um;mobile phase: [water(10mM NH
4HCO
3)- acetonitrile];B%: 25%-65%,9.5min) to give (S)-1-(3-((4-(3-chloro-2-fluoro-4- methoxyphenoxy)pyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-on (6.8 mg, 15.3 μmol, 30%) as a white solid. m/z ES+ [M+H]
+ 445.1;
1H NMR (400 MHz, CDCl
3) δ 8.69 (d, J = 3.6 Hz, 1H), 8.19 (t, J = 8.4 Hz, 1H), 7.35 - 7.28 (m, 1H), 7.26 - 7.22 (m, 1H), 6.83 (dd, J = 1.6, 9.2 Hz, 1H), 6.57 - 6.38 (m, 2H), 6.00 – 5.92 (m, 1H), 5.76 - 5.65 (m, 1H), 4.06 - 4.00 (m, 1H), 3.98 (s, 3H), 3.96 - 3.72 (m, 3H), 2.49 - 2.26 (m, 2H). Synthesis of Compound No. 161: (S)-1-(3-((4-(3-Chloro-4-morpholinophenoxy)pyrido[3,2- d]pyrimidin-6-yl)(methyl)amino)pyrrolidin-1-yl)prop-2-en-1-one
[2132] Step 1. To a mixture of 1-bromo-2-chloro-4-methoxy-benzene (2.00 g, 9.03 mmol) and morpholine (7.87 g, 90.3 mmol, 7.95 mL) in toluene (5mL) was added sodium tert-butoxide (1.30 g, 13.6 mmol) and (2,2’-bis(diphenylphosphino)-1,1’-binaphthyl) (281 mg, 452 μmol) under nitrogen. Then tris(dibenzylideneacetone)dipalladium(0) (248 mg, 271 μmol) was added at 20 °C. The mixture was stirred at 110 °C for 5 h under nitrogen. On completion, the resulting mixture was diluted in water (5 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography [petroleum ether/ethyl acetate = 80/1 to 30/1] to give 4-(2-chloro-4-methoxy-phenyl)morpholine (1.8 g, 88%) as an orange solid.
1H NMR (400 MHz, CDCl
3) δ 7.00 (d, J = 8.8 Hz, 1H), 6.97 (d, J = 2.8 Hz, 1H), 6.79 (dd, J = 2.8, 8.9 Hz, 1H), 3.91 - 3.84 (m, 4H), 3.78 (s, 3H), 3.02 - 2.94 (m, 4H).
[2133] Step 2. Boron tribromide (880 mg, 3.51 mmol, 339 μL) was added dropwise to a solution of 4-(2-chloro-4-methoxy-phenyl) morpholine (100 mg, 439 μmol) in dichloromethane (1 mL) at -78 °C. The reaction was stirred at -78 °C for 1.5 h, then it was slowly warmed to 20 °C and stirred at 20 °C for 3 h. On completion, the resulting mixture was quenched by saturated sodium bicarbonate (2 mL) and filtered. The filter cake was concentrated to give 3-chloro-4-morpholino- phenol (85 mg, 91%) as a white solid.
1H NMR (400 MHz, DMSO-d
6) δ 7.01 (d, J = 8.8 Hz, 1H), 6.81 (d, J = 2.8 Hz, 1H), 6.70 (dd, J = 2.8, 8.6 Hz, 1H), 3.76 - 3.65 (m, 4H), 2.89 - 2.77 (m, 4H). [2134] Step 3. To a solution of 6-chloro-3-nitro-pyridine-2-carbonitrile (3.67 g, 20.0 mmol) in 1- methylpyrrolidin-2-one (40 mL) was added diisopropylethylamine (7.74 g, 59.9 mmol, 10.4 mL) and tert-butyl (3S)-3-(methylamino)pyrrolidine-1-carboxylate (4 g, 20.0 mmol). The mixture was stirred at 100 °C for 2 h. On completion, the mixture was quenched by 10% citric acid solution (50 mL) and stirred for 5 min. Then the mixture was washed with water (100 mL). The aqueous phase was extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with brine (100 mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo to give (S)-tert-butyl 3-((6-cyano-5-nitropyridin-2-yl)(methyl)amino)pyrrolidine-1-carboxylate (8.48 g, crude) as a brown oil.
