HK40012941B

HK40012941B - Macrocyclic broad spectrum antibiotics

Info

Publication number: HK40012941B
Application number: HK62020002459.9A
Authority: HK
Inventors: 彼得·安德鲁·史密斯; 塔克·柯伦·罗伯茨; 罗伯特·I·希古奇; 普拉苏纳·帕拉塞利; 迈克尔·F·T·凯勒; 雅各布·布拉德利·施瓦兹; 詹姆斯·约翰·克劳福德; 强·Q·李; 艾米丽·J·哈南; 胡慧勇; 陈永胜; 郁志勇; 保罗·科林·迈克尔·温希普; 卡卢姆·麦克劳德; 托比·布伦奇
Original assignee: 阿奇克斯制药公司; 健泰科生物技术公司
Priority date: 2017-02-15
Filing date: 2018-02-22
Publication date: 2023-04-21

Description

Macrocyclic broad spectrum antibiotics

Cross-referencing

This patent application claims the benefit of PCT application PCT/CN2017/073575 filed on day 2, month 15, 2017 and PCT application PCT/CN2017/085075 filed on day 19, month 5, 2017; each of which is incorporated herein by reference in its entirety.

Background

Antibiotic resistance is a serious and growing phenomenon in contemporary medicine and emerges as a major public health concern in the 21 st century. Thus, there is a need for novel classes of broad-spectrum antibiotics, particularly those targeted at novel mechanisms of action, for the treatment of multidrug-resistant pathogens.

Disclosure of Invention

Described herein are novel macrocyclic compounds useful for the treatment of microbial infections, for example for the treatment of bacterial infections. In various embodiments, the present invention provides lipopeptide macrocycles for use in the treatment of bacterial infections. In various embodiments, the present invention provides classes and subclasses of compounds that are structurally related to doxorubicin (arylomycin) for the treatment of bacterial infections. In various embodiments, the macrocycle acts by inhibiting bacterial type 1 signal peptidase (SpsB), an essential protein in bacteria. In some embodiments, the signal peptidase is a gram-negative signal peptidase. In some embodiments, the signal peptidase is LepB.

In one aspect, described herein are compounds of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

wherein:

R ¹ and R ² Are each independently H, - (C) ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-OR ²³ 、-CH ₂ CH(OH)CH ₂ NH ₂ 、-CH ₂ CH (Heterocyclylalkyl) CH ₂ NH ₂ 、-CH ₂ C(O)NH ₂ 、-CH ₂ C(O)N(H)CH ₂ CN、-(C ₁ -C ₆ ) alkyl-C (O) OR ²³ 、-(C ₁ -C ₆ ) alkyl-NR ²¹ R ²² 、-(C ₁ -C ₆ ) Alkane (I) and its preparation methodradical-C (O) NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) alkyl-N (R) ²³ )C(O)(C ₁ -C ₆ ) Alkyl radical NR ²¹ R ²² 、-(C ₁ -C ₆ ) alkyl-N (R) ²³ )C(O)(C ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-C (O) N (R) ²³ )(C ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-C (O) N (R) ²³ )(C ₁ -C ₆ ) Alkyl-heterocycloalkyl, - (C) ₁ -C ₆ ) alkyl-NR ²³ C(＝NH)NR ²¹ R ²² 、-(C ₁ -C ₆ ) alkyl-NR ²³ C(＝NH)R ²³ 、-(C ₁ -C ₆ ) Alkyl- [ (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² ] ₂ 、-(C ₁ -C ₆ ) Heteroalkyl or optionally substituted heterocycloalkyl;

or R ¹ And R ² And the atoms to which they are attached form an optionally substituted heterocycloalkyl ring;

R ³ is H or- (C) ₁ -C ₆ ) An alkyl group;

R ⁴ is H, - (C) ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-OH, - (C) ₃ -C ₆ ) Cycloalkyl or-C (O) NH ₂ (ii) a Or R ³ And R ⁴ Combine to form a heterocycloalkyl ring;

R ⁵ is H or- (C) ₁ -C ₆ ) An alkyl group;

or R ⁴ And R ⁵ And the carbon atom to which they are attached form a cyclopropyl ring;

R ⁶ 、R ⁷ and R ⁸ Each independently is H, fluoro, hydroxy, amino, optionally substituted alkyl, optionally substituted heteroalkyl, or- (C) ₁ -C ₆ ) An alkyl group;

R ⁹ is H, - (C) ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) Haloalkyl or- (C) ₃ -C ₆ ) A cycloalkyl group;

R ¹⁰ is H, - (C) ₁ -C ₆ ) Alkyl radical、-(C ₁ -C ₆ ) Haloalkyl or- (C) ₃ -C ₆ ) A cycloalkyl group;

or R ⁹ And R ¹⁰ Combined to form a heterocycloalkyl or cycloalkyl ring

R ¹¹ And R ¹² Each independently of the other is H, -NH ₂ 、-(C ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-OR ²³ 、-(C ₁ -C ₆ ) alkyl-SR ²³ 、-(C ₁ -C ₆ ) alkyl-C (O) OR ²³ 、-(C ₁ -C ₆ ) alkyl-NR ²¹ R ²² 、-(C ₁ -C ₆ ) alkyl-NR ²³ OR ²³ 、-(C ₁ -C ₆ ) alkyl-NHC (O) NR ²³ OR ²³ 、-(C ₁ -C ₆ ) alkyl-O- (C) ₁ -C ₆ ) alkyl-NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) alkyl-CN, - (C) ₁ -C ₆ ) alkyl-NR ²³ C(O)R ²³ 、-(C ₁ -C ₆ ) alkyl-C (O) NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) heteroalkyl-CO ₂ H、-(C ₁ -C ₆ ) alkyl-S (O) (C) ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-N (H) CH = NH, - (C) ₁ -C ₆ ) alkyl-C (NH) ₂ )＝NH、-(C ₁ -C ₆ ) alkyl-N (H) C (= NH) NH ₂ 、-(C ₁ -C ₆ ) alkyl-N (H) S (O) ₂ NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) alkyl-N (H) S (O) ₂ (C ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-N (H) -C (O) NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) Alkyl C (O) N (H) [ optionally substituted (C) ₂ -C ₆ ) Alkyl radical]-OR ²³ 、-(C ₁ -C ₆ ) Alkyl N (H) C (O) (C) ₁ -C ₆ ) alkyl-OR ²³ 、-(C ₁ -C ₆ ) Alkyl C (O) N (H) heterocycloalkyl, - (C) ₁ -C ₆ ) Alkyl C (O) NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) alkyl-N (H) -C (O) - (C) ₁ -C ₆ ) alkyl-NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) alkyl-N (H) - (C) ₁ -C ₆ ) Alkyl C (O) NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) Alkyl-heterocycloalkyl, optionally substituted- (C) ₁ -C ₆ ) alkyl-N (H) heterocycloalkyl or- (C) ₁ -C ₆ ) Alkyl-heteroaryl;

or R ¹¹ And R ¹⁸ Combine to form an optionally substituted heterocycloalkyl ring; and R is ¹² Is H;

R ¹⁵ 、R ¹⁶ 、R ¹⁷ and R ¹⁸ Are each independently H, - (C) ₁ -C ₆ ) Alkyl, - (C) ₃ -C ₆ ) A cycloalkyl group, a,

-(C ₁ -C ₆ ) alkyl-OR ²³ 、-(C ₁ -C ₆ ) alkyl-C (O) OR ²³ Or- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² ；

X is optionally substituted- (C) ₁ -C ₆ ) Alkyl-, - (C) ₂ -C ₆ ) Alkenyl-, - (C) ₂ -C ₆ ) Alkynyl, optionally substituted- (C) ₃ -C ₇ ) Cycloalkyl-, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -O- (C) ₁ -C ₆ ) Alkyl-, -N (R) ²⁴ )(C ₁ -C ₆ ) Alkyl-, -N (R) ²⁴ )(C ₆ -C ₁₀ ) aryl-or-SO ₂ (C ₁ -C ₆ ) Alkyl-;

y is a bond, -O-, -S-, optionally substituted- (C) ₁ -C ₆ ) Alkyl-, - (C) ₂ -C ₆ ) Alkenyl-, - (C) ₂ -C ₆ ) Alkynyl, - (C) ₁ -C ₆ ) alkyl-N (R) ²⁴ )(C ₁ -C ₆ ) Alkyl-, -O- (C) ₁ -C ₆ ) Alkyl-, -oaryl-, -N (R) ²⁴ )(C ₁ -C ₆ ) Alkyl-, -N (R) ²⁴ )SO ₂ (C ₁ -C ₆ ) Alkyl-, -N (R) ²⁴ )C(O)(C ₁ -C ₆ ) Alkyl-, -C (O) (C) ₁ -C ₆ ) Alkyl-, -S (C) ₁ -C ₆ ) Alkyl-, -SO ₂ (C ₁ -C ₆ ) Alkyl-, -C (O) NH (C) ₁ -C ₆ ) Alkyl-, optionally substituted- (C) ₃ -C ₇ ) Cycloalkyl-, optionally substituted-C (O) N (R) ²⁴ ) Aryl-, optionally substituted-N (R) ²⁴ ) C (O) aryl-, optionally substituted-N (R) ²⁴ )SO ₂ Aryl-, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

z is H, halogen, -NH ₂ 、-CN、-CF ₃ 、-CO ₂ H、-(C ₁ -C ₁₂ ) Alkyl, - (C) ₂ -C ₁₂ ) Alkenyl, -CH = ((C) ₃ -C ₇ ) Cycloalkyl), - (C) ₂ -C ₁₂ ) Alkynyl, -C (O) NR ²⁵ R ²⁶ 、-O-(C ₁ -C ₁₂ ) Alkyl, -S- (C) ₁ -C ₁₂ ) Alkyl, -O- (C) ₃ -C ₁₀ ) [ optionally substituted (C) ₃ -C ₇ ) Cycloalkyl radicals]、-O-(C ₁ -C ₆ ) alkyl-OR ²³ 、-(C ₁ -C ₁₂ ) alkyl-OR ²³ 、-(C ₁ -C ₁₂ ) alkyl-CN, -S- (C) ₁ -C ₁₂ ) Alkyl, -N (R) ²⁴ )(C ₁ -C ₁₂ ) Alkyl, -N (R) ²⁴ )C(O)(C ₁ -C ₁₂ ) Alkyl, optionally substituted- (C) ₃ -C ₇ ) Cycloalkyl, - (C) ₁ -C ₆ ) Alkyl- (C) ₃ -C ₇ ) Cycloalkyl, - (C) ₁ -C ₆ ) Alkyl-heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

each R ²¹ And R ²² Independently of one another is H, - (C) ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) Heteroalkyl, - (C) ₁ -C ₆ ) alkyl-CO ₂ H、-C(O)(C ₁ -C ₆ ) Alkyl, -C (O) O (C) ₁ -C ₆ ) Alkyl, -C (O) O (C) ₁ -C ₆ ) Haloalkyl, -C (= NH) (C) ₁ -C ₆ ) Alkyl, -C (= NH) N (R) ³¹ ) ₂ 、-C(O)N(R ³¹ ) ₂ or-SO ₂ N(R ³¹ ) ₂ (ii) a Or R ²¹ And R ²² And the nitrogen to which they are attachedThe atoms form a heterocycloalkyl ring;

each R ³¹ Independently is H or- (C) ₁ -C ₆ ) An alkyl group; or two R ³¹ And the nitrogen atom to which they are attached form a heterocycloalkyl ring;

each R ²³ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

each R ²⁴ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

each R ²⁵ And R ²⁶ Independently is H or optionally substituted- (C) ₁ -C ₆ ) An alkyl group;

or R ²⁵ And R ²⁶ And the nitrogen atom to which they are attached form a heterocycloalkyl ring;

each R ²⁷ Independently halogen, -NR ²³ R ²⁴ 、-NHC(O)R ²³ 、-NHC(O)NR ²³ R ²⁴ Nitro, hydroxy, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted- (C) ₁ -C ₆ ) Heteroalkyl, optionally substituted- (C) ₁ -C ₆ ) Heteroalkyloxy, optionally substituted- (C) ₁ -C ₆ ) Heteroalkylamino radical, - (C) ₁ -C ₆ ) Alkoxy, -C (O) (C) ₁ -C ₆ ) Alkyl or-S (O) ₂ (C ₁ -C ₆ ) An alkyl group;

or R ¹ And R ²⁷ And the atoms to which they are attached form an optionally substituted 5-or 6-membered heterocycloalkyl ring;

each R ²⁸ Independently halogen, -NR ²³ R ²⁴ 、-NHC(O)R ²³ 、-NHC(O)NR ²³ R ²⁴ Nitro, hydroxy, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted- (C) ₁ -C ₆ ) Heteroalkyl, optionally substituted- (C) ₁ -C ₆ ) Heteroalkyloxy, optionally substituted- (C) ₁ -C ₆ ) Heteroalkylamino, - (C) ₁ -C ₆ ) Alkoxy, -C (O) (C) ₁ -C ₆ ) Alkyl or-S (O) ₂ (C ₁ -C ₆ ) An alkyl group;

or R ² And R ²⁸ And the atoms to which they are attached form an optionally substituted 5-or 6-membered heterocycloalkyl ring;

p is 0, 1 or 2; and is

q is 0, 1 or 2.

In another embodiment are compounds of formula (I) having the structure of formula (Ia):

in another embodiment are compounds of formula (I) or (Ia), wherein R ⁶ 、R ⁷ And R ⁸ Is H. In another embodiment are compounds of formula (I) or (Ia), wherein R ¹⁵ And R ¹⁶ Is H. In another embodiment are compounds of formula (I) or (Ia) having the structure of formula (Ib):

in another embodiment are compounds of formula (I), (Ia) or (Ib), wherein R ¹⁷ is-CH ₃ . In another embodiment are compounds of formula (I), (Ia) or (Ib), wherein R ¹⁸ Is H. In another embodiment are compounds of formula (I), (Ia) or (Ib), wherein R ⁵ Is H. In another embodiment are compounds of formula (I), (Ia) or (Ib), wherein R ⁴ Is H. In another embodiment are compounds of formula (I), (Ia) or (Ib), wherein R ⁴ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (I), (Ia) or (Ib), wherein R ⁴ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (I), (Ia) or (Ib) wherein R ⁴ And R ⁵ And the carbon atoms to which they are attached form a cyclopropyl ring. In another embodiment are compounds of formula (I), (Ia) or (Ib), wherein R ⁹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (I), (Ia) or (Ib),wherein R is ⁹ is-CH ₃ . In another embodiment are compounds of formula (I), (Ia) or (Ib) having the structure of formula (Ic):

in another embodiment are compounds of formula (I) or (Ia) - (Ic) wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-OR ²³ . In another embodiment are compounds of formula (I) or (Ia) - (Ic), wherein R ¹¹ is-CH ₂ CH ₂ And (5) OH. In another embodiment are compounds of formula (I) or (Ia) - (Ic) wherein R ¹¹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (I) or (Ia) - (Ic), wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (I) or (Ia) - (Ic), wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-NH ₂ . In another embodiment are compounds of formula (I) or (Ia) - (Ic), wherein R ¹¹ is-CH ₂ NH ₂ . In another embodiment are compounds of formula (I) or (Ia) - (Ic), wherein R ¹¹ is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (I) or (Ia) - (Ic) wherein R ¹¹ is-CH ₂ CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (I) or (Ia) - (Ic), wherein R ¹¹ is-CH ₂ CH ₂ CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (I) or (Ia) - (Ic), wherein R ¹ And R ² Each independently is H or- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (I) or (Ia) - (Ic), wherein R ¹ And R ² Each independently is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (I) or (Ia) - (Ic), wherein R ¹ And R ² Each is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (I) or (Ia) - (Ic), wherein R ¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² And R is ² Is H. In another embodiment are compounds of formula (I) or (Ia) - (Ic), wherein R ¹ is-CH ₂ CH ₂ NH ₂ And R is ² Is H. In another embodiment are compounds of formula (I) or (Ia) - (Ic), wherein R ¹ Is H and R ² Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (I) or (Ia) - (Ic), wherein R ¹ Is H and R ² is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (I) or (Ia) - (Ic), wherein R ¹ Is H and R ² Is H. In another embodiment are compounds of formula (I) or (Ia) - (Ic) having the structure of formula (Id):

wherein R is ¹¹ is-CH ₂ CH ₂ NH ₂ or-CH ₂ CH ₂ CH ₂ NH ₂ 。

In one aspect, described herein is a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

wherein:

R ¹ and R ² Are each independently H, - (C) ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-OR ²³ 、-CH ₂ CH(OH)CH ₂ NH ₂ 、-CH ₂ CH (Heterocyclylalkyl) CH ₂ NH ₂ 、-CH ₂ C(O)NH ₂ 、-CH ₂ C(O)N(H)CH ₂ CN、-(C ₁ -C ₆ ) alkyl-C (O) OR ²³ 、-(C ₁ -C ₆ ) alkyl-NR ²¹ R ²² 、-(C ₁ -C ₆ ) alkyl-C (O) NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) alkyl-N (R) ²³ )C(O)(C ₁ -C ₆ ) Alkyl radical NR ²¹ R ²² 、-(C ₁ -C ₆ ) alkyl-N (R) ²³ )C(O)(C ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-C (O) N (R) ²³ )(C ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-C (O) N (R) ²³ )(C ₁ -C ₆ ) Alkyl-heterocycloalkyl, - (C) ₁ -C ₆ ) alkyl-NR ²³ C(＝NH)NR ²¹ R ²² 、-(C ₁ -C ₆ ) alkyl-NR ²³ C(＝NH)R ²³ 、-(C ₁ -C ₆ ) Alkyl- [ (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² ] ₂ 、-(C ₁ -C ₆ ) Heteroalkyl or optionally substituted heterocycloalkyl;

R ³ is H or- (C) ₁ -C ₆ ) An alkyl group;

R ⁵ is H or- (C) ₁ -C ₆ ) An alkyl group;

R ⁶ 、R ⁷ and R ⁸ Each independently is H or- (C) ₁ -C ₆ ) An alkyl group;

R ¹⁰ is H or- (C) ₁ -C ₆ ) An alkyl group;

R ¹¹ and R ¹² Each independently is H, -NH ₂ 、-(C ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-OR ²³ 、-(C ₁ -C ₆ ) alkyl-SR ²³ 、-(C ₁ -C ₆ ) alkyl-C (O) OR ²³ 、-(C ₁ -C ₆ ) alkyl-NR ²¹ R ²² 、-(C ₁ -C ₆ ) alkyl-NR ²³ OR ²³ 、-(C ₁ -C ₆ ) alkyl-NHC (O) NR ²³ OR ²³ 、-(C ₁ -C ₆ ) alkyl-O- (C) ₁ -C ₆ ) alkyl-NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) alkyl-CN, - (C) ₁ -C ₆ ) alkyl-NR ²³ C(O)R ²³ 、-(C ₁ -C ₆ ) alkyl-C (O) NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) heteroalkyl-CO ₂ H、-(C ₁ -C ₆ ) alkyl-S (O) (C) ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-N (H) CH = NH, - (C) ₁ -C ₆ ) alkyl-C (NH) ₂ )＝NH、-(C ₁ -C ₆ ) alkyl-N (H) C (= NH) NH ₂ 、-(C ₁ -C ₆ ) alkyl-N (H) S (O) ₂ NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) alkyl-N (H) S (O) ₂ (C ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-N (H) -C (O) NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) Alkyl C (O) N (H) [ optionally substituted (C) ₂ -C ₆ ) Alkyl radical]-OR ²³ 、-(C ₁ -C ₆ ) Alkyl N (H) C (O) (C) ₁ -C ₆ ) alkyl-OR ²³ 、-(C ₁ -C ₆ ) Alkyl C (O) N (H) heterocycloalkyl, - (C) ₁ -C ₆ ) Alkyl C (O) NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) alkyl-N (H) -C (O) - (C) ₁ -C ₆ ) alkyl-NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) alkyl-N (H) - (C) ₁ -C ₆ ) Alkyl C (O) NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) Alkyl-heterocycloalkyl, optionally substitutedOf (C) ₁ -C ₆ ) alkyl-N (H) heterocycloalkyl or- (C) ₁ -C ₆ ) Alkyl-heteroaryl;

R ¹³ and R ¹⁴ Each independently of the other is H, -NH ₂ 、-(C ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-OR ²³ 、-(C ₁ -C ₆ ) alkyl-SR ²³ 、-(C ₁ -C ₆ ) alkyl-C (O) OR ²³ 、-(C ₁ -C ₆ ) alkyl-NR ²¹ R ²² 、-(C ₁ -C ₆ ) alkyl-CN, - (C) ₁ -C ₆ ) alkyl-C (O) NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) alkyl-N (H) C (NH) NH ₂ 、-(C ₁ -C ₆ ) Alkyl-heterocycloalkyl or- (C) ₁ -C ₆ ) Alkyl-heteroaryl;

or R ¹³ And R ¹⁹ Combine to form an optionally substituted heterocycloalkyl ring; and R is ¹⁴ Is H;

R ¹⁵ 、R ¹⁶ 、R ¹⁷ 、R ¹⁸ and R ¹⁹ Are each independently H, - (C) ₁ -C ₆ ) Alkyl, - (C) ₃ -C ₆ ) Cycloalkyl, - (C) ₁ -C ₆ ) alkyl-OR ²³ 、-(C ₁ -C ₆ ) alkyl-C (O) OR ²³ Or- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² ；

y is a bond, -O-, -S-, optionally substituted- (C) ₁ -C ₆ ) Alkyl-, - (C) ₂ -C ₆ ) Alkenyl-, - (C) ₂ -C ₆ ) Alkynyl, - (C) ₁ -C ₆ ) alkyl-N (R) ²⁴ )(C ₁ -C ₆ ) Alkyl-, -O- (C) ₁ -C ₆ ) Alkyl-, -O (C) ₆ -C ₁₀ ) Aryl-, -N (R) ²⁴ )(C ₁ -C ₆ ) Alkyl-, -N (R) ²⁴ )SO ₂ (C ₁ -C ₆ ) Alkyl-, -N (R) ²⁴ )C(O)(C ₁ -C ₆ ) Alkyl-, -C (O) (C) ₁ -C ₆ ) Alkyl-, -S (C) ₁ -C ₆ ) Alkyl-, -SO ₂ (C ₁ -C ₆ ) Alkyl-, -C (O) NH (C) ₁ -C ₆ ) Alkyl-, optionally substituted- (C) ₃ -C ₇ ) Cycloalkyl-, optionally substituted-C (O) N (R) ²⁴ ) Aryl-, optionally substituted-N (R) ²⁴ ) C (O) aryl-, optionally substituted-N (R) ²⁴ )SO ₂ Aryl-, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

each R ²¹ And R ²² Independently of one another is H, - (C) ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) Heteroalkyl, - (C) ₁ -C ₆ ) alkyl-CO ₂ H、-C(O)(C ₁ -C ₆ ) Alkyl, -C (O) N (R) ³¹ ) ₂ or-SO ₂ N(R ³¹ ) ₂ (ii) a Or R ²¹ And R ²² And the nitrogen atom to which they are attached form a heterocycloalkyl ring;

each R ²³ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

each R ²⁴ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

each R ²⁷ Independently halogen, -NR ²³ R ²⁴ 、-NHC(O)R ²³ 、-NHC(O)NR ²³ R ²⁴ Nitro, hydroxy, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted- (C) ₁ -C ₆ ) Heteroalkyl, optionally substituted- (C) ₁ -C ₆ ) Heteroalkyloxy, optionally substituted- (C) ₁ -C ₆ ) Heteroalkylamino, - (C) ₁ -C ₆ ) Alkoxy, -C (O) (C) ₁ -C ₆ ) Alkyl or-S (O) ₂ (C ₁ -C ₆ ) An alkyl group;

each R ²⁸ Independently halogen, -NR ²³ R ²⁴ 、-NHC(O)R ²³ 、-NHC(O)NR ²³ R ²⁴ Nitro, hydroxy, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted- (C) ₁ -C ₆ ) Heteroalkyl, optionally substituted- (C) ₁ -C ₆ ) Heteroalkyloxy, optionally substituted- (C) ₁ -C ₆ ) Heteroalkylamino radical, - (C) ₁ -C ₆ ) Alkoxy, -C (O) (C) ₁ -C ₆ ) Alkyl or-S (O) ₂ (C ₁ -C ₆ ) An alkyl group;

n is 0 or 1;

p is 0, 1 or 2; and is provided with

q is 0, 1 or 2.

In another embodiment are compounds of formula (II) having the structure of formula (IIa):

in another embodiment are compounds of formula (II) or (IIa), wherein R ⁶ 、R ⁷ And R ⁸ Is H. In another embodiment are compounds of formula (II) or (IIa) wherein R ¹⁵ And R ¹⁶ Is H. In another embodiment are compounds of formula (II) or (IIa) having the structure of formula (IIb):

in another embodiment are compounds of formula (II), (IIa) or (IIb), wherein R ¹⁸ Is H. In another embodiment are compounds of formula (II), (IIa) or (IIb), wherein R ¹⁹ Is H. In another embodiment are compounds of formula (II), (IIa) or (IIb) wherein R ¹⁷ is-CH ₃ . In another embodiment are compounds of formula (II), (IIa) or (IIb), wherein R ⁵ Is H. In another embodiment are compounds of formula (II), (IIa) or (IIb), wherein R ⁴ Is H. In another embodiment are compounds of formula (II), (IIa) or (IIb), wherein R ⁴ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment of formula (II), (IIa)) Or (IIb) compound, wherein R ⁴ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (II), (IIa) or (IIb), wherein R ⁴ And R ⁵ And the carbon atoms to which they are attached form a cyclopropyl ring. In another embodiment are compounds of formula (II), (IIa) or (IIb), wherein R ⁹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (II), (IIa) or (IIb), wherein R ⁹ is-CH ₃ . In another embodiment are compounds of formula (II), (IIa) or (IIb) having the structure of formula (IIc):

Wherein R is ¹ And R ² Each independently is H or-CH ₂ CH ₂ NH ₂ 。

In another embodiment are compounds of formula (II) or (IIa) - (IIc), wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-OR ²³ . In another embodiment are compounds of formula (II) or (IIa) - (IIc), wherein R ¹¹ is-CH ₂ CH ₂ And (5) OH. In another embodiment are compounds of formula (II) or (IIa) - (IIc), wherein R ¹¹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (II) or (IIa) - (IIc), wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (II) or (IIa) - (IIc), wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-NH ₂ . In another embodiment are compounds of formula (II) or (IIa) - (IIc), wherein R ¹¹ is-CH ₂ NH ₂ . In another embodiment are compounds of formula (II) or (IIa) - (IIc), wherein R ¹¹ is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (II) or (IIa) - (IIc), wherein R ¹¹ is-CH ₂ CH ₂ CH ₂ NH ₂ . In another embodiment of formula (II) or (II)IIa) to IIc), wherein R ¹¹ is-CH ₂ CH ₂ CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (II) or (IIa) - (IIc), wherein R ¹³ Is- (C) ₁ -C ₆ ) alkyl-OR ²³ . In another embodiment are compounds of formula (II) or (IIa) - (IIc), wherein R ¹³ is-CH ₂ And (5) OH. In another embodiment are compounds of formula (II) or (IIa) - (IIc), wherein R ¹³ is-CH ₂ CH ₂ And (5) OH. In another embodiment are compounds of formula (II) or (IIa) - (IIc) having the structure of formula (IId):

in another embodiment are compounds of formula (II) or (IIa) - (IId) wherein R ¹⁷ is-CH ₃ . In another embodiment are compounds of formula (II) or (IIa) - (IId), wherein R ⁵ Is H. In another embodiment are compounds of formula (II) or (IIa) - (IId), wherein R ⁴ Is H. In another embodiment are compounds of formula (II) or (IIa) - (IId) wherein R ⁴ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (II) or (IIa) - (IId), wherein R ⁴ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (II) or (IIa) - (IId) wherein R ⁴ And R ⁵ And the carbon atoms to which they are attached form a cyclopropyl ring. In another embodiment are compounds of formula (II) or (IIa) - (IId) wherein R ⁹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (II) or (IIa) - (IId), wherein R ⁹ is-CH ₃ . In another embodiment are compounds of formula (II) or (IIa) - (IId), wherein R ¹ And R ² Each independently is H or- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (II) or (IIa) - (IId), wherein R ¹ And R ² Each independently is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (II) or (IIa) - (IId), wherein R ¹ And R ² Each is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (II) or (IIa) - (IId), wherein R ¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² And R is ² Is H. In another embodiment are compounds of formula (II) or (IIa) - (IId) wherein R ¹ is-CH ₂ CH ₂ NH ₂ And R is ² Is H. In another embodiment are compounds of formula (II) or (IIa) - (IId), wherein R ¹ Is H and R ² Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (II) or (IIa) - (IId), wherein R ¹ Is H and R ² is-CH ₂ CH ₂ NH ₂ . In another embodiment is a compound of formula (II) or (IIa) - (IId) having the structure of formula (IIe):

wherein R is ¹ And R ² Each independently is H or-CH ₂ CH ₂ NH ₂ 。

In another embodiment are compounds of formula (I), (Ia) - (Id), (II), or (IIa) - (IIe) wherein X is optionally substituted aryl. In another embodiment are compounds of formula (I), (Ia) - (Id), (II), or (IIa) - (IIe) wherein X is optionally substituted phenyl. In another embodiment are compounds of formula (I), (Ia) - (Id), (II), or (IIa) - (IIe) wherein X is optionally substituted heteroaryl. In another embodiment are compounds of formula (I), (Ia) - (Id), (II), or (IIa) - (IIe) wherein X is disubstituted heteroaryl. In another embodiment are compounds of formula (I), (Ia) - (Id), (II), or (IIa) - (IIe) wherein X is heteroaryl disubstituted with substituents each independently selected from the group consisting of halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl radical、OR ²³ 、-NR ²⁵ R ²⁶ and-NO ₂ . In another embodiment are compounds of formula (I), (Ia) - (Id), (II), or (IIa) - (IIe) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituents disubstituted heteroaryl. In another embodiment are compounds of formula (I), (Ia) - (Id), (II), or (IIa) - (IIe) wherein X is heteroaryl disubstituted with methyl. In another embodiment are compounds of formula (I), (Ia) - (Id), (II), or (IIa) - (IIe) wherein X is pyridyl disubstituted with substituents each independently selected from halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In another embodiment are compounds of formula (I), (Ia) - (Id), (II), or (IIa) - (IIe) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituent disubstituted pyridyl. In another embodiment are compounds of formula (I), (Ia) - (Id), (II), or (IIa) - (IIe) wherein X is pyridyl disubstituted with methyl. In another embodiment are compounds of formula (I), (Ia) - (Id), (II), or (IIa) - (IIe) wherein X is pyrimidinyl disubstituted with substituents each independently selected from halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In another embodiment are compounds of formula (I), (Ia) - (Id), (II), or (IIa) - (IIe) wherein X is selected from each independently- (C) ₁ -C ₆ ) Alkyl substituent disubstituted pyrimidinyl. In another embodiment are compounds of formula (I), (Ia) - (Id), (II), or (IIa) - (IIe) wherein X is pyrimidinyl disubstituted with methyl. In another embodiment are compounds of formula (I), (Ia) - (Id), (II), or (IIa) - (IIe) wherein X is optionally substituted- (C) ₁ -C ₆ ) An alkyl radical. In another embodiment are compounds of formula (I), (Ia) - (Id), (II), or (IIa) - (IIe) wherein Y is optionally substituted aryl. In another embodiment are compounds of formula (I), (Ia) - (Id), (II) or (IIa) - (IIe)Wherein Y is optionally substituted phenyl. In another embodiment are compounds of formula (I), (Ia) - (Id), (II), or (IIa) - (IIe) wherein Y is optionally substituted heteroaryl. In another embodiment are compounds of formula (I), (Ia) - (Id), (II), or (IIa) - (IIe) wherein Y is optionally substituted- (C) ₁ -C ₆ ) An alkyl group-. In another embodiment are compounds of formula (I), (Ia) - (Id), (II), or (IIa) - (IIe) wherein Y is optionally substituted (C) ₃ -C ₇ ) Cycloalkyl-. In another embodiment are compounds of formula (I), (Ia) - (Id), (II), or (IIa) - (IIe) wherein Y is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (I), (Ia) - (Id), (II), or (IIa) - (IIe) wherein Y is-O-. In another embodiment are compounds of formula (I), (Ia) - (Id), (II), or (IIa) - (IIe) wherein Y is- (C) ₂ -C ₆ ) Alkynyl. In another embodiment are compounds of formula (I), (Ia) - (Id), (II), or (IIa) - (IIe) wherein Y is-O- (C) ₁ -C ₆ ) An alkyl group-. In another embodiment are compounds of formula (I), (Ia) - (Id), (II), or (IIa) - (IIe) wherein Y is a bond. In another embodiment are compounds of formula (I), (Ia) - (Id), (II), or (IIa) - (IIe) wherein Z is- (C) ₁ -C ₁₂ ) An alkyl group. In another embodiment are compounds of formula (I), (Ia) - (Id), (II), or (IIa) - (IIe) wherein Z is n-butyl, isobutyl, or tert-butyl. In another embodiment are compounds of formula (I), (Ia) - (Id), (II), or (IIa) - (IIe) wherein Z is-O- (C) ₁ -C ₁₂ ) An alkyl group. In another embodiment are compounds of formula (I), (Ia) - (Id), (II), or (IIa) - (IIe) wherein Z is-O- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (I), (Ia) - (Id), (II), or (IIa) - (IIe) wherein Z is- (C) ₂ -C ₁₂ ) An alkenyl group. In another embodiment are compounds of formula (I), (Ia) - (Id), (II), or (IIa) - (IIe) wherein Z is optionally substituted aryl. In another embodiment are compounds of formula (I), (Ia) - (Id), (II), or (IIa) - (IIe) wherein Z is optionally substituted phenyl. In another embodiment are compounds of formula (I), (Ia) - (Id), (II), or (IIa) - (IIe) wherein Z is independently selected from- (C) ₁ -C ₈ ) Alkyl substituents are monosubstituted or disubstituted phenyl. In another embodiment are compounds of formula (I), (Ia) - (Id), (II) or (IIa) - (IIe) wherein Z is phenyl monosubstituted with n-butyl, isobutyl or tert-butyl. In another embodiment are compounds of formula (I), (Ia) - (Id), (II) or (IIa) - (IIe) wherein Z is phenyl monosubstituted with n-butyl. In another embodiment are compounds of formula (I), (Ia) - (Id), (II) or (IIa) - (IIe) wherein Z is phenyl monosubstituted with isobutyl. In another embodiment are compounds of formula (I), (Ia) - (Id), (II) or (IIa) - (IIe) wherein Z is phenyl monosubstituted with tert-butyl. In another embodiment are compounds of formula (I), (Ia) - (Id), (II), or (IIa) - (IIe) wherein Z is optionally substituted heteroaryl. In another embodiment are compounds of formula (I), (Ia) - (Id), (II), or (IIa) - (IIe) wherein Z is optionally substituted- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (I), (Ia) - (Id), (II), or (IIa) - (IIe) wherein Z is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (I), (Ia) - (Id), (II), or (IIa) - (IIe) wherein Z is halo. In another embodiment are compounds of formula (I), (Ia) - (Id), (II) or (IIa) - (IIe) wherein Z-Y-X-is notIn another embodiment is a compound of formula (I), (Ia) - (Id), (II), or (IIa) - (IIe), wherein the compound is selected from any of the compounds in table 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In one aspect, described herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable prodrug thereof, and a pharmaceutically acceptable excipient.

In one aspect, described herein is the use of a compound disclosed herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof, in the manufacture of a medicament for treating a bacterial infection in a patient.

In one aspect, described herein is a method of treating a bacterial infection in a mammal comprising administering to the mammal an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof, at a frequency and for a duration sufficient to provide a beneficial effect to the mammal

In one aspect, described herein is a method of treating a lepB-mediated infection in a mammal comprising administering to the mammal an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof, at a frequency and for a duration sufficient to provide a beneficial effect to the mammal.

Is incorporated by reference

All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

Detailed Description

Definition of

As used in the specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise.

As used herein, the term "about" when referring to an index value or range allows for a degree of variability in that value or range, e.g., within 10% or within 5% of the stated value or the stated limit range.

All compositional percentages are given in weight percent unless otherwise indicated.

All polymers have weight average molecular weights unless otherwise indicated.

As used herein, "individual" (as in a subject being treated) refers to both mammals and non-mammals. Mammals include, for example, humans; non-human primates, such as apes and monkeys; and non-primates such as dogs, cats, cows, horses, sheep, and goats. Non-mammals include, for example, fish and birds.

The terms "disease" or "disorder" or "adverse condition" are used interchangeably and are used to refer to a disease or condition that is: wherein the bacterial SPase play a role in biochemical mechanisms involved in a disease or adverse condition such that a therapeutically beneficial effect can be achieved by acting on the enzyme. "acting on" an SPase may include binding to and/or inhibiting the biological activity of the SPase.

The expression "effective amount" when used to describe treatment of a subject having a disorder refers to an amount of a compound described herein that is effective to inhibit or otherwise act on a SPase in the tissue of the subject, wherein the SPase associated with the disorder is active, wherein such inhibition or other action occurs to a sufficient extent to produce a beneficial therapeutic effect.

The term "substantially" as used herein means completely or almost completely; for example, a composition that is "substantially free" of a component is either free of that component or contains trace amounts of that component such that any relevant functional properties of the composition are not affected by the presence of the trace amounts, or the compound is "substantially pure" meaning that only negligible trace amounts of impurities are present.

As used herein, "treating" or "treatment" refers to alleviating a symptom associated with a disorder or disease, or inhibiting the further progression or worsening of the symptom, or preventing the disease or disorder, or curing the disease or disorder. Similarly, as used herein, an "effective amount" or "therapeutically effective amount" of a compound refers to an amount of the compound that completely or partially alleviates a symptom associated with a disorder or condition, or halts or delays further progression or worsening of the symptom, or prevents the disorder or condition, or provides prophylaxis of the disorder or condition. Specifically, a "therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic effect. A therapeutically effective amount also refers to an amount wherein the therapeutically beneficial effect outweighs any toxic or detrimental effects of the compounds described herein.

"chemically feasible" means a bonding arrangement or compound that does not violate commonly understood rules of organic structure; for example, structures that contain in some cases a pentavalent carbon atom that does not occur in nature within the scope of the claims are to be understood as not being within the scope of the claims. The structures disclosed herein are intended to include only "chemically feasible" structures in all embodiments herein, and no structure listed as chemically infeasible (e.g., in a structure shown as a variable atom or group) is intended to be disclosed or claimed herein.

When a substituent is designated as one or more atoms "or bonds" of a designated identity, the configuration is said to be when the substituent is a "bond", the groups immediately adjacent to the designated substituent are directly connected to each other in a chemically feasible bonding configuration.

Unless a particular stereochemistry or isomeric form is specifically indicated, all chiral, diastereomeric, racemic forms of a structure are intended to be encompassed. The compounds described herein may include optical isomers at any or all asymmetric atoms (apparent from the description) enriched or resolved in any degree of enrichment. Both racemic and diastereomeric mixtures, as well as individual optical isomers, may be separated or synthesized so as to be substantially free of the corresponding enantiomer or diastereomer, and these are within the scope of the invention.

Isotopic forms of a molecule that contain one or more atoms in a distribution different from the naturally occurring isotopes of atoms in nature are referred to as "isotopically labeled forms" of the molecule. Unless a particular isotopic form of an atom is indicated, all isotopic forms of an atom are alternatively encompassed in the composition of any molecule. For example, any hydrogen atom or collection thereof within a molecule can be in any isotopic form of hydrogen, i.e., protium (protium) in any combination ¹ H) Deuterium (1) ² H) Or tritium ( ³ H) In that respect Similarly, any carbon atom or collection thereof within a molecule can be any isotopic form of carbon, such as ¹¹ C、 ¹² C、 ¹³ C or ¹⁴ C, or any nitrogen atom or collection thereof within a molecule, may be any isotopic form of nitrogen, such as ¹³ N、 ¹⁴ N or ¹⁵ And N is added. The molecule may comprise the moietyAny combination of isotopic forms of the constituent atoms of the molecule, wherein the isotopic form of each atom forming the molecule is independently selected. In a multi-molecular sample of a compound, not every individual molecule necessarily has the same isotopic composition. For example, a sample of a compound may include molecules containing various isotopic compositions, such as in tritium or ¹⁴ C the radiolabeled sample contains radioactive atoms only in a certain portion of the molecular pool that constitutes the macroscopic sample. It will also be appreciated that many elements which are not artificially enriched in their isotopes are mixtures of naturally occurring isotopic forms, such as ¹⁴ N and ¹⁵ N， ³² s and ³⁴ s, and so on. The molecules described herein are defined to include isotopic forms of all of their constituent elements at various positions in the molecule. It is well known in the art that isotopically labeled compounds can be prepared by conventional chemical synthetic methods in addition to substituting isotopically labeled precursor molecules. The radiolabeled or stabilized isotope may be obtained by any method known in the art, such as by neutron absorption of a precursor nuclide in a nuclear reactor, by a cyclotron reaction, or by isotope separation (such as by mass spectrometry). Isotopic forms are incorporated into the precursors as needed for any particular synthetic route. For example, ¹⁴ C and ³ h may be prepared using neutrons generated in a nuclear reactor. After the transformation of the nucleus, the nucleus is transformed, ¹⁴ c and ³ h is incorporated into the precursor molecule as needed and is subsequently further described.

The term "amino protecting group" or "N-protected" as used herein refers to those groups that are used to protect an amino group from undesired reactions during synthesis and that can be subsequently removed to reveal the amine. Commonly used amino protecting Groups are disclosed in Protective Groups in Organic Synthesis, greene, t.w.; wuts, p.g.m., john Wiley & Sons, new York, NY, (third edition, 1999). Amino protecting groups include: acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, o-nitrophenoxyacetyl, α -chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl, and the like; alkoxy-carbonyl or aryloxy-carbonyl groups (which form carbamates with protected amines) such as benzyloxycarbonyl (Cbz), p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3, 4-dimethoxybenzyloxycarbonyl, 3, 5-dimethoxybenzyloxycarbonyl, 2, 4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4, 5-dimethoxybenzyloxycarbonyl, 3,4, 5-trimethoxybenzyloxycarbonyl, 1- (p-biphenylyl) -1-methylethoxycarbonyl, α -dimethyl-3, 5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butoxycarbonyl (Boc), diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl (Alloc), 2-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl (Teoc), phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl (Fmoc), cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, and the like; aralkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl, and the like; and silyl groups such as trimethylsilyl and the like. Amino protecting groups also include cyclic amino protecting groups such as phthaloyl and dithiosuccinimidyl groups that incorporate the amino nitrogen into the heterocycle. Typically, amino protecting groups include formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, alloc, teoc, benzyl, fmoc, boc and Cbz. The selection and use of suitable amino protecting groups for the synthesis task to be carried out is well within the skill of the ordinarily skilled artisan.

The term "hydroxyl protecting group" or "O-protected" as used herein refers to those groups that are used to protect OH groups from undesired reactions during synthesis and that can be subsequently removed to reveal the amine. Commonly used hydroxy protecting Groups are disclosed in Protective Groups in Organic Synthesis, greene, t.w.; wuts, p.g.m., john Wiley & Sons, new York, NY, (third edition, 1999). Hydroxyl protecting groups include: acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, o-nitrophenoxyacetyl, α -chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl, and the like; acyloxy groups (which form carbamates with protected amines) such as benzyloxycarbonyl (Cbz), p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3, 4-dimethoxybenzyloxycarbonyl, 3, 5-dimethoxybenzyloxycarbonyl, 2, 4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4, 5-dimethoxybenzyloxycarbonyl, 3,4, 5-trimethoxybenzyloxycarbonyl, 1- (p-biphenylyl) -1-methylethoxycarbonyl, α -dimethyl-3, 5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butoxycarbonyl (Boc), diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl (Alloc), 2-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl (Teoc), phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl (Fmoc), cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, and the like; aralkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl, and the like; and silyl groups such as trimethylsilyl and the like. The selection and use of suitable hydroxyl protecting groups for the synthesis task to be carried out is well within the skill of the ordinarily skilled artisan.

In general, "substituted" means that in an organic group as defined herein, one or more bonds to a hydrogen atom contained therein are replaced by one or more bonds to a non-hydrogen atom such as, but not limited to: halogen (i.e., F, cl, br, and I); oxygen atoms in groups such as hydroxyl groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo (carbonyl) groups, carboxyl groups (including carboxylic acids, carboxylates, and carboxylates); sulfur atoms in groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; such as amines, hydroxylamines, nitriles, nitro groups, N-oxidesNitrogen atoms in the group of hydrazides, azides and enamines; and other heteroatoms in various other groups. Non-limiting examples of substituents that may be bonded to a substituted carbon (or other) atom include: F. cl, br, I, OR ', OC (O) N (R') ₂ 、CN、NO、NO ₂ 、ONO ₂ Azido group, CF ₃ 、OCF ₃ R ', O (oxo), S (thio), C (O), S (O), methylenedioxy, ethylenedioxy, N (R') ₂ 、SR’、SOR’、SO ₂ R’、SO ₂ N(R’) ₂ 、SO ₃ R’、C(O)R’、C(O)C(O)R’、C(O)CH ₂ C(O)R’、C(S)R’、C(O)OR’、OC(O)R’、C(O)N(R’) ₂ 、OC(O)N(R’) ₂ 、C(S)N(R’) ₂ 、(CH ₂ ) _0-2 N(R’)C(O)R’、(CH ₂ ) _0-2 N(R’)N(R’) ₂ 、N(R’)N(R’)C(O)R’、N(R’)N(R’)C(O)OR’、N(R’)N(R’)CON(R’) ₂ 、N(R’)SO ₂ R’、N(R’)SO ₂ N(R’) ₂ 、N(R’)C(O)OR’、N(R’)C(O)R’、N(R’)C(S)R’、N(R’)C(O)N(R’) ₂ 、N(R’)C(S)N(R’) ₂ 、N(COR’)COR’、N(OR’)R’、C(＝NH)N(R’) ₂ C (O) N (OR ') R ' OR C (= NOR ') R ', wherein R ' may be hydrogen OR a carbon-based moiety, and wherein the carbon-based moiety itself may be further substituted.

When a substituent is monovalent, such as F or Cl, it is bonded to the atom it is substituted for by a single bond. When a substituent is more than monovalent, such as divalent O, it may be bonded to the atom it is substituted for by more than one bond, i.e. the divalent substituent is bonded by a double bond; for example, C substituted with O forms a carbonyl group, i.e., C = O, which can also be written as "CO", "C (O)" or "C (= O)", where C is double bonded to O. When a carbon atom is substituted with a doubly bonded oxygen (= O) group, the oxygen substituent is referred to as an "oxo" group. When a divalent substituent such as NR is double bonded to a carbon atom, the resulting C (= NR) group is referred to as an "imino" group. When a divalent substituent such as S is double bonded to a carbon atom, the resulting C (= S) group is referred to as a "thiocarbonyl" group.

In addition, divalent substituents are, for example, O, S, C (O), S (O) or S (O) ₂ May be attached to two different carbon atoms by two single bonds. For example, a divalent substituent O may be bonded to each of two adjacent carbon atoms to provide an epoxide group, or O may form a bridging ether group between adjacent or non-adjacent carbon atoms, referred to as an "oxo" group, e.g., bridging the 1, 4-carbon atoms of a cyclohexyl group to form [2.2.1 ] ]-oxabicyclic systems. In addition, any substituent may be substituted by a substituent such as (CH) ₂ ) _n Or (CR' ₂ ) _n (wherein n is a number of 1, 2, 3, or greater) is bonded to a carbon or other atom, and each R' is independently selected.

C (O) and S (O) ₂ The group may be bonded to one or two heteroatoms, such as nitrogen, rather than to carbon atoms. For example, when a C (O) group is combined with one carbon and one nitrogen atom, the resulting group is referred to as an "amide" or "carboxamide". When a C (O) group is bonded to two nitrogen atoms, the functional group is referred to as urea. When S (O) ₂ When a group is bonded to one carbon and one nitrogen atom, the resulting unit is referred to as a "sulfonamide". When S (O) ₂ When a group is bonded to two nitrogen atoms, the resulting unit is referred to as a "sulfamate group".

Substituted alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups, as well as other substituted groups, also include groups in which one or more bonds to a hydrogen atom are replaced with one or more bonds (including double or triple bonds) to a carbon atom or heteroatom such as, but not limited to: the oxygen in the carbonyl (oxo), carboxyl, ester, amide, imide, carbamate, and urea groups, and the nitrogen in the imine, hydroxyimine, oxime, hydrazone, amidine, guanidine, and nitrile groups.

Substituted ring groups such as substituted cycloalkyl, aryl, heterocyclyl, and heteroaryl groups also include rings and fused ring systems in which the bond to a hydrogen atom is replaced by a bond to a carbon atom. Thus, substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups may also be substituted with alkyl, alkenyl and alkynyl groups as defined herein.

The term "ring system" as used herein means a moiety comprising one, two, three or more rings, which moiety may be substituted by an acyclic group or other ring system or both, and may be fully saturated, partially unsaturated, fully unsaturated or aromatic, and when a ring system includes more than one ring, the rings may be fused, bridged or spiro. As is well known in the art, "spiro" means a class of structures in which two rings are fused at a single tetrahedral carbon atom.

With respect to any group described herein as comprising one or more substituents, it is to be understood that such group does not contain any substitution or substitution pattern that is not sterically impractical and/or synthetically non-feasible. In addition, the compounds of the presently disclosed subject matter include all stereochemically isomeric forms resulting from the substitution of such compounds.

Selected substituents in the compounds described herein occur with some degree of recursion. In this context, "recursive substituent" means that the substituent may refer to another instance of itself or may refer to another instance of another substituent that itself refers to the first substituent. Because of the recursion of such substituents, in theory, a large number of substituents may be present in any given claim. It will be understood by those of ordinary skill in the art of pharmaceutical and organic chemistry that the total number of such substituents is reasonably limited by the desired properties of the target compound. By way of example, but not limitation, such properties include physical properties such as molecular weight, solubility, or log P, application properties such as activity against a predetermined target, and practical properties such as ease of synthesis.

Recursive substituents are contemplated aspects of the disclosed subject matter. One of ordinary skill in the art of pharmaceutical and organic chemistry understands the diversity of such substituents. To the extent that recursive substituents are present in the claims of the disclosed subject matter, the total should be determined as described above.

Alkyl groups include straight and branched chain alkyl and cycloalkyl groups having from 1 to about 20 carbon atoms, typically from 1 to 12 carbon atoms, or in some embodiments, from 1 to 8 carbon atoms. Examples of the straight-chain alkyl group include those having 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl. Examples of branched alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl, isoamyl, and 2, 2-dimethylpropyl. As used herein, the term "alkyl" encompasses n-, iso-and trans-iso-alkyl groups as well as other branched forms of alkyl groups. Representative substituted alkyl groups may be substituted one or more times with any of the groups listed above, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halo groups.

Unless otherwise specified, the term "alkylene" means a straight chain saturated divalent hydrocarbon group of one to six carbon atoms or a branched saturated divalent hydrocarbon group of one to six carbon atoms, such as methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.

The term "carbonyl" refers to C = O.

The terms "carboxy" and "hydroxycarbonyl" refer to COOH.

Cycloalkyl is a cyclic alkyl group such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, cycloalkyl groups may have 3 to about 8-12 ring members, while in other embodiments the number of ring carbon atoms ranges from 3 to 4, 5, 6, or 7. Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl (camphenyl), isobornenyl (isocamphenyl), and carenyl (carenyl), fused rings such as, but not limited to, decahydronaphthyl, and the like. Cycloalkyl also includes rings substituted with straight or branched chain alkyl as defined above. Representative substituted cycloalkyl groups may be mono-substituted or more than once substituted, such as, but not limited to, 2-, 2,3-, 2,4-, 2,5-, or 2, 6-disubstituted cyclohexyl or mono-, di-, or tri-substituted norbornyl or cycloheptyl, and may be substituted with, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halo groups. The term "cycloalkenyl" alone or in combination denotes cyclic alkenyl.

The terms "carbocyclic", "carbocyclyl" and "carbocycle" denote ring structures in which the ring atoms are carbon, such as cycloalkyl or aryl. In some embodiments, carbocycles have 3 to 8 ring members, while in other embodiments the number of ring carbon atoms is 4, 5, 6 or 7. Unless specifically stated otherwise, carbocyclic rings may be substituted with up to N-1 substituents, where N is the size of the carbocyclic ring, for example by alkyl, alkenyl, alkynyl, amino, aryl, hydroxy, cyano, carboxy, heteroaryl, heterocyclyl, nitro, thio, alkoxy and halogen groups or other groups as listed above. The carbocyclic ring may be a cycloalkyl ring, a cycloalkenyl ring, or an aryl ring. Carbocyclyl may be monocyclic or polycyclic, and if polycyclic, each ring may independently be a cycloalkyl, cycloalkenyl, or aryl ring.

(cycloalkyl) alkyl, also denoted cycloalkylalkyl, is an alkyl group as defined above in which a hydrogen or carbon bond of the alkyl group is replaced by a bond to a cycloalkyl group as defined above.

Alkenyl includes straight and branched alkyl groups and cyclic alkyl groups as defined above except that at least one double bond between two carbon atoms is present. Thus, alkenyl groups have from 2 to about 20 carbon atoms, typically from 2 to 12 carbons, or in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to, vinyl, -CH = CH (CH) ₃ )、-CH＝C(CH ₃ ) ₂ 、-C(CH ₃ )＝CH ₂ 、-C(CH ₃ )＝CH(CH ₃ )、-C(CH ₂ CH ₃ )＝CH ₂ Cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, hexadienyl, and the like.

Cycloalkenyl includes cycloalkyl groups having at least one double bond between 2 carbons. Thus, for example, cycloalkenyl includes, but is not limited to, cyclohexenyl, cyclopentenyl, and cyclohexadienyl. Cycloalkenyl groups can have from 3 to about 8-12 ring members, while in other embodiments the number of ring carbon atoms ranges from 3 to 5, 6, or 7. Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphene, isobornene, and carene groups, fused rings (such as, but not limited to, decahydronaphthyl groups), and the like, provided that they include at least one double bond within the ring. Cycloalkenyl also includes rings substituted with straight or branched chain alkyl groups as defined above.

(cycloalkenyl) alkyl is an alkyl group as defined above in which a hydrogen or carbon bond of the alkyl group is replaced by a bond linking a cycloalkenyl group as defined above.

