HK1226736A1

HK1226736A1 - 2,6-substituted purine derivatives and their use in the treatment of proliferative disorders

Info

Publication number: HK1226736A1
Application number: HK17100377.4A
Authority: HK
Inventors: D．C．贝埃纳; H.程; S．卓-舒尔茨; T．O．Jr．约翰逊; J．C．卡特; A．永田; S.K.奈尔; S．P．普兰肯
Original assignee: 辉瑞公司
Priority date: 2013-11-21
Filing date: 2014-11-10
Publication date: 2017-10-06

Description

2, 6-substituted purine derivatives and their use in the treatment of proliferative diseases

Technical Field

The present invention relates to novel purine derivatives useful for treating abnormal cell growth, such as cancer, in mammals. The invention also relates to pharmaceutical compositions comprising said compounds and methods of using said compounds and compositions in the treatment of abnormal cell growth in mammals.

Background

Lung cancer is the leading cause of cancer death worldwide, with an estimated 120 million new cases diagnosed each year. In lung adenocarcinoma, the most common form of lung cancer, patients with Epidermal Growth Factor Receptor (EGFR) mutations comprise 10-30% of the total population. For this fraction of patients, EGFR inhibitors such as erlotinib or gefitinib may be the most effective (Paez et al, Science 2004; Lynch et al, NEJM 2004; Pao et al, PNAS 2004). The most common mutations associated with a good response to these inhibitors are deletions in exon 19 (e.g., E740-a750) and point mutations in the activation loop (exon 21, specifically L858R). Other somatic mutations identified to date (but to a lesser extent) include point mutations: G719S, G719C, G719A, L861 and Small insertions in exon 20 (Shigematsu et al, JNIC 2005; Fukuoka et al, JCO 2003; Kris et al, JAMA 2003 and Shepherd et al, NEJM 2004).

Although these agents are effective in treating the EGFR mutant sub-population, most patients who initially respond develop resistance. The most prominent mechanism of observed resistance in approximately 50% of patients is due to a secondary mutation (T790M) occurring in the gatekeeper threonine residue (Kosaka et al, CCR 2006; Balak et al, CCR 2006 and Engelman et al, Science 2007).

Thus, compounds that inhibit EGFR T790M are needed.

Summary of The Invention

Each embodiment described below may be combined with any other embodiment described herein, as long as there is no inconsistency in the combined embodiments. Further, various embodiments described herein include within their scope pharmaceutically acceptable salts of the compounds described herein. Thus, the phrase "or a pharmaceutically acceptable salt thereof" is implied in the description of all compounds described herein.

Embodiments described herein relate to compounds of formula (I):

wherein

R¹Is hydrogen, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, 4-6 membered heterocycloalkyl or 4-6 membered heteroaryl, wherein said C₁-C₆Alkyl is optionally substituted by one, two or three groups selected from halogen, hydroxy and C₁-C₃Substituent of alkoxy, and wherein said C₃-C₆Cycloalkyl, said 4-6 membered heterocycloalkyl and said 4-6 membered heteroaryl are each independently optionally substituted by one, two or three substituents selected from C₁-C₃Alkyl, hydroxy and C₁-C₃Substituent substitution of alkoxy;

ring A is C₆-C₁₀Aryl or 5-12 membered heteroaryl;

R²and R⁵Independently of one another are absent or are hydrogen, halogen,Cyano, difluoromethyl, trifluoromethyl, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Alkoxy, -N (R)¹⁰)(R¹¹)、C₃-C₅Cycloalkyl or 4-6 membered heterocycloalkyl, wherein said C₁-C₆Alkyl is optionally substituted by one, two or three groups selected from halogen, hydroxy, C₁-C₆Alkoxy and-N (R)¹²)(R¹³) Substituted with the substituent(s);

R³absent or hydrogen, halogen, C₁-C₆Alkyl radical, C₂-C₆Alkynyl, C₁-C₆Alkoxy radical, C₃-C₇Cycloalkyl or 3-7 membered heterocycloalkyl, wherein said C₁-C₆Alkyl and said C₁-C₆Each alkoxy group is optionally substituted by one, two or three R¹⁴Is substituted by radicals, and wherein said C₃-C₇Cycloalkyl and said 3-7 membered heterocycloalkyl are each optionally substituted with one, two or three R¹⁵Substituted by groups;

R⁴absent or hydrogen, halogen, C₁-C₆Alkyl or C₃-C₆A cycloalkyl group,

wherein R is²And R³Or R³And R⁴Can be combined to form C₅-C₇A cycloalkyl ring or a 5-7 membered heterocycloalkyl ring, and wherein said C₅-C₇(ii) the cycloalkyl ring and the 5-7 membered heterocycloalkyl ring are each independently optionally substituted with one, two or three R¹⁴Substituted by groups;

q is absent or is O, S or NR⁹；

Ring B is absent or is C₃-C₁₀Cycloalkyl, 3-10 membered heterocycloalkyl, C₆-C₁₀Aryl or 5-12 membered heteroaryl;

R⁶and R⁸Each independently of the other is absent or hydrogenHalogen, cyano, hydroxy, difluoromethyl, trifluoromethyl, C₁-C₃Alkyl radical, C₁-C₃Alkoxy or C₃-C₅Cycloalkyl, wherein said C₁-C₃Alkyl is optionally substituted by hydroxy, difluoromethyl, trifluoromethyl, C₁-C₃Alkoxy or C₃-C₅Cycloalkyl substitution;

R⁷is composed of

When R is⁷When the point of attachment on ring B is a nitrogen atom, then G is absent, and when ring B is absent or when R is present⁷When the point of attachment to ring B is a carbon atom, then G is-NR¹⁸-；

R⁹、R¹²And R¹³Each independently is hydrogen or C₁-C₃An alkyl group;

R¹⁰and R¹¹Each independently is hydrogen or C₁-C₆An alkyl group; or when R is¹⁰And R¹¹Each is C₁-C₃When alkyl, R¹⁰And R¹¹Can be combined together with the nitrogen to which they are attached to form a 4-7 membered heterocycloalkyl ring, wherein the 4-7 membered heterocycloalkyl ring formed is optionally substituted with one, two, three or four R¹⁵Substituted by groups;

R¹⁴each independently of the other being halogen, cyano, C₁-C₃Alkyl, hydroxy, C₁-C₆Alkoxy, -N (R)¹⁹)(R²⁰)、-CON(R²¹)(R²²) Or 3-7 membered heterocycloalkyl, wherein said 3-7 membered heterocycloalkyl is optionally substituted with one, two, three or four R¹⁵Substituted by groups;

R¹⁵each independently is halogen, C₁-C₃Alkyl, hydroxy, C₁-C₆Alkoxy radical,-NH₂、-NHCH₃or-N (CH)₃)₂；

R¹⁶And R¹⁷Each independently is hydrogen or C₁-C₆Alkyl radical, wherein said C₁-C₆Alkyl is optionally substituted by-N (R)²³)(R²⁴) The substitution is carried out by the following steps,

provided that R is¹⁶And R¹⁷Can form C₃-C₅A cycloalkyl ring;

R¹⁸is hydrogen or C₁-C₃An alkyl group;

R¹⁹、R²⁰、R²¹、R²²、R²³and R²⁴Each independently is hydrogen or C₁-C₃An alkyl group; and is

m is 0,1 or 2, with the proviso that when ring B is absent, m is 2; or

A pharmaceutically acceptable salt thereof.

Some embodiments relate to compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein R¹Is C₁-C₆Alkyl or C₃-C₆Cycloalkyl, wherein said C₁-C₆Alkyl is optionally substituted by hydroxy, and wherein said C₃-C₆Cycloalkyl optionally substituted by C₁-C₃Alkyl substitution.

Other embodiments are directed to compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein R¹Is methyl, ethyl, isopropyl or tert-butyl.

Other embodiments are directed to compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein R¹Is optionally substituted by C₁-C₃Alkyl-substituted cyclobutyl.

Some embodiments relate to compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein R²Is hydrogen, methyl, difluoromethyl or methoxy.

Other embodiments are directed to compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein R²Is hydrogen or methyl.

Some embodiments relate to compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein R⁵Is hydrogen, C₁-C₆Alkyl or C₁-C₆An alkoxy group.

Other embodiments are directed to compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein R⁵Is hydrogen, methyl or methoxy.

Other embodiments are directed to compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein R²And R⁵Is hydrogen.

Some embodiments relate to compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein R³Is C₁-C₆Alkyl or 3-7 membered heterocycloalkyl, wherein said C₁-C₆Alkyl is optionally substituted by one or two R¹⁴And wherein said 3-7 membered heterocycloalkyl is optionally substituted with C₁-C₃Alkyl substitution.

Other embodiments are directed to compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein R³Is azetidine, pyrrolidine or piperidine, wherein said azetidine, said pyrrolidine and said piperidine are each optionally substituted with C₁-C₃Alkyl substitution.

Other embodiments are directed to compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein R³Is methyl.

Some embodiments relate to compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein R³Is a 3-7 membered heterocycloalkyl, wherein said 3-7 membered heterocycloalkyl is optionally substituted with one, two or three R¹⁵And (4) substituting the group.

Further embodiments relate to compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein R³Is a taskGround selecting quilt C₁-C₃An alkyl substituted piperidine.

Further embodiments relate to compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein R³Is optionally substituted by C₁-C₃An alkyl substituted piperazine.

Other embodiments are directed to compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein R³Is piperazine optionally substituted with methyl.

Other embodiments are directed to compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein R³Is 4-methyl piperazine.

Other embodiments are directed to compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein R²Is hydrogen, halogen, trifluoromethyl, C₁-C₆Alkyl or C₁-C₆An alkoxy group.

Some embodiments relate to compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein R²Is hydrogen, fluorine, trifluoromethyl, methyl or methoxy.

Some embodiments relate to compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein R²Is hydrogen.

Further embodiments relate to compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein R⁴Is hydrogen.

Other embodiments are directed to compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein R⁴Is hydrogen, halogen or C₁-C₃An alkyl group.

Other embodiments relate to compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein Q is absent.

Other embodiments are directed to compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein Q is O.

Further embodiments relate to compounds of formula (I) or pharmaceutically acceptable salts thereofA salt of (I), wherein Q is NR⁹。

Some embodiments relate to compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein m is 0.

Other embodiments relate to compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein m is 1.

Other embodiments relate to compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring B is 3-10 membered heterocycloalkyl.

Some embodiments relate to compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring B is

Some embodiments relate to a compound or pharmaceutically acceptable salt of any embodiment of the compound of formula (I) having formula (Ia):

wherein

n is 0,1 or 2; and is

p is 0,1 or 2.

Some embodiments relate to a compound of formula (Ia) or a pharmaceutically acceptable salt thereof, wherein n is 0.

Other embodiments relate to compounds of formula (Ia) or a pharmaceutically acceptable salt thereof, wherein n is 1.

Other embodiments relate to compounds of formula (Ia) or a pharmaceutically acceptable salt thereof, wherein p is 1.

Other embodiments relate to compounds of formula (Ia) or a pharmaceutically acceptable salt thereof, wherein n is 1 and p is 1.

Further embodiments relate to compounds of formula (Ia) or a pharmaceutically acceptable salt thereof, wherein R⁶And R⁸Each independently of the others is hydrogen, halogen, C₁-C₃Alkyl or C₁-C₃An alkoxy group.

Some embodiments relate to compounds of formula (Ia) or a pharmaceutically acceptable salt thereof, wherein R⁶Is hydrogen, fluorine, methyl or methoxy.

Some embodiments relate to compounds of formula (Ia) or a pharmaceutically acceptable salt thereof, wherein R⁶Is fluorine.

Further embodiments relate to compounds of formula (Ia) or a pharmaceutically acceptable salt thereof, wherein R⁸Is hydrogen, fluorine or methyl.

Other embodiments are directed to compounds of formula (Ia) or a pharmaceutically acceptable salt thereof, wherein R⁸Is methyl.

Some embodiments relate to compounds of formula (Ia) or a pharmaceutically acceptable salt thereof, wherein R⁷Is composed of

Some embodiments relate to a compound or pharmaceutically acceptable salt of any embodiment of the compound of formula (I) having formula (Ib):

other embodiments are directed to compounds of formula (Ib), or a pharmaceutically acceptable salt thereof, wherein R⁶And R⁸Each independently of the others is hydrogen, halogen, C₁-C₃Alkyl or C₁-C₃An alkoxy group.

Further embodiments relate to formula (Ib)Or a pharmaceutically acceptable salt thereof, wherein R⁶Is hydrogen, fluorine, methyl or methoxy.

Some embodiments relate to compounds of formula (Ib) or a pharmaceutically acceptable salt thereof, wherein R⁶Is fluorine.

Other embodiments are directed to compounds of formula (Ib), or a pharmaceutically acceptable salt thereof, wherein R⁸Is hydrogen, fluorine or methyl.

Other embodiments are directed to compounds of formula (Ib), or a pharmaceutically acceptable salt thereof, wherein R⁸Is methyl.

Some embodiments relate to a compound or pharmaceutically acceptable salt of any embodiment of the compound of formula (I) having formula (Ic):

wherein

J is C or N;

q is 0,1, 2 or 3; and is

v is 0,1, 2 or 3,

provided that q and v cannot be 0 at the same time.

Other embodiments are directed to compounds of formula (Ic) or a pharmaceutically acceptable salt thereof, wherein J is C.

Other embodiments are directed to compounds of formula (Ic) or a pharmaceutically acceptable salt thereof, wherein J is N.

Some embodiments relate to a compound of formula (Ic) or a pharmaceutically acceptable salt thereof, wherein q is 1.

Some embodiments relate to a compound of formula (Ic) or a pharmaceutically acceptable salt thereof, wherein q is 2.

Further embodiments relate to compounds of formula (Ic) or a pharmaceutically acceptable salt thereof, wherein q is 3.

Further embodiments relate to compounds of formula (Ic) or a pharmaceutically acceptable salt thereof, wherein v is 1.

Other embodiments are directed to compounds of formula (Ic) or a pharmaceutically acceptable salt thereof, wherein q is 1 and v is 1.

Other embodiments are directed to compounds of formula (Ic) or a pharmaceutically acceptable salt thereof, wherein q is 2 and v is 1.

Other embodiments are directed to compounds of formula (Ic) or a pharmaceutically acceptable salt thereof, wherein q is 3 and v is 1.

Further embodiments relate to compounds of formula (Ic) or a pharmaceutically acceptable salt thereof, wherein R⁶Is hydrogen, halogen or C₁-C₃An alkoxy group.

Some embodiments relate to compounds of formula (Ic) or a pharmaceutically acceptable salt thereof, wherein R⁶Is hydrogen, fluorine or methoxy.

Further embodiments relate to compounds of formula (Ic) or a pharmaceutically acceptable salt thereof, wherein R⁸Is hydrogen or C₁-C₃An alkyl group.

Other embodiments are directed to compounds of formula (Ic) or a pharmaceutically acceptable salt thereof, wherein R⁸Is hydrogen or methyl.

Some embodiments relate to compounds of formula (Ic) or a pharmaceutically acceptable salt thereof, wherein R⁷Is composed of

Some embodiments relate to a compound or pharmaceutically acceptable salt of any embodiment of the compound of formula (I), wherein m is 0, having formula (Id):

wherein

Q is O or NR⁹。

Other embodiments are directed to compounds of formula (Id) or pharmaceutically acceptable salts thereof, wherein R⁶Is absent.

Further embodiments relate to compounds of formula (Id) or pharmaceutically acceptable salts thereof, wherein R⁷Is composed of

Other embodiments are directed to compounds of formula (Id) or pharmaceutically acceptable salts thereof, wherein R¹⁶、R¹⁷And R¹⁸Is hydrogen.

Some embodiments described herein relate to compounds of formula (II):

wherein

X is CH or N;

w is CR²Or the number of N is greater than the number of N,

provided that one of X and W is N and X and W cannot be both N, and further provided that when W is CR²When then R is³And R⁵At least one of which is hydrogen;

R¹is hydrogen, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, 4-6 membered heterocycloalkyl or 4-6 membered heteroaryl, wherein said C₁-C₆Alkyl radical orOptionally substituted by one, two or three groups selected from halogen, hydroxy and C₁-C₃Substituent of alkoxy, and wherein said C₃-C₆Cycloalkyl, said 4-6 membered heterocycloalkyl and said 4-6 membered heteroaryl are each independently optionally substituted by one, two or three substituents selected from C₁-C₃Alkyl, hydroxy and C₁-C₃Substituent substitution of alkoxy;

R²and R⁵Each independently of the others hydrogen, halogen, cyano, difluoromethyl, trifluoromethyl, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Alkoxy, -N (R)¹⁰)(R¹¹)、C₃-C₅Cycloalkyl or 4-6 membered heterocycloalkyl, wherein said C₁-C₆Alkyl is optionally substituted by one, two or three groups selected from halogen, hydroxy, C₁-C₆Alkoxy and-N (R)¹²)(R¹³) Substituted with the substituent(s);

q is absent or is O, S or NR⁹；

R⁶and R⁸Each independently being absent or hydrogen, halogen, cyano, hydroxy, difluoromethyl, trifluoromethyl, C₁-C₃Alkyl radical, C₁-C₃Alkoxy or C₃-C₅Cycloalkyl, wherein said C₁-C₃Alkyl is optionally substituted by hydroxy, difluoromethyl, trifluoromethyl, C₁-C₃Alkoxy or C₃-C₅Cycloalkyl substitution;

R⁷is composed of

R⁹、R¹²And R¹³Each independently is hydrogen or C₁-C₃An alkyl group;

R¹⁵each independently is halogen, C₁-C₃Alkyl, hydroxy, C₁-C₆Alkoxy, -NH₂、-NHCH₃or-N (CH)₃)₂；

provided that R is¹⁶And R¹⁷Can form C₃-C₅A cycloalkyl ring;

R¹⁸is hydrogen or C₁-C₃An alkyl group;

m is 0,1 or 2, with the proviso that when ring B is absent, m is 2; or

A pharmaceutically acceptable salt thereof.

Further embodiments relate to compounds of formula (II) or pharmaceutically acceptable salts thereof, wherein R¹Is C₁-C₆Alkyl or C₃-C₆Cycloalkyl, wherein said C₁-C₆Alkyl is optionally substituted by hydroxy, and wherein said C₃-C₆Cycloalkyl optionally substituted by C₁-C₃Alkyl substitution.

Some embodiments relate to compounds of formula (II) or a pharmaceutically acceptable salt thereof, wherein R¹Is methyl, ethyl, isopropyl or tert-butyl.

Some embodiments relate to compounds of formula (II) or a pharmaceutically acceptable salt thereof, wherein R¹Is optionally substituted by C₁-C₃Alkyl-substituted cyclobutyl.

Other embodiments are directed to compounds of formula (II) or a pharmaceutically acceptable salt thereof, wherein R²Is hydrogen, methyl, difluoromethyl or methoxy.

Other embodimentsA compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R²Is hydrogen or methyl.

Other embodiments are directed to compounds of formula (II) or a pharmaceutically acceptable salt thereof, wherein R⁵Is hydrogen, C₁-C₆Alkyl or C₁-C₆An alkoxy group.

Further embodiments relate to compounds of formula (II) or pharmaceutically acceptable salts thereof, wherein R⁵Is hydrogen, methyl or methoxy.

Some embodiments relate to compounds of formula (II) or a pharmaceutically acceptable salt thereof, wherein R²And R⁵Is hydrogen.

Some embodiments relate to compounds of formula (II) or a pharmaceutically acceptable salt thereof, wherein R³Is C₁-C₆Alkyl or 3-7 membered heterocycloalkyl, wherein said C₁-C₆Alkyl is optionally substituted by one or two R¹⁴And wherein said 3-7 membered heterocycloalkyl is optionally substituted with C₁-C₃Alkyl substitution.

Other embodiments are directed to compounds of formula (II) or a pharmaceutically acceptable salt thereof, wherein R³Is azetidine, pyrrolidine or piperidine, wherein said azetidine, said pyrrolidine and said piperidine are each optionally substituted with C₁-C₃Alkyl substitution.

Other embodiments are directed to compounds of formula (II) or a pharmaceutically acceptable salt thereof, wherein R³Is methyl.

Some embodiments relate to compounds of formula (II) or a pharmaceutically acceptable salt thereof, wherein R³Is a 3-7 membered heterocycloalkyl, wherein said 3-7 membered heterocycloalkyl is optionally substituted with one, two or three R¹⁵And (4) substituting the group.

Other embodiments are directed to compounds of formula (II) or a pharmaceutically acceptable salt thereof, wherein R³Is optionally substituted by C₁-C₃Alkyl radicalA substituted piperidine.

Further embodiments relate to compounds of formula (II) or pharmaceutically acceptable salts thereof, wherein Q is absent.

Other embodiments relate to compounds of formula (II) or pharmaceutically acceptable salts thereof, wherein Q is O.

Further embodiments relate to compounds of formula (II) or pharmaceutically acceptable salts thereof, wherein Q is NR⁹。

Other embodiments relate to compounds of formula (II) or pharmaceutically acceptable salts thereof, wherein m is 0.

Other embodiments relate to compounds of formula (II) or pharmaceutically acceptable salts thereof, wherein m is 1.

Further embodiments relate to compounds of formula (II) or pharmaceutically acceptable salts thereof, wherein ring B is 3-10 membered heterocycloalkyl.

Some embodiments relate to compounds of formula (II) or a pharmaceutically acceptable salt thereof, wherein ring B is

Some embodiments relate to a compound or pharmaceutically acceptable salt of any embodiment of the compound of formula (II) having formula (IIa):

wherein

n is 0,1 or 2; and is

p is 0,1 or 2.

Some embodiments relate to a compound of formula (IIa) or a pharmaceutically acceptable salt thereof, wherein n is 0.

Other embodiments relate to compounds of formula (IIa) or a pharmaceutically acceptable salt thereof, wherein n is 1.

Other embodiments relate to compounds of formula (IIa) or a pharmaceutically acceptable salt thereof, wherein p is 1.

Some embodiments relate to a compound of formula (IIa) or a pharmaceutically acceptable salt thereof, wherein n is 1 and p is 1.

Further embodiments relate to compounds of formula (IIa) or a pharmaceutically acceptable salt thereof, wherein R is⁶And R⁸Each independently of the others is hydrogen, halogen, C₁-C₃Alkyl or C₁-C₃An alkoxy group.

Further embodiments relate to compounds of formula (IIa) or a pharmaceutically acceptable salt thereof, wherein R is⁶Is hydrogen, fluorine, methyl or methoxy.

Some embodiments relate to compounds of formula (IIa) or a pharmaceutically acceptable salt thereof, wherein R is⁶Is fluorine.

Other embodiments are directed to compounds of formula (IIa) or a pharmaceutically acceptable salt thereof, wherein R is⁸Is hydrogen, fluorine or methyl.

Other embodiments are directed to compounds of formula (IIa) or a pharmaceutically acceptable salt thereof, wherein R is⁸Is methyl.

Some embodiments relate to compounds of formula (IIa) or a pharmaceutically acceptable salt thereof, wherein R is⁷Is composed of

Some embodiments relate to a compound of any embodiment of the compound of formula (II) or a pharmaceutically acceptable salt thereof, having formula (IIb):

other embodiments are directed to compounds of formula (IIb) or a pharmaceutically acceptable salt thereof, wherein R⁶And R⁸Each independently of the others is hydrogen, halogen, C₁-C₃Alkyl or C₁-C₃An alkoxy group.

Some embodiments relate to compounds of formula (IIb) or a pharmaceutically acceptable salt thereof, wherein R⁶Is hydrogen, fluorine, methyl or methoxy.

Some embodiments relate to compounds of formula (IIb) or a pharmaceutically acceptable salt thereof, wherein R⁶Is fluorine.

Other embodiments are directed to compounds of formula (IIb) or a pharmaceutically acceptable salt thereof, wherein R⁸Is hydrogen, fluorine or methyl.

Other embodiments are directed to compounds of formula (IIb) or a pharmaceutically acceptable salt thereof, wherein R⁸Is methyl.

Some embodiments relate to a compound or pharmaceutically acceptable salt of any embodiment of the compound of formula (II), wherein m is 0, having formula (IIc):

wherein

J is C or N;

q is 0,1, 2 or 3; and is

v is 0,1, 2 or 3,

provided that q and v cannot be 0 at the same time.

Some embodiments relate to compounds of formula (IIc) or a pharmaceutically acceptable salt thereof, wherein J is C.

Further embodiments relate to compounds of formula (IIc) or a pharmaceutically acceptable salt thereof, wherein J is N.

Further embodiments relate to compounds of formula (IIc) or a pharmaceutically acceptable salt thereof, wherein q is 1.

Other embodiments are directed to compounds of formula (IIc) or a pharmaceutically acceptable salt thereof, wherein q is 2.

Other embodiments are directed to compounds of formula (IIc) or a pharmaceutically acceptable salt thereof, wherein q is 3.

Some embodiments relate to a compound of formula (IIc) or a pharmaceutically acceptable salt thereof, wherein v is 1.

Some embodiments relate to a compound of formula (IIc) or a pharmaceutically acceptable salt thereof, wherein q is 1 and v is 1.

Many embodiments are directed to compounds of formula (IIc) or a pharmaceutically acceptable salt thereof, wherein q is 2 and v is 1.

Other embodiments are directed to compounds of formula (IIc) or a pharmaceutically acceptable salt thereof, wherein q is 3 and v is 1.

Other embodiments are directed to compounds of formula (IIc) or a pharmaceutically acceptable salt thereof, wherein R⁶Is hydrogen, halogen or C₁-C₃An alkoxy group.

Some embodiments relate to compounds of formula (IIc) or a pharmaceutically acceptable salt thereof, wherein R⁶Is hydrogen, fluorine or methoxy.

Some embodiments relate to compounds of formula (IIc) or a pharmaceutically acceptable salt thereof, wherein R⁸Is hydrogen or C₁-C₃An alkyl group.

Further embodiments relate to compounds of formula (IIc) or a pharmaceutically acceptable salt thereof, wherein R⁸Is hydrogen or methyl.

Further embodiments relate to compounds of formula (IIc) or pharmaceutically acceptable salts thereofA salt of (I) wherein R is⁷Is composed of

Some embodiments relate to a compound or pharmaceutically acceptable salt of any embodiment of the compound of formula (II), wherein m is 0, having formula (IId):

wherein

Q is O or NR⁹。

Other embodiments are directed to compounds of formula (IId) or a pharmaceutically acceptable salt thereof, wherein R⁶Is absent.

Some embodiments relate to compounds of formula (IId) or a pharmaceutically acceptable salt thereof, wherein R is⁷Is composed of

Further embodiments relate to compounds of formula (IId) or a pharmaceutically acceptable salt thereof, wherein R¹⁶、R¹⁷And R¹⁸Is hydrogen.

Some embodiments described herein relate to compounds of formula (III):

wherein

provided that R is²Or R⁵At least one of which is hydrogen;

q is absent or is O, S or NR⁹；

Ring B is absent or is C₃-C₁₀Cycloalkyl, 3-to 10-memberedHeterocycloalkyl radical, C₆-C₁₀Aryl or 5-12 membered heteroaryl;

R⁷is composed of

R⁹、R¹²And R¹³Each independently is hydrogen or C₁-C₃An alkyl group;

provided that R is¹⁶And R¹⁷Can form C₃-C₅A cycloalkyl ring;

R¹⁸is hydrogen or C₁-C₃An alkyl group;

m is 0,1 or 2, with the proviso that when ring B is absent, m is 2; or

A pharmaceutically acceptable salt thereof.

Some embodiments relate to compounds of formula (III) or a pharmaceutically acceptable salt thereof, wherein R¹Is C₁-C₆Alkyl or C₃-C₆Cycloalkyl, wherein said C₁-C₆Alkyl is optionally substituted by hydroxy, and wherein said C₃-C₆Cycloalkyl optionally substituted by C₁-C₃Alkyl substitution.

Other embodiments are directed to compounds of formula (III) or a pharmaceutically acceptable salt thereof, wherein R¹Is methyl, ethyl, isopropyl or tert-butyl.

Other embodiments are directed to compounds of formula (III) or a pharmaceutically acceptable salt thereof, wherein R¹Is optionally substituted by C₁-C₃Alkyl-substituted cyclobutyl.

Further embodiments relate to compounds of formula (III) or a pharmaceutically acceptable salt thereof, wherein R²Is hydrogen, methyl, difluoromethyl or methoxy.

Further embodiments relate to compounds of formula (III) or a pharmaceutically acceptable salt thereof, wherein R²Is hydrogen or methyl.

Some embodiments relate to compounds of formula (III) or a pharmaceutically acceptable salt thereof, wherein R⁵Is hydrogen, C₁-C₆Alkyl or C₁-C₆An alkoxy group.

Some embodiments relate to compounds of formula (III) or a pharmaceutically acceptable salt thereof, wherein R⁵Is hydrogen, methyl or methoxy.

Other embodiments are directed to compounds of formula (III) or a pharmaceutically acceptable salt thereof, wherein R²And R⁵Is hydrogen.

Some embodiments relate to compounds of formula (III) or a pharmaceutically acceptable salt thereof, wherein R³Is C₁-C₆Alkyl or 3-7 membered heterocycloalkyl, wherein said C₁-C₆Alkyl is optionally substituted by one or two R¹⁴And wherein said 3-7 membered heterocycloalkyl is optionally substituted with C₁-C₃Alkyl substitution.

Other embodiments are directed to compounds of formula (III) or a pharmaceutically acceptable salt thereof, wherein R³Is azetidine, pyrrolidine or piperidine, wherein said azetidine, said pyrrolidine and said piperidine are each optionally substituted with C₁-C₃Alkyl substitution.

Other embodiments are directed to compounds of formula (III) or a pharmaceutically acceptable salt thereof, wherein R³Is methyl.

Other embodiments are directed to compounds of formula (III) or a pharmaceutically acceptable salt thereof, wherein R³Is a 3-7 membered heterocycloalkyl group, wherein said 3-7 membered heterocycloalkyl groupOptionally substituted by one, two or three R¹⁵And (4) substituting the group.

Other embodiments are directed to compounds of formula (III) or a pharmaceutically acceptable salt thereof, wherein R³Is optionally substituted by C₁-C₃An alkyl substituted piperidine.

Some embodiments relate to a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein Q is absent.

Further embodiments relate to compounds of formula (III) or a pharmaceutically acceptable salt thereof, wherein Q is O.

Some embodiments relate to compounds of formula (III) or a pharmaceutically acceptable salt thereof, wherein Q is NR⁹。

Further embodiments relate to compounds of formula (III) or a pharmaceutically acceptable salt thereof, wherein m is 0.

Other embodiments are directed to compounds of formula (III) or a pharmaceutically acceptable salt thereof, wherein m is 1.

Some embodiments relate to compounds of formula (III) or a pharmaceutically acceptable salt thereof, wherein ring B is 3-10 membered heterocycloalkyl.

Other embodiments are directed to compounds of formula (III) or a pharmaceutically acceptable salt thereof, wherein ring B is

Some embodiments relate to a compound or pharmaceutically acceptable salt of any embodiment of the compound of formula (III) having formula (IIIa):

wherein

n is 0,1 or 2; and is

p is 0,1 or 2.

Further embodiments relate to compounds of formula (IIIa) or a pharmaceutically acceptable salt thereof, wherein n is 0.

Other embodiments relate to compounds of formula (IIIa) or a pharmaceutically acceptable salt thereof, wherein n is 1.

Other embodiments relate to compounds of formula (IIIa) or a pharmaceutically acceptable salt thereof, wherein p is 1.

Other embodiments relate to compounds of formula (IIIa) or a pharmaceutically acceptable salt thereof, wherein n is 1 and p is 1.