1H NMR (400 MHz, CDCl
3) δ 8.32 (d, J = 9.6 Hz, 1H), 6.74 (d, J = 9.6 Hz, 1H), 5.47 (br. s, 1H), 3.72 - 3.53 (m, 2H), 3.47 - 3.23 (m, 2H), 3.08 (s, 3H), 2.26 - 2.13 (m, 1H), 2.10 - 1.98 (m, 1H), 1.48 (s, 9H). [2135] Step 4. To a solution of tert-butyl (3S)-3-[(6-cyano-5-nitro-2-pyridyl)-methyl- amino]pyrrolidine-1-carboxylate (500 mg, 1.44 mmol) in ethanol (5mL) was added Raney Nickel (1.00 g, 17.0 mmol) and hydrazine hydrate (144 mg, 2.88 mmol, 134 μL). The mixture was stirred at 80 °C for 4 h. On completion, the mixture was filtered and concentrated in vacuo. The residue was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combine orangic layer was washed with brine (50 mL), dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography [petroleum ether/ethyl acetate = 50/1 to 0/1] to give (S)-tert-butyl 3-((5-amino-6-carbamoylpyridin-2-yl)(methyl)amino)pyrrolidine-1- carboxylate (482 mg, 99.84%) as a yellow oil. m/z ES+ [M+H]
+ 335.9 [2136] Step 5. A mixture of (S)-tert-butyl 3-((5-amino-6-carbamoylpyridin-2-yl)(methyl)- amino)pyrrolidine-1-carboxylate (600 mg, 1.79 mmol) in triethylorthoformate (15 mL) was stirred at 150 °C for 10 h. On completion, the reaction mixture was concentrated to give a residue. The residue was purified by re-crystallization from methyl tert-butyl ether (50 mL x 3) at 25 °C for 10
min to give (S)-tert-butyl 3-((4-hydroxypyrido[3,2-d]pyrimidin-6-yl)(methyl)amino)pyrrolidine- 1-carboxylate (200 mg, crude) as a brown solid. m/z ES+ [M+H]
+ 346.1 [2137] Step 6. To a solution of tert-butyl (3S)-3-[(4-hydroxypyrido[3,2-d]pyrimidin-6-yl)-methyl- amino]pyrrolidine-1-carboxylate (470 mg, 1.36 mmol) in toluene (10 mL) was added phosphoryl chloride (313 mg, 2.04 mmol, 190 μL) and diisopropylethylamine (879 mg, 6.80 mmol, 1.19 mL). The mixture was stirred at 80 °C for 3 h. On completion, the reaction mixture was concentrated under reduced pressure to remove phosphoryl chloride. The residue was diluted with sodium carbonate (50 mL) and extracted with dichloromethane (50 mL x 2). The combined organic phase was dried with anhydrous sodium sulfate, filtered and concentrated in vacuo to give (S)-tert-butyl 3-((4-chloropyrido[3,2-d]pyrimidin-6-yl)(methyl)amino)pyrrolidine-1-carboxylate (560 mg, crude) as a brown oil. m/z ES+ [M+H]
+ 364.1 [2138] Step 7. To a solution of tert-butyl (3S)-3-[(4-chloropyrido[3,2-d]pyrimidin-6-yl)-methyl- amino]pyrrolidine-1-carboxylate (70.0 mg, 192 μmol) in acetonitrile (1.5 mL) and dimethylformamide (1.5 mL) was added potassium carbonate (266 mg, 1.92 mmol) and 3-chloro- 4-morpholino-phenol (41.1 mg, 192 μmol). The mixture was stirred at 40 °C for 10 h. On completion, the reaction mixture was quenched by water (20 mL). The aqueous phase was extracted with dichloromethane (30 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by prep-TLC (silica, petroleum ether: ethyl acetate = 1:1) to give (S)-tert-butyl 3-((4-(3-chloro-4-morpholinophenoxy)pyrido[3,2-d]pyrimidin-6- yl)(methyl)amino)pyrrolidine-1-carboxylate (72 mg, 69%) as a yellow oil. m/z ES+ [M+H]
+ 541.1 [2139] Step 8. To a solution of (S)-tert-butyl 3-((4-(3-chloro-4-morpholinophenoxy)pyrido[3,2- d]pyrimidin-6-yl)(methyl)amino)pyrrolidine-1-carboxylate (67.0 mg, 124 μmol) in trifluoroacetic acid (0.1 mL) and dichloromethane (1 mL) was stirred at 20 °C for 1 h. On completion, the reaction solution was concentrated to dryness via nitrogen purge. The reaction mixture was adjusted to pH = 5 with saturated sodium bicarbonate solution to give (S)-4-(3-chloro-4-morpholinophenoxy)-N- methyl-N-(pyrrolidin-3-yl)pyrido[3,2-d]pyrimidin-6-amine (67 mg, crude, TFA salt) as a yellow oil. m/z ES+ [M+H]
+ 441.1 [2140] Step 9. To a solution of 4-(3-chloro-4-morpholino-phenoxy)-N-methyl-N-[(3S)- pyrrolidin-3-yl]pyrido[3,2-d]pyrimidin-6-amine (67 mg, 152 μmol, TFA salt) in tetrahydrofuran (1 mL) and water (0.25 mL) was added prop-2-enoyl chloride (12.4 mg, 137 μmol, 11.2 μL) at - 10 °C, then the mixture was stirred at between -10 and 0 °C for 2 h. On completion, the reaction
mixture was diluted with methanol (1 mL) and stirred for 2 min. The mixture was purified by prep- HPLC (column: Waters Xbridge BEH C18 100*30mm*10um;mobile phase: [water(10mM NH
4HCO
3)-acetonitrile];B%: 10%-50%,10min) to give (S)-1-(3-((4-(3-chloro-4- morpholinophenoxy)pyrido[3,2-d]pyrimidin-6-yl)(methyl)amino)pyrrolidin-1-yl)prop-2-en-1- one (4.2 mg, 8.49 μmol, 6 %) as a white solid. m/z ES+ [M+H]
+ 495.2;
1H NMR (400 MHz, CD
3OD) δ 8.42 (s, 1H), 8.05 (d, J = 9.6 Hz, 1H), 7.57 (dd, J = 4.8, 9.2 Hz, 1H), 7.35 (s, 1H), 7.27 - 7.21 (m, 1H), 7.20 – 7.15 (m, 1H), 6.69 - 6.56 (m, 1H), 6.28 (br. d, J = 16.0 Hz, 1H), 5.74 (br. d, J = 10.0 Hz, 1H), 5.61 - 5.42 (m, 1H), 4.10 - 3.94 (m, 1H), 3.91 - 3.81 (m, 5H), 3.77 - 3.61 (m, 1H), 3.60 - 3.43 (m, 1H), 3.17 (d, J = 2.0 Hz, 3H), 3.08 – 3.03 (m, 4H), 2.35 – 2.27 (m, 1H), 2.25 - 2.20 (m, 1H). Synthesis of Compound No. 162: (S)-1-(3-((4-((3-chloro-2-fluorophenyl)amino)-7- fluoropyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one