Alkynyl includes straight and branched chain alkyl groups except that at least one triple bond between two carbon atoms is present. Thus, alkynyl groups have from 2 to about 20 carbon atoms, typically from 2 to 12 carbons, or in some embodiments, from 2 to or 8 carbon atoms. Examples include, but are not limited to, -C ≡ CH, -C ≡ C (CH) ₃ )、-C≡C(CH ₂ CH ₃ )、-CH ₂ C≡CH、-CH ₂ C≡C(CH ₃ ) and-CH ₂ C≡C(CH ₂ CH ₃ ) And so on.

Unless otherwise indicated, the term "heteroalkyl," by itself or in combination with another term, means a stable straight or branched chain alkyl group consisting of the stated number of carbon atoms and one or two heteroatoms selected from O, N and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom may be located anywhere in the heteroalkyl group, including between the remainder of the heteroalkyl group and the segment to which it is attached, as well as the most distal carbon atom attached to the heteroalkyl group. Examples include: -O-CH ₂ -CH ₂ -CH ₃ 、-CH ₂ -CH ₂ CH ₂ -OH、-CH ₂ -CH ₂ -NH-CH ₃ 、-CH ₂ -S-CH ₂ -CH ₃ 、-CH ₂ CH ₂ -S(＝O)-CH ₃ and-CH ₂ CH ₂ -O-CH ₂ CH ₂ -O-CH ₃ . Up to two heteroatoms may be consecutive, e.g., -CH ₂ -NH-OCH ₃ or-CH ₂ -CH ₂ -S-S-CH ₃ 。

A "cycloheteroalkyl" ring is a cycloalkyl ring containing at least one heteroatom. The cycloheteroalkyl ring may also be referred to as "heterocyclyl" as described below.

Unless otherwise indicated, the term "heteroalkenyl" by itself or in combination with another term means a stable straight or branched chain mono-or di-unsaturated hydrocarbon radical consisting of the specified number of carbon atoms and one or two heteroatoms selected from O, N and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. Up to two heteroatoms may be placed in succession. Examples include-CH = CH-O-CH ₃ 、-CH＝CH-CH ₂ -OH、-CH ₂ -CH＝N-OCH ₃ 、-CH＝CH-N(CH ₃ )-CH ₃ 、-CH ₂ -CH＝CH-CH ₂ -SH and-CH = CH-O-CH ₂ CH ₂ -O-CH ₃ 。

Aryl is a cyclic aromatic hydrocarbon that does not contain heteroatoms in the ring. Thus, aryl groups include, but are not limited to: phenyl, azulenyl, heptalenyl, biphenyl, indacenyl fluorenyl, phenanthryl, triphenylene, pyrenyl, tetracenyl,Phenyl, biphenyl alkenyl, anthracenyl and naphthyl. In some embodiments, the aryl group contains from about 6 to about 14 carbons in the ring portion of the group. As defined above, an aryl group may be unsubstituted or substituted. Representative substituted aryl groups may be mono-substituted or more than once substituted, such as but not limited to 2-, 3-, 4-, 5-, or 6-substituted phenyl or 2-8 substituted naphthyl, which may be substituted with carbon or non-carbon groups (such as those listed above).

An aralkyl group is an alkyl group as defined above in which a hydrogen or carbon bond of the alkyl group is replaced by a bond to an aryl group as defined above. Representative aralkyl groups include benzyl and phenethyl and fused (cycloalkylaryl) alkyl groups, such as 4-ethyl-indanyl. An aralkenyl group is an alkenyl group as defined above in which a hydrogen or carbon bond of the alkyl group is replaced by a bond to an aryl group as defined above.

Heterocyclyl groups or the term "heterocyclyl" includes aromatic and non-aromatic ring compounds containing 3 or more ring members, one or more of which may be substituted And the heteroatom is such as but not limited to N, O and S. Thus, a heterocyclyl group can be a cycloheteroalkyl or heteroaryl group, or any combination thereof (if polycyclic). In some embodiments, heterocyclyl groups include 3 to about 20 ring members, while other such groups have 3 to about 15 ring members. Is designated as C ₂ The heterocyclic group of the heterocyclic group may be a 5-membered ring having two carbon atoms and three heteroatoms, a 6-membered ring having two carbon atoms and four heteroatoms, or the like. Likewise, C ₄ The heterocyclic group may be a 5-membered ring having one heteroatom, a 6-membered ring having two heteroatoms, or the like. The number of carbon atoms plus the number of heteroatoms totals the total number of ring atoms. Heterocyclyl rings may also contain one or more double bonds. Heteroaryl rings are a specific embodiment of heterocyclyl groups. The term "heterocyclyl group" includes fused ring species, including those species that contain fused aromatic and non-aromatic groups. For example, dioxolanyl rings and benzodioxolyl ring systems (methylenedioxybenzene ring systems) are all heterocyclyl groups within the scope of what is referred to herein. The term also includes polycyclic ring systems containing heteroatoms such as, but not limited to, quinuclidinyl. As noted above, heterocyclyl groups may be unsubstituted or substituted. Heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thienyl, benzothienyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl (benzothiadiazolyl), imidazopyridinyl, isoxazolopyridinyl (isoxazolopyridinyl), thianaphthyl (thianaphtalenyl), purinyl, xanthine, adenine, guanine, quinolyl, isoquinolyl, tetrahydroquinolyl, quinoxalyl, and quinazolinyl. Representative substituted heterocyclyl groups may be mono-substituted or more than once substituted, such as but not limited to piperidinyl or quinolinyl, which is 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with groups such as those listed above 。

Heteroaryl is an aromatic ring compound containing 5 or more ring members in which one or more atoms are heteroatoms such as, but not limited to, N, O and S; for example, a heteroaryl ring can have from 5 to about 8-12 ring members. Heteroaryl is a variety of heterocyclic groups having aromatic electronic structures. Is designated as C ₂ The heteroaryl group of the heteroaryl group may be a 5-membered ring having two carbon atoms and three heteroatoms, a 6-membered ring having two carbon atoms and four heteroatoms, or the like. Likewise, C ₄ The heteroaryl group may be a 5-membered ring having one heteroatom, a 6-membered ring having two heteroatoms, or the like. The number of carbon atoms plus the number of heteroatoms totals the total number of ring atoms. Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, thienyl, benzothienyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthyl, purinyl, xanthine, adenine, guanine, quinolyl, isoquinolyl, tetrahydroquinolyl, quinoxalinyl, and quinazolinyl. Heteroaryl groups may be unsubstituted or substituted with groups as discussed above. Representative substituted heteroaryl groups may be substituted one or more times with groups as set forth above.

Additional examples of aryl and heteroaryl groups include, but are not limited to: phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl, anthracyl (1-anthracyl, 2-anthracyl, 3-anthracyl), thienyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl), indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindolyl, benzhydryl, acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1, 2, 3-triazol-1-yl, 1,2, 3-triazol-2-yl, 1,2, 3-triazol-4-yl, 1,2, 4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolylA group, 5-oxazolyl group), a thiazolyl group (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), a pyridyl group (2-pyridyl, 3-pyridyl, 4-pyridyl), a pyrimidyl group (2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 6-pyrimidyl), a pyrazinyl group, a pyridazinyl group (3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl), a quinolyl group (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), an isoquinolyl group (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo [ b ] b ]Furyl (2-benzo [ b ]]Furyl, 3-benzo [ b ]]Furyl, 4-benzo [ b ]]Furyl, 5-benzo [ b ]]Furyl, 6-benzo [ b ]]Furyl, 7-benzo [ b ]]Furyl), 2, 3-dihydro-benzo [ b ]]Furyl (2- (2, 3-dihydro-benzo [ b ]]Furyl), 3- (2, 3-dihydro-benzo [ b)]Furyl), 4- (2, 3-dihydro-benzo [ b ]]Furyl), 5- (2, 3-dihydro-benzo [ b ]]Furyl), 6- (2, 3-dihydro-benzo [ b)]Furyl), 7- (2, 3-dihydro-benzo [ b)]Furyl)), benzo [ b ]]Thienyl (2-benzo [ b ]]Thienyl, 3-benzo [ b ]]Thienyl, 4-benzo [ b ]]Thienyl, 5-benzo [ b ]]Thienyl, 6-benzo [ b ]]Thienyl, 7-benzo [ b ]]Thienyl), 2, 3-dihydro-benzo [ b ]]Thienyl (2- (2, 3-dihydro-benzo [ b ]]Thienyl), 3- (2, 3-dihydro-benzo [ b ]]Thienyl), 4- (2, 3-dihydro-benzo [ b ]]Thienyl), 5- (2, 3-dihydro-benzo [ b ]]Thienyl), 6- (2, 3-dihydro-benzo [ b ]]Thienyl), 7- (2, 3-dihydro-benzo [ b ]]Thienyl)), indolyl (1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazolyl (1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl, 8-benzimidazolyl), benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl), benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl (1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenzo [ b, f ] benzo ]Aza derivatives(5H-dibenzo [ b, f ]]Aza derivatives-1-yl, 5H-dibenzo [ b, f ]]Aza derivatives-2-yl, 5H-dibenzo [ b, f ]]Aza derivatives-3-yl, 5H-dibenzo [ b, f ]]Aza derivatives-4-yl, 5H-dibenzo [ b, f ]]Aza derivatives-5-yl), 10, 11-dihydro-5H-dibenzo [ b, f)]Aza derivatives(10, 11-dihydro-5H-dibenzo [ b, f)]Aza derivatives-1-yl, 10, 11-dihydro-5H-dibenzo [ b, f]Aza derivatives-2-yl, 10, 11-dihydro-5H-dibenzo [ b, f]Aza derivatives-3-yl, 10, 11-dihydro-5H-dibenzo [ b, f]Aza derivatives-4-yl, 10, 11-dihydro-5H-dibenzo [ b, f]Aza derivatives-5-yl) and the like.

Heterocycloalkyl is an alkyl group as defined above wherein a hydrogen or carbon bond of the alkyl group as defined above is replaced by a bond of a heterocyclyl group as defined above. Representative heterocycloalkyl groups include, but are not limited to, furan-2-ylmethyl, furan-3-ylmethyl, pyridin-3-ylmethyl, tetrahydrofuran-2-ylethyl, and indol-2-ylpropyl.

Heteroarylalkyl is an alkyl group as defined above in which a hydrogen or carbon bond of the alkyl group is replaced by a bond to a heteroaryl group as defined above.

The term "alkoxy" refers to an oxygen atom attached to an alkyl group (including cycloalkyl groups as defined above). Examples of linear alkoxy groups include, but are not limited to: methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, and the like. Examples of branched alkoxy groups include, but are not limited to: isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like. Examples of cycloalkoxy groups include, but are not limited to: cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like. The alkoxy group may include 1 to about 12-20 carbon atoms bonded to an oxygen atom, and may further include a double or triple bond, and may also include heteroatoms. For example, allyloxy is an alkoxy group within the ranges indicated herein. Methoxyethoxy is also an alkoxy group within the scope of what is meant herein, and likewise methylenedioxy is an alkoxy group in which two adjacent atoms of a structure are substituted with it.

The term "thioalkoxy" refers to an alkyl group, as defined previously, attached to the parent molecular moiety through a sulfur atom.

The term "glycosyloxyloxy" refers to a glycoside that is attached to the parent molecular moiety through an oxygen atom.

The term "alkoxycarbonyl" denotes an ester group; i.e., an alkoxy group attached to the parent molecular moiety through a carbonyl group, such as methoxycarbonyl, ethoxycarbonyl, and the like.

Unless otherwise indicated, the terms "halo" or "halogen" or "halide" by themselves or as part of another substituent mean a fluorine, chlorine, bromine or iodine atom, preferably fluorine, chlorine or bromine.

"haloalkyl" includes monohaloalkyl, polyhaloalkyl (where all halogen atoms may be the same or different) and perhaloalkyl (where all hydrogen atoms are replaced by halogen atoms, such as fluorine). Examples of the haloalkyl group include a trifluoromethyl group, a 1, 1-dichloroethyl group, a 1, 2-dichloroethyl group, a 1, 3-dibromo-3, 3-difluoropropyl group, a perfluorobutyl group and the like.

"haloalkoxy" includes monohaloalkoxy, polyhaloalkoxy (wherein all halogen atoms may be the same or different), and perhaloalkoxy (wherein all hydrogen atoms are replaced by halogen atoms, such as fluorine). Examples of the haloalkoxy group include trifluoromethoxy group, 1-dichloroethoxy group, 1, 2-dichloroethoxy group, 1, 3-dibromo-3, 3-difluoropropoxy group, perfluorobutoxy group and the like.

Term "(C) _x -C _y ) Perfluoroalkyl radical "(where x<y) means an alkyl group having a minimum of x carbon atoms and a maximum of y carbon atoms, wherein all hydrogen atoms are replaced by fluorine atoms. Is preferably- (C) ₁ -C ₆ ) Perfluoroalkyl group, more preferably- (C) ₁ -C ₃ ) Perfluoroalkyl, most preferably-CF ₃ 。

Term "(C) _x -C _y ) Perfluoroalkylene "(where x<y) means an alkyl group having a minimum of x carbon atoms and a maximum of y carbon atoms, wherein all hydrogen atoms are replaced by fluorine atoms. Is preferably- (C) ₁ -C ₆ ) Perfluoroalkylene, more preferably- (C) ₁ -C ₃ ) Perfluoroalkylene, most preferably-CF ₂ -。

The terms "aryloxy" and "arylalkoxy" refer to aryl groups bonded to the oxygen atom and arylalkyl groups bonded to the oxygen atom of the alkyl moiety, respectively. Examples include, but are not limited to, phenoxy, naphthoxy, and benzyloxy.

The term "acyl" as used herein refers to a group containing a carbonyl moiety, wherein the group is bonded through the carbonyl carbon atom. The carbonyl carbon atom is also bonded to another carbon atom, which may be part of an alkyl group, an aryl group, an aralkyl group, a cycloalkyl group, a cycloalkylalkyl group, a heterocyclyl group, a heterocyclylalkyl group, a heteroaryl group, a heteroaralkyl group, and the like. In the particular case where the carbonyl carbon atom is bonded to hydrogen, the group is a "formyl" group, i.e., an acyl group as that term is defined herein. The acyl group may include from 0 to about 12-20 additional carbon atoms bonded to the carbonyl group. The acyl group may include a double bond or a triple bond within the ranges referred to herein. Acryloyl is an example of acyl. Acyl groups may also include heteroatoms within the range indicated herein. Nicotinoyl (pyridyl-3-carbonyl) is an example of an acyl group within the ranges referred to herein. Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl, and the like. When a group containing a carbon atom bonded to a carbonyl carbon atom contains a halogen, the group is referred to as a "haloacyl". An example is trifluoroacetyl.

The term "amine" includes compounds having, for example, the formula N (group) ₃ Wherein each group can independently be H or non-H, such as alkyl, aryl, and the like. Amines include, but are not limited to: R-NH ₂ For example, alkylamines, arylamines, alkylarylamines; r ₂ NH, wherein each R is independently selected, such as dialkylamines, diarylamines, arylalkylamines, heterocyclylamines, or the like; and R ₃ N, wherein each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, and the like. The term "amine" also includes ammonium ions as used herein.

The "amino" group being-NH ₂ 、-NHR、-NR ₂ 、-NR ₃ ⁺ Forms and by excluding non-protonatable-NR ₃ ⁺ Other than the above, wherein each R is independently selected. Thus, any compound substituted with an amino group can be considered an amine. The "amino group" in the context of this document may be a primary, secondary, tertiary or quaternary amino group. "alkylamino" groups include monoalkylamino, dialkylamino, and trialkylamino groups.

The "ammonium" ion includes unsubstituted ammonium NH ₄ ⁺ But unless otherwise indicated it also includes any protonated or quaternized form of the amine. Thus, both trimethylammonium hydrochloride and tetramethylammonium chloride are ammonium ions and amines within the ranges referred to herein.

The term "amide" (or "amide group") includes C-and N-amide groups, i.e., -C (O) NR, respectively ₂ and-NRC (O) R groups. Thus, amide groups include but are not limited toNot restricted to primary carboxamide groups (-C (O) NH) ₂ ) And carboxamide groups (-NHC (O) H). The "carboxamide" or "aminocarbonyl" group is of the formula C (O) NR ₂ Wherein R may be H, alkyl, aryl, and the like.

The term "azido" refers to N ₃ And (4) a base. The "azide" may be an organic azide or may be an azide anion (N) ₃ ^- ) A salt. The term "nitro" refers to NO bonded to an organic moiety ₂ A group. The term "nitroso" refers to a NO group bonded to an organic moiety. The term nitrate refers to ONO bonded to an organic moiety ₂ Radical or Nitrate (NO) ₃ ^- ) Salts of anions.

The term "carbamate" ("carbamoyl" OR "carbamoyl") includes N-and O-carbamate groups, i.e., -NRC (O) OR and-OC (O) NR, respectively ₂ A group.

The term "sulfonamide" (or "sulfonamide group") includes S-and N-sulfonamide groups, i.e., -SO groups, respectively ₂ NR ₂ and-NRSO ₂ And R group. Thus, sulfonamide groups include, but are not limited to, sulfonamide groups (-SO) ₂ NH ₂ ). An organosulfur structure represented by the formula-S (O) (NR) -is understood to mean a sulfoximine in which both the oxygen and nitrogen atoms are bonded to a sulfur atom that is also bonded to two carbon atoms.

The term "amidine" or "amidino" includes the formula-C (NR) NR ₂ A group of (1). Typically, the amidino group is-C (NH) NH ₂ 。

The term "guanidine" or "guanidino" includes the formula-NRC (NR) NR ₂ A group of (1). Typically, the guanidino group is-NHC (NH) NH ₂ 。

The term "sugar-derived ring" refers to a compound that forms a ring by removing a hydrogen atom from two hydroxyl groups of any sugar.

"salts" as known in the art include organic compounds in ionic form, such as carboxylic acids, sulfonic acids or amines, in combination with a counter ion. For example, their anionic forms of acids may form salts with cations such as: metal cations such as sodium, potassium, and the like; ammonium salts such as NH ₄ ⁺ Or various amine cations, including tetraalkylammonium salts, such as tetramethylammonium; or other cations such as trimethylsulfonium and the like. A "pharmaceutically acceptable" or "pharmacologically acceptable" salt is a salt that is formed from ions and is approved for human consumption and is generally non-toxic, such as a chloride or sodium salt. A "zwitterion" is, for example, an internal salt that can be formed within a molecule that has at least two ionizable groups, one group forming an anion and the other group forming a cation, and thus act in equilibrium with each other. For example, an amino acid such as glycine may be present in zwitterionic form. "zwitterions" are salts within the ranges indicated herein. The compounds described herein may take the form of salts. The term "salt" encompasses addition salts of the free acid or free base, which are compounds described herein. The salt may be a "pharmaceutically acceptable salt". The term "pharmaceutically acceptable salt" refers to salts having a toxicity profile within a range that provides utility in pharmaceutical applications. However, pharmaceutically unacceptable salts may have properties such as high crystallinity which have utility in the practice of the invention, for example in the synthesis, purification or formulation of the compounds of the invention.

Suitable pharmaceutically acceptable acid addition salts may be prepared from inorganic acids or from organic acids. Examples of the inorganic acid include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, and phosphoric acid. Suitable organic acids may be selected from the group consisting of aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, methylenepamoic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylsulfamic, stearic, alginic, β -hydroxybutyric, salicylic, galactaric and galacturonic acids. Examples of pharmaceutically unacceptable acid addition salts include, for example, perchlorate and tetrafluoroborate.

Suitable pharmaceutically acceptable base addition salts of the compounds of the present invention include, for example, metal salts, including alkali metal, alkaline earth metal and transition metal salts, such as calcium, magnesium, potassium, sodium and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts formed with basic amines such as N, N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. Examples of pharmaceutically unacceptable base addition salts include lithium salts and cyanate salts. Although pharmaceutically unacceptable salts are not generally useful as pharmaceuticals, such salts may be useful, for example, as intermediates in the synthesis of compounds of formulae (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V) or (Va) - (Vc), e.g., during purification thereof by recrystallization. All of these salts can be prepared in a conventional manner from the corresponding compounds according to formulae (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V) or (Va) - (Vc) by reacting, for example, the appropriate acid or base with a compound according to formulae (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V) or (Va) - (Vc). The term "pharmaceutically acceptable salts" refers to non-toxic inorganic or organic acid and/or base addition salts, see, e.g., lit et al, salt Selection for Basic Drugs (1986), int j. Pharm.,33,201-217, which are incorporated herein by reference.

A "hydrate" is a compound that exists in combination with a water molecule. The composition may include a stoichiometric amount of water, such as a monohydrate or a dihydrate, or may include a random amount of water. As the term is used herein, "hydrate" refers to a solid form, i.e., for a compound in aqueous solution, although it may be hydrated, not the hydrate to which the term is used herein.

"solvates" are similar compositions except that a solvent other than water is used in place of water. For example, methanol or ethanol may form "alcoholates", which may also be stoichiometric or non-stoichiometric. As the term is used herein, "solvate" refers to a solid form, i.e., for a compound in solution in a solvent, although it may be solvated, not the solvate to which the term is used herein.

A "prodrug" as known in the art is a substance that can be administered to a patient, wherein the substance is converted in vivo to an active pharmaceutical ingredient by the action of a biochemical substance, such as an enzyme, in the patient's body. Examples of prodrugs include esters of carboxylic acid groups which can be hydrolyzed by endogenous esterases found in the bloodstream of humans and other mammals. Other examples of prodrugs include boronic esters, which can be hydrolyzed under physiological conditions to yield the corresponding boronic acids. Conventional procedures for selecting and preparing suitable prodrug derivatives are described, for example, in "Design of produgs", h.

Furthermore, when features or aspects of the invention are described in the form of a markush group, those skilled in the art will recognize that the presently described compounds are also thereby described in the form of any individual member or subgroup of members of the markush group. For example, if X is described as being selected from the group consisting of bromine, chlorine, and iodine, it is sufficient to describe the claim that X is bromine with the claim that X is bromine and chlorine. Furthermore, when features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any combination of individual members or sub-groups of members of the Markush group. Thus, for example, if X is described as being selected from bromine, chlorine, and iodine, and Y is described as being selected from methyl, ethyl, and propyl, then the claims that X is bromine and Y is methyl are fully described.

If the value of a variable which is necessarily an integer, such as the number of carbon atoms in an alkyl group or the number of substituents on a ring, is described as a range of, for example, 0-4, it is meant that the value can be any integer between 0 and 4 (including 0 and 4), i.e., 0, 1, 2, 3, or 4.

In various embodiments, a compound or group of compounds used in the methods of the present invention may be any of the combinations and/or subcombinations of the above listed embodiments.

In various embodiments, compounds as shown in any of the examples or exemplary compounds are provided.

Conditions may apply to any disclosed class or embodiment, wherein any one or more other above-disclosed embodiments or classes may be excluded from such class or embodiment.

The invention further encompasses isolated compounds according to formula (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V) or (Va) - (Vc). The expression "isolated compound" refers to a preparation of a compound of formula (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V) or (Va) - (Vc) or a mixture of compounds according to formula (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V) or (Va) - (Vc), wherein said isolated compound has been separated from the reagents and/or by-products formed used in the synthesis of the compound or compounds. "isolated" does not mean that the formulation is industrially pure (homogeneous), but that it is sufficiently pure for the compound to be in a form that can be used therapeutically. Preferably, an "isolated compound" refers to a preparation of a compound of formula (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V) or (Va) - (Vc) or a mixture of compounds according to formula (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V) or (Va) - (Vc) comprising the compound in an amount of at least 10% by weight based on the total weight or a mixture of compounds according to formula (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V) or (Va) - (Vc). Preferably, the formulation comprises the compound or mixture of compounds in an amount of at least 50% by weight, more preferably at least 80% by weight, and most preferably at least 90%, at least 95% or at least 98% by weight, based on the total weight of the formulation.

The compounds and intermediates described herein can be isolated from their reaction mixtures and purified by standard techniques such as filtration, liquid-liquid extraction, solid phase extraction, distillation, recrystallization, or chromatography (including flash column chromatography or HPLC).

Isomerism and tautomerism of the compounds described herein

Tautomerism

In the present disclosure, it is understood that compounds of formula (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V), or (Va) - (Vc), or salts thereof, may exhibit tautomerism whereby two compounds can be readily converted to each other by exchanging hydrogen atoms between the two atoms, with either of the two atoms forming a covalent bond. Since tautomeric compounds exist in a form that is in dynamic equilibrium with each other, they can be considered as different isomeric forms of the same compound. It is to be understood that the structural formulae drawings in this specification may represent only one possible tautomeric form. However, it is also to be understood that the present invention encompasses any tautomeric form and is not to be limited solely to any one tautomeric form employed in the structural formulae drawings. The structural diagrams in this specification may represent only one possible tautomeric form and it is to be understood that the specification encompasses all possible tautomeric forms of the depicted compounds, not just those forms which are convenient for graphical presentation herein. For example, tautomerism can be manifested by a bonded pyrazolyl group represented by a wavy line. Although both substituents are referred to as 4-pyrazolyl, it is clear that different nitrogen atoms carry hydrogen atoms in the respective structures.

This tautomerism may also occur on substituted pyrazoles, such as 3-methyl, 5-methyl or 3, 5-dimethylpyrazole, and the like. Another example of tautomerism is amido-imide group (lactam-lactam, when cyclic) tautomerism, as observed in heterocyclic compounds having an epoxy atom adjacent to a ring nitrogen atom. For example, the balance:is an example of tautomerism. Thus, a structure depicted herein as one tautomer is also intended to include the other tautomer.

Optical isomerism

It will be appreciated that when a compound of the invention contains one or more chiral centers, the compound may exist as pure enantiomers or diastereomers or as a racemic mixture and may be resolved into the pure enantiomeric or diastereomeric forms. Thus, the present invention includes any possible enantiomer, diastereomer, racemate or mixture thereof, of the compounds described herein.

Isomers that arise due to the presence of chiral centers include a pair of non-superimposable isomers known as "enantiomers". The single enantiomers of pure compounds are optically active, i.e., they are capable of rotating the plane of plane polarized light. The single enantiomers are named according to the Cahn-Ingold-Prelog system. The substituents are prioritized based on atomic weight, with larger atomic weights having higher priority levels, as determined by the system program. Once the priority ranking of the four groups is determined, the molecules are oriented so that the lowest ranking group is farther away from the viewer. Then, if the other groups arranged in descending order of rank are clockwise, the molecule is named (R), and if the other groups arranged in descending order of rank are counterclockwise, the molecule is named (S). In the examples below, cahn-Ingold-Prelog has an ordering of A > B > C > D. The lowest-ranking D atom is oriented away from the viewer.

The present invention is intended to cover diastereomers as well as their racemic forms and resolved diastereomerically and enantiomerically pure forms and salts thereof. The diastereomeric pairs can be resolved by known separation techniques, including normal and reverse phase chromatography and crystallization.

"isolated optical isomers" refers to compounds that have been substantially purified from the corresponding optical isomers of the same general formula. Preferably, the isolated isomer is at least about 80%, more preferably at least 90% pure, even more preferably at least 98% pure, and most preferably at least about 99% pure by weight.

The isolated optical isomers can be purified from the racemic mixtures by well-known chiral separation techniques. According to one such method, a racemic mixture of the compounds described herein or a chiral intermediate thereof is passed through HPLC using a suitable chiral column, such asOf familyMembers of a series of columns (Daicel Chemical Industries, ltd., tokyo, japan) were separated into 99% by weight pure optical isomers. The column was operated according to the manufacturer's instructions.

Rotational isomerism

It will be appreciated that due to the chemical nature of the restricted rotation about the amide bond (as shown below), i.e. the resonance gives some double bond character to the C-N bond, individual rotamer species may be observed, and even in some cases the species may be separated (see below). It is also understood that certain structural units, including steric hindrance of or substituents on the amido nitrogen, may enhance the stability of rotamers to the extent that the compound may be separated into one stable rotamer and exist indefinitely. Thus, the present invention includes any possible stable rotamer of formula (I) that is biologically active in the treatment of cancer or other proliferative disease states.

Regio-isomerism

In some embodiments, the compounds described herein have a particular spatial arrangement of substituents on the aromatic ring that correlates with the structural activity relationship exhibited by the class of compounds. Typically such substituent arrangements are represented by a numbering system; but the numbering system is usually not consistent between different rings. In six-membered aromatic systems, the spatial arrangement is designated by the common nomenclature "pair" (for 1, 4-substitution), "m" (for 1, 3-substitution) and "o" (for 1, 2-substitution), as shown below.

In various embodiments, a compound or group of compounds (as used in the compounds of the invention or in the methods of the invention) may be any of any combination and/or subcombination of the embodiments listed above.

Compound (I)

wherein:

R ¹ and R ² Are each independently H, - (C) ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-OR ²³ 、-CH ₂ CH(OH)CH ₂ NH ₂ 、-CH ₂ CH (Heterocyclylalkyl) CH ₂ NH ₂ 、-CH ₂ C(O)NH ₂ 、-CH ₂ C(O)N(H)CH ₂ CN、-(C ₁ -C ₆ ) alkyl-C (O) OR ²³ 、-(C ₁ -C ₆ ) alkyl-NR ²¹ R ²² 、-(C ₁ -C ₆ ) alkyl-C (O) NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) alkyl-N (R) ²³ )C(O)(C ₁ -C ₆ ) Alkyl radical NR ²¹ R ²² 、-(C ₁ -C ₆ ) alkyl-N (R ²³ )C(O)(C ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-C (O) N (R) ²³ )(C ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-C (O) N (R) ²³ )(C ₁ -C ₆ ) Alkyl-heterocycloalkyl, - (C) ₁ -C ₆ ) alkyl-NR ²³ C(＝NH)NR ²¹ R ²² 、-(C ₁ -C ₆ ) alkyl-NR ²³ C(＝NH)R ²³ 、-(C ₁ -C ₆ ) Alkyl- [ (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² ] ₂ 、-(C ₁ -C ₆ ) Heteroalkyl or optionally substituted heterocycloalkyl;

R ³ is H or- (C) ₁ -C ₆ ) An alkyl group;

R ⁵ is H or- (C) ₁ -C ₆ ) An alkyl group;

R ¹⁰ is H, - (C) ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) Haloalkyl or- (C) ₃ -C ₆ ) A cycloalkyl group;

or R ⁹ And R ¹⁰ Combined to form a heterocycloalkyl or cycloalkyl ring

R ¹¹ And R ¹² Each independently is H, -NH ₂ 、-(C ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-OR ²³ 、-(C ₁ -C ₆ ) alkyl-SR ²³ 、-(C ₁ -C ₆ ) alkyl-C (O) OR ²³ 、-(C ₁ -C ₆ ) alkyl-NR ²¹ R ²² 、-(C ₁ -C ₆ ) alkyl-NR ²³ OR ²³ 、-(C ₁ -C ₆ ) alkyl-NHC (O) NR ²³ OR ²³ 、-(C ₁ -C ₆ ) alkyl-O- (C) ₁ -C ₆ ) alkyl-NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) alkyl-CN, - (C) ₁ -C ₆ ) alkyl-NR ²³ C(O)R ²³ 、-(C ₁ -C ₆ ) alkyl-C (O) NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) heteroalkyl-CO ₂ H、-(C ₁ -C ₆ ) alkyl-S (O) (C) ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-N (H) CH = NH, - (C) ₁ -C ₆ ) alkyl-C (NH) ₂ )＝NH、-(C ₁ -C ₆ ) alkyl-N (H) C (= NH) NH ₂ 、-(C ₁ -C ₆ ) alkyl-N (H) S (O) ₂ NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) alkyl-N (H) S (O) ₂ (C ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-N (H) -C (O) NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) Alkyl C (O) N (H) [ optionally substituted (C) ₂ -C ₆ ) Alkyl radical]-OR ²³ 、-(C ₁ -C ₆ ) Alkyl N (H) C (O) (C) ₁ -C ₆ ) alkyl-OR ²³ 、-(C ₁ -C ₆ ) Alkyl C (O) N (H) heterocycloalkyl, - (C) ₁ -C ₆ ) Alkyl C (O) NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) alkyl-N (H) -C (O) - (C) ₁ -C ₆ ) alkyl-NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) alkyl-N (H) - (C) ₁ -C ₆ ) Alkyl C (O) NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) Alkyl-heterocycloalkyl, optionally substituted- (C) ₁ -C ₆ ) alkyl-N (H) heterocycloalkyl or- (C) ₁ -C ₆ ) Alkyl-heteroaryl;

each R ²¹ And R ²² Independently of each other is H, - (C) ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) Heteroalkyl, - (C) ₁ -C ₆ ) alkyl-CO ₂ H、-C(O)(C ₁ -C ₆ ) Alkyl, -C (O) O (C) ₁ -C ₆ ) Alkyl, -C (O) O (C) ₁ -C ₆ ) Haloalkyl, -C (= NH) (C) ₁ -C ₆ ) Alkyl, -C (= NH) N (R) ³¹ ) ₂ 、-C(O)N(R ³¹ ) ₂ or-SO ₂ N(R ³¹ ) ₂ (ii) a Or R ²¹ And R ²² And the nitrogen atom to which they are attached form a heterocycloalkyl ring;

each R ³¹ Independently is H or- (C) ₁ -C ₆ ) An alkyl group; or two R ³¹ And the nitrogen atom to which they are attached form a hetero atomA cycloalkyl ring;

each R ²³ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

each R ²⁴ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

each R ²⁸ Independently halogen, -NR ²³ R ²⁴ 、-NHC(O)R ²³ 、-NC(O)NR ²³ R ²⁴ Nitro, hydroxy, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted- (C) ₁ -C ₆ ) Heteroalkyl, optionally substituted- (C) ₁ -C ₆ ) Heteroalkyloxy, optionally substituted- (C) ₁ -C ₆ ) Heteroalkylamino radical, - (C) ₁ -C ₆ ) Alkoxy, -C (O) (C) ₁ -C ₆ ) Alkyl or-S (O) ₂ (C ₁ -C ₆ ) An alkyl group;

p is 0, 1 or 2; and is

q is 0, 1 or 2.

In one embodiment are compounds of formula (I) wherein R ⁶ 、R ⁷ And R ⁸ Is H.

In another embodiment are compounds of formula (I) wherein R ¹⁵ And R ¹⁶ Is H.

In one embodiment are compounds of formula (I) wherein R ¹⁷ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (I) wherein R ¹⁷ is-CH ₃ . In another embodiment are compounds of formula (I) wherein R ¹⁷ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (I) wherein R ¹⁷ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (I) wherein R ¹⁷ Is cyclopropyl. In another embodiment are compounds of formula (I) wherein R ¹⁷ Is- (C) ₁ -C ₆ ) alkyl-C (O) OR ²³ . In another embodiment are compounds of formula (I) wherein R ¹⁷ is-CH ₂ CH ₂ And (5) OH. In another embodiment are compounds of formula (I) wherein R ¹⁷ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (I) wherein R ¹⁷ is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (I) wherein R ¹⁷ Is H.

In another embodiment are compounds of formula (I) wherein R ¹⁸ Is H.

In another embodiment are compounds of formula (I) wherein R ³ Is H.

In another embodiment are compounds of formula (I) wherein R ⁵ Is H.

In another embodiment are compounds of formula (I) wherein R ⁴ Is H. In another embodiment are compounds of formula (I) wherein R ⁴ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (I) wherein R ⁴ is-CH ₃ . In another embodiment is a compound of formula (I)Compound (I) wherein R ⁴ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (I) wherein R ⁴ Is- (C) ₁ -C ₆ ) alkyl-OH. In another embodiment are compounds of formula (I) wherein R ⁴ is-CH ₂ And (5) OH. In another embodiment are compounds of formula (I) wherein R ⁴ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (I) wherein R ⁴ Is cyclopropyl. In another embodiment are compounds of formula (I) wherein R ⁴ is-C (O) NH ₂ 。

In another embodiment are compounds of formula (I) wherein R ³ 、R ⁴ And R ⁵ Is H.

In another embodiment are compounds of formula (I) wherein R ⁴ And R ⁵ And the carbon atoms to which they are attached form a cyclopropyl ring.

In another embodiment are compounds of formula (I) wherein R ¹⁰ Is H.

In another embodiment are compounds of formula (I) wherein R ¹⁰ Is H and R ⁹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (I) wherein R ¹⁰ Is H and R ⁹ is-CH ₃ . In another embodiment are compounds of formula (I) wherein R ¹⁰ Is H and R ⁹ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (I) wherein R ¹⁰ Is H and R ⁹ Is- (C) ₁ -C ₆ ) A haloalkyl group. In another embodiment are compounds of formula (I) wherein R ¹⁰ Is H and R ⁹ is-CH ₂ F. In another embodiment are compounds of formula (I) wherein R ¹⁰ Is H and R ⁹ is-CHF ₂ . In another embodiment are compounds of formula (I) wherein R ¹⁰ Is H and R ⁹ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (I) wherein R ¹⁰ Is H and R ⁹ Is cyclopropyl. In another embodiment are compounds of formula (I) wherein R ¹⁰ Is H and R ⁹ Is H.

In another embodiment are compounds of formula (I) wherein R ¹² Is H.

In another embodiment are compounds of formula (I) wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (I) wherein R ¹² Is H and R ¹¹ is-CH ₃ . In another embodiment are compounds of formula (I) wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-OR ²³ . In another embodiment are compounds of formula (I) wherein R ¹² Is H and R ¹¹ is-CH ₂ And (5) OH. In another embodiment are compounds of formula (I) wherein R ¹² Is H and R ¹¹ is-CH ₂ CH ₂ And (5) OH. In another embodiment are compounds of formula (I) wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (I) wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (I) wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-NH ₂ . In another embodiment are compounds of formula (I) wherein R ¹² Is H and R ¹¹ is-CH ₂ NH ₂ . In another embodiment are compounds of formula (I) wherein R ¹² Is H and R ¹¹ is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (I) wherein R ¹² Is H and R ¹¹ is-CH ₂ CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (I) wherein R ¹² Is H and R ¹¹ is-CH ₂ CH ₂ CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (I) wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-CN. In another embodiment are compounds of formula (I) wherein R ¹² Is H and R ¹¹ is-CH ₂ CN. In another embodiment are compounds of formula (I) wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-C (O) NR ²⁵ R ²⁶ . In another embodiment are compounds of formula (I) wherein R ¹² Is H and R ¹¹ is-CH ₂ C(O)NH ₂ . In another embodiment are compounds of formula (I) wherein R ¹² Is H and R ¹¹ is-CH ₂ CH ₂ C(O)NH ₂ . In another embodiment are compounds of formula (I) wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) Alkyl-heteroaryl. In another embodiment are compounds of formula (I) wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-N (H) S (O) ₂ NR ²⁵ R ²⁶ . In another embodiment are compounds of formula (I) wherein R ¹² Is H and R ¹¹ is-CH ₂ N(H)S(O) ₂ NH ₂ . In another embodiment are compounds of formula (I) wherein R ¹² Is H and R ¹¹ Is H.

In another embodiment are compounds of formula (I) wherein R ¹¹ And R ¹⁸ Combine to form an optionally substituted heterocycloalkyl ring and R ¹² Is H.

In another embodiment are compounds of formula (I) wherein p is 1 and R ²⁷ Is a halogen. In another embodiment are compounds of formula (I) wherein p is 1 and R ²⁷ Is optionally substituted- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (I) wherein q is 0, p is 1 and R ²⁷ Is halogen. In another embodiment are compounds of formula (I) wherein q is 0, p is 1 and R ²⁷ Is optionally substituted- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (I) wherein q is 1 and R ²⁸ Is halogen. In another embodiment are compounds of formula (I) wherein q is 1 and R ²⁸ Is optionally substituted- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (I) wherein p is 0, q is 1 and R ²⁸ Is halogen. In another embodiment are compounds of formula (I), whichWherein p is 0, q is 1 and R ²⁸ Is optionally substituted- (C) ₁ -C ₆ ) An alkyl group.

In another embodiment are compounds of formula (I) wherein p is 0 and q is 0.

In another embodiment are compounds of formula (I) wherein R ¹ And R ² Each independently is H or- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (I) wherein R ¹ And R ² Each is H. In another embodiment are compounds of formula (I) wherein R ¹ And R ² Each independently is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (I) wherein R ¹ Is H, and R ² Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (I) wherein R ¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² And R is ² Is H. In another embodiment are compounds of formula (I) wherein R ¹ Is H, and R ² is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (I) wherein R ¹ is-CH ₂ CH ₂ NH ₂ And R is ² Is H. In another embodiment are compounds of formula (I) wherein R ¹ And R ² Each is-CH ₂ CH ₂ NH ₂ . In a further embodiment are compounds of formula (I) wherein R ¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² And R is ² Is H. In a further embodiment are compounds of formula (I) wherein R ¹ is-CH ₂ CH ₂ NH ₂ And R is ² Is H. In a further embodiment are compounds of formula (I) wherein R ¹ Is H and R ² Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In a further embodiment are compounds of formula (I) wherein R ¹ Is H and R ² is-CH ₂ CH ₂ NH ₂ . In a further embodiment isA compound of formula (I) wherein R ¹ And R ² And the atoms to which they are attached form an optionally substituted heterocycloalkyl ring. In another embodiment are compounds of formula (I) wherein R ¹ And R ² Are each independently H, - (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² or-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (I) wherein R ¹ And R ² Each independently is-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (I) wherein R ¹ Is H, and R ² is-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (I) wherein R ¹ is-CH ₂ CH(OH)CH ₂ NH ₂ And R is ² Is H.

In another embodiment are compounds of formula (I) wherein X is optionally substituted aryl. In a further embodiment are compounds of formula (I) wherein X is optionally substituted phenyl. In another embodiment are compounds of formula (I) wherein X is optionally substituted heteroaryl. In a further embodiment are compounds of formula (I) wherein X is disubstituted heteroaryl. In a further embodiment are compounds of formula (I) wherein X is heteroaryl disubstituted with substituents each independently selected from halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ and-NO ₂ . In a further embodiment are compounds of formula (I) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituents disubstituted heteroaryl. In a further embodiment are compounds of formula (I) wherein X is heteroaryl disubstituted with methyl. In a further embodiment are compounds of formula (I) wherein X is pyridyl disubstituted with substituents each independently selected from the group consisting of halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In a further embodiment are compounds of formula (I) wherein X is independently selected from- (C) ₁ -C ₆ ) A substituent of an alkyl group. In a further embodiment are compounds of formula (I) wherein X is pyridinyl disubstituted with methyl. In a further embodiment are compounds of formula (I) wherein X is pyrimidinyl disubstituted with substituents each independently selected from halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In a further embodiment are compounds of formula (I) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituent disubstituted pyrimidinyl. In a further embodiment are compounds of formula (I) wherein X is pyrimidinyl disubstituted with methyl. In another embodiment are compounds of formula (I) wherein X is optionally substituted- (C) ₁ -C ₆ ) An alkyl group-.

In another embodiment are compounds of formula (I) wherein Y is optionally substituted aryl. In a further embodiment are compounds of formula (I) wherein Y is optionally substituted phenyl. In another embodiment are compounds of formula (I) wherein Y is optionally substituted heteroaryl. In another embodiment are compounds of formula (I) wherein Y is optionally substituted- (C) ₁ -C ₆ ) An alkyl radical. In another embodiment are compounds of formula (I) wherein Y is optionally substituted (C) ₃ -C ₇ ) Cycloalkyl-. In another embodiment are compounds of formula (I) wherein Y is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (I) wherein Y is-O-. In another embodiment are compounds of formula (I) wherein Y is- (C) ₂ -C ₆ ) Alkynyl. In another embodiment are compounds of formula (I) wherein Y is-O- (C) ₁ -C ₆ ) An alkyl radical. In another embodiment are compounds of formula (I) wherein Y is a bond.

In another embodiment are compounds of formula (I) wherein Z is- (C) ₁ -C ₁₂ ) An alkyl group. In a further embodiment isA compound of formula (I) wherein Z is n-butyl, isobutyl or tert-butyl. In another embodiment are compounds of formula (I) wherein Z is-O- (C) ₁ -C ₁₂ ) An alkyl group. In another embodiment are compounds of formula (I) wherein Z is-O- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (I) wherein Z is- (C) ₂ -C ₁₂ ) An alkenyl group. In another embodiment are compounds of formula (I) wherein Z is optionally substituted aryl. In a further embodiment are compounds of formula (I) wherein Z is optionally substituted phenyl. In a further embodiment are compounds of formula (I) wherein Z is independently selected from- (C) ₁ -C ₈ ) Alkyl substituents are monosubstituted or disubstituted phenyl. In a further embodiment are compounds of formula (I) wherein Z is phenyl monosubstituted with n-butyl, isobutyl, or tert-butyl. In a further embodiment are compounds of formula (I) wherein Z is phenyl monosubstituted with n-butyl. In a further embodiment are compounds of formula (I) wherein Z is phenyl monosubstituted with isobutyl. In a further embodiment are compounds of formula (I) wherein Z is phenyl monosubstituted with tert-butyl. In another embodiment are compounds of formula (I) wherein Z is optionally substituted heteroaryl. In another embodiment are compounds of formula (I) wherein Z is optionally substituted- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (I) wherein Z is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (I) wherein Z is halogen.

In another embodiment are compounds of formula (I) wherein Z-Y-X-is other than

wherein:

R ³ is H or- (C) ₁ -C ₆ ) An alkyl group;

R ⁵ is H or- (C) ₁ -C ₆ ) An alkyl group;

R ⁶ 、R ⁷ and R ⁸ Each independently is H, fluoro, hydroxy, amino, optionally substituted alkyl, heteroalkyl, or- (C) ₁ -C ₆ ) An alkyl group;

or R ⁹ And R ¹⁰ Combined to form a heterocycloalkyl or cycloalkyl ring

y is a bond, -O-, -S-, optionally substituted- (C) ₁ -C ₆ ) Alkyl radical-、-(C ₂ -C ₆ ) Alkenyl-, - (C) ₂ -C ₆ ) Alkynyl, - (C) ₁ -C ₆ ) alkyl-N (R) ²⁴ )(C ₁ -C ₆ ) Alkyl-, -O- (C) ₁ -C ₆ ) Alkyl-, -O (C) ₆ -C ₁₀ ) Aryl-, -N (R) ²⁴ )(C ₁ -C ₆ ) Alkyl-, -N (R) ²⁴ )SO ₂ (C ₁ -C ₆ ) Alkyl-, -N (R) ²⁴ )C(O)(C ₁ -C ₆ ) Alkyl-, -C (O) (C) ₁ -C ₆ ) Alkyl-, -S (C) ₁ -C ₆ ) Alkyl-, -SO ₂ (C ₁ -C ₆ ) Alkyl-, -C (O) NH (C) ₁ -C ₆ ) Alkyl-, optionally substituted- (C) ₃ -C ₇ ) Cycloalkyl-, optionally substituted-C (O) N (R) ²⁴ ) Aryl-, optionally substituted-N (R) ²⁴ ) C (O) aryl-, optionally substituted-N (R) ²⁴ )SO ₂ Aryl-, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

z is H, halogen, -NH ₂ 、-CN、-CF ₃ 、-CO ₂ H、-(C ₁ -C ₁₂ ) Alkyl, - (C) ₂ -C ₁₂ ) Alkenyl, -CH = ((C) ₃ -C ₇ ) Cycloalkyl), - (C) ₂ -C ₁₂ ) Alkynyl, -C (O) NR ²⁵ R ²⁶ 、-O-(C ₁ -C ₁₂ ) Alkyl, -S- (C) ₁ -C ₁₂ ) Alkyl, -O- (C) ₃ -C ₁₀ ) [ optionally substituted (C) ₃ -C ₇ ) Cycloalkyl radicals]、-O-(C ₁ -C ₆ ) alkyl-OR ²³ 、-(C ₁ -C ₁₂ ) alkyl-OR ²³ 、-(C ₁ -C ₁₂ ) alkyl-CN, -S- (C) ₁ -C ₁₂ ) Alkyl, -N (R) ²⁴ )(C ₁ -C ₁₂ ) Alkyl, -N (R) ²⁴ )C(O)(C ₁ -C ₁₂ ) Alkyl, optionally substituted- (C) ₃ -C ₇ ) Cycloalkyl, - (C) ₁ -C ₆ ) Alkyl radical- (C) ₃ -C ₇ ) Cycloalkyl, - (C) ₁ -C ₆ ) Alkyl-heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

each R ²¹ And R ²² Independently of one another is H, - (C) ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) Heteroalkyl, - (C) ₁ -C ₆ ) alkyl-CO ₂ H、-C(O)(C ₁ -C ₆ ) Alkyl, -C (O) O (C) ₁ -C ₆ ) Alkyl, -C (O) O (C) ₁ -C ₆ ) Haloalkyl, -C (= NH) (C) ₁ -C ₆ ) Alkyl, -C (= NH) N (R) ³¹ ) ₂ 、-C(O)N(R ³¹ ) ₂ or-SO ₂ N(R ³¹ ) ₂ (ii) a Or R ²¹ And R ²² And the nitrogen atom to which they are attached form a heterocycloalkyl ring;

Each R ²³ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

each R ²⁴ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

p is 0, 1 or 2; and is

q is 0, 1 or 2;

or a pharmaceutically acceptable salt, solvate or prodrug thereof. In one embodiment are compounds of formula (Ia), wherein R ⁶ 、R ⁷ And R ⁸ Is H.

In another embodiment are compounds of formula (Ia), wherein R ¹⁵ And R ¹⁶ Is H.

In one embodiment are compounds of formula (Ia), wherein R ¹⁷ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (Ia), wherein R ¹⁷ is-CH ₃ . In another embodiment are compounds of formula (Ia), wherein R ¹⁷ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (Ia), wherein R ¹⁷ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (Ia), wherein R ¹⁷ Is cyclopropyl. In another embodiment are compounds of formula (Ia), wherein R ¹⁷ Is- (C) ₁ -C ₆ ) alkyl-C (O) OR ²³ . In another embodiment are compounds of formula (Ia), wherein R ¹⁷ is-CH ₂ CH ₂ And (5) OH. In another embodiment are compounds of formula (Ia), wherein R ¹⁷ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment is a compound of formula (Ia)Compound (I) wherein R ¹⁷ is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (Ia), wherein R ¹⁷ Is H.

In another embodiment are compounds of formula (Ia), wherein R ¹⁸ Is H.

In another embodiment are compounds of formula (Ia), wherein R ³ Is H.

In another embodiment are compounds of formula (Ia), wherein R ⁵ Is H.

In another embodiment are compounds of formula (Ia), wherein R ⁴ Is H. In another embodiment are compounds of formula (Ia), wherein R ⁴ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (Ia), wherein R ⁴ is-CH ₃ . In another embodiment are compounds of formula (Ia), wherein R ⁴ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (Ia), wherein R ⁴ Is- (C) ₁ -C ₆ ) alkyl-OH. In another embodiment are compounds of formula (Ia), wherein R ⁴ is-CH ₂ And (5) OH. In another embodiment are compounds of formula (Ia), wherein R ⁴ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (Ia), wherein R ⁴ Is cyclopropyl. In another embodiment are compounds of formula (Ia), wherein R ⁴ is-C (O) NH ₂ 。

In another embodiment are compounds of formula (Ia), wherein R ⁴ And R ⁵ And the carbon atoms to which they are attached form a cyclopropyl ring.

In another embodiment are compounds of formula (Ia), wherein R ³ 、R ⁴ And R ⁵ Is H.

In another embodiment are compounds of formula (Ia), wherein R ¹⁰ Is H.

In another embodiment are compounds of formula (Ia), wherein R ¹⁰ Is H and R ⁹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (Ia), wherein R ¹⁰ Is H and R ⁹ is-CH ₃ . In another embodiment are compounds of formula (Ia), wherein R ¹⁰ Is H and R ⁹ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (Ia), wherein R ¹⁰ Is H and R ⁹ Is- (C) ₁ -C ₆ ) A haloalkyl group. In another embodiment are compounds of formula (Ia), wherein R ¹⁰ Is H and R ⁹ is-CH ₂ F. In another embodiment are compounds of formula (Ia), wherein R ¹⁰ Is H and R ⁹ is-CHF ₂ . In another embodiment are compounds of formula (Ia), wherein R ¹⁰ Is H and R ⁹ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (Ia), wherein R ¹⁰ Is H and R ⁹ Is cyclopropyl. In another embodiment are compounds of formula (Ia), wherein R ¹⁰ Is H and R ⁹ Is H.

In another embodiment are compounds of formula (Ia), wherein R ¹² Is H.

In another embodiment are compounds of formula (Ia), wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (Ia), wherein R ¹² Is H and R ¹¹ is-CH ₃ . In another embodiment are compounds of formula (Ia), wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-OR ²³ . In another embodiment are compounds of formula (Ia), wherein R ¹² Is H and R ¹¹ is-CH ₂ And (5) OH. In another embodiment are compounds of formula (Ia), wherein R ¹² Is H and R ¹¹ is-CH ₂ CH ₂ And (5) OH. In another embodiment are compounds of formula (Ia), wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (Ia), wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (Ia), wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-NH ₂ . In another embodiment are compounds of formula (Ia), wherein R ¹² Is H and R ¹¹ is-CH ₂ NH ₂ . In another embodiment are compounds of formula (Ia), wherein R ¹² Is H and R ¹¹ is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (Ia), wherein R ¹² Is H and R ¹¹ is-CH ₂ CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (Ia), wherein R ¹² Is H and R ¹¹ is-CH ₂ CH ₂ CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (Ia), wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-CN. In another embodiment are compounds of formula (Ia), wherein R ¹² Is H and R ¹¹ is-CH ₂ And (C) CN. In another embodiment are compounds of formula (Ia), wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-C (O) NR ²⁵ R ²⁶ . In another embodiment are compounds of formula (Ia), wherein R ¹² Is H and R ¹¹ is-CH ₂ C(O)NH ₂ . In another embodiment are compounds of formula (Ia), wherein R ¹² Is H and R ¹¹ is-CH ₂ CH ₂ C(O)NH ₂ . In another embodiment are compounds of formula (Ia), wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) Alkyl-heteroaryl. In another embodiment are compounds of formula (Ia), wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-N (H) S (O) ₂ NR ²⁵ R ²⁶ . In another embodiment are compounds of formula (Ia), wherein R ¹² Is H and R ¹¹ is-CH ₂ N(H)S(O) ₂ NH ₂ . In another embodiment are compounds of formula (Ia), wherein R ¹² Is H and R ¹¹ Is H.

In another embodiment are compounds of formula (Ia), wherein R ¹¹ And R ¹⁸ Combined to form an optionally substituted heterocycloalkyl ring and R ¹² Is H.

In another embodiment are compounds of formula (Ia) wherein p is 1 and R is ²⁷ Is a halogen. In another embodiment are compounds of formula (Ia) wherein p is 1 and R ²⁷ Is optionally substituted- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (Ia) wherein q is 0, p is 1 and R is ²⁷ Is a halogen. In another embodiment are compounds of formula (Ia) wherein q is 0, p is 1 and R is ²⁷ Is optionally substituted- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (Ia) wherein q is 1 and R is ²⁸ Is halogen. In another embodiment are compounds of formula (Ia) wherein q is 1 and R is ²⁸ Is optionally substituted- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (Ia) wherein p is 0, q is 1, and R is ²⁸ Is a halogen. In another embodiment are compounds of formula (Ia) wherein p is 0, q is 1, and R is ²⁸ Is optionally substituted- (C) ₁ -C ₆ ) An alkyl group.