Further embodiments relate to compounds of formula (IIIa) or a pharmaceutically acceptable salt thereof, wherein R⁶And R⁸Each independently of the others is hydrogen, halogen, C₁-C₃Alkyl or C₁-C₃An alkoxy group.

Further embodiments relate to compounds of formula (IIIa) or a pharmaceutically acceptable salt thereof, wherein R⁶Is hydrogen, fluorine, methyl or methoxy.

Some embodiments relate to compounds of formula (IIIa) or a pharmaceutically acceptable salt thereof, wherein R is⁶Is fluorine.

Some embodiments relate to compounds of formula (IIIa) or a pharmaceutically acceptable salt thereof, wherein R is⁸Is hydrogen, fluorine or methyl.

Further embodiments relate to compounds of formula (IIIa) or a pharmaceutically acceptable salt thereof, wherein R⁸Is methyl.

Further embodiments relate to compounds of formula (IIIa) or a pharmaceutically acceptable salt thereof, wherein R⁷Is composed of

Some embodiments relate to a compound or pharmaceutically acceptable salt of any embodiment of the compound of formula (III) having formula (IIIb):

further embodiments relate to compounds of formula (IIIb) or a pharmaceutically acceptable salt thereof, wherein R⁶And R⁸Each independently of the others is hydrogen, halogen, C₁-C₃Alkyl or C₁-C₃An alkoxy group.

Some embodiments relate to compounds of formula (IIIb) or a pharmaceutically acceptable salt thereof, wherein R is⁶Is hydrogen, fluorine, methyl or methoxy.

Other embodiments are directed to compounds of formula (IIIb) or a pharmaceutically acceptable salt thereof, wherein R⁶Is fluorine.

Other embodiments are directed to compounds of formula (IIIb) or a pharmaceutically acceptable salt thereof, wherein R⁸Is hydrogen, fluorine or methyl.

Further embodiments relate to compounds of formula (IIIb) or a pharmaceutically acceptable salt thereof, wherein R⁸Is methyl.

Some embodiments relate to a compound or pharmaceutically acceptable salt of any embodiment of the compound of formula (III) having formula (IIIc):

wherein

J is C or N;

q is 0,1, 2 or 3; and is

v is 0,1, 2 or 3,

provided that q and v cannot be 0 at the same time.

Some embodiments relate to a compound of formula (IIIc) or a pharmaceutically acceptable salt thereof, wherein J is C.

Some embodiments relate to a compound of formula (IIIc) or a pharmaceutically acceptable salt thereof, wherein J is N.

Other embodiments are directed to compounds of formula (IIIc) or a pharmaceutically acceptable salt thereof, wherein q is 1.

Other embodiments are directed to compounds of formula (IIIc) or a pharmaceutically acceptable salt thereof, wherein q is 2.

Other embodiments are directed to compounds of formula (IIIc) or a pharmaceutically acceptable salt thereof, wherein q is 3.

Other embodiments are directed to compounds of formula (IIIc) or a pharmaceutically acceptable salt thereof, wherein v is 1.

Further embodiments relate to compounds of formula (IIIc) or a pharmaceutically acceptable salt thereof, wherein q is 1 and v is 1.

Some embodiments relate to a compound of formula (IIIc) or a pharmaceutically acceptable salt thereof, wherein q is 2 and v is 1.

Further embodiments relate to compounds of formula (IIIc) or a pharmaceutically acceptable salt thereof, wherein q is 3 and v is 1.

Some embodiments relate to compounds of formula (IIIc) or a pharmaceutically acceptable salt thereof, wherein R is⁶Is hydrogen, halogen or C₁-C₃An alkoxy group.

Other embodiments are directed to compounds of formula (IIIc) or a pharmaceutically acceptable salt thereof, wherein R⁶Is hydrogen, fluorine or methoxy.

Some embodiments relate to compounds of formula (IIIc) or a pharmaceutically acceptable salt thereof, wherein R is⁸Is hydrogen or C₁-C₃An alkyl group.

Other embodiments are directed to compounds of formula (IIIc) or a pharmaceutically acceptable salt thereof, wherein R⁸Is hydrogen or methyl.

Other embodiments are directed to compounds of formula (IIIc) or a pharmaceutically acceptable salt thereof, wherein R⁷Is composed of

Some embodiments relate to a compound or pharmaceutically acceptable salt of any embodiment of the compound of formula (III), wherein m is 0, having formula (IIId):

wherein

Q is O or NR⁹。

Other embodiments are directed to compounds of formula (IIId) or a pharmaceutically acceptable salt thereof, wherein R⁶Is absent.

Further embodiments relate to compounds of formula (IIId) or a pharmaceutically acceptable salt thereof, wherein R⁷Is composed of

Other embodiments are directed to compounds of formula (IIId) or a pharmaceutically acceptable salt thereof, wherein R¹⁶、R¹⁷And R¹⁸Is hydrogen.

Some embodiments described herein relate to compounds of formula (IV):

wherein

Y is CR⁴Or N:

z is a group selected from the group consisting of CH and N,

provided that Y and Z cannot both be N;

R²is hydrogen, halogen, cyano, difluoromethyl, trifluoromethyl, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Alkoxy, -N (R)¹⁰)(R¹¹)、C₃-C₅Cycloalkyl or 4-6 membered heterocycloalkyl, wherein said C₁-C₆Alkyl is optionally substituted by one, two or three groups selected from halogen, hydroxy, C₁-C₆Alkoxy and-N (R)¹²)(R¹³) Substituted with the substituent(s);

R³is hydrogen, halogen, C₁-C₆Alkyl radical, C₂-C₆Alkynyl, C₁-C₆Alkoxy radical, C₃-C₇Cycloalkyl or 3-7 membered heterocycloalkyl, wherein said C₁-C₆Alkyl and said C₁-C₆Each alkoxy group is optionally substituted by one, two or three R¹⁴Radical take-offAnd wherein said C is₃-C₇Cycloalkyl and said 3-7 membered heterocycloalkyl are each optionally substituted with one, two or three R¹⁵Substituted by groups;

R⁴is hydrogen, halogen, C₁-C₆Alkyl or C₃-C₆A cycloalkyl group,

wherein R is³And R⁴Can be combined to form C₅-C₇A cycloalkyl ring or a 5-7 membered heterocycloalkyl ring, and wherein said C₅-C₇(ii) the cycloalkyl ring and the 5-7 membered heterocycloalkyl ring are each independently optionally substituted with one, two or three R¹⁴Substituted by groups;

q is absent or is O, S or NR⁹；

R⁷is composed of

R⁹、R¹²And R¹³Each independently is hydrogen or C₁-C₃An alkyl group;

R¹⁰and R¹¹Each independently is hydrogen or C₁-C₆An alkyl group; or R¹⁰And R¹¹Can be combined together with the nitrogen to which they are attached to form a 4-7 membered heterocycloalkyl ring, wherein the 4-7 membered heterocycloalkyl ring formed is optionally substituted with one, two, three or four R¹⁵Substituted by groups;

provided that R is¹⁶And R¹⁷Can form C₃-C₅A cycloalkyl ring;

R¹⁸is hydrogen or C₁-C₃An alkyl group;

m is 0,1 or 2, with the proviso that when ring B is absent, m is 2; or

A pharmaceutically acceptable salt thereof.

Some embodiments relate to compounds of formula (IV) or a pharmaceutically acceptable salt thereof, wherein Y is CR⁴。

Further embodiments relate to compounds of formula (IV) or a pharmaceutically acceptable salt thereof, wherein Z is CH.

Some embodiments relate to compounds of formula (IV) or a pharmaceutically acceptable salt thereof, wherein Y is CR⁴And Z is CH.

Further embodiments relate to compounds of formula (IV) or a pharmaceutically acceptable salt thereof, wherein Y is CR⁴And Z is N.

Other embodiments relate to compounds of formula (IV) or a pharmaceutically acceptable salt thereof, wherein Y is N and Z is CH.

Other embodiments are directed to compounds of formula (IV) or a pharmaceutically acceptable salt thereof, wherein R¹Is C₁-C₆Alkyl or C₃-C₆Cycloalkyl, wherein said C₁-C₆Alkyl is optionally substituted by hydroxy, and wherein said C₃-C₆Cycloalkyl optionally substituted by C₁-C₃Alkyl substitution.

Other embodiments are directed to compounds of formula (IV) or a pharmaceutically acceptable salt thereof, wherein R¹Is methyl, ethyl, isopropyl or tert-butyl.

Some embodiments relate to compounds of formula (IV) or a pharmaceutically acceptable salt thereof, wherein R¹Is optionally substituted by C₁-C₃Alkyl-substituted cyclobutyl.

Some embodiments relate to compounds of formula (IV) or a pharmaceutically acceptable salt thereof, wherein R³Is a 3-7 membered heterocycloalkyl, wherein said 3-7 membered heterocycloalkyl is optionally substituted with one, two or three R¹⁵And (4) substituting the group.

Further embodiments relate to compounds of formula (IV) or a pharmaceutically acceptable salt thereof, wherein R³To be optionally coveredC₁-C₃An alkyl substituted piperidine.

Other embodiments are directed to compounds of formula (IV) or a pharmaceutically acceptable salt thereof, wherein R³Is optionally substituted by C₁-C₃An alkyl substituted piperazine.

Other embodiments are directed to compounds of formula (IV) or a pharmaceutically acceptable salt thereof, wherein R³Is piperazine optionally substituted with methyl.

Some embodiments relate to compounds of formula (IV) or a pharmaceutically acceptable salt thereof, wherein R³Is 4-methyl piperazine.

Further embodiments relate to compounds of formula (IV) or a pharmaceutically acceptable salt thereof, wherein R²Is hydrogen, halogen, trifluoromethyl, C₁-C₆Alkyl or C₁-C₆An alkoxy group.

Other embodiments are directed to compounds of formula (IV) or a pharmaceutically acceptable salt thereof, wherein R²Is hydrogen, fluorine, trifluoromethyl, methyl or methoxy.

Other embodiments are directed to compounds of formula (IV) or a pharmaceutically acceptable salt thereof, wherein R²Is hydrogen.

Some embodiments relate to compounds of formula (IV) or a pharmaceutically acceptable salt thereof, wherein R⁴Is hydrogen.

Some embodiments relate to compounds of formula (IV) or a pharmaceutically acceptable salt thereof, wherein R⁴Is hydrogen, halogen or C₁-C₃An alkyl group.

Further embodiments relate to compounds of formula (IV) or a pharmaceutically acceptable salt thereof, wherein Q is absent.

Further embodiments relate to compounds of formula (IV) or a pharmaceutically acceptable salt thereof, wherein Q is O.

Other embodiments relate to compounds of formula (IV) or pharmaceutically acceptable salts thereofAn acceptable salt wherein Q is NR⁹。

Other embodiments are directed to compounds of formula (IV) or a pharmaceutically acceptable salt thereof, wherein m is 0.

Some embodiments relate to a compound of formula (IV) or a pharmaceutically acceptable salt thereof, wherein m is 1.

Some embodiments relate to compounds of formula (IV) or a pharmaceutically acceptable salt thereof, wherein ring B is 3-10 membered heterocycloalkyl.

Other embodiments are directed to compounds of formula (IV) or a pharmaceutically acceptable salt thereof, wherein ring B is

Some embodiments relate to a compound or pharmaceutically acceptable salt of any embodiment of the compound of formula (IV) having formula (IVa):

wherein

n is 0,1 or 2; and is

p is 0,1 or 2.

Some embodiments relate to a compound of formula (IVa) or a pharmaceutically acceptable salt thereof, wherein n is 0.

Further embodiments relate to compounds of formula (IVa) or a pharmaceutically acceptable salt thereof, wherein n is 1.

Further embodiments relate to compounds of formula (IVa) or a pharmaceutically acceptable salt thereof, wherein p is 1.

Some embodiments relate to a compound of formula (IVa) or a pharmaceutically acceptable salt thereof, wherein n is 1 and p is 1.

Some embodiments relate to compounds of formula (IVa) or a pharmaceutically acceptable salt thereof, wherein R⁶And R⁸Each independently of the others is hydrogen, halogen, C₁-C₃Alkyl or C₁-C₃An alkoxy group.

Other embodiments are directed to compounds of formula (IVa) or a pharmaceutically acceptable salt thereof, wherein R⁶Is hydrogen, fluorine, methyl or methoxy.

Other embodiments are directed to compounds of formula (IVa) or a pharmaceutically acceptable salt thereof, wherein R⁶Is fluorine.

Other embodiments are directed to compounds of formula (IVa) or a pharmaceutically acceptable salt thereof, wherein R⁸Is hydrogen, fluorine or methyl.

Some embodiments relate to compounds of formula (IVa) or a pharmaceutically acceptable salt thereof, wherein R⁸Is methyl.

Other embodiments are directed to compounds of formula (IVa) or a pharmaceutically acceptable salt thereof, wherein R⁷Is composed of

Some embodiments relate to a compound or pharmaceutically acceptable salt of any embodiment of the compound of formula (IV) having formula (IVb):

further embodiments relate to compounds of formula (IVb) or a pharmaceutically acceptable salt thereof, wherein R⁶And R⁸Each independently of the others is hydrogen, halogen, C₁-C₃Alkyl or C₁-C₃An alkoxy group.

Some implementationsThe scheme relates to compounds of formula (IVb) or pharmaceutically acceptable salts thereof, wherein R⁶Is hydrogen, fluorine, methyl or methoxy.

Further embodiments relate to compounds of formula (IVb) or a pharmaceutically acceptable salt thereof, wherein R⁶Is fluorine.

Other embodiments are directed to compounds of formula (IVb) or a pharmaceutically acceptable salt thereof, wherein R⁸Is hydrogen, fluorine or methyl.

Other embodiments are directed to compounds of formula (IVb) or a pharmaceutically acceptable salt thereof, wherein R⁸Is methyl.

Some embodiments relate to a compound or pharmaceutically acceptable salt of any embodiment of the compound of formula (IV) having formula (IVc):

wherein

J is C or N;

q is 0,1, 2 or 3; and is

v is 0,1, 2 or 3,

provided that q and v cannot be 0 at the same time.

Some embodiments relate to a compound of formula (IVc) or a pharmaceutically acceptable salt thereof, wherein J is C.

Further embodiments relate to compounds of formula (IVc) or a pharmaceutically acceptable salt thereof, wherein J is N.

Further embodiments relate to compounds of formula (IVc) or a pharmaceutically acceptable salt thereof, wherein q is 1.

Some embodiments relate to a compound of formula (IVc) or a pharmaceutically acceptable salt thereof, wherein q is 2.

Some embodiments relate to a compound of formula (IVc) or a pharmaceutically acceptable salt thereof, wherein q is 3.

Other embodiments relate to compounds of formula (IVc) or a pharmaceutically acceptable salt thereof, wherein v is 1.

Other embodiments relate to compounds of formula (IVc) or a pharmaceutically acceptable salt thereof, wherein q is 1 and v is 1.

Other embodiments relate to compounds of formula (IVc) or a pharmaceutically acceptable salt thereof, wherein q is 2 and v is 1.

Some embodiments relate to a compound of formula (IVc) or a pharmaceutically acceptable salt thereof, wherein q is 3 and v is 1.

Some embodiments relate to compounds of formula (IVc) or a pharmaceutically acceptable salt thereof, wherein R⁶Is hydrogen, halogen or C₁-C₃An alkoxy group.

Further embodiments relate to compounds of formula (IVc) or a pharmaceutically acceptable salt thereof, wherein R⁶Is hydrogen, fluorine or methoxy.

Further embodiments relate to compounds of formula (IVc) or a pharmaceutically acceptable salt thereof, wherein R⁸Is hydrogen or C₁-C₃An alkyl group.

Other embodiments are directed to compounds of formula (IVc) or a pharmaceutically acceptable salt thereof, wherein R⁸Is hydrogen or methyl.

Other embodiments are directed to compounds of formula (IVc) or a pharmaceutically acceptable salt thereof, wherein R⁷Is composed of

Some embodiments relate to a compound or pharmaceutically acceptable salt of any embodiment of the compounds of formula (IV), wherein m is 0, having formula (IVd):

wherein

Q is O or NR⁹。

Other embodiments are directed to compounds of formula (IVd) or a pharmaceutically acceptable salt thereof, wherein R⁶Is absent.

Some embodiments relate to compounds of formula (IVd) or a pharmaceutically acceptable salt thereof, wherein R⁷Is composed of

Other embodiments are directed to compounds of formula (IVd) or a pharmaceutically acceptable salt thereof, wherein R¹⁶、R¹⁷And R¹⁸Is hydrogen.

In some embodiments, the compound is selected from:

(S) -N- (1- (9-isopropyl-6- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -9H-purin-2-yl) pyrrolidin-3-yl) acrylamide;

n- ((3R,4R) -4-fluoro-1- (9-isopropyl-6- ((1-methyl-1H-pyrazol-4-yl) amino) -9H-purin-2-yl) pyrrolidin-3-yl) acrylamide;

n- (3- ((9-isopropyl-6- ((1-methyl-1H-pyrazol-4-yl) amino) -9H-purin-2-yl) oxy) phenyl) acrylamide trifluoroacetate;

(S) -N- (1- (9-isopropyl-6- ((1-methyl-1H-pyrazol-4-yl) amino) -9H-purin-2-yl) pyrrolidin-3-yl) acrylamide;

n- ((3R,4R) -4-fluoro-1- (6- ((3-methoxy-1- (1-methylazetidin-3-yl) -1H-pyrazol-4-yl) amino) -9-methyl-9H-purin-2-yl) pyrrolidin-3-yl) acrylamide;

1- (3- (9-isopropyl-6- ((1-methyl-1H-pyrazol-4-yl) amino) -9H-purin-2-yl) piperidin-1-yl) prop-2-en-1-one;

n- ((3R,4R) -4-fluoro-1- (6- ((3-methoxy-1-methyl-1H-pyrazol-4-yl) amino) -9-methyl-9H-purin-2-yl) pyrrolidin-3-yl) acrylamide;

n- (1- (9- (tert-butyl) -6- ((1-methyl-1H-pyrazol-4-yl) amino) -9H-purin-2-yl) -3-methylazetidin-3-yl) acrylamide;

(S) -N- (1- (9- (tert-butyl) -6- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -9H-purin-2-yl) pyrrolidin-3-yl) acrylamide;

n- (1- (9-isopropyl-6- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -9H-purin-2-yl) -3-methylpyrrolidin-3-yl) acrylamide;

(S) -N- (1- (9-isopropyl-6- ((3-methoxy-1-methyl-1H-pyrazol-4-yl) amino) -9H-purin-2-yl) pyrrolidin-3-yl) acrylamide;

n- (1- (9-isopropyl-6- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -9H-purin-2-yl) -3-methylazetidin-3-yl) acrylamide;

n- (1- (9-isopropyl-6- ((1-methyl-1H-pyrazol-4-yl) amino) -9H-purin-2-yl) -3-methylazetidin-3-yl) acrylamide;

n- ((trans) -3- ((9-isopropyl-6- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -9H-purin-2-yl) oxy) cyclobutyl) acrylamide;

(S) -N- (1- (9-cyclobutyl-6- ((4- (4- (methylpiperazin-1-yl) phenyl) amino) -9H-purin-2-yl) pyrrolidin-3-yl) acrylamide;

1- ((cis) -5- (9-ethyl-6- ((1-methyl-1H-pyrazol-4-yl) amino) -9H-purin-2-yl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) prop-2-en-1-one;

1- ((cis) -5- (6- ((1, 5-dimethyl-1H-pyrazol-4-yl) amino) -9-isopropyl-9H-purin-2-yl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) prop-2-en-1-one;

1- ((cis) -5- (9- (tert-butyl) -6- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -9H-purin-2-yl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) prop-2-en-1-one;

1- ((trans) -3-fluoro-4- ((9-isopropyl-6- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -9H-purin-2-yl) amino) pyrrolidin-1-yl) prop-2-en-1-one;

1- ((trans) -3-fluoro-4- ((9-methyl-6- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -9H-purin-2-yl) amino) pyrrolidin-1-yl) prop-2-en-1-one;

1- ((cis) -5- (9-isopropyl-6- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -9H-purin-2-yl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) prop-2-en-1-one;

n- (3- ((9-isopropyl-6- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -9H-purin-2-yl) oxy) phenyl) acrylamide;

n- (1- (9-isopropyl-6- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -9H-purin-2-yl) azetidin-3-yl) acrylamide;

n- (1- (9-isopropyl-6- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -9H-purin-2-yl) azetidin-3-yl) -N-methacrylamide;

1- ((cis) -5- (9-isopropyl-6- ((1-methyl-1H-pyrazol-4-yl) amino) -9H-purin-2-yl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) prop-2-en-1-one;

(R) -1- (3- ((9-isopropyl-6- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -9H-purin-2-yl) oxy) pyrrolidin-1-yl) prop-2-en-1-one;

(R) -1- (3- ((9-isopropyl-6- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -9H-purin-2-yl) amino) pyrrolidin-1-yl) prop-2-en-1-one;

n- ((trans) -3- ((9-isopropyl-6- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -9H-purin-2-yl) amino) cyclobutyl) -N-methacrylamide;

n- ((trans) -3- ((9-isopropyl-6- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -9H-purin-2-yl) oxy) cyclobutyl) -N-methacrylamide;

1- ((trans) -3-fluoro-4- ((9-isopropyl-6- ((1-methyl-1H-pyrazol-4-yl) amino) -9H-purin-2-yl) amino) pyrrolidin-1-yl) prop-2-en-1-one;

n- (1- (9-isopropyl-6- ((1-methyl-1H-pyrazol-4-yl) amino) -9H-purin-2-yl) azetidin-3-yl) -N-methacrylamide;

1- (3- ((9-isopropyl-6- ((1-methyl-1H-pyrazol-4-yl) amino) -9H-purin-2-yl) amino) -3-methylazetidin-1-yl) prop-2-en-1-one;

1- ((cis) -5- (9-methyl-6- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -9H-purin-2-yl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) prop-2-en-1-one;

1- ((cis) -5- (9-methyl-6- ((1-methyl-1H-pyrazol-4-yl) amino) -9H-purin-2-yl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) prop-2-en-1-one;

(S) -N- (1- (9-ethyl-6- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -9H-purin-2-yl) pyrrolidin-3-yl) acrylamide;

(S) -N- (1- (9-isopropyl-6- ((4- (4-isopropylpiperazin-1-yl) phenyl) amino) -9H-purin-2-yl) pyrrolidin-3-yl) acrylamide;

(S) -N- (1- (6- ((1, 3-dimethyl-1H-pyrazol-4-yl) amino) -9-isopropyl-9H-purin-2-yl) pyrrolidin-3-yl) acrylamide;

(S) -N- (1- (9-methyl-6- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -9H-purin-2-yl) pyrrolidin-3-yl) acrylamide;

n- (1- (9-isopropyl-6- ((1- (1-methylpiperidin-4-yl) -1H-pyrazol-4-yl) amino) -9H-purin-2-yl) -3-methylazetidin-3-yl) acrylamide;

(S) -N- (1- (6- ((4- (4-ethylpiperazin-1-yl) phenyl) amino) -9-isopropyl-9H-purin-2-yl) pyrrolidin-3-yl) acrylamide;

(S) -N- (1- (9-isopropyl-6- ((1- (1-methylpiperidin-4-yl) -1H-pyrazol-4-yl) amino) -9H-purin-2-yl) pyrrolidin-3-yl) acrylamide;

n- (1- (6- ((1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-yl) amino) -9-isopropyl-9H-purin-2-yl) -3-methylazetidin-3-yl) acrylamide;

(S) -N- (1- (6- ((1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-yl) amino) -9-isopropyl-9H-purin-2-yl) pyrrolidin-3-yl) acrylamide;

n- (1- (9-isopropyl-6- ((1- (1-methylpyrrolidin-3-yl) -1H-pyrazol-4-yl) amino) -9H-purin-2-yl) -3-methylazetidin-3-yl) acrylamide;

n- ((3S) -1- (9-isopropyl-6- ((1- (1-methylpyrrolidin-3-yl) -1H-pyrazol-4-yl) amino) -9H-purin-2-yl) pyrrolidin-3-yl) acrylamide;

(S) -N- (1- (9- (2-hydroxyethyl) -6- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -9H-purin-2-yl) pyrrolidin-3-yl) acrylamide;

n- ((trans) -1- (9-isopropyl-6- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -9H-purin-2-yl) -4-methoxypyrrolidin-3-yl) acrylamide;

n- ((3S) -1- (9- (1-hydroxypropan-2-yl) -6- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -9H-purin-2-yl) pyrrolidin-3-yl) acrylamide;

n- ((3R,4S) -1- (9- (tert-butyl) -6- ((1-methyl-1H-pyrazol-4-yl) amino) -9H-purin-2-yl) -4-fluoropyrrolidin-3-yl) acrylamide;

n- ((cis x) -1- (9-isopropyl-6- ((1-methyl-1H-pyrazol-4-yl) amino) -9H-purin-2-yl) -4-methoxypyrrolidin-3-yl) acrylamide;

n- ((3S,4R) -1- (9-isopropyl-6- ((1-methyl-1H-pyrazol-4-yl) amino) -9H-purin-2-yl) -4-methylpyrrolidin-3-yl) acrylamide;

n- ((3R,4R) -1- (9- (tert-butyl) -6- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -9H-purin-2-yl) -4-fluoropyrrolidin-3-yl) acrylamide;

n- ((3R,4R) -4-fluoro-1- (9-isopropyl-6- ((3-methoxy-1-methyl-1H-pyrazol-4-yl) amino) -9H-purin-2-yl) pyrrolidin-3-yl) acrylamide;

n- ((3R,4R) -1- (9- (tert-butyl) -6- ((3-methoxy-1-methyl-1H-pyrazol-4-yl) amino) -9H-purin-2-yl) -4-fluoropyrrolidin-3-yl) acrylamide;

n- ((3R,4R) -4-fluoro-1- (9-isopropyl-6- ((3-methyl-1- (1-methylpyrrolidin-3-yl) -1H-pyrazol-4-yl) amino) -9H-purin-2-yl) pyrrolidin-3-yl) acrylamide;

n- (1- (9-ethyl-6- ((1-methyl-1H-pyrazol-4-yl) amino) -9H-purin-2-yl) -3-methylazetidin-3-yl) acrylamide;

(R) -1- (3- ((9-isopropyl-6- ((1-methyl-1H-pyrazol-4-yl) amino) -9H-purin-2-yl) oxy) piperidin-1-yl) prop-2-en-1-one;

(R) -1- (3- ((9-isopropyl-6- ((1-methyl-1H-pyrazol-4-yl) amino) -9H-purin-2-yl) oxy) pyrrolidin-1-yl) prop-2-en-1-one;

(S) -N- (1- (6- ((1-methyl-1H-pyrazol-4-yl) amino) -9- (1-methylcyclopropyl) -9H-purin-2-yl) pyrrolidin-3-yl) acrylamide;

n- ((3R,4R) -1- (6- ((1, 3-dimethyl-1H-pyrazol-4-yl) amino) -9-isopropyl-9H-purin-2-yl) -4-fluoropyrrolidin-3-yl) acrylamide;

n- ((3R,4R) -1- (9-isopropyl-6- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -9H-purin-2-yl) -4-methoxypyrrolidin-3-yl) acrylamide;

n- ((3R,4R) -1- (9-isopropyl-6- ((1-methyl-1H-pyrazol-4-yl) amino) -9H-purin-2-yl) -4-methoxypyrrolidin-3-yl) acrylamide;

1- ((cis) -5- (9-isopropyl-6- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -9H-purin-2-yl) -3 a-methoxy hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) prop-2-en-1-one;

1- ((3R,4R) -3- (((9-isopropyl-6- ((1-methyl-1H-pyrazol-4-yl) amino) -9H-purin-2-yl) oxy) methyl) -4-methoxypyrrolidin-1-yl) prop-2-en-1-one;

n- ((3S,4S) -1- (6- ((1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-yl) amino) -9-isopropyl-9H-purin-2-yl) -4-fluoropyrrolidin-3-yl) acrylamide;

n- ((3R,4R) -1- (9- (tert-butyl) -6- ((1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-yl) amino) -9H-purin-2-yl) -4-fluoropyrrolidin-3-yl) acrylamide;

n- ((S) -1- (9-isopropyl-6- ((1- ((S) -1-methylpyrrolidin-3-yl) -1H-pyrazol-4-yl) amino) -9H-purin-2-yl) pyrrolidin-3-yl) acrylamide;

n- ((3R,4R) -1- (9- (tert-butyl) -6- ((1- (1-methylpiperidin-4-yl) -1H-pyrazol-4-yl) amino) -9H-purin-2-yl) -4-fluoropyrrolidin-3-yl) acrylamide;

n- ((3R,4R) -4-fluoro-1- (9-isopropyl-6- ((1- (1-methylpiperidin-4-yl) -1H-pyrazol-4-yl) amino) -9H-purin-2-yl) pyrrolidin-3-yl) acrylamide;

n- ((3R,4R) -4-fluoro-1- (9-isopropyl-6- ((3-methoxy-1- ((R) -1-methylpyrrolidin-3-yl) -1H-pyrazol-4-yl) amino) -9H-purin-2-yl) pyrrolidin-3-yl) acrylamide;

1- (cis-3 a-fluoro-5- (9-isopropyl-6- ((1-methyl-1H-pyrazol-4-yl) amino) -9H-purin-2-yl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) prop-2-en-1-one;

(R) -N- (4, 4-difluoro-1- (9-isopropyl-6- ((1-methyl-1H-pyrazol-4-yl) amino) -9H-purin-2-yl) pyrrolidin-3-yl) acrylamide;

n- ((3R,4R) -1- (9-ethyl-6- ((3-methoxy-1- (1-methylpyrrolidin-3-yl) -1H-pyrazol-4-yl) amino) -9H-purin-2-yl) -4-fluoropyrrolidin-3-yl) acrylamide;

n- ((3R,4R) -1- (6- ((1, 3-dimethyl-1H-pyrazol-4-yl) amino) -9-ethyl-9H-purin-2-yl) -4-fluoropyrrolidin-3-yl) acrylamide;

n- ((3R,4R) -1- (9-ethyl-6- ((3-methoxy-1-methyl-1H-pyrazol-4-yl) amino) -9H-purin-2-yl) -4-fluoropyrrolidin-3-yl) acrylamide;

n- ((3R,4R) -1- (6- ((3-ethyl-1-methyl-1H-pyrazol-4-yl) amino) -9-isopropyl-9H-purin-2-yl) -4-fluoropyrrolidin-3-yl) acrylamide;

n- ((3R,4R) -4-fluoro-1- (6- ((3-methoxy-1- (1-methylpyrrolidin-3-yl) -1H-pyrazol-4-yl) amino) -9-methyl-9H-purin-2-yl) pyrrolidin-3-yl) acrylamide;

n- ((3R,4R) -1- (9-ethyl-6- ((3-methyl-1- (1-methylpyrrolidin-3-yl) -1H-pyrazol-4-yl) amino) -9H-purin-2-yl) -4-fluoropyrrolidin-3-yl) acrylamide;

n- ((3R,4R) -4-fluoro-1- (9-methyl-6- ((3-methyl-1- (1-methylpyrrolidin-3-yl) -1H-pyrazol-4-yl) amino) -9H-purin-2-yl) pyrrolidin-3-yl) acrylamide;

n- ((3R,4R) -1- (6- ((1, 3-dimethyl-1H-pyrazol-4-yl) amino) -9-methyl-9H-purin-2-yl) -4-fluoropyrrolidin-3-yl) acrylamide;

n- ((3R,4R) -4-fluoro-1- (6- ((1- (2-hydroxypropyl) -3-methoxy-1H-pyrazol-4-yl) amino) -9-methyl-9H-purin-2-yl) pyrrolidin-3-yl) acrylamide;

n- ((3R,4R) -4-fluoro-1- (6- ((1- (2-hydroxypropyl) -3-methoxy-1H-pyrazol-4-yl) amino) -9-isopropyl-9H-purin-2-yl) pyrrolidin-3-yl) acrylamide;

n- ((3R,4R) -4-fluoro-1- (9-isopropyl-6- ((5-methyl-1- ((R) -1-methylpyrrolidin-3-yl) -1H-pyrazol-4-yl) amino) -9H-purin-2-yl) pyrrolidin-3-yl) acrylamide;

n- ((3R,4R) -1- (9-ethyl-6- ((1- (2-hydroxypropyl) -3-methoxy-1H-pyrazol-4-yl) amino) -9H-purin-2-yl) -4-fluoropyrrolidin-3-yl) acrylamide;

n- ((3R,4R) -4-fluoro-1- (9-isopropyl-6- ((3-methoxy-1- ((S) -1-methylpyrrolidin-3-yl) -1H-pyrazol-4-yl) amino) -9H-purin-2-yl) pyrrolidin-3-yl) acrylamide;

n- ((3R,4R) -1- (6- ((1-ethyl-3-methoxy-1H-pyrazol-4-yl) amino) -9-methyl-9H-purin-2-yl) -4-fluoropyrrolidin-3-yl) acrylamide;

n- ((3R,4R) -1- (6- ((4- (4- (dimethylamino) piperidin-1-yl) phenyl) amino) -9-isopropyl-9H-purin-2-yl) -4-fluoropyrrolidin-3-yl) acrylamide; and

n- ((3R,4R) -1- (6- ((4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) amino) -9-isopropyl-9H-purin-2-yl) -4-fluoropyrrolidin-3-yl) acrylamide, or

A pharmaceutically acceptable salt thereof.