[2141] Step 1. To a solution of 6-bromo-7-fluoro-pyrido[3,2-d]pyrimidin-4-ol (20.0 g, 82.0 mmol) and DIPEA (42.4 g, 327 mmol) in toluene (240 mL) was added phosphoryl chloride (18.9 g, 123 mmol). The reaction mixture was stirred at 110 °C for 2 h. On completion, the mixture was quenched with water (250 mL) and extracted with ethyl acetate (250 mL × 3). The combined
organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO
2, Petroleum ether: Ethyl acetate=1/0 to 5/1) to give compound 6-bromo-4-chloro-7-fluoro-pyrido[3,2-d]pyrimidine (15.0 g, 57.2 mmol, 69%) as a yellow solid. MS (ESI) m/z 263.9 [M+H]
+;
1H NMR (400 MHz, CDCl3) δ ppm 9.06 (s, 1H), 7.94 (d, J = 6.8 Hz, 1H). [2142] Step 2. A mixture of 6-bromo-4-chloro-7-fluoro-pyrido[3,2-d]pyrimidine (15.0 g, 57.2 mmol) and 3-chloro-2-fluoro-aniline (8.73 g, 60.0 mmol) in MeCN (150 mL) was stirred at 25 °C for 1 h. On completion, the mixture was filtered and the filter cake was washed with acetonitrile (100 mL) to give 6-bromo-N-(3-chloro-2-fluoro-phenyl)-7-fluoro-pyrido[3,2-d]pyrimidin-4- amine (20.5 g, 55.2 mmol, 96%) as a yellow solid. MS (ESI) m/z 373.0 [M+H]
+;
1H NMR (400 MHz, DMSO-d
6) δ ppm 10.10 (s, 1H), 8.89 (s, 1H), 8.45 (d, J = 8.4 Hz, 1H), 7.69 - 7.62 (m, 2H), 7.41 - 7.38 (m, 1H). [2143] Step 3. To a mixture of 6-bromo-N-(3-chloro-2-fluoro-phenyl)-7-fluoro-pyrido[3,2- d]pyrimidin-4-amine (19.5 g, 52.5 mmol) in toluene (195 mL) was added Cs
2CO
3 (51.3 g, 157 mmol), Pd
2(dba)
3 (2.40 g, 2.64 mmol) and di-tert-butyl-[2-(1,3,5-triphenylpyrazol-4-yl)pyrazol- 3-yl]phosphane (2.65 g, 5.25 mmol). The mixture was stirred at 85 °C for 0.2 h under N
2. Then tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (19.7 g, 105 mmol) in toluene (180 mL) was added into the mixture, and the mixture was stirred at 85 °C for 17 h under N
2. On completion, the reaction mixture was filtered. The filtrate was poured into water (200 mL) and extracted with ethyl acetate (300 mL x 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography (SiO
2, petroleum ether/eEthyl acetate/dichloromethane=1/0/0 to 5/1/1) to give compound tert-butyl (3S)-3-[4-(3-chloro-2-fluoro-anilino)-7-fluoro-pyrido[3,2-d]pyrimidin-6- yl]oxypyrrolidine-1-carboxylate (3.5 g, 7.32 mmol, 14%) as a yellow solid. MS (ESI) m/z 478.2 [M+H]
+;
1H NMR (400 MHz, CDCl
3) δ ppm 8.79 - 8.68 (m, 3H), 7.71 (d, J = 9.6 Hz, 1H), 7.13 - 7.05 (m, 2H), 5.70 – 5.60 (m, 1H), 3.79 - 3.55 (m, 4H), 2.35 – 2.25 (m, 2H), 1.42 (s, 9H). [2144] Step 4. A mixture of tert-butyl (3S)-3-[4-(3-chloro-2-fluoro-anilino)-7-fluoro-pyrido[3,2- d]pyrimidin-6-yl]oxypyrrolidine-1-carboxylate (2.8 g, 5.86 mmol) in HCl/ethyl acetate (4 M, 30 mL) was stirred at 25 °C for 0.5 h. On completion, the reaction mixture was concentrated under reduced pressure to give compound (S)-N-(3-chloro-2-fluorophenyl)-7-fluoro-6-(pyrrolidin-3- yloxy)pyrido[3,2-d]pyrimidin-4-amine (2.2 g, 5.82 mmol, crude, HCl salt) as a yellow solid. MS
(ESI) m/z 377.9 [M+H]
+; [2145] Step 5. To a mixture of (S)-N-(3-chloro-2-fluorophenyl)-7-fluoro-6-(pyrrolidin-3- yloxy)pyrido[3,2-d]pyrimidin-4-amine (2.2 g, 5.82 mmol, HCl salt) and NaHCO
3 (1.47 g, 17.5 mmol) in tetrahydrofuran (20 mL) and water (10 mL) was added prop-2-enoyl chloride (580 mg, 6.41 mmol) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 10 min. On completion, the reaction mixture was triturated with methanol/water (1/1, 20 mL) at 25
oC for 10 min and then filtered. The filter cake was washed with ethyl acetate (10 mL) then dried under vacuum to give compound 1-[(3S)-3-[4-(3-chloro-2-fluoro-anilino)-7-fluoro-pyrido[3,2-d]pyrimidin-6- yl]oxypyrrolidin-1-yl]prop-2-en-1-one (1.66 g, 3.66 mmol, 63%, 95% purity) as a yellow solid. MS (ESI) m/z 432.2 [M+H]
+;
1H NMR (400 MHz, DMSO-d
6) δ ppm 9.70 (s, 1H), 8.53 (s, 1H), 8.10 (dd, J = 2.4, 10.4 Hz, 1H), 7.87 - 7.77 (m, 1H), 7.50 (t, J = 7.2 Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H), 6.66 - 6.51 (m, 1H), 6.20 - 6.07 (m, 2H), 5.73 - 5.62 (m, 1H), 4.12 - 3.50 (m, 4H), 2.45 - 2.20 (m, 2H). Synthesis of Compound No. 164: (S)-1-(3-((4-((5-ethynyl-2-fluoropyridin-3-yl)amino)-7- fluoropyrido[3,2-d]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one
[2146] Step 1. To a solution of 5-bromo-2-fluoro-3-nitro-pyridine (3 g, 13.6 mmol) in ethyl acetate (50 mL) was added Pt/V/C (883 mg, 136 μmol, 3% loading) under an inert nitrogen atmosphere. The suspension was degassed under vacuum and purged with H
2 several times. Then the mixture was stirred under H
2 (15 psi) at 25 °C for 2 h. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give 5-bromo-2-fluoropyridin-3-amine (2.4 g, crude) as a yellow solid. m/z ES+ [M+H]
+ 191.0;
1H NMR (400 MHz, CDCl
3) δ ppm 7.58 (t, J = 2.0 Hz, 1H), 7.21 (dd, J = 2.0, 9.2 Hz, 1H), 3.90 (s, 2H).