In another embodiment are compounds of formula (Ia) wherein p is 0 and q is 0.

In another embodiment are compounds of formula (Ia), wherein R ¹ And R ² Each independently is H or- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (Ia), wherein R ¹ And R ² Each is H. In another embodiment are compounds of formula (Ia), wherein R ¹ And R ² Each independently is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (Ia), wherein R ¹ Is H, and R ² Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (Ia), wherein R ¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² And R is ² Is H. In another embodiment are compounds of formula (Ia), wherein R ¹ Is H, and R ² is-CH ₂ CH ₂ NH ₂ . In another embodimentIn one embodiment are compounds of formula (Ia), wherein R ¹ is-CH ₂ CH ₂ NH ₂ And R is ² Is H. In another embodiment are compounds of formula (Ia), wherein R ¹ And R ² Each is-CH ₂ CH ₂ NH ₂ . In a further embodiment are compounds of formula (Ia), wherein R ¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² And R is ² Is H. In a further embodiment are compounds of formula (Ia), wherein R ¹ is-CH ₂ CH ₂ NH ₂ And R is ² Is H. In a further embodiment are compounds of formula (Ia), wherein R ¹ Is H and R ² Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In a further embodiment are compounds of formula (Ia), wherein R ¹ Is H and R ² is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (Ia), wherein R ¹ And R ² Are each independently H, - (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² or-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (Ia), wherein R ¹ And R ² Each independently is-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (Ia), wherein R ¹ Is H, and R ² is-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (Ia), wherein R ¹ is-CH ₂ CH(OH)CH ₂ NH ₂ And R is ² Is H.

In a further embodiment are compounds of formula (Ia), wherein R ¹ And R ² And the atoms to which they are attached form an optionally substituted heterocycloalkyl ring.

In another embodiment are compounds of formula (Ia) wherein X is optionally substituted aryl. In a further embodiment are compounds of formula (Ia) wherein X is optionally substituted phenyl. In another embodiment are compounds of formula (Ia) wherein X is optionally substituted heteroaryl. In a further embodimentCompounds of formula (Ia) wherein X is disubstituted heteroaryl. In a further embodiment are compounds of formula (Ia) wherein X is heteroaryl disubstituted with substituents each independently selected from halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ and-NO ₂ . In a further embodiment are compounds of formula (Ia) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituents disubstituted heteroaryl. In a further embodiment are compounds of formula (Ia) wherein X is heteroaryl disubstituted with methyl. In a further embodiment are compounds of formula (Ia) wherein X is pyridinyl disubstituted with substituents each independently selected from the group consisting of halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In a further embodiment are compounds of formula (Ia) wherein X is independently selected from- (C) ₁ -C ₆ ) A substituent of an alkyl group. In a further embodiment are compounds of formula (Ia) wherein X is pyridinyl disubstituted with methyl. In a further embodiment are compounds of formula (Ia) wherein X is pyrimidinyl disubstituted with substituents each independently selected from halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In a further embodiment are compounds of formula (Ia) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituent disubstituted pyrimidinyl. In a further embodiment are compounds of formula (Ia) wherein X is pyrimidinyl disubstituted with methyl. In another embodiment are compounds of formula (Ia), wherein X is optionally substituted- (C) ₁ -C ₆ ) An alkyl group-.

In another embodiment are compounds of formula (Ia) wherein Y is optionally substituted aryl. In a further implementationIn one embodiment are compounds of formula (Ia) wherein Y is optionally substituted phenyl. In another embodiment are compounds of formula (Ia) wherein Y is optionally substituted heteroaryl. In another embodiment are compounds of formula (Ia), wherein Y is optionally substituted- (C) ₁ -C ₆ ) An alkyl group-. In another embodiment are compounds of formula (Ia), wherein Y is optionally substituted (C) ₃ -C ₇ ) Cycloalkyl-. In another embodiment are compounds of formula (Ia) wherein Y is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (Ia), wherein Y is-O-. In another embodiment are compounds of formula (Ia), wherein Y is- (C) ₂ -C ₆ ) Alkynyl. In another embodiment are compounds of formula (Ia), wherein Y is-O- (C) ₁ -C ₆ ) An alkyl group-. In another embodiment are compounds of formula (Ia) wherein Y is a bond.

In another embodiment are compounds of formula (Ia), wherein Z is- (C) ₁ -C ₁₂ ) An alkyl group. In a further embodiment are compounds of formula (Ia) wherein Z is n-butyl, isobutyl, or tert-butyl. In another embodiment are compounds of formula (Ia), wherein Z is-O- (C) ₁ -C ₁₂ ) An alkyl group. In another embodiment are compounds of formula (Ia), wherein Z is-O- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (Ia), wherein Z is- (C) ₂ -C ₁₂ ) An alkenyl group. In another embodiment are compounds of formula (Ia) wherein Z is optionally substituted aryl. In a further embodiment are compounds of formula (Ia) wherein Z is optionally substituted phenyl. In a further embodiment are compounds of formula (Ia) wherein Z is independently selected from- (C) ₁ -C ₈ ) Alkyl substituents are monosubstituted or disubstituted phenyl. In a further embodiment are compounds of formula (Ia) wherein Z is phenyl monosubstituted with n-butyl, isobutyl, or tert-butyl. In a further embodiment are compounds of formula (Ia) wherein Z is phenyl monosubstituted with n-butyl. In a further embodiment are compounds of formula (Ia) wherein Z is phenyl monosubstituted with isobutyl. In a further embodiment are compounds of formula (Ia) wherein Z is t-butylA monosubstituted phenyl group. In another embodiment are compounds of formula (Ia) wherein Z is optionally substituted heteroaryl. In another embodiment are compounds of formula (Ia), wherein Z is optionally substituted- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (Ia) wherein Z is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (Ia) wherein Z is halogen.

In another embodiment are compounds of formula (Ia) wherein Z-Y-X-is not

In another embodiment are compounds of formula (I) having the structure of formula (Ib):

wherein:

R ⁴ is H, - (C) ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-OH, - (C) ₃ -C ₆ ) Cycloalkyl or-C (O) NH ₂ ；

R ⁵ Is H or- (C) ₁ -C ₆ ) An alkyl group;

R ¹¹ is H, -NH ₂ 、-(C ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-OR ²³ 、-(C ₁ -C ₆ ) alkyl-SR ²³ 、-(C ₁ -C ₆ ) alkyl-C (O) OR ²³ 、-(C ₁ -C ₆ ) alkyl-NR ²¹ R ²² 、-(C ₁ -C ₆ ) alkyl-NR ²³ OR ²³ 、-(C ₁ -C ₆ ) alkyl-NHC (O) NR ²³ OR ²³ 、-(C ₁ -C ₆ ) alkyl-O- (C) ₁ -C ₆ ) alkyl-NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) alkyl-CN, - (C) ₁ -C ₆ ) alkyl-NR ²³ C(O)R ²³ 、-(C ₁ -C ₆ ) alkyl-C (O) NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) heteroalkyl-CO ₂ H、-(C ₁ -C ₆ ) alkyl-S (O) (C) ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-N (H))CH＝NH、-(C ₁ -C ₆ ) alkyl-C (NH) ₂ )＝NH、-(C ₁ -C ₆ ) alkyl-N (H) C (= NH) NH ₂ 、-(C ₁ -C ₆ ) alkyl-N (H) S (O) ₂ NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) alkyl-N (H) S (O) ₂ (C ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-N (H) -C (O) NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) Alkyl C (O) N (H) [ optionally substituted (C) ₂ -C ₆ ) Alkyl radical]-OR ²³ 、-(C ₁ -C ₆ ) Alkyl N (H) C (O) (C) ₁ -C ₆ ) alkyl-OR ²³ 、-(C ₁ -C ₆ ) Alkyl C (O) N (H) heterocycloalkyl, - (C) ₁ -C ₆ ) Alkyl C (O) NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) alkyl-N (H) -C (O) - (C) ₁ -C ₆ ) alkyl-NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) alkyl-N (H) - (C) ₁ -C ₆ ) Alkyl C (O) NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) Alkyl-heterocycloalkyl, optionally substituted- (C) ₁ -C ₆ ) alkyl-N (H) heterocycloalkyl or- (C) ₁ -C ₆ ) Alkyl-heteroaryl;

R ¹⁷ and R ¹⁸ Are each independently H, - (C) ₁ -C ₆ ) Alkyl, - (C) ₃ -C ₆ ) Cycloalkyl, - (C) ₁ -C ₆ ) alkyl-OR ²³ 、-(C ₁ -C ₆ ) alkyl-C (O) OR ²³ Or- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² ；

X is optionally substituted- (C) ₁ -C ₆ ) Alkyl-, - (C) ₂ -C ₆ ) Alkenyl-, - (C) ₂ -C ₆ ) Alkynyl, optionally substituted- (C) ₃ -C ₇ ) Cycloalkyl-, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -O- (C) ₁ -C ₆ ) Alkyl-, -N (R) ²⁴ )(C ₁ -C ₆ ) Alkyl radical-、-N(R ²⁴ )(C ₆ -C ₁₀ ) aryl-or-SO ₂ (C ₁ -C ₆ ) Alkyl-;

z is H, halogen, -NH ₂ 、-CN、-CF ₃ 、-CO ₂ H、-(C ₁ -C ₁₂ ) Alkyl, - (C) ₂ -C ₁₂ ) Alkenyl, -CH = ((C) ₃ -C ₇ ) Cycloalkyl), - (C) ₂ -C ₁₂ ) Alkynyl, -C (O) NR ²⁵ R ²⁶ 、-O-(C ₁ -C ₁₂ ) Alkyl, -S- (C) ₁ -C ₁₂ ) Alkyl, -O- (C) ₃ -C ₁₀ ) [ optionally substituted (C) ₃ -C ₇ ) Cycloalkyl radicals]、-O-(C ₁ -C ₆ ) alkyl-OR ²³ 、-(C ₁ -C ₁₂ ) alkyl-OR ²³ 、-(C ₁ -C ₁₂ ) alkyl-CN, -S- (C) ₁ -C ₁₂ ) Alkyl, -N (R) ²⁴ )(C ₁ -C ₁₂ ) Alkyl, -N (R) ²⁴ )C(O)(C ₁ -C ₁₂ ) Alkyl, optionally substituted- (C) ₃ -C ₇ ) Cycloalkyl, - (C) ₁ -C ₆ ) Alkane (I) and its preparation methodRadical- (C) ₃ -C ₇ ) Cycloalkyl, - (C) ₁ -C ₆ ) Alkyl-heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

each R ²³ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

each R ²⁴ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

or R ²⁵ And R ²⁶ And the nitrogen atom to which they are attached form a heterocycloalkyl ring; and

or a pharmaceutically acceptable salt, solvate or prodrug thereof. In one embodiment are compounds of formula (Ib) wherein R ¹⁷ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (Ib) wherein R ¹⁷ is-CH ₃ . In another embodiment are compounds of formula (Ib) wherein R ¹⁷ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (Ib) wherein R ¹⁷ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (Ib)In which R is ¹⁷ Is cyclopropyl. In another embodiment are compounds of formula (Ib) wherein R ¹⁷ Is- (C) ₁ -C ₆ ) alkyl-C (O) OR ²³ . In another embodiment are compounds of formula (Ib) wherein R ¹⁷ is-CH ₂ CH ₂ And (5) OH. In another embodiment are compounds of formula (Ib) wherein R ¹⁷ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (Ib) wherein R ¹⁷ is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (Ib) wherein R ¹⁷ Is H.

In another embodiment are compounds of formula (Ib) wherein R ¹⁸ Is H.

In another embodiment are compounds of formula (Ib) wherein R ⁵ Is H.

In another embodiment are compounds of formula (Ib) wherein R ⁴ Is H. In another embodiment are compounds of formula (Ib) wherein R ⁴ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (Ib) wherein R ⁴ is-CH ₃ . In another embodiment are compounds of formula (Ib) wherein R ⁴ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (Ib) wherein R ⁴ Is- (C) ₁ -C ₆ ) alkyl-OH. In another embodiment are compounds of formula (Ib) wherein R ⁴ is-CH ₂ And (5) OH. In another embodiment are compounds of formula (Ib) wherein R ⁴ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (Ib) wherein R ⁴ Is cyclopropyl. In another embodiment are compounds of formula (Ib) wherein R ⁴ is-C (O) NH ₂ 。

In another embodiment are compounds of formula (Ib) wherein R ⁴ And R ⁵ And the carbon atoms to which they are attached form a cyclopropyl ring.

In another embodiment are compounds of formula (Ib) wherein R ⁹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (Ib) wherein R ⁹ is-CH ₃ . In another embodiment are compounds of formula (Ib) wherein R ⁹ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (Ib) wherein R ⁹ Is- (C) ₁ -C ₆ ) A haloalkyl group. In another embodiment are compounds of formula (Ib) wherein R ⁹ is-CH ₂ F. In another embodiment are compounds of formula (Ib) wherein R ⁹ is-CHF ₂ . In another embodiment are compounds of formula (Ib) wherein R ⁹ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (Ib) wherein R ⁹ Is cyclopropyl. In another embodiment are compounds of formula (Ib) wherein R ⁹ Is H.

In another embodiment are compounds of formula (Ib) wherein R ¹¹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (Ib) wherein R ¹¹ is-CH ₃ . In another embodiment are compounds of formula (Ib) wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-OR ²³ . In another embodiment are compounds of formula (Ib) wherein R ¹¹ is-CH ₂ And (5) OH. In another embodiment are compounds of formula (Ib) wherein R ¹¹ is-CH ₂ CH ₂ And (5) OH. In another embodiment are compounds of formula (Ib) wherein R ¹¹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (Ib) wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (Ib) wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-NH ₂ . In another embodiment are compounds of formula (Ib) wherein R ¹¹ is-CH ₂ NH ₂ . In another embodiment are compounds of formula (Ib) wherein R ¹¹ is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (Ib) wherein R ¹¹ is-CH ₂ CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (Ib) wherein R ¹¹ is-CH ₂ CH ₂ CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (Ib) wherein R ¹¹ Is- (C) ₁ -C ₆ ) An alkyl-CN group. In another embodiment are compounds of formula (Ib) wherein R ¹¹ is-CH ₂ And (C) CN. In another embodiment are compounds of formula (Ib) wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-C (O) NR ²⁵ R ²⁶ . In another embodiment are compounds of formula (Ib) wherein R ¹¹ is-CH ₂ C(O)NH ₂ . In another embodiment are compounds of formula (Ib) wherein R ¹¹ is-CH ₂ CH ₂ C(O)NH ₂ . In another embodiment are compounds of formula (Ib) wherein R ¹¹ Is- (C) ₁ -C ₆ ) Alkyl-heteroaryl. In another embodiment are compounds of formula (Ib) wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-N (H) S (O) ₂ NR ²⁵ R ²⁶ . In another embodiment are compounds of formula (Ib) wherein R ¹¹ is-CH ₂ N(H)S(O) ₂ NH ₂ . In another embodiment are compounds of formula (Ib) wherein R ¹¹ Is H.

In another embodiment are compounds of formula (Ib) wherein R ¹¹ And R ¹⁸ Combine to form an optionally substituted heterocycloalkyl ring.

In another embodiment are compounds of formula (Ib) wherein R ¹ And R ² Each independently is H or- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (Ib) wherein R ¹ And R ² Each is H. In another embodiment are compounds of formula (Ib) wherein R ¹ And R ² Each independently is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (Ib) wherein R ¹ Is H, and R ² Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . At another placeIn one embodiment are compounds of formula (Ib), wherein R ¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² And R is ² Is H. In another embodiment are compounds of formula (Ib) wherein R ¹ Is H, and R ² is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (Ib) wherein R ¹ is-CH ₂ CH ₂ NH ₂ And R is ² Is H. In another embodiment are compounds of formula (Ib) wherein R ¹ And R ² Each is-CH ₂ CH ₂ NH ₂ . In a further embodiment are compounds of formula (Ib) wherein R is ¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² And R is ² Is H. In a further embodiment are compounds of formula (Ib) wherein R ¹ is-CH ₂ CH ₂ NH ₂ And R is ² Is H. In a further embodiment are compounds of formula (Ib) wherein R is ¹ Is H and R ² Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In a further embodiment are compounds of formula (Ib) wherein R is ¹ Is H and R ² is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (Ib) wherein R ¹ And R ² Are each independently H, - (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² or-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (Ib) wherein R ¹ And R ² Each independently is-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (Ib) wherein R ¹ Is H, and R ² is-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (Ib) wherein R ¹ is-CH ₂ CH(OH)CH ₂ NH ₂ And R is ² Is H.

In a further embodiment are compounds of formula (Ib) wherein R is ¹ And R ² And the atoms to which they are attached form an optionally substituted heterocycloalkyl ring.

In another embodiment are compounds of formula (Ib) wherein X is optionally substituted aryl. In a further embodiment are compounds of formula (Ib) wherein X is optionally substituted phenyl. In another embodiment are compounds of formula (Ib) wherein X is optionally substituted heteroaryl. In a further embodiment are compounds of formula (Ib) wherein X is disubstituted heteroaryl. In a further embodiment are compounds of formula (Ib) wherein X is heteroaryl disubstituted with substituents each independently selected from halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ and-NO ₂ . In a further embodiment are compounds of formula (Ib) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituents disubstituted heteroaryl. In a further embodiment are compounds of formula (Ib) wherein X is heteroaryl disubstituted with methyl. In a further embodiment are compounds of formula (Ib) wherein X is pyridyl disubstituted with substituents each independently selected from the group consisting of halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In a further embodiment are compounds of formula (Ib) wherein X is independently selected from- (C) ₁ -C ₆ ) A substituent of an alkyl group. In a further embodiment are compounds of formula (Ib) wherein X is pyridinyl disubstituted with methyl. In a further embodiment are compounds of formula (Ib) wherein X is pyrimidinyl disubstituted with substituents each independently selected from halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In a further embodiment are compounds of formula (Ib) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituent disubstituted pyrimidinyl. In a further embodiment is formula (II) (Ib) compounds wherein X is pyrimidinyl disubstituted with methyl. In another embodiment are compounds of formula (Ib) wherein X is optionally substituted- (C) ₁ -C ₆ ) An alkyl radical.

In another embodiment are compounds of formula (Ib) wherein Y is optionally substituted aryl. In a further embodiment are compounds of formula (Ib) wherein Y is optionally substituted phenyl. In another embodiment are compounds of formula (Ib) wherein Y is optionally substituted heteroaryl. In another embodiment are compounds of formula (Ib) wherein Y is optionally substituted- (C) ₁ -C ₆ ) An alkyl group-. In another embodiment are compounds of formula (Ib) wherein Y is optionally substituted (C) ₃ -C ₇ ) Cycloalkyl-. In another embodiment are compounds of formula (Ib) wherein Y is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (Ib) wherein Y is-O-. In another embodiment are compounds of formula (Ib) wherein Y is- (C) ₂ -C ₆ ) Alkynyl. In another embodiment are compounds of formula (Ib) wherein Y is-O- (C) ₁ -C ₆ ) An alkyl radical. In another embodiment are compounds of formula (Ib) wherein Y is a bond.

In another embodiment are compounds of formula (Ib) wherein Z is- (C) ₁ -C ₁₂ ) An alkyl group. In a further embodiment are compounds of formula (Ib) wherein Z is n-butyl, isobutyl, or tert-butyl. In another embodiment are compounds of formula (Ib) wherein Z is-O- (C) ₁ -C ₁₂ ) An alkyl group. In another embodiment are compounds of formula (Ib) wherein Z is-O- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (Ib) wherein Z is- (C) ₂ -C ₁₂ ) An alkenyl group. In another embodiment are compounds of formula (Ib) wherein Z is optionally substituted aryl. In a further embodiment are compounds of formula (Ib) wherein Z is optionally substituted phenyl. In a further embodiment are compounds of formula (Ib) wherein Z is independently selected from- (C) ₁ -C ₈ ) Alkyl substituents are monosubstituted or disubstituted phenyl. In a further embodiment are compounds of formula (Ib) wherein Z is n-butylPhenyl monosubstituted with an isobutyl group or a tert-butyl group. In a further embodiment are compounds of formula (Ib) wherein Z is phenyl monosubstituted with n-butyl. In a further embodiment are compounds of formula (Ib) wherein Z is phenyl monosubstituted with isobutyl. In a further embodiment are compounds of formula (Ib) wherein Z is phenyl monosubstituted with tert-butyl. In another embodiment are compounds of formula (Ib) wherein Z is optionally substituted heteroaryl. In another embodiment are compounds of formula (Ib) wherein Z is optionally substituted- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (Ib) wherein Z is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (Ib) wherein Z is halo.

In another embodiment are compounds of formula (Ib) wherein Z-Y-X-is other than

In another embodiment are compounds of formula (I) having the structure of formula (Ic):

wherein:

R ¹¹ is H, -NH ₂ 、-(C ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-OR ²³ 、-(C ₁ -C ₆ ) alkyl-SR ²³ 、-(C ₁ -C ₆ ) alkyl-C (O) OR ²³ 、-(C ₁ -C ₆ ) alkyl-NR ²¹ R ²² 、-(C ₁ -C ₆ ) alkyl-NR ²³ OR ²³ 、-(C ₁ -C ₆ ) alkyl-NHC (O) NR ²³ OR ²³ 、-(C ₁ -C ₆ ) alkyl-O- (C) ₁ -C ₆ ) alkyl-NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) alkyl-CN, - (C) ₁ -C ₆ ) alkyl-NR ²³ C(O)R ²³ 、-(C ₁ -C ₆ ) alkyl-C (O) NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) heteroalkyl-CO ₂ H、-(C ₁ -C ₆ ) alkyl-S (O) (C) ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-N (H) CH = NH, - (C) ₁ -C ₆ ) alkyl-C (NH) ₂ )＝NH、-(C ₁ -C ₆ ) alkyl-N (H) C (= NH) NH ₂ 、-(C ₁ -C ₆ ) alkyl-N (H) S (O) ₂ NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) alkyl-N (H) S (O) ₂ (C ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-N (H) -C (O) NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) Alkyl C (O) N (H) [ optionally substituted (C) ₂ -C ₆ ) Alkyl radical]-OR ²³ 、-(C ₁ -C ₆ ) Alkyl N (H) C (O) (C) ₁ -C ₆ ) alkyl-OR ²³ 、-(C ₁ -C ₆ ) Alkyl C (O) N (H) heterocycloalkyl, - (C) ₁ -C ₆ ) Alkyl C (O) NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) alkyl-N (H) -C (O) - (C) ₁ -C ₆ ) alkyl-NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) alkyl-N (H) - (C) ₁ -C ₆ ) Alkyl C (O) NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) Alkyl-heterocycloalkyl, optionally substituted- (C) ₁ -C ₆ ) alkyl-N (H) heterocycloalkyl or- (C) ₁ -C ₆ ) Alkyl-heteroaryl;

each R ²¹ And R ²² Independently of each other is H, - (C) ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) Heteroalkyl, - (C) ₁ -C ₆ ) alkyl-CO ₂ H、-C(O)(C ₁ -C ₆ ) Alkyl, -C (O) O (C) ₁ -C ₆ ) Alkyl, -C (O) O (C) ₁ -C ₆ ) Haloalkyl, -C (= NH) (C) ₁ -C ₆ ) Alkyl, -C (= NH) N (R) ³¹ ) ₂ 、-C(O)N(R ³¹ ) ₂ or-SO ₂ N(R ³¹ ) ₂ (ii) a Or R ²¹ And R ²² And the nitrogen atom form to which they are attachedTo form a heterocycloalkyl ring;

each R ²³ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

each R ²⁴ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

or a pharmaceutically acceptable salt, solvate or prodrug thereof. In another embodiment are compounds of formula (Ic) wherein R ¹¹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (Ic), wherein R ¹¹ is-CH ₃ . In another embodiment are compounds of formula (Ic), wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-OR ²³ . In another embodiment are compounds of formula (Ic), wherein R ¹¹ is-CH ₂ And (5) OH. In another embodiment are compounds of formula (Ic), wherein R ¹¹ is-CH ₂ CH ₂ And (5) OH. In another embodiment are compounds of formula (Ic), wherein R ¹¹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (Ic), wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (Ic), wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-NH ₂ . In another embodiment are compounds of formula (Ic), wherein R ¹¹ is-CH ₂ NH ₂ . In another embodiment are compounds of formula (Ic), wherein R ¹¹ is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (Ic), wherein R ¹¹ is-CH ₂ CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (Ic), wherein R ¹¹ is-CH ₂ CH ₂ CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (Ic), wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-CN. In another embodiment are compounds of formula (Ic) wherein R ¹¹ is-CH ₂ And (C) CN. In another embodiment are compounds of formula (Ic), wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-C (O) NR ²⁵ R ²⁶ . In another embodiment are compounds of formula (Ic), wherein R ¹¹ is-CH ₂ C(O)NH ₂ . In another embodiment are compounds of formula (Ic), wherein R ¹¹ is-CH ₂ CH ₂ C(O)NH ₂ . In another embodiment are compounds of formula (Ic) wherein R ¹¹ Is- (C) ₁ -C ₆ ) Alkyl-heteroaryl. In another embodiment are compounds of formula (Ic), wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-N (H) S (O) ₂ NR ²⁵ R ²⁶ . In another embodiment are compounds of formula (Ic) wherein R ¹¹ is-CH ₂ N(H)S(O) ₂ NH ₂ . In another embodiment are compounds of formula (Ic) wherein R ¹¹ Is H.

In another embodiment are compounds of formula (Ic), wherein R ¹ And R ² Each independently is H or- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (Ic) wherein R ¹ And R ² Each is H. In another embodiment are compounds of formula (Ic), wherein R ¹ And R ² Each independently is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (Ic), wherein R ¹ Is H, and R ² Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (Ic), wherein R ¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² And R is ² Is H. In another implementationIn the scheme are compounds of formula (Ic) wherein R ¹ Is H, and R ² is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (Ic), wherein R ¹ is-CH ₂ CH ₂ NH ₂ And R is ² Is H. In another embodiment are compounds of formula (Ic), wherein R ¹ And R ² Each is-CH ₂ CH ₂ NH ₂ . In a further embodiment are compounds of formula (Ic) wherein R is ¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² And R is ² Is H. In a further embodiment are compounds of formula (Ic) wherein R is ¹ is-CH ₂ CH ₂ NH ₂ And R is ² Is H. In a further embodiment are compounds of formula (Ic) wherein R ¹ Is H and R ² Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In a further embodiment are compounds of formula (Ic) wherein R is ¹ Is H and R ² is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (Ic) wherein R ¹ And R ² Are each independently H, - (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² or-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (Ic), wherein R ¹ And R ² Each independently is-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (Ic), wherein R ¹ Is H, and R ² is-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (Ic), wherein R ¹ is-CH ₂ CH(OH)CH ₂ NH ₂ And R is ² Is H.

In a further embodiment are compounds of formula (Ic) wherein R is ¹ And R ² And the atoms to which they are attached form an optionally substituted heterocycloalkyl ring.

In another embodiment are compounds of formula (Ic) wherein X is optionally substituted aryl. In a further embodiment are compounds of formula (Ic), whereinX is optionally substituted phenyl. In another embodiment are compounds of formula (Ic) wherein X is optionally substituted heteroaryl. In a further embodiment are compounds of formula (Ic) wherein X is disubstituted heteroaryl. In a further embodiment are compounds of formula (Ic) wherein X is heteroaryl disubstituted with substituents each independently selected from halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ and-NO ₂ . In a further embodiment are compounds of formula (Ic) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituents disubstituted heteroaryl. In a further embodiment are compounds of formula (Ic) wherein X is heteroaryl disubstituted with methyl. In a further embodiment are compounds of formula (Ic) wherein X is pyridyl disubstituted with substituents each independently selected from the group consisting of halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In a further embodiment are compounds of formula (Ic) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituent disubstituted pyridyl. In a further embodiment are compounds of formula (Ic) wherein X is pyridyl disubstituted with methyl. In a further embodiment are compounds of formula (Ic) wherein X is pyrimidinyl disubstituted with substituents each independently selected from halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In a further embodiment are compounds of formula (Ic) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituent disubstituted pyrimidinyl. In a further embodiment are compounds of formula (Ic) wherein X is pyrimidinyl disubstituted with methyl. In another embodiment are compounds of formula (Ic) wherein X is optionally substituted- (C) ₁ -C ₆ ) An alkyl group-.

In another embodiment are compounds of formula (Ic) wherein Y is optionally substituted aryl. In a further embodiment are compounds of formula (Ic) wherein Y is optionally substituted phenyl. In another embodiment are compounds of formula (Ic) wherein Y is optionally substituted heteroaryl. In another embodiment are compounds of formula (Ic) wherein Y is optionally substituted- (C) ₁ -C ₆ ) An alkyl group-. In another embodiment are compounds of formula (Ic) wherein Y is optionally substituted (C) ₃ -C ₇ ) Cycloalkyl-. In another embodiment are compounds of formula (Ic) wherein Y is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (Ic) wherein Y is-O-. In another embodiment are compounds of formula (Ic) wherein Y is- (C) ₂ -C ₆ ) Alkynyl. In another embodiment are compounds of formula (Ic) wherein Y is-O- (C) ₁ -C ₆ ) An alkyl radical. In another embodiment are compounds of formula (Ic) wherein Y is a bond.

In another embodiment are compounds of formula (Ic) wherein Z is- (C) ₁ -C ₁₂ ) An alkyl group. In a further embodiment are compounds of formula (Ic) wherein Z is n-butyl, isobutyl, or tert-butyl. In another embodiment are compounds of formula (Ic) wherein Z is-O- (C) ₁ -C ₁₂ ) An alkyl group. In another embodiment are compounds of formula (Ic) wherein Z is-O- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (Ic) wherein Z is- (C) ₂ -C ₁₂ ) An alkenyl group. In another embodiment are compounds of formula (Ic) wherein Z is optionally substituted aryl. In a further embodiment are compounds of formula (Ic) wherein Z is optionally substituted phenyl. In a further embodiment are compounds of formula (Ic) wherein Z is independently selected from- (C) ₁ -C ₈ ) Alkyl substituents are monosubstituted or disubstituted phenyl. In a further embodiment are compounds of formula (Ic) wherein Z is phenyl monosubstituted with n-butyl, isobutyl, or tert-butyl. In a further embodiment are compounds of formula (Ic) wherein Z is phenyl monosubstituted with n-butyl. In a further embodimentIs a compound of formula (Ic) wherein Z is phenyl monosubstituted with isobutyl. In a further embodiment are compounds of formula (Ic) wherein Z is phenyl monosubstituted with tert-butyl. In another embodiment are compounds of formula (Ic) wherein Z is optionally substituted heteroaryl. In another embodiment are compounds of formula (Ic) wherein Z is optionally substituted- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (Ic) wherein Z is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (Ic) wherein Z is halogen.

In another embodiment are compounds of formula (Ic) wherein Z-Y-X-is other than

In another embodiment are compounds of formula (I) having the structure of formula (Id):

wherein:

R ¹¹ is-CH ₂ NH ₂ 、-CH ₂ CH ₂ NH _Or -CH ₂ CH ₂ CH ₂ NH ₂ ；

each R ²³ Independently is H or- (C) ₁ -C ₆ ) Alkyl radical；

Each R ²⁴ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

or a pharmaceutically acceptable salt, solvate or prodrug thereof. In one embodiment are compounds of formula (Id), wherein R ¹¹ is-CH ₂ NH ₂ . In another embodiment are compounds of formula (Id), wherein R ¹¹ is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (Id) wherein R ¹¹ is-CH ₂ CH ₂ CH ₂ NH ₂ 。

In another embodiment are compounds of formula (Id) wherein X is optionally substituted aryl. In a further embodiment are compounds of formula (Id) wherein X is optionally substituted phenyl. In another embodiment are compounds of formula (Id) wherein X is optionally substituted heteroaryl. In a further embodiment are compounds of formula (Id) wherein X is disubstituted heteroaryl. In a further embodiment are compounds of formula (Id) wherein X is heteroaryl disubstituted with substituents each independently selected from halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ and-NO ₂ . In a further embodiment are compounds of formula (Id) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituents disubstituted heteroaryl. In a further embodiment are compounds of formula (Id) wherein X is heteroaryl disubstituted with methyl. In a further embodiment are compounds of formula (Id) wherein X is pyridyl disubstituted with substituents each independently selected from the group consisting of halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, aryl, heteroaryl, and heteroaryl,OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In a further embodiment are compounds of formula (Id) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituent disubstituted pyridyl. In a further embodiment are compounds of formula (Id) wherein X is pyridyl disubstituted with methyl. In a further embodiment are compounds of formula (Id) wherein X is pyrimidinyl disubstituted with substituents each independently selected from the group consisting of halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In a further embodiment are compounds of formula (Id), wherein X is selected from- (C) and- (C) is a group ₁ -C ₆ ) Alkyl substituent disubstituted pyrimidinyl. In a further embodiment are compounds of formula (Id) wherein X is pyrimidinyl disubstituted with methyl. In another embodiment are compounds of formula (Id) wherein X is optionally substituted- (C) ₁ -C ₆ ) An alkyl radical.

In another embodiment are compounds of formula (Id) wherein Y is optionally substituted aryl. In a further embodiment are compounds of formula (Id) wherein Y is optionally substituted phenyl. In another embodiment are compounds of formula (Id) wherein Y is optionally substituted heteroaryl. In another embodiment are compounds of formula (Id) wherein Y is optionally substituted- (C) ₁ -C ₆ ) An alkyl group-. In another embodiment are compounds of formula (Id) wherein Y is optionally substituted (C) ₃ -C ₇ ) Cycloalkyl-. In another embodiment are compounds of formula (Id) wherein Y is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (Id) wherein Y is-O-. In another embodiment are compounds of formula (Id) wherein Y is- (C) ₂ -C ₆ ) Alkynyl. In another embodiment are compounds of formula (Id) wherein Y is-O- (C) ₁ -C ₆ ) An alkyl radical. In another embodiment are compounds of formula (Id) wherein Y is a bond.

In another embodiment are compounds of formula (Id) wherein Z is-(C ₁ -C ₁₂ ) An alkyl group. In a further embodiment are compounds of formula (Id) wherein Z is n-butyl, isobutyl, or tert-butyl. In another embodiment are compounds of formula (Id) wherein Z is-O- (C) ₁ -C ₁₂ ) An alkyl group. In another embodiment are compounds of formula (Id) wherein Z is-O- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (Id) wherein Z is- (C) ₂ -C ₁₂ ) An alkenyl group. In another embodiment are compounds of formula (Id) wherein Z is optionally substituted aryl. In a further embodiment are compounds of formula (Id) wherein Z is optionally substituted phenyl. In a further embodiment are compounds of formula (Id) wherein Z is independently selected from- (C) ₁ -C ₈ ) Alkyl substituents are monosubstituted or disubstituted phenyl. In a further embodiment are compounds of formula (Id) wherein Z is phenyl monosubstituted with n-butyl, isobutyl, or tert-butyl. In a further embodiment are compounds of formula (Id) wherein Z is phenyl monosubstituted with n-butyl. In a further embodiment are compounds of formula (Id) wherein Z is phenyl monosubstituted with isobutyl. In a further embodiment are compounds of formula (Id) wherein Z is phenyl monosubstituted with tert-butyl. In another embodiment are compounds of formula (Id) wherein Z is optionally substituted heteroaryl. In another embodiment are compounds of formula (Id) wherein Z is optionally substituted- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (Id) wherein Z is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (Id) wherein Z is halo.

In another embodiment are compounds of formula (Id) wherein Z-Y-X-is other than

In another embodiment are compounds of formula (I) having the structure of formula (Ie):

wherein:

R ² is H, - (C) ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-OR ²³ 、-CH ₂ CH(OH)CH ₂ NH ₂ 、-CH ₂ CH (heterocycloalkyl) CH ₂ NH ₂ 、-CH ₂ C(O)NH ₂ 、-CH ₂ C(O)N(H)CH ₂ CN、-(C ₁ -C ₆ ) alkyl-C (O) OR ²³ 、-(C ₁ -C ₆ ) alkyl-NR ²¹ R ²² 、-(C ₁ -C ₆ ) alkyl-C (O) NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) alkyl-N (R) ²³ )C(O)(C ₁ -C ₆ ) Alkyl radical NR ²¹ R ²² 、-(C ₁ -C ₆ ) alkyl-N (R) ²³ )C(O)(C ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-C (O) N (R) ²³ )(C ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-C (O) N (R) ²³ )(C ₁ -C ₆ ) Alkyl-heterocycloalkyl, (C) ₁ -C ₆ ) Heteroalkyl or optionally substituted heterocycloalkyl;

R ⁵ Is H or- (C) ₁ -C ₆ ) An alkyl group;

each R ²³ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

each R ²⁴ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

or a pharmaceutically acceptable salt, solvate or prodrug thereof. In one embodiment are compounds of formula (Ie) wherein R ¹⁷ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (Ie) wherein R ¹⁷ is-CH ₃ . In another embodiment are compounds of formula (Ie) wherein R ¹⁷ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (Ie) wherein R ¹⁷ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (Ie) wherein R ¹⁷ Is cyclopropyl. In another embodiment are compounds of formula (Ie) wherein R ¹⁷ Is- (C) ₁ -C ₆ ) alkyl-C (O) OR ²³ . In another embodiment are compounds of formula (Ie) wherein R ¹⁷ is-CH ₂ CH ₂ And (5) OH. In another embodiment are compounds of formula (Ie) wherein R ¹⁷ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (Ie) wherein R ¹⁷ is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (Ie) wherein R ¹⁷ Is H.

In another embodiment are compounds of formula (Ie) wherein R ¹⁸ Is H.

In another embodiment are compounds of formula (Ie) wherein R ⁵ Is H.

In another embodiment are compounds of formula (Ie) wherein R ⁴ Is H. In another embodiment are compounds of formula (Ie) wherein R ⁴ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (Ie) wherein R ⁴ is-CH ₃ . In addition toIn one embodiment are compounds of formula (Ie) wherein R ⁴ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (Ie) wherein R ⁴ Is- (C) ₁ -C ₆ ) alkyl-OH. In another embodiment are compounds of formula (Ie) wherein R ⁴ is-CH ₂ And (5) OH. In another embodiment are compounds of formula (Ie) wherein R ⁴ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (Ie) wherein R ⁴ Is cyclopropyl. In another embodiment are compounds of formula (Ie) wherein R ⁴ is-C (O) NH ₂ 。

In another embodiment are compounds of formula (Ie) wherein R ⁴ And R ⁵ And the carbon atoms to which they are attached form a cyclopropyl ring.

In another embodiment are compounds of formula (Ie) wherein R ⁹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (Ie) wherein R ⁹ is-CH ₃ . In another embodiment are compounds of formula (Ie) wherein R ⁹ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (Ie) wherein R ⁹ Is- (C) ₁ -C ₆ ) A haloalkyl group. In another embodiment are compounds of formula (Ie) wherein R ⁹ is-CH ₂ F. In another embodiment are compounds of formula (Ie) wherein R ⁹ is-CHF ₂ . In another embodiment are compounds of formula (Ie) wherein R ⁹ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (Ie) wherein R ⁹ Is cyclopropyl. In another embodiment are compounds of formula (Ie) wherein R ⁹ Is H.

In another embodiment are compounds of formula (Ie) wherein R ¹¹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (Ie) wherein R ¹¹ is-CH ₃ . In another embodiment are compounds of formula (Ie) wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-OR ²³ . In another embodimentIn one embodiment are compounds of formula (Ie) wherein R ¹¹ is-CH ₂ And (5) OH. In another embodiment are compounds of formula (Ie) wherein R ¹¹ is-CH ₂ CH ₂ And (5) OH. In another embodiment are compounds of formula (Ie) wherein R ¹¹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (Ie) wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (Ie) wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-NH ₂ . In another embodiment are compounds of formula (Ie) wherein R ¹¹ is-CH ₂ NH ₂ . In another embodiment are compounds of formula (Ie) wherein R ¹¹ is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (Ie) wherein R ¹¹ is-CH ₂ CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (Ie) wherein R ¹¹ is-CH ₂ CH ₂ CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (Ie) wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-CN. In another embodiment are compounds of formula (Ie) wherein R ¹¹ is-CH ₂ And (C) CN. In another embodiment are compounds of formula (Ie) wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-C (O) NR ²⁵ R ²⁶ . In another embodiment are compounds of formula (Ie) wherein R ¹¹ is-CH ₂ C(O)NH ₂ . In another embodiment are compounds of formula (Ie) wherein R ¹¹ is-CH ₂ CH ₂ C(O)NH ₂ . In another embodiment are compounds of formula (Ie) wherein R ¹¹ Is- (C) ₁ -C ₆ ) Alkyl-heteroaryl. In another embodiment are compounds of formula (Ie) wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-N (H) S (O) ₂ NR ²⁵ R ²⁶ . In another embodiment are compounds of formula (Ie) wherein R ¹¹ is-CH ₂ N(H)S(O) ₂ NH ₂ . In another embodiment are compounds of formula (Ie) wherein R ¹¹ Is H.

In another embodiment are compounds of formula (Ie) wherein R ¹¹ And R ¹⁸ Combine to form an optionally substituted heterocycloalkyl ring.

In another embodiment are compounds of formula (Ie) wherein R ² Is H or- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (Ie) wherein R ² Is H. In another embodiment are compounds of formula (Ie) wherein R ² Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (Ie) wherein R ² is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (Ie) wherein R ² is-CH ₂ CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (Ie) wherein R ² is-CH ₂ NH ₂ . In another embodiment are compounds of formula (Ie) wherein R ² Is H, - (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² or-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (Ie) wherein R ² is-CH ₂ CH(OH)CH ₂ NH ₂ 。

In another embodiment are compounds of formula (Ie) wherein X is optionally substituted aryl. In a further embodiment are compounds of formula (Ie) wherein X is optionally substituted phenyl. In another embodiment are compounds of formula (Ie) wherein X is optionally substituted heteroaryl. In a further embodiment are compounds of formula (Ie) wherein X is mono-or di-substituted heteroaryl. In a further embodiment are compounds of formula (Ie) wherein X is disubstituted heteroaryl. In a further embodiment are compounds of formula (Ie) wherein X is heteroaryl, mono-or di-substituted with substituents each independently selected from halo, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl radical、OR ²³ 、-NR ²⁵ R ²⁶ and-NO ₂ . In a further embodiment are compounds of formula (Ie) wherein X is heteroaryl, mono-or di-substituted with substituents each independently selected from- (C) ₁ -C ₆ ) An alkyl group. In a further embodiment are compounds of formula (Ie) wherein X is heteroaryl, mono-or di-substituted with methyl. In a further embodiment are compounds of formula (Ie) wherein X is pyridinyl mono-or disubstituted with substituents each independently selected from the group consisting of halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In a further embodiment are compounds of formula (Ie) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituent monosubstituted or disubstituted pyridyl. In a further embodiment are compounds of formula (Ie) wherein X is pyridinyl mono-or di-substituted with methyl. In a further embodiment are compounds of formula (Ie) wherein X is pyrimidinyl mono-or di-substituted with substituents each independently selected from halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In a further embodiment are compounds of formula (Ie) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituent monosubstituted or disubstituted pyrimidinyl. In a further embodiment are compounds of formula (Ie) wherein X is pyrimidinyl mono-or di-substituted with methyl. In another embodiment are compounds of formula (Ie) wherein X is optionally substituted- (C) ₁ -C ₆ ) An alkyl group-.

In another embodiment are compounds of formula (Ie) wherein Y is optionally substituted aryl. In a further embodiment are compounds of formula (Ie) wherein Y is optionally substituted phenyl. In another embodiment are compounds of formula (Ie) wherein Y is optionally substituted heteroaryl. In another embodiment are compounds of formula (Ie) whereinY is optionally substituted- (C) ₁ -C ₆ ) An alkyl group-. In another embodiment are compounds of formula (Ie) wherein Y is optionally substituted (C) ₃ -C ₇ ) Cycloalkyl-. In another embodiment are compounds of formula (Ie) wherein Y is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (Ie) wherein Y is-O-. In another embodiment are compounds of formula (Ie) wherein Y is- (C) ₂ -C ₆ ) Alkynyl. In another embodiment are compounds of formula (Ie) wherein Y is-O- (C) ₁ -C ₆ ) An alkyl group-. In another embodiment are compounds of formula (Ie) wherein Y is a bond.

In another embodiment are compounds of formula (Ie) wherein Z is- (C) ₁ -C ₁₂ ) An alkyl group. In a further embodiment are compounds of formula (Ie) wherein Z is n-butyl, isobutyl, or tert-butyl. In another embodiment are compounds of formula (Ie) wherein Z is-O- (C) ₁ -C ₁₂ ) An alkyl group. In another embodiment are compounds of formula (Ie) wherein Z is-O- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (Ie) wherein Z is- (C) ₂ -C ₁₂ ) An alkenyl group. In another embodiment are compounds of formula (Ie) wherein Z is optionally substituted aryl. In a further embodiment are compounds of formula (Ie) wherein Z is optionally substituted phenyl. In a further embodiment are compounds of formula (Ie) wherein Z is independently selected from- (C) ₁ -C ₈ ) Alkyl substituents are monosubstituted or disubstituted phenyl. In a further embodiment are compounds of formula (Ie) wherein Z is phenyl monosubstituted with n-butyl, isobutyl, or tert-butyl. In a further embodiment are compounds of formula (Ie) wherein Z is phenyl monosubstituted with n-butyl. In a further embodiment are compounds of formula (Ie) wherein Z is phenyl monosubstituted with isobutyl. In a further embodiment are compounds of formula (Ie) wherein Z is phenyl monosubstituted with tert-butyl. In another embodiment are compounds of formula (Ie) wherein Z is optionally substituted heteroaryl. In another embodiment are compounds of formula (Ie) wherein Z is optionally substituted- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (Ie) wherein Z is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (Ie) wherein Z is halo.

In another embodiment are compounds of formula (I) having the structure of formula (If):

wherein:

R ¹ is H, - (C) ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-OR ²³ 、-CH ₂ CH(OH)CH ₂ NH ₂ 、-CH ₂ CH (Heterocyclylalkyl) CH ₂ NH ₂ 、-CH ₂ C(O)NH ₂ 、-CH ₂ C(O)N(H)CH ₂ CN、-(C ₁ -C ₆ ) alkyl-C (O) OR ²³ 、-(C ₁ -C ₆ ) alkyl-NR ²¹ R ²² 、-(C ₁ -C ₆ ) alkyl-C (O) NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) alkyl-N (R) ²³ )C(O)(C ₁ -C ₆ ) Alkyl radical NR ²¹ R ²² 、-(C ₁ -C ₆ ) alkyl-N (R) ²³ )C(O)(C ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-C (O) N (R) ²³ )(C ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-C (O) N (R) ²³ )(C ₁ -C ₆ ) Alkyl-heterocycloalkyl, (C) ₁ -C ₆ ) Heteroalkyl or optionally substituted heterocycloalkyl;

R ⁵ Is H or- (C) ₁ -C ₆ ) An alkyl group;

y is a bond, -O-, -S-, optionally substituted- (C) ₁ -C ₆ ) Alkyl-, - (C) ₂ -C ₆ ) Alkenyl-, - (C) ₂ -C ₆ ) Alkynyl, - (C) ₁ -C ₆ ) alkyl-N (R) ²⁴ )(C ₁ -C ₆ ) Alkyl-, -O- (C) ₁ -C ₆ ) Alkyl-, -O (C) ₆ -C ₁₀ ) Aryl-, -N (R) ²⁴ )(C ₁ -C ₆ ) Alkyl-, -N (R) ²⁴ )SO ₂ (C ₁ -C ₆ ) Alkyl-, -N (R) ²⁴ )C(O)(C ₁ -C ₆ ) Alkyl-, -C (O) (C) ₁ -C ₆ ) Alkyl-, -S (C) ₁ -C ₆ ) Alkyl-, -SO ₂ (C ₁ -C ₆ ) Alkyl-, -C (O) NH (C) ₁ -C ₆ ) Alkyl-, optionally substituted- (C) ₃ -C ₇ ) Cycloalkyl-, optionally substituted-C (O) N (R) ²⁴ ) Aryl radical-, optionally substituted-N (R) ²⁴ ) C (O) aryl-, optionally substituted-N (R) ²⁴ )SO ₂ Aryl-, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

each R ³¹ Independently is H or- (C) ₁ -C ₆ ) An alkyl group; or two R ³¹ And to which they are attachedThe attached nitrogen atom forms a heterocycloalkyl ring;

each R ²³ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

each R ²⁴ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

or a pharmaceutically acceptable salt, solvate or prodrug thereof. In one embodiment are compounds of formula (If), wherein R is ¹⁷ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (If), wherein R is ¹⁷ is-CH ₃ . In another embodiment are compounds of formula (If) wherein R ¹⁷ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (If) wherein R ¹⁷ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (If), wherein R is ¹⁷ Is cyclopropyl. In another embodiment are compounds of formula (If), wherein R is ¹⁷ Is- (C) ₁ -C ₆ ) alkyl-C (O) OR ²³ . In another embodiment are compounds of formula (If) wherein R ¹⁷ is-CH ₂ CH ₂ And (5) OH. In another embodiment are compounds of formula (If), wherein R is ¹⁷ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (If), wherein R is ¹⁷ is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (If), wherein R is ¹⁷ Is H.

In another embodiment are compounds of formula (If), wherein R is ¹⁸ Is H.

In another embodiment are compounds of formula (If) wherein R ⁵ Is H.

In another embodiment are compounds of formula (If) wherein R ⁴ Is H. At another placeIn one embodiment are compounds of formula (If), wherein R is ⁴ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (If), wherein R is ⁴ is-CH ₃ . In another embodiment are compounds of formula (If), wherein R is ⁴ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (If), wherein R is ⁴ Is- (C) ₁ -C ₆ ) alkyl-OH. In another embodiment are compounds of formula (If), wherein R is ⁴ is-CH ₂ And (5) OH. In another embodiment are compounds of formula (If), wherein R is ⁴ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (If) wherein R ⁴ Is cyclopropyl. In another embodiment are compounds of formula (If), wherein R is ⁴ is-C (O) NH ₂ 。

In another embodiment are compounds of formula (If), wherein R is ⁴ And R ⁵ And the carbon atoms to which they are attached form a cyclopropyl ring.

In another embodiment are compounds of formula (If) wherein R ⁹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (If), wherein R is ⁹ is-CH ₃ . In another embodiment are compounds of formula (If), wherein R is ⁹ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (If), wherein R is ⁹ Is- (C) ₁ -C ₆ ) A haloalkyl group. In another embodiment are compounds of formula (If) wherein R ⁹ is-CH ₂ F. In another embodiment are compounds of formula (If), wherein R is ⁹ is-CHF ₂ . In another embodiment are compounds of formula (If), wherein R is ⁹ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (If), wherein R is ⁹ Is cyclopropyl. In another embodiment are compounds of formula (If) wherein R ⁹ Is H.

In another embodiment are compounds of formula (If), wherein R is ¹¹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment of formula (If)) A compound of formula (I) wherein R ¹¹ is-CH ₃ . In another embodiment are compounds of formula (If) wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-OR ²³ . In another embodiment are compounds of formula (If), wherein R is ¹¹ is-CH ₂ And (5) OH. In another embodiment are compounds of formula (If), wherein R is ¹¹ is-CH ₂ CH ₂ And (5) OH. In another embodiment are compounds of formula (If) wherein R ¹¹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (If), wherein R is ¹¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (If) wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-NH ₂ . In another embodiment are compounds of formula (If) wherein R ¹¹ is-CH ₂ NH ₂ . In another embodiment are compounds of formula (If) wherein R ¹¹ is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (If) wherein R ¹¹ is-CH ₂ CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (If) wherein R ¹¹ is-CH ₂ CH ₂ CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (If), wherein R is ¹¹ Is- (C) ₁ -C ₆ ) alkyl-CN. In another embodiment are compounds of formula (If), wherein R is ¹¹ is-CH ₂ And (C) CN. In another embodiment are compounds of formula (If), wherein R is ¹¹ Is- (C) ₁ -C ₆ ) alkyl-C (O) NR ²⁵ R ²⁶ . In another embodiment are compounds of formula (If) wherein R ¹¹ is-CH ₂ C(O)NH ₂ . In another embodiment are compounds of formula (If), wherein R is ¹¹ is-CH ₂ CH ₂ C(O)NH ₂ . In another embodiment are compounds of formula (If) wherein R ¹¹ Is- (C) ₁ -C ₆ ) Alkyl-heteroaryl. In another embodiment are compounds of formula (If), wherein R is ¹¹ Is- (C) ₁ -C ₆ ) alkyl-N (H) S (O) ₂ NR ²⁵ R ²⁶ . In another embodiment are compounds of formula (If) wherein R ¹¹ is-CH ₂ N(H)S(O) ₂ NH ₂ . In another embodiment are compounds of formula (If), wherein R is ¹¹ Is H.

In another embodiment are compounds of formula (If), wherein R is ¹¹ And R ¹⁸ Combine to form an optionally substituted heterocycloalkyl ring.

In another embodiment are compounds of formula (If) wherein R ¹ Is H or- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (If) wherein R ¹ Is H. In another embodiment are compounds of formula (If), wherein R is ¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (If), wherein R is ¹ is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (If), wherein R is ¹ is-CH ₂ CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (If), wherein R is ¹ is-CH ₂ NH ₂ . In another embodiment are compounds of formula (If), wherein R is ¹ Is H, - (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² or-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (If), wherein R is ¹ is-CH ₂ CH(OH)CH ₂ NH ₂ 。

In another embodiment are compounds of formula (If) wherein X is optionally substituted aryl. In a further embodiment are compounds of formula (If) wherein X is optionally substituted phenyl. In another embodiment are compounds of formula (If) wherein X is optionally substituted heteroaryl. In a further embodiment are compounds of formula (If) wherein X is mono-or di-substituted heteroaryl. In a further embodiment are compounds of formula (If) wherein X is disubstituted heteroaryl. In a further embodiment are compounds of formula (If) wherein X is substitutedOptionally mono-or disubstituted heteroaryl, each of which substituents is independently selected from halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ and-NO ₂ . In a further embodiment are compounds of formula (If) wherein X is heteroaryl, mono-or di-substituted with substituents each independently selected from- (C) ₁ -C ₆ ) An alkyl group. In a further embodiment are compounds of formula (If) wherein X is heteroaryl, mono-or di-substituted with methyl. In a further embodiment are compounds of formula (If) wherein X is pyridinyl mono-or disubstituted with substituents each independently selected from the group consisting of halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In a further embodiment are compounds of formula (If), wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituent monosubstituted or disubstituted pyridyl. In a further embodiment are compounds of formula (If) wherein X is pyridinyl mono-or di-substituted with methyl. In a further embodiment are compounds of formula (If) wherein X is pyrimidinyl mono-or di-substituted with substituents each independently selected from halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In a further embodiment are compounds of formula (If) wherein X is pyrimidinyl mono-or di-substituted with a substituent each independently selected from- (C) ₁ -C ₆ ) An alkyl group. In a further embodiment are compounds of formula (If) wherein X is pyrimidinyl mono-or di-substituted with methyl. In another embodiment are compounds of formula (If) wherein X is optionally substituted- (C) ₁ -C ₆ ) An alkyl radical.