In certain embodiments, the compound is selected from:

A pharmaceutically acceptable salt thereof.

Some embodiments relate to a pharmaceutical composition comprising a compound of any embodiment of the compounds of formula (I), formula (II), formula (III), or formula (IV), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

Other embodiments relate to a combination of a compound of any embodiment of the compounds of formula (I), formula (II), formula (III) or formula (IV), or a pharmaceutically acceptable salt thereof, and an anti-neoplastic agent for treating cancer.

Further embodiments relate to methods of treating abnormal cell growth in a mammal comprising administering to the mammal a composition of a compound of any embodiment of the compounds of formula (I), formula (II), formula (III) or formula (IV), or a pharmaceutically acceptable salt thereof, in an amount effective to treat abnormal cell growth.

Other embodiments are directed to methods of treating abnormal cell growth in a mammal comprising administering to the mammal an amount of a compound of any embodiment of the compounds of formula (I), formula (II), formula (III), or formula (IV), or a pharmaceutically acceptable salt thereof, effective to treat abnormal cell growth.

Other embodiments relate to methods of treating abnormal cell growth, wherein the abnormal cell growth is cancer.

Other embodiments relate to methods of treating cancer, wherein the cancer is selected from basal cell carcinoma, medulloblastoma, liver cancer, rhabdomyosarcoma, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, endometrial cancer, cervical cancer, vaginal cancer, vulval cancer, hodgkin's disease, esophageal cancer, small bowel cancer, cancer of the endocrine system, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, renal pelvis cancer, tumors of the central nervous system, primary central nervous system lymphoma, vertebral axis tumors, spinal axis tumors, and combinations thereof, A brain stem glioma and a pituitary adenoma or a combination of one or more of the foregoing cancers.

Other embodiments are directed to methods of treating lung cancer, wherein the lung cancer is non-small cell lung cancer.

Detailed Description

The following abbreviations may be used herein: aq (aqueous/water-containing); boc (tert-butyl ether)Butoxycarbonyl); boc₂O (di-tert-butyl dicarbonate); ca. (about); CBZ-Cl (carbobenzoxy chloride); DAST ((diethylamino) sulfur trifluoride); DBAD (dibenzylazodicarboxylate); DCM (dichloromethane); DEA (diethylamine); DIEA (diisopropylethylamine); DIPEA (N, N-diisopropylethylamine); DMAP (4-dimethylaminopyridine); DMF (dimethylformamide); DMSO (dimethyl sulfoxide); dppf (1,1' -bis (diphenylphosphino) ferrocene); EDC (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide); ee (enantiomeric excess); eq (equivalent); et (ethyl); EtOH (ethanol); EtOAc (ethyl acetate); FBS (fetal bovine serum); HOAc (acetic acid); HOBt (hydroxybenzotriazole); HPLC (high performance liquid chromatography); hr (hours); iPrOH (isopropanol); iPrOAc (isopropyl acetate); LAH (lithium aluminum hydride); LCMS (liquid chromatography-mass spectrometry); LRMS (low resolution mass spectrometry); mCPBA (m-chloroperoxybenzoic acid); me (methyl); MeOH (methanol); min (minutes); MTBE (methyl tert-butyl ether); n (standard); N/A (not available); nBuLi (n-butyl lithium); nBuOH (n-butanol); N/D (not measured); NMM (N-methylmorpholine); NMR (nuclear magnetic resonance); Pd/C (palladium on carbon); ph (phenyl); RPMI (Roswell Park clinical institute); rt (room temperature); sat. (saturated); SFC (supercritical fluid chromatography); TEA (triethylamine); tert-PentOH (tert-amyl alcohol); TFA (trifluoroacetic acid); THF (tetrahydrofuran); TLC (thin layer chromatography); TsOH (p-toluenesulfonic acid)); and UPLC (ultra performance liquid chromatography).

As used herein, the term "halogen" refers to a fluorine, chlorine, bromine or iodine atom or a fluoro, chloro, bromo or iodo atom. In addition, the term "halogen" means F, Cl, Br or I. For example, the terms fluorine, fluoro and F are to be understood herein as equivalent.

As used herein, the term "alkyl" refers to a saturated monovalent hydrocarbon radical, which in certain embodiments contains one to six or one to three carbon atoms, with a straight or branched chain group. The term "C₁-C₆Alkyl "refers to an alkyl group containing one to six carbon atoms with a straight or branched chain group. The term "C₁-C₆Alkyl "includes in its definition the term" C₁-C₃Alkyl "and" C₁-C₄Alkyl groups ". Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, (R) -2-methylbutyl, (S) -2-methylbutyl, 3-methylbutyl, 2, 3-dimethylpropyl, 2, 3-dimethylbutyl, hexyl, and the like.

As used herein, the term "alkenyl" refers to a saturated monovalent hydrocarbon radical having at least one carbon-carbon double bond, and in certain embodiments, two to six carbon atoms. Alkenyl groups include straight or branched chain groups. The term "C₂-C₆Alkenyl "means an alkenyl group containing two to six carbon atoms with a straight or branched chain group. The double bond may or may not be the point of attachment of another group. Alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-methyl-2-propenyl, butenyl, pentenyl, 3-hexenyl, and the like.

As used herein, the term "alkynyl" refers to a saturated monovalent hydrocarbon radical having at least one carbon-carbon triple bond, and in certain embodiments, containing two to six carbon atoms. Alkynyl includes straight or branched chain groups. The term "C₂C₆Alkynyl "refers to alkynyl groups containing two to six carbon atoms with straight or branched chain groups. The triple bond may or may not be the point of attachment of another group. Alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-methyl-2-propynyl, butynyl, pentynyl, 3-hexynyl, and the like.

As used herein, the term "alkoxy" refers to an alkyl group singly bonded to an oxygen atom. The point of attachment of the alkoxy group to the molecule is through an oxygen atom. Alkoxy groups may be described as alkyl-O-. The term "C₁-C₆Alkoxy "refers to an alkoxy group containing one to six carbon atoms with a straight or branched chain group. The term "C₁-C₆Alkoxy "includes in its definition the term" C₁-C₃Alkoxy ". Alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxyAlkyl, butoxy, hexyloxy, and the like.

As used herein, the term "cycloalkyl" refers to a non-aromatic monocyclic, fused or bridged bicyclic or tricyclic carbocyclic group, which in certain embodiments contains from three to ten carbon atoms. As used herein, a cycloalkyl group may optionally contain one or two double bonds. The term "cycloalkyl" also includes spirocycloalkyl groups, which comprise polycyclic ring systems connected by a single atom. The term "C₃-C₁₀Cycloalkyl group "," C₃-C₇Cycloalkyl group "," C₃-C₆Cycloalkyl group "," C₃-C₅Cycloalkyl group "," C₃-C₄Cycloalkyl radicals "and" C₅-C₇Cycloalkyl "includes three to ten, three to seven, three to six, three to five, three to four, and five to seven carbon atoms, respectively. Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, octahydropentalenyl, octahydro-1H-indenyl, bicyclo [2.2.1 ] n]Heptylalkyl, bicyclo [3.2.1]Octyl, bicyclo [5.2.0 ]]Nonyl, adamantyl, and the like.

As used herein, the term "heterocycloalkyl" refers to a non-aromatic monocyclic, fused or bridged bicyclic or tricyclic or spiro ring group, which in certain embodiments, contains a total of three to ten ring atoms, of which one to four ring atoms are heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein the sulfur atom may be optionally oxidized by one or two oxygen atoms, with the remainder of the ring atoms being carbon, provided that such ring system may not contain two adjacent oxygen atoms or two adjacent sulfur atoms. The heterocycloalkyl ring may also be substituted with oxo (═ O) on any available carbon atom. The ring may also have one or more double bonds. Further, such groups may be bonded to the remainder of the compounds of the embodiments disclosed herein through a carbon atom or a heteroatom (if possible). The terms "3-10 membered heterocycloalkyl", "3-7 membered heterocycloalkyl" and "4-6 membered heterocycloalkyl" include three to ten, three to seven and three to six carbon atoms, respectively. Examples of heterocycloalkyl groups include, but are not limited to:

as used herein, the term "aryl" refers to a group derived from an aromatic hydrocarbon, which in certain embodiments, contains from six to ten carbon atoms. The term "C₆-C₁₀Aryl "contains six to ten carbon atoms. Examples of such groups include, but are not limited to, phenyl and naphthyl. The term "aryl" also includes fused polycyclic aromatic ring systems in which an aromatic ring is fused to one or more rings. Examples include, but are not limited to, 1-naphthyl, 2-naphthyl, 1-anthryl, and 2-anthryl. Also included within the scope of the term "aryl" as used herein are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phenanthridinyl, or tetrahydronaphthyl, where the linking group or point of attachment is on the aromatic ring.

As used herein, the term "heteroaryl" refers to an aromatic monocyclic or bicyclic heterocyclic group having a total of 5 to 12 atoms in its ring and containing 2 to 9 carbon atoms and one to four heteroatoms each independently selected from nitrogen, oxygen and sulfur, with the proviso that the ring of the group does not contain two adjacent oxygen atoms or two adjacent sulfur atoms. The terms "5-12 membered heteroaryl", "4-6 membered heteroaryl", and "3-5 membered heteroaryl" encompass five to twelve, four to six ring atoms, and three to five ring atoms, respectively. The heteroaryl group includes benzo-fused ring systems. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, furazanyl (furazanyl), thiadiazolyl, thiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, indolyl, isoindolyl, indolizinyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, furo [3,2-b ] pyridyl, benzothiazolyl, benzofurazanyl, purinyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnolinyl, phthalazinyl, pyrido [3,4-d ] pyrimidinyl, pteridinyl, and the like.

Also included within the scope of the term "5-12 membered heteroaryl" as used herein is a benzofused unsaturated nitrogen heterocycle, which refers to a heterocyclic group in which a heteroaromatic ring is fused to one or more aromatic rings. Examples include, but are not limited to, indolinyl, isoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

The term "treating" as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progression of, or preventing the disorder or condition to which the term applies, or one or more symptoms of such disorder or condition. The term "treatment" as used herein refers to the "treatment" behavior defined above, unless otherwise indicated.

As used herein, an "effective" amount refers to an amount of a substance, agent, compound, or composition that is an amount sufficient to cause a reduction in the severity of disease symptoms, an increase in the frequency and duration of disease symptom-free periods, or to prevent impairment or disability due to affliction with the disease, either as a single dose, or according to a multiple dose regimen, alone or in combination with other agents or substances. One of ordinary skill in the art will be able to determine such amounts based on factors such as the size of the individual, the severity of the individual's symptoms, and the particular composition or route of administration selected. The subject may be a human or non-human mammal (e.g., a rabbit, rat, mouse, monkey, or other lower-grade primate).

Embodiments disclosed herein include isotopically-labeled compounds, which are identical to those recited in formula (I), formula (II), formula (III), or formula (IV), but for the fact that one or more atoms are substituted with an atomic mass or mass number commonly found in natureAtoms of different atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of embodiments disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as, but not limited to, respectively²H、³H、¹³C、¹⁴C、¹⁵N、¹⁸O、¹⁷O、³¹P、³²P、³⁵S、¹⁸F and³⁶and (4) Cl. Compounds described herein, as well as pharmaceutically acceptable salts of the compounds, that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this embodiment. Certain isotopically-labeled compounds of the embodiments disclosed herein (e.g., incorporation of a radioactive isotope therein (such as³H and¹⁴C) those) can be used in drug and/or substrate tissue distribution studies. Tritiated (i.e., tritiated) is particularly preferred due to their ease of preparation and detectability³H) And carbon-14 (i.e.¹⁴C) An isotope. In addition, heavier isotopes are used (e.g. deuterium, i.e.²H) Substitution may provide certain therapeutic benefits resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and thus may be preferred in some circumstances. Isotopically labeled compounds of the embodiments disclosed herein can generally be prepared by carrying out the procedures disclosed in the schemes and/or in the examples and preparations below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

Some embodiments relate to pharmaceutically acceptable salts of the compounds described herein. Pharmaceutically acceptable salts of the compounds described herein include acid addition salts and base addition salts thereof.

Some embodiments also relate to pharmaceutically acceptable acid addition salts of the compounds described herein. Suitable acid addition salts are formed from acids which form non-toxic salts. Non-limiting examples of suitable acid addition salts (i.e., salts comprising pharmaceutically acceptable anions) include, but are not limited to, acetate, acidic citrate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, bitartrate, borate, camsylate, citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydroxybenzoylbenzoate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthenate, 2-naphthalenesulfonate, and the like, Nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, p-toluenesulfonate, trifluoroacetate and xinafoate (xinofoate).

Other embodiments relate to base addition salts of the compounds described herein. Suitable base addition salts are formed from bases which form non-toxic salts. Non-limiting examples of suitable base salts include aluminum, arginine, benzathine, calcium, choline, diethylamine, diethanolamine, glycinate, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine and zinc salts.

The compounds described herein, which are basic in nature, are capable of forming a wide variety of salts with a wide variety of inorganic and organic acids. Acids useful for preparing pharmaceutically acceptable acid addition salts of such basic compounds as described herein are those that form non-toxic acid addition salts (e.g., salts comprising pharmaceutically acceptable anions), such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, mesylate, esylate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e. 1,1' -methylene-bis- (2-hydroxy-3-naphthoate)). In addition to the acids mentioned above, the compounds described herein that contain a basic group (such as an amino group) can form pharmaceutically acceptable salts with a variety of amino acids.

Chemical bases that can be used as reagents for preparing pharmaceutically acceptable basic salts of those compounds described herein that are acidic in nature are those that form non-toxic basic salts with such compounds. Such non-toxic basic salts include, but are not limited to, those derived from such pharmaceutically acceptable cations, such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium salts or water-soluble amine addition salts such as N-methylglucamine- (meglumine), and the basic salts of lower alkanolammonium and other pharmaceutically acceptable organic amines.

The compounds of the embodiments described herein include all stereoisomers (e.g., cis and trans isomers) and all optical isomers (e.g., R and S enantiomers) of the compounds described herein, as well as racemates, diastereomers and other mixtures of such isomers. Although all stereoisomers are contemplated within the scope of our claims, one skilled in the art will recognize that a particular stereoisomer may be preferred.

In some embodiments, the compounds described herein may exist in several tautomeric forms, including enol and imine forms, as well as keto and enamine forms and geometric isomers and mixtures thereof. All such tautomeric forms are included within the scope of the present embodiments. Tautomers exist in solution as mixtures of tautomeric groups. In solid form, usually a tautomer predominates. Although one tautomer may be described, this embodiment includes all tautomers of the present compounds.

This embodiment also includes atropisomers of the compounds described herein. Atropisomers refer to compounds which can be separated into rotation-constrained isomers.

Hemisalts of acids and bases, such as hemisulfate and hemicalcium salts, may also be formed.

For an overview of suitable Salts, see Handbook of Pharmaceutical Salts, Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds described herein are known to those skilled in the art.

The term "solvate" is used herein to describe a molecular complex comprising a compound described herein and one or more pharmaceutically acceptable solvent molecules (e.g., ethanol).

The compounds described herein may also exist in unsolvated and solvated forms. Thus, some embodiments relate to hydrates and solvates of the compounds described herein.

Compounds described herein that contain one or more asymmetric carbon atoms may exist as two or more stereoisomers. When the compounds described herein contain an alkenyl or alkenylene group, it may be the geometric cis/trans (or Z/E) isomer. Tautomerism ("tautomerism") can occur when structural isomers can interconvert through a low energy barrier. This may be proton tautomerism of the compounds described herein comprising, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds comprising an aromatic group. A single compound may exhibit more than one type of isomerism.

Included within the scope of this embodiment are all stereoisomers, geometric isomers and tautomeric forms of the compounds described herein, including compounds exhibiting more than one type of isomerism, i.e. mixtures of one or more thereof. Also included are acid addition salts and base addition salts in which the counterion is optically active, for example the d-lactate or l-lysine salt, or racemic, for example the dl-tartrate or dl-arginine salt.

The cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization.

Conventional techniques for the preparation/separation of single enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or a salt or derivative), for example using chiral High Pressure Liquid Chromatography (HPLC).

Alternatively, the racemate (or racemic precursor) may be reacted with a suitable optically active compound, for example an alcohol, or, where the compounds described herein contain acidic or basic groups, with a base or acid, for example 1-phenylethylamine or tartaric acid. The resulting mixture of diastereomers can be separated by chromatography and/or fractional crystallization and one or both diastereomers converted to the corresponding pure enantiomers by means well known to those skilled in the art.

Unless otherwise indicated, "abnormal cell growth" as used herein refers to cell growth that is not subject to normal regulatory mechanisms (e.g., loss of contact inhibition). It includes abnormal growth of: (1) tumor cells (tumors) that proliferate by expressing a mutant tyrosine kinase or overexpression of a receptor tyrosine kinase; (2) benign and malignant cells of other proliferative diseases in which abnormal tyrosine kinase activation occurs; (3) any tumor that proliferates via receptor tyrosine kinases; (4) any tumor that proliferates through abnormal serine/threonine kinase activation; and (5) benign and malignant cells of other proliferative diseases in which aberrant serine/threonine kinase activation occurs.

Other embodiments relate to methods of treating abnormal cell growth in a mammal. Other embodiments are directed to methods of treating abnormal cell growth in a mammal comprising administering to the mammal an amount of a compound described herein effective to treat abnormal cell growth.

In other embodiments, the abnormal cell growth is cancer.

In some embodiments, the cancer is selected from lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, hodgkin's disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, tumors of the Central Nervous System (CNS), primary CNS lymphoma, tumors of the spinal axis, brain stem glioma and pituitary adenoma, or a combination of two or more of the foregoing cancers.

Other embodiments relate to methods of treating a cancer solid tumor in a mammal. Some embodiments relate to a method of treating a cancer solid tumor in a mammal comprising administering to the mammal an amount of a compound described herein effective to treat the cancer solid tumor.

In other embodiments, the cancer solid tumor is breast cancer, lung cancer, colon cancer, brain cancer, prostate cancer, stomach cancer, pancreatic cancer, ovarian cancer, skin cancer (melanoma), endocrine cancer, uterine cancer, testicular cancer, or bladder cancer.

Other embodiments relate to methods of treating lung cancer. Other embodiments relate to methods of treating non-small cell lung cancer. Other embodiments relate to methods of treating non-small cell lung cancer that is resistant to treatment with gefitinib or erlotinib.

Other embodiments are directed to methods of treating abnormal cell growth in a mammal comprising administering to the mammal an amount of a compound described herein in combination with an anti-neoplastic agent effective to treat abnormal cell growth. The antineoplastic agent can be selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, radiation, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxins, anti-hormones, and anti-androgens.

Other embodiments relate to a combination of a compound of formula (I), formula (II), formula (III) or formula (IV), or a pharmaceutically acceptable salt thereof, and an anti-tumor agent, for use in treating cancer. The antineoplastic agent can be selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, radiation, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxins, anti-hormones, and anti-androgens.

Further embodiments relate to a pharmaceutical composition for treating abnormal cell growth in a mammal, comprising an amount of a compound described herein effective to treat abnormal cell growth and a pharmaceutically acceptable carrier.

Other embodiments are directed to methods of treating abnormal cell growth in a mammal (including a human) comprising administering to the mammal an amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, effective to treat abnormal cell growth. In one embodiment of this method, the abnormal cell growth is cancer, it includes, but is not limited to, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, hodgkin's disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, tumors of the Central Nervous System (CNS), primary CNS lymphoma, spinal axis tumors, brain stem glioma and pituitary adenoma, or a combination of one or more of. In one embodiment, the method comprises administering to a mammal an amount of a compound described herein effective to treat the cancer solid tumor. In a preferred embodiment, the solid tumor is a breast, lung, colon, brain, prostate, stomach, pancreas, ovary, skin (melanoma), endocrine, uterine, testicular, and bladder cancer.

In another embodiment of the method, the abnormal cell growth is a benign proliferative disease including, but not limited to, psoriasis, benign prostatic hypertrophy or restenosis.

Some embodiments relate to a method of treating abnormal cell growth in a mammal comprising administering to the mammal an amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in combination with an anti-neoplastic agent effective to treat abnormal cell growth. The antineoplastic agent may be selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxins, anti-hormones, and anti-androgens.

Other embodiments are directed to pharmaceutical compositions for treating abnormal cell growth in a mammal, including a human, comprising an amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, effective to treat abnormal cell growth and a pharmaceutically acceptable carrier. In one embodiment of the composition, the abnormal cell growth is cancer, it includes, but is not limited to, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, hodgkin's disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, tumors of the Central Nervous System (CNS), primary CNS lymphoma, spinal axis tumors, brain stem glioma and pituitary adenoma, or a combination of one or more of. In another embodiment of the pharmaceutical composition, the abnormal cell growth is a benign proliferative disease including, but not limited to, psoriasis, benign prostatic hypertrophy or restenosis.

Other embodiments are directed to methods of treating abnormal cell growth in a mammal comprising administering to the mammal a compound described herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof, in combination with another anti-neoplastic agent, in an amount effective to treat abnormal cell growth. The antineoplastic agent may be selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxins, anti-hormones, and anti-androgens. Some embodiments encompass pharmaceutical compositions for treating abnormal cell growth, wherein the composition comprises a compound described herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof, effective to treat abnormal cell growth, and another anti-neoplastic agent. The antineoplastic agent may be selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxins, anti-hormones, and anti-androgens.

Further embodiments relate to methods of treating an angiogenesis-related disorder in a mammal (including a human) comprising administering to the mammal a compound as described herein or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof as defined above in combination with one or more anti-neoplastic agents in an amount effective to treat the disorder. The disorders include cancerous tumors, such as melanoma; ocular disorders such as age-related macular degeneration, ocular pseudohistoplasmosis syndrome, and retinal neovascularization from proliferative diabetic retinopathy; rheumatoid arthritis; bone loss disorders such as osteoporosis, paget's disease, humoral hypercalcemia from malignancies, hypercalcemia from tumors metastasized to bone, and osteoporosis induced by glucocorticoid therapy; restenosis of the coronary arteries; and certain microbial infections including those associated with microbial pathogens selected from the group consisting of adenovirus, hantavirus, borrelia burgdorferi, yersinia, bordetella pertussis, and streptococcus group a.

Some embodiments relate to a method of treating abnormal cell growth in a mammal (and to a pharmaceutical composition for such treatment), comprising combining an amount of a compound described herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof, with an amount of one or more substances selected from the group consisting of: anti-angiogenic agents, signal transduction inhibitors (e.g., means for inhibiting regulatory molecules that govern the fundamental processes of cell growth, differentiation and survival transmitted in the cell), and antiproliferative agents, in amounts that together are effective in treating the abnormal cell growth.

In the methods and pharmaceutical compositions described herein, anti-angiogenic agents, such as MMP-2 (matrix-metalloproteinase 2) inhibitors, MMP-9 (matrix-metalloproteinase 9) inhibitors, and COX-II (cyclooxygenase II) inhibitors, can be used in combination with the compounds described herein. Examples of COX-II inhibitors that may be used include CELEBREX^TM(celecoxib), Bextra (valdecoxib), parecoxib, Vioxx (rofecoxib), and Arcoxia (etoricoxib). Examples of matrix metalloproteinase inhibitors that may be used are disclosed in WO 96/33172 (published in October 24 of 1996), WO 96/27583 (published in March 7 of 1996), European patent application 97304971.1 (published in July 8 of 1997), European patent application 99308617.2 (published in October 29 of 1999), WO 98/07697 (published in February 26 of 1998), WO 98/03516 (published in February 29 of 1998), WO 98/34918 (published in August 13 of 1998), WO 98/34915 (published in August 13 of 1998), WO 98/33768 (published in August 6 of 1998), WO 98/30566 (published in July 6 of 1998), European patent publication 606,046 (published in July 13 of 1994), European patent publication 931,788 (published in July 28 of 1999), WO 90/05719 (published in May 331 of 1990)Kakai), WO 99/52910 (published on october 21 of 1999), WO 99/52889 (published on october 21 of 1999), WO 99/29667 (published on october 17 of 1999), PCT international application No. PCT/IB98/01113 (filed on july 21 of 1998), european patent application No. 99302232.1 (filed on march 25 of 1999), british patent application No. 9912961.1 (filed on july 3 of 1999), us provisional application No. 60/148,464 (filed on august 12 of 1999), us patent 5,863,949 (granted on january 26 of 1999), us patent 5,861,510 (granted on january 19 of 1999), and european patent publication No. 780,386 (published on june 25 of 1997), all of which are incorporated herein by reference in their entirety. Preferred MMP-2 and MMP-9 inhibitors are those that are either nearly inactive or inactive in inhibiting MMP-1. More preferred are those that selectively inhibit MMP-2 and/or MMP-9 relative to other matrix-matrix metalloproteinases (i.e., MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).

Some specific examples of MMP inhibitors that may be used in combination with the compositions described herein are AG-3340, RO32-3555, RS 13-0830, and the following compounds:

3- [ [4- (4-fluoro-phenoxy) -benzenesulfonyl ] - (1-hydroxycarbamoyl-cyclopentyl) -amino ] -propionic acid;

3-exo-3- [4- (4-fluoro-phenoxy) -benzenesulfonylamino ] -8-oxa-bicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide;

(2R,3R)1- [4- (2-chloro-4-fluoro-benzyloxy) -benzenesulfonyl ] -3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide;

4- [4- (4-fluoro-phenoxy) -benzenesulfonylamino ] -tetrahydro-pyran-4-carboxylic acid hydroxyamide;

3- [ [4- (4-fluoro-phenoxy) -benzenesulfonyl ] - (1-hydroxycarbamoyl-cyclobutyl) -amino ] -propionic acid;

4- [4- (4-chloro-phenoxy) -benzenesulfonylamino ] -tetrahydro-pyran-4-carboxylic acid hydroxyamide;

3- [4- (4-chloro-phenoxy) -benzenesulfonylamino ] -tetrahydro-pyran-3-carboxylic acid hydroxyamide;

(2R,3R)1- [4- (4-fluoro-2-methyl-benzyloxy) -benzenesulfonyl ] -3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide;

3- [ [4- (4-fluoro-phenoxy) -benzenesulfonyl ] - (1-hydroxycarbamoyl-1-methyl-ethyl) -amino ] -propionic acid;

3- [ [4- (4-fluoro-phenoxy) -benzenesulfonyl ] - (4-hydroxycarbamoyl-tetrahydro-pyran-4-yl) -amino ] -propionic acid;

3-exo-3- [4- (4-chloro-phenoxy) -benzenesulfonylamino ] -8-oxa-bicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide;

3-endo-3- [4- (4-fluoro-phenoxy) -benzenesulfonylamino ] -8-oxa-bicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide; and

3- [4- (4-fluoro-phenoxy) -benzenesulfonylamino ] -tetrahydro-furan-3-carboxylic acid hydroxyamide;

and pharmaceutically acceptable salts and solvates of said compounds.

VEGF inhibitors (e.g., sunitinib and axitinib) may also be combined with the compounds described herein. VEGF inhibitors are disclosed in, for example, WO 99/24440 (published 20/5/1999), PCT International application PCT/IB99/00797 (filed 3/5/1999), WO 95/21613 (published 17/8/1995), WO 99/61422 (published 2/12/1999), US 5,834,504 (granted 10/11/1998), WO 98/50356 (published 12/11/1998), US 5,883,113 (granted 16/3/1999), US 5,886,020 (granted 23/1999), US 5,792,783 (granted 11/8/11/1999), US 6,653,308 (granted 25/11/2003), WO99/10349 (published 4/3/1999), WO 97/32856 (published 12/1997), WO 97/22596 (published 26/1997), WO 98/54093 (published 3/1998), WO 98/02438 (published 22/1/1998), WO99/16755 (published 8/4/1999), and WO 98/02437 (published 22/1/1998), all of which are incorporated herein by reference in their entirety. Other examples of some specific VEGF inhibitors are IM862(Cytran inc. of Kirkland, Washington, usa); avastin (monoclonal antibody against VEGF) (Genentech, inc. of South san francisco, California); and vascular enzymes (angiozymes), which are synthetic ribozymes from Ribozyme (Boulder, Colorado) and Chiron (Emeryville, California).

ErbB2 receptor inhibitors such as GW-282974(Glaxo Wellcome plc) and monoclonal antibodies AR-209(Aronex Pharmaceuticals Inc. of The Woodlans, Texas, USA) and 2B-1(Chiron) can be administered in combination with The compounds described herein. Such erbB2 inhibitors include herceptin, 2C4, and pertuzumab. Such erbB2 inhibitors include those described in WO 98/02434 (published 22/1/1998), WO 99/35146 (published 15/7/1999), WO 99/35132 (published 15/7/1999), WO 98/02437 (published 22/1/1998), WO 97/13760 (published 17/4/1997), WO 95/19970 (published 27/7/1995), U.S. Pat. No. 5,587,458 (issued 24/12/1996) and U.S. Pat. No. 5,877,305 (issued 2/3/1999), each of which is incorporated herein by reference in its entirety. ErbB2 receptor inhibitors useful in the embodiments described herein are also described in U.S. provisional application No. 60/117,341 filed on 27.1.1999 and U.S. provisional application No. 60/117,346 filed on 27.1.1999, both of which are incorporated herein by reference in their entirety. Other erbb2 receptor inhibitors include TAK-165(Takeda) and GW-572016 (Glaxo-Wellcome).