[2147] Step 2. To a solution of 5-bromo-2-fluoro-pyridin-3-amine (2.0 g, 10.5 mmol) and ethynyl(trimethyl)silane (3.09 g, 31.4 mmol) in dimethylformamide (20 mL) was added CuI (199 mg, 1.05 mmol), Pd(PPh
3)
2Cl
2 (735 mg, 1.05 mmol) and TEA (3.18 g, 31.4 mmol, 4.37 mL). The mixture was stirred at 80 °C for 12 h under N2 atmosphere. On completion, the reaction mixture was diluted with H
2O (150 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over Na
2SO
4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1 to 8/1) to give 2-fluoro-5-((trimethylsilyl)ethynyl)pyridin-3- amine (2 g, 8.74 mmol, 83%, 91% purity) as a yellow solid. m/z ES+ [M+H]
+ 209.4; [2148] Step 3. To a solution of 2-fluoro-5-(2-trimethylsilylethynyl) pyridin-3-amine (1.8 g, 8.64 mmol) in methanol (30 mL) was added potassium carbonate (597 mg, 4.32 mmol). The mixture was stirred at 25 °C for 2 h. On completion, the reaction mixture was concentrated under reduced pressure. The residue was diluted with sat. aqueous ammonium chloride (60 mL) and extracted with ethyl acetate (90 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1 to 6/1) to give (5-ethynyl-2- fluoropyridin-3-amine (780 mg, 5.44 mmol, 63%) as a brown solid.
1H NMR (400 MHz, CDCl
3) δ ppm 7.68 (t, J = 2.0 Hz, 1H), 7.16 (dd, J = 2.0, 10.0 Hz, 1H), 3.89 (s, 2H), 3.11 (s, 1H). [2149] Step 4. To a solution of 6-bromo-7-fluoro-pyrido[3,2-d]pyrimidin-4-ol (2.5 g, 10.3 mmol) in toluene (30 mL) was added diisopropylethylamine (4.63 g, 35.7 mmol, 6.25 mL) and phosphoryl chloride (2.04 g, 13.3 mmol, 1.24 mL). The mixture was stirred at 100 °C for 2 h. On completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate=5/1) to give 6-bromo-4- chloro-7-fluoropyrido[3, 2-d]pyrimidine (2.2 g, 7.54 mmol, 74%) as a yellow solid. m/z ES+ [M+H]
+ 264.2; [2150] Step 5. To a solution of 6-bromo-4-chloro-7-fluoro-pyrido[3,2-d]pyrimidine (1.15 g, 4.38 mmol) in acetonitrile (10 mL) was added 5-ethynyl-2-fluoro-pyridin-3-amine (716 mg, 5.26 mmol). The mixture was stirred at 25 °C for 12 h. On completion, the reaction mixture was filtered. The filtered cake was triturated with petroleum ether (5 mL) to give 6-bromo-N-(5-ethynyl-2- fluoropyridin-3-yl)-7-fluoropyrido [3, 2-d] pyrimidin-4-amine (1.5 g, 3.94 mmol, 90%) as a yellow solid. m/z ES+ [M+H]
+ 362.1;
1H NMR (400 MHz, DMSO-d
6) δ ppm 10.52 (br s, 1H),
8.75 (s, 1H), 8.45 - 8.38 (m, 1H), 8.34 (d, J = 8.8 Hz, 1H), 8.29 (s, 1H), 4.52 (s, 1H). [2151] Step 6. To a mixture of 6-bromo-N-(5-ethynyl-2-fluoro-3-pyridyl)-7-fluoro-pyrido [3, 2-d] pyrimidin-4-amine (1.1 g, 3.04 mmol) in toluene (30 mL) was added caesium carbonate (2.97 g, 9.11 mmol), tris(dibenzylideneacetone)dipalladium(0) (139 mg, 152 μmol) and di-tert-butyl-[2- (1,3,5-triphenylpyrazol-4-yl)pyrazol-3-yl]phosphane (154 mg, 304 μmol). The mixture was stirred at 85 °C for 0.2 h under N
2 atmosphere. tert-Butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (1.13 g, 6.01 mmol) in toluene (80 mL) was added into the mixture, and the mixture was stirred at 85 °C for 14 h under N
2 atmosphere. On completion, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1 to 3/1) to give tert-butyl (3S)-3-[4-[(5- ethynyl-2-fluoro-3-pyridyl)amino]-7-fluoro-pyrido [3, 2-d] pyrimidin-6-yl] oxypyrrolidine-1- carboxylate (300 mg, 602 μmol, 20%) as a yellow solid. m/z ES+ [M+H]
+ 469.2; [2152] Step 7. To a solution of tert-butyl (3S)-3-[4-[(5-ethynyl-2-fluoro-3-pyridyl)amino]-7- fluoro-pyrido [3, 2-d] pyrimidin-6-yl] oxypyrrolidine-1-carboxylate (300 mg, 640 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). The mixture was stirred at 25 °C for 0.5 h. On completion, the reaction mixture was concentrated under reduced pressure to give (S)-N-(5-ethynyl-2-fluoropyridin-3-yl)-7-fluoro-6-(pyrrolidin-3-yloxy) pyrido [3, 2-d] pyrimidin- 4-amine (320 mg, crude, TFA salt) as a yellow oil. m/z ES+ [M+H]
+ 369.3; [2153] Step 8. To a solution of (S)-N-(5-ethynyl-2-fluoropyridin-3-yl)-7-fluoro-6-(pyrrolidin-3- yloxy) pyrido [3, 2-d] pyrimidin-4-amine (320 mg, 663 μmol, TFA salt) in tetrahydrofuran (2 mL) and water (2 mL) was added prop-2-enoyl chloride (60.0 mg, 663 μmol) and sodium bicarbonate (195 mg, 2.32 mmol) at 0 °C. The mixture was stirred at 0 °C for 10 min. On completion, the reaction mixture was quenched by water (30 mL) and filtered. The filtered cake was triturated with methanol (5 mL) to give (S)-1-(3-((4-((5-ethynyl-2-fluoropyridin-3-yl) amino)-7-fluoropyrido [3, 2-d] pyrimidin-6-yl)oxy) pyrrolidin-1-yl) prop-2-en-1-one (157 mg, 353 μmol, 53%, 95% purity) as a yellow solid. m/z ES+ [M+H]
+ 423.1;
1H NMR (400 MHz, DMSO-d