In another embodiment are compounds of formula (If) wherein Y is optionally substituted aryl. In a further implementationIn this scheme are compounds of formula (If) wherein Y is optionally substituted phenyl. In another embodiment are compounds of formula (If) wherein Y is optionally substituted heteroaryl. In another embodiment are compounds of formula (If), wherein Y is optionally substituted- (C) ₁ -C ₆ ) An alkyl radical. In another embodiment are compounds of formula (If) wherein Y is optionally substituted (C) ₃ -C ₇ ) Cycloalkyl-. In another embodiment are compounds of formula (If) wherein Y is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (If) wherein Y is-O-. In another embodiment are compounds of formula (If), wherein Y is- (C) ₂ -C ₆ ) Alkynyl. In another embodiment are compounds of formula (If), wherein Y is-O- (C) ₁ -C ₆ ) An alkyl group-. In another embodiment are compounds of formula (If) wherein Y is a bond.

In another embodiment are compounds of formula (If), wherein Z is- (C) ₁ -C ₁₂ ) An alkyl group. In a further embodiment are compounds of formula (If) wherein Z is n-butyl, isobutyl, or tert-butyl. In another embodiment are compounds of formula (If), wherein Z is-O- (C) ₁ -C ₁₂ ) An alkyl group. In another embodiment are compounds of formula (If) wherein Z is-O- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (If), wherein Z is- (C) ₂ -C ₁₂ ) An alkenyl group. In another embodiment are compounds of formula (If) wherein Z is optionally substituted aryl. In a further embodiment are compounds of formula (If) wherein Z is optionally substituted phenyl. In a further embodiment are compounds of formula (If), wherein Z is independently selected from- (C) ₁ -C ₈ ) Alkyl substituents are monosubstituted or disubstituted phenyl. In a further embodiment are compounds of formula (If) wherein Z is phenyl monosubstituted with n-butyl, isobutyl, or tert-butyl. In a further embodiment are compounds of formula (If) wherein Z is phenyl monosubstituted with n-butyl. In a further embodiment are compounds of formula (If) wherein Z is phenyl monosubstituted with isobutyl. In a further embodiment are compounds of formula (If) wherein Z is t-butylA monosubstituted phenyl group. In another embodiment are compounds of formula (If) wherein Z is optionally substituted heteroaryl. In another embodiment are compounds of formula (If), wherein Z is optionally substituted- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (If) wherein Z is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (If) wherein Z is halo.

In another aspect, described herein are compounds of formula (II), or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

wherein:

R ³ is H or- (C) ₁ -C ₆ ) An alkyl group;

Or R ³ And R ⁴ Combine to form a heterocycloalkyl ring;

R ⁵ is H or- (C) ₁ -C ₆ ) An alkyl group;

R ¹⁰ is H or- (C) ₁ -C ₆ ) An alkyl group;

R ¹³ and R ¹⁴ Each independently is H, -NH ₂ 、-(C ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-OR ²³ 、-(C ₁ -C ₆ ) alkyl-SR ²³ 、-(C ₁ -C ₆ ) alkyl-C (O) OR ²³ 、-(C ₁ -C ₆ ) alkyl-NR ²¹ R ²² 、-(C ₁ -C ₆ ) alkyl-CN, - (C) ₁ -C ₆ ) alkyl-C (O) NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) alkyl-N (H) C (NH) NH ₂ 、-(C ₁ -C ₆ ) Alkyl-heterocycloalkyl or- (C) ₁ -C ₆ ) Alkyl-heteroaryl;

y is a bond, -O-, -S-, optionally substituted- (C) ₁ -C ₆ ) Alkyl-, - (C) ₂ -C ₆ ) Alkenyl-, - (C) ₂ -C ₆ ) Alkynyl, - (C) ₁ -C ₆ ) alkyl-N (R) ²⁴ )(C ₁ -C ₆ ) Alkyl-, -O- (C) ₁ -C ₆ ) Alkyl-, -O (C) ₆ -C ₁₀ ) Aryl-, -N (R) ²⁴ )(C ₁ -C ₆ ) Alkyl-, -N (R) ²⁴ )SO ₂ (C ₁ -C ₆ ) Alkyl-, -N (R) ²⁴ )C(O)(C ₁ -C ₆ ) Alkyl-, -C (O) (C) ₁ -C ₆ ) Alkyl-, -S (C) ₁ -C ₆ ) Alkyl-, -SO ₂ (C ₁ -C ₆ ) Alkyl-, -C (O) NH (C) ₁ -C ₆ ) Alkyl-, optionally substituted- (C) ₃ -C ₇ ) Cycloalkyl-, optionally substituted-C (O) N (R) ²⁴ ) Aryl-, optionally substituted-N (R) ²⁴ ) C (O) aryl-, optionally substituted-N (R) ²⁴ )SO ₂ Aryl-, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroarylSubstituted heteroaryl;

Each R ²¹ And R ²² Independently of each other is H, - (C) ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) Heteroalkyl, - (C) ₁ -C ₆ ) alkyl-CO ₂ H、-C(O)(C ₁ -C ₆ ) Alkyl, -C (O) N (R) ³¹ ) ₂ or-SO ₂ N(R ³¹ ) ₂ (ii) a Or R ²¹ And R ²² And the nitrogen atom to which they are attached form a heterocycloalkyl ring;

each R ²³ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

each R ²⁴ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

each R ²⁵ And R ²⁶ Independently is H orOptionally substituted- (C) ₁ -C ₆ ) An alkyl group;

n is 0 or 1;

p is 0, 1 or 2; and is

q is 0, 1 or 2.

In one embodiment are compounds of formula (II) wherein n is 0. In another embodiment are compounds of formula (II) wherein n is 1.

In another embodiment are compounds of formula (II) wherein R ⁶ 、R ⁷ And R ⁸ Is H.

In another embodiment are compounds of formula (II) wherein R ¹⁵ And R ¹⁶ Is H.

In one embodiment are compounds of formula (II) wherein R ¹⁷ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (II) wherein R ¹⁷ is-CH ₃ . In another embodiment are compounds of formula (II) wherein R ¹⁷ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (II) wherein R ¹⁷ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (II) wherein R ¹⁷ Is cyclopropyl. In another embodiment are compounds of formula (II) wherein R ¹⁷ Is- (C) ₁ -C ₆ ) alkyl-C (O) OR ²³ . In another embodiment are compounds of formula (II) wherein R ¹⁷ is-CH ₂ CH ₂ And (5) OH. In another embodiment are compounds of formula (II) wherein R ¹⁷ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (II) wherein R ¹⁷ is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (II) wherein R ¹⁷ Is H.

In another embodiment are compounds of formula (II) wherein R ¹⁸ Is H.

In another embodiment are compounds of formula (II) wherein R ¹⁹ Is H.

In another embodiment are compounds of formula (II) wherein R ³ Is H.

In another embodiment are compounds of formula (II) wherein R ⁵ Is H.

In another embodiment are compounds of formula (II) wherein R ⁴ Is H. In another embodiment are compounds of formula (II) wherein R ⁴ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (II) wherein R ⁴ is-CH ₃ . In another embodimentIn the formula (II), wherein R is ⁴ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (II) wherein R ⁴ Is- (C) ₁ -C ₆ ) alkyl-OH. In another embodiment are compounds of formula (II) wherein R ⁴ is-CH ₂ And (5) OH. In another embodiment are compounds of formula (II) wherein R ⁴ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (II) wherein R ⁴ Is cyclopropyl. In another embodiment are compounds of formula (II) wherein R ⁴ is-C (O) NH ₂ 。

In another embodiment are compounds of formula (II) wherein R ³ 、R ⁴ And R ⁵ Is H.

In another embodiment are compounds of formula (II) wherein R ⁴ And R ⁵ And the carbon atoms to which they are attached form a cyclopropyl ring.

In another embodiment are compounds of formula (II) wherein R ¹⁰ Is H.

In another embodiment are compounds of formula (II) wherein R ¹⁰ Is H and R ⁹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (II) wherein R ¹⁰ Is H and R ⁹ is-CH ₃ . In another embodiment are compounds of formula (II) wherein R ¹⁰ Is H and R ⁹ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (II) wherein R ¹⁰ Is H and R ⁹ Is- (C) ₁ -C ₆ ) A haloalkyl group. In another embodiment are compounds of formula (II) wherein R ¹⁰ Is H and R ⁹ is-CH ₂ F. In another embodiment are compounds of formula (II) wherein R ¹⁰ Is H and R ⁹ is-CHF ₂ . In another embodiment are compounds of formula (II) wherein R ¹⁰ Is H and R ⁹ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (II) wherein R ¹⁰ Is H and R ⁹ Is cyclopropyl. In another embodiment are compounds of formula (II)Wherein R is ¹⁰ Is H and R ⁹ Is H.

In another embodiment are compounds of formula (II) wherein R ¹² Is H.

In another embodiment are compounds of formula (II) wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (II) wherein R ¹² Is H and R ¹¹ is-CH ₃ . In another embodiment are compounds of formula (II) wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-OR ²³ . In another embodiment are compounds of formula (II) wherein R ¹¹ is-CH ₂ And (5) OH. In another embodiment are compounds of formula (II) wherein R ¹² Is H and R ¹¹ is-CH ₂ CH ₂ And (5) OH. In another embodiment are compounds of formula (II) wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (II) wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (II) wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-NH ₂ . In another embodiment are compounds of formula (II) wherein R ¹² Is H and R ¹¹ is-CH ₂ NH ₂ . In another embodiment are compounds of formula (II) wherein R ¹² Is H and R ¹¹ is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (II) wherein R ¹² Is H and R ¹¹ is-CH ₂ CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (II) wherein R ¹² Is H and R ¹¹ is-CH ₂ CH ₂ CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (II) wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-CN. In another embodiment are compounds of formula (II) wherein R ¹² Is H and R ¹¹ is-CH ₂ And (C) CN. In another embodiment are compounds of formula (II) wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-C (O) NR ²⁵ R ²⁶ . In another embodiment are compounds of formula (II) wherein R ¹² Is H and R ¹¹ is-CH ₂ C(O)NH ₂ . In another embodiment are compounds of formula (II) wherein R ¹² Is H and R ¹¹ is-CH ₂ CH ₂ C(O)NH ₂ . In another embodiment are compounds of formula (II) wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) Alkyl-heteroaryl. In another embodiment are compounds of formula (II) wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-N (H) S (O) ₂ NR ²⁵ R ²⁶ . In another embodiment are compounds of formula (II) wherein R ¹² Is H and R ¹¹ is-CH ₂ N(H)S(O) ₂ NH ₂ . In another embodiment are compounds of formula (II) wherein R ¹² Is H and R ¹¹ Is H.

In another embodiment are compounds of formula (II) wherein R ¹¹ And R ¹⁸ Combined to form an optionally substituted heterocycloalkyl ring and R ¹² Is H.

In another embodiment are compounds of formula (II) wherein R ¹⁴ Is H.

In another embodiment are compounds of formula (II) wherein R ¹⁴ Is H and R ¹³ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (II) wherein R ¹⁴ Is H and R ¹³ is-CH ₃ . In another embodiment are compounds of formula (II) wherein R ¹⁴ Is H and R ¹³ Is- (C) ₁ -C ₆ ) alkyl-OR ²³ . In another embodiment are compounds of formula (II) wherein R ¹⁴ Is H and R ¹³ is-CH ₂ And (5) OH. In another embodiment are compounds of formula (II) wherein R ¹⁴ Is H and R ¹³ is-CH ₂ CH ₂ And (5) OH. In another embodiment is a compound of formula (II)In which R is ¹⁴ Is H and R ¹³ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (II) wherein R ¹⁴ Is H and R ¹³ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (II) wherein R ¹⁴ Is H and R ¹³ Is- (C) ₁ -C ₆ ) alkyl-NH ₂ . In another embodiment are compounds of formula (II) wherein R ¹⁴ Is H and R ¹³ is-CH ₂ NH ₂ . In another embodiment are compounds of formula (II) wherein R ¹⁴ Is H and R ¹³ is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (II) wherein R ¹⁴ Is H and R ¹³ is-CH ₂ CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (II) wherein R ¹⁴ Is H and R ¹³ is-CH ₂ CH ₂ CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (II) wherein R ¹⁴ Is H and R ¹³ Is- (C) ₁ -C ₆ ) An alkyl-CN group. In another embodiment are compounds of formula (II) wherein R ¹⁴ Is H and R ¹³ is-CH ₂ And (C) CN. In another embodiment are compounds of formula (II) wherein R ¹⁴ Is H and R ¹³ Is- (C) ₁ -C ₆ ) alkyl-C (O) NR ²⁵ R ²⁶ . In another embodiment are compounds of formula (II) wherein R ¹⁴ Is H and R ¹³ is-CH ₂ C(O)NH ₂ . In another embodiment are compounds of formula (II) wherein R ¹⁴ Is H and R ¹³ is-CH ₂ CH ₂ C(O)NH ₂ . In another embodiment are compounds of formula (II) wherein R ¹⁴ Is H and R ¹³ Is- (C) ₁ -C ₆ ) Alkyl-heteroaryl. In another embodiment are compounds of formula (II) wherein R ¹⁴ Is H and R ¹³ Is H.

In another embodiment are compounds of formula (II) wherein R ¹³ And R ¹⁹ Combined to form an arbitrary selectionSubstituted heterocycloalkyl ring and R ¹⁴ Is H.

In another embodiment are compounds of formula (II) wherein p is 1 and R ²⁷ Is halogen. In another embodiment are compounds of formula (II) wherein p is 1 and R ²⁷ Is optionally substituted- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (II) wherein q is 0, p is 1 and R ²⁷ Is a halogen. In another embodiment are compounds of formula (II) wherein q is 0, p is 1 and R ²⁷ Is optionally substituted- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (II) wherein q is 1 and R ²⁸ Is a halogen. In another embodiment are compounds of formula (II) wherein q is 1 and R ²⁸ Is optionally substituted- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (II) wherein p is 0, q is 1, and R is ²⁸ Is halogen. In another embodiment are compounds of formula (II) wherein p is 0, q is 1, and R is ²⁸ Is optionally substituted- (C) ₁ -C ₆ ) An alkyl group.

In another embodiment are compounds of formula (II) wherein p is 0 and q is 0.

In another embodiment are compounds of formula (II) wherein R ¹ And R ² Each independently is H or- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (II) wherein R ¹ And R ² Each is H. In another embodiment are compounds of formula (II) wherein R ¹ And R ² Each independently is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (II) wherein R ¹ Is H, and R ² Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (II) wherein R ¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² And R is ² Is H. In another embodiment are compounds of formula (II) wherein R ¹ Is H, and R ² is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (II) wherein R ¹ is-CH ₂ CH ₂ NH ₂ And R is ² Is H. In another embodiment are compounds of formula (II) wherein R ¹ And R ² Each is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (II) wherein R ¹ And R ² Are each independently H, - (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² or-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (II) wherein R ¹ And R ² Each independently is-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (II) wherein R ¹ Is H, and R ² is-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (II) wherein R ¹ is-CH ₂ CH(OH)CH ₂ NH ₂ And R is ² Is H. In a further embodiment are compounds of formula (II) wherein R ¹ And R ² And the atoms to which they are attached form an optionally substituted heterocycloalkyl ring.

In another embodiment are compounds of formula (II) wherein X is optionally substituted aryl. In a further embodiment are compounds of formula (II) wherein X is optionally substituted phenyl. In another embodiment are compounds of formula (II) wherein X is optionally substituted heteroaryl. In a further embodiment are compounds of formula (II) wherein X is disubstituted heteroaryl. In a further embodiment are compounds of formula (II) wherein X is heteroaryl disubstituted with substituents each independently selected from halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ and-NO ₂ . In a further embodiment are compounds of formula (II) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituents disubstituted heteroaryl. In a further embodiment are compounds of formula (II) wherein X is temephrinaAryl disubstituted with a substituent. In a further embodiment are compounds of formula (II) wherein X is pyridinyl disubstituted with substituents each independently selected from the group consisting of halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In a further embodiment are compounds of formula (II) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituent disubstituted pyridyl. In a further embodiment are compounds of formula (II) wherein X is pyridinyl disubstituted with methyl. In a further embodiment are compounds of formula (II) wherein X is pyrimidinyl disubstituted with substituents each independently selected from the group consisting of halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In a further embodiment are compounds of formula (II) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituent disubstituted pyrimidinyl. In a further embodiment are compounds of formula (II) wherein X is pyrimidinyl disubstituted with methyl. In another embodiment are compounds of formula (II) wherein X is optionally substituted- (C) ₁ -C ₆ ) An alkyl group-.

In another embodiment are compounds of formula (II) wherein Y is optionally substituted aryl. In a further embodiment are compounds of formula (II) wherein Y is optionally substituted phenyl. In another embodiment are compounds of formula (II) wherein Y is optionally substituted heteroaryl. In another embodiment are compounds of formula (II) wherein Y is optionally substituted- (C) ₁ -C ₆ ) An alkyl group-. In another embodiment are compounds of formula (II) wherein Y is optionally substituted (C) ₃ -C ₇ ) Cycloalkyl-. In another embodiment are compounds of formula (II) wherein Y is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (II) wherein Y is-O-. In another embodiment are compounds of formula (II) wherein Y is- (C) ₂ -C ₆ ) Alkynyl. In another embodiment are compounds of formula (II) wherein Y is-O- (C) ₁ -C ₆ ) An alkyl radical. In another embodiment are compounds of formula (II) wherein Y is a bond.

In another embodiment are compounds of formula (II) wherein Z is- (C) ₁ -C ₁₂ ) An alkyl group. In a further embodiment are compounds of formula (II) wherein Z is n-butyl, isobutyl, or tert-butyl. In another embodiment are compounds of formula (II) wherein Z is-O- (C) ₁ -C ₁₂ ) An alkyl group. In another embodiment are compounds of formula (II) wherein Z is-O- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (II) wherein Z is- (C) ₂ -C ₁₂ ) An alkenyl group. In another embodiment are compounds of formula (II) wherein Z is optionally substituted aryl. In a further embodiment are compounds of formula (II) wherein Z is optionally substituted phenyl. In a further embodiment are compounds of formula (II) wherein Z is independently selected from- (C) ₁ -C ₈ ) Alkyl substituents are monosubstituted or disubstituted phenyl. In a further embodiment are compounds of formula (II) wherein Z is phenyl monosubstituted with n-butyl, isobutyl, or tert-butyl. In a further embodiment are compounds of formula (II) wherein Z is phenyl monosubstituted with n-butyl. In a further embodiment are compounds of formula (II) wherein Z is phenyl monosubstituted with isobutyl. In a further embodiment are compounds of formula (II) wherein Z is phenyl monosubstituted with tert-butyl. In another embodiment are compounds of formula (II) wherein Z is optionally substituted heteroaryl. In another embodiment are compounds of formula (II) wherein Z is optionally substituted- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (II) wherein Z is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (II) wherein Z is halo.

In another embodiment, described herein are compounds of formula (II) having the structure of formula (IIa):

wherein:

R ³ is H or- (C) ₁ -C ₆ ) An alkyl group;

Or R ³ And R ⁴ Combine to form a heterocycloalkyl ring;

R ⁵ is H or- (C) ₁ -C ₆ ) An alkyl group;

R ¹⁰ is H or- (C) ₁ -C ₆ ) An alkyl group;

each R ²³ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

each R ²⁴ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

n is 0 or 1;

p is 0, 1 or 2; and is

q is 0, 1 or 2;

or a pharmaceutically acceptable salt, solvate or prodrug thereof. In one embodiment are compounds of formula (IIa) wherein n is 0. In another embodiment are compounds of formula (IIa) wherein n is 1.

In another embodiment are compounds of formula (IIa) wherein R ⁶ 、R ⁷ And R ⁸ Is H.

In another embodiment are compounds of formula (IIa) wherein R is ¹⁵ And R ¹⁶ Is H.

In one embodiment are compounds of formula (IIa) wherein R ¹⁷ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IIa) wherein R ¹⁷ is-CH ₃ . In another embodiment are compounds of formula (IIa) wherein R ¹⁷ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (IIa) wherein R is ¹⁷ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (IIa) wherein R is ¹⁷ Is cyclopropyl. In another embodiment are compounds of formula (IIa) wherein R is ¹⁷ Is- (C) ₁ -C ₆ ) alkyl-C (O) OR ²³ . In another embodiment are compounds of formula (IIa) wherein R is ¹⁷ is-CH ₂ CH ₂ And (5) OH. In another embodiment are compounds of formula (IIa) wherein R ¹⁷ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (IIa) wherein R ¹⁷ is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IIa) wherein R is ¹⁷ Is H.

In another embodiment are compounds of formula (IIa) wherein R is ¹⁸ Is H.

In another embodiment are compounds of formula (IIa) wherein R ¹⁹ Is H.

In another embodiment are compounds of formula (IIa) wherein R is ³ Is H.

In another embodiment are compounds of formula (IIa) wherein R ⁵ Is H.

In another embodiment are compounds of formula (IIa) wherein R is ⁴ Is H. In another embodiment are compounds of formula (IIa) wherein R is ⁴ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IIa) wherein R is ⁴ is-CH ₃ . In another embodiment are compounds of formula (IIa) wherein R is ⁴ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (IIa) wherein R is ⁴ Is- (C) ₁ -C ₆ ) alkyl-OH. In another embodiment are compounds of formula (IIa) wherein R is ⁴ is-CH ₂ And (5) OH. In another embodiment are compounds of formula (IIa) wherein R is ⁴ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (IIa) wherein R is ⁴ Is cyclopropyl. In another embodiment are compounds of formula (IIa) wherein R is ⁴ is-C (O) NH ₂ 。

In another embodiment are compounds of formula (IIa) wherein R is ³ 、R ⁴ And R ⁵ Is H.

In another embodiment are compounds of formula (IIa) wherein R ⁴ And R ⁵ And the carbon atoms to which they are attached form a cyclopropyl ring.

In another embodiment are compounds of formula (IIa) wherein R is ¹⁰ Is H.

In another embodiment are compounds of formula (IIa) wherein R is ¹⁰ Is H and R ⁹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IIa) wherein R is ¹⁰ Is H and R ⁹ is-CH ₃ . In another embodiment are compounds of formula (IIa) wherein R ¹⁰ Is H and R ⁹ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (IIa) wherein R ¹⁰ Is H and R ⁹ Is- (C) ₁ -C ₆ ) A haloalkyl group. In another embodiment are compounds of formula (IIa) wherein R ¹⁰ Is H and R ⁹ is-CH ₂ F. In another embodiment are compounds of formula (IIa) wherein R is ¹⁰ Is H and R ⁹ is-CHF ₂ . In another embodiment are compounds of formula (IIa) wherein R is ¹⁰ Is H and R ⁹ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (IIa) wherein R is ¹⁰ Is H and R ⁹ Is cyclopropyl. In another embodiment are compounds of formula (IIa) wherein R is ¹⁰ Is H and R ⁹ Is H.

In another embodiment are compounds of formula (IIa) wherein R is ¹² Is H.

In another embodiment are compounds of formula (IIa) wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IIa) wherein R is ¹² Is H and R ¹¹ is-CH ₃ . In another embodiment are compounds of formula (IIa) wherein R is ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-OR ²³ . In another embodiment are compounds of formula (IIa) wherein R ¹¹ is-CH ₂ And (5) OH. In another embodiment are compounds of formula (IIa) wherein R ¹² Is H and R ¹¹ is-CH ₂ CH ₂ And (5) OH. In another embodiment are compounds of formula (IIa) wherein R is ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IIa) wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (IIa) wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-NH ₂ . In another embodiment are compounds of formula (IIa) wherein R is ¹² Is H and R ¹¹ is-CH ₂ NH ₂ . In another embodiment are compounds of formula (IIa) wherein R ¹² Is H and R ¹¹ is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IIa) wherein R is ¹² Is H and R ¹¹ is-CH ₂ CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IIa) wherein R is ¹² Is H and R ¹¹ is-CH ₂ CH ₂ CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IIa) wherein R is ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-CN. In another embodiment are compounds of formula (IIa) wherein R is ¹² Is H and R ¹¹ is-CH ₂ And (C) CN. In another embodiment are compounds of formula (IIa) wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-C (O) NR ²⁵ R ²⁶ . In another embodiment are compounds of formula (IIa) wherein R is ¹² Is H and R ¹¹ is-CH ₂ C(O)NH ₂ . In another embodiment are compounds of formula (IIa) wherein R is ¹² Is H and R ¹¹ is-CH ₂ CH ₂ C(O)NH ₂ . In another embodiment is a compound of formula (IIa)In which R is ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) Alkyl-heteroaryl. In another embodiment are compounds of formula (IIa) wherein R is ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-N (H) S (O) ₂ NR ²⁵ R ²⁶ . In another embodiment are compounds of formula (IIa) wherein R ¹² Is H and R ¹¹ is-CH ₂ N(H)S(O) ₂ NH ₂ . In another embodiment are compounds of formula (IIa) wherein R is ¹² Is H and R ¹¹ Is H.

In another embodiment are compounds of formula (IIa) wherein R is ¹¹ And R ¹⁸ Combine to form an optionally substituted heterocycloalkyl ring and R ¹² Is H.

In another embodiment are compounds of formula (IIa) wherein R is ¹⁴ Is H.

In another embodiment are compounds of formula (IIa) wherein R ¹⁴ Is H and R ¹³ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IIa) wherein R is ¹⁴ Is H and R ¹³ is-CH ₃ . In another embodiment are compounds of formula (IIa) wherein R is ¹⁴ Is H and R ¹³ Is- (C) ₁ -C ₆ ) alkyl-OR ²³ . In another embodiment are compounds of formula (IIa) wherein R is ¹⁴ Is H and R ¹³ is-CH ₂ And (5) OH. In another embodiment are compounds of formula (IIa) wherein R is ¹⁴ Is H and R ¹³ is-CH ₂ CH ₂ And (5) OH. In another embodiment are compounds of formula (IIa) wherein R is ¹⁴ Is H and R ¹³ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IIa) wherein R ¹⁴ Is H and R ¹³ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (IIa) wherein R ¹⁴ Is H and R ¹³ Is- (C) ₁ -C ₆ ) alkyl-NH ₂ . In another embodiment are compounds of formula (IIa) wherein R ¹⁴ Is H and R ¹³ is-CH ₂ NH ₂ . In another embodiment are compounds of formula (IIa) wherein R ¹⁴ Is H and R ¹³ is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IIa) wherein R is ¹⁴ Is H and R ¹³ is-CH ₂ CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IIa) wherein R ¹⁴ Is H and R ¹³ is-CH ₂ CH ₂ CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IIa) wherein R is ¹⁴ Is H and R ¹³ Is- (C) ₁ -C ₆ ) alkyl-CN. In another embodiment are compounds of formula (IIa) wherein R is ¹⁴ Is H and R ¹³ is-CH ₂ And (C) CN. In another embodiment are compounds of formula (IIa) wherein R is ¹⁴ Is H and R ¹³ Is- (C) ₁ -C ₆ ) alkyl-C (O) NR ²⁵ R ²⁶ . In another embodiment are compounds of formula (IIa) wherein R is ¹⁴ Is H and R ¹³ is-CH ₂ C(O)NH ₂ . In another embodiment are compounds of formula (IIa) wherein R is ¹⁴ Is H and R ¹³ is-CH ₂ CH ₂ C(O)NH ₂ . In another embodiment are compounds of formula (IIa) wherein R is ¹⁴ Is H and R ¹³ Is- (C) ₁ -C ₆ ) Alkyl-heteroaryl. In another embodiment are compounds of formula (IIa) wherein R ¹⁴ Is H and R ¹³ Is H.

In another embodiment are compounds of formula (IIa) wherein R ¹³ And R ¹⁹ Combined to form an optionally substituted heterocycloalkyl ring and R ¹⁴ Is H.

In another embodiment are compounds of formula (IIa) wherein p is 1 and R ²⁷ Is halogen. In another embodiment are compounds of formula (IIa) wherein p is 1 and R ²⁷ Is optionally substituted- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IIa) wherein q is 0, p is 1 and R is ²⁷ Is halogen. In another embodiment are compounds of formula (IIa) wherein q is 0, p is 1 and R is ²⁷ Is optionally substituted- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IIa) wherein q is 1 and R ²⁸ Is a halogen. In another embodiment are compounds of formula (IIa) wherein q is 1 and R ²⁸ Is optionally substituted- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IIa) wherein p is 0, q is 1 and R is ²⁸ Is halogen. In another embodiment are compounds of formula (IIa) wherein p is 0, q is 1 and R is ²⁸ Is optionally substituted- (C) ₁ -C ₆ ) An alkyl group.

In another embodiment are compounds of formula (IIa) wherein p is 0 and q is 0.

In another embodiment are compounds of formula (IIa) wherein R is ¹ And R ² Each independently is H or- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (IIa) wherein R ¹ And R ² Each is H. In another embodiment are compounds of formula (IIa) wherein R ¹ And R ² Each independently is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (IIa) wherein R is ¹ Is H, and R ² Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (IIa) wherein R is ¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² And R is ² Is H. In another embodiment are compounds of formula (IIa) wherein R is ¹ Is H, and R ² is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IIa) wherein R is ¹ is-CH ₂ CH ₂ NH ₂ And R is ² Is H. In another embodiment are compounds of formula (IIa) wherein R is ¹ And R ² Each is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IIa) wherein R is ¹ And R ² Are each independently H, - (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² or-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (IIa) wherein R is ¹ And R ² Each independently is-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (IIa) wherein R ¹ Is H, and R ² is-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (IIa) wherein R is ¹ is-CH ₂ CH(OH)CH ₂ NH ₂ And R is ² Is H. In a further embodiment are compounds of formula (IIa), wherein R is ¹ And R ² And the atoms to which they are attached form an optionally substituted heterocycloalkyl ring.

In another embodiment are compounds of formula (IIa) wherein X is optionally substituted aryl. In a further embodiment are compounds of formula (IIa) wherein X is optionally substituted phenyl. In another embodiment are compounds of formula (IIa) wherein X is optionally substituted heteroaryl. In a further embodiment are compounds of formula (IIa) wherein X is disubstituted heteroaryl. In a further embodiment are compounds of formula (IIa) wherein X is heteroaryl disubstituted with substituents each independently selected from halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ and-NO ₂ . In a further embodiment are compounds of formula (IIa) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituents disubstituted heteroaryl. In a further embodiment are compounds of formula (IIa) wherein X is heteroaryl disubstituted with methyl. In a further embodiment are compounds of formula (IIa) wherein X is pyridyl disubstituted with substituents each independently selected from the group consisting of halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In a further embodiment are compounds of formula (IIa) wherein X is independently selected from- (C) ₁ -C ₆ ) A substituent of an alkyl group. In a further embodiment are compounds of formula (IIa) wherein X is pyridinyl disubstituted with methyl. In a further embodiment are compounds of formula (IIa) wherein X is pyrimidinyl disubstituted with substituents each independently selected from halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In a further embodiment are compounds of formula (IIa) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituent disubstituted pyrimidinyl. In a further embodiment are compounds of formula (IIa) wherein X is pyrimidinyl disubstituted with methyl. In another embodiment are compounds of formula (IIa) wherein X is optionally substituted- (C) ₁ -C ₆ ) An alkyl group-.

In another embodiment are compounds of formula (IIa) wherein Y is optionally substituted aryl. In a further embodiment are compounds of formula (IIa) wherein Y is optionally substituted phenyl. In another embodiment are compounds of formula (IIa) wherein Y is optionally substituted heteroaryl. In another embodiment are compounds of formula (IIa) wherein Y is optionally substituted- (C) ₁ -C ₆ ) An alkyl group-. In another embodiment are compounds of formula (IIa) wherein Y is optionally substituted (C) ₃ -C ₇ ) Cycloalkyl-. In another embodiment are compounds of formula (IIa) wherein Y is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (IIa) wherein Y is-O-. In another embodiment are compounds of formula (IIa) wherein Y is- (C) ₂ -C ₆ ) Alkynyl. In another embodiment are compounds of formula (IIa) wherein Y is-O- (C) ₁ -C ₆ ) An alkyl group-. In another embodiment are compounds of formula (IIa) wherein Y is a bond.

In another embodiment are compounds of formula (IIa) wherein Z is- (C) ₁ -C ₁₂ ) An alkyl group. In a further embodiment are compounds of formula (IIa) wherein Z is n-butyl, isobutyl, or tert-butyl. In another implementationIn this scheme are compounds of formula (IIa) wherein Z is-O- (C) ₁ -C ₁₂ ) An alkyl group. In another embodiment are compounds of formula (IIa) wherein Z is-O- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (IIa) wherein Z is- (C) ₂ -C ₁₂ ) An alkenyl group. In another embodiment are compounds of formula (IIa) wherein Z is optionally substituted aryl. In a further embodiment are compounds of formula (IIa) wherein Z is optionally substituted phenyl. In a further embodiment are compounds of formula (IIa) wherein Z is independently selected from- (C) ₁ -C ₈ ) Alkyl substituents are monosubstituted or disubstituted phenyl. In a further embodiment are compounds of formula (IIa) wherein Z is phenyl monosubstituted with n-butyl, isobutyl, or tert-butyl. In a further embodiment are compounds of formula (IIa) wherein Z is phenyl monosubstituted with n-butyl. In a further embodiment are compounds of formula (IIa) wherein Z is phenyl monosubstituted with isobutyl. In a further embodiment are compounds of formula (IIa) wherein Z is phenyl monosubstituted with tert-butyl. In another embodiment are compounds of formula (IIa) wherein Z is optionally substituted heteroaryl. In another embodiment are compounds of formula (IIa) wherein Z is optionally substituted- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (IIa) wherein Z is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (IIa) wherein Z is halogen.

In another embodiment, described herein are compounds of formula (II) having the structure of formula (IIb):

wherein:

R ¹ and R ² Are each independently H, - (C) ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-OR ²³ 、-CH ₂ CH(OH)CH ₂ NH ₂ 、-CH ₂ CH (heterocycloalkyl) CH ₂ NH ₂ 、-CH ₂ C(O)NH ₂ 、-CH ₂ C(O)N(H)CH ₂ CN、-(C ₁ -C ₆ ) alkyl-C (O) OR ²³ 、-(C ₁ -C ₆ ) alkyl-NR ²¹ R ²² 、-(C ₁ -C ₆ ) alkyl-C (O) NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) alkyl-N (R) ²³ )C(O)(C ₁ -C ₆ ) Alkyl radical NR ²¹ R ²² 、-(C ₁ -C ₆ ) alkyl-N (R) ²³ )C(O)(C ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-C (O) N (R) ²³ )(C ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-C (O) N (R) ²³ )(C ₁ -C ₆ ) Alkyl-heterocycloalkyl, - (C) ₁ -C ₆ ) alkyl-NR ²³ C(＝NH)NR ²¹ R ²² 、-(C ₁ -C ₆ ) alkyl-NR ²³ C(＝NH)R ²³ 、-(C ₁ -C ₆ ) Alkyl- [ (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² ] ₂ 、-(C ₁ -C ₆ ) Heteroalkyl or optionally substituted heterocycloalkyl;

R ⁵ Is H or- (C) ₁ -C ₆ ) An alkyl group;

R ¹³ is H, -NH ₂ 、-(C ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-OR ²³ 、-(C ₁ -C ₆ ) alkyl-SR ²³ 、-(C ₁ -C ₆ ) alkyl-C (O) OR ²³ 、-(C ₁ -C ₆ ) alkyl-NR ²¹ R ²² 、-(C ₁ -C ₆ ) alkyl-CN, - (C) ₁ -C ₆ ) alkyl-C (O) NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) alkyl-N (H) C (NH) NH ₂ 、-(C ₁ -C ₆ ) Alkyl-heterocycloalkyl or- (C) ₁ -C ₆ ) Alkyl-heteroaryl;

R ¹⁷ 、R ¹⁸ and R ¹⁹ Are each independently H, - (C) ₁ -C ₆ ) Alkyl, - (C) ₃ -C ₆ ) Cycloalkyl, - (C) ₁ -C ₆ ) alkyl-OR ²³ 、-(C ₁ -C ₆ ) alkyl-C (O) OR ²³ Or- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² ；

y is a bond, -O-, -S-, optionally substituted- (C) ₁ -C ₆ ) Alkyl-, - (C) ₂ -C ₆ ) Alkenyl-, - (C) ₂ -C ₆ ) Alkynyl, - (C) ₁ -C ₆ ) alkyl-N (R) ²⁴ )(C ₁ -C ₆ ) Alkyl-, -O- (C) ₁ -C ₆ ) Alkyl-, -O (C) ₆ -C ₁₀ ) Aryl-, -N (R) ²⁴ )(C ₁ -C ₆ ) Alkyl-, -N (R) ²⁴ )SO ₂ (C ₁ -C ₆ ) Alkyl-, -N (R) ²⁴ )C(O)(C ₁ -C ₆ ) Alkyl radical-、-C(O)(C ₁ -C ₆ ) Alkyl-, -S (C) ₁ -C ₆ ) Alkyl-, -SO ₂ (C ₁ -C ₆ ) Alkyl-, -C (O) NH (C) ₁ -C ₆ ) Alkyl-, optionally substituted- (C) ₃ -C ₇ ) Cycloalkyl-, optionally substituted-C (O) N (R) ²⁴ ) Aryl-, optionally substituted-N (R) ²⁴ ) C (O) aryl-, optionally substituted-N (R) ²⁴ )SO ₂ Aryl-, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

each R ²³ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

each R ²⁴ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

each R ²⁵ And R ²⁶ Independently is H or optionally substituted- (C) ₁ -C ₆ ) An alkyl group; and is

or a pharmaceutically acceptable salt, solvate or prodrug thereof. In one embodiment are compounds of formula (IIb) wherein R ¹⁷ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IIb) wherein R ¹⁷ is-CH ₃ . In another embodiment are compounds of formula (IIb) wherein R ¹⁷ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (IIb) wherein R ¹⁷ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (IIb) wherein R ¹⁷ Is cyclopropyl. In another embodiment are compounds of formula (IIb) wherein R ¹⁷ Is- (C) ₁ -C ₆ ) alkyl-C (O) OR ²³ . In another embodiment are compounds of formula (IIb) wherein R ¹⁷ is-CH ₂ CH ₂ And (5) OH. In another embodiment are compounds of formula (IIb) wherein R ¹⁷ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (IIb) wherein R ¹⁷ is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IIb) wherein R ¹⁷ Is H.

In another embodiment are compounds of formula (IIb) wherein R ¹⁸ Is H.

In another embodiment are compounds of formula (IIb) wherein R ¹⁹ Is H.

In another embodiment are compounds of formula (IIb) wherein R ⁵ Is H.

In another embodiment are compounds of formula (IIb) wherein R ⁴ Is H. In another embodiment are compounds of formula (IIb) wherein R ⁴ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IIb) wherein R ⁴ is-CH ₃ . In another embodiment are compounds of formula (IIb) wherein R ⁴ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (IIb) wherein R ⁴ Is- (C) ₁ -C ₆ ) alkyl-OH. In another embodiment are compounds of formula (IIb) wherein R ⁴ is-CH ₂ And (5) OH. In another embodiment are compounds of formula (IIb) wherein R ⁴ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (IIb) wherein R ⁴ Is cyclopropyl. In another embodiment are compounds of formula (IIb) wherein R ⁴ is-C (O) NH ₂ 。

In another embodiment are compounds of formula (IIb) wherein R ⁴ And R ⁵ Is H.

In another embodiment are compounds of formula (IIb) wherein R ⁴ And R ⁵ And the carbon atoms to which they are attached form a cyclopropyl ring.

In another embodiment are compounds of formula (IIb) wherein R ⁹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IIb) wherein R ⁹ is-CH ₃ . In another embodiment are compounds of formula (IIb) wherein R ⁹ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (IIb) wherein R ⁹ Is- (C) ₁ -C ₆ ) A haloalkyl group. In another embodiment are compounds of formula (IIb) wherein R ⁹ is-CH ₂ F. In another embodiment are compounds of formula (IIb) wherein R ⁹ is-CHF ₂ . In another embodiment are compounds of formula (IIb) wherein R ⁹ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (IIb) wherein R ⁹ Is cyclopropyl. In another embodiment are compounds of formula (IIb) wherein R ⁹ Is H.

In another embodiment are compounds of formula (IIb) wherein R ¹¹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IIb) wherein R ¹¹ is-CH ₃ . In another embodiment are compounds of formula (IIb) wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-OR ²³ . In another embodiment are compounds of formula (IIb) wherein R ¹¹ is-CH ₂ And (5) OH. In another embodiment are compounds of formula (IIb) wherein R ¹¹ is-CH ₂ CH ₂ And (5) OH. In another embodiment are compounds of formula (IIb) wherein R ¹¹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IIb) wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (IIb) wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-NH ₂ . In another embodiment are compounds of formula (IIb) wherein R ¹¹ is-CH ₂ NH ₂ . In another embodiment are compounds of formula (IIb) wherein R ¹¹ is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IIb) wherein R ¹¹ is-CH ₂ CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IIb) wherein R ¹¹ is-CH ₂ CH ₂ CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IIb) wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-CN. In another embodiment are compounds of formula (IIb) wherein R ¹¹ is-CH ₂ And (C) CN. In another embodiment are compounds of formula (IIb) wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-C (O) NR ²⁵ R ²⁶ . In another embodiment are compounds of formula (IIb),wherein R is ¹¹ is-CH ₂ C(O)NH ₂ . In another embodiment are compounds of formula (IIb) wherein R ¹¹ is-CH ₂ CH ₂ C(O)NH ₂ . In another embodiment are compounds of formula (IIb) wherein R ¹¹ Is- (C) ₁ -C ₆ ) Alkyl-heteroaryl. In another embodiment are compounds of formula (IIb) wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-N (H) S (O) ₂ NR ²⁵ R ²⁶ . In another embodiment are compounds of formula (IIb) wherein R ¹¹ is-CH ₂ N(H)S(O) ₂ NH ₂ . In another embodiment are compounds of formula (IIb) wherein R ¹¹ Is H.

In another embodiment are compounds of formula (IIb) wherein R ¹¹ And R ¹⁸ Combined to form an optionally substituted heterocycloalkyl ring and R ¹² Is H.

In another embodiment are compounds of formula (IIb) wherein R ¹³ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IIb) wherein R ¹³ is-CH ₃ . In another embodiment are compounds of formula (IIb) wherein R ¹³ Is- (C) ₁ -C ₆ ) alkyl-OR ²³ . In another embodiment are compounds of formula (IIb) wherein R ¹³ is-CH ₂ And (5) OH. In another embodiment are compounds of formula (IIb) wherein R ¹³ is-CH ₂ CH ₂ And (5) OH. In another embodiment are compounds of formula (IIb) wherein R ¹³ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IIb) wherein R ¹³ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (IIb) wherein R ¹³ Is- (C) ₁ -C ₆ ) alkyl-NH ₂ . In another embodiment are compounds of formula (IIb) wherein R ¹³ is-CH ₂ NH ₂ . In another embodiment are compounds of formula (IIb) wherein R ¹³ is-CH ₂ CH ₂ NH ₂ . In another embodimentIn the formula (IIb), in which R is ¹³ is-CH ₂ CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IIb) wherein R ¹³ is-CH ₂ CH ₂ CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IIb) wherein R ¹³ Is- (C) ₁ -C ₆ ) alkyl-CN. In another embodiment are compounds of formula (IIb) wherein R ¹³ is-CH ₂ And (C) CN. In another embodiment are compounds of formula (IIb) wherein R ¹³ Is- (C) ₁ -C ₆ ) alkyl-C (O) NR ²⁵ R ²⁶ . In another embodiment are compounds of formula (IIb) wherein R ¹³ is-CH ₂ C(O)NH ₂ . In another embodiment are compounds of formula (IIb) wherein R ¹³ is-CH ₂ CH ₂ C(O)NH ₂ . In another embodiment are compounds of formula (IIb) wherein R ¹³ Is- (C) ₁ -C ₆ ) Alkyl-heteroaryl. In another embodiment are compounds of formula (IIb) wherein R ¹³ Is H.

In another embodiment are compounds of formula (IIb) wherein R ¹³ And R ¹⁹ Combine to form an optionally substituted heterocycloalkyl ring and R ¹⁴ Is H.

In another embodiment are compounds of formula (IIb) wherein R ¹ And R ² Each independently is H or- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (IIb) wherein R ¹ And R ² Each is H. In another embodiment are compounds of formula (IIb) wherein R ¹ And R ² Each independently is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (IIb) wherein R ¹ Is H, and R ² Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (IIb) wherein R ¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² And R is ² Is H. In addition toIn one embodiment are compounds of formula (IIb) wherein R ¹ Is H, and R ² is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IIb) wherein R ¹ is-CH ₂ CH ₂ NH ₂ And R is ² Is H. In another embodiment are compounds of formula (IIb) wherein R ¹ And R ² Each is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IIb) wherein R ¹ And R ² Are each independently H, - (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² or-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (IIb) wherein R ¹ And R ² Each independently is-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (IIb) wherein R ¹ Is H, and R ² is-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (IIb) wherein R ¹ is-CH ₂ CH(OH)CH ₂ NH ₂ And R is ² Is H. In a further embodiment are compounds of formula (IIb), wherein R is ¹ And R ² And the atoms to which they are attached form an optionally substituted heterocycloalkyl ring.

In another embodiment are compounds of formula (IIb) wherein X is optionally substituted aryl. In a further embodiment are compounds of formula (IIb) wherein X is optionally substituted phenyl. In another embodiment are compounds of formula (IIb) wherein X is optionally substituted heteroaryl. In a further embodiment are compounds of formula (IIb) wherein X is disubstituted heteroaryl. In a further embodiment are compounds of formula (IIb) wherein X is heteroaryl disubstituted with substituents each independently selected from halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ and-NO ₂ . In a further embodiment are compounds of formula (IIb) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituents disubstituted heteroaryl. In a further embodiment are compounds of formula (IIb) wherein X is heteroaryl disubstituted with methyl. In a further embodiment are compounds of formula (IIb) wherein X is pyridyl disubstituted with substituents each independently selected from the group consisting of halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In a further embodiment are compounds of formula (IIb) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituent disubstituted pyridyl. In a further embodiment are compounds of formula (IIb) wherein X is pyridinyl disubstituted with methyl. In a further embodiment are compounds of formula (IIb) wherein X is pyrimidinyl disubstituted with substituents each independently selected from halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In a further embodiment are compounds of formula (IIb) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituent disubstituted pyrimidinyl. In a further embodiment are compounds of formula (IIb) wherein X is pyrimidinyl disubstituted with methyl. In another embodiment are compounds of formula (IIb) wherein X is optionally substituted- (C) ₁ -C ₆ ) An alkyl group-.

In another embodiment are compounds of formula (IIb) wherein Y is optionally substituted aryl. In a further embodiment are compounds of formula (IIb) wherein Y is optionally substituted phenyl. In another embodiment are compounds of formula (IIb) wherein Y is optionally substituted heteroaryl. In another embodiment are compounds of formula (IIb) wherein Y is optionally substituted- (C) ₁ -C ₆ ) An alkyl radical. In another embodiment are compounds of formula (IIb) wherein Y is optionally substituted (C) ₃ -C ₇ ) Cycloalkyl-. In another embodiment are compounds of formula (IIb) wherein Y is optionally substituted heterocycleAn alkyl group. In another embodiment are compounds of formula (IIb) wherein Y is-O-. In another embodiment are compounds of formula (IIb) wherein Y is- (C) ₂ -C ₆ ) Alkynyl. In another embodiment are compounds of formula (IIb) wherein Y is-O- (C) ₁ -C ₆ ) An alkyl radical. In another embodiment are compounds of formula (IIb) wherein Y is a bond.

In another embodiment are compounds of formula (IIb) wherein Z is- (C) ₁ -C ₁₂ ) An alkyl group. In a further embodiment are compounds of formula (IIb) wherein Z is n-butyl, isobutyl, or tert-butyl. In another embodiment are compounds of formula (IIb) wherein Z is-O- (C) ₁ -C ₁₂ ) An alkyl group. In another embodiment are compounds of formula (IIb) wherein Z is-O- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (IIb) wherein Z is- (C) ₂ -C ₁₂ ) An alkenyl group. In another embodiment are compounds of formula (IIb) wherein Z is optionally substituted aryl. In a further embodiment are compounds of formula (IIb) wherein Z is optionally substituted phenyl. In a further embodiment are compounds of formula (IIb) wherein Z is independently selected from- (C) ₁ -C ₈ ) Alkyl substituents are monosubstituted or disubstituted phenyl. In a further embodiment are compounds of formula (IIb) wherein Z is phenyl monosubstituted with n-butyl, isobutyl, or tert-butyl. In a further embodiment are compounds of formula (IIb) wherein Z is phenyl monosubstituted with n-butyl. In a further embodiment are compounds of formula (IIb) wherein Z is phenyl monosubstituted with isobutyl. In a further embodiment are compounds of formula (IIb) wherein Z is phenyl monosubstituted with tert-butyl. In another embodiment are compounds of formula (IIb) wherein Z is optionally substituted heteroaryl. In another embodiment are compounds of formula (IIb) wherein Z is optionally substituted- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (IIb) wherein Z is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (IIb) wherein Z is halo.

In another embodiment, described herein are compounds of formula (II) having the structure of formula (IIc):

wherein:

R ¹ and R ² Each independently is H or-CH ₂ CH ₂ NH ₂ ；

R ¹¹ Is H, -NH ₂ 、-(C ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-OR ²³ 、-(C ₁ -C ₆ ) alkyl-SR ²³ 、-(C ₁ -C ₆ ) alkyl-C (O) OR ²³ 、-(C ₁ -C ₆ ) alkyl-NR ²¹ R ²² 、-(C ₁ -C ₆ ) alkyl-NR ²³ OR ²³ 、-(C ₁ -C ₆ ) alkyl-NHC (O) NR ²³ OR ²³ 、-(C ₁ -C ₆ ) alkyl-O- (C) ₁ -C ₆ ) alkyl-NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) alkyl-CN, - (C) ₁ -C ₆ ) alkyl-NR ²³ C(O)R ²³ 、-(C ₁ -C ₆ ) alkyl-C (O) NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) heteroalkyl-CO ₂ H、-(C ₁ -C ₆ ) alkyl-S (O) (C) ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-N (H) CH = NH, - (C) ₁ -C ₆ ) alkyl-C (NH) ₂ )＝NH、-(C ₁ -C ₆ ) alkyl-N (H) C (= NH) NH ₂ 、-(C ₁ -C ₆ ) alkyl-N (H) S (O) ₂ NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) alkyl-N (H) S (O) ₂ (C ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-N (H) -C (O) NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) Alkyl C (O) N (H) [ optionally substituted (C) ₂ -C ₆ ) Alkyl radical]-OR ²³ 、-(C ₁ -C ₆ ) Alkyl N (H) C (O) (C) ₁ -C ₆ ) alkyl-OR ²³ 、-(C ₁ -C ₆ ) Alkyl radicalRadical C (O) N (H) heterocycloalkyl, - (C) ₁ -C ₆ ) Alkyl C (O) NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) alkyl-N (H) -C (O) - (C) ₁ -C ₆ ) alkyl-NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) alkyl-N (H) - (C) ₁ -C ₆ ) Alkyl C (O) NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) Alkyl-heterocycloalkyl, optionally substituted- (C) ₁ -C ₆ ) alkyl-N (H) heterocycloalkyl or- (C) ₁ -C ₆ ) Alkyl-heteroaryl l;

Each R ²³ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

each R ²⁴ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

or a pharmaceutically acceptable salt, solvate or prodrug thereof. In another embodiment are compounds of formula (IIc) wherein R ¹¹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IIc) wherein R ¹¹ is-CH ₃ . In another embodiment are compounds of formula (IIc) wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-OR ²³ . In another embodiment are compounds of formula (IIc) wherein R ¹¹ is-CH ₂ And (5) OH. In another embodiment are compounds of formula (IIc) wherein R ¹¹ is-CH ₂ CH ₂ And (5) OH. In another embodiment are compounds of formula (IIc) wherein R ¹¹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IIc) wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (IIc) wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-NH ₂ . In another embodiment are compounds of formula (IIc) wherein R ¹¹ is-CH ₂ NH ₂ . In another embodiment are compounds of formula (IIc) wherein R ¹¹ is-CH ₂ CH ₂ NH ₂ . In another embodimentIn one embodiment are compounds of formula (IIc) wherein R ¹¹ is-CH ₂ CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IIc) wherein R ¹¹ is-CH ₂ CH ₂ CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IIc) wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-CN. In another embodiment are compounds of formula (IIc) wherein R ¹¹ is-CH ₂ And (C) CN. In another embodiment are compounds of formula (IIc) wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-C (O) NR ²⁵ R ²⁶ . In another embodiment are compounds of formula (IIc) wherein R ¹¹ is-CH ₂ C(O)NH ₂ . In another embodiment are compounds of formula (IIc) wherein R ¹¹ is-CH ₂ CH ₂ C(O)NH ₂ . In another embodiment are compounds of formula (IIc) wherein R ¹¹ Is- (C) ₁ -C ₆ ) Alkyl-heteroaryl. In another embodiment are compounds of formula (IIc) wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-N (H) S (O) ₂ NR ²⁵ R ²⁶ . In another embodiment are compounds of formula (IIc) wherein R ¹¹ is-CH ₂ N(H)S(O) ₂ NH ₂ . In another embodiment are compounds of formula (IIc) wherein R ¹¹ Is H.