Various other compounds, such as styrene derivatives, have also been shown to have tyrosine kinase inhibitory properties and some tyrosine kinase inhibitors have been identified as erbB2 receptor inhibitors. Recently, five european patent publications, namely EP 0566226 a1 (published at 10/20/1993), EP 0602851 a1 (published at 22/6/1995), EP 0635507 a1 (published at 25/1/1995), EP 0635498 a1 (published at 25/1/1995) and EP 0520722 a1 (published at 30/12/1992), have proposed certain bicyclic derivatives, in particular quinazoline derivatives, which have anti-cancer properties deriving from their tyrosine kinase inhibitory properties. In addition, international patent application WO 92/20642 (published 11/26 1992) mentions certain bis-mono and bicyclic aryl and heteroaryl compounds as tyrosine kinase inhibitors useful for inhibiting abnormal cell proliferation. International patent applications WO 96/16960 (published 6.6.1996), WO 96/09294 (published 6.3.1996), WO97/30034 (published 21.8.1997), WO 98/02434 (published 22.1.1998), WO 98/02437 (published 22.1.1998) and WO 98/02438 (published 22.1.1998) also mention substituted bicyclic heteroaromatic derivatives as tyrosine kinase inhibitors useful for the same purpose. Other patent applications for which anticancer compounds are mentioned are international patent applications WO 00/44728 (published on 8/3/2000), EP 1029853a1 (published on 8/3/2000) and WO01/98277 (published on 12/2001), all of which are incorporated herein by reference in their entirety.

Epidermal Growth Factor Receptor (EGFR) inhibitors may be administered in combination with the compounds of the present invention. Such EGFR inhibitors include gefitinib (gefinitib), erlotinib (icotinib), afatinib (afatinib), and dacatinib. Monoclonal antibody inhibitors of EGFR (such as cetuximab) may also be combined with the compounds of the present invention.

The c-Met inhibitor may be administered in combination with a compound of the present invention. Such c-Met inhibitors include crizotinib (crizotinib) and ARQ-197. Monoclonal antibody inhibitors of c-Met (such as METMab) may also be combined with the compounds of the invention.

Inhibitors of programmed cell death 1(PD-1) may be administered in combination with the compounds of the present invention. Such anti-PD-1 immuno-tumor agents include anti-PD-1 monoclonal antibodies, nivolumab, and pembrolizumab.

Other antiproliferative agents that may be used with the compounds described herein include farnesyl protein transferase inhibitors and receptor tyrosine kinase PDGFr inhibitors, including the compounds disclosed and claimed in the following U.S. patent applications: 09/221946 (filed 12 months and 28 days 1998); 09/454058 (filed on 12/2/1999); 09/501163 (filed 2 months and 9 days 2000); 09/539930 (filed 3 months and 31 days in 2000); 09/202796 (submitted on 22/5 in 1997); 09/384339 (filed 8/26 in 1999); and 09/383755 (filed 8/26/1999); and the compounds disclosed and claimed in the following U.S. provisional patent applications: 60/168207 (filed on 30/11 in 1999); 60/170119 (filed 10.12.1999); 60/177718 (submitted on 21/1/2000); 60/168217 (filed 11/30/1999) and 60/200834 (filed 5/1/2000). Each of the above-mentioned patent applications and provisional patent applications is incorporated herein by reference in its entirety.

The compounds described herein may also be used with other agents useful in the treatment of abnormal cell growth or cancer, including but not limited to agents capable of enhancing an anti-tumor immune response, such as CTLA4 (cytotoxic lymphocyte antigen 4) antibodies, and other agents capable of blocking CTLA 4; and antiproliferative agents, such as other farnesyl protein transferase inhibitors, e.g., as described in the references cited in the "background" section above. Specific CTLA4 antibodies useful in this embodiment include those described in U.S. provisional application 60/113,647 (filed 12/23 of 1998), which is incorporated herein by reference in its entirety.

The compounds described herein may be administered as monotherapy or may include one or more other anti-tumor substances, for example those selected from: for example mitotic inhibitors such as vinblastine; alkylating agents such as cisplatin, oxaliplatin, carboplatin, and cyclophosphamide; antimetabolites, such as 5-fluorouracil, capecitabine, cytarabine and hydroxyurea, or one of the preferred antimetabolites disclosed, for example, in european patent application No. 239362, such as N- (5- [ N- (3, 4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl) -N-methylamino ] -2-thenoyl) -L-glutamic acid; a growth factor inhibitor; a cell cycle inhibitor; intercalating antibiotics, such as doxorubicin and bleomycin; enzymes, such as interferon; and anti-hormones, for example anti-estrogens such as norvadex (Nolvadex) (tamoxifen), or for example anti-androgens such as Casodex (4 '-cyano-3- (4-fluorophenylsulphonyl) -2-hydroxy-2-methyl-3' - (trifluoromethyl) propionylaniline).

The compounds described herein may be used alone or in combination with one or more of a variety of anti-cancer agents or supportive care agents. For example, the compounds described herein may be used with cytotoxic agents, such as one or more selected from the group consisting of: camptothecin, irinotecan HCl (phenoxator), eltrocaline, SU-11248, epirubicin (elence), docetaxel (Taxotere), paclitaxel, rituximab (Rituxan), bevacizumab (Avastin), imatinib mesylate (Gleevac), erbitux, gefitinib (Iressa), and combinations thereof. Some embodiments also encompass the use of the compounds described herein with hormonal therapy such as exemestane (arnosine), leuprolide acetate (Lupron), anastrozole (Arimidex), tamoxifen citrate (navadex), triptorelin (Trelstar), and combinations thereof. Further, some embodiments provide a compound described herein alone or in combination with one or more supportive care products, such as a product selected from the group consisting of: filgrastim (oupaujin), ondansetron (Zofran), faamin (Fragmin), erythropoietin α (Procrit), Aloxi, emetic (enden), or combinations thereof. Such combination therapy may be achieved by the simultaneous, sequential or separate administration of the individual therapeutic components.

The compounds described herein may be used with antineoplastic agents, alkylating agents, antimetabolites, antibiotics, plant-derived antineoplastic agents, camptothecin derivatives, tyrosine kinase inhibitors, antibodies, interferons, and/or biological response modifiers. In this regard, the following is a non-limiting list of examples of second agents that may be used with the compounds described herein.

Alkylating agents, including but not limited to nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, melphalan, busulfan, dibromomannitol, carboquone, thiotepa, ranimustine, nimustine, temozolomide, AMD-473, altretamine, AP-5280, apaziquone, bromtalicin, bendamustine, carmustine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, phosphoramide, and dibromodulcitol; platinum coordination type alkylating compounds, including but not limited to cisplatin, carboplatin, eptaplatin, lobaplatin, nedaplatin, oxaliplatin or satraplatin (satraplatin).

Antimetabolites including, but not limited to, methotrexate, 6-mercaptopurine nucleosides, mercaptopurine, 5-fluorouracil (5-FU), tegafur, UFT, doxifluridine, carmofur, cytarabine oxford (cytarabine oxfosfate), enocitabine, S-1, gemcitabine, fludarabine (fludarabin), 5-azacitidine, capecitabine, cladribine, clofarabine, decitabine, efluorornithine, ethynylcytidine, cytarabine, hydroxyurea, TS-1, melphalan, nelarabine, nolatrexed, oxford (ocfosfate), disodium pemetrexed (disimiumpremetrexed), penstatin, ritrexed, raltitrexed, trialippine (triapine), adenosine, vincristine, vinorelbine; or one of the preferred antimetabolites disclosed, for example, in European patent application No. 239362, such as N- (5- [ N- (3, 4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl) -N-methylamino ] -2-thenoyl) -L-glutamic acid.

Antibiotics, including but not limited to, doxorubicin, actinomycin D, amrubicin, anthracycline (annamycin), bleomycin, daunorubicin, doxorubicin, elsamicin, epirubicin, garrubicin, idarubicin, mitomycin C, nerubicin, neocarzinostain, pelomomycin, pirarubicin, fringemycin, stimalamer, streptozocin, valrubicin, or neat stastatin.

Hormone therapy agents, such as exemestane (aromas), leuprolide acetate, anastrozole (Arimidex), doxercalciferol, fadrozole, formestane; antiestrogens such as tamoxifen citrate (novadex) and fulvestrant, terestal (Trelstar), toremifene, raloxifene, lasofoxifene, letrozole (frelon (Femara)); or antiandrogens such as bicalutamide, flutamide, mifepristorKetone, nilutamide,(4 '-cyano-3- (4-fluorophenylsulfonyl) -2-hydroxy-2-methyl-3' - (trifluoromethyl) propionylaniline) and combinations thereof.

Plant-derived antitumor substances, including for example those selected from mitotic inhibitors, such as vinblastine, docetaxel (taxotere) and paclitaxel.

A cytotoxic topoisomerase inhibitor comprising one or more agents selected from the group consisting of: aclarubicin, amonafide, belotecan, camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin, diflucan, irinotecan HCl (Camptosar), eltrocaline, epirubicin (Ellence), etoposide, exatecan, gemmacetan, lurtotecan, mitoxantrone, pirarubicin, Pickerogen, rubitecan, sobuzotene, SN-38, tafluoroporphoside, and topotecan, and combinations thereof.

Immunopharmaceuticals, including interferons and various other immunopotentiators. The interferon includes interferon alpha, interferon alpha-2 a, interferon alpha-2 b, interferon beta, interferon gamma-1 a or interferon gamma-n 1. Other agents include PF3512676, filgrastim, lentinan, schizophyllan, TheraCys, ubenimex, WF-10, aldesleukin, alemtuzumab, BAM-002, dacarbazine, daclizumab, dinilukine, gemtuzumab ogamicin, ibritumomab (ibritumomab), imiqimod, legungsin, lentinan, melanoma vaccine (Corixa), moraxest, Oncovax-CL, sargrastim, tasonnine, tekugin (tecleukin), thymosin (thymolasin), tositumomab, vulizine, Z-100, epratuzumab, mitomumab, oguzumab, panitumumab (mtpemumomab), Provene (Provene).

A biological response modifier, which is an agent that modifies the defense mechanism of a living organism or the biological response (such as survival, growth, or differentiation) of a tissue cell to direct it to have anti-tumor activity. These agents include coriolus intracellular glycopeptides, lentinan, cezopyran, bisinbib or ubenimex.

Other anti-cancer agents, include alitretinol, apremide, atrasentan, bexarotene, bortezomib, bosentan, calcitriol, epsiprenaline, finasteride, fotemustine, ibandronic acid, miltefosine, mitoxantrone, l-asparaginase, procarbazine, dacarbazine, hydroxyurea, pemetrexed, pentostatin, tazarotene (tazarotene), TLK-286, velcade, teroka, or tretinoin.

Other anti-angiogenic compounds include Avermectin, fenretinide, thalidomide, zoledronic acid, angiogenesis inhibitor, marine cyclic peptide (aplidine), cilengitide (cilengtlide), combretastatin A-4, endostatin, halofuginone, rimostat, Removab, Revlimid, squalamine, ukraine, and Vitaxin.

Platinum coordination compounds including, but not limited to, cisplatin, carboplatin, nedaplatin, or oxaliplatin.

Camptothecin derivatives, including but not limited to camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin, irinotecan, SN-38, irinotecan and topotecan.

Tyrosine kinase inhibitors, including for example Iressa and SU 5416.

Antibodies, including, for example, herceptin, erbitux, avastin, and rituximab.

Interferons include, for example, interferon alpha-2 a, interferon alpha-2 b, interferon beta, interferon gamma-1 a, or interferon gamma-n 1.

Biological response modifiers, including agents that modulate the defense mechanisms of living organisms or the biological response (such as survival, growth, or differentiation) of tissue cells to direct them to have anti-tumor activity. Such agents include, for example, polystictus intracellular glycopeptides, lentinan, cezopyran, bisinbibib and ubenimex.

Other antineoplastic agents include, for example, mitoxantrone, l-asparaginase, procarbazine, dacarbazine, hydroxyurea, pentostatin, and tretinoin. In addition, PI3K inhibitors and RAS-targeted cancer therapies can be combined with the compounds described herein.

Some embodiments also relate to a pharmaceutical composition comprising a compound of formula (I), formula (II), formula (III) or formula (IV) as defined herein above, or a pharmaceutically acceptable salt or solvate thereof, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

Other embodiments relate to pharmaceutical compositions comprising a compound of formula (I), formula (II), formula (III) or formula (IV), or a pharmaceutically acceptable salt or solvate thereof, as defined herein before, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

For the above therapeutic uses, the dosage administered will, of course, vary with the compound employed, the mode of administration, the desired treatment and the indication. The daily dose of a compound of formula (I), formula (II), formula (III) or formula (IV), or a pharmaceutically acceptable salt thereof, may be from 1mg to 1g, preferably from 1mg to 250mg, more preferably from 10mg to 100 mg.

Embodiments of the present invention also encompass sustained release compositions.

Administration of the compounds described herein (hereinafter "active compounds") can be accomplished by any method that is capable of delivering the compound to the site of action. These methods include oral, intraduodenal, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical and rectal administration.

The active compound may be administered as monotherapy or may include one or more other anti-tumour agents, for example those selected from: for example mitotic inhibitors such as vinblastine; alkylating agents such as cisplatin, carboplatin, and cyclophosphamide; antimetabolites, such as 5-fluorouracil, cytarabine and hydroxyurea, or preferred antimetabolites, such as those disclosed in European patent application No. 239362A, such as N- (5- [ N- (3, 4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl) -N-methylamino]-2-thenoyl) -L-glutamic acid; a growth factor inhibitor; a cell cycle inhibitor; intercalating antibiotics, such as doxorubicin and bleomycin; enzymes, such as interferon; and anti-hormones, e.g. anti-oestrogens, such as norwalk(tamoxifen), or e.g. antiandrogens, such as combretan(4 '-cyano-3- (4-fluorophenylsulfonyl) -2-hydroxy-2-methyl-3' - (trifluoromethyl) propionylaniline). Such combination therapy may be achieved by the simultaneous, sequential or separate administration of the individual therapeutic components.

The pharmaceutical composition may be in a form suitable, for example, for oral administration, such as tablets, capsules, pills, powders, sustained release formulations, solutions, suspensions; suitable for parenteral injection, such as sterile solution, suspension or emulsion; forms suitable for topical administration, such as ointments or creams; or in a form suitable for rectal administration, such as a suppository. The pharmaceutical composition may be in unit dosage form suitable for single administration of precise dosages. The pharmaceutical compositions will comprise conventional pharmaceutical carriers or excipients and the compounds described herein as the active ingredient. In addition, it may contain other medicinal or pharmaceutical substances, carriers, adjuvants, etc.

Exemplary parenteral administration forms include solutions or suspensions of the active compounds in sterile aqueous solutions (e.g., aqueous propylene glycol or dextrose). Such dosage forms may be suitably buffered if desired.

Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents. The pharmaceutical composition may contain additional ingredients such as flavoring agents, binders, excipients, and the like, if desired. Thus, for oral administration, tablets containing various excipients (e.g., citric acid) may be employed along with various disintegrants (e.g., starch, alginic acid and certain complex silicates) and binding agents (e.g., sucrose, gelatin and acacia). In addition, for tableting purposes, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often used. Solid compositions of a similar type may also be employed in soft-filled gelatin capsules and hard-filled gelatin capsules. For this purpose, preferred materials include lactose (lactose) or lactose (milk sugar) and high molecular weight polyethylene glycols. When an aqueous suspension or elixir is desired for oral administration of the active compound, the active compound can be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if desired, emulsifying or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin or combinations thereof.

The examples and preparations provided below further illustrate and exemplify the compounds described herein and methods of making such compounds. The scope of the embodiments described herein is in no way limited by the following examples and preparations. In the following examples, molecules with a single chiral center are present in the form of a racemic mixture, unless otherwise indicated. Unless otherwise indicated, molecules having two or more chiral centers exist as racemic mixtures of diastereomers. The single enantiomers/diastereomers may be obtained by methods known to those skilled in the art.

In the examples shown, during HPLC-based chromatographic purification, separation in the form of salts occasionally occurs due to mobile phase additives. In these cases, salts (such as formate, trifluoroacetate and acetate) were isolated and tested without further treatment. It will be appreciated that the free base form can be obtained by standard methods by one of ordinary skill in the art, such as simple basic extraction using an ion exchange column or using a weakly basic aqueous solution.

In general, the compounds described herein can be prepared by methods known in the chemical art, in particular in accordance with the description contained herein. Certain methods for preparing the compounds described herein are provided as additional features of embodiments and are illustrated in the reaction schemes provided below and in the experimental sections.

Unless otherwise indicated, the variables in routes a-F have the same meaning as defined herein.

Route a:

as illustrated in scheme A, 2, 6-dichloro-9H-purine derivative A-1 is subjected to nucleophilic aromatic substitution, defined as displacement of a reactive aromatic halide ion by a nucleophile, and generally referred to herein as S_nAnd Ar condition. Said S_nAr conditions are acid mediated (such as treatment with a suitable amino heterocycle (such as TFA salt or HCl salt of an amino heterocycle) in the presence of a suitable acid in a suitable solvent (such as iPrOH), or base mediated (such as treatment with a suitable amino heterocycle in the presence of a suitable base (such as DIPEA) in a suitable solvent (such as nBuOH)) to afford 2-chloropurine A-2. Followed by a palladium mediated process or at S_nDisplacement of the chlorine treated under Ar conditions gives substituted purine a-3. Deprotection (removal of the protecting group) under standard conditions known in the art affords A-4. Acylation with an acid chloride or amide coupling procedure with a suitable acid affords A-5.

Route B:

as illustrated in scheme B, exposure of 2, 6-dichloro-9H-purine derivative A-1 to S_nAnd Ar condition. Said S_nAr conditions are acid-mediated (such as treatment with a suitable amino heterocycle (e.g. TFA salt or HCl salt of an amino heterocycle) in the presence of a suitable acid in a suitable solvent (such as iPrOH), or base-mediated (such as treatment with a suitable base (such as DIPEA) in a suitable solvent (such as nBuOH)Treated with a suitable amino heterocycle in the presence) to give 2-chloropurine a-2. Subsequent chloro-displacement with aniline by either a palladium mediated process or a phenoxide salt (generated by using a suitable base such as sodium hydride in THF) gives substituted purine B-1. Reduction of the nitro group under standard conditions known in the art gives B-2. Acylation with an acid chloride or amide coupling method with a suitable acid gives B-3.

Route C:

as illustrated in scheme C, exposure of 2-fluoro-6-chloro-9H-purine derivative C-1 to S_nAnd Ar condition. Said S_nAr conditions are acid mediated (such as treatment with a suitable amino heterocycle (such as TFA salt or HCl salt of an amino heterocycle) in the presence of a suitable acid in a suitable solvent (such as iPrOH), or base mediated (such as treatment with a suitable amino heterocycle in the presence of a suitable base (such as DIPEA) in a suitable solvent (such as nBuOH)) to afford 2-fluoropurine C-2. At S_nSubsequent treatment under Ar conditions gives substituted purine A-3. Deprotection (removal of the protecting group) under standard conditions known in the art affords A-4. Acylation with an acid chloride or amide coupling procedure with a suitable acid affords A-5.

Route D:

as illustrated in scheme D, exposure of 2-fluoro-6-chloro-9H-purine derivative C-1 to S_nAnd Ar condition. Said S_nAr conditions are acid-mediated (such as treatment with a suitable amino heterocycle (such as TFA salt or HCl salt of an amino heterocycle) in the presence of a suitable acid in a suitable solvent (such as iPrOH), or base-mediated (such as treatment with a suitable amino heterocycle in a suitable solvent (such as nBuOH) in the presence of a suitable base (such as DIPEA)Physical) to obtain 2-fluoropurine C-2. S with subsequent masking of acrylamide with sulfone form_nAr gives the substituted purine D-1. Alternatively, ring A of C-2 comprises a protected amine or alcohol, which is deprotected under standard conditions known in the art, and in some cases, at the second S_nPrior to the Ar step, the modification may be by alkylation or reductive amination. Sulfone elimination is achieved by treatment with a suitable base, such as potassium tert-butoxide, to give A-5.

Route E:

as illustrated in scheme E, exposure of 2, 6-dichloro-9H-purine derivative A-1 to S_nAnd Ar condition. Said S_nAr conditions are acid mediated (such as treatment with a suitable amino heterocycle (such as TFA salt or HCl salt of the amino heterocycle) in the presence of a suitable acid in a suitable solvent (such as iPrOH), or base mediated (such as treatment with a suitable amino heterocycle in the presence of a suitable base (such as DIPEA) in a suitable solvent (such as nBuOH)) to afford 2-fluoropurine a-2. Subsequent displacement of chlorine by palladium mediated methods (such as reaction with a suitable borate or boronic acid) affords substituted purine E-1. Reduction of the intermediate by standard conditions known in the art gives carbocyclic E-2, followed by deprotection (removal of the protecting group) and acylation by acid chloride or amide coupling methods with suitable acids under standard conditions known in the art gives E-3.

Route F:

as illustrated in scheme F, 6-chloro-2-fluoro-9H-purine F-1 is exposed to S_nAnd Ar condition. Said S_nAr conditions are acid mediated (such as in a suitable solvent (such as iPrOH), with a suitable amino group in the presence of a suitable acidTreatment of the heterocycle (e.g., TFA salt or HCl salt of the amino heterocycle), or base-mediated (such as treatment with a suitable amino heterocycle in a suitable solvent (such as nBuOH) in the presence of a suitable base (such as DIPEA)) to afford the 2-fluoropurine derivative F-2. Alkylation of the purine core with alkyl halides or dialkyl sulfates yields C-2. S with subsequent masking of acrylamide with sulfone form_nAr gives the substituted purine D-1. Alternatively, ring A of C-2 comprises a protected amine or alcohol, which is deprotected under standard conditions known in the art, and in some cases, at the second S_nPrior to the Ar step, the modification may be by alkylation or reductive amination. Sulfone elimination is achieved by treatment with a suitable base, such as potassium tert-butoxide, to give A-5.

Examples

Example 1 (route a): (S) -N- (1- (9-isopropyl-6- ((4- (4-methylpiperazin-1-yl) phenyl) amino) - Preparation of 9H-purin-2-yl) pyrrolidin-3-yl) acrylamide

Step 1: preparation of 2, 6-dichloro-9-isopropyl-9H-purine

A500 mL round bottom flask was charged with 2, 6-dichloro-9H-purine (1.89g,10mmol), isopropanol (3.1mL,40mmol,4mol eq), THF (150mL), and triphenylphosphine (polystyrene bound, about 3mmol/g,6.7g, or about 20mmol loading), and the resulting mixture was stirred under nitrogen and cooled in a water bath. A solution of DBAD (4.85g,20mmol) in THF (50mL) was added dropwise over 30 minutes through an addition funnel and the resulting reaction mixture was stirred at ambient temperature for 20 hours. The resin was removed by filtration and washed thoroughly with ethyl acetate. The combined filtrates were evaporated to give a light yellow solid which was purified by flash column chromatography (dry loading with silica/DCM) with a gradient of 0-50% ethyl acetate in heptane to give:

1. the title product: 2, 6-dichloro-9-isopropyl-9H-purine (2.81g, containing DBAD by-product by¹H NMR measurement, 0.9mol eq).¹H NMR (400MHz, DMSO-d6) ppm 8.86(s,1H)4.71-4.94(m,1H)1.55(d, J ═ 6.85Hz,6H) with 1.39(s,16H, DBAD byproduct). For C₈H₈Cl₂N₄M/z (APCI +)231.1(M + H)⁺With a Cl isotope pattern.

2. Other minor regioisomers: 2, 6-dichloro-7-isopropyl-7H-purine (229mg, 10% yield).¹H NMR (400MHz, DMSO-d6) ppm 9.06(s,1H)5.13(dt, J ═ 13.36,6.71Hz,1H)1.59(d, J ═ 6.72Hz, 6H). For C₈H₈Cl₂N₄M/z (APCI +)231.1(M + H)⁺With a Cl isotope pattern.

Step 2: preparation of 2-chloro-9-isopropyl-N- (4- (4-methylpiperazin-1-yl) phenyl) -9H-purin-6-amine

To a reaction vial was added 2, 6-dichloro-9-isopropyl-9H-purine (containing 6.3mmol), 4- (4-methylpiperazin-1-yl) aniline (1.2g,6.3mmol), isopropanol (32mL,0.2M) and TFA (1mL,13 mmol). The reaction vial was capped, stirred and heated at 78 ℃ (blocking temperature) for 20 hours. The volatiles were removed to give a dark residue. Adding NaHCO₃Saturated aqueous solution (40 mL). A dark sticky solid precipitated out. The product was extracted using ethyl acetate (2x120mL) and DCM (2x80 mL). The combined organic layers were washed with Na₂SO₄Dried and evaporated to give a dark residue which is washed on silica with 100% ethyl acetate to 10% aqueous ammonia (7N) -90% in methanolGradient purification of ethyl acetate to give the title product as a light yellow solid (2.1g, 86% yield).¹H NMR (400MHz, DMSO-d6) ppm 10.04(s,1H)8.38(s,1H)7.61(d, J ═ 8.56Hz,2H)6.93(d, J ═ 8.93Hz,2H)4.71(dt, J ═ 13.39,6.63Hz,1H)3.10(br.s.,4H)2.45(m, J ═ 4.16Hz,4H)2.22(s,3H)1.52(d, J ═ 6.72Hz, 6H). For C₁₉H₂₄ClN₇M/z (APCI +)386.2(M + H)⁺With a Cl isotope pattern. The regiochemistry of the product was also confirmed by small molecule X-ray crystallography.

And step 3: (S) - (1- (9-isopropyl-6- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -9H-purine-2- Preparation of Yl) Pyrrolidin-3-yl) carbamic acid Tert-butyl ester

2-chloro-9-isopropyl-N- (4- (4-methylpiperazin-1-yl) phenyl) -9H-purin-6-amine (2.32g,6mmol), (S) -pyrrolidin-3-yl-carbamic acid tert-butyl ester (1.45g,7.8mmol,1.3mol eq) and Cs₂CO₃A mixture of (7.82g,24mmol,4mol eq) in tert-amyl alcohol (60mL,0.1M) was degassed with nitrogen. (bis-2-norbornylphosphino) (2-dimethylaminomethylferrocen-1-yl) palladium (II) chloride (CAS #614753-51-4,375mg,0.6mmol,0.1moleq) was added and the mixture was degassed for an additional 1 minute. The vial was capped, stirred and heated at 100 ℃ (blocking temperature) for 20 hours. The reaction was cooled, diluted with water (25mL) and ethyl acetate (150mL), and the organic layer was separated. The aqueous layer was extracted with more ethyl acetate (50mL) and the combined organic layers were extracted with Na₂SO₄Dried and evaporated to give a residue which was purified by silica flash chromatography with a gradient of 50% heptane-50% ethyl acetate to 100% ethyl acetate, then to 10% aqueous ammonia (7N in methanol) -90% ethyl acetate to give the title product as a light yellow solid (3.20g, 99% yield).¹H NMR(400MHz,DMSO d6)ppm 9.14(s,1H)7.90(s,1H)7.85(d,J＝9.05Hz,2H)7.14(d,J＝5.01Hz,1H)6.87(d,J＝9.17Hz,2H)4.61(quin,J＝6.72Hz,1H)4.05-4.27(m,2H)3.60-3.80(m,2H)3.50(dt, J ═ 10.55,7.08Hz,1H)3.35(dd, J ═ 10.82,4.83Hz,1H)3.02-3.11(m,4H)2.40-2.48(m,4H)2.22(s,3H)1.79-1.92(m,1H)1.50(d, J ═ 6.85Hz,6H)1.40(s, 9H). For C₂₈H₄₁N₉O₂M/z (APCI +)536.4(M + H)⁺。

And 4, step 4: (S) -2- (3-Aminopyrrolidin-1-yl) -9-isopropyl-N- (4- (4-methylpiperazin-1-yl) phenyl) - Preparation of 9H-purin-6-amines

To a solution of tert-butyl (S) - (1- (9-isopropyl-6- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -9H-purin-2-yl) pyrrolidin-3-yl) carbamate (1.40g,2.61mmol) in DCM (30mL) was added TFA (2.11mL,21 mmol). The reaction vial was capped and stirred for 3 hours. The volatiles were then removed and methanol (50mL) and aqueous LiOH (2M,20mL) were added and the mixture was stirred for 16 hours. Volatiles were removed to give a white solid residue. Water (30mL) was added and the mixture was sonicated to give a white suspension. The solid was collected by filtration and dried to give the title product as a white solid (1.26g, 111% yield, about 90% purity).¹H NMR (400MHz, DMSO-d6) ppm 9.10(br.s.,1H)7.76-7.94(m,3H)6.87(d, J ═ 8.80Hz,2H)4.60(dt, J ═ 13.33,6.66Hz,1H)3.58-3.72(m,2H)3.51(dd, J ═ 10.64,5.99Hz,2H)3.06(br.s.,4H)2.45(br.s.,4H)2.22(s,3H)1.95-2.10(m,2H)1.58-1.73(m,3H)1.50(d, J ═ 6.72Hz, 6H). For C₂₃H₃₃N₉M/z (APCI +)436.4(M + H)⁺。

And 5: (S) -N- (1- (9-isopropyl-6- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -9H-purine-2- Preparation of yl) pyrrolidin-3-yl) acrylamide

(S) -2- (3-Aminopyrrolidin-1-yl) -9-isopropyl-N- (4- (4-methylpiperazin-1-yl) phenyl) -9H-purin-6-amine (315mg,0.7mmol) was dissolved in DCM: tert-amyl alcohol (15mL:1.5mL) and NaHCO was added in one portion₃Saturated aqueous solution (6 mL). The biphasic mixture was stirred vigorously and acryloyl chloride (90 μ L,1.1mmol,1.5moleq) was added in one portion and the resulting mixture stirred at ambient temperature for 2 hours. The reaction was diluted with DCM (30mL) and the organic layer was separated and the product extracted with more DCM: t-amyl alcohol (9:1,30 mL). The combined organic layers were washed with Na₂SO₄Dried and evaporated to give a residue which is purified by silica flash chromatography with a gradient of 100% ethyl acetate to 100% ethanol to give a crude purity of about 90%. The crude product was triturated with ethyl acetate heptane (4:1,15 mL). The resulting white solid was collected by filtration, washed with ethyl acetate: heptane (4:1,10mL), and dried to give the title product as a white solid (118mg, 33% yield, about 95% purity).¹H NMR (400MHz, DMSO-d6) ppm 9.16(s,1H)8.36(d, J ═ 6.72Hz,1H)7.91(s,1H)7.85(d, J ═ 8.80Hz,2H)6.87(d, J ═ 8.93Hz,2H)6.18-6.34(m,1H)6.03-6.15(m,1H)5.59(dd, J ═ 9.96,2.02Hz,1H)4.62(dt, J ═ 13.33,6.54Hz,1H)4.43(d, J ═ 5.14Hz,1H)3.71-3.87(m,1H)3.63(dt, J ═ 12.62,6.46, 2H)3.43(dd, J ═ 11.25, J ═ 4.65, J ═ 4.5, 1H)3.65 (dd, J ═ 4.9.9, 2.87 (dd, 1H)3.9, 1H)3.9 (dd, 1H)4.9, 6.9 Hz,1H, 6H, and 1H). For C₂₆H₃₅N₉O M/z (APCI +)490.2(M + H)⁺。

(S) -N- (1- (9-isopropyl-6- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -9H-purin-2-yl) pyri-dine Alternative preparation of pyrrolidin-3-yl) acrylamides

(S) -2- (3-Aminopyrrolidin-1-yl) -9-isopropyl-N- (4- (4-methylpiperazin-1-yl) phenyl) -9H-purin-6-amine (436mg,1mmol) was suspended in DMF (3.3 mL). DIPEA (0.53mL,3mmol,3mol eq) and acrylic acid (73. mu.L, 1.05mmol,1.05mol eq) were added to give a suspension. Propylphosphonic anhydride (CAS 68957-94-8, 50% in DMF, 0.7mL,1.2mmol,1.2mol eq) was added in one portion. The reaction mixture was warmed slightly to give a solution. After 15 minutes, addInto Na₂CO₃Aqueous solution (1M,2mL,2mmol) and stirred for 30 min. Water (10mL) and ethyl acetate (50mL) were added. The organic layer was separated, washed with water (3 × 10mL) and Na₂SO₄Dried and evaporated to give a pale yellow foamy solid which was purified by SFC (column zymor sphere HADP 150x21.2mm i.d.,5 μm particles modifier: ethanol, gradient 21% (held 2min) to 24% (held 1min) at 1.5%/min flow rate (58mL/min) to give the title product (167mg, 34% yield,>95% purity).¹H NMR (400MHz, DMSO-d6) ppm 9.17(s,1H)8.36(d, J ═ 6.85Hz,1H)7.91(s,1H)7.85(d, J ═ 9.05Hz,2H)6.87(d, J ═ 9.05Hz,2H)6.19-6.32(m,1H)6.05-6.16(m,1H)5.59(dd, J ═ 10.09,2.38Hz,1H)4.62(quin, J ═ 6.72Hz,1H)4.34-4.48(m,1H)3.76(dd, J ═ 11.31,6.30Hz,1H)3.54-3.70(m,2H)3.43(dd, J ═ 11.19,3.85, 1H) 3.3.3.3.3.3.7 (d,2H) 3.47, 1H) 3.3.3.3.3.3.3.3 (d,1H) 3.3.3.3.3.3.3, 2H) 3.3.3.3.3.3, 2H) 3.3.1H) 3.. For C₂₆H₃₅N₉O M/z (APCI +)490.4(M + H)⁺。

Example 2 (route a): n- ((3R,4R) -4-fluoro-1- (9-isopropyl-6- ((1-methyl-1H-pyrazol-4-yl) amino) Preparation of yl) -9H-purin-2-yl) pyrrolidin-3-yl) acrylamide

Step 1: preparation of 2-chloro-9-isopropyl-N- (1-methyl-1H-pyrazol-4-yl) -9H-purin-6-amine

2, 6-dichloro-9-isopropyl-9H-purine (1.16g,5mmol), prepared as in step 1 of example 1, was mixed with 4-amino-1-methylpyrazole (1.02g,10mmol) and DIPEA (1.74mL,10mmol) in nBuOH (33mL) and heated and stirred at 100 deg.C (barrier temperature) for 1 hour. Will be provided withThe reaction was cooled and the volatiles were removed under vacuum to give a dark residue. Ethyl acetate (120mL) was added and the mixture was washed with saturated NaHCO₃Washed with aqueous solution (3 × 30mL) and Na₂SO₄Dried and evaporated to give a dark residue. The residue was dissolved in ethyl acetate, passed through a thin pad of silica gel, and eluted with 90% ethyl acetate-10% aqueous ammonia (7N in methanol). The eluent was evaporated to give the title compound as a dark solid (1.43g, 98% yield).¹H NMR (400MHz, DMSO-d6) ppm 10.41(br.s.,1H)8.38(s,1H)8.00(s,1H)7.68(s,1H)4.71(quin, J ═ 6.72Hz,1H)3.84(s,3H)1.52(d, J ═ 6.72Hz, 6H). For C₁₂H₁₄ClN₇M/z (APCI +)292.1 of (a) has a Cl isotope pattern (M + H)⁺。

Step 2: 2- ((trans) -3-amino-4-fluoropyrrolidin-1-yl) -9-isopropyl-N- (1-methyl-1H-pyrazole-4- Preparation of yl) -9H-purin-6-amines

To 2-chloro-9-isopropyl-N- (1-methyl-1H-pyrazol-4-yl) -9H-purin-6-amine (292mg,1.00mmol) and [ (3, 4-trans) -4-fluoropyrrolidin-3-yl]A solution of benzyl carbamate (357mg,1.5mmol) in t-amyl alcohol (10mL) was added Cs₂CO₃(1.32g,4 mmol). The reaction mixture was degassed with nitrogen for 2 minutes, then the catalyst (di-2-norbornylphosphino) (2-dimethylaminomethylferrocen-1-yl) palladium (II) chloride (CAS #614753-51-4,60mg,0.1mmol) was added. The reaction vial was capped, stirred and heated at 100 ℃ (blocking temperature) for 20 hours. Ethanol (40mL) was added to the reaction mixture and any insoluble material was removed by filtration. The filtrate was then hydrogenated using 10% Pd/C (120mg) and hydrogen balloon for 20 hours. The catalyst was filtered off and the filtrate was evaporated to give a dark residue which was purified by flash column chromatography (gradient from 50% ethyl acetate-50% heptane to 100% ethyl acetate, then to 10% ammonia (7N) -90% ethyl acetate in methanol). The fractions containing the title product were evaporated to give a crude residueSlag, which is used in the next step.