6) δ ppm 9.58 (br s, 1H), 8.60 - 8.53 (m, 2H), 8.23 (s, 1H), 8.13 (dd, J = 2.0, 10.8 Hz, 1H), 6.75 - 6.53 (m, 1H), 6.17 (ddd, J = 2.4, 6.4, 16.8 Hz, 1H), 6.12 - 6.01 (m, 1H), 5.69 (ddd, J = 2.4, 10.4, 17.6 Hz, 1H), 4.50 (s, 1H), 4.13 - 3.82 (m, 2H), 3.74 - 3.49 (m, 2H), 2.39 - 2.22 (m, 2H).
Synthesis of Compound No. 165-236. [2154] Compound Nos.165-236 were synthesized following the procedures described herein and were characterized by
1H NMR and LCMS. See the Table below.
Example 2. Inhibition Activity of Exemplary Compounds of the Present Disclosure [2155] Retroviral Production: EGFR mutants were subcloned into pMXs-IRES-Blasticidin (RTV- 016, Cell Biolabs, San Diego, CA). Retroviral expression vector retrovirus was produced by transient transfection of HEK 293T cells with the retroviral EGFR mutant expression vector pMXs-IRES-Blasticidin (RTV-016, Cell Biolabs), pCMV-Gag-Pol vector and pCMV-VSV-G- Envelope vector. Briefly, HEK 293T/17 cells were plated in 100mm collagen coated plate (354450, Corning Life Sciences, Tewksbury, MA) (4 10
5 per plate) and incubated overnight. The next day, retroviral plasmids (3 Pg of EGFR mutant, 1.0 Pg of pCMV-Gag-Pol and 0.5 Pg pCMV-VSV-G) were mixed in 500 Pl of Optimem (31985, Life Technologies). The mixture was incubated at room temperature for 5 min and then added to Optimem containing transfection reagent Lipofectamine (11668, Invitrogen) and incubated for 20 minutes. Mixture was then added dropwise to HEK 293T cells. The next day the medium was replaced with fresh culture medium and retrovirus was harvested @ 24 and 48 hrs. [2156] Generation of EGFR mutant stable cell lines: BaF3 cells (1.5E5 cells) were infected with 1 ml of viral supernatant supplemented with 8 Pg/ml polybrene by centrifuging for 30 min at 1000 rpm. Cells were placed in a 37°C incubator overnight. Cells were then spun for 5 minutes to pellet
the cells. Supernatant was removed and cells re-infected a fresh 1 ml of viral supernatant supplemented with 8 Pg/ml polybrene by centrifuging for 30 min at 1000 rpm. Cells were placed in 37°C incubator overnight. Cells were then maintained in RPMI containing 10% Heat Inactivated FBS, 2% L-glutamine containing 10 ng/ml IL-3. After 48 hours cells were selected for retroviral infection in 10 Pg/ml Blasticidin for one week. Blasticidin resistant populations were washed twice in phosphate buffered saline before plating in media lacking IL-3 to select for IL-3 independent growth. [2157] Assay for cell proliferation: BaF3 cell lines were resuspended at 1.3E5 c/ml in RPMI containing 10% Heat Inactivated FBS, 2% L-glutamine and 1% Pen/Strep and dispensed in triplicate (17.5E4 c/well) into 96 well plates. To determine the effect of drug on cell proliferation, cells incubated for 3 days in the presence of vehicle control or test drug at varying concentrations. Inhibition of cell growth was determined by luminescent quantification of intracellular ATP content using CellTiterGlo (Promega), according to the protocol provided by the manufacturer. Comparison of cell number on day 0 versus 72 hours post drug treatment was used to plot dose- response curves. The number of viable cells was determined and normalized to vehicle-treated controls. Inhibition of proliferation, relative to vehicle-treated controls was expressed as a fraction of 1 and graphed using PRISM
® software (Graphpad Software, San Diego, CA). EC
50 values were determined with the same application. [2158] Cellular protein analysis: Cell extracts were prepared by detergent lysis (RIPA, R0278, Sigma, St Louis, MO) containing 10 mM Iodoacetamide (786-228, G-Biosciences, St, Louis, MO), protease inhibitor (P8340, Sigma, St. Louis, MO) and phosphatase inhibitors (P5726, P0044, Sigma, St. Louis, MO) cocktails. The soluble protein concentration was determined by micro-BSA assay (Pierce, Rockford IL). Protein immunodetection was performed by electrophoretic transfer of SDS-PAGE separated proteins to nitrocellulose, incubation with antibody, and chemiluminescent second step detection. Nitrocellulose membranes were blocked with 5% nonfat dry milk in TBS and incubated overnight with primary antibody in 5% bovine serum albumin. The following primary antibodies from Cell Signaling Technology were used at 1:1000 dilution: phospho-EGFR[Y1173] and total EGFR. β-Actin antibody, used as a control for protein loading, was purchased from Sigma Chemicals. Horseradish peroxidase-conjugated secondary antibodies were obtained from Cell Signaling Technology and used at 1:5000 dilution. Horseradish peroxidase-conjugated secondary antibodies were incubated in nonfat dry milk for 1 hour.