In another embodiment are compounds of formula (IIc) wherein R ¹³ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IIc) wherein R ¹³ is-CH ₃ . In another embodiment are compounds of formula (IIc) wherein R ¹³ Is- (C) ₁ -C ₆ ) alkyl-OR ²³ . In another embodiment are compounds of formula (IIc) wherein R ¹³ is-CH ₂ And (5) OH. In another embodiment are compounds of formula (IIc) wherein R ¹³ is-CH ₂ CH ₂ And (5) OH. In another embodiment are compounds of formula (IIc) wherein R ¹³ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment is formula (II)(IIc) Compound wherein R ¹³ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (IIc) wherein R ¹³ Is- (C) ₁ -C ₆ ) alkyl-NH ₂ . In another embodiment are compounds of formula (IIc) wherein R ¹³ is-CH ₂ NH ₂ . In another embodiment are compounds of formula (IIc) wherein R ¹³ is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IIc) wherein R ¹³ is-CH ₂ CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IIc) wherein R ¹³ is-CH ₂ CH ₂ CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IIc) wherein R ¹³ Is- (C) ₁ -C ₆ ) alkyl-CN. In another embodiment are compounds of formula (IIc) wherein R ¹³ is-CH ₂ And (C) CN. In another embodiment are compounds of formula (IIc) wherein R ¹³ Is- (C) ₁ -C ₆ ) alkyl-C (O) NR ²⁵ R ²⁶ . In another embodiment are compounds of formula (IIc) wherein R ¹³ is-CH ₂ C(O)NH ₂ . In another embodiment are compounds of formula (IIc) wherein R ¹³ is-CH ₂ CH ₂ C(O)NH ₂ . In another embodiment are compounds of formula (IIc) wherein R ¹³ Is- (C) ₁ -C ₆ ) Alkyl-heteroaryl. In another embodiment are compounds of formula (IIc) wherein R ¹³ Is H.

In another embodiment are compounds of formula (IIc) wherein R ¹ And R ² Each is H. In another embodiment are compounds of formula (IIc) wherein R ¹ Is H, and R ² is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IIc) wherein R ¹ is-CH ₂ CH ₂ NH ₂ And R is ² Is H. In another embodiment are compounds of formula (IIc) wherein R ¹ And R ² Each is-CH ₂ CH ₂ NH ₂ . In a further embodiment are compounds of formula (IIc) wherein R ¹ And R ² And the atoms to which they are attached form an optionally substituted heterocycloalkyl ring.

In another embodiment are compounds of formula (IIc) wherein X is optionally substituted aryl. In a further embodiment are compounds of formula (IIc) wherein X is optionally substituted phenyl. In another embodiment are compounds of formula (IIc) wherein X is optionally substituted heteroaryl. In a further embodiment are compounds of formula (IIc) wherein X is disubstituted heteroaryl. In a further embodiment are compounds of formula (IIc) wherein X is heteroaryl disubstituted with substituents each independently selected from halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ and-NO ₂ . In a further embodiment are compounds of formula (IIc) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituents disubstituted heteroaryl. In a further embodiment are compounds of formula (IIc) wherein X is heteroaryl disubstituted with methyl. In a further embodiment are compounds of formula (IIc) wherein X is pyridyl disubstituted with substituents each independently selected from the group consisting of halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In a further embodiment are compounds of formula (IIc) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituent disubstituted pyridyl. In a further embodiment are compounds of formula (IIc) wherein X is pyridyl disubstituted with methyl. In a further embodiment are compounds of formula (IIc) wherein X is pyrimidinyl disubstituted with substituents each independently selected from halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In a further embodiment are compounds of formula (IIc) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituent disubstituted pyrimidinyl. In a further embodiment are compounds of formula (IIc) wherein X is pyrimidinyl disubstituted with methyl. In another embodiment are compounds of formula (IIc) wherein X is optionally substituted- (C) ₁ -C ₆ ) An alkyl group-.

In another embodiment are compounds of formula (IIc) wherein Y is optionally substituted aryl. In a further embodiment are compounds of formula (IIc) wherein Y is optionally substituted phenyl. In another embodiment are compounds of formula (IIc) wherein Y is optionally substituted heteroaryl. In another embodiment are compounds of formula (IIc) wherein Y is optionally substituted- (C) ₁ -C ₆ ) An alkyl radical. In another embodiment are compounds of formula (IIc) wherein Y is optionally substituted (C) ₃ -C ₇ ) Cycloalkyl-. In another embodiment are compounds of formula (IIc) wherein Y is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (IIc) wherein Y is-O-. In another embodiment are compounds of formula (IIc) wherein Y is- (C) ₂ -C ₆ ) Alkynyl. In another embodiment are compounds of formula (IIc) wherein Y is-O- (C) ₁ -C ₆ ) An alkyl group-. In another embodiment are compounds of formula (IIc) wherein Y is a bond.

In another embodiment are compounds of formula (IIc) wherein Z is- (C) ₁ -C ₁₂ ) An alkyl group. In a further embodiment are compounds of formula (IIc) wherein Z is n-butyl, isobutyl, or tert-butyl. In another embodiment are compounds of formula (IIc) wherein Z is-O- (C) ₁ -C ₁₂ ) An alkyl group. In another embodiment are compounds of formula (IIc) wherein Z is-O- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (IIc) wherein Z is- (C) ₂ -C ₁₂ ) An alkenyl group. In another embodiment are compounds of formula (IIc) wherein Z is optionally substituted aryl. In a further embodiment are compounds of formula (IIc) wherein Z is optionally substituted phenyl. In thatIn a further embodiment are compounds of formula (IIc) wherein Z is independently selected from- (C) ₁ -C ₈ ) Alkyl substituents are monosubstituted or disubstituted phenyl. In a further embodiment are compounds of formula (IIc) wherein Z is phenyl monosubstituted with n-butyl, isobutyl, or tert-butyl. In a further embodiment are compounds of formula (IIc) wherein Z is phenyl monosubstituted with n-butyl. In a further embodiment are compounds of formula (IIc) wherein Z is phenyl monosubstituted with isobutyl. In a further embodiment are compounds of formula (IIc) wherein Z is phenyl monosubstituted with tert-butyl. In another embodiment are compounds of formula (IIc) wherein Z is optionally substituted heteroaryl. In another embodiment are compounds of formula (IIc) wherein Z is optionally substituted- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (IIc) wherein Z is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (IIc) wherein Z is halo.

In another embodiment, described herein are compounds of formula (II) having the structure of formula (IId):

wherein:

R ⁵ Is H or- (C) ₁ -C ₆ ) An alkyl group;

R ¹⁷ is H, - (C) ₁ -C ₆ ) Alkyl, - (C) ₃ -C ₆ ) Cycloalkyl, - (C) ₁ -C ₆ ) alkyl-OR ²³ 、-(C ₁ -C ₆ ) alkyl-C (O) OR ²³ Or- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² ；

z is H, halogen, -NH ₂ 、-CN、-CF ₃ 、-CO ₂ H、-(C ₁ -C ₁₂ ) Alkyl, - (C) ₂ -C ₁₂ ) Alkenyl, -CH = ((C) ₃ -C ₇ ) Cycloalkyl), - (C) ₂ -C ₁₂ ) Alkynyl, -C (O) NR ²⁵ R ²⁶ 、-O-(C ₁ -C ₁₂ ) Alkyl, -S- (C) ₁ -C ₁₂ ) Alkyl, -O- (C) ₃ -C ₁₀ ) [ optionally substituted (C) ₃ -C ₇ ) Cycloalkyl radicals]、-O-(C ₁ -C ₆ ) alkyl-OR ²³ 、-(C ₁ -C ₁₂ ) alkyl-OR ²³ 、-(C ₁ -C ₁₂ ) alkyl-CN, -S- (C) ₁ -C ₁₂ ) Alkyl, -N (R) ²⁴ )(C ₁ -C ₁₂ ) Alkyl, -N (R) ²⁴ )C(O)(C ₁ -C ₁₂ ) Alkyl, optionally substituted- (C) ₃ -C ₇ ) A cycloalkyl group, a,-(C ₁ -C ₆ ) Alkyl radical- (C) ₃ -C ₇ ) Cycloalkyl, - (C) ₁ -C ₆ ) Alkyl-heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

each R ²³ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

each R ²⁴ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

or a pharmaceutically acceptable salt, solvate or prodrug thereof. In one embodiment are compounds of formula (IId), wherein R is ¹⁷ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IId) wherein R ¹⁷ is-CH ₃ . In another embodiment are compounds of formula (IId) wherein R ¹⁷ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (IId) wherein R ¹⁷ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (IId) wherein R ¹⁷ Is cyclopropyl. In another embodiment are compounds of formula (IId), wherein R is ¹⁷ Is- (C) ₁ -C ₆ ) Alkyl radicalradical-C (O) OR ²³ . In another embodiment are compounds of formula (IId), wherein R is ¹⁷ is-CH ₂ CH ₂ And (5) OH. In another embodiment are compounds of formula (IId), wherein R is ¹⁷ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (IId) wherein R ¹⁷ is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IId) wherein R ¹⁷ Is H.

In another embodiment are compounds of formula (IId), wherein R is ⁵ Is H.

In another embodiment are compounds of formula (IId) wherein R ⁴ Is H. In another embodiment are compounds of formula (IId), wherein R is ⁴ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IId), wherein R is ⁴ is-CH ₃ . In another embodiment are compounds of formula (IId), wherein R is ⁴ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (IId), wherein R is ⁴ Is- (C) ₁ -C ₆ ) alkyl-OH. In another embodiment are compounds of formula (IId), wherein R is ⁴ is-CH ₂ And (5) OH. In another embodiment are compounds of formula (IId), wherein R is ⁴ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (IId), wherein R is ⁴ Is cyclopropyl. In another embodiment are compounds of formula (IId), wherein R is ⁴ is-C (O) NH ₂ 。

In another embodiment are compounds of formula (IId) wherein R ⁴ And R ⁵ Is H.

In another embodiment are compounds of formula (IId), wherein R is ⁴ And R ⁵ And the carbon atoms to which they are attached form a cyclopropyl ring.

In another embodiment are compounds of formula (IId), wherein R is ⁹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IId), wherein R is ⁹ is-CH ₃ . In anotherIn an embodiment are compounds of formula (IId), wherein R ⁹ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (IId), wherein R is ⁹ Is- (C) ₁ -C ₆ ) A haloalkyl group. In another embodiment are compounds of formula (IId) wherein R ⁹ is-CH ₂ F. In another embodiment are compounds of formula (IId) wherein R ⁹ is-CHF ₂ . In another embodiment are compounds of formula (IId), wherein R is ⁹ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (IId), wherein R is ⁹ Is cyclopropyl. In another embodiment are compounds of formula (IId), wherein R is ⁹ Is H.

In another embodiment are compounds of formula (IId) wherein R ¹ And R ² Each independently is H or- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (IId), wherein R is ¹ And R ² Each is H. In another embodiment are compounds of formula (IId), wherein R is ¹ And R ² Each independently is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (IId) wherein R ¹ Is H, and R ² Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (IId), wherein R is ¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² And R is ² Is H. In another embodiment are compounds of formula (IId), wherein R is ¹ Is H, and R ² is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IId) wherein R ¹ is-CH ₂ CH ₂ NH ₂ And R is ² Is H. In another embodiment are compounds of formula (IId), wherein R is ¹ And R ² Each is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IId), wherein R is ¹ And R ² Are each independently H, - (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² or-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (IId), wherein R is ¹ And R ² Each independently is-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (IId), wherein R is ¹ Is H, and R ² is-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (IId), wherein R is ¹ is-CH ₂ CH(OH)CH ₂ NH ₂ And R is ² Is H. In a further embodiment are compounds of formula (IId), wherein R is ¹ And R ² And the atoms to which they are attached form an optionally substituted heterocycloalkyl ring.

In another embodiment are compounds of formula (IId) wherein X is optionally substituted aryl. In a further embodiment are compounds of formula (IId) wherein X is optionally substituted phenyl. In another embodiment are compounds of formula (IId) wherein X is optionally substituted heteroaryl. In a further embodiment are compounds of formula (IId) wherein X is disubstituted heteroaryl. In a further embodiment are compounds of formula (IId) wherein X is heteroaryl disubstituted with substituents each independently selected from halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ and-NO ₂ . In a further embodiment are compounds of formula (IId) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituents disubstituted heteroaryl. In a further embodiment are compounds of formula (IId) wherein X is heteroaryl disubstituted with methyl. In a further embodiment are compounds of formula (IId) wherein X is pyridyl disubstituted with substituents each independently selected from halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In a further embodiment are compounds of formula (IId) wherein X is independentlyIs selected from- (C) ₁ -C ₆ ) Alkyl substituent disubstituted pyridyl. In a further embodiment are compounds of formula (IId) wherein X is pyridyl disubstituted with methyl. In a further embodiment are compounds of formula (IId) wherein X is pyrimidinyl disubstituted with substituents each independently selected from halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In a further embodiment are compounds of formula (IId) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituent disubstituted pyrimidinyl. In a further embodiment are compounds of formula (IId) wherein X is pyrimidinyl disubstituted with methyl. In another embodiment are compounds of formula (IId) wherein X is optionally substituted- (C) ₁ -C ₆ ) An alkyl group-.

In another embodiment are compounds of formula (IId) wherein Y is optionally substituted aryl. In a further embodiment are compounds of formula (IId) wherein Y is optionally substituted phenyl. In another embodiment are compounds of formula (IId) wherein Y is optionally substituted heteroaryl. In another embodiment are compounds of formula (IId) wherein Y is optionally substituted- (C) ₁ -C ₆ ) An alkyl group-. In another embodiment are compounds of formula (IId) wherein Y is optionally substituted (C) ₃ -C ₇ ) Cycloalkyl-. In another embodiment are compounds of formula (IId) wherein Y is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (IId) wherein Y is-O-. In another embodiment are compounds of formula (IId) wherein Y is- (C) ₂ -C ₆ ) Alkynyl. In another embodiment are compounds of formula (IId) wherein Y is-O- (C) ₁ -C ₆ ) An alkyl group-. In another embodiment are compounds of formula (IId) wherein Y is a bond.

In another embodiment are compounds of formula (IId) wherein Z is- (C) ₁ -C ₁₂ ) An alkyl group. In a further embodiment are compounds of formula (IId) wherein Z is n-butyl, isobutyl, or tert-butylA butyl group. In another embodiment are compounds of formula (IId) wherein Z is-O- (C) ₁ -C ₁₂ ) An alkyl group. In another embodiment are compounds of formula (IId) wherein Z is-O- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (IId) wherein Z is- (C) ₂ -C ₁₂ ) An alkenyl group. In another embodiment are compounds of formula (IId) wherein Z is optionally substituted aryl. In a further embodiment are compounds of formula (IId) wherein Z is optionally substituted phenyl. In a further embodiment are compounds of formula (IId) wherein Z is independently selected from- (C) ₁ -C ₈ ) Alkyl substituents are monosubstituted or disubstituted phenyl. In a further embodiment are compounds of formula (IId) wherein Z is phenyl monosubstituted with n-butyl, isobutyl, or tert-butyl. In a further embodiment are compounds of formula (IId) wherein Z is phenyl monosubstituted with n-butyl. In a further embodiment are compounds of formula (IId) wherein Z is phenyl monosubstituted with isobutyl. In a further embodiment are compounds of formula (IId) wherein Z is phenyl monosubstituted with tert-butyl. In another embodiment are compounds of formula (IId) wherein Z is optionally substituted heteroaryl. In another embodiment are compounds of formula (IId) wherein Z is optionally substituted- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (IId) wherein Z is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (IId) wherein Z is halo.

In another embodiment, described herein are compounds of formula (II) having the structure of formula (IIe):

wherein:

R ¹ and R ² Each independently is H or-CH ₂ CH ₂ NH ₂ ；

X is optionally substituted- (C) ₁ -C ₆ ) Alkyl-, - (C) ₂ -C ₆ ) Alkenyl radical-、-(C ₂ -C ₆ ) Alkynyl, optionally substituted- (C) ₃ -C ₇ ) Cycloalkyl-, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -O- (C) ₁ -C ₆ ) Alkyl-, -N (R) ²⁴ )(C ₁ -C ₆ ) Alkyl-, -N (R) ²⁴ )(C ₆ -C ₁₀ ) aryl-or-SO ₂ (C ₁ -C ₆ ) Alkyl-;

each R ²³ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

each R ²⁴ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

or a pharmaceutically acceptable salt, solvate or prodrug thereof.

In one embodiment are compounds of formula (IIe) wherein R is ¹ And R ² Each is H. In another embodiment are compounds of formula (IIe) wherein R is ¹ Is H, and R ² is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IIe) wherein R is ¹ is-CH ₂ CH ₂ NH ₂ And R is ² Is H. In another embodiment are compounds of formula (IIe) wherein R is ¹ And R ² Each is-CH ₂ CH ₂ NH ₂ 。

In another embodiment are compounds of formula (IIe) wherein X is optionally substituted aryl. In a further embodiment are compounds of formula (IIe) wherein X is optionally substituted phenyl. In another embodiment are compounds of formula (IIe) wherein X is optionally substituted heteroaryl. In a further embodiment are compounds of formula (IIe) wherein X is disubstituted heteroaryl. In a further embodiment are compounds of formula (IIe) wherein X is substituted (iii) heteroaryl disubstituted with substituents each independently selected from halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ and-NO ₂ . In a further embodiment are compounds of formula (IIe) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituents disubstituted heteroaryl. In a further embodiment are compounds of formula (IIe) wherein X is heteroaryl disubstituted with methyl. In a further embodiment are compounds of formula (IIe) wherein X is pyridyl disubstituted with substituents each independently selected from the group consisting of halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In a further embodiment are compounds of formula (IIe) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituent disubstituted pyridyl. In a further embodiment are compounds of formula (IIe) wherein X is pyridyl disubstituted with methyl. In a further embodiment are compounds of formula (IIe) wherein X is pyrimidinyl disubstituted with substituents each independently selected from halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In a further embodiment are compounds of formula (IIe) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituent disubstituted pyrimidinyl. In a further embodiment are compounds of formula (IIe) wherein X is pyrimidinyl disubstituted with methyl. In another embodiment are compounds of formula (IIe) wherein X is optionally substituted- (C) ₁ -C ₆ ) An alkyl radical.

In another embodiment are compounds of formula (IIe) wherein Y is optionally substituted aryl. In a further embodiment are compounds of formula (IIe) wherein Y is optionally substituted phenyl. In another embodiment are compounds of formula (IIe),wherein Y is optionally substituted heteroaryl. In another embodiment are compounds of formula (IIe) wherein Y is optionally substituted- (C) ₁ -C ₆ ) An alkyl radical. In another embodiment are compounds of formula (IIe) wherein Y is optionally substituted (C) ₃ -C ₇ ) Cycloalkyl-. In another embodiment are compounds of formula (IIe) wherein Y is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (IIe) wherein Y is-O-. In another embodiment are compounds of formula (IIe) wherein Y is- (C) ₂ -C ₆ ) Alkynyl. In another embodiment are compounds of formula (IIe) wherein Y is-O- (C) ₁ -C ₆ ) An alkyl radical. In another embodiment are compounds of formula (IIe) wherein Y is a bond.

In another embodiment are compounds of formula (IIe) wherein Z is- (C) ₁ -C ₁₂ ) An alkyl group. In a further embodiment are compounds of formula (IIe) wherein Z is n-butyl, isobutyl, or tert-butyl. In another embodiment are compounds of formula (IIe) wherein Z is-O- (C) ₁ -C ₁₂ ) An alkyl group. In another embodiment are compounds of formula (IIe) wherein Z is-O- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (IIe) wherein Z is- (C) ₂ -C ₁₂ ) An alkenyl group. In another embodiment are compounds of formula (IIe) wherein Z is optionally substituted aryl. In a further embodiment are compounds of formula (IIe) wherein Z is optionally substituted phenyl. In a further embodiment are compounds of formula (IIe) wherein Z is independently selected from- (C) ₁ -C ₈ ) Alkyl substituents are monosubstituted or disubstituted phenyl. In a further embodiment are compounds of formula (IIe) wherein Z is phenyl monosubstituted with n-butyl, isobutyl, or tert-butyl. In a further embodiment are compounds of formula (IIe) wherein Z is phenyl monosubstituted with n-butyl. In a further embodiment are compounds of formula (IIe) wherein Z is phenyl monosubstituted with isobutyl. In a further embodiment are compounds of formula (IIe) wherein Z is phenyl monosubstituted with tert-butyl. In another embodiment are compounds of formula (IIe) wherein Z is optionally substituted A heteroaryl group. In another embodiment are compounds of formula (IIe) wherein Z is optionally substituted- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (IIe) wherein Z is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (IIe) wherein Z is halo.

In one aspect, described herein are compounds of formula (III), or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

wherein:

R ³ is H or- (C) ₁ -C ₆ ) An alkyl group;

Or R ³ And R ⁴ Combine to form a heterocycloalkyl ring;

R ⁵ is H or- (C) ₁ -C ₆ ) An alkyl group;

R ⁶ 、R ⁷ and R ⁸ Each independently H, fluoro, hydroxy, amino, optionally substituted alkyl, heteroalkyl, or- (C) ₁ -C ₆ ) An alkyl group;

or R ⁹ And R ¹⁰ Combined to form a heterocycloalkyl or cycloalkyl ring

R ¹⁵ 、R ¹⁶ 、R ¹⁷ and R ¹⁸ Are each independently H, - (C) ₁ -C ₆ ) Alkyl, - (C) ₃ -C ₆ ) CycloalkanesA base,

X is disubstituted heteroaryl;

each R ²³ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

each R ²⁴ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

each R ²⁷ Independently halogen, -NR ²³ R ²⁴ 、-NHC(O)R ²³ 、-NHC(O)NR ²³ R ²⁴ Nitro, hydroxy, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted- (C) ₁ -C ₆ ) Heteroalkyl, optionally substituted- (C) ₁ -C ₆ ) Heteroalkyloxy, optionally substituted-(C ₁ -C ₆ ) Heteroalkylamino radical, - (C) ₁ -C ₆ ) Alkoxy, -C (O) (C) ₁ -C ₆ ) Alkyl or-S (O) ₂ (C ₁ -C ₆ ) An alkyl group;

p is 0, 1 or 2; and is

q is 0, 1 or 2.

In one embodiment are compounds of formula (III) wherein R ⁶ 、R ⁷ And R ⁸ Is H.

In another embodiment are compounds of formula (III) wherein R ¹⁵ And R ¹⁶ Is H.

In one embodiment are compounds of formula (III) wherein R ¹⁷ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (III) wherein R ¹⁷ is-CH ₃ . In another embodiment are compounds of formula (III) wherein R ¹⁷ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (III) wherein R ¹⁷ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (III) wherein R ¹⁷ Is cyclopropyl. In another embodiment are compounds of formula (III) wherein R ¹⁷ Is- (C) ₁ -C ₆ ) alkyl-C (O) OR ²³ . In another embodiment are compounds of formula (III) wherein R ¹⁷ is-CH ₂ CH ₂ And (5) OH. In another embodiment are compounds of formula (III) wherein R ¹⁷ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (III) wherein R ¹⁷ is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (III) wherein R ¹⁷ Is H.

In another embodiment are compounds of formula (III) wherein R ¹⁸ Is H.

In another embodiment are compounds of formula (III) wherein R ³ Is H.

In another embodiment are compounds of formula (III) wherein R ⁵ Is H.

In another embodiment are compounds of formula (III) wherein R ⁴ Is H. In another embodiment are compounds of formula (III) wherein R ⁴ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (III) wherein R ⁴ is-CH ₃ . In another embodiment are compounds of formula (III) wherein R ⁴ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (III) wherein R ⁴ Is- (C) ₁ -C ₆ ) alkyl-OH. In another embodiment are compounds of formula (III) wherein R ⁴ is-CH ₂ And (5) OH. In another embodiment are compounds of formula (III) wherein R ⁴ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (III) wherein R ⁴ Is cyclopropyl. In another embodiment are compounds of formula (III) wherein R ⁴ is-C (O) NH ₂ 。

In another embodiment are compounds of formula (III) wherein R ³ 、R ⁴ And R ⁵ Is H.

In another embodiment are compounds of formula (III) wherein R ⁴ And R ⁵ And to which they are attachedThe carbon atom forms a cyclopropyl ring.

In another embodiment are compounds of formula (III) wherein R ¹⁰ Is H.

In another embodiment are compounds of formula (III) wherein R ¹⁰ Is H and R ⁹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (III) wherein R ¹⁰ Is H and R ⁹ is-CH ₃ . In another embodiment are compounds of formula (III) wherein R ¹⁰ Is H and R ⁹ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (III) wherein R ¹⁰ Is H and R ⁹ Is- (C) ₁ -C ₆ ) A haloalkyl group. In another embodiment are compounds of formula (III) wherein R ¹⁰ Is H and R ⁹ is-CH ₂ F. In another embodiment are compounds of formula (III) wherein R ¹⁰ Is H and R ⁹ is-CHF ₂ . In another embodiment are compounds of formula (III) wherein R ¹⁰ Is H and R ⁹ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (III) wherein R ¹⁰ Is H and R ⁹ Is cyclopropyl. In another embodiment are compounds of formula (III) wherein R ¹⁰ Is H and R ⁹ Is H.

In another embodiment are compounds of formula (III) wherein R ¹² Is H.

In another embodiment are compounds of formula (III) wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (III) wherein R ¹² Is H and R ¹¹ is-CH ₃ . In another embodiment are compounds of formula (III) wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-OR ²³ . In another embodiment are compounds of formula (III) wherein R ¹² Is H and R ¹¹ is-CH ₂ And (5) OH. In another embodiment are compounds of formula (III) wherein R ¹² Is H and R ¹¹ is-CH ₂ CH ₂ And (5) OH. In another implementationIn the scheme are compounds of formula (III) wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (III) wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (III) wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-NH ₂ . In another embodiment are compounds of formula (III) wherein R ¹² Is H and R ¹¹ is-CH ₂ NH ₂ . In another embodiment are compounds of formula (III) wherein R ¹² Is H and R ¹¹ is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (III) wherein R ¹² Is H and R ¹¹ is-CH ₂ CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (III) wherein R ¹² Is H and R ¹¹ is-CH ₂ CH ₂ CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (III) wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-CN. In another embodiment are compounds of formula (III) wherein R ¹² Is H and R ¹¹ is-CH ₂ And (C) CN. In another embodiment are compounds of formula (III) wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-C (O) NR ²⁵ R ²⁶ . In another embodiment are compounds of formula (III) wherein R ¹² Is H and R ¹¹ is-CH ₂ C(O)NH ₂ . In another embodiment are compounds of formula (III) wherein R ¹² Is H and R ¹¹ is-CH ₂ CH ₂ C(O)NH ₂ . In another embodiment are compounds of formula (III) wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) Alkyl-heteroaryl. In another embodiment are compounds of formula (III) wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-N (H) S (O) ₂ NR ²⁵ R ²⁶ . In another implementationIn the scheme are compounds of formula (III) wherein R ¹² Is H and R ¹¹ is-CH ₂ N(H)S(O) ₂ NH ₂ . In another embodiment are compounds of formula (III) wherein R ¹² Is H and R ¹¹ Is H.

In another embodiment are compounds of formula (III) wherein R ¹¹ And R ¹⁸ Combined to form an optionally substituted heterocycloalkyl ring and R ¹² Is H.

In another embodiment are compounds of formula (III) wherein p is 1 and R ²⁷ Is halogen. In another embodiment are compounds of formula (III) wherein p is 1 and R ²⁷ Is optionally substituted- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (III) wherein q is 0, p is 1 and R ²⁷ Is halogen. In another embodiment are compounds of formula (III) wherein q is 0, p is 1 and R ²⁷ Is optionally substituted- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (III) wherein q is 1 and R ²⁸ Is halogen. In another embodiment are compounds of formula (III) wherein q is 1 and R ²⁸ Is optionally substituted- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (III) wherein p is 0, q is 1, and R is ²⁸ Is halogen. In another embodiment are compounds of formula (III) wherein p is 0, q is 1 and R ²⁸ Is optionally substituted- (C) ₁ -C ₆ ) An alkyl group.

In another embodiment are compounds of formula (III) wherein p is 0 and q is 0.

In another embodiment are compounds of formula (III) wherein R ¹ And R ² Each independently is H or- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (III) wherein R ¹ And R ² Each is H. In another embodiment are compounds of formula (III) wherein R ¹ And R ² Each independently is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (III) wherein R ¹ Is H, and R ² Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (III) wherein R ¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² And R is ² Is H. In another embodiment are compounds of formula (III) wherein R ¹ Is H, and R ² is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (III) wherein R ¹ is-CH ₂ CH ₂ NH ₂ And R is ² Is H. In another embodiment are compounds of formula (III) wherein R ¹ And R ² Each is-CH ₂ CH ₂ NH ₂ . In a further embodiment are compounds of formula (III), wherein R ¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² And R is ² Is H. In a further embodiment are compounds of formula (III), wherein R ¹ is-CH ₂ CH ₂ NH ₂ And R is ² Is H. In a further embodiment are compounds of formula (III), wherein R ¹ Is H and R ² Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In a further embodiment are compounds of formula (III) wherein R ¹ Is H and R ² is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (III) wherein R ¹ And R ² Are each independently H, - (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² or-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (III) wherein R ¹ And R ² Each independently is-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (III) wherein R ¹ Is H, and R ² is-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (III) wherein R ¹ is-CH ₂ CH(OH)CH ₂ NH ₂ And R is ² Is H. In a further embodiment are compounds of formula (III), wherein R ¹ And R ² And the atoms to which they are attached form an optionally substituted heterocycloalkyl ring.

In another embodiment are compounds of formula (III) wherein X is heteroaryl disubstituted with substituents each independently selected from halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ and-NO ₂ . In a further embodiment are compounds of formula (III) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituents disubstituted heteroaryl. In a further embodiment are compounds of formula (III) wherein X is heteroaryl disubstituted with methyl. In a further embodiment are compounds of formula (III) wherein X is pyridinyl disubstituted with substituents each independently selected from halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In a further embodiment are compounds of formula (III) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituent disubstituted pyridyl. In a further embodiment are compounds of formula (III) wherein X is pyridinyl disubstituted with methyl. In a further embodiment are compounds of formula (III) wherein X is pyrimidinyl disubstituted with substituents each independently selected from the group consisting of halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In a further embodiment are compounds of formula (III) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituent disubstituted pyrimidinyl. In a further embodiment are compounds of formula (III) wherein X is pyrimidinyl disubstituted with methyl.

In another embodiment are compounds of formula (III) wherein Y is optionally substituted aryl. In a further embodiment are compounds of formula (III) wherein Y is optionally substitutedA phenyl group. In another embodiment are compounds of formula (III) wherein Y is optionally substituted heteroaryl. In another embodiment are compounds of formula (III) wherein Y is optionally substituted- (C) ₁ -C ₆ ) An alkyl group-. In another embodiment are compounds of formula (III) wherein Y is optionally substituted (C) ₃ -C ₇ ) Cycloalkyl-. In another embodiment are compounds of formula (III) wherein Y is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (III) wherein Y is-O-. In another embodiment are compounds of formula (III) wherein Y is- (C) ₂ -C ₆ ) Alkynyl. In another embodiment are compounds of formula (III) wherein Y is-O- (C) ₁ -C ₆ ) An alkyl group-. In another embodiment are compounds of formula (III) wherein Y is a bond.

In another embodiment are compounds of formula (III) wherein Z is- (C) ₁ -C ₁₂ ) An alkyl group. In a further embodiment are compounds of formula (III) wherein Z is n-butyl, isobutyl, or tert-butyl. In another embodiment are compounds of formula (III) wherein Z is-O- (C) ₁ -C ₁₂ ) An alkyl group. In another embodiment are compounds of formula (III) wherein Z is-O- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (III) wherein Z is- (C) ₂ -C ₁₂ ) An alkenyl group. In another embodiment are compounds of formula (III) wherein Z is optionally substituted aryl. In a further embodiment are compounds of formula (III) wherein Z is optionally substituted phenyl. In a further embodiment are compounds of formula (III) wherein Z is independently selected from- (C) ₁ -C ₈ ) Alkyl substituents are monosubstituted or disubstituted phenyl. In a further embodiment are compounds of formula (III) wherein Z is phenyl monosubstituted with n-butyl, isobutyl, or tert-butyl. In a further embodiment are compounds of formula (III) wherein Z is phenyl monosubstituted with n-butyl. In a further embodiment are compounds of formula (III) wherein Z is phenyl monosubstituted with isobutyl. In a further embodiment are compounds of formula (III) wherein Z is phenyl monosubstituted with tert-butyl. In another embodimentIn an embodiment are compounds of formula (III) wherein Z is optionally substituted heteroaryl. In another embodiment are compounds of formula (III) wherein Z is optionally substituted- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (III) wherein Z is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (III) wherein Z is halo.

In another embodiment are compounds of formula (III) wherein Z-Y-X-is other than

In another embodiment are compounds of formula (III) having the structure of formula (IIIa):

wherein:

R ³ is H or- (C) ₁ -C ₆ ) An alkyl group;

Or R ³ And R ⁴ Combine to form a heterocycloalkyl ring;

R ⁵ is H or- (C) ₁ -C ₆ ) An alkyl group;

or R ⁹ And R ¹⁰ Combined to form a heterocycloalkyl or cycloalkyl ring

R ¹⁵ 、R ¹⁶ 、R ¹⁷ and R ¹⁸ Are each independently H, - (C) ₁ -C ₆ ) Alkyl, - (C) ₃ -C ₆ ) Cycloalkyl, - (C) ₁ -C ₆ ) alkyl-OR ²³ 、-(C ₁ -C ₆ ) alkyl-C (O) OR ²³ Or- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² ；

X is disubstituted heteroaryl;

each R ²³ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

each R ²⁴ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

p is 0, 1 or 2; and is

q is 0, 1 or 2;

or a pharmaceutically acceptable salt, solvate or prodrug thereof. In one embodiment are compounds of formula (IIIa) wherein R ⁶ 、R ⁷ And R ⁸ Is H.

In another embodiment are compounds of formula (IIIa), wherein R ¹⁵ And R ¹⁶ Is H.

In one embodiment are compounds of formula (IIIa), wherein R ¹⁷ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IIIa), wherein R ¹⁷ is-CH ₃ . In another embodiment are compounds of formula (IIIa), wherein R ¹⁷ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (IIIa), wherein R ¹⁷ Is- (C) ₃ -C ₆ ) Ring (C)An alkyl group. In another embodiment are compounds of formula (IIIa) wherein R ¹⁷ Is cyclopropyl. In another embodiment are compounds of formula (IIIa) wherein R ¹⁷ Is- (C) ₁ -C ₆ ) alkyl-C (O) OR ²³ . In another embodiment are compounds of formula (IIIa) wherein R ¹⁷ is-CH ₂ CH ₂ And (5) OH. In another embodiment are compounds of formula (IIIa) wherein R ¹⁷ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (IIIa), wherein R ¹⁷ is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IIIa), wherein R ¹⁷ Is H.

In another embodiment are compounds of formula (IIIa), wherein R ¹⁸ Is H.

In another embodiment are compounds of formula (IIIa), wherein R ³ Is H.

In another embodiment are compounds of formula (IIIa), wherein R ⁵ Is H.

In another embodiment are compounds of formula (IIIa), wherein R ⁴ Is H. In another embodiment are compounds of formula (IIIa), wherein R ⁴ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IIIa) wherein R ⁴ is-CH ₃ . In another embodiment are compounds of formula (IIIa), wherein R ⁴ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (IIIa), wherein R ⁴ Is- (C) ₁ -C ₆ ) alkyl-OH. In another embodiment are compounds of formula (IIIa) wherein R ⁴ is-CH ₂ And (5) OH. In another embodiment are compounds of formula (IIIa), wherein R ⁴ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (IIIa), wherein R ⁴ Is cyclopropyl. In another embodiment are compounds of formula (IIIa) wherein R ⁴ is-C (O) NH ₂ 。

In another embodiment are compounds of formula (IIIa) wherein R ⁴ And R ⁵ And the carbon atoms to which they are attached form a cyclopropyl ring.

In another embodiment are compounds of formula (IIIa), wherein R ³ 、R ⁴ And R ⁵ Is H.

In another embodiment are compounds of formula (IIIa), wherein R ¹⁰ Is H.

In another embodiment are compounds of formula (IIIa), wherein R ¹⁰ Is H and R ⁹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IIIa), wherein R ¹⁰ Is H and R ⁹ is-CH ₃ . In another embodiment are compounds of formula (IIIa) wherein R ¹⁰ Is H and R ⁹ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (IIIa) wherein R ¹⁰ Is H and R ⁹ Is- (C) ₁ -C ₆ ) A haloalkyl group. In another embodiment are compounds of formula (IIIa) wherein R ¹⁰ Is H and R ⁹ is-CH ₂ F. In another embodiment are compounds of formula (IIIa), wherein R ¹⁰ Is H and R ⁹ is-CHF ₂ . In another embodiment are compounds of formula (IIIa), wherein R ¹⁰ Is H and R ⁹ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (IIIa) wherein R ¹⁰ Is H and R ⁹ Is cyclopropyl. In another embodiment are compounds of formula (IIIa), wherein R ¹⁰ Is H and R ⁹ Is H.

In another embodiment are compounds of formula (IIIa) wherein R ¹² Is H.

In another embodiment are compounds of formula (IIIa), wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IIIa), wherein R ¹² Is H and R ¹¹ is-CH ₃ . In another embodiment are compounds of formula (IIIa) wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-OR ²³ . In another embodiment are compounds of formula (IIIa), wherein R ¹² Is H and R ¹¹ is-CH ₂ And (5) OH. In another embodiment are compounds of formula (IIIa) wherein R ¹² Is H and R ¹¹ is-CH ₂ CH ₂ And (5) OH. In another embodiment are compounds of formula (IIIa), wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IIIa) wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (IIIa), wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-NH ₂ . In another embodiment are compounds of formula (IIIa), wherein R ¹² Is H and R ¹¹ is-CH ₂ NH ₂ . In another embodiment are compounds of formula (IIIa), wherein R ¹² Is H and R ¹¹ is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IIIa) wherein R ¹² Is H and R ¹¹ is-CH ₂ CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IIIa) wherein R ¹² Is H and R ¹¹ is-CH ₂ CH ₂ CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IIIa) wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) An alkyl-CN group. In another embodiment are compounds of formula (IIIa), wherein R ¹² Is H and R ¹¹ is-CH ₂ And (C) CN. In another embodiment are compounds of formula (IIIa), wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-C (O) NR ²⁵ R ²⁶ . In another embodiment are compounds of formula (IIIa), wherein R ¹² Is H and R ¹¹ is-CH ₂ C(O)NH ₂ . In another embodiment are compounds of formula (IIIa), wherein R ¹² Is H and R ¹¹ is-CH ₂ CH ₂ C(O)NH ₂ . In another embodiment are compounds of formula (IIIa), wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) Alkane (I) and its preparation methodA-heteroaryl group. In another embodiment are compounds of formula (IIIa), wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-N (H) S (O) ₂ NR ²⁵ R ²⁶ . In another embodiment are compounds of formula (IIIa), wherein R ¹² Is H and R ¹¹ is-CH ₂ N(H)S(O) ₂ NH ₂ . In another embodiment are compounds of formula (IIIa) wherein R ¹² Is H and R ¹¹ Is H.

In another embodiment are compounds of formula (IIIa) wherein R ¹¹ And R ¹⁸ Combined to form an optionally substituted heterocycloalkyl ring and R ¹² Is H.

In another embodiment are compounds of formula (IIIa) wherein p is 1 and R ²⁷ Is a halogen. In another embodiment are compounds of formula (IIIa) wherein p is 1 and R ²⁷ Is optionally substituted- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IIIa) wherein q is 0, p is 1 and R ²⁷ Is halogen. In another embodiment are compounds of formula (IIIa) wherein q is 0, p is 1 and R ²⁷ Is optionally substituted- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IIIa) wherein q is 1 and R ²⁸ Is halogen. In another embodiment are compounds of formula (IIIa) wherein q is 1 and R ²⁸ Is optionally substituted- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IIIa) wherein p is 0, q is 1 and R ²⁸ Is halogen. In another embodiment are compounds of formula (IIIa) wherein p is 0, q is 1 and R ²⁸ Is optionally substituted- (C) ₁ -C ₆ ) An alkyl group.

In another embodiment are compounds of formula (IIIa) wherein p is 0 and q is 0.

In another embodiment are compounds of formula (IIIa), wherein R ¹ And R ² Each independently is H or- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (IIIa), wherein R ¹ And R ² Each is H. In anotherIn an embodiment are compounds of formula (IIIa), wherein R ¹ And R ² Each independently is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (IIIa), wherein R ¹ Is H, and R ² Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (IIIa) wherein R ¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² And R is ² Is H. In another embodiment are compounds of formula (IIIa) wherein R ¹ Is H, and R ² is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IIIa) wherein R ¹ is-CH ₂ CH ₂ NH ₂ And R is ² Is H. In another embodiment are compounds of formula (IIIa), wherein R ¹ And R ² Each is-CH ₂ CH ₂ NH ₂ . In a further embodiment are compounds of formula (IIIa) wherein R ¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² And R is ² Is H. In a further embodiment are compounds of formula (IIIa), wherein R ¹ is-CH ₂ CH ₂ NH ₂ And R is ² Is H. In a further embodiment are compounds of formula (IIIa), wherein R ¹ Is H and R ² Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In a further embodiment are compounds of formula (IIIa) wherein R ¹ Is H and R ² is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IIIa), wherein R ¹ And R ² Are each independently H, - (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² or-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (IIIa), wherein R ¹ And R ² Each independently is-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (IIIa), wherein R ¹ Is H, and R ² is-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (IIIa), wherein R ¹ is-CH ₂ CH(OH)CH ₂ NH ₂ And R is ² Is H. In a further embodiment are compounds of formula (IIIa), wherein R ¹ And R ² And the atoms to which they are attached form an optionally substituted heterocycloalkyl ring.

In another embodiment are compounds of formula (IIIa) wherein X is heteroaryl disubstituted with substituents each independently selected from halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ and-NO ₂ . In a further embodiment are compounds of formula (IIIa) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituents disubstituted heteroaryl. In a further embodiment are compounds of formula (IIIa) wherein X is heteroaryl disubstituted with methyl. In a further embodiment are compounds of formula (IIIa) wherein X is pyridyl disubstituted with substituents each independently selected from halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In a further embodiment are compounds of formula (IIIa) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituent disubstituted pyridyl. In a further embodiment are compounds of formula (IIIa) wherein X is pyridinyl disubstituted with methyl. In a further embodiment are compounds of formula (IIIa) wherein X is pyrimidinyl disubstituted with substituents each independently selected from halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In a further embodiment are compounds of formula (IIIa) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituent disubstituted pyrimidinyl. In a further embodiment is of formula (II)Ia) compounds wherein X is pyrimidinyl disubstituted with methyl.

In another embodiment are compounds of formula (IIIa) wherein Y is optionally substituted aryl. In a further embodiment are compounds of formula (IIIa) wherein Y is optionally substituted phenyl. In another embodiment are compounds of formula (IIIa) wherein Y is optionally substituted heteroaryl. In another embodiment are compounds of formula (IIIa) wherein Y is optionally substituted- (C) ₁ -C ₆ ) An alkyl group-. In another embodiment are compounds of formula (IIIa) wherein Y is optionally substituted (C) ₃ -C ₇ ) Cycloalkyl-. In another embodiment are compounds of formula (IIIa) wherein Y is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (IIIa) wherein Y is-O-. In another embodiment are compounds of formula (IIIa) wherein Y is- (C) ₂ -C ₆ ) Alkynyl. In another embodiment are compounds of formula (IIIa) wherein Y is-O- (C) ₁ -C ₆ ) An alkyl group-. In another embodiment are compounds of formula (IIIa) wherein Y is a bond.

In another embodiment are compounds of formula (IIIa) wherein Z is- (C) ₁ -C ₁₂ ) An alkyl group. In a further embodiment are compounds of formula (IIIa) wherein Z is n-butyl, isobutyl, or tert-butyl. In another embodiment are compounds of formula (IIIa) wherein Z is-O- (C) ₁ -C ₁₂ ) An alkyl group. In another embodiment are compounds of formula (IIIa) wherein Z is-O- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (IIIa) wherein Z is- (C) ₂ -C ₁₂ ) An alkenyl group. In another embodiment are compounds of formula (IIIa) wherein Z is optionally substituted aryl. In a further embodiment are compounds of formula (IIIa) wherein Z is optionally substituted phenyl. In a further embodiment are compounds of formula (IIIa) wherein Z is independently selected from- (C) ₁ -C ₈ ) Alkyl substituents are monosubstituted or disubstituted phenyl. In a further embodiment are compounds of formula (IIIa) wherein Z is phenyl monosubstituted with n-butyl, isobutyl, or tert-butyl. In a further embodimentIs a compound of formula (IIIa) wherein Z is phenyl monosubstituted with n-butyl. In a further embodiment are compounds of formula (IIIa) wherein Z is phenyl monosubstituted with isobutyl. In a further embodiment are compounds of formula (IIIa) wherein Z is phenyl monosubstituted with tert-butyl. In another embodiment are compounds of formula (IIIa) wherein Z is optionally substituted heteroaryl. In another embodiment are compounds of formula (IIIa) wherein Z is optionally substituted- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (IIIa) wherein Z is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (IIIa) wherein Z is halo.

In another embodiment are compounds of formula (IIIa) wherein Z-Y-X-is not

In another embodiment are compounds of formula (III) having the structure of formula (IIIb):

wherein:

R ⁵ Is H or- (C) ₁ -C ₆ ) An alkyl group;

X is disubstituted heteroaryl;

each R ²³ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

each R ²⁴ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

or a pharmaceutically acceptable salt, solvate or prodrug thereof. In one embodiment are compounds of formula (IIIb), wherein R ¹⁷ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IIIb), wherein R ¹⁷ is-CH ₃ . In another embodiment are compounds of formula (IIIb), wherein R ¹⁷ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (IIIb), wherein R ¹⁷ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (IIIb), wherein R ¹⁷ Is cyclopropyl. In another embodiment are compounds of formula (IIIb), wherein R ¹⁷ Is- (C) ₁ -C ₆ ) alkyl-C (O) OR ²³ . In another implementationIn the scheme are compounds of formula (IIIb), wherein R ¹⁷ is-CH ₂ CH ₂ And (5) OH. In another embodiment are compounds of formula (IIIb), wherein R ¹⁷ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (IIIb), wherein R ¹⁷ is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IIIb), wherein R ¹⁷ Is H.

In another embodiment are compounds of formula (IIIb), wherein R ¹⁸ Is H.

In another embodiment are compounds of formula (IIIb), wherein R ⁵ Is H.

In another embodiment are compounds of formula (IIIb), wherein R ⁴ Is H. In another embodiment are compounds of formula (IIIb), wherein R ⁴ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IIIb), wherein R ⁴ is-CH ₃ . In another embodiment are compounds of formula (IIIb) wherein R ⁴ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (IIIb), wherein R ⁴ Is- (C) ₁ -C ₆ ) alkyl-OH. In another embodiment are compounds of formula (IIIb), wherein R ⁴ is-CH ₂ And (5) OH. In another embodiment are compounds of formula (IIIb), wherein R ⁴ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (IIIb), wherein R ⁴ Is cyclopropyl. In another embodiment are compounds of formula (IIIb), wherein R ⁴ is-C (O) NH ₂ 。

In another embodiment are compounds of formula (IIIb), wherein R ⁴ And R ⁵ And the carbon atoms to which they are attached form a cyclopropyl ring.

In another embodiment are compounds of formula (IIIb), wherein R ⁹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IIIb), wherein R ⁹ is-CH ₃ . In another embodiment are compounds of formula (IIIb),wherein R is ⁹ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (IIIb) wherein R ⁹ Is- (C) ₁ -C ₆ ) A haloalkyl group. In another embodiment are compounds of formula (IIIb) wherein R ⁹ is-CH ₂ F. In another embodiment are compounds of formula (IIIb) wherein R ⁹ is-CHF ₂ . In another embodiment are compounds of formula (IIIb) wherein R ⁹ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (IIIb) wherein R ⁹ Is cyclopropyl. In another embodiment are compounds of formula (IIIb), wherein R ⁹ Is H.

In another embodiment are compounds of formula (IIIb), wherein R ¹¹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IIIb), wherein R ¹¹ is-CH ₃ . In another embodiment are compounds of formula (IIIb) wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-OR ²³ . In another embodiment are compounds of formula (IIIb) wherein R ¹¹ is-CH ₂ And (5) OH. In another embodiment are compounds of formula (IIIb) wherein R ¹¹ is-CH ₂ CH ₂ And (5) OH. In another embodiment are compounds of formula (IIIb), wherein R ¹¹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IIIb), wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (IIIb), wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-NH ₂ . In another embodiment are compounds of formula (IIIb), wherein R ¹¹ is-CH ₂ NH ₂ . In another embodiment are compounds of formula (IIIb) wherein R ¹¹ is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IIIb), wherein R ¹¹ is-CH ₂ CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IIIb), wherein R ¹¹ is-CH ₂ CH ₂ CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IIIb), wherein R ¹¹ Is- (C) ₁ -C ₆ ) An alkyl-CN group. In another embodiment are compounds of formula (IIIb), wherein R ¹¹ is-CH ₂ And (C) CN. In another embodiment are compounds of formula (IIIb) wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-C (O) NR ²⁵ R ²⁶ . In another embodiment are compounds of formula (IIIb) wherein R ¹¹ is-CH ₂ C(O)NH ₂ . In another embodiment are compounds of formula (IIIb) wherein R ¹¹ is-CH ₂ CH ₂ C(O)NH ₂ . In another embodiment are compounds of formula (IIIb) wherein R ¹¹ Is- (C) ₁ -C ₆ ) Alkyl-heteroaryl. In another embodiment are compounds of formula (IIIb), wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-N (H) S (O) ₂ NR ²⁵ R ²⁶ . In another embodiment are compounds of formula (IIIb), wherein R ¹¹ is-CH ₂ N(H)S(O) ₂ NH ₂ . In another embodiment are compounds of formula (IIIb), wherein R ¹¹ Is H.

In another embodiment are compounds of formula (IIIb) wherein R ¹¹ And R ¹⁸ Combine to form an optionally substituted heterocycloalkyl ring.

In another embodiment are compounds of formula (IIIb), wherein R ¹ And R ² Each independently is H or- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (IIIb) wherein R ¹ And R ² Each is H. In another embodiment are compounds of formula (IIIb), wherein R ¹ And R ² Each independently is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (IIIb), wherein R ¹ Is H, and R ² Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (IIIb), wherein R ¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² And R is ² Is H. In another embodiment are compounds of formula (IIIb), wherein R ¹ Is H, and R ² is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IIIb), wherein R ¹ is-CH ₂ CH ₂ NH ₂ And R is ² Is H. In another embodiment are compounds of formula (IIIb) wherein R ¹ And R ² Each is-CH ₂ CH ₂ NH ₂ . In a further embodiment are compounds of formula (IIIb), wherein R ¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² And R is ² Is H. In a further embodiment are compounds of formula (IIIb), wherein R ¹ is-CH ₂ CH ₂ NH ₂ And R is ² Is H. In a further embodiment are compounds of formula (IIIb), wherein R ¹ Is H and R ² Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In a further embodiment are compounds of formula (IIIb), wherein R ¹ Is H and R ² is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IIIb) wherein R ¹ And R ² Are each independently H, - (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² or-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (IIIb), wherein R ¹ And R ² Each independently is-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (IIIb), wherein R ¹ Is H, and R ² is-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (IIIb), wherein R ¹ is-CH ₂ CH(OH)CH ₂ NH ₂ And R is ² Is H. In a further embodiment are compounds of formula (IIIb) wherein R ¹ And R ² And the atoms to which they are attached form an optionally substituted heterocycloalkyl ring.

In another embodiment are compounds of formula (IIIb), wherein X is takenOptionally disubstituted heteroaryl, each of which substituents is independently selected from halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ and-NO ₂ . In a further embodiment are compounds of formula (IIIb), wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituents disubstituted heteroaryl. In a further embodiment are compounds of formula (IIIb) wherein X is heteroaryl disubstituted with methyl. In a further embodiment are compounds of formula (IIIb) wherein X is pyridyl disubstituted with substituents each independently selected from halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In a further embodiment are compounds of formula (IIIb), wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituent disubstituted pyridyl. In a further embodiment are compounds of formula (IIIb) wherein X is pyridinyl disubstituted with methyl. In a further embodiment are compounds of formula (IIIb) wherein X is pyrimidinyl disubstituted with substituents each independently selected from halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In a further embodiment are compounds of formula (IIIb) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituent disubstituted pyrimidinyl. In a further embodiment are compounds of formula (IIIb) wherein X is pyrimidinyl disubstituted with methyl.

In another embodiment are compounds of formula (IIIb) wherein Y is optionally substituted aryl. In a further embodiment are compounds of formula (IIIb) wherein Y is optionally substituted phenyl. In another embodiment are compounds of formula (IIIb) wherein Y is optionally substituted heteroaryl. In another embodiment are compounds of formula (IIIb), wherein Y is optionally substitutedIs of (C) ₁ -C ₆ ) An alkyl radical. In another embodiment are compounds of formula (IIIb) wherein Y is optionally substituted (C) ₃ -C ₇ ) Cycloalkyl-. In another embodiment are compounds of formula (IIIb) wherein Y is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (IIIb) wherein Y is-O-. In another embodiment are compounds of formula (IIIb), wherein Y is- (C) ₂ -C ₆ ) Alkynyl. In another embodiment are compounds of formula (IIIb) wherein Y is-O- (C) ₁ -C ₆ ) An alkyl group-. In another embodiment are compounds of formula (IIIb), wherein Y is a bond.

In another embodiment are compounds of formula (IIIb), wherein Z is- (C) ₁ -C ₁₂ ) An alkyl group. In a further embodiment are compounds of formula (IIIb) wherein Z is n-butyl, isobutyl, or tert-butyl. In another embodiment are compounds of formula (IIIb), wherein Z is-O- (C) ₁ -C ₁₂ ) An alkyl group. In another embodiment are compounds of formula (IIIb), wherein Z is-O- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (IIIb), wherein Z is- (C) ₂ -C ₁₂ ) An alkenyl group. In another embodiment are compounds of formula (IIIb) wherein Z is optionally substituted aryl. In a further embodiment are compounds of formula (IIIb) wherein Z is optionally substituted phenyl. In a further embodiment are compounds of formula (IIIb) wherein Z is independently selected from the group consisting of ₁ -C ₈ ) Alkyl substituents are monosubstituted or disubstituted phenyl. In a further embodiment are compounds of formula (IIIb) wherein Z is phenyl monosubstituted with n-butyl, isobutyl, or tert-butyl. In a further embodiment are compounds of formula (IIIb) wherein Z is phenyl monosubstituted with n-butyl. In a further embodiment are compounds of formula (IIIb) wherein Z is phenyl monosubstituted with isobutyl. In a further embodiment are compounds of formula (IIIb) wherein Z is phenyl monosubstituted with tert-butyl. In another embodiment are compounds of formula (IIIb) wherein Z is optionally substituted heteroaryl. In another embodiment are compounds of formula (IIIb), wherein Z is optionally substituted -(C ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (IIIb) wherein Z is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (IIIb) wherein Z is halo.