And step 3: n- ((3R,4R) -4-fluoro-1- (9-isopropyl-6- ((1-methyl-1H-pyrazol-4-yl) amino) -9H-purine Preparation of pterin-2-yl) pyrrolidin-3-yl) acrylamide

Crude 2- ((trans) -3-amino-4-fluoropyrrolidin-1-yl) -9-isopropyl-N- (1-methyl-1H-pyrazol-4-yl) -9H-purin-6-amine (assumed about 1mmol) was dissolved in DCM (30mL) and saturated NaHCO₃The aqueous solution (10mL) was partitioned between and vigorously stirred. Acryloyl chloride (121 μ L,1.5mmol) was added in one portion, and the mixture was stirred for 30 min. The mixture was then diluted with DCM (50mL) and the organic layer was separated and Na was used₂SO₄Dried and evaporated to give a dark residue which was subjected to chiral SFC purification to separate the two trans-isomers (Chiralpak AD-H21.2X 250mm 5. mu.column in CO₂Was maintained at 38 ℃ and 100bar, eluted with 30% EtOH (200 relative loudness), about 60.0mL/min, and UV peak 1(-) eluted at λ 260nm for 3.99-4.68 min. Peak 2(+) eluted 5.80-6.38 min). Obtaining:

n- ((3R,4R) -4-fluoro-1- (9-isopropyl-6- ((1-methyl-1H-pyrazol-4-yl) amino) -9H-purin-2-yl) pyrrolidin-3-yl) acrylamide (absolute stereochemistry determined later by small molecule crystallography of key intermediates), 30.26mg, 7% yield (3 steps), about 99% ee, 90% purity. optical rotation [ α ]]D₂₂＝+28.9°(c 0.09,EtOH).¹HNMR (600MHz, DMSO-17mm) ppm9.65(br.s.,1H)8.50(d, J ═ 6.97Hz,1H)8.00(s,1H)7.92(s,1H)7.69(s,1H)6.20-6.29(m,1H)6.08-6.18(m,1H)5.63(d, J ═ 10.82Hz,1H)5.03-5.25(m,1H)4.43-4.70(m,2H)3.88(br.s.,2H)3.82(s,3H)3.70(d, J ═ 10.45Hz,2H)1.50(d, J ═ 6.42Hz, 6H). For C₁₉H₂₄FN₉O M/z (APCI +)414.1(M + H)⁺。

N- ((3S,4S) -4-fluoro-1- (9-isopropyl-6- ((1-methyl-1H-pyrazol-4-yl) amino) -9H-purin-2-yl)) Pyrrolidin-3-yl) acrylamide, 36.7mg, 9% yield (step 3),>99% ee, 95% purity and optical rotation [ α ]]D₂₂＝-19.06°(c 0.08,EtOH).¹H NMR (600MHz, DMSO-17mm) ppm9.65(br.s.,1H)8.50(d, J ═ 6.42Hz,1H)8.00(s,1H)7.92(s,1H)7.69(s,1H)6.19-6.29(m,1H)6.11-6.18(m,1H)5.63(d, J ═ 11.92Hz,1H)5.08-5.22(m,1H)4.46-4.69(m,2H)3.88(br.s.,2H)3.82(s,3H)3.64-3.79(m,2H)1.50(d, J ═ 6.79Hz, 6H). For C₁₉H₂₄FN₉O M/z (APCI +)414.1(M + H)⁺。

Alternative method of example 2 (route C): n- ((3R,4R) -4-fluoro-1- (9-isopropyl-6- ((1-methyl) Preparation of 1H-pyrazol-4-yl) amino) -9H-purin-2-yl) pyrrolidin-3-yl) acrylamide

Step 1: preparation of 6-chloro-2-fluoro-9-isopropyl-9H-purine

A solution of 6-chloro-2-fluoro-9H-purine (616mg,3.57mmol) in THF (18mL) was cooled in an ice-water bath under nitrogen and iPrOH (858mg,14.3mmol), polymer-bound triphenylphosphine (2.38g,7.14mmol, ca. 3mmol/g) and di-tert-butyl azodicarboxylate (1.730g,7.14mmol) were added. The reaction mixture was allowed to warm to ambient temperature and stirred for 16 hours. The solid resin was removed and washed thoroughly with ethyl acetate (50 mL). The filtrate was concentrated in vacuo to give a pale yellow solid residue. It was then loaded onto silica and purified by flash chromatography (eluting with 30-50% ethyl acetate in heptane) to give the title product as a white solid (445mg, 58% yield).¹H NMR (400MHz, DMSO-d6) ppm 8.83(s,1H)4.72-4.92(m,1H)1.57(d, J ═ 6.85Hz, 6H). For C₈H₈FN₄M/z (APCI +)217.10,215.10(M + H) of Cl⁺。

Step 2: 2-fluoro-9-isopropyl-N- (1-methyl-1H-pyri-dinePreparation of oxazol-4-yl) -9H-purin-6-amines

A mixture of 6-chloro-2-fluoro-9-isopropyl-9H-purine (215mg,1mmol), 1-methyl-1H-pyrazol-4-amine (116mg,1.2mmol) in nBuOH (5mL,0.2M), and DIPEA (0.7mL,4mmol) was stirred at ambient temperature for 2 days. LCMS indicated the main title product with M +1 ═ 276.2 amu. The crude product was used in the next step without isolation.

And step 3: ((3R,4R) -4-fluoro-1- (9-isopropyl-6- ((1-methyl-1H-pyrazol-4-yl) amino) -9H-purine Preparation of benzyl (2-yl) pyrrolidin-3-yl) carbamate

To the above solution of crude 2-fluoro-9-isopropyl-N- (1-methyl-1H-pyrazol-4-yl) -9H-purin-6-amine was added [ (3R,4R) -4-fluoropyrrolidin-3-yl group]Benzyl carbamate (238mg,1 mmol). The resulting solution was heated at 100 ℃ (blocking temperature) and stirred for 14 hours. After cooling, the volatiles were removed and the residue was purified by flash chromatography (with 100% heptane to 100% ethyl acetate, then to 10% ammonia (gradient of 7N in methanol) -90% ethyl acetate) to give the title compound as a light yellow solid (402mg, 82% yield (2 steps)).¹H NMR(400MHz,DMSO-d6)ppm 9.62(s,1H)7.98(s,1H)7.91(s,1H)7.80(d,J＝5.75Hz,1H)7.71(s,1H)7.27-7.41(m,5H)4.98-5.30(m,3H)4.55-4.68(m,1H)4.16-4.34(m,1H)3.76-3.96(m,6H)3.64-3.71(m,1H)1.50(d,J＝6.72Hz,6H)。¹⁹F NMR (376MHz, DMSO-d6) ppm-178.93(br.s., 1F). For C₂₄H₂₈FN₉O₂M/z (APCI +)494.2(M + H)⁺. Chiral purity was determined as follows (using racemic samples for comparison):

chiralcel OD-H4.6X 100mm column in CO₂A gradient of medium 5-60% MeOH/DEA at 120bar for 3min, 4mL/min the title sample showed a ratio of about 88(2.50min):12(2.75min), about 76% ee. [ α ]]D₂₂＝+15.6°(c 0.17,EtOH)。

And 4, step 4: 2- ((3R,4R) -3-amino-4-fluoropyrrolidin-1-yl) -9-isopropyl-N- (1-methyl-1H-pyrazole- Preparation of 4-yl) -9H-purin-6-amines

A mixture of benzyl ((3R,4R) -4-fluoro-1- (9-isopropyl-6- ((1-methyl-1H-pyrazol-4-yl) amino) -9H-purin-2-yl) pyrrolidin-3-yl) carbamate (390mg,0.8mmol), ammonium formate (514mg,8mmol) in ethanol (20mL) was degassed for 3 minutes and then 10% -Pd/C (50mg) was added. The reaction was stirred and heated to slight reflux for 45 minutes. The catalyst was removed by filtration and washed thoroughly with ethanol (40 mL). The combined liquids were concentrated to give a residue, which was taken up in water (5mL) and extracted with DCM-isopropanol (9:1,2 × 70 mL). The combined organic extracts were extracted with saturated NaHCO₃(5mL) washed with Na₂SO₄Dried and evaporated to give the title compound as a pale yellow solid (272mg, 96% yield).¹H NMR(400MHz,DMSO-d6)ppm 9.58(s,1H)8.00(s,2H)7.90(s,2H)7.73(s,1H)4.89-5.08(m,1H)4.56-4.66(m,1H)3.86-4.00(m,1H)3.81-3.85(m,3H)3.58-3.80(m,3H)3.53(d,J＝11.13Hz,1H)1.51(d,J＝6.72Hz,6H)。¹⁹F NMR (376MHz, DMSO-d6) ppm-177.42(s, 1F). For C₁₆H₂₂FN₉M/z (APCI +)360.2(M + H)⁺. Chiral purity was determined as follows (using racemic samples for comparison):

chiralcel OD-H4.6X 100mm column in CO₂A gradient of medium 5-60% MeOH/DEA at 120bar for 3min, 4mL/min the title sample showed a ratio of about 86(2.04min):14(2.21min), about 72% ee. [ α ]]D₂₂＝+4.5°(c 0.14,EtOH)。

And 5: n- ((3R,4R) -4-fluoro-1- (9-isopropyl-6- ((1-methyl-1H-pyrazol-4-yl) amino) -9H-purine Preparation of pterin-2-yl) pyrrolidin-3-yl) acrylamide

A mixture of 2- ((3R,4R) -3-amino-4-fluoropyrrolidin-1-yl) -9-isopropyl-N- (1-methyl-1H-pyrazol-4-yl) -9H-purin-6-amine (260mg, 85% purity, corrected for 0.62mmol) in DCM: tert-amyl alcohol (20mL:2mL) and saturated NaHCO₃The aqueous solution (6mL) was stirred at ambient temperature. Acryloyl chloride (60 μ L,0.74mmol,1.2moleq) was added and stirring was continued for 30 min. The organic layer was separated and the aqueous layer was extracted with more DCM: tert-amyl alcohol (2X20mL:2 mL). The combined organic layers were washed with Na₂SO₄Drying and evaporating to obtain a residue; the chiral purity was determined as follows:

chiralpak AD-H4.6X 250mm column, 30% EtOH at 140bar, 3mL/min (about 80% ee, [ α ]]D₂₂＝+17.1°(c 1.0,EtOH))。

The title product was purified using chiral SFC (preparation: Chiralpak AD-H (5. mu.) 21.2X250mm column, 36 ℃ C. in CO₂Was further purified by elution with 30% EtOH (HPLC grade, 200 relative intensity), 60.0mL/min), maintained at 100bar, to give the title compound as a white solid (124mg, 49% yield),>99% ee, optical rotation [ α]D₂₂＝+47.8°(c0.13EtOH)。¹H NMR(400MHz,DMSO-d6)ppm 9.65(s,1H)8.48(d,J＝6.48Hz,1H)8.00(s,1H)7.93(s,1H)7.71(s,1H)6.09-6.30(m,2H)5.59-5.66(m,1H)5.06-5.25(m,1H)4.63(quin,J＝6.76Hz,1H)4.50(dt,J＝11.65,5.85Hz,1H)3.85-3.96(m,2H)3.83(s,3H)3.71(d,J＝11.86Hz,2H)1.51(d,J＝6.72Hz,6H)。¹⁹F NMR (376MHz, DMSO-d6) ppm-177.73(s, 1F). For C₁₉H₂₄FN₉O M/z (APCI +)414.1(M + H)⁺。

Example 3 (route B): n- (3- ((9-isopropyl-6- ((1-methyl-1H-pyrazol-4-yl) amino)) -9H-purine- Preparation of 2-yl) oxy) phenyl) acrylamide trifluoroacetate salt

Step 1: 9-isopropyl-N- (1-methyl-1H-pyrazol-4-yl) -2- (3-nitrophenoxy) -9H-purin-6-amine The preparation of (1):

to a solution of 3-nitrophenol (143mg,1.03mmol) in DMF (15mL) was slowly added sodium hydride (56mg,1.4mmol) and the mixture was stirred at room temperature for 30 min. 2-chloro-9-isopropyl-N- (1-methyl-1H-pyrazol-4-yl) -9H-purin-6-amine (200mg,0.69mmol), prepared as in example 2, step 1, was added slowly. After the addition, the mixture was stirred at 110 ℃ overnight. The cooled reaction mixture was poured into water (100mL) and extracted with EtOAc (2 × 30 mL). The combined organic extracts were washed with Na₂SO₄Dried, concentrated, and the residue was purified by flash column chromatography (MeOH: EtOAc ═ 1:10) to give the title compound as a pale yellow oil (50mg, 18% yield).

Step 2: 2- (3-aminophenoxy) -9-isopropyl-N- (1-methyl-1H-pyrazol-4-yl) -9H-purin-6-amine Preparation of

Mixing 9-isopropyl-N- (1-methyl-1H-pyrazol-4-yl) -2- (3-nitrophenoxy) -9H-purin-6-amine (50mg,0.14mmol), Fe (39mg,0.7mmol), and NH₄A mixture of Cl (75mg,1.4mmol) in EtOAc (10mL) and water (10mL) was stirred at room temperature. The mixture was filtered and the filtrate was extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with Na₂SO₄Drying and concentratingWas condensed to give the crude product (46mg, 100% yield), which was used in the next step without further purification.

And step 3: n- (3- ((9-isopropyl-6- ((1-methyl-1H-pyrazol-4-yl) amino) -9H-purin-2-yl) oxy) Phenyl) acrylamide trifluoroacetate preparation

To a solution of 2- (3-aminophenoxy) -9-isopropyl-N- (1-methyl-1H-pyrazol-4-yl) -9H-purin-6-amine (46mg,0.14mmol) in EtOAc (10mL) was added saturated Na₂CO₃Aqueous solution (10mL), and the mixture was stirred at room temperature for 10 minutes. Acryloyl chloride (15.2mg,0.17mmol) was then added dropwise, and the mixture was stirred at room temperature for 1 hour. The mixture was then extracted with EtOAc (2 × 10mL) and the combined organic layers were washed with water (10mL), brine (10mL), Na₂SO₄Dried and concentrated. The crude product was purified by preparative HPLC to give the title compound as a white solid (15mg, 26% yield).¹H NMR(400MHz,DMSO-d₆) ppm 10.38(s,1H),10.18(s,1H),8.23(s,1H),7.62-7.63(d,2H),7.44-7.49(t,2H),7.33(s,1H),7.16(s,1H),6.94-6.96(d,1H),6.41-6.45(t,1H),6.23-6.27(d,1H),5.75-5.78(d,1H),4.67-4.70(m,1H),3.56(s,3H),1.53-1.54(d, 6H). For C₂₁H₂₂N₈O₂M/z 419.0(M + H) +.

Example 4 (route D): (S) -N- (1- (9-isopropyl-6- ((1-methyl-1H-pyrazol-4-yl) amino) -9H-purine Preparation of pterin-2-yl) pyrrolidin-3-yl) acrylamide

To the 6-chloro-2-fluoro prepared in step 1 of the other alternative method of example 2-9-isopropyl-9H-purine (200mg,0.932mmol) in nBuOH (4.66mL) 1-methyl-1H-pyrazol-4-amine (109mg,1.12mmol) and DIPEA (482mg,3.73mmol) were added and the mixture was stirred at ambient temperature for 6 hours to give crude 2-fluoro-9-isopropyl-N- (1-methyl-1H-pyrazol-4-yl) -9H-purin-6-amine. (S) -3- (methylsulfonyl) -N- (pyrrolidin-3-yl) propionamide hydrochloride (289mg,1.12mmol) was then added to the reaction mixture and heated at 100 ℃ for 16 Hr. LCMS showed unreacted intermediate, so the reaction was heated at 110 ℃ for another 24 hours. The reaction was then cooled to ambient temperature and potassium tert-butoxide (3.73mL,3.73mmol) was added and the resulting mixture stirred at ambient temperature for 30 minutes. Water was added and the reaction was extracted with DCM (3X50mL) and then the aqueous layer was extracted with ethyl acetate (2X50 mL). The combined organic layers were washed with Na₂SO₄Dried, concentrated, loaded onto silica and purified by flash chromatography using 0-20% EtOH/EtOAc to give the title compound as a pink solid (290mg, 78% yield),¹h NMR (400MHz, DMSO-d6) ppm 9.56(s,1H)8.38(d, J ═ 6.72Hz,1H)7.97(s,1H)7.89(s,1H)7.75(s,1H)6.20-6.34(m,1H)6.05-6.18(m,1H)5.60(dd, J ═ 10.03,2.32Hz,1H)4.56-4.73(m,1H)4.43(br.s.,1H)3.76-3.92(m,4H)3.68(d, J ═ 5.14Hz,2H)3.43-3.51(m,1H)2.15-2.28(m,1H)1.87-1.99(m,1H)1.51 (J ═ 6.85H). For C₁₉H₂₅N₉M/z 397.25 and 396.30(M + H) + of O.

Example 5 (route D): n- ((3R,4R) -4-fluoro-1- (6- ((3-methoxy-1- (1-methylazetidine-3-) Preparation of yl) -1H-pyrazol-4-yl) amino) -9-methyl-9H-purin-2-yl) pyrrolidin-3-yl) acrylamide

TFA (4mL) was added to a solution of crude tert-butyl 3- (4- ((2- ((3R,4R) -3-fluoro-4- (3- (methylsulfonyl) propionylamino) pyrrolidin-1-yl) -9-methyl-9H-purin-6-yl) amino) -3-methoxy-1H-pyrazol-1-yl) azetidine-1-carboxylate (theoretically 0.63mmol,1.00eq) (prepared using the general method exemplified in example 4) in DCM (50 mL). After stirring for 1 hour, the reaction mixture was concentrated to dryness and used in the next step without further purification.

To a solution of the above generated amine in MeOH (15mL) was added diisopropylethylamine (300 μ L,1.81mmol,2.87eq) and the aqueous formaldehyde solution (150 μ L,2.02mmol,3.21eq,37 wt%) and the reaction mixture was stirred at ambient temperature. After 15 minutes, add NaBH₄(65.0mg,1.72mmol,2.72eq) and the reaction mixture was stirred for 11 h. LCMS showed incomplete reaction and additional portions of aqueous formaldehyde (500. mu.L, 6.73mmol,10.7eq,37 wt%) and NaBH were added₄(250mg,6.61mmol,10.5 eq). After another 1 hour, the reaction mixture was concentrated and used in the next step without further purification.

To a stirred solution of crude N-methylazetidine produced above in THF (25mL) was added a solution of potassium tert-butoxide (2.50mL,2.50mmol,3.97eq, 1M). After 2 hours, the reaction mixture was treated with acetic acid (200 μ L) and concentrated. The residue was suspended in DMSO, purified by reverse phase chromatography (eluting with Xbridge Prep C18 column (250mmx30mmx5 μm) from 5% acetonitrile (0.1% HOAc) in water to 25% acetonitrile (0.1% HOAc) in water) and lyophilized to give the title compound as a white solid (53.7mg, 16% yield).¹H NMR (400MHz, DMSO-d6) ppm8.20(br.s.,1H)8.14(br.s.,1H)7.71(br.s.,1H)6.24(dd, J ═ 10.0,16.0Hz,1H)6.14(d, J ═ 16.0Hz,1H)5.60(d, J ═ 9.3Hz,1H)5.16(d, J ═ 51.0Hz,1H)4.80(br.s.,1H)4.58-4.41(m,1H)3.99-3.77(m,7H)3.72-3.55(m, 6H). For C₂₁H₂₈FN₁₀O₂M/z (APCI +)471.2(M + H)⁺。

Example 6 (route E): (-) -1- (3- (9-isopropyl-6- ((1-methyl-1H-pyrazol-4-yl) amino) -9H-purine Preparation of pterin-2-yl) piperidin-1-yl) prop-2-en-1-one

Step 1: 3- (9-isopropyl-6- ((1-methyl-1H-pyrazol-4-yl) amino) -9H-purin-2-yl) -5, 6-di Preparation of tert-butyl hydroxypyridine-1 (2H) -carboxylate

2-chloro-9-isopropyl-N- (1-methyl-1H-pyrazol-4-yl) -9H-purin-6-amine (600mg,2mmol), tert-butyl 5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate (700mg,2.3mmol,1.1mol eq), tripotassium phosphate (1.11g,5.1mmol,2.5mol eq), PdCl, prepared as in example 2, step 1₂(dppf) (75mg,0.1mmol,0.05mol eq) in dioxane (10mL) and water (5mL) was degassed, stirred and heated at 80 ℃ (using microwaves at normal absorption levels) for 30 minutes. The reaction was then diluted with ethyl acetate (120mL), washed with brine (20mL), and Na₂SO₄Dried and evaporated to give a residue which was purified by flash chromatography (gradient from 50% ethyl acetate-50% heptane to 100% ethyl acetate, then to 10% ammonia (7N) -90% ethyl acetate in methanol) to give the title product as a red solid (901mg, 100% yield).¹H NMR (400MHz, DMSO-d6) ppm 9.89(s,1H)8.29(s,1H)8.00(br.s.,1H)7.79(br.s.,1H)7.22(br.s.,1H)4.77(dt, J ═ 13.39,6.76Hz,1H)4.45(br.s.,2H)3.84(s,3H)3.50(t, J ═ 5.38Hz,2H)2.36(d, J ═ 3.18Hz,2H)1.57(d, J ═ 6.72Hz,6H)1.44(s, 9H). For C₂₂H₃₀N₈O₂M/z (APCI +)439.3(M + H)⁺。

Step 2: 3- (9-isopropyl-6- ((1-methyl-1H-pyrazol-4-yl) amino) -9H-purin-2-yl) piperidine-1- Preparation of tert-butyl carboxylate

A solution of tert-butyl 3- (9-isopropyl-6- ((1-methyl-1H-pyrazol-4-yl) amino) -9H-purin-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylate (821mg,1.87mmol) in ethanol (35mL) was degassed with nitrogen and to this was added 10% -Pd/C (150mg) and ammonium formate (650mg,10 mmol). The resulting mixture was stirred and heated at 60 ℃ for 3 hours. The reaction was cooled to ambient temperature and the catalyst was removed by filtration. The filtrate was evaporated to give a residue, which was taken up in ethyl acetate (100mL), and the solution was washed with water (30mL), brine (30mL), and Na₂SO₄Dried and evaporated to give a residue which was purified by flash chromatography (gradient from 100% heptane to 100% ethyl acetate) to give the title compound (620mg) which was used in the next step.

And step 3: preparation of 9-isopropyl-N- (1-methyl-1H-pyrazol-4-yl) -2- (piperidin-3-yl) -9H-purin-6-amine Prepare for

To a solution of tert-butyl 3- (9-isopropyl-6- ((1-methyl-1H-pyrazol-4-yl) amino) -9H-purin-2-yl) piperidine-1-carboxylate (620mg) in DCM (15mL) was added TFA (1.2 mL). The resulting solution was stirred at ambient temperature for 1 hour. The volatiles were removed to give the crude title compound, which was used in the next step without further purification.