SuperSignal chemiluminescent reagent (Pierce Biotechnology) was used according to the manufacturer's directions and blots were imaged using the Alpha Innotech image analyzer and AlphaEaseFC software (Alpha Innotech, San Leandro CA). [2159] Tables A and B assign each compound a potency code: A, B, C, D, E, or F. According to the code, A represents an IC50 value ≤10 nM; B represents an IC50 value >10 nM and ≤50 nM; C represents an IC50 value >50 nM and ≤100 nM; D represents an IC50 value >100 nM and ≤200 nM; E represents an IC50 value >200 nM and ≤333 nM; and F represents an IC50 value >333 nM. Table A. Activity for Inhibiting EGFR
Table B. Activity for Inhibiting HER2
EQUIVALENTS [2160] The details of one or more embodiments of the disclosure are set forth in the accompanying description above. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms include plural referents unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated by reference. [2161] The foregoing description has been presented only for the purposes of illustration and is not intended to limit the disclosure to the precise form disclosed, but by the claims appended hereto.
wherein: W is =CH–, =COMe–, =CMe– or =N–; Z is a 4 to 6 membered saturated nitrogen heterocycle or a 5 to 8 membered saturated nitrogen heterobicycle, wherein a nitrogen atom forms an amide with R1-C(O)- and wherein the 4 to 6 membered saturated nitrogen heterocycle or the 5 to 8 membered saturated nitrogen heterobicycle is unsubstituted or substituted with one or more of C1-4 alkyl, C3-4 heterocycloalkyl, CHF2 or C3-4 cycloalkyl; X1 is –NH–, –NMe– or –O–; X2 is –NH–, –N(C1-4 alkyl)–, –O– or –S–; Y is a 6 membered aryl or a 5-9 membered heteroaryl, wherein the 6 membered aryl or the 5-9 membered heteroaryl is unsubstituted or substituted with one or more of a group selected from halogen, CF3, HCF2, OCF3, hydroxy, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylhydroxyl, unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryloxy, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted C1-3 alkoxy-aryl, unsubstituted or substituted C1-3 alkoxy-heteroaryl, unsubstituted or substituted C1-3 alkoxy-heterocycloalkyl, unsubstituted or
substituted C1-3 alkylamino-heterocycloalkyl, unsubstituted or substituted C1-3 alkylamino-aryl, unsubstituted or substituted C1-3 alkylamino-heteroaryl; R1 is –HC=CH2 or –C≡C–Me. [0006] In some embodiments, Z is of formula i
wherein: R2 is hydrogen, C1-4 alkyl, CHF2 or C3-4 cycloalkyl; Ra, Rb are each independently selected from hydrogen, C1-4 alkyl or form togehther an oxiranyl; Rc, Rd are each independently selected from hydrogen, C1-4 alkyl; or one of Ra and Rb and one of Rc and Rd form together with the C-atoms they are attached to a 7 membered or 8 membered nitrogen heterobicycle; m is 1, 2 or 3; and n is 1 or 2. [0007] In some embodiments, the present disclosure provides the compound or the pharmaceutically acceptable salt or stereoisomer thereof of formula I-1 or I-2
wherein: W is =CH–, =COMe–, =CMe– or =N–; X1 is –NH–, –NMe– or –O–; X2 is –NH–, –N(C1-4 alkyl)–, –O– or –S–;
Y is a 6 membered aryl or a 5-9 membered heteroaryl, wherein the 6 membered aryl or the 5-9 membered heteroaryl is unsubstituted or substituted with one or more of a group selected from halogen, CF3, HCF2, OCF3, hydroxy, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylhydroxyl, unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryloxy, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted C1-3 alkoxy-aryl, unsubstituted or substituted C1-3 alkoxy-heteroaryl, unsubstituted or substituted C1-3 alkoxy-heterocycloalkyl, unsubstituted or substituted C1-3 alkylamino-heterocycloalkyl, unsubstituted or substituted C1-3 alkylamino-aryl, unsubstituted or substituted C1-3 alkylamino-heteroaryl; R1 is –HC=CH2 or –C≡C–Me; R2 is hydrogen, C1-4 alkyl, CHF2 or C3-4 cycloalkyl; Ra, Rb are each independently selected from hydrogen, C1-4 alkyl or form together an unsubstituted oxiranyl; Rc, Rd are each independently selected from hydrogen, C1-4 alkyl; m is 1, 2 or 3; n is 1 or 2; and r is 1 or 2. [0008] In some embodiments, Y is of formula ii or iia