In another embodiment are compounds of formula (IIIb), wherein Z-Y-X-is other than

In another embodiment are compounds of formula (III) having the structure of formula (IIIc):

wherein:

R ¹¹ is H, -NH ₂ 、-(C ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-OR ²³ 、-(C ₁ -C ₆ ) alkyl-SR ²³ 、-(C ₁ -C ₆ ) alkyl-C (O) OR ²³ 、-(C ₁ -C ₆ ) alkyl-NR ²¹ R ²² 、-(C ₁ -C ₆ ) alkyl-NR ²³ OR ²³ 、-(C ₁ -C ₆ ) alkyl-NHC (O) NR ²³ OR ²³ 、-(C ₁ -C ₆ ) alkyl-O- (C) ₁ -C ₆ ) alkyl-NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) alkyl-CN, - (C) ₁ -C ₆ ) alkyl-NR ²³ C(O)R ²³ 、-(C ₁ -C ₆ ) alkyl-C (O) NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) heteroalkyl-CO ₂ H、-(C ₁ -C ₆ ) alkyl-S (O) (C) ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-N (H) CH = NH, - (C) ₁ -C ₆ ) alkyl-C (NH) ₂ )＝NH、-(C ₁ -C ₆ ) alkyl-N (H) C (= NH) NH ₂ 、-(C ₁ -C ₆ ) alkyl-N (H) S (O) ₂ NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) alkyl-N (H) S (O) ₂ (C ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-N (H) -C (O) NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) Alkyl C (O) N (H) [ optionally substituted (C) ₂ -C ₆ ) Alkyl radical]-OR ²³ 、-(C ₁ -C ₆ ) Alkyl N (H) C (O) (C) ₁ -C ₆ ) alkyl-OR ²³ 、-(C ₁ -C ₆ ) Alkyl C (O) N (H) heterocycloalkyl, - (C) ₁ -C ₆ ) Alkyl C (O) NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) Alkane (I) and its preparation methodradical-N (H) -C (O) - (C) ₁ -C ₆ ) alkyl-NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) alkyl-N (H) - (C) ₁ -C ₆ ) Alkyl C (O) NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) Alkyl-heterocycloalkyl, optionally substituted- (C) ₁ -C ₆ ) alkyl-N (H) heterocycloalkyl or- (C) ₁ -C ₆ ) Alkyl-heteroaryl;

x is disubstituted heteroaryl;

z is H, halogen, -NH ₂ 、-CN、-CF ₃ 、-CO ₂ H、-(C ₁ -C ₁₂ ) Alkyl, - (C) ₂ -C ₁₂ ) Alkenyl, -CH = ((C) ₃ -C ₇ ) Cycloalkyl), - (C) ₂ -C ₁₂ ) Alkynyl, -C (O) NR ²⁵ R ²⁶ 、-O-(C ₁ -C ₁₂ ) Alkyl, -S- (C) ₁ -C ₁₂ ) Alkyl, -O- (C) ₃ -C ₁₀ ) [ optionally substituted (C) ₃ -C ₇ ) Cycloalkyl radicals]、-O-(C ₁ -C ₆ ) alkyl-OR ²³ 、-(C ₁ -C ₁₂ ) Alkane (I) and its preparation methodradical-OR ²³ 、-(C ₁ -C ₁₂ ) alkyl-CN, -S- (C) ₁ -C ₁₂ ) Alkyl, -N (R) ²⁴ )(C ₁ -C ₁₂ ) Alkyl, -N (R) ²⁴ )C(O)(C ₁ -C ₁₂ ) Alkyl, optionally substituted- (C) ₃ -C ₇ ) Cycloalkyl, - (C) ₁ -C ₆ ) Alkyl radical- (C) ₃ -C ₇ ) Cycloalkyl, - (C) ₁ -C ₆ ) Alkyl-heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

each R ²³ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

each R ²⁴ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

or a pharmaceutically acceptable salt, solvate or prodrug thereof. In another embodiment are compounds of formula (IIIc), wherein R ¹¹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment isA compound of formula (IIIc) wherein R ¹¹ is-CH ₃ . In another embodiment are compounds of formula (IIIc), wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-OR ²³ . In another embodiment are compounds of formula (IIIc), wherein R ¹¹ is-CH ₂ And (5) OH. In another embodiment are compounds of formula (IIIc) wherein R ¹¹ is-CH ₂ CH ₂ And (5) OH. In another embodiment are compounds of formula (IIIc) wherein R ¹¹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IIIc), wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (IIIc) wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-NH ₂ . In another embodiment are compounds of formula (IIIc), wherein R ¹¹ is-CH ₂ NH ₂ . In another embodiment are compounds of formula (IIIc) wherein R ¹¹ is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IIIc) wherein R ¹¹ is-CH ₂ CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IIIc) wherein R ¹¹ is-CH ₂ CH ₂ CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IIIc), wherein R ¹¹ Is- (C) ₁ -C ₆ ) An alkyl-CN group. In another embodiment are compounds of formula (IIIc) wherein R ¹¹ is-CH ₂ And (C) CN. In another embodiment are compounds of formula (IIIc), wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-C (O) NR ²⁵ R ²⁶ . In another embodiment are compounds of formula (IIIc), wherein R ¹¹ is-CH ₂ C(O)NH ₂ . In another embodiment are compounds of formula (IIIc) wherein R ¹¹ is-CH ₂ CH ₂ C(O)NH ₂ . In another embodiment are compounds of formula (IIIc), wherein R ¹¹ Is- (C) ₁ -C ₆ ) Alkyl-heteroaryl. In another embodiment are compounds of formula (IIIc),wherein R is ¹¹ Is- (C) ₁ -C ₆ ) alkyl-N (H) S (O) ₂ NR ²⁵ R ²⁶ . In another embodiment are compounds of formula (IIIc) wherein R ¹¹ is-CH ₂ N(H)S(O) ₂ NH ₂ . In another embodiment are compounds of formula (IIIc), wherein R ¹¹ Is H.

In another embodiment are compounds of formula (IIIc), wherein R ¹ And R ² Each independently is H or- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (IIIc), wherein R ¹ And R ² Each is H. In another embodiment are compounds of formula (IIIc) wherein R ¹ And R ² Each independently is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (IIIc), wherein R ¹ Is H, and R ² Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (IIIc), wherein R ¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² And R is ² Is H. In another embodiment are compounds of formula (IIIc) wherein R ¹ Is H, and R ² is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IIIc), wherein R ¹ is-CH ₂ CH ₂ NH ₂ And R is ² Is H. In another embodiment are compounds of formula (IIIc), wherein R ¹ And R ² Each is-CH ₂ CH ₂ NH ₂ . In a further embodiment are compounds of formula (IIIc), wherein R ¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² And R is ² Is H. In a further embodiment are compounds of formula (IIIc) wherein R ¹ is-CH ₂ CH ₂ NH ₂ And R is ² Is H. In a further embodiment are compounds of formula (IIIc) wherein R ¹ Is H and R ² Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In a further implementationIn scheme (IIIc), the compound of formula (IIIc) wherein R ¹ Is H and R ² is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IIIc), wherein R ¹ And R ² Are each independently H, - (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² or-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (IIIc), wherein R ¹ And R ² Each independently is-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (IIIc) wherein R ¹ Is H, and R ² is-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (IIIc), wherein R ¹ is-CH ₂ CH(OH)CH ₂ NH ₂ And R is ² Is H. In a further embodiment are compounds of formula (IIIc), wherein R ¹ And R ² And the atoms to which they are attached form an optionally substituted heterocycloalkyl ring.

In another embodiment are compounds of formula (IIIc) wherein X is heteroaryl disubstituted with substituents each independently selected from halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ and-NO ₂ . In a further embodiment are compounds of formula (IIIc) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituents disubstituted heteroaryl. In a further embodiment are compounds of formula (IIIc) wherein X is heteroaryl disubstituted with methyl. In a further embodiment are compounds of formula (IIIc) wherein X is pyridinyl disubstituted with substituents each independently selected from the group consisting of halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In a further embodiment are compounds of formula (IIIc) wherein X is independently selected from- (C) ₁ -C ₆ ) Disubstituted with alkyl substituentsA pyridyl group of (a). In a further embodiment are compounds of formula (IIIc) wherein X is pyridinyl disubstituted with methyl. In a further embodiment are compounds of formula (IIIc) wherein X is pyrimidinyl disubstituted with substituents each independently selected from the group consisting of halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In a further embodiment are compounds of formula (IIIc) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituent disubstituted pyrimidinyl. In a further embodiment are compounds of formula (IIIc) wherein X is pyrimidinyl disubstituted with methyl.

In another embodiment are compounds of formula (IIIc) wherein Y is optionally substituted aryl. In a further embodiment are compounds of formula (IIIc) wherein Y is optionally substituted phenyl. In another embodiment are compounds of formula (IIIc) wherein Y is optionally substituted heteroaryl. In another embodiment are compounds of formula (IIIc) wherein Y is optionally substituted- (C) ₁ -C ₆ ) An alkyl radical. In another embodiment are compounds of formula (IIIc) wherein Y is optionally substituted (C) ₃ -C ₇ ) Cycloalkyl-. In another embodiment are compounds of formula (IIIc) wherein Y is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (IIIc) wherein Y is-O-. In another embodiment are compounds of formula (IIIc) wherein Y is- (C) ₂ -C ₆ ) Alkynyl. In another embodiment are compounds of formula (IIIc) wherein Y is-O- (C) ₁ -C ₆ ) An alkyl group-. In another embodiment are compounds of formula (IIIc) wherein Y is a bond.

In another embodiment are compounds of formula (IIIc) wherein Z is- (C) ₁ -C ₁₂ ) An alkyl group. In a further embodiment are compounds of formula (IIIc) wherein Z is n-butyl, isobutyl, or tert-butyl. In another embodiment are compounds of formula (IIIc) wherein Z is-O- (C) ₁ -C ₁₂ ) An alkyl group. In another embodiment are compounds of formula (IIIc), whichWherein Z is-O- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (IIIc) wherein Z is- (C) ₂ -C ₁₂ ) An alkenyl group. In another embodiment are compounds of formula (IIIc) wherein Z is optionally substituted aryl. In a further embodiment are compounds of formula (IIIc) wherein Z is optionally substituted phenyl. In a further embodiment are compounds of formula (IIIc) wherein Z is independently selected from- (C) ₁ -C ₈ ) Alkyl substituents are monosubstituted or disubstituted phenyl. In a further embodiment are compounds of formula (IIIc) wherein Z is phenyl monosubstituted with n-butyl, isobutyl, or tert-butyl. In a further embodiment are compounds of formula (IIIc) wherein Z is phenyl monosubstituted with n-butyl. In a further embodiment are compounds of formula (IIIc) wherein Z is phenyl monosubstituted with isobutyl. In a further embodiment are compounds of formula (IIIc) wherein Z is phenyl monosubstituted with tert-butyl. In another embodiment are compounds of formula (IIIc) wherein Z is optionally substituted heteroaryl. In another embodiment are compounds of formula (IIIc) wherein Z is optionally substituted- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (IIIc) wherein Z is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (IIIc) wherein Z is halo.

In another embodiment are compounds of formula (IIIc) wherein Z-Y-X-is other than

In one aspect, described herein are compounds of formula (IV), or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

wherein:

R ³ is H or- (C) ₁ -C ₆ ) An alkyl group;

Or R ³ And R ⁴ Combine to form a heterocycloalkyl ring;

R ⁵ is H or- (C) ₁ -C ₆ ) An alkyl group;

or R ⁹ And R ¹⁰ Combined to form a heterocycloalkyl or cycloalkyl ring

R ¹¹ And R ¹² Each independently is H or- (C) ₁ -C ₆ ) alkyl-N (H) S (O) ₂ NR ²⁵ R ²⁶ ；

each R ²³ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

each R ²⁴ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

each R ²⁸ Independently halogen, -NR ²³ R ²⁴ 、-NHC(O)R ²³ 、-NC(O)NR ²³ R ²⁴ Nitro, hydroxy, optionally substituted- (C) ₁ -C ₆ ) Alkyl radical, NOptionally substituted- (C) ₁ -C ₆ ) Heteroalkyl, optionally substituted- (C) ₁ -C ₆ ) Heteroalkyloxy, optionally substituted- (C) ₁ -C ₆ ) Heteroalkylamino, - (C) ₁ -C ₆ ) Alkoxy, -C (O) (C) ₁ -C ₆ ) Alkyl or-S (O) ₂ (C ₁ -C ₆ ) An alkyl group;

p is 0, 1 or 2; and is

q is 0, 1 or 2.

In one embodiment are compounds of formula (IV) wherein R ⁶ 、R ⁷ And R ⁸ Is H.

In another embodiment are compounds of formula (IV) wherein R ¹⁵ And R ¹⁶ Is H.

In one embodiment are compounds of formula (IV) wherein R ¹⁷ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IV) wherein R ¹⁷ is-CH ₃ . In another embodiment are compounds of formula (IV) wherein R ¹⁷ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (IV) wherein R ¹⁷ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (IV) wherein R ¹⁷ Is cyclopropyl. In another embodiment are compounds of formula (IV) wherein R ¹⁷ Is- (C) ₁ -C ₆ ) alkyl-C (O) OR ²³ . In another embodiment are compounds of formula (IV) wherein R ¹⁷ is-CH ₂ CH ₂ And (5) OH. In another embodiment are compounds of formula (IV) wherein R ¹⁷ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (IV) wherein R ¹⁷ is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IV) wherein R ¹⁷ Is H.

In another embodiment are compounds of formula (IV) wherein R ¹⁸ Is H.

In another embodiment are compounds of formula (IV) wherein R ³ Is H.

In another embodiment are compounds of formula (IV) wherein R ⁵ Is H.

In another embodiment are compounds of formula (IV) wherein R ⁴ Is H. In another embodiment are compounds of formula (IV) wherein R ⁴ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IV) wherein R ⁴ is-CH ₃ . In another embodiment are compounds of formula (IV) wherein R ⁴ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (IV) wherein R ⁴ Is- (C) ₁ -C ₆ ) alkyl-OH. In another embodiment are compounds of formula (IV) wherein R ⁴ is-CH ₂ And (5) OH. In another embodiment are compounds of formula (IV) wherein R ⁴ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (IV) wherein R ⁴ Is cyclopropyl. In another embodiment are compounds of formula (IV) wherein R ⁴ is-C (O) NH ₂ 。

In another embodiment are compounds of formula (IV) wherein R ³ 、R ⁴ And R ⁵ Is H.

In another embodiment are compounds of formula (IV) wherein R ⁴ And R ⁵ And the carbon atoms to which they are attached form a cyclopropyl ring.

In another embodiment are compounds of formula (IV) wherein R ¹⁰ Is H.

In another embodiment are compounds of formula (IV) wherein R ¹⁰ Is H and R ⁹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IV) wherein R ¹⁰ Is H and R ⁹ is-CH ₃ . In another embodiment are compounds of formula (IV) wherein R ¹⁰ Is H and R ⁹ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (IV) wherein R ¹⁰ Is H and R ⁹ Is- (C) ₁ -C ₆ ) A haloalkyl group. In another embodiment are compounds of formula (IV) wherein R ¹⁰ Is H and R ⁹ is-CH ₂ F. In another embodiment are compounds of formula (IV) wherein R ¹⁰ Is H and R ⁹ is-CHF ₂ . In another embodiment are compounds of formula (IV) wherein R ¹⁰ Is H and R ⁹ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (IV) wherein R ¹⁰ Is H and R ⁹ Is cyclopropyl. In another embodiment are compounds of formula (IV) wherein R ¹⁰ Is H and R ⁹ Is H.

In another embodiment are compounds of formula (IV) wherein R ¹² Is H.

In another embodiment are compounds of formula (IV) wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-N (H) S (O) ₂ NR ²⁵ R ²⁶ . In another embodiment are compounds of formula (IV) wherein R ¹² Is H and R ¹¹ is-CH ₂ N(H)S(O) ₂ NH ₂ 。

In another embodiment are compounds of formula (IV) wherein p is 1 and R ²⁷ Is a halogen. In another embodiment are compounds of formula (IV) wherein p is 1 and R ²⁷ Is optionally substituted- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IV) wherein q is 0, p is 1 and R is ²⁷ Is a halogen. In another embodiment are compounds of formula (IV) wherein q is 0, p is 1 and R ²⁷ Is optionally substituted- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IV) wherein q is 1 and R ²⁸ Is halogen. In another embodiment are compounds of formula (IV) wherein q is 1 and R ²⁸ Is optionally substituted- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IV) wherein p is 0, q is 1, and R is ²⁸ Is halogen. In another embodiment are compounds of formula (IV) wherein p is 0, q is 1, and R is ²⁸ Is optionally substituted- (C) ₁ -C ₆ ) An alkyl group.

In another embodiment are compounds of formula (IV) wherein p is 0 and q is 0.

In another embodiment are compounds of formula (IV) wherein R ¹ And R ² Each independently is H or- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (IV) wherein R ¹ And R ² Each is H. In another embodiment are compounds of formula (IV) wherein R ¹ And R ² Each independently is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (IV) wherein R ¹ Is H, and R ² Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (IV) wherein R ¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² And R is ² Is H. In another embodiment are compounds of formula (IV) wherein R ¹ Is H, and R ² is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IV) wherein R ¹ is-CH ₂ CH ₂ NH ₂ And R is ² Is H. In another embodiment are compounds of formula (IV) wherein R ¹ And R ² Each is-CH ₂ CH ₂ NH ₂ . In a further embodiment are compounds of formula (IV) wherein R ¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² And R is ² Is H. In a further embodiment are compounds of formula (IV) wherein R ¹ is-CH ₂ CH ₂ NH ₂ And R is ² Is H. In a further embodiment are compounds of formula (IV) wherein R ¹ Is H and R ² Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In a further embodiment are compounds of formula (IV) wherein R ¹ Is H and R ² is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IV) wherein R ¹ And R ² Each independentlyIs H, - (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² or-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (IV) wherein R ¹ And R ² Each independently is-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (IV) wherein R ¹ Is H, and R ² is-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (IV) wherein R ¹ is-CH ₂ CH(OH)CH ₂ NH ₂ And R is ² Is H. In a further embodiment are compounds of formula (IV) wherein R ¹ And R ² And the atoms to which they are attached form an optionally substituted heterocycloalkyl ring.

In another embodiment are compounds of formula (IV) wherein X is optionally substituted aryl. In a further embodiment are compounds of formula (IV) wherein X is optionally substituted phenyl. In another embodiment are compounds of formula (IV) wherein X is optionally substituted heteroaryl. In a further embodiment are compounds of formula (IV) wherein X is disubstituted heteroaryl. In a further embodiment are compounds of formula (IV) wherein X is heteroaryl disubstituted with substituents each independently selected from halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ and-NO ₂ . In a further embodiment are compounds of formula (IV) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituents disubstituted heteroaryl. In a further embodiment are compounds of formula (IV) wherein X is heteroaryl disubstituted with methyl. In a further embodiment are compounds of formula (IV) wherein X is pyridyl disubstituted with substituents each independently selected from the group consisting of halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In a further embodiment are of formula (I)V) compounds, wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituent disubstituted pyridyl. In a further embodiment are compounds of formula (IV) wherein X is pyridinyl disubstituted with methyl. In a further embodiment are compounds of formula (IV) wherein X is pyrimidinyl disubstituted with substituents each independently selected from halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In a further embodiment are compounds of formula (IV) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituent disubstituted pyrimidinyl. In a further embodiment are compounds of formula (IV) wherein X is pyrimidinyl disubstituted with methyl. In another embodiment are compounds of formula (IV) wherein X is optionally substituted- (C) ₁ -C ₆ ) An alkyl group-.

In another embodiment are compounds of formula (IV) wherein Y is optionally substituted aryl. In a further embodiment are compounds of formula (IV) wherein Y is optionally substituted phenyl. In another embodiment are compounds of formula (IV) wherein Y is optionally substituted heteroaryl. In another embodiment are compounds of formula (IV) wherein Y is optionally substituted- (C) ₁ -C ₆ ) An alkyl group-. In another embodiment are compounds of formula (IV) wherein Y is optionally substituted (C) ₃ -C ₇ ) Cycloalkyl-. In another embodiment are compounds of formula (IV) wherein Y is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (IV) wherein Y is-O-. In another embodiment are compounds of formula (IV) wherein Y is- (C) ₂ -C ₆ ) Alkynyl. In another embodiment are compounds of formula (IV) wherein Y is-O- (C) ₁ -C ₆ ) An alkyl radical. In another embodiment are compounds of formula (IV) wherein Y is a bond.

In another embodiment are compounds of formula (IV) wherein Z is- (C) ₁ -C ₁₂ ) An alkyl group. In a further embodiment are compounds of formula (IV) wherein Z is n-butylAn isobutyl group or a tert-butyl group. In another embodiment are compounds of formula (IV) wherein Z is-O- (C) ₁ -C ₁₂ ) An alkyl group. In another embodiment are compounds of formula (IV) wherein Z is-O- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (IV) wherein Z is- (C) ₂ -C ₁₂ ) An alkenyl group. In another embodiment are compounds of formula (IV) wherein Z is optionally substituted aryl. In a further embodiment are compounds of formula (IV) wherein Z is optionally substituted phenyl. In a further embodiment are compounds of formula (IV) wherein Z is independently selected from- (C) ₁ -C ₈ ) Alkyl substituents are monosubstituted or disubstituted phenyl. In a further embodiment are compounds of formula (IV) wherein Z is phenyl monosubstituted with n-butyl, isobutyl, or tert-butyl. In a further embodiment are compounds of formula (IV) wherein Z is phenyl monosubstituted with n-butyl. In a further embodiment are compounds of formula (IV) wherein Z is phenyl monosubstituted with isobutyl. In a further embodiment are compounds of formula (IV) wherein Z is phenyl monosubstituted with tert-butyl. In another embodiment are compounds of formula (IV) wherein Z is optionally substituted heteroaryl. In another embodiment are compounds of formula (IV) wherein Z is optionally substituted- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (IV) wherein Z is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (IV) wherein Z is halo.

In another embodiment are compounds of formula (IV) having the structure of formula (IVa):

wherein:

R ³ is H or- (C) ₁ -C ₆ ) An alkyl group;

Or R ³ And R ⁴ Combine to form a heterocycloalkyl ring;

R ⁵ is H or- (C) ₁ -C ₆ ) An alkyl group;

R ⁶ 、R ⁷ and R ⁸ Each independently H, fluoro, hydroxy, amino, optionally substituted alkyl, heteroalkyl, or- (C) ₁ -C ₆ ) Alkyl radical；

or R ⁹ And R ¹⁰ Combined to form a heterocycloalkyl or cycloalkyl ring

R ¹¹ And R ¹² Each independently is H and- (C) ₁ -C ₆ ) alkyl-N (H) S (O) ₂ NR ²⁵ R ²⁶ ；

each R ²¹ And R ²² Independently of each other is H, - (C) ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) Heteroalkyl, - (C) ₁ -C ₆ ) alkyl-CO ₂ H、-C(O)(C ₁ -C ₆ ) Alkyl, -C (O) O (C) ₁ -C ₆ ) Alkyl, -C (O) O (C) ₁ -C ₆ ) Haloalkyl, -C (= NH) (C) ₁ -C ₆ ) Alkyl, -C (= C)NH)N(R ³¹ ) ₂ 、-C(O)N(R ³¹ ) ₂ or-SO ₂ N(R ³¹ ) ₂ (ii) a Or R ²¹ And R ²² And the nitrogen atom to which they are attached form a heterocycloalkyl ring;

each R ²³ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

each R ²⁴ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

each R ²⁸ Independently halogen, -NR ²³ R ²⁴ 、-NHC(O)R ²³ 、-NHC(O)NR ²³ R ²⁴ Nitro, hydroxy, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted- (C) ₁ -C ₆ ) Heteroalkyl, optionally substituted- (C) ₁ -C ₆ ) Heteroalkyloxy, optionally substituted- (C) ₁ -C ₆ ) Heteroalkylamino(C ₁ -C ₆ ) Alkoxy, -C (O) (C) ₁ -C ₆ ) Alkyl or-S (O) ₂ (C ₁ -C ₆ ) An alkyl group;

p is 0, 1 or 2; and is

q is 0, 1 or 2;

or a pharmaceutically acceptable salt, solvate or prodrug thereof. In one embodiment are compounds of formula (IVa), wherein R ⁶ 、R ⁷ And R ⁸ Is H.

In another embodiment are compounds of formula (IVa), wherein R ¹⁵ And R ¹⁶ Is H.

In one embodiment are compounds of formula (IVa) wherein R ¹⁷ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IVa), wherein R ¹⁷ is-CH ₃ . In another embodiment are compounds of formula (IVa), wherein R ¹⁷ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (IVa), wherein R ¹⁷ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (IVa), wherein R ¹⁷ Is cyclopropyl. In another embodiment are compounds of formula (IVa), wherein R ¹⁷ Is- (C) ₁ -C ₆ ) alkyl-C (O) OR ²³ . In another embodiment are compounds of formula (IVa) wherein R ¹⁷ is-CH ₂ CH ₂ And (5) OH. In another embodiment are compounds of formula (IVa) wherein R ¹⁷ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (IVa) wherein R ¹⁷ is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IVa) wherein R ¹⁷ Is H.

In another embodiment are compounds of formula (IVa), wherein R ¹⁸ Is H.

In another embodiment are compounds of formula (IVa) whereinR ³ Is H.

In another embodiment are compounds of formula (IVa), wherein R ⁵ Is H.

In another embodiment are compounds of formula (IVa), wherein R ⁴ Is H. In another embodiment are compounds of formula (IVa), wherein R ⁴ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IVa), wherein R ⁴ is-CH ₃ . In another embodiment are compounds of formula (IVa), wherein R ⁴ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (IVa), wherein R ⁴ Is- (C) ₁ -C ₆ ) alkyl-OH. In another embodiment are compounds of formula (IVa), wherein R ⁴ is-CH ₂ And (5) OH. In another embodiment are compounds of formula (IVa), wherein R ⁴ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (IVa), wherein R ⁴ Is cyclopropyl. In another embodiment are compounds of formula (IVa), wherein R ⁴ is-C (O) NH ₂ 。

In another embodiment are compounds of formula (IVa), wherein R ⁴ And R ⁵ And the carbon atoms to which they are attached form a cyclopropyl ring.

In another embodiment are compounds of formula (IVa) wherein R ³ 、R ⁴ And R ⁵ Is H.

In another embodiment are compounds of formula (IVa), wherein R ¹⁰ Is H.

In another embodiment are compounds of formula (IVa), wherein R ¹⁰ Is H and R ⁹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IVa), wherein R ¹⁰ Is H and R ⁹ is-CH ₃ . In another embodiment are compounds of formula (IVa) wherein R ¹⁰ Is H and R ⁹ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (IVa), wherein R ¹⁰ Is H and R ⁹ Is- (C) ₁ -C ₆ ) A haloalkyl group. In another embodimentIs a compound of formula (IVa) wherein R ¹⁰ Is H and R ⁹ is-CH ₂ F. In another embodiment are compounds of formula (IVa), wherein R ¹⁰ Is H and R ⁹ is-CHF ₂ . In another embodiment are compounds of formula (IVa), wherein R ¹⁰ Is H and R ⁹ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (IVa), wherein R ¹⁰ Is H and R ⁹ Is cyclopropyl. In another embodiment are compounds of formula (IVa) wherein R ¹⁰ Is H and R ⁹ Is H.

In another embodiment are compounds of formula (IVa), wherein R ¹² Is H.

In another embodiment are compounds of formula (IVa), wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-N (H) S (O) ₂ NR ²⁵ R ²⁶ . In another embodiment are compounds of formula (IVa) wherein R ¹² Is H and R ¹¹ is-CH ₂ N(H)S(O) ₂ NH ₂ 。

In another embodiment are compounds of formula (IVa) wherein p is 1 and R ²⁷ Is halogen. In another embodiment are compounds of formula (IVa) wherein p is 1 and R ²⁷ Is optionally substituted- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IVa) wherein q is 0, p is 1 and R is ²⁷ Is halogen. In another embodiment are compounds of formula (IVa) wherein q is 0, p is 1 and R is ²⁷ Is optionally substituted- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IVa) wherein q is 1 and R ²⁸ Is a halogen. In another embodiment are compounds of formula (IVa) wherein q is 1 and R ²⁸ Is optionally substituted- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IVa) wherein p is 0, q is 1 and R is ²⁸ Is a halogen. In another embodiment are compounds of formula (IVa) wherein p is 0, q is 1 and R is ²⁸ Is optionally substituted- (C) ₁ -C ₆ ) An alkyl group.

In another embodiment are compounds of formula (IVa), wherein p is 0 and q is 0.

In another embodiment are compounds of formula (IVa) wherein R ¹ And R ² Each independently is H or- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (IVa) wherein R ¹ And R ² Each is H. In another embodiment are compounds of formula (IVa) wherein R ¹ And R ² Each independently is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (IVa), wherein R ¹ Is H, and R ² Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (IVa), wherein R ¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² And R is ² Is H. In another embodiment are compounds of formula (IVa) wherein R ¹ Is H, and R ² is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IVa) wherein R ¹ is-CH ₂ CH ₂ NH ₂ And R is ² Is H. In another embodiment are compounds of formula (IVa) wherein R ¹ And R ² Each is-CH ₂ CH ₂ NH ₂ . In a further embodiment are compounds of formula (IVa), wherein R ¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² And R is ² Is H. In a further embodiment are compounds of formula (IVa), wherein R ¹ is-CH ₂ CH ₂ NH ₂ And R is ² Is H. In a further embodiment are compounds of formula (IVa) wherein R ¹ Is H and R ² Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In a further embodiment are compounds of formula (IVa) wherein R ¹ Is H and R ² is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IVa), wherein R ¹ And R ² Are each independently H, - (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² or-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (IVa), wherein R ¹ And R ² Each independently is-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (IVa), wherein R ¹ Is H, and R ² is-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (IVa), wherein R ¹ is-CH ₂ CH(OH)CH ₂ NH ₂ And R is ² Is H. In a further embodiment are compounds of formula (IVa), wherein R ¹ And R ² And the atoms to which they are attached form an optionally substituted heterocycloalkyl ring.

In another embodiment are compounds of formula (IVa), wherein X is optionally substituted aryl. In a further embodiment are compounds of formula (IVa), wherein X is optionally substituted phenyl. In another embodiment are compounds of formula (IVa), wherein X is optionally substituted heteroaryl. In a further embodiment are compounds of formula (IVa), wherein X is disubstituted heteroaryl. In a further embodiment are compounds of formula (IVa) wherein X is heteroaryl disubstituted with substituents each independently selected from halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ and-NO ₂ . In a further embodiment are compounds of formula (IVa) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituents disubstituted heteroaryl. In a further embodiment are compounds of formula (IVa), wherein X is heteroaryl disubstituted with methyl. In a further embodiment are compounds of formula (IVa), wherein X is pyridinyl disubstituted with substituents each independently selected from halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In a further embodiment are compounds of formula (IVa) wherein X is independently selected from-(C ₁ -C ₆ ) Alkyl substituent disubstituted pyridyl. In a further embodiment are compounds of formula (IVa), wherein X is pyridinyl disubstituted with methyl. In a further embodiment are compounds of formula (IVa) wherein X is pyrimidinyl disubstituted with substituents each independently selected from halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In a further embodiment are compounds of formula (IVa) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituent disubstituted pyrimidinyl. In a further embodiment are compounds of formula (IVa), wherein X is pyrimidinyl disubstituted with methyl. In another embodiment are compounds of formula (IVa) wherein X is optionally substituted- (C) ₁ -C ₆ ) An alkyl radical.

In another embodiment are compounds of formula (IVa), wherein Y is optionally substituted aryl. In a further embodiment are compounds of formula (IVa), wherein Y is optionally substituted phenyl. In another embodiment are compounds of formula (IVa), wherein Y is optionally substituted heteroaryl. In another embodiment are compounds of formula (IVa) wherein Y is optionally substituted- (C) ₁ -C ₆ ) An alkyl radical. In another embodiment are compounds of formula (IVa) wherein Y is optionally substituted (C) ₃ -C ₇ ) Cycloalkyl-. In another embodiment are compounds of formula (IVa), wherein Y is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (IVa) wherein Y is-O-. In another embodiment are compounds of formula (IVa) wherein Y is- (C) ₂ -C ₆ ) Alkynyl. In another embodiment are compounds of formula (IVa) wherein Y is-O- (C) ₁ -C ₆ ) An alkyl group-. In another embodiment are compounds of formula (IVa), wherein Y is a bond.

In another embodiment are compounds of formula (IVa) wherein Z is- (C) ₁ -C ₁₂ ) An alkyl group. In a further embodiment are compounds of formula (IVa), wherein Z is n-butyl, isobutyl or tert-butyl.In another embodiment are compounds of formula (IVa) wherein Z is-O- (C) ₁ -C ₁₂ ) An alkyl group. In another embodiment are compounds of formula (IVa) wherein Z is-O- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (IVa) wherein Z is- (C) ₂ -C ₁₂ ) An alkenyl group. In another embodiment are compounds of formula (IVa), wherein Z is optionally substituted aryl. In a further embodiment are compounds of formula (IVa), wherein Z is optionally substituted phenyl. In a further embodiment are compounds of formula (IVa) wherein Z is independently selected from- (C) ₁ -C ₈ ) Alkyl substituents are monosubstituted or disubstituted phenyl. In a further embodiment are compounds of formula (IVa), wherein Z is phenyl monosubstituted with n-butyl, isobutyl or tert-butyl. In a further embodiment are compounds of formula (IVa), wherein Z is phenyl monosubstituted with n-butyl. In a further embodiment are compounds of formula (IVa), wherein Z is phenyl monosubstituted with isobutyl. In a further embodiment are compounds of formula (IVa), wherein Z is phenyl monosubstituted with tert-butyl. In another embodiment are compounds of formula (IVa), wherein Z is optionally substituted heteroaryl. In another embodiment are compounds of formula (IVa) wherein Z is optionally substituted- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (IVa), wherein Z is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (IVa), wherein Z is halogen.

In another embodiment are compounds of formula (IV) having the structure of formula (IVb):

wherein:

R ⁵ Is H or- (C) ₁ -C ₆ ) An alkyl group;

R ¹¹ is- (C) ₁ -C ₆ ) alkyl-N (H) S (O) ₂ NR ²⁵ R ²⁶ ；

z isH. Halogen, -NH ₂ 、-CN、-CF ₃ 、-CO ₂ H、-(C ₁ -C ₁₂ ) Alkyl, - (C) ₂ -C ₁₂ ) Alkenyl, -CH = ((C) ₃ -C ₇ ) Cycloalkyl), - (C) ₂ -C ₁₂ ) Alkynyl, -C (O) NR ²⁵ R ²⁶ 、-O-(C ₁ -C ₁₂ ) Alkyl, -S- (C) ₁ -C ₁₂ ) Alkyl, -O- (C) ₃ -C ₁₀ ) [ optionally substituted (C) ₃ -C ₇ ) Cycloalkyl radicals]、-O-(C ₁ -C ₆ ) alkyl-OR ²³ 、-(C ₁ -C ₁₂ ) alkyl-OR ²³ 、-(C ₁ -C ₁₂ ) alkyl-CN, -S- (C) ₁ -C ₁₂ ) Alkyl, -N (R) ²⁴ )(C ₁ -C ₁₂ ) Alkyl, -N (R) ²⁴ )C(O)(C ₁ -C ₁₂ ) Alkyl, optionally substituted- (C) ₃ -C ₇ ) Cycloalkyl, - (C) ₁ -C ₆ ) Alkyl radical- (C) ₃ -C ₇ ) Cycloalkyl, - (C) ₁ -C ₆ ) Alkyl-heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

each R ²³ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

each R ²⁴ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

or a pharmaceutically acceptable salt, solvate or prodrug thereof. In one embodiment are compounds of formula (IVb) wherein R ¹⁷ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IVb), wherein R ¹⁷ is-CH ₃ . In another embodiment are compounds of formula (IVb) wherein R ¹⁷ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (IVb), wherein R ¹⁷ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (IVb), wherein R ¹⁷ Is cyclopropyl. In another embodiment are compounds of formula (IVb) wherein R ¹⁷ Is- (C) ₁ -C ₆ ) alkyl-C (O) OR ²³ . In another embodiment are compounds of formula (IVb), wherein R ¹⁷ is-CH ₂ CH ₂ And (5) OH. In another embodiment are compounds of formula (IVb), wherein R ¹⁷ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (IVb), wherein R ¹⁷ is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IVb), wherein R ¹⁷ Is H.

In another embodiment are compounds of formula (IVb), wherein R ¹⁸ Is H.

In another embodiment are compounds of formula (IVb), wherein R ⁵ Is H.

In another embodiment are compounds of formula (IVb), wherein R ⁴ Is H. In another embodiment are compounds of formula (IVb), wherein R ⁴ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IVb), wherein R ⁴ is-CH ₃ . In another embodimentIn the formula (IVb), R ⁴ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (IVb), wherein R ⁴ Is- (C) ₁ -C ₆ ) alkyl-OH. In another embodiment are compounds of formula (IVb), wherein R ⁴ is-CH ₂ And (5) OH. In another embodiment are compounds of formula (IVb), wherein R ⁴ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (IVb), wherein R ⁴ Is cyclopropyl. In another embodiment are compounds of formula (IVb), wherein R ⁴ is-C (O) NH ₂ 。

In another embodiment are compounds of formula (IVb) wherein R ⁴ And R ⁵ And the carbon atoms to which they are attached form a cyclopropyl ring.

In another embodiment are compounds of formula (IVb), wherein R ⁹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (IVb), wherein R ⁹ is-CH ₃ . In another embodiment are compounds of formula (IVb), wherein R ⁹ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (IVb), wherein R ⁹ Is- (C) ₁ -C ₆ ) A haloalkyl group. In another embodiment are compounds of formula (IVb), wherein R ⁹ is-CH ₂ F. In another embodiment are compounds of formula (IVb), wherein R ⁹ is-CHF ₂ . In another embodiment are compounds of formula (IVb) wherein R ⁹ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (IVb), wherein R ⁹ Is cyclopropyl. In another embodiment are compounds of formula (IVb), wherein R ⁹ Is H.

In another embodiment are compounds of formula (IVb), wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-N (H) S (O) ₂ NR ²⁵ R ²⁶ . In another embodiment are compounds of formula (IVb) wherein R ¹¹ is-CH ₂ N(H)S(O) ₂ NH ₂ 。

In another implementationIn the scheme are compounds of formula (IVb) wherein R ¹ And R ² Each independently is H or- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (IVb), wherein R ¹ And R ² Each is H. In another embodiment are compounds of formula (IVb), wherein R ¹ And R ² Each independently is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (IVb), wherein R ¹ Is H, and R ² Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (IVb) wherein R ¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² And R is ² Is H. In another embodiment are compounds of formula (IVb), wherein R ¹ Is H, and R ² is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IVb), wherein R ¹ is-CH ₂ CH ₂ NH ₂ And R is ² Is H. In another embodiment are compounds of formula (IVb), wherein R ¹ And R ² Each is-CH ₂ CH ₂ NH ₂ . In a further embodiment are compounds of formula (IVb), wherein R ¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² And R is ² Is H. In a further embodiment are compounds of formula (IVb) wherein R ¹ is-CH ₂ CH ₂ NH ₂ And R is ² Is H. In a further embodiment are compounds of formula (IVb), wherein R ¹ Is H and R ² Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In a further embodiment are compounds of formula (IVb), wherein R ¹ Is H and R ² is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IVb), wherein R ¹ And R ² Are each independently H, - (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² or-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment of formula (II)(IVb) Compound wherein R ¹ And R ² Each independently is-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (IVb), wherein R ¹ Is H, and R ² is-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (IVb), wherein R ¹ is-CH ₂ CH(OH)CH ₂ NH ₂ And R is ² Is H. In a further embodiment are compounds of formula (IVb), wherein R ¹ And R ² And the atoms to which they are attached form an optionally substituted heterocycloalkyl ring.

In another embodiment are compounds of formula (IVb) wherein X is optionally substituted aryl. In a further embodiment are compounds of formula (IVb) wherein X is optionally substituted phenyl. In another embodiment are compounds of formula (IVb) wherein X is optionally substituted heteroaryl. In a further embodiment are compounds of formula (IVb) wherein X is disubstituted heteroaryl. In a further embodiment are compounds of formula (IVb) wherein X is heteroaryl disubstituted with substituents each independently selected from halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ and-NO ₂ . In a further embodiment are compounds of formula (IVb) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituents disubstituted heteroaryl. In a further embodiment are compounds of formula (IVb) wherein X is heteroaryl disubstituted with methyl. In a further embodiment are compounds of formula (IVb) wherein X is pyridyl disubstituted with substituents each independently selected from halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In a further embodiment are compounds of formula (IVb) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituent disubstituted pyridyl. In a further embodimentIs a compound of formula (IVb) wherein X is pyridyl disubstituted with methyl. In a further embodiment are compounds of formula (IVb) wherein X is pyrimidinyl disubstituted with substituents each independently selected from halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In a further embodiment are compounds of formula (IVb) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituent disubstituted pyrimidinyl. In a further embodiment are compounds of formula (IVb) wherein X is pyrimidinyl disubstituted with methyl. In another embodiment are compounds of formula (IVb) wherein X is optionally substituted- (C) ₁ -C ₆ ) An alkyl radical.

In another embodiment are compounds of formula (IVb) wherein Y is optionally substituted aryl. In a further embodiment are compounds of formula (IVb) wherein Y is optionally substituted phenyl. In another embodiment are compounds of formula (IVb) wherein Y is optionally substituted heteroaryl. In another embodiment are compounds of formula (IVb) wherein Y is optionally substituted- (C) ₁ -C ₆ ) An alkyl group-. In another embodiment are compounds of formula (IVb) wherein Y is optionally substituted (C) ₃ -C ₇ ) Cycloalkyl-. In another embodiment are compounds of formula (IVb) wherein Y is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (IVb) wherein Y is-O-. In another embodiment are compounds of formula (IVb) wherein Y is- (C) ₂ -C ₆ ) Alkynyl. In another embodiment are compounds of formula (IVb) wherein Y is-O- (C) ₁ -C ₆ ) An alkyl group-. In another embodiment are compounds of formula (IVb) wherein Y is a bond.

In another embodiment are compounds of formula (IVb) wherein Z is- (C) ₁ -C ₁₂ ) An alkyl group. In a further embodiment are compounds of formula (IVb) wherein Z is n-butyl, isobutyl, or tert-butyl. In another embodiment are compounds of formula (IVb) wherein Z is-O- (C) ₁ -C ₁₂ ) An alkyl group.In another embodiment are compounds of formula (IVb) wherein Z is-O- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (IVb) wherein Z is- (C) ₂ -C ₁₂ ) An alkenyl group. In another embodiment are compounds of formula (IVb) wherein Z is optionally substituted aryl. In a further embodiment are compounds of formula (IVb) wherein Z is optionally substituted phenyl. In a further embodiment are compounds of formula (IVb) wherein Z is independently selected from- (C) ₁ -C ₈ ) Alkyl substituents are monosubstituted or disubstituted phenyl. In a further embodiment are compounds of formula (IVb) wherein Z is phenyl monosubstituted with n-butyl, isobutyl, or tert-butyl. In a further embodiment are compounds of formula (IVb) wherein Z is phenyl monosubstituted with n-butyl. In a further embodiment are compounds of formula (IVb) wherein Z is phenyl monosubstituted with isobutyl. In a further embodiment are compounds of formula (IVb) wherein Z is phenyl monosubstituted with tert-butyl. In another embodiment are compounds of formula (IVb) wherein Z is optionally substituted heteroaryl. In another embodiment are compounds of formula (IVb) wherein Z is optionally substituted- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (IVb) wherein Z is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (IVb), wherein Z is halogen.

In another embodiment are compounds of formula (IV) having the structure of formula (IVc):

wherein:

R ¹¹ is- (C) ₁ -C ₆ ) alkyl-N (H) S (O) ₂ NR ²⁵ R ²⁶ ；

each R ²¹ And R ²² Independently of each other is H, - (C) ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) Heteroalkyl, - (C) ₁ -C ₆ ) Alkyl radical-CO ₂ H、-C(O)(C ₁ -C ₆ ) Alkyl, -C (O) O (C) ₁ -C ₆ ) Alkyl, -C (O) O (C) ₁ -C ₆ ) Haloalkyl, -C (= NH) (C) ₁ -C ₆ ) Alkyl, -C (= NH) N (R) ³¹ ) ₂ 、-C(O)N(R ³¹ ) ₂ or-SO ₂ N(R ³¹ ) ₂ (ii) a Or R ²¹ And R ²² And the nitrogen atom to which they are attached form a heterocycloalkyl ring;

each R ²³ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

each R ²⁴ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

or a pharmaceutically acceptable salt, solvate or prodrug thereof.

In another embodiment are compounds of formula (IVc) wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-N (H) S (O) ₂ NR ²⁵ R ²⁶ . In another embodiment are compounds of formula (IVc) wherein R ¹¹ is-CH ₂ N(H)S(O) ₂ NH ₂ 。

In another embodiment are compounds of formula (IVc) wherein R ¹ And R ² Each independently is H or- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (IVc) wherein R ¹ And R ² Each is H. In another embodiment are compounds of formula (IVc) wherein R ¹ And R ² Each independently is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment of the formula (I), (II), (III)IVc) compounds in which R ¹ Is H, and R ² Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (IVc) wherein R ¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² And R is ² Is H. In another embodiment are compounds of formula (IVc) wherein R ¹ Is H, and R ² is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IVc) wherein R ¹ is-CH ₂ CH ₂ NH ₂ And R is ² Is H. In another embodiment are compounds of formula (IVc) wherein R ¹ And R ² Each is-CH ₂ CH ₂ NH ₂ . In a further embodiment are compounds of formula (IVc) wherein R ¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² And R is ² Is H. In a further embodiment are compounds of formula (IVc) wherein R ¹ is-CH ₂ CH ₂ NH ₂ And R is ² Is H. In a further embodiment are compounds of formula (IVc) wherein R ¹ Is H and R ² Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In a further embodiment are compounds of formula (IVc) wherein R ¹ Is H and R ² is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (IVc) wherein R ¹ And R ² Are each independently H, - (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² or-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (IVc) wherein R ¹ And R ² Each independently is-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (IVc) wherein R ¹ Is H, and R ² is-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (IVc) wherein R ¹ is-CH ₂ CH(OH)CH ₂ NH ₂ And R is ² Is H. In a further embodiment are compounds of formula (IVc)In which R is ¹ And R ² And the atoms to which they are attached form an optionally substituted heterocycloalkyl ring.

In another embodiment are compounds of formula (IVc) wherein X is optionally substituted aryl. In a further embodiment are compounds of formula (IVc) wherein X is optionally substituted phenyl. In another embodiment are compounds of formula (IVc) wherein X is optionally substituted heteroaryl. In a further embodiment are compounds of formula (IVc) wherein X is disubstituted heteroaryl. In a further embodiment are compounds of formula (IVc) wherein X is heteroaryl disubstituted with substituents each independently selected from halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ and-NO ₂ . In a further embodiment are compounds of formula (IVc) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituents disubstituted heteroaryl. In a further embodiment are compounds of formula (IVc) wherein X is heteroaryl disubstituted with methyl. In a further embodiment are compounds of formula (IVc) wherein X is pyridyl disubstituted with substituents each independently selected from halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In a further embodiment are compounds of formula (IVc) wherein X is independently selected from- (C) ₁ -C ₆ ) A substituent of an alkyl group. In a further embodiment are compounds of formula (IVc) wherein X is pyridinyl disubstituted with methyl. In a further embodiment are compounds of formula (IVc) wherein X is pyrimidinyl disubstituted with substituents each independently selected from halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In a further embodiment are compounds of formula (IVc) wherein X isIs independently selected from- (C) ₁ -C ₆ ) Alkyl substituent disubstituted pyrimidinyl. In a further embodiment are compounds of formula (IVc) wherein X is pyrimidinyl disubstituted with methyl. In another embodiment are compounds of formula (IVc) wherein X is optionally substituted- (C) ₁ -C ₆ ) An alkyl group-.

In another embodiment are compounds of formula (IVc) wherein Y is optionally substituted aryl. In a further embodiment are compounds of formula (IVc) wherein Y is optionally substituted phenyl. In another embodiment are compounds of formula (IVc) wherein Y is optionally substituted heteroaryl. In another embodiment are compounds of formula (IVc) wherein Y is optionally substituted- (C) ₁ -C ₆ ) An alkyl radical. In another embodiment are compounds of formula (IVc) wherein Y is optionally substituted (C) ₃ -C ₇ ) Cycloalkyl-. In another embodiment are compounds of formula (IVc) wherein Y is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (IVc) wherein Y is-O-. In another embodiment are compounds of formula (IVc) wherein Y is- (C) ₂ -C ₆ ) Alkynyl. In another embodiment are compounds of formula (IVc) wherein Y is-O- (C) ₁ -C ₆ ) An alkyl radical. In another embodiment are compounds of formula (IVc) wherein Y is a bond.

In another embodiment are compounds of formula (IVc) wherein Z is- (C) ₁ -C ₁₂ ) An alkyl group. In a further embodiment are compounds of formula (IVc) wherein Z is n-butyl, isobutyl, or tert-butyl. In another embodiment are compounds of formula (IVc) wherein Z is-O- (C) ₁ -C ₁₂ ) An alkyl group. In another embodiment are compounds of formula (IVc) wherein Z is-O- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (IVc) wherein Z is- (C) ₂ -C ₁₂ ) An alkenyl group. In another embodiment are compounds of formula (IVc) wherein Z is optionally substituted aryl. In a further embodiment are compounds of formula (IVc) wherein Z is optionally substituted phenyl. In a further embodiment are compounds of formula (IVc) wherein Z is independently selected from- (C) ₁ -C ₈ ) Alkyl substituents are monosubstituted or disubstituted phenyl. In a further embodiment are compounds of formula (IVc) wherein Z is phenyl monosubstituted with n-butyl, isobutyl, or tert-butyl. In a further embodiment are compounds of formula (IVc) wherein Z is phenyl monosubstituted with n-butyl. In a further embodiment are compounds of formula (IVc) wherein Z is phenyl monosubstituted with isobutyl. In a further embodiment are compounds of formula (IVc) wherein Z is phenyl monosubstituted with tert-butyl. In another embodiment are compounds of formula (IVc) wherein Z is optionally substituted heteroaryl. In another embodiment are compounds of formula (IVc) wherein Z is optionally substituted- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (IVc) wherein Z is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (IVc) wherein Z is halogen.

In some embodiments, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (II), (IIa), (IIb), (IIc), (IId), (IIe), (III), (IIIa), (IIIb), (IIIc), (IV), (IVa), (IVb), and (IVc) are selected from compounds in table 1, or pharmaceutically acceptable salts, solvates, or prodrugs thereof.

TABLE 1

In one aspect, described herein are compounds of formula (V), or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

wherein:

or R ⁹ And R ¹⁰ Combined to form a heterocycloalkyl or cycloalkyl ring

R ¹¹ And R ¹² Each independently of the other is H, -NH ₂ 、-(C ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-OR ²³ 、-(C ₁ -C ₆ ) alkyl-SR ²³ 、-(C ₁ -C ₆ ) alkyl-C (O) OR ²³ 、-(C ₁ -C ₆ ) alkyl-NR ²¹ R ²² 、-(C ₁ -C ₆ ) alkyl-NR ²³ OR ²³ 、-(C ₁ -C ₆ ) alkyl-NHC (O) NR ²³ OR ²³ 、-(C ₁ -C ₆ ) alkyl-O- (C) ₁ -C ₆ ) alkyl-NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) alkyl-CN, - (C) ₁ -C ₆ ) alkyl-NR ²³ C(O)R ²³ 、-(C ₁ -C ₆ ) alkyl-C (O) NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) heteroalkyl-CO ₂ H、-(C ₁ -C ₆ ) alkyl-S (O) (C) ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-N (H) CH = NH, - (C) ₁ -C ₆ ) alkyl-C (NH) ₂ )＝NH、-(C ₁ -C ₆ ) alkyl-N (H) C (= NH) NH ₂ 、-(C ₁ -C ₆ ) Alkyl radical-N(H)S(O) ₂ NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) alkyl-N (H) S (O) ₂ (C ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-N (H) -C (O) NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) Alkyl C (O) N (H) [ optionally substituted (C) ₂ -C ₆ ) Alkyl radical]-OR ²³ 、-(C ₁ -C ₆ ) Alkyl N (H) C (O) (C) ₁ -C ₆ ) alkyl-OR ²³ 、-(C ₁ -C ₆ ) Alkyl C (O) N (H) heterocycloalkyl, - (C) ₁ -C ₆ ) Alkyl C (O) NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) alkyl-N (H) -C (O) - (C) ₁ -C ₆ ) alkyl-NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) alkyl-N (H) - (C) ₁ -C ₆ ) Alkyl C (O) NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) Alkyl-heterocycloalkyl, optionally substituted- (C) ₁ -C ₆ ) alkyl-N (H) heterocycloalkyl or- (C) ₁ -C ₆ ) Alkyl-heteroaryl;

X is optionally substituted heteroaryl;

each R ²¹ And R ²² Independently of each other is H, - (C) ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) Heteroalkyl, - (C) ₁ -C ₆ ) alkyl-CO ₂ H、-C(O)(C ₁ -C ₆ ) Alkyl, -C (O) O (C) ₁ -C ₆ ) Alkyl, -C (O) O (C) ₁ -C ₆ ) Haloalkyl, -C (= NH) (C) ₁ -C ₆ ) Alkyl, -C (= NH)N(R ³¹ ) ₂ 、-C(O)N(R ³¹ ) ₂ or-SO ₂ N(R ³¹ ) ₂ (ii) a Or R ²¹ And R ²² And the nitrogen atom to which they are attached form a heterocycloalkyl ring;

each R ²³ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

each R ²⁴ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

p is 0, 1 or 2; and is

q is 0, 1 or 2.

In one embodiment are compounds of formula (V) wherein R ⁶ 、R ⁷ And R ⁸ Is H.

In another embodiment are compounds of formula (V) wherein R ¹⁵ And R ¹⁶ Is H.

In one embodiment are compounds of formula (V) wherein R ¹⁷ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (V) wherein R ¹⁷ is-CH ₃ . In another embodiment are compounds of formula (V), wherein R ¹⁷ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (V) wherein R ¹⁷ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (V), wherein R ¹⁷ Is cyclopropyl. In another embodiment are compounds of formula (V) wherein R ¹⁷ Is- (C) ₁ -C ₆ ) alkyl-C (O) OR ²³ . In another embodiment are compounds of formula (V) wherein R ¹⁷ is-CH ₂ CH ₂ And (5) OH. In another embodiment are compounds of formula (V) wherein R ¹⁷ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (V), wherein R ¹⁷ is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (V) wherein R ¹⁷ Is H.

In another embodiment are compounds of formula (V) wherein R ¹⁸ Is H.

In another embodiment are compounds of formula (V), wherein R ¹⁰ Is H.