And 4, step 4: (-) -1- (3- (9-isopropyl-6- ((1-methyl-1H-pyrazol-4-yl) amino) -9H-purin-2-yl) Preparation of piperidin-1-yl) prop-2-en-1-one

To the 9-isopropyl-N- (1-methyl-1H-pyrazol-4-yl) -2- (piperidin-3-yl) product obtained from the previous reaction) -9H-purin-6-amine saturated NaHCO was added₃Aqueous solution (12mL) and ethyl acetate (30 mL). The mixture was stirred for 10 min, acryloyl chloride (148 μ L,1.8mmol) was added, and stirred at ambient temperature for 15 min. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (30 mL). The combined organic phases were washed with Na₂SO₄Dried and evaporated to give a foamy solid (600mg) which was subjected to chiral SFC purification to separate the two enantiomers (Chiralcel OJ-H4.6 x250mm column, 20% EtOH,140bar,3.0 mL/min.) peak 1(+) eluted at 3.18 min. peak 2(-) (title product) eluted at 5.03 min) (86.4mg, about 98% ee,3 steps 16% yield) [ α ]]D₂₂＝-76.0°(c 0.14,EtOH).¹H NMR (700MHz, DMSO-17mm) ppm 9.87(br.s.,1H)8.28(br.s.,1H)7.96-8.13(m,1H)7.74(d, J ═ 7.26Hz,1H)6.76-6.91(m,1H)5.99-6.17(m,1H)5.53-5.75(m,1H)4.69-4.84(m,2H)4.03-4.30(m,2H)3.84(s,3H)2.74-3.02(m,2H)2.11-2.28(m,1H)1.75-2.01(m,2H)1.54(d, J ═ 2.64Hz, 7H). For C₂₀H₂₆N₈O M/z (APCI +)395.1(M + H)⁺。

Example 7 (route F): n- ((3R,4R) -4-fluoro-1- (6- ((3-methoxy-1-methyl-1H-pyrazol-4-yl) amino) Preparation of yl) -9-methyl-9H-purin-2-yl) pyrrolidin-3-yl) acrylamide

Step 1: preparation of 2-fluoro-N- (3-methoxy-1-methyl-1H-pyrazol-4-yl) -9H-purin-6-amine

A suspension of 6-chloro-2-fluoro-9H-purine (5.49g,31.8mmol,1.00eq), 3-methoxy-1-methyl-1H-pyrazol-4-amine hydrochloride (6.60g,40.34mmol,1.26eq) and N, N-diisopropylethylamine (16.6mL,95.5mmol,3.00eq) in DMSO (31.8mL)Stir at ambient temperature for 19 hours. The mixture was then concentrated in vacuo at 50 ℃, poured into water (250mL), and stirred vigorously at 0 ℃ for 1 hour. The resulting solid was filtered off, washed with ice-cold water (20mL) and dried at 50 ℃ for 16 hours to give the title compound as a pale yellow solid (7.26g, 87% yield, 96% purity).¹H NMR (400MHz, DMSO-d6) ppm 13.03(br.s.,1H)9.21(br.s, 1H)8.18(br.s, 1H)7.74(br.s, 1H)3.81(br.s, 3H)3.71(s, 3H). For C₁₀H₁₁FN₇O M/z (APCI +)264.2(M + H)⁺。

Step 2: preparation of 2-fluoro-N- (3-methoxy-1-methyl-1H-pyrazol-4-yl) -9-methyl-9H-purin-6-amine

To a vigorously stirred suspension of 2-fluoro-N- (3-methoxy-1-methyl-1H-pyrazol-4-yl) -9H-purin-6-amine (7.25g,27.5mmol,1.00eq) and potassium carbonate (7.61g,55.1mmol,2.00eq) in 1, 4-dioxane (92.0mL) was added dimethyl sulfate (2.90mL,30.3mmol,1.10eq) dropwise over 3 minutes. After 4 hours, additional portions of 1, 4-dioxane (50.0mL), potassium carbonate (3.80g,27.5mmol,1.00eq) and dimethyl sulfate (1.00mL,10.4mmol,0.30eq) were added to the reaction mixture. After 16h, the reaction mixture was concentrated in vacuo, diluted with water (120mL), and stirred at ambient temperature for 1 h. The resulting solid was filtered, washed with water (20mL) and dried at 60 ℃ for 16 hours to give the title compound as a pale yellow solid (6.42g, 84% yield, 95% purity).¹H NMR (400MHz, DMSO-d6) ppm 9.23(br.s.,1H)8.13(br.s.,1H)7.67(s,1H)3.78(s,3H)3.70(s,3H)3.69(br.s., 3H). For C₁₁H₁₃FN₇O M/z (APCI +)278.2(M + H)⁺。

And step 3: n- ((3R,4R) -4-fluoro-1- (6- ((3-methoxy-1-methyl-1H-pyrazol-4-yl) amino) -9-methyl Preparation of Yl-9H-purin-2-Yl) pyrrolidin-3-Yl) acrylamide

To a stirred suspension of 2-fluoro-N- (3-methoxy-1-methyl-1H-pyrazol-4-yl) -9-methyl-9H-purin-6-amine (554mg,2.00mmol,1.00eq) and N- ((3R,4R) -4-fluoropyrrolidin-3-yl) -3- (methylsulfonyl) propionamide (500mg,2.10mmol,1.05eq) in DMSO (4.2mL) was added N, N-diisopropylethylamine (0.83mL,5.00mmol,2.50 eq). The reaction was then heated at 100 ℃ for 16h, cooled to ambient temperature, diluted with THF (4mL), and treated with potassium tert-butoxide (4.00mL, 1M in THF, 2.00 eq). After 1 hour, an additional portion of potassium tert-butoxide (0.50mL, 1M in THF, 0.25eq) was added to the reaction mixture. After an additional 1 hour, the reaction mixture was poured into phosphate buffer (50mL, pH 7) and water (50mL) and extracted with ethyl acetate (5 × 40 mL). The combined organic layers were combined and dried (Na)₂SO₄) And concentrated under reduced pressure. The crude product was then dissolved in ethyl acetate (40mL) at 60 ℃ and treated with heptane (20mL) at which time the solution became cloudy and allowed to cool to ambient temperature and then to 0 ℃. After 16h at 0 ℃, the resulting solid was filtered and dried at ambient temperature to give the title compound as a white powder (620.5mg, 75% yield).¹H NMR (400MHz, DMSO-d6) ppm8.44(d, J ═ 6.5Hz,1H)7.97(s,1H)7.82(s,1H)7.78(s,1H)6.23(dd, J ═ 10.0,17.0Hz,1H)6.14(dd, J ═ 2.8,17.0Hz,1H)5.62(dd, J ═ 2.8,10.0Hz,1H)5.12(d, J ═ 51.0Hz,1H)4.46(td, J ═ 6.0,11.9Hz,1H)3.88-3.6(m,4H)3.82(s,3H)3.71(s,3H)3.62(s, 3H). For C₁₈H₂₃FN₉O₂M/z (APCI +)416.3(M + H)⁺。

Example 7A (route F): n- ((3R,4R) -4-fluoro-1- (6- ((3-methoxy-1-methyl-1H-pyrazol-4-yl) Preparation of amino) -9-methyl-9H-purin-2-yl) pyrrolidin-3-yl) acrylamide

Preparation step 1A: preparation of (3R,4R) -1-benzyl-3, 4-dihydroxypyrrolidine-2, 5-dione

A mixture of xylene (1.2L), benzylamine (120g,1.10mol,1.0eq) and L- (+) -tartaric acid (173g,1.15mol,1.05eq) was heated at 135 ℃ at 12Hr (flask jacket temperature). After completion of the reaction, the mixture was cooled to 65 ℃ and MeOH (120mL,1vol) was added. The resulting mixture was stirred for 1 hour, and the resulting suspension was cooled to 20 ℃ before adding EtOAc (480 mL). Stirring was continued for 2 hours at 10 ℃. The crude product was isolated by filtration and washed with EtOAc (120mL) and dried on the filter. The crude product was then dissolved in MeOH (480mL) and heated under slight reflux for 1 hour, then cooled to 20 ℃ and pelletized for 1 hour. The suspension was filtered and the precipitate was washed with MeOH (240mL) and dried to give the title compound as a white particulate solid (191g,864mmol, 79%).¹H NMR (400MHz, DMSO-d6) ppm 7.38-7.30(m,2H)7.30-7.22(m,3H)6.32(br.s.,1H)4.59(d, J ═ 14.8Hz,1H)4.53(d, J ═ 14.8Hz,1H)4.40(br.d., J ═ 4.3Hz, 2H). For C₁₁H₁₁NO₄M/z (EI +)221.0(M)⁺。

Preparation step 2A: preparation of (3S,4S) -1-benzylpyrrolidine-3, 4-diol

To a mixture of (3R,4R) -1-benzyl-3, 4-dihydroxypyrrolidine-2, 5-dione (44g,199mmol,1.0eq) and THF (176mL) at 20 ℃ (vessel jacket temperature) was added borane-tetrahydrofuran complex in THF (1.0mol/L) (800mL,800mmol,1.0mol/L,4.0eq) at a rate that maintained the temperature at 20 ℃ to 25 ℃.The jacket temperature was raised to 60 ℃ over 1 hour, and then maintained for 1 hour. Upon completion, the reaction was cooled to 30 ℃ and quenched by the slow dropwise addition of MeOH (97mL,12eq) to the mixture at a rate that controlled gassing off. The reaction mixture was then heated to reflux and concentrated to a low stirred volume. The reaction solvent THF was then replaced by a constant volume displacement with MeOH (1.5L total). Once the THF content had been reduced to less than 1 wt%, MeOH was replaced with EtOAc (1.5L total) by constant volume displacement to reduce the MeOH content to less than 1 wt%. The total volume of EtOAc was then adjusted to about 250mL (6vol) and then cooled to 5 ℃ to crystallize the product. The desired product was isolated by filtration, washed with cold EtOAc (88mL), and dried to give the title compound (27.0g,140mmol, 70%). The second harvest of product was isolated by: the combined filtrates were concentrated and the cake washed to half volume, then cooled to 5 ℃, filtered and washed with cold EtOAc (50mL) to give additional title compound (4.5g,23mmol, 12%).¹H NMR (400MHz, DMSO-d6) ppm 7.33-7.26(m,4H)7.25-7.20(m,1H)4.48(d, J ═ 4.8Hz,2H)3.38-3.31(m,2H),3.57(d, J ═ 13.0Hz,1H)3.46(d, J ═ 13.0Hz,1H)2.74(dd, J ═ 9.4,5.9Hz,2H)2.30(dd, J ═ 9.4,4.4Hz, 2H). For C₁₁H₁₅NO₂M/z (EI +)194.2(M + H)⁺。

Preparation step 3A: (3aR,6aS) -5-benzyl-2, 2-dioxo-tetrahydro-1-oxa-2. lamda. ⁶ -thia-3-5-dinitrogen Hetero-pentalene-3-carboxylic acid tert-butyl esterPreparation of

To a 5L jacketed reactor (reactor 1) were added 1, 4-dioxane (1.8L), (3S,4S) -1-benzylpyrrolidine-3, 4-diol (180g,0.932mol,1.0eq) and TEA (792mL,5.68mol,6.1eq) and the resulting mixture was stirred at 10 ℃.

To a 2L jacketed reactor (reactor 2) were added 1, 4-dioxane (1.6L) and chlorosulfonyl isocyanate (596g,2.80mol,3.0eq) and the resulting solution was cooled to 10 ℃. A solution of tert-butanol (211g,2.85mol,3.05eq) in 1, 4-dioxane (180mL) was added over 45min while maintaining the temperature at 10 deg.C-20 deg.C, and the resulting solution was stirred at 10 deg.C for 15 min.

The solution in the reactor 2 was transferred into the reactor 1 within 50 minutes while controlling the internal temperature of the reactor 1 to 10 ℃ to 20 ℃. Once the addition was complete, the jacket temperature was warmed at 20 ℃ and the resulting mixture was stirred for 16 hours. When the UPLC analysis confirms complete formation of the bis-alkylated intermediate (target)<3% monoalkylated intermediate), the entire batch was filtered and the filtrate was placed in a clean reactor. The residual TEA-HCl cake was washed with dioxane (300mL) and the washings were combined with the filtrate. The resulting dioxane solution was then heated to 80 ℃ and held for 3 hours. At the completion of the reaction (<1% of intermediate remaining), the batch is distilled under partial vacuum (400mbar) (pot temperature 80 ℃) to less than normal volume. The reaction mixture was diluted with EtOAc (2L) and washed twice with water (2 × 2L). The mixture was then washed with 0.5N sodium bicarbonate (2L), then dried over sodium sulfate (360g,2wt eq) and filtered into a clean dry reactor. The EtOAc solution was concentrated under partial vacuum to a total volume of about 400mL, resulting in the formation of a thick slurry. The mixture was cooled to 0 ℃ and stirred for 1h, then filtered and washed with cold EtOAc (200mL) and then dried in a vacuum oven at 40 ℃ to give 173g of the title compound. The second harvest of product was isolated by: the filtrate was concentrated and then cooled, granulated and filtered to give an additional 28.4g of the desired product. In total, the title compound was isolated in 61% (201g,568mmol) yield.¹H NMR (400MHz, DMSO-d6) ppm 7.37-7.29(m,4H)7.29-7.23(m,1H)5.36(dd, J ═ 7.3,3.8Hz,1H)4.79-4.73(m,1H)4.48(d, J ═ 4.8Hz,2H)3.38-3.31(m,2H),3.70(d, J ═ 13.4Hz,1H)3.62(d, J ═ 13.4Hz,1H)3.13-2.99(m,2H)2.48-2.40(m,2H)1.46(s, 9H). For C₁₆H₂₂N₂O₅M/z (EI +)355.2(M + H) of S⁺。

Preparation ofStep 4A: preparation of (3R,4R) -1-benzyl-4-fluoropyrrolidine-3-amine bis-toluene sulfonate

A solution of 1M tetrabutylammonium fluoride in THF (1.27L,1.27mol,2.5eq) and (3aR,6aS) -5-benzyl-2, 2-dioxo-tetrahydro-1-oxa-2. lambda⁶Tert-butyl-thia-3-5-diaza-pentalene-3-carboxylate (180g,0.508mol,1.0eq) was heated at 60 ℃ (jacket temperature) for 2 Hr. After completion of the reaction, the mixture was partially distilled under vacuum to remove THF. After concentration to low stirred volume, THF was replaced with EtOAc (2X500 mL). After again reducing to a low stirred volume, EtOAc (3.6L) and p-toluenesulfonic acid monohydrate (396g,2.10mol,4.1eq) were charged and heated at 80 ℃ for 2 h. The mixture was cooled to 10 ℃ over 1.5 hours and then granulated at 10 ℃ for 2 hours. The solid product was filtered and washed with EtOAc (2X900mL) and dried in a vacuum oven at 50 ℃ for 12 hours. The title compound was isolated as an air stable crystalline solid in 83% yield (231g,419 mmol).¹H NMR(400MHz,D₂O) ppm 7.69-7.61(m,4H)7.56-7.42(m,5H)7.36-7.29(m,4H)5.65-5.49(m,1H)4.47(br.s.,2H)4.37-4.23(m,1H)4.15(ddd, J-12.8, 8.2,1.4Hz,1H)3.88(dd, J-19.1, 1.2Hz,1H),3.74(ddd, J-33.2, 14.0,5.5Hz,1H)3.44(dd, J-12.8, 8.2Hz,1H)2.34(s, 6H). For C₁₁H₁₅FN₂M/z (EI +)194.8(M + H)⁺。

Preparation step 5A: n- ((3R,4R) -1-benzyl-4-fluoropyrrolidin-3-yl) -3- (methylsulfonyl) propanamide

A suspension of 1,1' -carbonyldiimidazole (73.0g,441mmol,1.1eq) in acetonitrile (3.3L) was stirred at 20 ℃ until a clear solution was obtained. 3- (methylsulfonyl) propionic acid (67.0g,440mmol,1.1eq) was then added and the mixture was cooledThe mixture was stirred at 25 ℃ for 3 hours. (3R,4R) -1-benzyl-4-fluoropyrrolidin-3-amine bismesylate (220g,400mmol,1.0eq) was added and the mixture was stirred at 25 ℃ for 16h to give a fine white slurry. The solid was filtered off and the by-product cake was washed with acetonitrile (600 mL). The acetonitrile solution was then concentrated to a low stirred volume, then dissolved in EtOAc (2.0L) and washed with 1N aqueous sodium bicarbonate (1.3L). The aqueous layer was back-extracted with EtOAc (500mL) and the combined EtOAc layers were washed with water (1.0L). The resulting EtOAc solution was distilled to remove about 2.0L of filtrate, then replaced with 2-propanol under atmospheric conditions until the internal temperature rose to 78 ℃, while maintaining a total volume of 2L. The batch was then cooled to 20 ℃ and granulated at 20 ℃ for 12 hours, allowing the product to crystallize. The desired product was isolated by filtration and the filter cake was washed with 2-propanol (600mL) and then dried in an oven at 40 ℃ under reduced pressure for 12 hours. The title compound was isolated in 77% yield (108g,308 mmol).¹H NMR(400MHz,DMSO-d6)ppm 8.36(br.d.,J＝7.0Hz,1H)7.37-7.29(m,4H)7.29-7.23(m,1H)4.90(ddt,J＝53.4,5.3,2X1.7Hz,1H)4.25(dddd,J＝26.4,13.9,7.0,1.4Hz,1H)3.61(d,J＝13.2Hz,1H)3.57(d,J＝13.2Hz,1H)3.36-3.28(m,2H)3.03(dd,J＝9.3,7.5Hz,1H)2.97(s,3H)2.80(dd,J＝24.0,11.6Hz,1H)2.66(ddd,J＝30.6,11.6,5.3Hz,1H)2.57(td,2X7.7,1.4Hz,2H)2.18(dd,J＝9.4,6.7Hz,1H)。C₁₅H₂₁FN₂O₃M/z (EI +)329.7(M + H) of S⁺。

Preparation step 6A: n- ((3R,4R) -4-fluoropyrrolidin-3-yl) -3- (methylsulfonyl) propanamide

To a Parr reactor was added N- ((3R,4R) -1-benzyl-4-fluoropyrrolidin-3-yl) -3- (methylsulfonyl) propionamide (86.5g,263mmol,1.0eq), palladium hydroxide (20% on carbon, 2.59g,3.69mmol,3 wt/wt%) and MeOH (430 mL). The reactor was purged three times with nitrogen (50psi) and then three times with hydrogen (20 psi). The reactor is heated at 50 ℃ and thenPressurized to 50psi with stirring at 1200 rpm. The material was hydrogenated for 7 hours, then cooled to 20 ℃ and purged with nitrogen. The mixture was filtered to remove catalyst and the filter cake was washed with MeOH (173 mL). The combined filtrate and washings were concentrated to about 200mL, followed by the addition of MTBE (200mL), and then concentrated to a low stirred volume. Additional MTBE (200mL) was added and the resulting slurry was granulated for 16 hours at 20 ℃. The desired product was isolated by filtration, washed with MTBE (300mL) and then dried in an oven at 40 ℃ for 12 hours. The title compound was isolated in 90% yield (53.3g,224mmol) as a white crystalline solid.¹H NMR (400MHz, DMSO-d6) ppm8.15 (br.d., J ═ 6.8Hz,1H)4.96-4.78(m,1H)4.14-4.01(m,1H)3.32(dd, J ═ 8.0,7.3Hz,2H)3.13(dd, J ═ 11.8,6.8Hz,1H)3.01-2.93(m,1H)2.98(s,3H)2.88(d, J ═ 3.0Hz,1H)2.60(br.s.,1H)2.57-2.52(m, 3H). For C₈H₁₅FN₂O₃M/z (EI +)239.1(M + H) of S⁺。

A suspension of 6-chloro-2-fluoro-9H-purine (88% potency, 5.90kg,30.20mol,1.00eq), 3-methoxy-1-methyl-1H-pyrazol-4-amine hydrochloride (98% potency, 5.55kg,33.22mol,1.10eq) and sodium bicarbonate (10.1kg,120.81mol,4.00eq) in EtOAc (106L) was stirred at 50 ℃ for 12 Hr. The reaction mixture was then cooled to 20 ℃, granulated for 1 hour, filtered and the solid washed with EtOAc (18L) and dried on the filter. The crude product was charged back to the reactor and suspended in water (106L) and stirred at 35 ℃ for 2 h. The resulting slurry was cooled to 20 ℃ and the desired product was isolated by filtration, washed through the filter cake with water (30L) then EtOAc (30L) and dried at 50 ℃ for 16h to give the title compound as a pale yellow solid (6.26kg,23.8mol, 79% yield).¹H NMR(400MHz,DMSO-d6)ppm 13.03(br.s.,1H)9.21(br.s.,1H)8.18(br.s.,1H)7.74(br.s.,1H)3.81(br.s3H)3.71(s, 3H). For C₁₀H₁₁FN₇O M/z (APCI +)264.2(M + H)⁺。

To a 100L reactor equipped with a caustic scrubber was added 2-methyltetrahydrofuran (44.0L), 2-fluoro-N- (3-methoxy-1-methyl-1H-pyrazol-4-yl) -9H-purin-6-amine (2.20kg,8.36mol,1.00eq) and potassium phosphate (7.10kg,33.43mol mmol,4.00 eq). The resulting mixture was stirred at 5 ℃, dimethyl sulfate (1.42kg,11.28mol,1.35eq) was added, and the resulting mixture was stirred at 5 ℃ for 1 hour. The mixture was warmed from 5 ℃ to 15 ℃ over 2 hours and then held at 15 ℃ for 20 hours. The reaction mixture was cooled to 5 ℃ and quenched with water (44.0L) while maintaining the internal temperature below 10 ℃. The mixture was then heated at 50 ℃ for 2 hours, then cooled to 10 ℃ and granulated for 2 hours. The product was isolated by filtration and washed with water (11.0L) then 2-methyltetrahydrofuran (11.0L). The filter cake was dried under vacuum at 40 ℃ for 8 hours to give the title compound as an off-white solid (1.99kg,7.18mol, 86% yield).¹H NMR (400MHz, DMSO-d6) ppm 9.23(br.s.,1H)8.13(br.s.,1H)7.67(s,1H)3.78(s,3H)3.70(s,3H)3.69(br.s., 3H). For C₁₁H₁₃FN₇O M/z (APCI +)278.2(M + H)⁺。

To 200L of Hastell heated to 40 deg.CSulfolane (22.4L) and N- ((3R,4R) -4-fluoropyrrolidin-3-yl) -3- (methylsulfonyl) propionamide (4.03kg,16.9mol,1.05eq) were added to the oy reactor and the resulting mixture was stirred until all solids were dissolved. To this solution was added 2-fluoro-N- (3-methoxy-1-methyl-1H-pyrazol-4-yl) -9-methyl-9H-purin-6-amine (4.47kg,16.1mol,1.00eq) and N, N-diisopropylethylamine (8.50L,48.7mol,3.0eq), and the mixture was heated at 115 ℃ for 16 Hr. The reaction mixture was cooled to 30 ℃ and a solution of potassium hydroxide (2.26kg,40.3mol,2.5eq) in water (44.7L) was added. After stirring for 4 hours, the reaction mixture was cooled to 20 ℃, water (44.7L) was added, and the resulting mixture was granulated for 12 hours. The crude product was isolated on a Nutsche filter and washed with water (27L) and then dried on the filter under nitrogen. The reactor was cleaned and then charged with water (35.8L) and acetone (53.6L). The crude product cake was charged back into the reactor and heated to 60 ℃ until all solids were dissolved. The batch was then cooled to 40 ℃ and then transferred through an in-line 10 μm filter into a spotless 100L reactor. The 200L reactor, lines and filters were rinsed with acetone (5L) and sent to the 100L reactor. The batch was concentrated under partial vacuum with a jacket temperature set at 70 ℃ until the acetone content had dropped to 5 wt% (as determined by gas headspace chromatography). The batch was then cooled to 20 ℃ and pelletized for 4 hours. The product was filtered, washed with water (18L) and dried in a vacuum oven at 55 ℃ for 8 hours. The title compound (3.942kg,9.49mol, 59%) was isolated as a white crystalline solid.¹H NMR (400MHz, DMSO-d6) ppm8.44(d, J ═ 6.5Hz,1H)7.97(s,1H)7.82(s,1H)7.78(s,1H)6.23(dd, J ═ 10.0,17.0Hz,1H)6.14(dd, J ═ 2.8,17.0Hz,1H)5.62(dd, J ═ 2.8,10.0Hz,1H)5.12(d, J ═ 51.0Hz,1H)4.46(td, J ═ 6.0,11.9Hz,1H)3.88-3.6(m,4H)3.82(s,3H)3.71(s,3H)3.62(s, 3H). For C₁₈H₂₃FN₉O₂M/z (APCI +)416.3(M + H)⁺。

Other alternatives to the general route described above:

route a: acid mediated S _n Ar (with HCl salt). 2-chloro-N- (1, 3-dimethyl-1H-pyrazol-4-yl) -9-isopropyl Process for preparing 1H-purin-6-aminesPreparation of

To a solution of 2, 6-dichloro-9-isopropyl-9H-purine (421mg,1.82mmol), prepared as in step 1 of example 1, in iPrOH (9mL) in a 20mL microwave container was added 1, 3-dimethyl-1H-pyrazol-4-amine hydrochloride (300mg,2.19mmol), and the mixture was heated in the microwave at 130 ℃ for 1.5 hours. The white precipitate formed in the reaction vial was collected to give the title compound (424mg, 72% yield).¹H NMR (400MHz, DMSO-d6) ppm 9.87(br.s.,1H)8.65(br.s.,1H)7.82(s,1H)4.62-4.85(m,1H)3.79(s,3H)2.12(s,3H)1.53(d, J ═ 6.72Hz, 6H). For C₁₃H₁₆ClN₇M/z (APCI +)306.2(M + H)⁺。

Route a: base mediated S _n And Ar. (S) - (1- (9-isopropyl-6- ((4- (4-methylpiperazin-1-yl) phenyl) amino) Preparation of Yl) -9H-purin-2-Yl) pyrrolidin-3-Yl) carbamic acid Tert-butyl ester

A mixture of 2-chloro-9-isopropyl-N- (4- (4-methylpiperazin-1-yl) phenyl) -9H-purin-6-amine (200mg,0.52mmol) and tert-butyl (S) -pyrrolidin-3-ylcarbamate (290g,1.56mmol) prepared as in step 2 of example 1 in a sealed tube was stirred at 120 ℃ for 48 hours. TLC (CH)₂Cl₂MeOH 10/1) indicated some starting material remained. The reaction mixture was concentrated in vacuo to give the crude product, which was purified by flash Chromatography (CH)₂Cl₂MeOH 50/1-10/1) to give the title compound as a brown gum (250mg, 90% yield).

Preparation 1: preparation of 2, 6-dichloro-9-cyclobutyl-9H-purine

Step 1: preparation of 2, 6-dichloro-N-cyclobutyl-5-nitropyrimidin-4-amine

Cyclobutylamine (0.485mL,5.68mmol) in iPrOH (20mL) was added dropwise to a solution of 2,4, 6-trichloro-5-nitropyrimidine (1.29g,5.65mmol) in iPrOH (40mL) at-78 ℃ via an addition funnel. After the addition was complete, the mixture was allowed to warm to room temperature over 30 minutes, then DIEA (0.940mL,5.66mmol) was added and the mixture was stirred at room temperature for 10 minutes. The solvent was removed under reduced pressure and dried to give the title compound as a pale yellow oil, which was used without purification.

Step 2: 2, 6-dichloro-N ⁴ Preparation of (E) -cyclobutyl pyrimidine-4, 5-diamine

Fe powder (631mg,11.3mmol) was added to a solution of 2, 6-dichloro-N-cyclobutyl-5-nitropyrimidin-4-amine (crude, 5.65mmol) in HOAc (5mL), and the mixture was stirred at room temperature for 30 min. Passing the mixture throughFiltration and volatiles were removed under reduced pressure. The resulting residue was diluted with EtOAc (80mL) and saturated NaHCO with water (80mL)₃(80mL) and brine (80 mL). The organic layer was washed with Na₂SO₄Dried and concentrated to give the title compound as a brown oil, which was used without purification. For C₈H₁₀Cl₂N₄M/z (APCI +)233.15/235.10(M + H)⁺。

And step 3: preparation of 2, 6-dichloro-9-cyclobutyl-9H-purine

2, 6-dichloro-N in diethoxymethyl acetate (8mL)⁴Cyclobutylpyrimidine-4, 5-diamine (crude, 5.65mmol) was stirred and heated at 80 ℃ for 16 h. The mixture was cooled to room temperature, diluted with EtOAc (80mL), and washed with water (80mL), saturated NaHCO₃(80mL) and brine (80 mL). The organic layer was washed with Na₂SO₄Dried and concentrated. The crude product was purified by flash chromatography (eluting with 20-50% EtOAc/heptane) to give the title compound as an off-white solid (727mg, 53% yield).¹H NMR(400MHz,DMSO-d₆) ppm 8.95(1H, s)5.07(1H, quin, J ═ 8.56Hz)2.59-2.77(2H, m)2.42-2.50(2H, m)1.71-1.96(2H, m); for C₉H₈Cl₂N₄M/z (APCI +)243.10(M + H)⁺。

Preparation 2: preparation of 9- (tert-butyl) -2, 6-dichloro-9H-purine

To 2, 6-dichloro-9H-purine (8.00g,40mmol,1.00eq) and Na₂SO₄(96.2g,677mmol,16.0 eq.) suspension in tert-butanol (380mL) concentrated H was added₂SO₄(11.3mL,211mmol,5 eq). The reaction mixture was heated at 120 ℃ under vigorous stirring under a reflux condenser [ note: gas generation]. During the subsequent 10 hours, additional H was added to the reaction mixture in several portions₂SO₄(26mL)、Na₂SO₄(75g) And tert-butanol (350 mL). After heating for a further 6 hours, the reaction mixture was cooled to ambient temperature with NaHCO added in portions₃(s) [ note: gas generation]The reaction is terminated, anDilute with water (300mL) and EtOAc (300 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (2 × 300 mL). The combined organic layers were washed with saturated NaHCO₃The aqueous solution and brine were washed and concentrated under reduced pressure. The crude reaction mixture was purified by flash chromatography (eluting with a gradient of 0-50% EtOAc in heptane) to give the title compound as a white solid (4.09g, 40% yield).¹H NMR (400MHz, DMSO-d6) ppm 8.73(s,1H)1.73(s, 9H). For C₉H₁₀Cl₂N₄M/z (APCI +)245.1/247.1(M + H)⁺。

Preparation 3: [ (3, 4-trans) -4-fluoropyrrolidin-3-yl)]Preparation of benzyl carbamate

Step 1: 6-oxa-3-azabicyclo [3.1.0]Preparation of Hexane-3-Carboxylic acid Tert-butyl ester

To tert-butyl 2, 5-dihydro-1H-pyrrole-1-carboxylate (130g,0.77mol) in CH at 5 deg.C₂Cl₂mCPBA (233g,1.15mol) was added portionwise to the stirred solution in (0.8L). After addition, the resulting mixture was warmed to room temperature and stirred overnight. The resulting solid was filtered off and the filtrate was taken up with saturated Na₂SO₃The aqueous solution was washed to pH 7-8 and then saturated NaHCO₃Aqueous (3 × 200mL) and brine (0.2L). The organic layer was concentrated, and the residue was distilled under reduced pressure to give the title compound (110g, 77% yield) as a pale yellow liquid. In this form, is used in the next step.

Step 2: preparation of tert-butyl (trans) -3-azido-4-hydroxypyrrolidine-1-carboxylate

To 6-oxa-3-azabicyclo [3.1.0]A stirred solution of tert-butyl hexane-3-carboxylate (110g,0.595mol) in MeOH/water (1200mL/200mL) was added NaN₃(77.6g,1.19mol) and NH₄Cl (32g,0.598 mol). The resulting mixture was stirred at 60 ℃ overnight. NaOH (0.5N,200mL) was added and the mixture was concentrated to remove MeOH. Using CH for residue₂Cl₂(3 × 400mL) and the combined organic extracts were washed with water, brine, and Na₂SO₄Dried and then concentrated to give the title compound as a yellow liquid (quantitative yield). In this form, is used in the next step.

And step 3: preparation of tert-butyl (trans) -3-azido-4-fluoropyrrolidine-1-carboxylate

To a solution of tert-butyl (trans) -3-azido-4-hydroxypyrrolidine-1-carboxylate (120g,0.44mol,5/6 pure, containing DCM) in DCM (1.2L) was added dropwise DAST (141g,0.88mol) in DCM (200mL) at-78 ℃. After the addition, the mixture was stirred at-78 ℃ for 1 hour, then warmed to room temperature and stirred overnight. The reaction mixture was slowly poured into saturated Na₂CO₃(2L), the DCM phase is then washed with water (1L), saturated NaCl and with Na₂SO₄And (5) drying. Concentrated and purified by flash chromatography (petroleum ether/EtOAc 20/1-10/1) to give the title compound as a pale yellow oil (48g, 48% yield).

And 4, step 4: preparation of tert-butyl (3, 4-trans) -3-amino-4-fluoropyrrolidine-1-carboxylate

To a stirred solution of tert-butyl (trans) -3-azido-4-fluoropyrrolidine-1-carboxylate (45g,0.196mol) in THF (0.5L) was added PPh portionwise at 0-5 deg.C₃(67.5g,0.25 mol). The resulting mixture was warmed to room temperature and stirred for 2 hours. 50mL of water was added and the resulting mixture was heated to reflux overnight. The reaction mixture was then cooled and concentrated to remove volatiles. The residue was diluted with EtOAc (0.2L) and washed with saturated citric acid (200 mL). The aqueous layer was washed with EtOAc (2 × 50mL) and then saturated K₂CO₃The pH was adjusted to 7-8 with aqueous solution and extracted with EtOAc (5 × 100 mL). The combined organic extracts were washed with brine (100mL) and Na₂SO₄Dry, concentrate, and then dry in vacuo to give the title compound as a pale yellow oil (solidified upon standing) (22.28g, 56% yield).¹H NMR(400MHz,DMSO-d₆) ppm 4.65-4.45(d,1H),3.65-3.49(m,1H),3.48-3.35(m,3H),3.21-3.12(d,1H),1.73(brs,2H),1.39(s, 9H). For C₉H₁₇FN₂O₂M/z (APCI +)149.07(M + H-56) +.

And 5: (3, 4-trans) -3- { [ (benzyloxy) carbonyl]Preparation of amino } -4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester

A solution of tert-butyl (3, 4-trans) -3-amino-4-fluoropyrrolidine-1-carboxylate (408mg,2mmol) in DCM (20mL) was cooled in an ice/water bath. DIPEA (0.38mL,2.2mmol) and CBZ-Cl (0.3mL,2mmol) were added and the resulting solution was capped, stirred in an ice bath, and allowed to gradually warm to room temperature over 2 hours. The reaction was diluted with DCM (30mL) and saturated NaHCO was added₃Aqueous solution (20 mL). The organic layer was separated and washed with saturated NaHCO₃Washed with aqueous solution (20mL) and Na₂SO₄Dried and evaporated to give a colourless residue which is purified by flash chromatography (gradient 100% heptane to 50% ethyl acetate-50% heptane) to give the title product as a colourless oil (635mg, 94% yield))。¹H NMR (400MHz, chloroform-d) ppm 7.27-7.47(m,5H)5.12(br.s.,2H)4.28(br.s.,1H)3.31-3.79(m,3H)1.47(s, 9H). For C₁₇H₂₃FN₂O₄M/z (APCI +)239.2(M + H)⁺(Boc group with loss of parent MW).