wherein: R3, R4, R3’, R4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF3 and OCF3; R5a is hydrogen, halogen, e.g., F or Cl, CF3, HCF2, OCF3, hydroxy, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylhydroxyl, unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryloxy, unsubstituted or substituted C1-3 alkoxy-aryl, unsubstituted or substituted C1-3 alkoxy-heteroaryl or unsubstituted or substituted C1-3 alkoxy-heterocycloalkyl; X3 is –NH– or –NMe–. [0009] In some embodiments, Y is of formula iii or iv
wherein: R3, R4, R3’, R4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF3 and OCF3; R5 is hydrogen, halogen, e.g., F or Cl, CF3, HCF2, OCF3, hydroxy, C1-4 alkoxy or C1-4 alkylhydroxyl; X4 is –O–, –NH–, –NMe–; L is a covalent bond or linear or branched C1-3 alkyl; A is a C6 aryl, a 6 membered heterocycloalkyl or a 5-6 membered heteroaryl, wherein the C6 aryl, 6 membered heterocycloalkyl or 5-6 membered heteroaryl is unsubstituted or substituted with one or more of C1-4 alkyl, OCH2F, HCF2, or halogen, e.g., F or Cl. å [0010] In some embodiments, Y is of formula iii, v, vi or vii
wherein: R3, R4, R3’, R4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF3 and OCF3;
R5 is hydrogen, halogen, e.g., F or Cl, CF3, HCF2, OCF3, hydroxy, C1-4 alkoxy or C1-4 alkylhydroxyl; R6 is hydrogen, C1-4 alkyl, e.g., methyl, HCF2, OCH2F or halogen, e.g., F, Cl; X4 is –O–, –NH–, –NMe–; X5, X5’, X6, X6’, X7, X8, X9, X9’ are independently of each other –N= or –CH=; X8’ is –O–, –S–, –NH– or –NMe–; and L is a covalent bond or linear or branched C1-3 alkyl. [0011] In some embodiments, Y is of formula iii, v-a, e.g., v-a-1 or v-a-2, or vi-a, e.g., vi-a-1, or vii-a, e.g., vii-a-1
wherein: R3, R4, R3’, R4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF3 and OCF3; R5 is hydrogen, halogen, e.g., F or Cl, CF3, HCF2, OCF3, hydroxy, C1-4 alkoxy or C1-4 alkylhydroxyl; R6 is hydrogen, C1-4 alkyl, e.g., methyl, HCF2, OCH2F or halogen, e.g., F, Cl;
X5, X5’, X6, X6’, X7, X8, X9, X9’ are independently of each other –N= or –CH=; X8’ is –O–, –S–, –NH– or –NMe–; and s is 0, 1, 2, 3. [0012] In some embodiments, Y is of formula iii, v-a(i), v-a(ii), e.g., v-a(i)-1, v-a(ii)-1, v-a(i)-2, v-a(ii)-2, or vi-a(i), e.g., vi-a(i)-1, or vii-a(i) or vii-a(ii), e.g., vii-a(i)-1 or vii-a(ii)-1
wherein R3, R4, R3’, R4’ are each independently selected from hydrogen, halogen, e.g., F or Cl, CF3 and OCF3; R5 is hydrogen, halogen, e.g., F or Cl, CF3, HCF2, OCF3, hydroxy, C1-4 alkoxy or C1-4 alkylhydroxyl; R6 is hydrogen, C1-4 alkyl, e.g., methyl, HCF2, OCH2F or halogen, e.g., F, Cl; X5, X5’, X6, X6’, X7, X8, X9, X9’ are independently of each other –N= or –CH=;
X8’ is –O–, –S–, –NH– or –NMe–; and s is 0 or 1. [0013] In some embodiments, wherein Y is of formula v-a(i), v-a(ii), v-a(i)-1, v-a(ii)-1, v-a(i)-2 or v-a(ii)-2, (i) X5, X5’, X6, X6’, X7 are -CH=, or (ii) X5 is =N- and X5’, X6, X6’, X7 are -CH=, or (iii) X6 is =N- and X5, X5’, X6’, X7 are -CH=, or (iv) X7 is =N- and X5, X5’, X6, X6’ are -CH=, or (v) X5 and X6 are –N= and X5’, X6’, X7 are –CH=, or (vi) X5 and X5’ are –N= and X6, X6’, X7 are –CH=, or (vii) X5 and X6’ are –N= and X6, X5’, X7 are –CH=, or (viii) X5 and X7 are –N= and X5’, X6, X6’ are –CH=, or (ix) X6 and X6’ are =N- and X5, X5’, X7 are –CH-, or (x) X6 and X7 are =N- and X5, X5’, X6’ are –CH–. [0014] In some embodiments, wherein Y is of formula vii-a(i), vii-a(ii), vii-a(i)-1 or vii-a(ii)-1, (i) X8’ is –O–, X8 and X9 are –N= and X9’ is –CH=, or (ii) X8’ is –S–, X8 and X9 are –N= and X9’ is – CH=, or (iii) X8’ is –O–, X8, X9 and X9’ is –CH=, or (iv) X8’ is –NH–, X8, X9 are –CH= and X9’ is –N=, or (v) X8’ is –NH–, X8, X9’ are –CH= and X9 is –N=, or (vi) X8’ is –NMe–, X8, X9 are –CH= and X9’ is –N=, or (vii) X8’ is –NMe–, X8, X9’ are –CH= and X9 is –N=, or (viii) X8’ is –NMe–, X9’ is –N=, X8 and X9 are –CH=, or (ix) X8’ is –NH–, X9’ is –N=, X8 and X9 are –CH=, or (x) X8’ is –S–, X8 is –N=, X9 and X9’ are –CH=. [0015] In some embodiments, Y is of formula iii, v-a-3, v-a-4 v-a-5, v-a-6, v-a-7, v-a-8, v-a-9, v- a-10, v-b-1, v-b-2, v-b-3, v-b-4, v-b-5, v-b-6, v-b-7, v-b-8, v-b-9, v-b-10, v-b-11, v-b-12, vi-a, vii- a-1, vii-a-2 or vii-a-3