In another embodiment isA compound of formula (V), wherein R ¹⁰ Is H and R ⁹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (V), wherein R ¹⁰ Is H and R ⁹ is-CH ₃ . In another embodiment are compounds of formula (V) wherein R ¹⁰ Is H and R ⁹ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (V), wherein R ¹⁰ Is H and R ⁹ Is- (C) ₁ -C ₆ ) A haloalkyl group. In another embodiment are compounds of formula (V) wherein R ¹⁰ Is H and R ⁹ is-CH ₂ F. In another embodiment are compounds of formula (V) wherein R ¹⁰ Is H and R ⁹ is-CHF ₂ . In another embodiment are compounds of formula (V), wherein R ¹⁰ Is H and R ⁹ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (V) wherein R ¹⁰ Is H and R ⁹ Is cyclopropyl. In another embodiment are compounds of formula (V), wherein R ¹⁰ Is H and R ⁹ Is H.

In another embodiment are compounds of formula (V) wherein R ¹² Is H.

In another embodiment are compounds of formula (V), wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (V) wherein R ¹² Is H and R ¹¹ is-CH ₃ . In another embodiment are compounds of formula (V), wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-OR ²³ . In another embodiment are compounds of formula (V), wherein R ¹² Is H and R ¹¹ is-CH ₂ And (5) OH. In another embodiment are compounds of formula (V) wherein R ¹² Is H and R ¹¹ is-CH ₂ CH ₂ And (5) OH. In another embodiment are compounds of formula (V) wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (V) wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) Alkyl radicalradical-NR ²¹ R ²² . In another embodiment are compounds of formula (V), wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-NH ₂ . In another embodiment are compounds of formula (V), wherein R ¹² Is H and R ¹¹ is-CH ₂ NH ₂ . In another embodiment are compounds of formula (V), wherein R ¹² Is H and R ¹¹ is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (V) wherein R ¹² Is H and R ¹¹ is-CH ₂ CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (V) wherein R ¹² Is H and R ¹¹ is-CH ₂ CH ₂ CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (V) wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-CN. In another embodiment are compounds of formula (V), wherein R ¹² Is H and R ¹¹ is-CH ₂ And (C) CN. In another embodiment are compounds of formula (V) wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-C (O) NR ²⁵ R ²⁶ . In another embodiment are compounds of formula (V) wherein R ¹² Is H and R ¹¹ is-CH ₂ C(O)NH ₂ . In another embodiment are compounds of formula (V) wherein R ¹² Is H and R ¹¹ is-CH ₂ CH ₂ C(O)NH ₂ . In another embodiment are compounds of formula (V), wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-N (H) S (O) ₂ NR ²⁵ R ²⁶ . In another embodiment are compounds of formula (V) wherein R ¹² Is H and R ¹¹ is-CH ₂ N(H)S(O) ₂ NH ₂ . In another embodiment are compounds of formula (V) wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) Alkyl-heteroaryl.

In another embodiment are compounds of formula (V), wherein R ¹² Is H and R ¹¹ Is H.

In another embodiment are compounds of formula (V) wherein R ¹¹ And R ¹⁸ Combine to form an optionally substituted heterocycloalkyl ring and R ¹² Is H.

In another embodiment are compounds of formula (V) wherein p is 1 and R ²⁷ Is halogen. In another embodiment are compounds of formula (V) wherein p is 1 and R ²⁷ Is optionally substituted- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (V) wherein q is 0, p is 1 and R is ²⁷ Is a halogen. In another embodiment are compounds of formula (V) wherein q is 0, p is 1 and R ²⁷ Is optionally substituted- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (V) wherein q is 1 and R ²⁸ Is halogen. In another embodiment are compounds of formula (V) wherein q is 1 and R ²⁸ Is optionally substituted- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (V) wherein p is 0, q is 1, and R is ²⁸ Is a halogen. In another embodiment are compounds of formula (V) wherein p is 0, q is 1, and R is ²⁸ Is optionally substituted- (C) ₁ -C ₆ ) An alkyl group.

In another embodiment are compounds of formula (V) wherein p is 0 and q is 0.

In another embodiment are compounds of formula (V) wherein R ¹ And R ² Each independently is H or- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (V), wherein R ¹ And R ² Each is H. In another embodiment are compounds of formula (V), wherein R ¹ And R ² Each independently is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (V) wherein R ¹ Is H, and R ² Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (V), wherein R ¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² And R is ² Is H. In addition toIn one embodiment are compounds of formula (V) wherein R ¹ Is H, and R ² is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (V) wherein R ¹ is-CH ₂ CH ₂ NH ₂ And R is ² Is H. In another embodiment are compounds of formula (V) wherein R ¹ And R ² Each is-CH ₂ CH ₂ NH ₂ . In a further embodiment are compounds of formula (V) wherein R ¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² And R is ² Is H. In a further embodiment are compounds of formula (V), wherein R ¹ is-CH ₂ CH ₂ NH ₂ And R is ² Is H. In a further embodiment are compounds of formula (V) wherein R ¹ Is H and R ² Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In a further embodiment are compounds of formula (V) wherein R ¹ Is H and R ² is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (V) wherein R ¹ And R ² Are each independently H, - (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² or-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (V), wherein R ¹ And R ² Each independently is-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (V) wherein R ¹ Is H, and R ² is-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (V) wherein R ¹ is-CH ₂ CH(OH)CH ₂ NH ₂ And R is ² Is H. In a further embodiment are compounds of formula (V), wherein R ¹ And R ² And the atoms to which they are attached form an optionally substituted heterocycloalkyl ring.

In another embodiment are compounds of formula (V) wherein X is optionally substituted heteroaryl. In a further embodiment are compounds of formula (V) wherein X is a mono-or di-substituted heteroarylAnd (4) a base. In a further embodiment are compounds of formula (V) wherein X is heteroaryl mono-or disubstituted with substituents independently selected from halo, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ and-NO ₂ . In a further embodiment are compounds of formula (V) wherein X is heteroaryl mono-or disubstituted with substituents independently selected from- (C) ₁ -C ₆ ) An alkyl group. In a further embodiment are compounds of formula (V) wherein X is heteroaryl, mono-or di-substituted with methyl. In a further embodiment are compounds of formula (V) wherein X is pyridyl, mono-or di-substituted with a substituent independently selected from the group consisting of halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In a further embodiment are compounds of formula (V) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituents are monosubstituted or disubstituted pyridinyl. In a further embodiment are compounds of formula (V) wherein X is pyridinyl mono-or di-substituted with methyl. In a further embodiment are compounds of formula (V) X is pyrimidinyl mono-or di-substituted with a substituent independently selected from the group consisting of halo, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In a further embodiment are compounds of formula (V) X is pyrimidinyl mono-or di-substituted with a substituent independently selected from- (C) ₁ -C ₆ ) An alkyl group. In a further embodiment are compounds of formula (V) X is pyrimidinyl mono-or di-substituted with methyl.

In another embodiment are compounds of formula (V) wherein Y is optionally substituted aryl. In a further embodiment are compounds of formula (V) wherein Y is optionally substituted phenyl. In another embodiment of formula (V)A compound wherein Y is optionally substituted heteroaryl. In another embodiment are compounds of formula (V) wherein Y is optionally substituted- (C) ₁ -C ₆ ) An alkyl group-. In another embodiment are compounds of formula (V) wherein Y is optionally substituted (C) ₃ -C ₇ ) Cycloalkyl-. In another embodiment are compounds of formula (V) wherein Y is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (V) wherein Y is-O-. In another embodiment are compounds of formula (V) wherein Y is- (C) ₂ -C ₆ ) Alkynyl. In another embodiment are compounds of formula (V) wherein Y is-O- (C) ₁ -C ₆ ) An alkyl radical. In another embodiment are compounds of formula (V) wherein Y is a bond.

In another embodiment are compounds of formula (V) wherein Z is- (C) ₁ -C ₁₂ ) An alkyl group. In a further embodiment are compounds of formula (V) wherein Z is n-butyl, isobutyl, or tert-butyl. In another embodiment are compounds of formula (V) wherein Z is-O- (C) ₁ -C ₁₂ ) An alkyl group. In another embodiment are compounds of formula (V) wherein Z is-O- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (V) wherein Z is- (C) ₂ -C ₁₂ ) An alkenyl group. In another embodiment are compounds of formula (V) wherein Z is optionally substituted aryl. In a further embodiment are compounds of formula (V) wherein Z is optionally substituted phenyl. In a further embodiment are compounds of formula (V) wherein Z is independently selected from- (C) ₁ -C ₈ ) Alkyl substituents are monosubstituted or disubstituted phenyl. In a further embodiment are compounds of formula (V) wherein Z is phenyl monosubstituted with n-butyl, isobutyl, or tert-butyl. In a further embodiment are compounds of formula (V) wherein Z is phenyl monosubstituted with n-butyl. In a further embodiment are compounds of formula (V) wherein Z is phenyl monosubstituted with isobutyl. In a further embodiment are compounds of formula (V) wherein Z is phenyl monosubstituted with tert-butyl. In another embodiment are compounds of formula (V) wherein Z is optionally substituted heteroaryl. In another embodimentIn one embodiment are compounds of formula (V) wherein Z is optionally substituted- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (V) wherein Z is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (V) wherein Z is halo.

In another embodiment are compounds of formula (V) having the structure of formula (Va):

wherein:

or R ¹ And R ² And their structuresThe attached atoms form an optionally substituted heterocycloalkyl ring;

or R ⁹ And R ¹⁰ Combined to form a heterocycloalkyl or cycloalkyl ring

X is optionally substituted heteroaryl;

y is a bond, -O-, -S-, optionally substituted- (C) ₁ -C ₆ ) Alkyl-, - (C) ₂ -C ₆ ) Alkenyl-, - (C) ₂ -C ₆ ) Alkynyl, - (C) ₁ -C ₆ ) alkyl-N (R) ²⁴ )(C ₁ -C ₆ ) Alkyl-, -O- (C) ₁ -C ₆ ) Alkyl-, -O (C) ₆ -C ₁₀ ) Aryl-, -N (R) ²⁴ )(C ₁ -C ₆ ) Alkyl-, -N (R) ²⁴ )SO ₂ (C ₁ -C ₆ ) Alkyl-, -N (R) ²⁴ )C(O)(C ₁ -C ₆ ) Alkyl-, -C (O) (C) ₁ -C ₆ ) Alkyl-, (ii) alkyl-),-S(C ₁ -C ₆ ) Alkyl-, -SO ₂ (C ₁ -C ₆ ) Alkyl-, -C (O) NH (C) ₁ -C ₆ ) Alkyl-, optionally substituted- (C) ₃ -C ₇ ) Cycloalkyl-, optionally substituted-C (O) N (R) ²⁴ ) Aryl-, optionally substituted-N (R) ²⁴ ) C (O) aryl-, optionally substituted-N (R) ²⁴ )SO ₂ Aryl-, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

each R ²¹ And R ²² Independently of each other is H, - (C) ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) Heteroalkyl, - (C) ₁ -C ₆ ) alkyl-CO ₂ H、-C(O)(C ₁ -C ₆ ) Alkyl, -C (O) O (C) ₁ -C ₆ ) Alkyl, -C (O) O (C) ₁ -C ₆ ) Haloalkyl, -C (= NH) (C) ₁ -C ₆ ) Alkyl, -C (= NH) N (R) ³¹ ) ₂ 、-C(O)N(R ³¹ ) ₂ or-SO ₂ N(R ³¹ ) ₂ (ii) a Or alternativelyR ²¹ And R ²² And the nitrogen atom to which they are attached form a heterocycloalkyl ring;

each R ²³ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

each R ²⁴ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

p is 0, 1 or 2; and is provided with

q is 0, 1 or 2;

or a pharmaceutically acceptable salt, solvate or prodrug thereof. In one embodiment are compounds of formula (Va) wherein R ⁶ 、R ⁷ And R ⁸ Is H.

In another embodiment are compounds of formula (Va), wherein R ¹⁵ And R ¹⁶ Is H.

In one embodiment are compounds of formula (Va) wherein R ¹⁷ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (Va) wherein R ¹⁷ is-CH ₃ . In another embodiment are compounds of formula (Va), wherein R ¹⁷ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (Va) wherein R ¹⁷ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (Va), wherein R ¹⁷ Is cyclopropyl. In another embodiment are compounds of formula (Va), wherein R ¹⁷ Is- (C) ₁ -C ₆ ) alkyl-C (O) OR ²³ . In another embodiment are compounds of formula (Va), wherein R ¹⁷ is-CH ₂ CH ₂ And (5) OH. In another embodiment are compounds of formula (Va), wherein R ¹⁷ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (Va), wherein R ¹⁷ is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (Va) wherein R ¹⁷ Is H.

In another embodiment are compounds of formula (Va), wherein R ¹⁸ Is H.

In another embodiment are compounds of formula (Va), wherein R ¹⁰ Is H.

In another embodiment are compounds of formula (Va), wherein R ¹⁰ Is H and R ⁹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (Va), wherein R ¹⁰ Is H and R ⁹ is-CH ₃ . In another embodiment are compounds of formula (Va) wherein R ¹⁰ Is H and R ⁹ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (Va) wherein R ¹⁰ Is H and R ⁹ Is- (C) ₁ -C ₆ ) A haloalkyl group. In another embodiment are compounds of formula (Va), wherein R ¹⁰ Is H and R ⁹ is-CH ₂ F. In another embodiment are compounds of formula (Va) wherein R ¹⁰ Is H and R ⁹ is-CHF ₂ . In another embodiment are compounds of formula (Va), wherein R ¹⁰ Is H and R ⁹ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (Va), wherein R ¹⁰ Is H and R ⁹ Is cyclopropyl. In another embodiment are compounds of formula (Va) wherein R ¹⁰ Is H and R ⁹ Is H.

In another embodiment are compounds of formula (Va), wherein R ¹² Is H.

In another embodiment are compounds of formula (Va), wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (Va) wherein R ¹² Is H and R ¹¹ is-CH ₃ . In another embodiment are compounds of formula (Va), wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-OR ²³ . In another embodiment are compounds of formula (Va), wherein R ¹² Is H and R ¹¹ is-CH ₂ And (5) OH. In another embodiment are compounds of formula (Va), wherein R ¹² Is H and R ¹¹ is-CH ₂ CH ₂ And (5) OH. In another embodiment are compounds of formula (Va), wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (Va), wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (Va), wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-NH ₂ . In another embodiment are compounds of formula (Va) wherein R ¹² Is H and R ¹¹ is-CH ₂ NH ₂ . In another embodiment are compounds of formula (Va), wherein R ¹² Is H and R ¹¹ is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (Va), wherein R ¹² Is H and R ¹¹ is-CH ₂ CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (Va), wherein R ¹² Is H and R ¹¹ is-CH ₂ CH ₂ CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (Va) wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-CN. In another embodiment are compounds of formula (Va), wherein R ¹² Is H and R ¹¹ is-CH ₂ And (C) CN. In another embodiment are compounds of formula (Va), wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-C (O) NR ²⁵ R ²⁶ . In another embodiment are compounds of formula (Va) wherein R ¹² Is H and R ¹¹ is-CH ₂ C(O)NH ₂ . In another embodiment are compounds of formula (Va), wherein R ¹² Is H and R ¹¹ is-CH ₂ CH ₂ C(O)NH ₂ . In another embodiment are compounds of formula (Va), wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) Alkyl-heteroaryl. In another embodiment are compounds of formula (Va) wherein R ¹² Is H and R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-N (H) S (O) ₂ NR ²⁵ R ²⁶ . In another embodiment are compounds of formula (Va), wherein R ¹² Is H and R ¹¹ is-CH ₂ N(H)S(O) ₂ NH ₂ . In another embodiment are compounds of formula (Va), wherein R ¹² Is H and R ¹¹ Is H.

In another embodimentIn which R is a compound of the formula (Va) ¹¹ And R ¹⁸ Combine to form an optionally substituted heterocycloalkyl ring and R ¹² Is H.

In another embodiment are compounds of formula (Va) wherein p is 1 and R ²⁷ Is a halogen. In another embodiment are compounds of formula (Va) wherein p is 1 and R ²⁷ Is optionally substituted- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (Va) wherein q is 0, p is 1 and R ²⁷ Is halogen. In another embodiment are compounds of formula (Va) wherein q is 0, p is 1, and R is ²⁷ Is optionally substituted- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (Va) wherein q is 1 and R ²⁸ Is a halogen. In another embodiment are compounds of formula (Va) wherein q is 1 and R ²⁸ Is optionally substituted- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (Va) wherein p is 0, q is 1, and R is ²⁸ Is a halogen. In another embodiment are compounds of formula (Va) wherein p is 0, q is 1, and R is ²⁸ Is optionally substituted- (C) ₁ -C ₆ ) An alkyl group.

In another embodiment are compounds of formula (Va) wherein p is 0 and q is 0.

In another embodiment are compounds of formula (Va), wherein R ¹ And R ² Each independently is H or- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (Va), wherein R ¹ And R ² Each is H. In another embodiment are compounds of formula (Va), wherein R ¹ And R ² Each independently is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (Va), wherein R ¹ Is H, and R ² Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (Va), wherein R ¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² And R is ² Is H. In another embodiment are compounds of formula (Va)In which R is ¹ Is H, and R ² is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (Va), wherein R ¹ is-CH ₂ CH ₂ NH ₂ And R is ² Is H. In another embodiment are compounds of formula (Va) wherein R ¹ And R ² Each is-CH ₂ CH ₂ NH ₂ . In a further embodiment are compounds of formula (Va) wherein R ¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² And R is ² Is H. In a further embodiment are compounds of formula (Va), wherein R ¹ is-CH ₂ CH ₂ NH ₂ And R is ² Is H. In a further embodiment are compounds of formula (Va), wherein R ¹ Is H and R ² Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In a further embodiment are compounds of formula (Va) wherein R ¹ Is H and R ² is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (Va) wherein R ¹ And R ² Are each independently H, - (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² or-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (Va) wherein R ¹ And R ² Each independently is-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (Va), wherein R ¹ Is H, and R ² is-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (Va), wherein R ¹ is-CH ₂ CH(OH)CH ₂ NH ₂ And R is ² Is H. In a further embodiment are compounds of formula (Va), wherein R ¹ And R ² And the atoms to which they are attached form an optionally substituted heterocycloalkyl ring.

In another embodiment are compounds of formula (Va) wherein X is optionally substituted heteroaryl. In a further embodiment are compounds of formula (Va) wherein X is mono-or di-substituted heteroaryl. In the further implementationIn one embodiment are compounds of formula (Va) wherein X is heteroaryl, mono-or di-substituted with a substituent independently selected from the group consisting of halo, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ and-NO ₂ . In a further embodiment are compounds of formula (Va) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituents are mono-or disubstituted heteroaryl. In a further embodiment are compounds of formula (Va) wherein X is heteroaryl, mono-or di-substituted with methyl. In a further embodiment are compounds of formula (Va) wherein X is pyridinyl mono-or di-substituted with a substituent independently selected from the group consisting of halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In a further embodiment are compounds of formula (Va) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituents are monosubstituted or disubstituted pyridinyl. In a further embodiment are compounds of formula (Va) wherein X is pyridinyl mono-or di-substituted with methyl. In a further embodiment are compounds of formula (Va) X is pyrimidinyl mono-or di-substituted with a substituent independently selected from halo, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In a further embodiment are compounds of formula (Va) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituent monosubstituted or disubstituted pyrimidinyl. In a further embodiment are compounds of formula (Va), X is pyrimidinyl mono-or di-substituted with methyl.

In another embodiment are compounds of formula (Va) wherein Y is optionally substituted aryl. In a further embodiment are compounds of formula (Va) wherein Y is optionally substituted phenyl. In another embodiment are compounds of formula (Va) wherein Y is optionally substitutedA heteroaryl group. In another embodiment are compounds of formula (Va) wherein Y is optionally substituted- (C) ₁ -C ₆ ) An alkyl group-. In another embodiment are compounds of formula (Va) wherein Y is optionally substituted (C) ₃ -C ₇ ) Cycloalkyl-. In another embodiment are compounds of formula (Va) wherein Y is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (Va) wherein Y is-O-. In another embodiment are compounds of formula (Va) wherein Y is- (C) ₂ -C ₆ ) Alkynyl. In another embodiment are compounds of formula (Va) wherein Y is-O- (C) ₁ -C ₆ ) An alkyl group-. In another embodiment are compounds of formula (Va) wherein Y is a bond.

In another embodiment are compounds of formula (Va) wherein Z is- (C) ₁ -C ₁₂ ) An alkyl group. In a further embodiment are compounds of formula (Va) wherein Z is n-butyl, isobutyl, or tert-butyl. In another embodiment are compounds of formula (Va) wherein Z is-O- (C) ₁ -C ₁₂ ) An alkyl group. In another embodiment are compounds of formula (Va) wherein Z is-O- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (Va) wherein Z is- (C) ₂ -C ₁₂ ) An alkenyl group. In another embodiment are compounds of formula (Va) wherein Z is optionally substituted aryl. In a further embodiment are compounds of formula (Va) wherein Z is optionally substituted phenyl. In a further embodiment are compounds of formula (Va) wherein Z is independently selected from- (C) ₁ -C ₈ ) Alkyl substituents are monosubstituted or disubstituted phenyl. In a further embodiment are compounds of formula (Va) wherein Z is phenyl monosubstituted with n-butyl, isobutyl, or tert-butyl. In a further embodiment are compounds of formula (Va) wherein Z is phenyl monosubstituted with n-butyl. In a further embodiment are compounds of formula (Va) wherein Z is phenyl monosubstituted with isobutyl. In a further embodiment are compounds of formula (Va) wherein Z is phenyl monosubstituted with tert-butyl. In another embodiment are compounds of formula (Va) wherein Z is optionally substituted heteroaryl. In another embodiment of formula (II)(Va) compounds in which Z is optionally substituted- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (Va) wherein Z is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (Va) wherein Z is halo.

In another embodiment are compounds of formula (V) having the structure of formula (Vb):

wherein:

or R ¹ And R ² And the atoms to which they are attachedForming an optionally substituted heterocycloalkyl ring;

X is optionally substituted heteroaryl;

each R ²³ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

each R ²⁴ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

each R ²⁵ And R ²⁶ Independently is H or optionallySubstituted- (C) ₁ -C ₆ ) An alkyl group;

or a pharmaceutically acceptable salt, solvate or prodrug thereof. In one embodiment are compounds of formula (Vb), wherein R ¹⁷ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (Vb), wherein R ¹⁷ is-CH ₃ . In another embodiment are compounds of formula (Vb), wherein R ¹⁷ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (Vb), wherein R ¹⁷ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (Vb), wherein R ¹⁷ Is cyclopropyl. In another embodiment are compounds of formula (Vb), wherein R ¹⁷ Is- (C) ₁ -C ₆ ) alkyl-C (O) OR ²³ . In another embodiment are compounds of formula (Vb), wherein R ¹⁷ is-CH ₂ CH ₂ And (5) OH. In another embodiment are compounds of formula (Vb), wherein R ¹⁷ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (Vb), wherein R ¹⁷ is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (Vb), wherein R ¹⁷ Is H.

In another embodiment are compounds of formula (Vb), wherein R ¹⁸ Is H.

In another embodiment are compounds of formula (Vb), wherein R ⁹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (Vb), wherein R ⁹ is-CH ₃ . In another embodiment are compounds of formula (Vb), wherein R ⁹ is-CH ₂ CH ₃ . In another embodiment are compounds of formula (Vb), wherein R ⁹ Is- (C) ₁ -C ₆ ) A haloalkyl group. In another embodiment are compounds of formula (Vb), wherein R ⁹ is-CH ₂ F. In another embodiment a compound of formula (Vb)In which R is ⁹ is-CHF ₂ . In another embodiment are compounds of formula (Vb), wherein R ⁹ Is- (C) ₃ -C ₆ ) A cycloalkyl group. In another embodiment are compounds of formula (Vb), wherein R ⁹ Is cyclopropyl. In another embodiment are compounds of formula (Vb), wherein R ⁹ Is H.

In another embodiment are compounds of formula (Vb), wherein R ¹¹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (Vb), wherein R ¹¹ is-CH ₃ . In another embodiment are compounds of formula (Vb), wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-OR ²³ . In another embodiment are compounds of formula (Vb), wherein R ¹¹ is-CH ₂ And (5) OH. In another embodiment are compounds of formula (Vb), wherein R ¹¹ is-CH ₂ CH ₂ And (5) OH. In another embodiment are compounds of formula (Vb), wherein R ¹¹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (Vb), wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (Vb), wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-NH ₂ . In another embodiment are compounds of formula (Vb), wherein R ¹¹ is-CH ₂ NH ₂ . In another embodiment are compounds of formula (Vb), wherein R ¹¹ is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (Vb), wherein R ¹¹ is-CH ₂ CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (Vb), wherein R ¹¹ is-CH ₂ CH ₂ CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (Vb), wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-CN. In another embodiment are compounds of formula (Vb), wherein R ¹¹ is-CH ₂ And (C) CN. In another embodiment are compounds of formula (Vb), wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-C (O) NR ²⁵ R ²⁶ . In another embodiment are compounds of formula (Vb), wherein R ¹¹ is-CH ₂ C(O)NH ₂ . In another embodiment are compounds of formula (Vb), wherein R ¹¹ is-CH ₂ CH ₂ C(O)NH ₂ . In another embodiment are compounds of formula (Vb), wherein R ¹¹ Is- (C) ₁ -C ₆ ) Alkyl-heteroaryl. In another embodiment are compounds of formula (Vb), wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-N (H) S (O) ₂ NR ²⁵ R ²⁶ . In another embodiment are compounds of formula (Vb), wherein R ¹¹ is-CH ₂ N(H)S(O) ₂ NH ₂ . In another embodiment are compounds of formula (Vb), wherein R ¹¹ Is H.

In another embodiment are compounds of formula (Vb), wherein R ¹¹ And R ¹⁸ Combine to form an optionally substituted heterocycloalkyl ring.

In another embodiment are compounds of formula (Vb), wherein R ¹ And R ² Each independently is H or- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (Vb), wherein R ¹ And R ² Each is H. In another embodiment are compounds of formula (Vb), wherein R ¹ And R ² Each independently is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (Vb), wherein R ¹ Is H, and R ² Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (Vb), wherein R ¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² And R is ² Is H. In another embodiment are compounds of formula (Vb), wherein R ¹ Is H, and R ² is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (Vb), wherein R ¹ is-CH ₂ CH ₂ NH ₂ And R is ² Is H. In another embodimentIn the formula (Vb), wherein R ¹ And R ² Each is-CH ₂ CH ₂ NH ₂ . In a further embodiment are compounds of formula (Vb), wherein R ¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² And R is ² Is H. In a further embodiment are compounds of formula (Vb), wherein R ¹ is-CH ₂ CH ₂ NH ₂ And R is ² Is H. In a further embodiment are compounds of formula (Vb), wherein R ¹ Is H and R ² Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In a further embodiment are compounds of formula (Vb), wherein R ¹ Is H and R ² is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (Vb), wherein R ¹ And R ² Are each independently H, - (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² or-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (Vb), wherein R ¹ And R ² Each independently is-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (Vb), wherein R ¹ Is H, and R ² is-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (Vb), wherein R ¹ is-CH ₂ CH(OH)CH ₂ NH ₂ And R is ² Is H. In a further embodiment are compounds of formula (Vb), wherein R ¹ And R ² And the atoms to which they are attached form an optionally substituted heterocycloalkyl ring.

In another embodiment are compounds of formula (Vb) wherein X is optionally substituted heteroaryl. In a further embodiment are compounds of formula (Vb) wherein X is mono-or di-substituted heteroaryl. In a further embodiment are compounds of formula (Vb) wherein X is heteroaryl, mono-or di-substituted with a substituent independently selected from halo, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ and-NO ₂ . In a further embodiment are compounds of formula (Vb) wherein X is independently selected from the group consisting of ₁ -C ₆ ) Alkyl substituents are mono-or disubstituted heteroaryl. In a further embodiment are compounds of formula (Vb) wherein X is heteroaryl, mono-or di-substituted with methyl. In a further embodiment are compounds of formula (Vb) wherein X is pyridyl, mono-or di-substituted with a substituent independently selected from the group consisting of halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In a further embodiment are compounds of formula (Vb) wherein X is independently selected from the group consisting of ₁ -C ₆ ) Alkyl substituents are monosubstituted or disubstituted pyridinyl. In a further embodiment are compounds of formula (Vb) wherein X is pyridinyl mono-or di-substituted with methyl. In a further embodiment are compounds of formula (Vb), X is pyrimidinyl mono-or di-substituted with a substituent independently selected from halo, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In a further embodiment are compounds of formula (Vb), X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituent monosubstituted or disubstituted pyrimidinyl. In a further embodiment is a compound of formula (Vb) X is pyrimidinyl mono-or di-substituted with methyl.

In another embodiment are compounds of formula (Vb), wherein Y is optionally substituted aryl. In a further embodiment are compounds of formula (Vb) wherein Y is optionally substituted phenyl. In another embodiment are compounds of formula (Vb) wherein Y is optionally substituted heteroaryl. In another embodiment are compounds of formula (Vb) wherein Y is optionally substituted- (C) ₁ -C ₆ ) An alkyl group-. In another embodiment are compounds of formula (Vb) wherein Y is optionally substituted (C) ₃ -C ₇ ) Cycloalkyl-. In anotherEmbodiments are compounds of formula (Vb) wherein Y is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (Vb) wherein Y is-O-. In another embodiment are compounds of formula (Vb) wherein Y is- (C) ₂ -C ₆ ) Alkynyl. In another embodiment are compounds of formula (Vb) wherein Y is-O- (C) ₁ -C ₆ ) An alkyl radical. In another embodiment are compounds of formula (Vb) wherein Y is a bond.

In another embodiment are compounds of formula (Vb) wherein Z is- (C) ₁ -C ₁₂ ) An alkyl group. In a further embodiment are compounds of formula (Vb) wherein Z is n-butyl, isobutyl, or tert-butyl. In another embodiment are compounds of formula (Vb) wherein Z is-O- (C) ₁ -C ₁₂ ) An alkyl group. In another embodiment are compounds of formula (Vb) wherein Z is-O- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (Vb), wherein Z is- (C) ₂ -C ₁₂ ) An alkenyl group. In another embodiment are compounds of formula (Vb), wherein Z is optionally substituted aryl. In a further embodiment are compounds of formula (Vb) wherein Z is optionally substituted phenyl. In a further embodiment are compounds of formula (Vb) wherein Z is independently selected from- (C) ₁ -C ₈ ) Alkyl substituents are monosubstituted or disubstituted phenyl. In a further embodiment are compounds of formula (Vb) wherein Z is phenyl monosubstituted with n-butyl, isobutyl, or tert-butyl. In a further embodiment are compounds of formula (Vb) wherein Z is phenyl monosubstituted with n-butyl. In a further embodiment are compounds of formula (Vb) wherein Z is phenyl monosubstituted with isobutyl. In a further embodiment are compounds of formula (Vb) wherein Z is phenyl monosubstituted with tert-butyl. In another embodiment are compounds of formula (Vb), wherein Z is optionally substituted heteroaryl. In another embodiment are compounds of formula (Vb) wherein Z is optionally substituted- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (Vb) wherein Z is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (Vb) wherein Z is halogen.

In another embodiment are compounds of formula (V) having the structure of formula (Vc):

wherein:

x is optionally substituted heteroaryl;

y is a bond, -O-, -S-) optionally substituted (A)C ₁ -C ₆ ) Alkyl-, - (C) ₂ -C ₆ ) Alkenyl-, - (C) ₂ -C ₆ ) Alkynyl, - (C) ₁ -C ₆ ) alkyl-N (R) ²⁴ )(C ₁ -C ₆ ) Alkyl-, -O- (C) ₁ -C ₆ ) Alkyl-, -O (C) ₆ -C ₁₀ ) Aryl-, -N (R) ²⁴ )(C ₁ -C ₆ ) Alkyl-, -N (R) ²⁴ )SO ₂ (C ₁ -C ₆ ) Alkyl-, -N (R) ²⁴ )C(O)(C ₁ -C ₆ ) Alkyl-, -C (O) (C) ₁ -C ₆ ) Alkyl-, -S (C) ₁ -C ₆ ) Alkyl-, -SO ₂ (C ₁ -C ₆ ) Alkyl-, -C (O) NH (C) ₁ -C ₆ ) Alkyl-, optionally substituted- (C) ₃ -C ₇ ) Cycloalkyl-, optionally substituted-C (O) N (R) ²⁴ ) Aryl-, optionally substituted-N (R) ²⁴ ) C (O) aryl-, optionally substituted-N (R) ²⁴ )SO ₂ Aryl-, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

each R ²³ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

each R ²⁴ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

or a pharmaceutically acceptable salt, solvate or prodrug thereof. In another embodiment are compounds of formula (Vc), wherein R ¹¹ Is- (C) ₁ -C ₆ ) An alkyl group. In another embodiment are compounds of formula (Vc), wherein R ¹¹ is-CH ₃ . In another embodiment are compounds of formula (Vc), wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-OR ²³ . In another embodiment are compounds of formula (Vc), wherein R ¹¹ is-CH ₂ And (5) OH. In another embodiment are compounds of formula (Vc), wherein R ¹¹ is-CH ₂ CH ₂ And (5) OH. In another embodiment are compounds of formula (Vc), wherein R ¹¹ Is- (C) ₁ -C ₆ ) An alkyl group. In another placeIn one embodiment are compounds of formula (Vc), wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (Vc), wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-NH ₂ . In another embodiment are compounds of formula (Vc), wherein R ¹¹ is-CH ₂ NH ₂ . In another embodiment are compounds of formula (Vc), wherein R ¹¹ is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (Vc), wherein R ¹¹ is-CH ₂ CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (Vc), wherein R ¹¹ is-CH ₂ CH ₂ CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (Vc), wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-CN. In another embodiment are compounds of formula (Vc), wherein R ¹¹ is-CH ₂ And (C) CN. In another embodiment are compounds of formula (Vc), wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-C (O) NR ²⁵ R ²⁶ . In another embodiment are compounds of formula (Vc), wherein R ¹¹ is-CH ₂ C(O)NH ₂ . In another embodiment are compounds of formula (Vc), wherein R ¹¹ is-CH ₂ CH ₂ C(O)NH ₂ . In another embodiment are compounds of formula (Vc), wherein R ¹¹ Is- (C) ₁ -C ₆ ) Alkyl-heteroaryl. In another embodiment are compounds of formula (Vc), wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-N (H) S (O) ₂ NR ²⁵ R ²⁶ . In another embodiment are compounds of formula (Vc), wherein R ¹¹ is-CH ₂ N(H)S(O) ₂ NH ₂ . In another embodiment are compounds of formula (Vc), wherein R ¹¹ Is H.

In another embodiment are compounds of formula (Vc), wherein R ¹ And R ² Each independently is H or- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodimentIn one embodiment are compounds of formula (Vc), wherein R ¹ And R ² Each is H. In another embodiment are compounds of formula (Vc), wherein R ¹ And R ² Each independently is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (Vc), wherein R ¹ Is H, and R ² Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In another embodiment are compounds of formula (Vc), wherein R ¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² And R is ² Is H. In another embodiment are compounds of formula (Vc), wherein R ¹ Is H, and R ² is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (Vc), wherein R ¹ is-CH ₂ CH ₂ NH ₂ And R is ² Is H. In another embodiment are compounds of formula (Vc), wherein R ¹ And R ² Each is-CH ₂ CH ₂ NH ₂ . In a further embodiment are compounds of formula (Vc), wherein R ¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² And R is ² Is H. In a further embodiment are compounds of formula (Vc), wherein R ¹ is-CH ₂ CH ₂ NH ₂ And R is ² Is H. In a further embodiment are compounds of formula (Vc), wherein R ¹ Is H and R ² Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² . In a further embodiment are compounds of formula (Vc), wherein R ¹ Is H and R ² is-CH ₂ CH ₂ NH ₂ . In another embodiment are compounds of formula (Vc), wherein R ¹ And R ² Are each independently H, - (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² or-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (Vc), wherein R ¹ And R ² Each independently is-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (Vc), wherein R ¹ Is H, and R ² is-CH ₂ CH(OH)CH ₂ NH ₂ . In another embodiment are compounds of formula (Vc), wherein R ¹ is-CH ₂ CH(OH)CH ₂ NH ₂ And R is ² Is H. In a further embodiment are compounds of formula (Vc), wherein R ¹ And R ² And the atoms to which they are attached form an optionally substituted heterocycloalkyl ring.

In another embodiment are compounds of formula (Vc) wherein X is optionally substituted heteroaryl. In a further embodiment are compounds of formula (Vc) wherein X is mono-or di-substituted heteroaryl. In a further embodiment are compounds of formula (Vc), wherein X is heteroaryl, mono-or di-substituted with a substituent independently selected from halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ and-NO ₂ . In a further embodiment are compounds of formula (Vc), wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituents are mono-or disubstituted heteroaryl. In a further embodiment are compounds of formula (Vc) wherein X is heteroaryl mono-or di-substituted with methyl. In a further embodiment are compounds of formula (Vc), wherein X is pyridyl, mono-or di-substituted with a substituent independently selected from halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In a further embodiment are compounds of formula (Vc), wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituent monosubstituted or disubstituted pyridyl. In a further embodiment are compounds of formula (Vc) wherein X is pyridinyl mono-or di-substituted with methyl. In a further embodiment are compounds of formula (Vc), X is pyrimidinyl mono-or di-substituted with a substituent independently selected from halogen, -CN, optionally substituted- (C) ₁ -C ₆ ) Alkyl, optionally substituted-O- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ . In a further embodiment are compounds of formula (Vc) wherein X is independently selected from- (C) ₁ -C ₆ ) Alkyl substituent monosubstituted or disubstituted pyrimidinyl. In a further embodiment are compounds of formula (Vc) X is pyrimidinyl mono-or di-substituted with methyl.

In another embodiment are compounds of formula (Vc) wherein Y is optionally substituted aryl. In a further embodiment are compounds of formula (Vc) wherein Y is optionally substituted phenyl. In another embodiment are compounds of formula (Vc) wherein Y is optionally substituted heteroaryl. In another embodiment are compounds of formula (Vc) wherein Y is optionally substituted- (C) ₁ -C ₆ ) An alkyl group-. In another embodiment are compounds of formula (Vc), wherein Y is optionally substituted (C) ₃ -C ₇ ) Cycloalkyl-. In another embodiment are compounds of formula (Vc) wherein Y is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (Vc), wherein Y is-O-. In another embodiment are compounds of formula (Vc), wherein Y is- (C) ₂ -C ₆ ) Alkynyl. In another embodiment are compounds of formula (Vc), wherein Y is-O- (C) ₁ -C ₆ ) An alkyl group-. In another embodiment are compounds of formula (Vc) wherein Y is a bond.

In another embodiment are compounds of formula (Vc), wherein Z is- (C) ₁ -C ₁₂ ) An alkyl group. In a further embodiment are compounds of formula (Vc) wherein Z is n-butyl, isobutyl, or tert-butyl. In another embodiment are compounds of formula (Vc), wherein Z is-O- (C) ₁ -C ₁₂ ) An alkyl group. In another embodiment are compounds of formula (Vc), wherein Z is-O- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (Vc), wherein Z is- (C) ₂ -C ₁₂ ) An alkenyl group. In another embodiment are compounds of formula (Vc) wherein Z is optionally substituted aryl. In a further embodiment are compounds of formula (Vc) wherein Z is optionally substituted phenyl. In a further embodiment are compounds of formula (Vc),wherein Z is independently selected from- (C) ₁ -C ₈ ) Alkyl substituents are monosubstituted or disubstituted phenyl. In a further embodiment are compounds of formula (Vc) wherein Z is phenyl monosubstituted with n-butyl, isobutyl, or tert-butyl. In a further embodiment are compounds of formula (Vc) wherein Z is phenyl monosubstituted with n-butyl. In a further embodiment are compounds of formula (Vc) wherein Z is phenyl monosubstituted with isobutyl. In a further embodiment are compounds of formula (Vc) wherein Z is phenyl monosubstituted with tert-butyl. In another embodiment are compounds of formula (Vc) wherein Z is optionally substituted heteroaryl. In another embodiment are compounds of formula (Vc) wherein Z is optionally substituted- (C) ₃ -C ₇ ) A cycloalkyl group. In another embodiment are compounds of formula (Vc) wherein Z is optionally substituted heterocycloalkyl. In another embodiment are compounds of formula (Vc) wherein Z is halogen.

In some embodiments, the compounds of formulae (V), (Va), (Vb), and (Vc) are selected from the compounds in table 2, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

TABLE 2

In another aspect are hydrates or metabolites of any of the above compounds.

In another aspect is a pharmaceutical composition comprising any of the above compounds and a pharmaceutically acceptable excipient.

In another aspect described herein is the use of a compound described herein in the manufacture of a medicament for treating a bacterial infection in a patient.

In another aspect is a method of treating a mammal in need of such treatment, the method comprising administering to the mammal an antibacterial effective amount of any of the compounds described above, at a frequency and for a duration sufficient to provide a beneficial effect to the mammal. In one embodiment, the mammal has a bacterial-associated infection that is resistant to arylomycin A2 treatment. In a further embodiment of the process of the present invention, the pathogenic bacteria infected by the bacterium are those related to Pseudomonas aeruginosa (Pseudomonas aeruginosa), pseudomonas fluorescens (Pseudomonas fluorescens), pseudomonas acidovorans (Pseudomonas acidovorans), pseudomonas alcaligenes (Pseudomonas alcaligenes), pseudomonas putida (Pseudomonas putida), stenotrophomonas maltophilia (Stenotrophora), burkholderia cepacia (Burkholderia papacia), aeromonas hydrophila (Aeromonas hydrophila), escherichia coli (Escherichia coli), citrobacter freundii (Citrobacter freundii), salmonella typhimurium (Salmonella typhimurium), salmonella typhi (Salmonella typhimurium), salmonella paratyphi (Salmonella typhi), salmonella paraella (Salmonella typhimurium), and Salmonella enterica (Salmonella anatipestifolia), salmonella typhimurium (Salmonella typhimurium) Shigella dysenteriae (Shigella dysenteriae), shigella flexneri (Shigella flexneri), shigella sojae (Shigella sonnei), enterobacter cloacae (Enterobacter cloacae), enterobacter aerogenes (Enterobacter aerogenes), klebsiella pneumoniae (Klebsiella pneumoniae), klebsiella oxytoca (Klebsiella oxytoca), serratia marcescens (Serratia marcescens), francisella tularensis (Franciselisella tularensis), morganella morganii (Morganella morganii), proteus mirabilis (Proteus mirabilis), proteus vulgaris (Proteus vulgarris), proteus Providencia alcaligenes (Proviia caligenes), proviella arvensis (Proviia multifamifera), proteus baumannii (Proteus nitissia), proteus Acinetobacter asiaticus (Proteus), proteus nitissius strain (Provinifera), provinifera (Proteus), proteus strain (Provinifera), provinifera (Provinifera) and/strain (Provinifera), <xnotran> (Acinetobacter calcoaceticus), (Acinetobacter haemolyticus), (Yersinia enterocolitica), (Yersinia pestis), (Yersinia pseudotuberculosis), (Yersinia intermedia), (Bordetella pertussis), (Bordetella parapertussis), (Bordetella bronchiseptica), (Haemophilus influenzae), (Haemophilus parainfluenzae), (Haemophilus haemolyticus), (Haemophilus parahaemolyticus), (Haemophilus ducreyi), (Pasteurella multocida), (Pasteurella haemolytica), (Branhamella catarrhalis), (Helicobacter pylori), (Campylobacter fetus), (Campylobacter jejuni), (Campylobacter coli), (Borrelia burgdorferi), (Vibrio cholerae), (Vibrio parahaemolyticus), (Legionella pneumophila), (Listeria monocytogenes), (Neisseria gonorrhoeae), (Neisseria meningitidis), (Kingella), (Moraxella), (Gardnerella vaginalis), (Bacteroides fragilis), </xnotran> Bacteroides distasonis (Bacteroides distasonis), bacteroides 3452A homologous group (Bacteroides 3452A homology group), bacteroides vulgatus (Bacteroides vulgatus), bacteroides ovatus (Bacteroides ovatus), bacteroides thetaiotaomicron (Bacteroides thetaiotaomicron), bacteroides uniflora (Bacteroides uniflora), bacteroides eggeretis (Bacteroides eggerthii), bacteroides visceral sporogenes (Bacteroides splanchnicus), clostridium difficile (Clostridium difficile), mycobacterium tuberculosis (Mycobacterium tuberculosis), mycobacterium avium (Mycobacterium avium), mycobacterium intracellulare (Mycobacterium intracellulare), mycobacterium tuberculosis (Mycobacterium integramularia), mycobacterium leprae (Mycobacterium tuberculosis), corynebacterium diphtheriae (Corynebacterium thermobacter) and Corynebacterium diphtheriae (Corynebacterium thermobacter) are disclosed. Corynebacterium ulcerosa (Corynebacterium ulcerans), streptococcus pneumoniae (Streptococcus pneumoniae), streptococcus agalactiae (Streptococcus agalactiae), streptococcus pyogenes (Streptococcus pycnes), enterococcus faecalis (Enterococcus faecalis), enterococcus faecium (Enterococcus faecium), staphylococcus aureus (Staphylococcus aureus), staphylococcus epidermidis (Staphylococcus epidermidis), staphylococcus saprophyticus (Staphylococcus saprophyticus), staphylococcus intermedius (Staphylococcus intermedius), staphylococcus suis (Staphylococcus hyicus), staphylococcus haemolyticus (Staphylococcus haemolyticus), human Staphylococcus aureus (Staphylococcus aureus) or Staphylococcus aureus (Staphylococcus aureus). In another embodiment, the bacterial infection is an infection involving a gram-negative bacterium. In another embodiment, the cell infection is a lepB-mediated infection. In a further embodiment, the bacterial infection is an infection involving a gram-positive bacterium.

In a further embodiment is a method of treating a mammal in need of such treatment, the method comprising administering to the mammal a second therapeutic agent for any of the foregoing methods of treatment. In another embodiment, the second therapeutic agent is not a SpsB inhibitor. In another embodiment, the second therapeutic agent is an aminoglycoside antibiotic, a fluoroquinolone antibiotic, a β -lactam antibiotic, a macrolide antibiotic, a glycopeptide antibiotic, rifampin, chloramphenicol, fludromycin, colistin, mupirocin, bacitracin, daptomycin, or linezolid.

In some embodiments is a method of treating a bacterial infection in a patient, preferably a human, wherein the treatment comprises administering a therapeutically or pharmacologically effective amount of a combination of: 1) A beta-lactam antibiotic; and 2) a compound of formula (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V) or (Va) - (Vc) or a pharmaceutically acceptable salt thereof; and 3) a pharmaceutically acceptable carrier. In embodiments where the beta-lactam antibiotic is used in combination with a compound of formula (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V) or (Va) - (Vc), the beta-lactam antibiotic may be a carbapenem, a cephalosporin, a cephamycin, a monobactam or a penicillin. Exemplary carbapenem antibiotics useful in the methods of the invention include ertapenem, imipenem, biapenem, and meropenem. Exemplary cephalosporin antibiotics useful in the methods of the invention include cefbipril, ceftaroline, cefpirome, cefozopran, cefepime, cefotaxime and ceftriaxone (ceftriazone). Exemplary penicillin antibiotics useful in the methods of the present invention include ampicillin, amoxicillin (amoxicillin), piperacillin, oxacillin, cloxacillin, methicillin, and nafcillin. In some embodiments of the invention, the beta-lactam may be administered with a beta-lactamase inhibitor. In some embodiments of the invention, the carbapenem may be administered with a DHP inhibitor such as cilastatin.

In various embodiments of the present invention in which the compounds of formulae (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V) or (Va) - (Vc) are used in combination with a β -lactam antibiotic, the β -lactam antibiotic and the compounds of formulae (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V) or (Va) - (Vc) may be administered sequentially or simultaneously. Preferably, the beta-lactam antibiotic is administered together with a compound of formula (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V) or (Va) - (Vc). When administered simultaneously, the β -lactam antibiotic and the compound of formula (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V) or (Va) - (Vc) may be administered in the same formulation or in different formulations. When administered sequentially, the β -lactam or any of the compounds of formulae (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V) or (Va) - (Vc) may be administered first. After administration of the first compound, for example within 1-60 minutes, for example within 1, 2, 3, 4, 5, 10, 15, 30 or 60 minutes, another compound is administered. In one aspect of the invention, when a beta-lactamase inhibitor is used, it may be administered alone or in a formulation comprising a compound of formula (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V) or (Va) - (Vc) and/or a beta-lactam antibiotic. In one aspect of the invention, when a DHP inhibitor is used to increase the stability of a carbapenem, it may be administered alone or in a formulation comprising a compound of formula (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V) or (Va) - (Vc) and/or a carbapenem.

Further described herein are pharmaceutical compositions comprising a compound of formula (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V) or (Va) - (Vc), a pharmaceutically acceptable carrier, and optionally a beta-lactam antibiotic. In embodiments where a combination is used, the β -lactam antibiotic and the compound of formula (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V) or (Va) - (Vc) are present in amounts such that the combination thereof comprises a therapeutically effective amount. Due to the enhancing effect of the compounds of formulae (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V) or (Va) - (Vc), the amount of beta-lactam antibiotic present in the combination can be less than the amount of beta-lactam antibiotic used alone. In certain embodiments, the composition further comprises a beta-lactamase antibiotic.

In other embodiments where the beta-lactam antibiotic is a carbapenem, a pharmaceutical composition is provided comprising a carbapenem antibiotic, a DHP inhibitor, a compound of formula (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V), or (Va) - (Vc), and a pharmaceutically acceptable carrier. In some embodiments where the beta-lactam antibiotic is a carbapenem, the carbapenem antibiotic is preferably selected from ertapenem, imipenem, and meropenem.

In some embodiments are compounds of formula (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V) or (Va) - (Vc) for use in the treatment of a bacterial infection. In some embodiments are compounds of formula (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V), or (Va) - (Vc), in combination with one or more additional therapeutic agents, including a β -lactam antibiotic, for use in the treatment of a bacterial infection. In some embodiments are compounds of formula (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V), or (Va) - (Vc) for use as a medicament in the treatment of a bacterial infection. In some embodiments are compounds of formula (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V), or (Va) - (Vc), in combination with one or more additional therapeutic agents, including a β -lactam antibiotic, for use as a medicament in the treatment of a bacterial infection. In some embodiments are compounds of formula (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V) or (Va) - (Vc) for use in the preparation of a medicament for treating a bacterial infection. In some embodiments are compounds of formula (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V), or (Va) - (Vc), in combination with one or more additional therapeutic agents, including a β -lactam antibiotic, for use in the preparation of a medicament for the treatment of a bacterial infection.

In some embodiments described herein, compounds of formula (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V), or (Va) - (Vc) can enhance the activity of a β -lactam antibacterial agent by inducing the sensitivity of a drug-resistant strain, such as MRSA, to the antibacterial agent. In some embodiments, compounds of formula (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V), or (Va) - (Vc) can enhance the activity of a β -lactam antibacterial agent by reducing the amount of antibacterial agent required for a therapeutic effect against a drug-resistant strain. For example, if a compound of formula (I), (I'), (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V), or (Va) - (Vc) reduces the Minimum Inhibitory Concentration (MIC) of the antibacterial agent in susceptible strains (where MIC is the lowest concentration at which the antibacterial agent completely inhibits growth), such treatment may be beneficial to achieve a reduction in the amount of antibacterial agent administered (which may reduce the side effects of the antibiotic), or to reduce the frequency of administration.

Synergists can be used to enhance the activity of antibacterial agents whose clinical efficacy is limited by the increasing prevalence of resistant strains. In some embodiments described herein, compounds of formula (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V), or (Va) - (Vc) are used as potentiators, wherein the compounds of formula (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V), or (Va) - (Vc) can be administered (simultaneously or sequentially) with a β -lactam antibiotic to allow for effective treatment of infections involving resistant bacteria, or to reduce the amount of antibacterial agent required to treat the infection.

In one embodiment are compounds described herein that exhibit antibiotic activity useful for treating bacterial infections, such as, by way of example only, various strains of staphylococcus aureus, streptococcus pneumoniae, enterococcus faecalis, enterococcus faecium, bacillus subtilis, and escherichia coli, including species resistant to many known antibiotics, such as methicillin-resistant staphylococcus aureus (MRSA), vancomycin-resistant enterococcus (VRE), multidrug-resistant enterococcus faecium, macrocyclic lactone-resistant staphylococcus aureus and staphylococcus epidermidis, and linezolid-resistant staphylococcus aureus and enterococcus faecium.

Methicillin-resistant staphylococcus aureus

Staphylococcus aureus, a type of spherical bacterium, is the most common cause of staphylococcal infection. Staphylococcus aureus is known to cause a range of diseases ranging from mild skin infections (such as papules, impetigo, boils, cellulitis, folliculitis, boils, carbuncles, scalded skin syndrome, abscesses) to life-threatening diseases (such as pneumonia, meningitis, osteomyelitis, endocarditis, toxic shock syndrome and sepsis). In addition, staphylococcus aureus is one of the most common causes of nosocomial infections, often causing post-operative wound infections.

Methicillin was introduced in the late 20 th century, the 50 s, and is used to treat infections caused by penicillin-resistant staphylococcus aureus. It has been previously reported that: staphylococcus aureus isolates have acquired resistance to methicillin (methicillin resistant Staphylococcus aureus, MRSA). The methicillin-resistant gene (mecA) encodes a methicillin-resistant penicillin-binding protein that is not present in susceptible strains. mecA is carried on the mobile genetic element staphylococcal cassette chromosome mec (SCCmec), four of which have been described as differing in size and genetic composition. Methicillin-resistant penicillin binding proteins cause resistance to beta-lactam antibiotics and preclude their clinical use during MRSA infection.

In one aspect is a method for treating a subject with resistant bacteria, the method comprising administering to the subject a compound of formula (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V), or (Va) - (Vc), or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In one embodiment, the bacterium is a gram-positive bacterium. In another embodiment, the gram-positive bacterium is staphylococcus aureus. In a further embodiment, the staphylococcus aureus is resistant or refractory to a beta-lactam antibiotic. In a still further embodiment, the β -lactam antibiotic belongs to the class of penicillins. In a further embodiment, the beta-lactam antibiotic is methicillin. In yet another embodiment, the subject has a bacterium that is resistant to methicillin-resistant staphylococcus aureus. In one embodiment, the beta-lactam antibiotic is flucloxacillin. In another embodiment is a method for treating a subject having a dicloxacillin-resistant bacterium, the method comprising administering to the subject a compound of formula (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V), or (Va) - (Vc), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the subject is dicloxacillin-resistant. Also disclosed herein are methods for treating a subject having a methicillin-resistant bacterium, the method comprising administering a compound of formula (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V), or (Va) - (Vc), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the subject has been determined to have a methicillin-resistant bacterium. In one embodiment, the subject is screened for anti-methicillin bacteria. In another embodiment, the screening of the subject is performed by nasal culture. In further embodiments, the anti-methicillin bacteria are detected by swabbing the nostrils of the subject and isolating the bacteria. In another embodiment, real-time PCR and/or quantitative PCR is used to determine whether a subject has methicillin-resistant bacteria.