Step 6: [ (trans) -4-fluoropyrrolidin-3-yl)]Preparation of benzyl carbamate

To (3, 4-trans) -3- { [ (benzyloxy) carbonyl]A solution of tert-butyl amino } -4-fluoropyrrolidine-1-carboxylate (630mg,1.9mmol) in DCM (19mL) was added TFA (0.56mL,5.6mmol,3mol eq) and the resulting reaction stirred at ambient temperature for 2 h. The volatiles were removed to give a colorless residue, which was then washed with DCM (80mL) and saturated NaHCO₃Partitioned in aqueous solution (15 mL). The organic layer was separated and the product was extracted with more DCM (30mL) and Na₂SO₄Dried and evaporated to give the title product as a colourless oil (427mg, 96% yield).¹H NMR (400MHz, chloroform-d) ppm7.30-7.42(m,5H)4.92-5.19(m,3H)4.06-4.34(m,1H)3.46(dd, J ═ 11.68,6.54Hz,1H)3.04-3.30(m,2H)2.80(d, J ═ 10.88Hz,1H)2.33(br.s., 2H).¹⁹F NMR (376MHz, chloroform-d) ppm-75.62(s, 1F). For C₁₂H₁₅FN₂O₂M/z (APCI +)239.1(M + H)⁺。

Preparation 4: preparation of tert-butyl ((3R,4R) -4-fluoropyrrolidin-3-yl) carbamate

Step 1: preparation of (trans) -3-azido-4-fluoropyrrolidine

To a solution of tert-butyl (trans) -3-azido-4-fluoropyrrolidine-1-carboxylate (25g,109mmol) prepared as in step 3 of preparation 3 in EtOAc (100mL) was added HCl/EtOAc (50mL) at 0-5 ℃. The mixture was then stirred at room temperature for 4 hours. The solid was filtered and washed with petroleum ether/EtOAc (2:1,40mL) to give the title compound (18g) as a grey solid, which was used directly in the next step.

Step 2: preparation of benzyl (trans) -3-azido-4-fluoropyrrolidine-1-carboxylate

To (trans) -3-azido-4-fluoropyrrolidine (18g) in CH₂Cl₂(120mL) was added DIPEA (35g,0.27mol,2.5eq) and then CBZ-Cl (22g,0.13mol) was added dropwise at 0-5 ℃. After the addition, the resulting mixture was stirred at room temperature overnight. The mixture was washed with saturated NH₄Aqueous Cl (150mL), saturated NaHCO₃Aqueous (3 × 40mL) and brine (40 mL). The organic layer was concentrated and purified by column (petroleum ether/EtOAc 10: 1-5: 1) to give the title compound as a pale yellow oil (30g, two steps about 100% yield, containing residual EtOAc and DCM).

And step 3: preparation of benzyl (trans) -3-amino-4-fluoropyrrolidine-1-carboxylate

To a stirred solution of benzyl (trans) -3-azido-4-fluoropyrrolidine-1-carboxylate (30g,0.114mol) in THF (0.3L) was added PPh portionwise at 0-5 deg.C₃(33g,0.126 mol). The resulting mixture was then warmed to room temperature and stirred for 2 hours. Then 30mL of water was added and the resulting mixture was heated to refluxOvernight. The reaction mixture was concentrated and the residue was diluted with EtOAc (0.2L) and extracted with saturated citric acid (4 × 100 mL). The combined aqueous extracts were washed with EtOAc (3 × 50mL) and then K₂CO₃The pH was adjusted to 8 with saturated aqueous solution and extracted with DCM (4 × 100 mL). The combined organic extracts were washed with brine (100mL) and Na₂SO₄Drying, concentration and then vacuum drying gave the title compound as a pale yellow oil which solidified on standing to give an off-white solid (16g, 59% yield).

And 4, step 4: preparation of benzyl (3R,4R) -3- ((tert-butoxycarbonyl) amino) -4-fluoropyrrolidine-1-carboxylate

To a solution of benzyl (trans) -3-amino-4-fluoropyrrolidine-1-carboxylate (16g,0.067mol) in DCM (0.15L) was added DIPEA (16g,0.124mol) and Boc at 0-5 deg.C₂O (18g,0.083mol) and the resulting mixture was stirred at room temperature overnight. The mixture was then saturated with NH₄Cl (3X50mL), saturated NaCl washes over Na₂SO₄Dried, concentrated and purified by silica gel flash chromatography (petroleum ether/EtOAc ═ 3:1) to give the racemic product as a pale yellow oil (solidified on standing to give a white solid) (19.40g, 86% yield). For C₁₇H₂₃FN₂O₄M/z (APCI +)361.01(M +23)⁺. The enantiomers were resolved using: chiralcel OJ-H21.2X 250mm 5 μ column (36 ℃ C.) eluent 14% MeOH in CO₂At 100bar, a flow rate of 60mL/min of sample in MeOH of about 35mg/mL,1.0 mL/inj.;

benzyl (3R,4R) -3- ((tert-butoxycarbonyl) amino) -4-fluoropyrrolidine-1-carboxylate;>99％ee(+)；¹h NMR (400MHz, chloroform-d) ppm 7.30-7.43(m,5H)5.15(s,2H)4.91-5.12(m,1H)4.10-4.72(m,2H)3.57-3.84(m,3H)3.38-3.55(m,1H)1.45(s,9H) [ α]D＝+22.3°(c 0.26,MeOH)。

Benzyl (3S,4S) -3- ((tert-butoxycarbonyl) amino) -4-fluoropyrrolidine-1-carboxylate; about 99% ee (-);¹h NMR (400MHz, chloroform-d) ppm 7.30-7.43(m,5H)5.15(s,2H)4.92-5.13(m,1H)4.12-4.62(m,2H)3.57-3.86(m,3H)3.38-3.54(m,1H)1.45(s,9H) [ α H ]]D＝-29.4°(c 0.16,MeOH)。

And 5: preparation of tert-butyl ((3R,4R) -4-fluoropyrrolidin-3-yl) carbamate

To a solution of benzyl (3R,4R) -3- ((tert-butoxycarbonyl) amino) -4-fluoropyrrolidine-1-carboxylate (3.0g,8.8mmol) in MeOH (50mL) under nitrogen was added wet Pd/C (0.3g, 10%). The suspension was degassed under vacuum and purged three times with hydrogen. The resulting mixture was stirred at room temperature under a hydrogen balloon for 3 hours. The reaction mixture was filtered and the filtrate was concentrated to give the title compound as a pale yellow oil (solidified upon standing) (1.6g, 88% yield).

Preparation 5: [ (3R,4R) -4-fluoropyrrolidin-3-yl)]Preparation of benzyl carbamate

Step 1: process for preparation of (2S) -2-phenylsuccinic acid- (3R,4R) -3-amino-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (1:1) Preparation of

(3, 4-trans) -3-amino-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (trans racemate, 500mg,2.45mmol) and (S) - (+) -phenylsuccinic acid ((R-phenyl-N-methyl-L-phenyl-L-methyl-L-butyl-phenyl-L-methyl>A mixture of 99% (CAS 4036-30-0,480mg,2.45mmol) in ethanol (24.5mL,0.1M) was stirred and heated at 80 deg.C (barrier temperature) for 30 min. Will be provided withAfter the resulting solution was removed from the hotplate and allowed to stand at ambient temperature for 16 hours, the resulting crystals were collected by filtration, washed with ethanol (2mL) and dried to give the title product as a white solid (500mg, 51% yield) with an ee of 95% (Chiralpak AY-h4.6xt250mm column, 6% isopropanol at 140bar, 4 mL/min.) the product was determined to be the (R, R) enantiomer based on the X-ray structure of the opposite enantiomer (S, S) resolved with (R) - (-) -phenylsuccinic acid [ α)]D₂₂＝+96.5°(c0.08,EtOH).¹H NMR(400MHz,DMSO-d6)ppm 7.50(br.s.,2H)7.19-7.36(m,5H)4.76-4.95(m,1H)3.86(dd,J＝9.90,4.89Hz,1H)3.32-3.71(m,4H)3.15(d,J＝10.88Hz,1H)2.91(dd,J＝16.75,9.90Hz,1H)2.54(dd,J＝16.75,4.89Hz,1H)1.40(s,9H)。¹⁹F NMR (376MHz, DMSO-d6) ppm-178.71-178.28(m, 1F). For C₁₉H₂₇FN₂O₆M/z (APCI +)105.3 (for the parent amine) (M + H)⁺。

Step 2: (3R,4R) -3- { [ (benzyloxy) carbonyl]Preparation of amino } -4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester

A solution of (2S) -tert-butyl 2-phenylsuccinate- (3R,4R) -3-amino-4-fluoropyrrolidine-1-carboxylate (1:1) (500mg,1.2mmol) in DCM (20mL) was cooled in an ice/water bath. DIPEA (0.69mL,4mmol,3.3mol eq) was added followed by CBZ-Cl (185. mu.L, 1.26mmol,1.05mol eq). The resulting reaction solution was capped, stirred in an ice bath, and allowed to warm to room temperature and stirred for 2 hours. The reaction was diluted with DCM (30mL) and saturated NaHCO₃Aqueous (10mL) wash. Separating organic layer, and adding Na₂SO₄Dried and evaporated to give a colourless residue which is purified by flash chromatography (eluting with a gradient of 100% heptane to 50% ethyl acetate-50% heptane) to give the title compound as a colourless oil (388mg, 96% yield).¹H NMR (400MHz, chloroform-d) ppm7.30-7.42(m,5H) 5.12(br.s.,2H)4.74-5.04(m,1H)4.28(br.s.,1H)3.28-3.80(m, 4H))1.47(s,9H)。¹⁹F NMR (376MHz, chloroform-d) ppm-180.76-178.52 (m, 1F). For C₁₇H₂₃FN₂O₄M/z (APCI +)239.2(M + H)⁺. Chiral purity was determined as follows (using racemic material for comparison):

chiralcel OJ-H4.6X 250mm column, 10% MeOH under 140bar,3 mL/min-76% ee [ α ]]D₂₀＝+14.3°(c 0.4,EtOH).

And step 3: [ (3R,4R) -4-fluoropyrrolidin-3-yl)]Preparation of benzyl carbamate

To (3R,4R) -3- { [ (benzyloxy) carbonyl]A solution of tert-butyl amino } -4-fluoropyrrolidine-1-carboxylate (380mg,1.2mmol) in DCM (20mL) was added TFA (0.34mL,3.4mmol,3mol eq). The resulting reaction was stirred at ambient temperature for 2 hours. More TFA (0.34mL,3.4mmol,3mol eq) was added and stirring continued at ambient temperature for another 2 hours. The volatiles were removed to give a colorless residue. DCM (30mL) and K were added₂CO₃Aqueous solution (1M,5 mL). The organic layer was separated, extracted with more DCM (30mL), and Na₂SO₄Dried and evaporated to give the title compound as a colourless gum (246mg, 92% yield).¹H NMR (400MHz, chloroform-d) ppm 7.29-7.43(m,5H)4.80-5.21(m,4H)4.07-4.28(m,1H)3.46(br.s.,1H)2.96-3.30(m,2H)2.74(br.s., 1H).¹⁹F NMR (376MHz, chloroform-d) ppm-72.38(s, 1F). For C₁₂H₁₅FN₂O₂M/z (APCI +)239.2(M + H)⁺. Chiral purity was determined as follows (using racemic samples for comparison):

chiralpak AD-H4.6X 100mm column, 40% MeOH/DEA at 120bar, 4mL/min approximately 75% ee [ α ]]D₂₂＝-3.3°(C 0.24,MeOH)。

Preparation 6: preparation of N- ((3R,4R) -4-fluoropyrrolidin-3-yl) -3- (methylsulfonyl) propanamide

Step 1: preparation of benzyl (3R,4R)) -3-fluoro-4- (3- (methylsulfonyl) propionylamino) pyrrolidine-1-carboxylate

To a solution of benzyl (3R,4R) -3- ((tert-butoxycarbonyl) amino) -4-fluoropyrrolidine-1-carboxylate (2.00g,5.91mmol,1.00eq) in dichloromethane (30mL) as prepared in step 4 of preparation 4 was added trifluoroacetic acid (1.4mL,18.3mmol,3.10 eq). After 2.5 h, another portion of trifluoroacetic acid (3.0mL,39.2mmol,6.63eq) was added. After an additional 3 hours, the reaction mixture was concentrated in vacuo (1mm Hg) to a slurry and the crude trifluoroacetate salt was used without further purification.

The material obtained above was dissolved in dichloromethane (20mL) and treated with 4-methylmorpholine (3.0mL,27.2mmol,4.61eq), 3- (methylsulfonyl) propionic acid (1.20g,7.89mmol,1.34eq) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (1.30g,6.78mmol,1.15 eq). After stirring at ambient temperature for 20 h, the reaction mixture was taken up with dichloromethane (50mL) and saturated NaHCO₃Aqueous solution (50 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (3 × 30 mL). The combined organic layers were combined and dried (Na)₂SO₄) And concentrated under reduced pressure. The crude reaction mixture was purified by flash chromatography (eluting with a gradient of 3-10% EtOH in EtOAc) to give the title compound as a white solid (1.56g, 70.9% yield).¹H NMR (400MHz, DMSO-d6) ppm 8.43(d, J ═ 6.2Hz,1H)7.38(d, J ═ 4.4Hz,4H)7.37-7.28(m,1H)5.10(s,2H)5.08-4.91(m,1H)4.29(br.s.,1H)3.72-3.50(m,3H)3.40(dd, J ═ 5.2,11.6Hz,1H)3.36-3.30(m,2H)2.97(s,3H)2.60-2.53(m, 2H). For C₁₆H₂₂FN₂O₅M/z (APCI +)373.2(M + H) of S⁺。

Step 2: preparation of N- ((3R,4R)) -4-fluoropyrrolidin-3-yl) -3- (methylsulfonyl) propanamide

A nitrogen sparged suspension of benzyl (3R,4R) -3-fluoro-4- (3- (methylsulfonyl) propionylamino) pyrrolidine-1-carboxylate (2.80g,7.52mmol,1.00eq) and 10% Pd/C (300mg) in ethanol (250mL) was stirred under a hydrogen atmosphere (1atm) for 16 hours. The reaction mixture was then sparged with nitrogen and passedThe pad of (a) is filtered. Will be provided withWash with additional ethanol (50 mL). The combined filtrates were concentrated under reduced pressure to give the title compound as a white solid (1.75g, 98% yield, 95% purity).¹H NMR (400MHz, DMSO-d6) ppm 8.13(d, J ═ 6.7Hz,1H)4.73-5.02(m,1H)3.99-4.20(m,1H)3.32(t, J ═ 7.6Hz,2H)3.14(dd, J ═ 11.7,6.8Hz,2H)2.94-3.01(m,4H)2.87-2.91(m,1H)2.52-2.59(m, 3H). For C₈H₁₆FN₂O₃M/z (APCI +)239.2(M + H) of S⁺。

Preparation 7: preparation of 3-methyl-1- (1-methylpyrrolidin-3-yl) -1H-pyrazol-4-amine

Step 1: preparation of 3- (3-methyl-4-nitro-1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of 3-methyl-4-nitro-1H-pyrazole (3.0g,23.6mmol,1.00eq), tert-butyl 3-hydroxypyrrolidine-1-carboxylate (4.42g,23.6mmol,1.00eq) and triphenylphosphine (6.19g,23.6mmol,1.00eq) in THF (60mL) was added dropwise a solution of diethyl azodicarboxylate (4.34mL,23.6mmol,1.00eq) in THF (10mL) over 30 minutes. The reaction mixture was stirred at ambient temperature for 20 hours and then concentrated. The crude reaction mixture was purified by repeated flash chromatography on silica gel (eluting with a gradient of 0-35% EtOAc in heptane) to give the title compound as a colourless oil (2.48g, 35% yield) as the earlier eluate of the two structural isomers.¹H NMR(400MHz,CDCl₃) ppm8.15(s,1H)4.80(quin, J ═ 5.7Hz,1H)3.83(dd, J ═ 6.0,12.0Hz,1H)3.79-3.45(m,3H)2.52(s,3H)2.38(q, J ═ 7.0Hz,2H)1.46(s, 9H). For C₁₃H₂₁N₄O₄M/z (APCI +)197.2(M + H)⁺。

Step 2: preparation of 3-methyl-1- (1-methylpyrrolidin-3-yl) -1H-pyrazol-4-amine

A nitrogen-purged round-bottom flask was charged with tert-butyl 3- (3-methyl-4-nitro-1H-pyrazol-1-yl) pyrrolidine-1-carboxylate (980mg,3.31mmol,1.00eq), 10% Pd/C (400mg), and methanol (35 mL). The reaction mixture was purged with hydrogen for 5 minutes and then vigorously stirred under a hydrogen atmosphere for 12 hours. The reaction mixture was then purged with nitrogen gas byFiltered, concentrated and azeotroped with toluene (2 × 20mL) to give a pale red oil which was used in the next step without further purification.

To a solution of the amine obtained above in THF (13mL) was added dropwise a solution of LAH (13.0mL,13.0mmol,4.00eq, 1M in THF) over 5 minutes. Additional THF (20mL) was added after 15 minutes to facilitate stirring. 24 hoursThereafter, the reaction mixture was placed in an ambient temperature bath and subsequently treated with water (1mL), 1M aqueous NaOH (1mL) and water (3 mL). After stirring for 30 min, the reaction mixture was diluted with EtOAc (50mL) and filtered. The resulting solid was washed with additional portion of EtOAc (20mL) and the combined solids were concentrated. The crude reaction mixture was purified by flash chromatography on silica gel (with 0-5% 7N methanolic ammonia/DCM) to give the title compound as a colourless oil (113mg, 19% yield).¹H NMR (400MHz, DMSO-d6) ppm 7.00(s,1H)4.59(tdd, J ═ 4.8,7.3,9.5Hz,1H)3.55(br.s.,2H)2.74-2.61(m,2H)2.57(dd, J ═ 5.0,9.5Hz,1H)2.41(dt, J ═ 6.2,8.4Hz,1H)2.25(s,3H)2.24-2.17(m,1H)1.97(s,3H)1.96-1.85(m, 1H). For C₉H₁₇N₄M/z (APCI +)181.2(M + H)⁺。

Preparation 8: preparation of N- (4, 4-difluoropyrrolidin-3-yl) -3- (methylsulfonyl) propanamide hydrochloride

Step 1: preparation of 2, 2-difluorovinyl-4-methylbenzenesulfonate

To a three-necked flask with stir bar (oven dry), water cooled condenser and internal thermometer was added 2,2, 2-trifluoroethyl-4-methylbenzenesulfonate (25.4g,100mmol), followed by THF (333mL, 0.3M). The mixture was stirred and cooled in an acetone/dry ice bath (internal temperature-78 ℃). nBuLi (10M in hexane, 20mL,200mmol) was added via syringe over 10 minutes at an internal temperature of about-65 ℃. The reaction mixture turned dark and was stirred at-78 ℃ for 20 minutes. A mixture of water (50mL) and THF (50mL) was added dropwise through the addition funnel to stop the reaction (maintaining the internal temperature at about-70 deg.C). The mixture was warmed to ambient temperature and ethyl acetate (400mL) was added. An organic layer is formedThe aqueous layer was separated and extracted with ethyl acetate (2 × 80 mL). The combined organic layers were washed with brine (50mL) and Na₂SO₄Dried and evaporated to give a dark oil (29.3g) which was purified on silica (220g column, 60mL/min) with a gradient of 100% heptane to 40% ethyl acetate-60% heptane to give the title product as a colourless oil (22.73g, 97% yield).¹H NMR (400MHz, chloroform-d) ppm 7.83(d, J-8.31 Hz,2H)7.39(d, J-8.19 Hz,2H)6.09(dd, J-14.31, 3.91Hz,1H)2.48(s, 3H).¹⁹F NMR (376MHz, chloroform-d) ppm-92.88- -88.40(m,1F) -110.58- -107.12(m, 1F). The title product was not ionized in LCMS.

Step 2: preparation of 1-benzyl-4, 4-difluoropyrrolidin-3-yl-4-methylbenzenesulfonate

Into a 250mL flask was added 2, 2-difluorovinyl-4-methylbenzenesulfonate (14.0g,60mmol) and pure N-benzyl-1-methoxy-N- [ (trimethylsilyl) methyl]Methylamine (61mL,240mmol,4mol eq). The flask was purged with nitrogen, placed under a nitrogen atmosphere, equipped with a water-cooled condenser, and then placed in a preheating bath (130 ℃) and stirred for 5 minutes. TFA (0.6mL,6mmol,0.1mol eq) was added carefully over about 5 minutes. Note that: during TFA addition there was smoke and volatile material formation. Stirring and heating was continued for 30 minutes. The volatiles were removed to give a residue. TEA (0.6mL, ca. 6mmol) was added to ensure free base. The crude material was purified on silica (220g,60mL/min) with a gradient of 100% heptane to 20% ethyl acetate-80% heptane to give the title product as a pale yellow oil (21.85g, 100% yield,>85% purity).¹H NMR (400MHz, chloroform-d) ppm 7.81(d, J ═ 8.31Hz,2H)7.29-7.36(m,5H)7.23-7.26(m,2H)4.76-4.92(m,1H)3.61(d, J ═ 9.66Hz,2H)3.20(dd, J ═ 10.39,6.72Hz,1H)2.97-3.12(m,1H)2.71-2.84(m,1H)2.66(ddd, J ═ 10.45,6.30,1.47Hz,1H)2.45(s, 3H).¹⁹F NMR (376MHz, chloroform-d) ppm-100.41-97.15 (m,1F) -111.60-107.32 (m, 1F). For C₁₈H₁₉F₂NO₃M/z (APCI +)368.1(M + H) + of S.

And step 3: preparation of 1-benzyl-4, 4-difluoropyrrolidin-3-ol

To a 250mL three-necked flask equipped with a stir bar, water-cooled condenser, and internal thermometer, 1-benzyl-4, 4-difluoropyrrolidin-3-yl-4-methylbenzenesulfonate (10.6g, 25mmol after purity correction) and methanol (80mL) were charged. The mixture was stirred under a nitrogen atmosphere and cooled in an ice/water bath (internal temperature about 10 ℃). Magnesium turnings (3g,123mmol,5mol eq) were added in small portions. After Mg addition, the flask was removed from the bath and the internal temperature was allowed to warm to 20 ℃. LCMS of the reaction mixture indicated that the main starting material remained. The reaction was stirred, and after 1 hour, the internal temperature was 30 ℃ (the internal temperature reached 40 ℃ in a short time, and then the reaction started to cool). After 4 hours, the internal temperature dropped to about 23 ℃ and LCMS indicated completion of the reaction with a small amount of solid Mg remaining. The reaction was cooled in a water bath and water (5mL) was added slowly. The internal temperature rose to about 30 ℃ within a few minutes. The mixture is solidified. Aqueous HCl (6N,30mL total) was added slowly. The solid became soluble (pH about 6). The volatiles were removed to minimum volume and aqueous KOH was added to adjust pH 8 and the mixture was extracted with DCM (3 × 200 mL). The organic layer was cloudy and evaporated to a residue. Ethyl acetate (300mL) was added to give a fine suspension which was stirred at room temperature overnight. Insoluble material was removed by filtration and the filtrate was evaporated to give a brown oil (7.9 g). TLC indicated Rf 0.6 (predominant) in 50% heptane-50% ethyl acetate. The crude material was purified on silica (120g) with a gradient of 100% heptane to 30% ethyl acetate-70% heptane to give the title product as a pale yellow oil (4.64g, 89% yield, about 90% purity).¹H NMR (400MHz, chloroform-d) ppm 7.27-7.39(m,5H)4.17-4.29(m,1H)3.56-3.75(m,2H)3.08(ddd, J ═ 10.15,5.93,0.79Hz,1H)2.86-3.02(m,2H)2.62(ddd, J ═ 10.15,4.89,2.45Hz,1H)2.31 (br).s.,1H)。¹⁹F NMR (376MHz, chloroform-d) ppm-102.24-98.98 (m,1F) -115.46-111.80 (m, 1F). For C₁₁H₁₃F₂M/z (APCI +)214.3(M + H) + of NO.

And 4, step 4: preparation of tert-butyl 33-difluoro-4-hydroxypyrrolidine-1-carboxylate

To a 500mL flask was added 1-benzyl-4, 4-difluoropyrrolidin-3-ol (4.6g,21.6mmol), ethanol (200mL), and Boc anhydride (5.65g,26mmol,1.2mol eq). The resulting solution was degassed with nitrogen for 5 minutes. 20% Pd (OH) on carbon addition₂And the resulting mixture was stirred under a hydrogen atmosphere (using 2 balloons) at ambient temperature for 20 hours. The reaction was degassed with nitrogen. The catalyst was removed by filtration. The filtrate was evaporated to give a colourless oil which was purified on silica (40g) with a gradient of 100% heptane to 30% ethyl acetate-70% heptane to give the title product as a colourless oil (3.97g, 82% yield, about 95% purity).¹H NMR (400MHz, chloroform-d) ppm 4.20-4.32(m,1H)3.63-3.82(m,3H)3.39-3.58(m,1H)2.52(d, J ═ 3.67Hz,1H)1.47(s, 9H).¹⁹F NMR (376MHz, chloroform-d) ppm-110.98-107.93 (m,1F) -125.43-121.77 (m, 1F). For C₉H₁₅F₂NO₃M/z (APCI +) of 124.3(M + H) +.

And 5: 3, 3-difluoro-4- { [ (trifluoromethyl) sulfonyl]Preparation of tert-butyl oxy } pyrrolidine-1-carboxylate

A solution of tert-butyl 3, 3-difluoro-4-hydroxypyrrolidine-1-carboxylate (3.4g,15.2mmol) in DCM (152mL) was cooled to-10 ℃ (bath temperature, methanol/ice) under nitrogen atmosphere and pyridine (6.2mL,76mmol,5mol eq) was added. Add three via addition funnel over 30 minutesFluoromethanesulfonic anhydride (1M, 38mL,38mmol,2.5mol eq in DCM). The solution became colorless to light brown/yellow and was stirred in the ice bath for an additional 30 minutes. The reaction was quenched with citric acid buffer (0.5M, using about 30mL) to give a pH of 4.5. The organic layer was separated, extracted with more DCM (50mL), and the combined organic layers were extracted with Na₂SO₄Dried and evaporated to give the title product as a red oil (5.56g, 96% yield, about 95% purity).¹H NMR indicated the presence of pyridine (0.3mol eq).¹H NMR (400MHz, chloroform-d) ppm 5.18(d, J ═ 1.96Hz,1H)3.65-4.01(m,4H)1.49(s, 9H).¹⁹F NMR (376MHz, chloroform-d) ppm-75.59- -72.94(m,2F) -78.39(s,1F) -109.56- -105.09(m,1F) -122.17- -117.49(m, 1F). The title product was not stable enough under LCMS conditions.

Step 6: preparation of 4-azido-3, 3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester

Coupling 3, 3-difluoro-4- { [ (trifluoromethyl) sulfonyl]Oxy } pyrrolidine-1-carboxylic acid tert-butyl ester (5.56g,15.2mmol) was dissolved in DMF (20mL) and cooled in an ice bath under a nitrogen atmosphere. Tetrabutylammonium azide (TBA-N) in DMF (15mL) was added slowly over 15 minutes through the addition funnel₃4.8g,17mmol,1.1mol eq). The reaction mixture was stirred in an ice bath and allowed to gradually warm to ambient temperature. After 16h, the reaction was diluted with MTBE (300mL) and saturated NaHCO₃Aqueous solution (2x30mL) and brine (2x30mL) washed with Na₂SO₄Dried and evaporated to give a residue. The crude material was purified on silica (40g) with a gradient of 100% heptane to 20% ethyl acetate-80% heptane to give the title product as a colourless oil (3.02g, 80% yield,>95% purity).¹H NMR (400MHz, chloroform-d) ppm 4.06(dtd, J ═ 8.86,5.41,5.41,3.91Hz,1H)3.65-3.83(m,3H)3.36-3.57(m,1H)1.47(s, 9H).¹⁹FNMR (376MHz, chloroform-d) ppm-106.10-102.44 (m,1F) -120.14-116.68 (m, 1F). For C₉H₁₄F₂N₄O₂M/z (ESI +)149 (small)/123 (M + H) +.

And 7: preparation of 4-amino-3, 3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester

A solution of tert-butyl 4-azido-3, 3-difluoropyrrolidine-1-carboxylate (3.01g,12.1mmol) in ethanol (300mL) was degassed with nitrogen and 20% Pd/C (300mg) was added. The resulting mixture was stirred under a hydrogen atmosphere for 16 hours. The catalyst was removed by filtration. The filtrate was evaporated to give the title product as an oil (2.63g, 98% yield,>85% purity).¹H NMR (400Mhz, chloroform-d) ppm 3.73-3.87(m,2H)3.69(d, J ═ 10.64Hz,1H)3.50-3.62(m,1H)3.13(d, J ═ 6.85Hz,1H)1.45-1.48(m, 9H).¹⁹F NMR (376MHz, chloroform-d) ppm-115.05-110.78 (m,1F) -120.95-117.90 (m, 1F). For C₉H₁₆F₂N₂O₂m/z(APCI+)123(M+H)⁺.

And 8: 3, 3-difluoro-4- { [3- (methylsulfonyl) propanoyl group]Preparation of tert-butyl amino } pyrrolidine-1-carboxylate Prepare for

To the reaction flask was added tert-butyl 4-amino-3, 3-difluoropyrrolidine-1-carboxylate (1.36g,6.12mmol), 3- (methylsulfonyl) propionic acid (1.02g,6.73mmol,1.1mol eq), DCM (31mL,0.4M), NMM (1.35mL,12.2mmol,2mol eq), HOBt (1.31g,9.2mmol,1.5mol eq), and EDC-HCl (1.85g,9.2mmol,1.5mol q). The resulting suspension was stirred at ambient temperature for 2 hours under nitrogen atmosphere. The reaction was diluted with DCM (80mL) and NaHCO₃Aqueous (2 × 30mL) wash and organic layer washed with Na₂SO₄Drying and evaporating to obtain a residue which is rapidly colored by silicaPurification by chromatography (eluting with a gradient of 100% heptane to 100% ethyl acetate) to give the title product as a white foamy solid (1.65g, 76% yield,>95% purity).¹H NMR (400Mhz, chloroform-d) ppm 6.45(br.s.,1H)4.68-4.89(m,1H)3.94(dd, J ═ 10.70,8.62Hz,1H)3.62-3.86(m,2H)3.43(t, J ═ 7.15Hz,2H)3.18(br.s.,1H)2.97(s,3H)2.84(td, J ═ 7.15,1.96Hz,2H)1.47(s, 9H).¹⁹F NMR (376MHz, chloroform-d) ppm-112.79- -110.52(m,1F) -114.51- -113.30(m, 1F). For C₁₃H₂₂F₂N₂O₅M/z (APCI +)257.1(M + H) + of S.

And step 9: preparation of N- (4, 4-difluoropyrrolidin-3-yl) -3- (methylsulfonyl) propanamide hydrochloride

To 3, 3-difluoro-4- { [3- (methylsulfonyl) propanoyl group]Amino } pyrrolidine-1-carboxylic acid tert-butyl ester (1.60g,4.5mmol) in acetonitrile (45mL) HCl (4M in dioxane, 4.5mL,18mmol,4mol eq) was added. After 1 hour, the resulting solution became a white suspension which was stirred at ambient temperature for 3 hours. The volatiles were removed to dryness to give a white solid, which was suspended in ethyl acetate (100 mL). The white solid was collected by filtration, washed with diethyl ether (20mL), and dried to give the title product as a white solid (1.26g, 96% yield,>95% purity, assuming it is 1HCl salt).¹H NMR(400MHz,DMSO-d6)ppm 9.99(br.s.,2H)8.75(br.s.,1H)4.71-4.95(m,1H)3.58-3.89(m,3H)3.28-3.43(m,2H)3.16(t,J＝10.88Hz,2H)2.99(s,3H)2.67(t,J＝7.58Hz,2H)。¹⁹F NMR (376MHz, DMSO-d6) ppm-108.27- -107.26(m,1F) -109.70- -108.82(m, 1F). For C₈H₁₄F₂N₂O₃M/z (APCI +)257.2(M + H) + of S.