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: W is =CH–, =C(-O(C1-C6 alkyl))–, =C(C1-C6 alkyl)–, =C(halogen)–, or =N–; Z is 3- to 8-membered heterocycloalkyl optionally substituted with one or more RZ; each RZ independently is halogen, C1-C6 alkyl, C3-C8 cycloalkyl, or 3- to 8-membered heterocycloalkyl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, or 3- to 8-membered heterocycloalkyl is optionally substituted with one or more halogen; X1 is –NH–, –N(C1-C6 alkyl)–, or –O–; X2 is –CH2–, –NH–, –N(C1-C6 alkyl)–, –O–, or –S–; Y is C6 aryl or 5- to 9-membered heteroaryl, wherein the C6 aryl or 5- to 9-membered heteroaryl is optionally substituted with one or more RY; each RY independently: is oxo, halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)-NH-C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3- to 10- membered cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10- membered heteroaryl, -O-(3- to 10-membered cycloalkyl), -O-(3- to 10-membered heterocycloalkyl), -O-(C6-C10 aryl), -O-(5- to 10-membered heteroaryl), -(C1-C6 alkyl)-(3- to 10-membered cycloalkyl), -(C1-C6 alkyl)-(3- to 10-membered heterocycloalkyl), -(C1- C6 alkyl)-(C6-C10 aryl), -(C1-C6 alkyl)-(5- to 10-membered heteroaryl), -O-(C1-C6 alkyl)- (3- to 10-membered cycloalkyl), -O-(C1-C6 alkyl)-(3- to 10-membered heterocycloalkyl), -O-(C1-C6 alkyl)-(C6-C10 aryl), -O-(C1-C6 alkyl)-(5- to 10-membered heteroaryl), -NH-(C1- C6 alkyl)-(3- to 10-membered heterocycloalkyl), -NH-(C1-C6 alkyl)-(C6-C10 aryl), or -NH- (C1-C6 alkyl)-(5- to 10-membered heteroaryl); wherein the -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)-NH-C1-C6 alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -O-(3- to 10-membered cycloalkyl), -O-(3- to 10-membered
heterocycloalkyl), -O-(C6-C10 aryl), -O-(5- to 10-membered heteroaryl), -(C1-C6 alkyl)-(3- to 10-membered cycloalkyl), -(C1-C6 alkyl)-(3- to 10-membered heterocycloalkyl), -(C1- C6 alkyl)-(C6-C10 aryl), -(C1-C6 alkyl)-(5- to 10-membered heteroaryl), -O-(C1-C6 alkyl)- (3- to 10-membered cycloalkyl), -O-(C1-C6 alkyl)-(3- to 10-membered heterocycloalkyl), -O-(C1-C6 alkyl)-(C6-C10 aryl), -O-(C1-C6 alkyl)-(5- to 10-membered heteroaryl), -NH-(C1- C6 alkyl)-(3- to 10-membered heterocycloalkyl), -NH-(C1-C6 alkyl)-(C6-C10 aryl), or -NH- (C1-C6 alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more RYa; or together with another RY and the intervening atoms attached thereto, form 4- to 10- membered cycloalkyl or 4- to 10-membered hetero cycloalkyl, wherein the 4- to 10- membered cycloalkyl or 4- to 10-membered hetero cycloalkyl is optionally substituted with one or more RYa ; each RYa independently is halogen, CN, -OH, -NH2, C1-C6 alkyl, -O(C1-C6 alkyl), -C(=O)- (C1-C6 alkyl), wherein the C1-C6 alkyl or -O(C1-C6 alkyl) is optionally substituted with one or more halogen; and R1 is –HC=CH2 or –C≡C–(C1-C6 alkyl). 
, in which # indicates attachment to R1-C(=O)-. 
which # indicates attachment to R1-C(=O)-. 
, in which # indicates attachment to R1-C(=O)-.
which # indicates attachment to R1-C(=O)-. 
in which # indicates at 1
tachment to R -C(=O)-. 
. 
or a pharmaceutically acceptable salt or stereoisomer thereof. 
or a pharmaceutically acceptable salt or stereoisomer thereof. 
or a pharmaceutically acceptable salt or stereoisomer thereof. 
or a pharmaceutically acceptable salt or stereoisomer thereof. 
or a pharmaceutically acceptable salt or stereoisomer thereof. 
or a pharmaceutically acceptable salt or stereoisomer thereof. 
or a pharmaceutically acceptable salt or stereoisomer thereof. 
or a pharmaceutically acceptable salt or stereoisomer thereof. 
or a pharmaceutically acceptable salt or stereoisomer thereof.