Preparation 9: (+/-) -cis-3 a-methoxy-hexahydropyrrolo [3, 4-c)]Preparation of pyrrole-2 (1H) -carboxylic acid tert-butyl ester Prepare for

Step 1: preparation of 3, 3-dimethoxypyrrolidine-2, 5-dione

Bromine (24.8g,154mmol) was added dropwise to a solution of maleimide (10g,103mmol) in MeOH (400mL) at 0 deg.C. The reaction mixture was stirred at room temperature for 16 hours and then concentrated in vacuo. Sodium (9.6g,412mmol) was added to MeOH (400mL) at 0 deg.C. Once the methanol was dissolved, the crude material in MeOH (200mL) was added dropwise. The reaction mixture was stirred at room temperature overnight. The mixture was neutralized by slowly adding dropwise 6M HCl, which was then separated between water and EtOAc (100 mL). The aqueous layer was washed with EtOAc (2 × 100mL), then the combined organic extracts were washed with brine (100mL), MgSO₄Dried and concentrated to give the title compound as a yellow solid (12.3g, 75% yield).

Step 2: preparation of 3-methoxy-1H-pyrrole-2, 5-dione

To a solution of 3, 3-dimethoxypyrrolidine-2, 5-dione (12.3g,77mmol) in toluene (500mL) was added TsOH. water (1.46g,7.7 mmol). A Dean Stark trap was attached and the reaction mixture refluxed overnight. TLC (petroleum ether/EtOAc ═ 1/1) indicated complete reaction. The mixture was concentrated and purified by column chromatography (from petroleum ether/EtOAc-2/1 to petroleum ether/EtOAc-1/1) to give 3-methoxy-1H-pyrrole-2, 5-dione as an orange solid (6.9g, 70% yield).

And step 3: (+/-) -cis-5-benzyl-3 a-methoxytetrahydropyrrolo [3,4-c]Pyrrole-1, 3(2H,3aH) -bis Preparation of ketones

Note that: the preparation was done in 5 batches in parallel.

To a mixture of 3-methoxy-1H-pyrrole-2, 5-dione (3g,24mmol) and TFA (0.34g,3mmol) in CH₂Cl₂(300mL) to enable maintenance of internal reaction temperature<N- (methoxymethyl) -N- (trimethylsilylmethyl) benzylamine (14.2g,48mmol) in CH was added slowly at a rate of 2 deg.C₂Cl₂(100 mL). The resulting solution was slowly warmed to ambient temperature and stirred overnight. TLC (petroleum ether/EtOAc ═ 1/1) indicated complete reaction. The combined five batches of the reaction mixture were diluted with saturated sodium bicarbonate (100mL) and the organic layer was diluted with MgSO₄Dried, concentrated and purified by column chromatography (from petroleum ether/EtOAc 10/1 to petroleum ether/EtOAc 1/1) to give the title product as a pale yellow oil (18g, 58% yield for 5 batches), which was further purified by preparative HPLC to give the pure title product as an oil (4.5g, 14.6% yield).

And 4, step 4: (+/-) -cis-2-benzyl-3 a-methoxyoctahydropyrrolo [3, 4-c)]Preparation of azoles

To a solution of (+/-) -cis-5-benzyl-3 a-methoxytetrahydropyrrolo [3,4-c ] pyrrole-1, 3(2H,3aH) -dione (4.5g,17mmol) in THF (200mL) at 0 deg.C was added a solution of LAH (35mL,35mmol, 1M in THF). The resulting mixture was stirred at 45 ℃ overnight. TLC (petroleum ether/EtOAc ═ 1/1) indicated complete reaction. The mixture was quenched by water (3mL) and filtered. The filtrate was concentrated to give the crude title compound (3.7g, crude) which was used directly in the next step.

And 5: (+/-) -cis-5-benzyl-3 a-methoxy-hexahydropyrrolo [3, 4-c)]Pyrrole-2 (1H) -carboxylic acid tert-butyl ester Preparation of esters

To (+/-) -cis-2-benzyl-3 a-methoxyoctahydropyrrolo [3, 4-c)]Pyrrole (3.7g, crude) in CH₃Boc was added as a solution in CN (150mL)₂O(7.63g,35mmol)、Et₃N (7.07g,70mmol) and DMAP (0.43g,3.5 mmol). The resulting mixture was stirred at 45 ℃ for three days. The mixture was concentrated and purified by column chromatography (from petroleum ether/EtOAc-20/1 to 2/1) to give the title compound as a red oil (1.5g, 26% yield over two steps).

Step 6: (+/-) -cis-3 a-methoxy-hexahydropyrrolo [3, 4-c)]Preparation of pyrrole-2 (1H) -carboxylic acid tert-butyl ester Prepare for

(+/-) -cis-5-benzyl-3 a-methoxy-hexahydropyrrolo [3,4-c ] under nitrogen]Pyrrole-2 (1H) -carboxylic acid tert-butyl ester (1.5g,4.5mmol) in MeOH (100mL) was added Pd (OH)₂C (300 mg). The suspension was degassed under vacuum and purged three times with hydrogen. The mixture was stirred under hydrogen (45psi) at 40-50 ℃ overnight. TLC (petroleum ether/EtOAc ═ 2/1) indicated complete reaction. The mixture was filtered, concentrated and purified by column Chromatography (CH)₂Cl₂MeOH 15/1) to give the title compound as a yellow gum (454mg, 41% yield).¹H NMR(400MHz,CDCl₃)3.95 (br., 2H),3.51-3.78(m,3H),3.36-3.50(m,2H),3.14-3.35(m,4H),2.83-3.08(m,2H),2.75 (br., 1H),1.45(s, 9H). For C₁₂H₂₂N₂O₃M/z (APCI +) [ M-56+ H]⁺。

Preparation 10: (+/-) -cis-2-benzyl-3 a-fluorooctahydropyrrolo [3, 4-c)]Preparation of azoles

Step 1: preparation of 4- (benzylamino) -3, 3-difluoro-4-oxobutanoic acid

Trifluoroacetic anhydride (2.34mL,16.7mmol) was added in one portion to a solution of 2, 2-difluorosuccinic acid (2.15g,14.0mmol) in iPrOAc (23mL) at ambient temperature. The reaction solution was stirred at 50 ℃ for 2 hours. The reaction solution was cooled to 5 ℃ in an ice bath. Benzylamine (2.29mL,20.9mmol) was added dropwise while maintaining the reaction temperature below 20 ℃. The solution was stirred at ambient temperature for 2 hours. The reaction was quenched with water (10mL) and then saturated Na₂CO₃To a pH of 8-9. The separated organic phase was discarded. The aqueous phase was acidified to pH 1 with 6N HCl and extracted with EtOAc (2 × 100 mL). The combined organic phases were washed with 2N HCl, brine (100mL) and MgSO₄Dried, filtered and concentrated. The intermediate (2.89g, 56.8% yield) was carried over to the next step without further purification.¹H NMR(400MHz,CDCl₃)ppm 7.28-7.42(m,5H)7.14-7.21(m,1H)6.77(br.s.,1H)4.54(d,J＝5.87Hz,2H)3.39(t,J＝14.18Hz,2H)。

Step 2: preparation of 1-benzyl-3, 3-difluoropyrrolidine-2, 5-dione

To a solution of crude 4- (benzylamino) -3, 3-difluoro-4-oxobutanoic acid in iPrOAc (40mL) at ambient temperature was added SOCl₂(2.04mL,27.9mmol,2 eq). The reaction solution was stirred at 55 ℃ for 4 hours. Reacting the reactantsCooling to 0-5 deg.C. Half-saturated brine (50mL) was added slowly to quench excess SOCl₂. The organic phase was washed with brine (70mL) and 2M Na₂CO₃(ca. 50mL) was adjusted to pH 8-9 and extracted twice with EtOAc. The combined organic layers were washed with brine (50mL) and the organic phase was MgSO₄Dried, filtered and concentrated. The crude residue is treated with CH₂Cl₂Diluted and filtered to remove the precipitate. The concentrated filtrate was purified by column chromatography (eluting with 2-20% EtOAc/heptane) to give the title compound (1.74g, 65%) as a clear oil.¹H NMR(400MHz,CDCl₃)ppm 7.30-7.43(m,5H)4.76(s,2H)3.18(t,J＝12.53Hz,2H)。

And step 3: (+/-) -cis-2, 5-dibenzyl-3 a-fluorotetrahydropyrrolo [3,4-c]Pyrrole-1, 3(2H,3aH) -bis Preparation of ketones

To a solution of 1-benzyl-3, 3-difluoropyrrolidine-2, 5-dione (325mg,1.44mmol) in acetonitrile (3.6mL) was added LiF (56mg,1.50eq) and a stir bar. The reaction mixture was sonicated at room temperature for 2.5 hours. N- (methoxymethyl) -N- (trimethylsilylmethyl) benzylamine (0.4mL,1.59mmol,1.10eq) and LiF (37mg,1.44mmol,1eq) were added and sonication continued for 0.5 h. The reaction mixture was concentrated and the salts were removed by filtration. The crude residue was purified by column chromatography eluting with 2-20% EtOAc/heptane and further purified with 2-10% EtOAc/heptane. The desired moiety is weakly UV active but with KMNO₄The staining was visible. The title compound (196mg, 40% yield) was isolated as a yellow oil.¹H NMR(400MHz,DMSO-d₆) ppm7.10-7.43(m,10H)4.57-4.75(m,2H)3.63(s,2H)3.56-3.65(m,1H)3.33-3.41(m,1H)3.13(d, J ═ 9.29Hz,1H)2.74(dd, J ═ 9.35,7.03Hz,1H)2.57-2.70(m, 1H). For C₂₀H₂₀FN₂O₂M/z (APCI +)339.20(M + H)⁺。

And 4, step 4: (+/-) -cis-5-benzyl-3 a-fluoro-4, 6-dioxohexahydropyrrolo [3, 4-c)]Pyrrole-2 (1H) - Preparation of tert-butyl carboxylate

To (+/-) -cis-2, 5-dibenzyl-3 a-fluorotetrahydropyrrolo [3,4-c]Pyrrole-1, 3(2H,3aH) -dione (195mg,0.576mmol) in EtOH (3mL) in a nitrogen purged solution 20% Pd (OH)₂C (60 mg). The reaction was evacuated and refilled with hydrogen three times, then Boc was added₂O (151mg,0.691mmol,1.2 eq). The reaction was evacuated and refilled with hydrogen three times again, then carried out under a hydrogen atmosphere (balloon). After 1.5 hours, another 20% Pd (OH) was added₂C (40mg) and stirred for 18 h. The reaction mixture was filtered and washed with MeOH. The filtrate was concentrated and placed on a column eluting with 2-25% EtOAc/heptane to give the title compound (160mg, 80% yield).¹H NMR(400MHz,DMSO-d₆) ppm 7.25-7.39(m,3H)7.21(d, J ═ 7.34Hz,2H)4.62(s,2H)3.89-4.08(m,2H)3.60-3.83(m,3H)1.37(s, 9H). For C₁₈H₂₁FN₂O₄-C₂H₉O₅M/z (APCI +)249.20(M + H-Boc)⁺。

And 5: (+/-) -cis-2-benzyl-3 a-fluorooctahydropyrrolo [3, 4-c)]Preparation of azoles

(+/-) -cis-5-benzyl-3 a-fluoro-4, 6-dioxohexahydropyrrolo [3, 4-c)]Pyrrole-2 (1H) -carboxylic acid tert-butyl ester (160mg,0.459mmol) was dissolved in THF (4.5mL) and BH was added at ambient temperature₃·Me₂S (0.174mL,1.84mmol,4.00 eq). The reaction mixture was stirred at 55 ℃ for 1.5 hours. A thin slurry is formed during the reaction. The reaction was then cooled to 0 ℃ and quenched with dropwise addition of dry MeOH (2mL)The reaction was stopped and then brought to pH 4 by concentrated HCl. The reaction solution was stirred at 0 to 10 ℃ for 1 hour. The temperature was raised to 55 ℃ for 1.5 hours, then cooled to room temperature and stirred for 20 hours. The reaction mixture was concentrated under reduced pressure, diluted with MeOH, passed through SCX column with MeOH then 7N NH₃MeOH and the free amine was obtained. The title product (100mg, crude) was carried on to the next step without further purification. For C₁₃H₁₇FN₂M/z (APCI +)221.25(M + H)⁺。

Preparation of 3- (4-amino-3-methoxy-1H-pyrazol-1-yl) azetidine-1-carboxylic acid tert-butyl ester

Step 1: preparation of 3- (3-methoxy-4-nitro-1H-pyrazol-1-yl) azetidine-1-carboxylic acid tert-butyl ester

To a cooled (0 ℃) suspension of 3-methoxy-4-nitro-1H-pyrazole (1.00g,6.99mmol,1.00eq), tert-butyl 3-hydroxypyrrolidine-1-carboxylate (2.12g,12.2mmol,1.75eq) and polyphenylacetic acid-bound triphenylphosphine (4.06g,12.2mmol,1.75eq, 3mmol/g) in THF (45mL) was added dropwise diethyl azodicarboxylate (2.42mL,13.0mmol,1.90eq) over 3 minutes. The reaction mixture was allowed to warm to ambient temperature and stirred for 15 hours. The reaction mixture was then diluted with EtOAc (60mL), filtered, and the filtrate was concentrated. The crude reaction mixture was purified by flash chromatography on silica gel (eluting with a gradient of 0-60% EtOAc in heptane) to give the title compound as a white solid (1.52g, 72.9% yield).¹H NMR(400MHz,CDCl₃) ppm 8.12(s,1H)4.87(tt, J ═ 5.6,7.5Hz,1H)4.40-4.28(m,4H)4.09(s,3H)1.48(s, 9H). For C₇H₁₁N₄O₃M/z (APCI +)198.9(M-Boc + H)⁺。

Step 2: preparation of 3- (4-amino-3-methoxy-1H-pyrazol-1-yl) azetidine-1-carboxylic acid tert-butyl ester

A nitrogen purged round bottom flask was charged with tert-butyl 3- (3-methoxy-4-nitro-1H-pyrazol-1-yl) azetidine-1-carboxylate (188mg,0.63mmol,1.00eq), 10% Pd/C (100mg), and methanol (10 mL). The reaction mixture was sparged with hydrogen for 5 minutes and then stirred vigorously under a hydrogen atmosphere for 18 hours. The reaction mixture was then sparged with nitrogen gas, byFiltered, concentrated and azeotroped with toluene (2x20mL) to give an oil, which was used without further purification.¹H NMR (400MHz, DMSO-d6) ppm 7.04(s,1H),4.82(tt, J ═ 5.4,7.9Hz,1H),4.15(t, J ═ 8.3Hz,2H),4.04-3.95(m,2H),3.79(s,3H),3.44(br.s.,2H),1.40(s, 9H). For C₇H₁₃N₄O M/z (APCI +)169.2(M-Boc + H)⁺。

Preparation 11: preparation of 1- (3-methoxy-4-amino-1H-pyrazol-1-yl) propan-2-ol

Step 1: preparation of 1- (3-methoxy-4-nitro-1H-pyrazol-1-yl) propan-2-ol

To a suspension of 3-methoxy-4-nitro-1H-pyrazole (2.00g,14.0mmol,1.00eq) and cesium carbonate (13.7g,41.9mmol,3.0eq) was added 1-bromo-2-propanol (2.70mL,22.4mmol,1.60eq, 70% purity) and the reaction mixture is heated at 60 ℃. After 3.5 hours, another portion of 1-bromo-2-propanol (2.70mL,22.4mmol,1.60eq, 70% purity) was added. After an additional 12 hours, the reaction mixture was cooled to ambient temperature and diluted with water (100mL) and EtOAc (50 mL). The layers were separated and the aqueous phase was extracted with EtOAc (4 × 50 mL). The combined organic layers were washed with water (50mL) and brine (50mL), dried (Na)₂SO₄) Concentrated and purified by flash chromatography on silica gel (eluting with a gradient of 0-50% EtOAc in heptane) to give the title compound as a white solid (945mg, 34% yield).¹H NMR(400MHz,CDCl₃) ppm 8.09(s,1H),4.32-4.22(m,1H),4.06(s,3H),4.05(dd, J ═ 5.0,13.0Hz,1H),3.87(dd, J ═ 8.0,13.0Hz,1H),2.60(br.s.,1H),1.29(d, J ═ 6.4Hz, 3H). For C₇H₁₂N₃O₄M/z (APCI +)201.9(M + H)⁺。

Step 2: preparation of 1- (3-methoxy-4-amino-1H-pyrazol-1-yl) propan-2-ol

A nitrogen-purged round-bottom flask was charged with 1- (3-methoxy-4-nitro-1H-pyrazol-1-yl) propan-2-ol (345mg,1.72mmol,1.00eq), 10% Pd/C (200mg), and methanol (20 mL). The reaction mixture was sparged with hydrogen for 10 minutes and then stirred vigorously under a hydrogen atmosphere for 14 hours. The reaction mixture was then sparged with nitrogen gas, byFiltered and concentrated to give the title compound as an oil, which was used without further purification.¹H NMR (400MHz, DMSO-d6) ppm 6.92(s,1H)4.70(d, J ═ 4.9Hz,1H)3.89-3.77(m,1H)3.74(s,3H)3.73-3.55(m,2H)0.97(d, J ═ 6.2Hz, 3H). For C₇H₁₄N₃O₂M/z (APCI +)172.3(M + H)⁺。

Preparation 12: (S) -3-methoxy-Preparation of 1- (1-methylpyrrolidin-3-yl) -1H-pyrazol-4-amine

Step 1: preparation of (S) -3-methoxy-1- (1-methylpyrrolidin-3-yl) -4-nitro-1H-pyrazole

To a suspension of 3-methoxy-4-nitro-1H-pyrazole (2.00g,14.0mmol,1.00eq), (R) -1-methyl-pyrrolidin-3-ol (1.56g,15.4mmol,1.10eq) and polystyrene-bound triphenylphosphine (6.53g,19.6mmol,1.40eq,3mmol/gram) in THF (140mL) was added di-tert-butyl azodicarboxylate (4.51g,19.6mmol,1.40eq) in THF (25mL) dropwise over 5 min. The reaction mixture was stirred for 18 hours. The reaction mixture was then diluted with EtOAc (100mL), filtered, and the filtrate was concentrated. The crude reaction mixture was purified by flash chromatography on silica gel (eluting with 50-100% EtOAc in heptane, then a gradient to 10% 7N methanolic ammonia/EtOAc) to give the title compound as a white solid (2.39g, 80% yield).¹H NMR (400MHz, DMSO-d6) ppm 8.69(s,1H),4.84-4.72(m,1H),3.94(s,3H),2.86-2.75(m,2H),2.72(dd, J ═ 7.0,10.0Hz,1H),2.40(dt, J ═ 6.2,8.4Hz,1H),2.36-2.29(m,1H),2.28(s,3H),2.16-2.06(m, 1H). For C₉H₁₅N₄O₃M/z (APCI +)227.2(M + H)⁺。

Step 2: preparation of (S) -3-methoxy-1- (1-methylpyrrolidin-3-yl) -1H-pyrazol-4-amine

A nitrogen purged round bottom flask was charged with (S) -3-methoxy-1- (1-methylpyrrolidin-3-yl) -4-nitro-1HPyrazole (300mg,1.33mmol,1.00eq), 10% Pd/C (200mg) and methanol (20 mL). The reaction mixture was sparged with hydrogen for 10 minutes and then stirred vigorously under a hydrogen atmosphere for 16 hours. The reaction mixture was then sparged with nitrogen gas, byFiltered and concentrated to give an oil, which was used without further purification.¹H NMR (400MHz, DMSO-d6) ppm6.99(s,1H),4.51(tdd, J ═ 4.8,7.3,9.3Hz,1H),3.74(s,3H),3.36(br.s.,2H),2.71-2.61(m,2H),2.57(dd, J ═ 4.8,9.5Hz,1H),2.40(dt, J ═ 6.5,8.3Hz,1H),2.25(s,3H),2.23-2.14(m,1H),1.94-1.84(m, 1H). For C₉H₁₇N₄O M/z (APCI +)197.3(M + H)⁺。

One skilled in the art will appreciate that the following examples are prepared with no key changes or substitutions associated with the exemplary operations.

TABLE 1

pEGFR Y1068ELISA assay:

to characterize the effect of EGFR T790M inhibitors in cells with different EGFR mutation profiles, inhibition of EGFR phosphorylation at Tyrl068(Y1068) was determined in cells with wild-type EGFR or multiple EGFR mutants (EGFR single mutant (L858R, E746-a750 deletion) or EGFR double mutant (L858R + I790M, deletion + I790M).

By passingSandwich ELISA kit for phosphorylated-EGF receptor (Tryl068) (II)Phospho-EGF Receptor(Try1068)Sandwich ELISA kit，#7240,Cell SignalingDanvers, MA) measures phosphorylation of EGFR at Y1068.The phosphorylation-EGF receptor (Tryl068) sandwich ELISA kit is a solid phase sandwich enzyme-linked immunosorbent assay (ELISA) which detects the endogenous level of phosphorylation-EGF receptor (Tyrl068) protein. The following non-small cell lung cancer (NSCLC) cell lines were evaluated in this assay: a549(EGFR wild type, endogenous), NCI-H1975(EGFR L858R + I790M, endogenous), NCI-H3255(EGFRL858R), PC9(EGFR del) and PC9-DRH (EGFR del/T790M). A549 and NCI-H1975 cells were purchased from the American Type Culture Collection (Manassas, Va.). Pc9 cells were purchased from RIKENBIOResource Center (Japan). NCI-H3255 cells were permissive by NCI. PC9-DRH cells were generated by long-term maintenance in the presence of dacomitinib to acquire resistance to dacomitinib and acquire the T790M mutation. All cells were cultured according to the recommendations of ATCC. A549, NCI-H1975, PC9 and NCI-H3255 cells were grown in RPMI medium (Invitrogen, Carlsbad, CA) supplemented with 10% FBS (Sigma, St Louis, Mo) and 1% Penn/strep (Invitrogen). PC9-DRH cells were grown in RPMI containing 10% FBS and 1. mu.M dactinoib.

Cells were plated in complete medium (50 μ L/well) at 40,000/well on the bottom of tissue culture treated clear microtiter plates (#3595, Corning Inc, Corning, NY) and allowed to incubate at 37 ℃ with 5% CO₂Attach overnight. The following day, compound dilution plates were prepared in 96-well clear V-bottom 0.5mL polypropylene block plates (#3956, Corning, Inc). Each compound was prepared as a DMSO stock solution (10 mM). Compounds on each plate were tested in duplicate on an 11-point serial dilution curve (1:3 dilution). Compound treatment (50 μ L) was added from the compound dilution plate to the cell plate. The highest concentration of compound was 1 μ M or 10 μ M (final concentration), with a final concentration of DMSO (# D-5879, Sigma) of 0.3%. The plates were then incubated at 37 ℃ with 5% C0₂Incubate for 2 hours. For the a549(EGFR wild-type) assay, cells were plated in whole serum (10%) medium for 24 hours prior to compound treatment(ii) a Cells were treated in the whole serum medium and then stimulated with EGF (40 ng/mL/starvation medium, Invitrogen) for 10 min. Immediately before the end of incubation, ice-cold lysis buffer (lx Cell lysis buffer in purified water (#9803, Cell Signaling Technology), 1mM sodium orthovanadate (Na)₃VO₄#96508, Sigma), 1mM phenylmethanesulfonyl fluoride (PMSF, 52332, Calbiochem/EMD Chemicals), a complete small EDTA-free protease inhibitor Cocktail (Cocktail) tablet (1 tablet/l 0mL, #11836170001, Roche, Indianapolis, IN), and a Phostop phosphatase inhibitor Cocktail tablet (1 tablet/10 mL, #04906837001, Roche)). At the end of 2 hours, the medium was gently shaken off and the cells were treated with ice-cold 1mM Na in PBS₃VO₄(100. mu.L/well, Invitrogen) was washed once. The wash was then gently shaken off and ice-cold lysis buffer (50 μ L/well) was added to the cells. The plate was shaken at 4 ℃ for 20-30 minutes to completely lyse the cells. Sample diluent (50 μ L/well) was added to the ELISA plate and lysate (50 μ L) was diluted into the sample diluent in each well of the ELISA plate. The plates were sealed and incubated overnight at 4 ℃ with shaking. The next day, wells were washed four times with lx wash buffer; after the final wash, the plates were wrapped with lint-free paper, and Add detection antibody (green, 100 μ Ι _ per well) was then added to each well and incubated for 1 hour at 37 ℃. After incubation, the wells were washed as described. Secondary HRP-linked antibody (red, 100 μ Ι _ per well) was added to each well and incubated at 37 ℃ for 30 minutes. After incubation, the wells were washed as described. TMB substrate (100 μ L/well) was added to each well and the plates were incubated at 37 ℃ for 10 minutes or at the highest room temperature for 30 minutes. At the end of incubation, stop solution (100 μ Ι/well) was added to each well and the plate was warmed and shaken for several seconds. Within 30 minutes after addition of the stop solution, on a Perkin Elmer EnVision Excite Multilabel Reader Method for detecting absorbance or on a Molecular devices SpectraMax for detecting absorbance³⁸⁴The absorbance at 450nm was read on a Reader. Data were analyzed using a four parameter fit in Microsoft Excel.

The results of the pEGFR Y1068ELISA assay for the compounds tested are listed in table 2.

TABLE 2

Claims

1. A compound of formula (I):

wherein

R¹Is hydrogen, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl, 4-6 membered heterocycloalkyl or 4-6 membered heteroaryl, wherein said C₁-C₆Alkyl radicalOptionally substituted by one, two or three groups selected from halogen, hydroxy and C₁-C₃Substituent of alkoxy, and wherein said C₃-C₆Cycloalkyl, said 4-6 membered heterocycloalkyl and said 4-6 membered heteroaryl are each independently optionally substituted by one, two or three substituents selected from C₁-C₃Alkyl, hydroxy and C₁-C₃Substituent substitution of alkoxy;

ring A is C₆-C₁₀Aryl or 5-12 membered heteroaryl;

R²and R⁵Each independently being absent or hydrogen, halogen, cyano, difluoromethyl, trifluoromethyl, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Alkoxy, -N (R)¹⁰)(R¹¹)、C₃-C₅Cycloalkyl or 4-6 membered heterocycloalkyl, wherein said C₁-C₆Alkyl is optionally substituted by one, two or three groups selected from halogen, hydroxy, C₁-C₆Alkoxy and-N (R)¹²)(R¹³) Substituted with the substituent(s);

R⁴absent or hydrogen, halogen, C₁-C₆Alkyl or C₃-C₆A cycloalkyl group,

wherein R is²And R³Or R³And R⁴Can be combined to form C₅-C₇A cycloalkyl ring or a 5-7 membered heterocycloalkyl ring, and wherein said C₅-C₇Cycloalkyl ring and said 5-7 membered heterocyclic ringEach alkyl ring is independently optionally substituted with one, two or three R¹⁴Substituted by groups;

q is absent or is O, S or NR⁹；

R⁷is composed of

R⁹、R¹²And R¹³Each independently is hydrogen or C₁-C₃An alkyl group;

provided that R is¹⁶And R¹⁷Can form C₃-C₅A cycloalkyl ring;

R¹⁸is hydrogen or C₁-C₃An alkyl group;

m is 0,1 or 2, with the proviso that when ring B is absent, m is 2; or

A pharmaceutically acceptable salt thereof.

2. A compound or salt of claim 1, wherein R¹Is C₁-C₆Alkyl or C₃-C₆Cycloalkyl, wherein said C₁-C₆Alkyl is optionally substituted by hydroxy, and wherein said C₃-C₆Cycloalkyl optionally substituted by C₁-C₃Alkyl substitution.

3. A compound or salt of claim 1, wherein R¹Is methyl, ethyl, isopropyl or tert-butyl.

4. A compound or salt of any one of claims 1-3, wherein R²Is hydrogen, methyl, difluoromethyl or methoxy.

5. A compound or salt of any one of claims 1-3, wherein R⁵Is hydrogen, C₁-C₆Alkyl or C₁-C₆An alkoxy group.

6. A compound or salt of any one of claims 1-3, wherein R⁵Is hydrogen, methyl or methoxy.

7. A compound or salt thereof according to any one of claims 1-3, wherein R³Is C₁-C₆Alkyl or 3-7 membered heterocycloalkyl, wherein said C₁-C₆Alkyl is optionally substituted by one or two R¹⁴And wherein said 3-7 membered heterocycloalkyl is optionally substituted with C₁-C₃Alkyl substitution.

8. A compound or salt of any one of claims 1-3, wherein R³Is methyl.

9. The compound or salt of any one of claims 1-8, wherein Q is absent.

10. The compound or salt of any one of claims 1-8 wherein Q is O.

11. The compound or salt of any one of claims 1-8 wherein Q is NR⁹。

12. The compound or salt of any one of claims 1-11, wherein m is 0.

13. The compound or salt of claims 1-9 wherein B is 3-10 membered heterocycloalkyl.

14. The compound or salt of any one of claims 1-13, having formula (II):

wherein

X is CH or N;

w is CR²Or the number of N is greater than the number of N,

R²and R⁵Each independently of the others hydrogen, halogen, cyano, difluoromethyl, trifluoromethyl, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Alkoxy, -N (R)¹⁰)(R¹¹)、C₃-C₅Cycloalkyl or 4-6 membered heterocycloalkyl, wherein said C₁-C₆Alkyl is optionally substituted by one, two or three groups selected from halogen, hydroxyBase, C₁-C₆Alkoxy and-N (R)¹²)(R¹³) Substituted with the substituent(s);

q is absent or is O, S or NR⁹；

R⁷is composed of

R⁹、R¹²And R¹³Each independently is hydrogen or C₁-C₃An alkyl group;

provided that R is¹⁶And R¹⁷Can form C₃-C₅A cycloalkyl ring;

R¹⁸is hydrogen or C₁-C₃An alkyl group;

m is 0,1 or 2, with the proviso that when ring B is absent, m is 2; or

A pharmaceutically acceptable salt thereof.

15. The compound or salt of any one of claims 1-13, having formula (III):

wherein

provided that R is²Or R⁵At least one of which is hydrogen;

q is absent or is O, S or NR⁹；

R⁷is composed of

R⁹、R¹²And R¹³Each independently is hydrogen or C₁-C₃An alkyl group;

provided that R is¹⁶And R¹⁷Can form C₃-C₅A cycloalkyl ring;

R¹⁸is hydrogen or C₁-C₃An alkyl group;

m is 0,1 or 2, with the proviso that when ring B is absent, m is 2; or

A pharmaceutically acceptable salt thereof.

16. The compound or salt of claim 15, having formula (IIIa):

wherein

n is 0,1 or 2; and is

p is 0,1 or 2.

17. The compound or salt of claim 16, wherein n is 0.

18. The compound or salt of claim 15 or 16, wherein R⁶And R⁸Each independently of the others is hydrogen, halogen, C₁-C₃Alkyl or C₁-C₃An alkoxy group.

19. The compound or salt of claim 15 or 16, wherein R⁶Is hydrogen, fluorine, methyl or methoxy.

20. The compound or salt of claim 15 or 16, wherein R⁶Is fluorine.

21. The compound or salt of claim 15 or 16, wherein R⁸Is hydrogen, fluorine or methyl.

22. The compound or salt of any one of claims 16-21, having formula (IIIb):

23. a compound which is

A pharmaceutically acceptable salt thereof.

24. A pharmaceutical composition comprising a compound according to any preceding claim, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

25. A combination of a compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, and an anti-neoplastic agent for the treatment of cancer.

26. A method of treating abnormal cell growth in a mammal, comprising administering to the mammal an amount of a compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, effective to treat abnormal cell growth.