In one embodiment is a method for treating a subject having a first generation cephalosporin resistant bacterium, the method comprising administering a compound of formula (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V), or (Va) - (Vc), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the subject is first generation cephalosporin refractory. In one embodiment, the bacterium is resistant to a first generation cephalosporin. In a further embodiment, the bacterium is resistant to cefaclonitrile (cefacetril). In another embodiment, the bacterium is resistant to cefadroxil. In yet another embodiment, the bacterium is resistant to cephalexin. In one embodiment, the bacterium is resistant to cefalexin. In another embodiment, the bacterium is resistant to cephalonine. In another embodiment, the bacterium is resistant to ceftiofur. In yet another embodiment, the bacterium is resistant to cephalothin. In a further embodiment, the bacterium is resistant to cefapirin. In a still further embodiment, the bacterium is resistant to ceftriazine. In one embodiment, the bacterium is resistant to cefazeflur (cefazaflur). In another embodiment, the bacterium is resistant to cefazedone. In yet another embodiment, the bacterium is resistant to cefazolin. In a further embodiment, the bacterium is resistant to cephradine. In a still further embodiment, the bacterium is resistant to cefixadine. In one embodiment, the bacterium is resistant to ceftezole.

In one embodiment is a method for treating a subject having a second generation cephalosporin resistant bacterium, the method comprising administering a compound of formula (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V), or (Va) - (Vc), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the subject is second generation cephalosporin refractory. In another embodiment, the bacterium is resistant to a second generation cephalosporin. In a further embodiment, the bacterium is resistant to cefaclor. In another embodiment, the bacterium is resistant to cefonicid. In a further embodiment, the bacterium is resistant to cefprozil. In one embodiment, the bacterium is resistant to cefuroxime. In another embodiment, the bacterium is resistant to ceftizone. In another embodiment, the bacterium is resistant to cefmetazole. In a further embodiment, the bacterium is resistant to cefotetan. In a further embodiment, the bacterium is resistant to cefoxitin.

In one embodiment is a method for treating a subject having a third generation cephalosporin resistant bacterium, the method comprising administering a compound of formula (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V), or (Va) - (Vc), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the subject is third generation cephalosporin refractory. In another embodiment, the bacterium is resistant to a third generation cephalosporin. In a further embodiment, the bacterium is resistant to cefcapene. In another embodiment, the bacterium is resistant to cefdaxime. In a further embodiment, the bacterium is resistant to cefdinir. In one embodiment, the bacterium is resistant to cefditoren. In another embodiment, the bacterium is resistant to cefixime. In another embodiment, the bacterium is resistant to cefmenoxime. In a further embodiment, the bacterium is resistant to cefodizime. In a further embodiment, the bacterium is resistant to cefotaxime. In a still further embodiment, the bacterium is resistant to cephamazole. In one embodiment, the bacterium is resistant to cefpodoxime. In another embodiment, the bacterium is resistant to cefteram. In a further embodiment, the bacterium is resistant to ceftibuten. In a further embodiment, the bacterium is resistant to ceftiofur. In a still further embodiment, the bacterium is resistant to cefotaxime. In one embodiment, the bacterium is resistant to ceftizoxime. In another embodiment, the bacterium is resistant to ceftriaxone. In a further embodiment, the bacterium is resistant to cefoperazone. In a still further embodiment, the bacterium is resistant to ceftazidime.

In one embodiment is a method for treating a subject with fourth generation cephalosporin resistant bacteria, the method comprising administering a compound of formula (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V), or (Va) - (Vc), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the subject is fourth generation cephalosporin refractory. In another embodiment, the bacterium is resistant to a fourth generation cephalosporin. In a further embodiment, the bacterium is resistant to cefaclor. In another embodiment, the bacterium is resistant to cefepime. In a further embodiment, the bacterium is resistant to ceforenan. In one embodiment, the bacterium is resistant to cefoselis. In another embodiment, the bacterium is resistant to cefozopran. In another embodiment, the bacterium is resistant to cefpirome. In yet another embodiment, the bacterium is cefquinome refractory.

In one embodiment is a method for treating a subject with a carbapenem-resistant bacterium, the method comprising administering a compound of formula (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V), or (Va) - (Vc), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the subject is carbapenem-refractory. In another embodiment, the bacterium is resistant to carbapenem. In a further embodiment, the bacterium is resistant to imipenem. In another embodiment, the bacterium is resistant to meropenem. In yet another embodiment, the bacterium is resistant to ertapenem. In one embodiment, the bacterium is resistant to faropenem. In another embodiment, the bacterium is resistant to doripenem. In another embodiment, the bacterium is resistant to panipenem. In yet another embodiment, the bacterium is resistant to biapenem.

Vancomycin-mediating and vancomycin-resistant staphylococcus aureus

Vancomycin-mediating and anti-vancomycin s are specific types of antimicrobial resistant staphylococci that are refractory to vancomycin treatment. Staphylococcus aureus isolates with a vancomycin MIC of 4-8. Mu.g/mL were classified as vancomycin-mediated, whereas isolates with a vancomycin MIC of greater than or equal to 16. Mu.g/mL were classified as vancomycin-resistant (Clinical and Laboratory Standards Institute/NCCLS. Performance Standards for Antimicrobial Succinity testing. Sixteenth edition information supplement. M100-S16.Wayne, PA: CLSI, 2006).

As used herein, the term "minimum inhibitory concentration" (MIC) refers to the lowest concentration of antibiotic required to inhibit the growth of a bacterial isolate in vitro. A common method for determining the MIC of an antibiotic is to prepare several tubes containing serial dilutions of the antibiotic and then inoculate the bacterial isolate of interest. The MIC of the antibiotic was determined by the lowest concentration tube that showed no turbidity (no growth).

In one aspect is a method of treating a subject having a bacterial infection, the method comprising administering to the subject a compound of formula (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V), or (Va) - (Vc), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the bacterial infection comprises a vancomycin-mediated staphylococcus aureus bacterium. In one embodiment, the vancomycin-mediating staphylococcus aureus bacterium has a MIC of about 4 to about 8 μ g/mL. In another embodiment, the vancomycin-mediating staphylococcus aureus bacterium has a MIC of about 4 μ g/mL. In yet another embodiment, the vancomycin-mediating staphylococcus aureus bacterium has a MIC of about 5 μ g/mL. In a further embodiment, the vancomycin-mediating staphylococcus aureus bacterium has a MIC of about 6 μ g/mL. In still further embodiments, the vancomycin-mediating staphylococcus aureus bacterium has a MIC of about 7 μ g/mL. In one embodiment, the vancomycin-mediating staphylococcus aureus bacterium has a MIC of about 8 μ g/mL.

In another aspect is a method of treating a subject having a bacterial infection, the method comprising administering to the subject a compound of formula (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V), or (Va) - (Vc), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the bacterial infection comprises an vancomycin-resistant staphylococcus aureus bacterium. In one embodiment, the vancomycin-resistant staphylococcus aureus bacterium has a MIC of about 16 μ g/mL. In another embodiment, the vancomycin-resistant Staphylococcus aureus bacterium has a MIC of about ≧ 16 μ g/mL. In yet another embodiment, the anti-vancomycin staphylococcus aureus bacterium has a MIC of about 20 μ g/mL. In a further embodiment, the anti-vancomycin staphylococcus aureus bacterium has a MIC of about 25 μ g/mL.

In one embodiment, conditions treated with the compounds described herein include, but are not limited to: endocarditis, osteomyelitis, meningitis (meningitis), skin and skin tissue infections, urogenital infections, abscesses, and necrotic infections. In another embodiment, the compounds disclosed herein are used to treat conditions such as, but not limited to: diabetic foot infections, bedsores, burn infections, animal or human bite wound infections, synergistic necrotic gangrene (necrotizing gangrene), necrotizing fasciitis, intra-abdominal infections associated with intestinal barrier injury (sleeping), pelvic infections associated with intestinal barrier injury (sleeping), aspiration pneumonia, and post-operative wound infections. In another embodiment, the conditions listed herein are due to, comprise, or result in the presence of VISA and/or VRSA.

Vancomycin-resistant enterococcus

Enterococci are bacteria that normally exist in the human intestine and in the female reproductive tract and are commonly found in the environment. These bacteria sometimes cause infections. In some cases, enterococci have become vancomycin resistant (also known as vancomycin-resistant enterococci or VRE). A common form of vancomycin resistance occurs in enterococcal strains that involve the acquisition of a set of genes that encode proteins that direct peptidoglycan precursors to merge with D-Ala-D-Lac rather than D-Ala-D-Ala. The six different types of vancomycin resistance exhibited by enterococci are: van-A, van-B, van-C, van-D, van-E, and Van-F. In some cases, the Van-A VRE is resistant to both vancomycin and teicoplanin, while in other cases, the Van-B VRE is resistant to vancomycin but sensitive to teicoplanin; in other cases, van-C is partially resistant to vancomycin and sensitive to teicoplanin.

In one aspect is a method of treating a subject having vancomycin-resistant enterococci, the method comprising administering to the subject a compound of formula (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V), or (Va) - (Vc), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the enterococci has developed vancomycin resistance. In one embodiment, the subject has been previously treated with vancomycin for a sustained period of time. In another embodiment, the subject has been admitted to treatment. In yet another embodiment, the subject has a weakened immune system, such as a patient in an intensive care unit or in a cancer or transplant ward. In further embodiments, the subject has undergone a surgical procedure, e.g., an abdominal or thoracic procedure. In yet a further embodiment, the subject has established VRE colonization (colonized). In one embodiment, the subject has already developed an infection using the medical device. In another embodiment, the medical device is a urinary catheter or a central Intravenous (IV) catheter.

In another embodiment is a method of treating a subject having vancomycin-resistant enterococcus, the method comprising administering to the subject a compound of formula (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V), or (Va) - (Vc), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the enterococcus has Van-a resistance.

In another embodiment is a method of treating a subject having vancomycin-resistant enterococcus, the method comprising administering to the subject a compound of formula (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V), or (Va) - (Vc), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the enterococcus has resistance to Van-B.

In another embodiment is a method of treating a subject having vancomycin-resistant enterococcus, the method comprising administering to the subject a compound of formula (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V), or (Va) - (Vc), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the enterococcus has Van-C resistance.

Administration and pharmaceutical compositions

The pharmaceutical compositions described herein comprise a therapeutically effective amount of a compound described herein (i.e., a compound of any one of formulas (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V), or (Va) - (Vc)) formulated with one or more pharmaceutically acceptable carriers. As used herein, the term "pharmaceutically acceptable carrier" means any type of nontoxic, inert solid, semi-solid, or liquid filler, diluent, encapsulating material, or formulation aid. Some examples of substances that can serve as pharmaceutically acceptable carriers are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols, such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; ringer's solution; ethanol and phosphate buffer solution; other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, and coloring, releasing, coating, sweetening, flavoring and perfuming agents, preservatives and antioxidants may also be present in the composition, according to the judgment of the formulator. The pharmaceutical compositions described herein may be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), buccally, or as an oral or nasal spray or liquid aerosol or dry powder formulation for inhalation.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms optionally contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Injectable preparations (e.g., sterile injectable aqueous or oleaginous suspensions) are optionally formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation is optionally a sterile injectable solution, suspension or emulsion in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol. Acceptable carriers and solvents optionally used are water, ringer's solution u.s.p., and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. Any bland fixed oil may be employed for this purpose including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by admixture with a sterilizing agent in the form of a sterile solid composition which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

In order to prolong the effect of the drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This is optionally achieved by using a liquid suspension of crystalline or amorphous material which is poorly water soluble. The rate of absorption of a drug depends on its dissolution rate, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is optionally achieved by dissolving or suspending the drug in an oily vehicle. Injectable depot forms are prepared by forming a microencapsulated matrix of the drug in a biodegradable polymer such as polylactide-polyglycolide. The rate of drug release can be controlled depending on the ratio of drug to polymer and the nature of the particular polymer used. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Long acting injectable formulations are optionally prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds described herein (i.e. compounds of any of formulae (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V) or (Va) - (Vc)) with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol or a suppository wax, which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity and releases the active compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol and silicic acid, b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) dissolution retarders such as paraffin, f) absorption promoters such as quaternary ammonium compounds, g) humectants such as acetyl alcohol and glycerol monostearate, h) adsorbents such as kaolin and bentonite, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms optionally contain buffering agents.

Solid compositions of a similar type optionally employ excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like as fillers in soft and hard-filled gelatin capsules.

Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings known in the pharmaceutical formulating art. They optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the intestinal tract, optionally, in a delayed manner. Examples of embedding components that can be used include polymeric substances and waxes.

The active compound may also be in microencapsulated form with one or more excipients as described above. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, controlled release coatings, and other coatings known in the pharmaceutical formulating art. In such solid dosage forms, the active compound is optionally mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms optionally include, under normal circumstances, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms optionally contain buffering agents. They optionally contain opacifying agents and may also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding components that can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of the compounds described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and optionally any required preservatives or buffers. Ophthalmic preparations, ear drops, and the like are also contemplated.

Ointments, pastes, creams and gels may contain, in addition to an active compound described herein, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, polysiloxanes, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

The compositions described herein are optionally formulated for delivery as a liquid aerosol or an inhalable dry powder. The liquid aerosol formulation is optionally aerosolized primarily to a particle size that can be delivered to the extremities and respiratory bronchioles where bacteria reside in patients with bronchial infections such as chronic bronchitis and pneumonia. Pathogenic bacteria are usually present throughout the airways to the bronchi, bronchioles and lung parenchyma, especially in the distal and respiratory bronchioles. Bacteria may also be present in the alveoli during the exacerbation of the infection. The liquid aerosol and inhalable dry powder formulations are preferably delivered through the entire bronchial tree to the terminal bronchioles, and ultimately to the parenchymal tissue.

The aerosolized formulations described herein are optionally delivered using an aerosol-forming device such as a jet, vibrating perforated plate, or ultrasonic nebulizer, which is preferably selected to allow formation of aerosol particles having a mass median average diameter predominantly between 1 and 5 μ. In addition, the formulation preferably has a balanced osmolarity and chloride concentration and a minimum nebulizable volume that is capable of delivering an effective dose of a compound described herein (i.e., a compound of any of formulas (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V), or (Va) - (Vc)) to the site of infection. Furthermore, the aerosolized formulation preferably does not negatively impair the function of the airways and cause undesirable side effects.

Nebulizing devices suitable for administration of the aerosol formulations described herein include, for example, sprays, vibrating perforated plates, ultrasonic nebulizers, and stimulating dry powder inhalers, which are capable of nebulizing a formulation into aerosol particles having a particle size predominantly in the size range of 1-5 μ. By "predominantly" in this application is meant that at least 70%, but preferably more than 90% of all generated aerosol particles are in the range of 1-5 μ. Jet nebulizers work by breaking up a liquid solution into aerosol droplets with air pressure. Vibrating perforated plate atomizers work by forcing small droplets of solvent through a perforated plate using a sonic vacuum created by rapidly vibrating the perforated plate. Ultrasonic atomizers work by shearing a liquid into piezoelectric crystals of small aerosol droplets. Various suitable devices are available, including, for example, aeroNeb ^TM And AeroDose ^TM Vibrating perforated plate atomizers (AeroGen, inc., sunnyvale, california),Atomizer (Medic-Aid Ltd., west Sussex, england), pariAnd Pari LCJet atomizers (Pari Respiratory Equipment, inc., richmond, virginia) and Aerosonic ^TM (DeVilbiss Medizinische Produkte (Deutschland) GmbH, heiden, germany) and(Omron Healthcare, inc., vernon Hills, illinois) ultrasonic atomizers.

In some embodiments, the compounds described herein (i.e., compounds of any of formulas (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V), or (Va) - (Vc)) are formulated for use as topical powders and sprays that contain, in addition to the compounds described herein, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. Sprays optionally contain conventional propellants such as chlorofluorocarbons.

Transdermal patches have the additional advantage of providing controlled delivery of compounds to the body. Such dosage forms may be prepared by dissolving or dispersing the compound in the appropriate medium. Absorption enhancers may also be used to increase the flux of a compound through the skin. The rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

According to the treatment methods described herein, bacterial infections are treated or prevented in patients, such as humans or lower mammals, by administering to the patient an effective amount of a compound described herein in an amount and for a time necessary to achieve the desired result. A "therapeutically effective amount" of a compound as described herein refers to a sufficient amount of the compound to be able to treat a bacterial infection at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily amount of the compounds and compositions described herein will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the condition being treated and the severity of the condition; the activity of the particular compound employed; the specific composition employed; the age, weight, general health, sex, and diet of the patient; the time of administration, route of administration, and rate of excretion of the particular compound employed; the duration of the treatment; drugs used in combination or together with the particular compound used; and similar factors known in the medical arts.

The total daily dose of a compound described herein (i.e., a compound of any of formulae (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V), or (Va) - (Vc)) administered to a human or other mammal in a single or divided dose can be, for example, an amount of from 0.01 to 50mg/kg body weight, or more usually, from 0.1 to 25mg/kg body weight. A single dose composition may contain such an amount or a factor thereof to constitute a daily dose. Typically, the treatment regimens described herein comprise administering to a patient in need of such treatment from about 10mg to about 2000mg of a compound described herein in a single or multiple doses per day.

Examples

The compounds disclosed herein are prepared by the methods described in the reaction schemes shown below. The procedures provided herein, in combination with the knowledge of organic synthesis chemists having ordinary skill in the art, are in some embodiments used to prepare a full range of compounds as disclosed and claimed herein.

The starting materials and reagents used in the preparation of these compounds are available from commercial suppliers such as Aldrich Chemical co. (Milwaukee, wis.), bachem (Torrance, calif.), or Sigma (st. Louis, mo.), or are prepared by methods known to those skilled in the art following procedures set forth in references such as the following: reagents for Organic Synthesis, vol.1-17, of Fieser and Fieser (John Wiley and Sons, 1991); the Chemistry of Carbon Compounds, volumes 1-5 and supplements, by Rodd (Elsevier Science Publishers, 1989); organic Reactions, vol.1-40 (John Wiley and Sons, 1991), advanced Organic Chemistry by March (John Wiley and Sons, 4 th edition) and Comprehensive Organic Transformations by Larock (VCH Publishers Inc., 1989). These schemes are merely illustrative of the methods by which the compounds disclosed herein can be synthesized in some embodiments, and various modifications to these schemes can be made and will be suggested to one skilled in the art having reference to this disclosure. If desired, the starting materials and intermediates, as well as the final product of the reaction, can be isolated and purified using conventional techniques including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials may be characterized using conventional means including physical constants and spectral data. AcCN/H is generally used as additive with formic acid ₂ O Compound by reverse phase HPLCSeparated into formate. In some cases, purification is performed in the absence of formic acid and the compound is isolated as the free base.

LCMS analysis method was as follows:

LCMS (method 5-95AB, ESI): ESI,5% AcCN/H ₂ O,0.7min; to 95% AcCN/H ₂ O，0.4min；1.5mL/min，Merck RP-18e，2x 25mm。

LCMS (method 10-80AB,2min, ESI): ESI,10% AcCN/H ₂ O (0.04% TFA), 0.9min to 80% AcCN/H ₂ O (0.04% TFA), then hold for 0.6min;1.2mL/min, xtimate C18,3 μm,2.1x 30mm).

LCMS (method 10-80AB,7min, ESI): ESI,10% AcCN/H ₂ O (0.04% TFA), 6min to 80% AcCN/H ₂ O (0.04% TFA), then held for 0.9min;0.8mL/min, xtimate C18,3 μm,2.1x 30mm).

Example A: synthesis of methyl (S) -2-amino-3- (4-methoxy-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) propanoate

Step 1: to a solution of methyl (S) -2- ((tert-butoxycarbonyl) amino) -3- (4-hydroxyphenyl) propionate (100g, 0.323mol) in acetone (2.0L) was added K ₂ CO ₃ (37g, 0.34mol). After addition, meI (32ml, 0.97mol) was added dropwise and the reaction mixture was stirred at room temperature for 72 hours and monitored by TLC. The reaction has not proceeded to completion, so NaOH (0.1 eq) was added to the reaction mixture. After 2 hours, the reaction was complete. The solid was filtered and the solvent was removed. The residue was dissolved in ethyl acetate and washed with H ₂ O wash and extract with ethyl acetate (300mL. Times.3). The combined organic layers were washed with brine, over Na ₂ SO ₄ Drying and concentrating to give (S) -2- ((tert-butoxycarbonyl)Methyl amino) -3- (4-methoxyphenyl) propionate (100g, 95.4%).

Step 2: to a solution of methyl (S) -2- ((tert-butoxycarbonyl) amino) -3- (4-methoxyphenyl) propionate (80 g, 40g x 2 each, run in separate two batches for a total of 259 mmol) in methanol (1.5L in each of two flasks) was added Ag in order ₂ SO ₄ (85g, 272mmol,1/2 addition to each flask) and I ₂ (72g, 283mmol,1/2 was added to each flask). The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. When all of the (S) -methyl 2- ((tert-butoxycarbonyl) amino) -3- (4-methoxyphenyl) propanoate was consumed, 10% (w/w) sodium thiosulfate solution was added until the reaction turned light yellow. The solid was filtered and most of the methanol was evaporated by rotary evaporation. Water and ethyl acetate were added to each batch. The aqueous layer was extracted with ethyl acetate (3x 200mL) and the combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The crude materials were combined for the two batches and purified together by flash silica gel column chromatography (25% then 35% then 40% ethyl acetate in hexanes) to give methyl (S) -2- ((tert-butoxycarbonyl) amino) -3- (3-iodo-4-methoxyphenyl) propionate (97g, 89%).

And 3, step 3: methyl (S) -2- ((tert-butoxycarbonyl) amino) -3- (3-iodo-4-methoxyphenyl) propanoate (92 g, 46g,211mmol in separate runs were dissolved in anhydrous DMSO (1.5L, 1/2 addition per run) under argon, and bis (pinacolato) diboron (80.5g, 317mmol, 1/2 addition per run) and KOAc (103g, 1.05mol, 1/2 addition per run) were added to the solution. The mixture was degassed with argon for 20 min, then Pd (dppf) Cl was added ₂ (4.6g, 6mmol, 1/2 of each portion added). The mixture was degassed 5 times with argon and then kept under argon and heated to 80 ℃ for 3 hours. TLC showed the reaction was complete and the reaction mixture was cooled to room temperature and filtered. The reaction mixture is dissolved in EA and taken up with H ₂ And (4) washing. The aqueous layer was extracted with ethyl acetate (3x 200mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give the crude product. The batches were then combined and purified by flash silica gel column chromatography (3% ethyl acetate in hexane, then 20% to 25% in hexane)Ethyl acetate) were purified together to give methyl (S) -2- ((tert-butoxycarbonyl) amino) -3- (4-methoxy-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) propanoate (70g, 76%).

And 4, step 4: methyl (S) -2- ((tert-butoxycarbonyl) amino) -3- (4-methoxy-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) propanoate (22g, 50.6 mmol) was dissolved in dichloromethane (150 mL) and treated with trifluoroacetic acid (50 mL). The reaction mixture was stirred at room temperature and the reaction was monitored by HPLC. When all starting materials had been consumed, the solvent was evaporated, DCM was added and Na was added ₂ CO ₃ To neutralize the TFA. The mixture was filtered and the solution was concentrated. DCM was added to the concentrated oil and the mixture was cooled at 0 ℃ for 1 hour, at which time the solid precipitate formed was filtered. The filtrate was concentrated to give methyl (S) -2-amino-3- (4-methoxy-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) propionate. This material was used without further purification.

Example B: synthesis of (S) -2- ((tert-butoxycarbonyl) amino) -2- (4-hydroxyphenyl) acetic acid

Step 1: to a stirred mixture of (S) -2-amino-2- (4-hydroxyphenyl) acetic acid (100g, 0.6mol,1 eq.) in a mixture of acetone (400 mL) and water (400 mL) were added di-tert-butyl dicarbonate (130.5g, 0.6mol,1 eq.) and NaHCO ₃ (75.4g, 0.9mol,1.5 equivalents). The mixture was allowed to stir at 25 ℃ overnight. After HPLC showed the reaction was complete, the mixture was acidified with 5% citric acid (pH-3). The mixture was filtered and the filter cake was washed with water and then dried to give (S) -2- ((tert-butoxycarbonyl) amino) -2- (4-hydroxyphenyl) acetic acid (140g, 87.5%). The crude product was used without further purification.

Step 2: to a solution of (S) -2- ((tert-butoxycarbonyl) amino) -2- (4-hydroxyphenyl) acetic acid (45g, 0.17mol) in anhydrous benzene (500 mL) were added paraformaldehyde (75.6 g,0.84mol,5 eq.) and p-toluenesulfonic acid (1.6 g, 8).5mmol,0.05 eq). A Dean-Stark instrument with an attached condenser was then fitted to the top of the flask and the mixture was heated at about 120 ℃ until LC-MS showed the reaction was complete, then the reaction was cooled and the benzene was evaporated. The residue was dissolved in ethyl acetate and taken up with saturated NaHCO ₃ Washed (2x 150mL), then dried over sodium sulfate, and filtered. The solvent was removed to give (S) -tert-butyl 4- (4-hydroxyphenyl) -5-oxooxazolidine-3-carboxylate (36g, 76.5%).

And step 3: (S) -tert-butyl 4- (4-hydroxyphenyl) -5-oxooxazolidine-3-carboxylate (36g, 0.13mol,1 eq) was dissolved in trifluoroacetic acid (75 mL) at 0 deg.C and then treated with triethylsilane (80mL, 4 eq). The mixture was stirred at room temperature overnight. After LC-MS showed the reaction was complete, TFA was evaporated to give (S) -2- (4-hydroxyphenyl) -2- (methylamino) acetic acid, which was used without further purification.

And 4, step 4: the resulting (S) -2- (4-hydroxyphenyl) -2- (methylamino) acetic acid was dissolved in water (85 mL), to which was added solid NaHCO ₃ Until a pH of 7 is reached. The solution was cooled to 0 ℃ and then Na was added ₂ CO ₃ Until a pH of 9 was reached. A solution of di-tert-butyl dicarbonate (28.3g, 1.0 eq.) in THF (75 mL) was added to the mixture. The mixture was allowed to warm to room temperature and stirred overnight. After HPLC showed the reaction was complete, THF was evaporated. The aqueous solution was extracted 2 times with hexane and then acidified with citric acid to pH = 3-4. The acidified solution was then extracted with ethyl acetate (200mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give (S) -2- ((tert-butoxycarbonyl) (methyl) amino) -2- (4-hydroxyphenyl) acetic acid (35 g, 97% over 2 steps).

Example C: synthesis of Compound 101-B

Step 1: to a solution of (S) -2- ((tert-butoxycarbonyl) (methyl) amino) -2- (4-hydroxyphenyl) acetic acid (35g, 0.12mol) in DMF (300 mL) was added triethylamine (18.4 mL,0.14mol,1.1 eq), and HOBt (16.2g, 0.12mol,1 equivalent), ala-OMe HCl (19.5g, 0.14mol,1.1 equivalent) and EDC (26.7g, 0.14mol,1.1 equivalent), and the reaction was stirred overnight. After LC-MS showed the reaction was complete, water and EtOAc were added. The aqueous layer was extracted with EtOAc (3X 150 mL) and saturated NaHCO with 5% citric acid (pH-3) ₃ The combined organic layers were washed (aqueous), water and brine. The combined organic layers were then dried over sodium sulfate, filtered, and concentrated to give methyl (S) -2- ((tert-butoxycarbonyl) (methyl) amino) -2- (4-hydroxyphenyl) acetamido) propionate as a white foam (30g, 65.8%). The crude product was used directly in the next step without further purification.

Step 2: to a solution of methyl (S) -2- ((S) -2- ((tert-butoxycarbonyl) (methyl) amino) -2- (4-hydroxyphenyl) acetamido) propionate (30g, 82mmol) in acetone (400 mL) was added K ₂ CO ₃ (56.6g, 0.41mol,5 eq.) and methyl iodide (20.8mL, 0.41mol,5 eq.) the reaction was stirred at reflux overnight. After LC-MS showed the reaction was complete, the reaction was cooled to room temperature and the mixture was filtered. The filtrate was concentrated and the residue was dissolved in water and ethyl acetate. The aqueous phase was extracted with EtOAc (3x 150mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give methyl (S) -2- ((tert-butoxycarbonyl) (methyl) amino) -2- (4-methoxyphenyl) acetamido) propionate as a white foam (28g, 90%).

And 3, step 3: to a solution of methyl (S) -2- ((S) -2- ((tert-butoxycarbonyl) (methyl) amino) -2- (4-methoxyphenyl) acetamido) propionate (85g, 0.22mol,1 eq) in methanol (1000 mL) was added Ag in sequence ₂ SO ₄ (72.6 g,0.23mol,1.05 eq.) and I ₂ (59.6g, 1.05 eq.). After LC-MS showed the reaction was complete, a 10% (w/w) solution of sodium thiosulfate was added until the reaction turned pale yellow. Most of the methanol was evaporated by rotary evaporation, then water and ethyl acetate were added. The aqueous layer was extracted with ethyl acetate (3x 300mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to give methyl (S) -2- ((tert-butoxycarbonyl) (methyl) amino) -2- (3-iodo-4-methoxyphenyl) acetamido) propionate (100g, 88.5%).

And 4, step 4: to methyl (S) -2- ((tert-butoxycarbonyl) (methyl) amino) -2- (3-iodo-4-methoxyphenyl) acetamido) propionate (25g, 49.4mmol,1 eq) in THF (300 mL) was added 0.2M LiOH (500ml, 98.8mmol,2 eq). The solution was stirred until TLC showed that all starting material had been consumed. 5% citric acid (pH-3) was added to pH-3, and THF was then evaporated by rotary evaporation. The aqueous layer was extracted with EtOAc (3X 100mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give (S) -2- ((tert-butoxycarbonyl) (methyl) amino) -2- (3-iodo-4-methoxyphenyl) acetamido) propanoic acid (23g, 94.6%) which was used without further purification.

And 5: to a solution of methyl (S) -2-amino-3- (4-methoxy-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) propanoate (6.5g, 19.4mmol,1 equivalent) and (S) -2- ((S) -2- ((tert-butoxycarbonyl) (methyl) amino) -2- (3-iodo-4-methoxyphenyl) acetamido) propanoic acid (10g, 20.3mmol,1.05 equivalent) in acetonitrile DMF (2.2. The reaction was stirred at room temperature overnight. After LC-MS showed the reaction was complete, dilute citric acid (pH-3) was added and the aqueous layer was extracted with EtOAc (3X 150mL). The combined organic layers were then washed with saturated NaHCO ₃ The solution was washed with brine and dried over sodium sulfate. The mixture was filtered and the filtrate was concentrated to give a crude product of methyl (6S, 9S, 12S) -6- (3-iodo-4-methoxyphenyl) -12- (4-methoxy-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) -2, 5, 9-tetramethyl-4, 7, 10-trioxo-3-oxa-5, 8, 11-triazatridecane-13-oate, which was used without further purification.

And 6: (6S, 9S, 12S) -6- (3-iodo-4-methoxyphenyl) -12- (4-methoxy-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) -2, 5, 9-tetramethyl-4, 7, 10-trioxo-3-oxa-5, 8, 11-triazatridecane-13-oic acid methyl ester (1lg, 19.4mmol,1 eq.) and NaHCO ₃ (16.3g, 0.19mol) was sealed in a flask with a condenser and placed under argon atmosphere. Then, DMF (600 mL) in a round flask was purged several times by cycling with vacuum and Ar, and then PdCl was added to the DMF ₂ (dppf) (3.3g, 4.5mmol). The reactionThe solution was then degassed with Ar for 15 minutes. Then, pdCl dissolved in DMF ₂ (dppf) solution was transferred via syringe to a container containing substrate and NaHCO ₃ In a flask of (1). The resulting mixture was subjected to several cycles of vacuum and Ar, then heated to 120 ℃ overnight. After LCMS showed the reaction was complete, DMF was evaporated under vacuum. The crude material was subjected to brief column chromatography (40% EA in PE) to remove most of the Pd species (species) and then purified by preparative HPLC to give compound 101-A (2.1g, 19.5% over 2 steps).

And 7: to a stirred solution of compound 101-A (2.1g, 3.78mmol) in DCM (25 mL) was added TFA (2 mL). The reaction was monitored by TLC and when starting material was consumed, the solvent was evaporated under vacuum. The residue was then dissolved in EtOAc and the organic layer was washed with saturated NaHCO ₃ (10 mL), dried over sodium sulfate and concentrated to give compound 101-B (1.7g, 98.8%). MS (ESI) M/z 456.2 (M + H) ⁺ 。

Example D: synthesis of Compound 101-G

Step 1: in N ₂ To a solution of compound 101-B (5.0 g,11.0 mmol) in EtSH (116mL, 1.61mol) at 0 deg.C was slowly added AlBr ₃ (165mL, 165mmol). The mixture was stirred for 18h. The volatiles were removed under reduced pressure and the residue was quenched with water (50 mL), which was further washed with DCM (20mL × 3). The aqueous layer was purified by preparative HPLC (acetonitrile 1-20%/0.1% aqueous TFA) to give compound 101-C as a white solid (4.5g, 99.2% yield).

Step 2: to compound 101-C (4.7g, 8.9mmol) in 1, 4-dioxane/H ₂ To a solution in O (9. Then a solution of Cbz-OSu (6.66g, 26.7 mmol) dissolved in 1, 4-dioxane (50 mL) was added. After stirring for 1h, naOH (1.07g, 26.7 mmol) was added to the reaction followed by MeOH (60 mL). The resulting mixture was stirred for 20 minutes. Then dilute citric acid (10% v/v,50 mL) was added to the reactionThe aqueous layer was extracted with EtOAc (3X 150mL), and the combined organic layers were washed with brine (3X 100mL), over Na ₂ SO ₄ Dried and concentrated to give the crude product. The residue was diluted with DCM (50 mL) and the suspension was filtered to give the desired compound (3.2 g). The DCM phase was concentrated and the residue was purified on a silica gel column (eluting with 10-20% methanol in EtOAc) to give the desired compound (1.0 g). The batches were combined to give compound 101-D as a white solid (4.2g, 86.1% yield).

And step 3: to compound 101-D (4.3g, 7.85mmol) was added a solution of 1.25M HCl in MeOH (128 mL) and the reaction was stirred at 0 ℃. The volatiles were removed to give compound 101-E as a white solid (4.15g, 94.1% yield), which was used directly in the next step.

And 4, step 4: to compounds 101-E (3.9g, 6.94mmol) and K at 0 deg.C ₂ CO ₃ (14.4 g, 104mmol) to a solution in DMF (50 mL) was added tert-butyl 2-bromoethylcarbamate (15.6 g,69.5 mmol). The mixture was stirred at room temperature for 48h. The mixture was filtered and the filtrate was diluted with EtOAc (500 mL). The EtOAc layer was washed with brine (2X 400mL) over Na ₂ SO ₄ Drying, concentration, and purification by silica gel chromatography (solvent gradient: 0-60% EtOAc in petroleum ether) afforded compound 101-F as a white solid (4.8 g,81.5% yield).

And 5: to a solution of compounds 101-F (4.8g, 5.7 mmol) in MeOH (100 mL) at room temperature was added carbon-supported 10% Pd/C (1.26g, 1.18mmol). The reaction mixture was stirred under hydrogen atmosphere (15 psi) at the same temperature for 1h. The filtrate was then concentrated to give compound 101-G (4.0G, 99% yield) as a white solid.

Example E: synthesis of Compounds 101-I, 101-J, 101-K, and 101-L

Step 1: to a solution of compound 101-G (3.5g, 4.9mmol) and (S) -2- (((benzyloxy) carbonyl) amino) -6- ((tert-butoxycarbonyl) amino) hexanoic acid (2.4g, 6.4mmol) in DCM (30 mL) at 0 deg.CHATU (3.7g, 9.8mmol) and DIPEA (1.9g, 14.7mmol) were added. The resulting mixture was gradually warmed to room temperature and stirred for 2h. The reaction mixture was diluted with DCM (100 mL) and washed with brine (100mL × 3). Subjecting the organic layer to Na ₂ SO ₄ Drying, concentration, and purification of the residue by silica gel column chromatography gave compound 101-H as a white solid (5.3g, 99% yield).

Step 2: using compound 101-H (1.5g, 1.4 mmol), the hydrogenation step was carried out using example D to give compound 101-I as a white solid (1.2g, 93% yield). LCMS (method 5-95AB, ESI): t is t _R ＝0.711，[M+H] ⁺ ＝942.6。

Compound 101-J was prepared from compound 101-G and (S) -2- (((benzyloxy) carbonyl) amino) -5- ((tert-butoxycarbonyl) amino) pentanoic acid as described above. LCMS (methods 5-95AB, ESI): t _R ＝0.841,[M+H] ⁺ ＝928.4。

Compound 101-K was prepared from compound 101G and (S) -2- (((benzyloxy) carbonyl) amino) -4- ((tert-butoxycarbonyl) amino) butanoic acid as described above. LCMS (method 5-95AB, ESI): t _R ＝0.838,[M+H] ⁺ ＝914.5。

Compound 101-L was prepared from compound 101G and (S) -2- (((benzyloxy) carbonyl) amino) -3- ((tert-butoxycarbonyl) amino) propionic acid as described above. LCMS (methods 5-95AB, ESI): t _R ＝0.833,[M+H] ⁺ ＝900.5。

Example F: synthesis of 3- ((tert-butoxycarbonyl) (decyl) amino) propionic acid

To a solution of methyl acrylate (2.2g, 26mmol) in THF (20 mL) at 0 ℃ was added a solution of deca-1-amine (6 g, 38mmol) in THF (20 mL). The reaction mixture was stirred at 30 ℃ for 48h. The resulting solution was concentrated to give methyl 3- (decylamino) propionate (6.4 g).

Step 2: to crude methyl 3- (decylamino) propionate (6.4g, 15mmol) and Et at 0 deg.C ₃ Boc was added dropwise to a solution of N (4g, 40mmol) in DCM (30 mL) ₂ A solution of O (5.7g, 26mmol) in DCM (20 mL). The reaction mixture was then gradually warmed to 30 ℃ and stirred for 18h. After the reaction was complete, H was added ₂ O (50 mL), and the resulting aqueous layer was further extracted with DCM (50 mL. Times.2). The combined organic layers were concentrated and the residue was purified on a silica gel column (PE/EtOAc =50/1 to 20/1) to give methyl 3- ((tert-butoxycarbonyl) (decyl) amino) propionate as a colorless oil (6.5g, 73%).

And step 3: to a solution of methyl 3- ((tert-butoxycarbonyl) (decyl) amino) propionate (8.2g, 23.9mmol, crude) in EtOH (40 mL) at 0 deg.C was added LiOH (1.15g, 48mmol) in H ₂ Solution in O (20 mL). The reaction mixture was then gradually warmed to 30 ℃ and stirred for 18h. After the reaction was complete, etOH was removed under reduced pressure. The remaining aqueous solution was then adjusted to pH = 2-3 with 6N HCl, followed by extraction with EtOAc (50 mL × 3). The combined EtOAc layer was washed with Na ₂ SO ₄ Dried and concentrated to give 3- ((tert-butoxycarbonyl) (decyl) amino) propionic acid (7g, 88.6%) as a colourless oil. ¹ H NMR(400MHz,CDCl ₃ )δ3.47-3.43(t,J＝6.8Hz,2H),3.19-3.15(t,J＝7.2Hz,2H),2.61(brs,2H),1.51-1.39(m,11H),1.24-1.22(m,14H),0.88-0.84(t,J＝6.8Hz,3H)。

Example G: synthesis of Compound 101

Step 1: example E was applied to compound 101-I (1.0g, 1.27mmol) and 3- ((tert-butoxycarbonyl) (decyl) amino) propionic acid (504mg, 1.53mmol) to give compound 101-M as a white solid (1.3g, 82% yield).

And 2, step: to compound 101-M (1.3g, 1.04mmol) in THF/H at 0 deg.C ₂ To a solution in O (40ml, 1). The mixture was gradually warmed to room temperature and stirred for 1h. Most of the THF was removed under reduced pressure and the resulting mixture was adjusted to pH =5 with saturated citric acid, which was further extracted with EtOAc (30mL x 3). The combined organic layers were washed with brine (100 mL) and Na ₂ SO ₄ Drying and concentration gave compound 101-N as a white solid (1.1g, 86% yield).

And 3, step 3 and step 4: to a solution of compound 101-N (180mg, 0.15mmol), aminoacetonitrile hydrochloride (31mg, 0.33mmol), and DIPEA (38mg, 0.29mmol) in DCM/DMF (3 ml, 2) at 0 ℃ was added HATU (56mg, 0.15mmol) while stirring. The resulting mixture was stirred at room temperature for 1h. Most of the DCM was removed under reduced pressure and the residue was poured into water (10 mL) and extracted with EtOAc (20mLx 3). The combined organic layers were washed with brine (50 mL) and Na ₂ SO ₄ Drying and concentration to give a residue, which was purified by flash chromatography to give compound 101-O as a white solid (140mg, 76%).

Compound 101-O (130mg, 0.10mmol) was added to HFIP (6.5 mL) containing 5% TFA, and the mixture was stirred at room temperature for 2h. The volatiles were removed under reduced pressure and the resulting crude was redissolved with DMF (5 mL) and taken up with solid NaHCO ₃ And (4) neutralizing. The filtrate was then purified by HPLC to give compound 101 as a white solid (54mg, 60% yield). LCMS (methods 5-95AB, ESI): t _R ＝0.710,M+H ⁺ ＝877.6； ¹ HNMR(400MHz,MeOH-d4)δ8.51(brs,2H,HCOOH),7.28-7.25(m,2H),7.20(d,J＝8Hz,1H),7.18(d,J＝8Hz,1H),6.90(brs,1H),6.84(brs,1H),6.37(s,1H),4.82-4.79(m,3H),4.28-4.20(m,4H),4.21(s,2H),3.33-3.26(m,2H),3.26-3.16(m,5H),3.16-3.12(m,1H),3.11-2.95(m,2H),2.95-2.91(m,2H),2.90(s,3H),2.73-2.66(m,2H),1.75-1.65(m,6H),1.64-1.51(m,1H),1.50-1.16(m,18H),0.92(t,J＝6.8Hz,3H)。

Example H: synthesis of 4'- (tert-butyl) -3-methyl- [1,1' -biphenyl ] -4-carboxylic acid

Step 1: to a solution of 4-tert-butylboronic acid (151.6mg, 0.85mmol) in 1, 4-dioxane (5 mL) and water (1 mL) were added potassium carbonate (181.0mg, 1.31mmol), 1' -bis (diphenylphosphino) ferrocene palladium dichloride (47.9mg, 0.07mmol), and methyl 4-bromo-2-methylbenzoate (150.0mg, 0.65mmol). The reaction mixture is stirred under N ₂ Stirred at 100 ℃ for 2h and concentrated. The residue was taken up in EtOAc (20 mL) and washed with water (20mL. Times.2) and brine (20 mL). The organic layer was MgSO ₄ Dried and concentrated. The residue was purified by flash column chromatography (5% etoac in petroleum ether, rf = 0.7) to give 4- (4-tert-butylphenyl) -2-methyl-benzoic acid methyl ester as a colorless oil (120mg, 64.9% yield). LCMS (5-95AB _1.5min); t is t _R ＝0.972min,[M+H] ⁺ ＝281.9。

And 2, step: methyl 4- (4-tert-butylphenyl) -2-methyl-benzoate (120.0 mg, 0.430mmol) was hydrolyzed to give 4'- (tert-butyl) -3-methyl- [1,1' -biphenyl ] -4-carboxylic acid as a white solid (100mg, 0.3726mmol,87.7% yield).

Example I: synthesis of methyl 4- (5-isobutylpyrazin-2-yl) -2-methylbenzoate

To a solution of 2, 5-dibromopyrazine (200.0mg, 0.84mmol) in toluene (5 mL) and water (1 mL) were added potassium carbonate (348.6 mg, 2.52mmol), methyl 2-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoate (232.2mg, 0.84mmol), and tetrakis (triphenylphosphine) palladium (0) (97.2mg, 0.08mmol). The reaction mixture was stirred at 80 ℃ for 16h and filtered. The filtrate is treated with H ₂ O (20 mL) was diluted and extracted with EtOAc (40mL. Times.2). The combined organic layers were washed with water (80)mL x 3) and brine (80 mL), over Na ₂ SO ₄ Dried and concentrated. The residue was purified by preparative TLC (7.5% etoac in petroleum ether) to give methyl 4- (5-bromopyrazin-2-yl) -2-methylbenzoate as a white solid (150mg, 58.1% yield). ¹ H NMR(400MHz,CDCl ₃ ):δ8.81(s,1H),8.75(d,J＝1.2Hz,1H),8.04(d,J＝8.4Hz,1H),7.88(s,1H),7.85(d,J＝8.4Hz,1H),3.93(s,3H),2.70(s,3H)。

To a solution of isobutylboronic acid (99.6mg, 0.98mmol) in toluene (3 mL) and water (0.3 mL) were added tetrakis (triphenylphosphine) palladium (0) (56.4 mg, 0.05mmol), potassium carbonate (202.5mg, 1.47mmol), and methyl 4- (5-bromopyrazin-2-yl) -2-methylbenzoate (150.0 mg, 0.49mmol). The reaction mixture was stirred at 100 ℃ for 16h and filtered. The filtrate is treated with H ₂ O (20 mL) was diluted and extracted with EtOAc (40mL x 2). The combined organic layers were washed with water (80mL x 3) and brine (80 mL), over Na ₂ SO ₄ Dried and concentrated. The residue was purified by preparative TLC (9.5% etoac in petroleum ether, rf = 0.4) to give methyl 4- (5-isobutylpyrazin-2-yl) -2-methylbenzoate as a yellow oil (52mg, 37.4% yield). LCMS (method 5-95AB, ESI): t _R ＝0.956min,[M+H] ⁺ ＝284.9。

Example J: synthesis of ethyl 2-bromo-4-methylpyrimidine-5-carboxylate

To ethyl 2-amino-4-methylpyrimidine-5-carboxylate (4.0 g, 22mmol) in CHBr ₃ To the solution (66 mL) was added isoamyl nitrite (44 mL), and the mixture was stirred at 85 ℃ for 4h. The volatiles were removed and the residue was taken up in EtOAc (100 mL) and washed with brine (100mL x 2). The organic layer was washed with Na ₂ SO ₄ Dried, concentrated, and the residue was purified by silica gel flash column to give ethyl 2-bromo-4-methylpyrimidine-5-carboxylate as a white solid (3.0 g,55.5% yield). ¹ H NMR(400MHz,CDCl ₃ ):δ8.93(s,1H),4.41(q,J＝7.2Hz,2H),2.82(s,3H),1.41(t,J＝7.0Hz,3H)。

Example K: synthesis of 2-fluoro-4-octylbenzoic acid

A mixture of methyl 4-bromo-2-fluorobenzoate (500.0mg, 2.15mmol), oct-1-yne (702.9mg, 6.44mmol), bis (triphenylphosphine) palladium (II) dichloride (75.3mg, 0.11mmol), and copper (I) iodide (20.4mg, 0.11mmol) in triethylamine (9.83mL, 70.9mmol) was stirred under nitrogen at 100 ℃ for 2h. LCMS (5-95 AB/1.5 min): tR =1.006min, [ M + H ] ⁺ 262.9 showed a DP of 60%. The reaction was quenched with water (15 mL) and extracted with dichloromethane (3X 25 mL). The combined organic extracts were washed with brine (2X 25 mL) and dried over anhydrous Na ₂ SO ₄ Dried and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (eluting with 5% ethyl acetate in petroleum ether, rf = 0.5) to give methyl 2-fluoro-4- (oct-1-yn-1-yl) benzoate as a brown solid (550mg, 97.7% yield). LCMS (5-95AB (u 1.5 min): t) _R ＝1.006min,[M+H] ⁺ 262.9。

To a solution of methyl 2-fluoro-4- (oct-1-yn-1-yl) benzoate (550.0 mg,2.1 mmol) in methanol (25 mL) was added 10% palladium on carbon (111.56mg, 0.10 mmol). The mixture was stirred under hydrogen (40 psi), 30 ℃ for 16h. The reaction was filtered through a pad of Celite and concentrated. The residue was purified by silica gel column chromatography (eluting with petroleum ether/ethyl acetate 100. LCMS (5-95AB (u 1.5 min): t) _R ＝1.033min,[M+H] ⁺ 266。

To a solution of methyl 2-fluoro-4-octylbenzoate (500.0 mg, 1.88mmol) in methanol (5 mL) was added NaOH (1000.0 mg, 25mmol) in water (5 mL). The mixture was stirred at 100 ℃ for 2h, cooled to room temperature, and hydrochloric acid (1.0M) was added until pH =3-4. The mixture was extracted with ethyl acetate (3X 30 mL). The combined organic extracts were washed with brine (2 × 30 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated to give 2-fluoro-4-octylbenzoic acid (450mg 5% yield). ¹ H NMR(400MHz,CDCl ₃ ):δ7.94(t,J＝8.0Hz,1H),7.06(d,J＝8.4Hz,1H),6.99(d,J＝12.0Hz,1H),2.66(t,J＝7.4Hz,2H),1.65-1.62(m,2H),1.31–1.28(m,10H),0.89(t,J＝6.8Hz,3H)。

Example L: synthesis of 4- (tert-butyl) -2- (difluoromethyl) benzoic acid

To a dry ice acetone bath were added 4-tert-butyl-2-methyl-benzoic acid (192.0mg, 1mmol), sodium persulfate (1.19g, 4.99mmol), and Selectfluor (1.77g, 4.99mmol) in acetonitrile (4.77g, 4.99mmol)

mL) and water (4 mL) was added silver nitrate (17.0 mg,0.10 mmol). The mixture was degassed by three freeze pump-thaw cycles and heated at 80 ℃ for 16h. Water (10 mL) was added, and the mixture was extracted with EtOAc (15mL. Times.2). The combined organic layers were concentrated and the residue was purified by preparative TLC (petroleum ether/EtOAc/HOAc 2/1/0.01, rf = 0.3) to give 4- (tert-butyl) -2- (difluoromethyl) benzoic acid as a white solid (75mg, 32.9% yield). Example M: synthesis of 3-butyl-2-methylbenzoic acid

Step 1: to a mixture of 3-bromo-2-methylbenzoic acid (5.0 g, 23mmol) in MeOH (80 mL) at 20 deg.C was added SOCl ₂ (11.0 g, 93mmol). The mixture was stirred at 70 ℃ for 1.5h. The volatiles were removed and the residue was taken up in EtOAc (100 mL), which in turn was taken up in saturated NaHCO ₃ And a brine wash (100 mL each). The EtOAc layer was washed with Na ₂ SO ₄ Drying, concentration and purification of the residue by flash column chromatography gave methyl 3-bromo-2-methylbenzoate as a red solid (5.3g, 99% yield).

Step 2: methyl 3-bromo-2-methylbenzoate (500mg, 2.2mmol), n-butylboronic acid (890mg, 8.7mmol), and Pd (PPh) ₃ ) ₄ (252mg，0.22mmol) and K ₂ CO ₃ A solution of (905mg, 6.6 mmol) in toluene (20 mL) was stirred at 100 ℃ for 4h. After filtration, the filtrate was washed with brine (20mL. Times.3) and Na ₂ SO ₄ Dried and concentrated. The residue was purified by HPLC to give methyl 3-butyl-2-methylbenzoate as a colorless oil (120mg, 27% yield). LCMS (methods 5-95AB, ESI): t _R ＝0.871,[M+H] ⁺ ＝206.9。

And step 3: methyl 3-butyl-2-methylbenzoate (120mg, 0.58mmol) was subjected to the ester hydrolysis method with NaOH as previously described (example H) to give 3-butyl-2-methylbenzoic acid as a white solid (110mg, 98% yield).

Example N: synthesis of methyl 2- [ (E) -3-tert-butoxy-3-oxo-prop-1-enyl ] -4-octyl-benzoate

Step 1: to a solution of methyl 2-chloro-4-octyl-benzoate (350.0mg, 1.24mmol) in 1, 4-dioxane (2 mL) was added tert-butyl acrylate (174.5mg, 1.36mmol), bis (tri-tert-butylphosphine) palladium (0) (9.5mg, 0.02mmol), tris (dibenzylideneacetone) dipalladium (0) (34.0mg, 0.04mmol), and N, N-dicyclohexylmethylamine (265.9mg, 1.36mmol). Placing the mixture in N ₂ Stirred at 25 ℃ for 16h and filtered. The filtrate was diluted with water (10 mL) and extracted with EtOAc (10mL. Times.3). The combined organic layers were washed with Na ₂ SO ₄ Dried, filtered, and concentrated. The residue was purified by preparative TLC (10% etoac in petroleum ether, rf = 0.7) to give 2- [ (E) -3-tert-butoxy-3-oxo-prop-1-enyl) as a yellow oil]-4-octyl-benzoic acid methyl ester (290mg, 62.6% yield). ¹ H NMR(400MHz,CDCl ₃ ):δ8.35(d,J＝16.0Hz,1H),7.86(d,J＝8.0Hz,1H),7.39(s,1H),7.22(d,J＝8.0Hz,1H),6.23(d,J＝15.9Hz,1H),3.91(s,3H),2.64(t,J＝7.8Hz,2H),1.65-1.55(m,2H),1.54(s,9H),1.33-1.22(m,10H),0.88(t,J＝6.6Hz,3H)。

And 2, step: to 2- [ (E) -3-tert-butoxy-3-oxo-prop-1-enyl]-4-octyl-benzoic acid methyl ester (290.0 mg)0.77 mmol) in 1, 2-dichloroethane (2 mL) was added trimethyltin hydroxide (1400.2 mg, 7.74mmol) and the mixture was stirred at 80 ℃ for 16h. LCMS (5-95 AB/1.5 min): t _R ＝1.158min,[M+Na]+383.1 shows 36% DP and 51% SM. Mixing the mixture with 0.1N KHSO ₄ Diluted (5 mL) and extracted with EtOAc (10mL × 3). The combined organic layers were washed with brine, over Na ₂ SO ₄ Dried, filtered, and concentrated. The residue was purified by preparative TLC (50% etoac in petroleum ether, rf = 0.2) to give 2- [ (E) -3-tert-butoxy-3-oxo-prop-1-enyl) as a yellow solid]-4-octyl-benzoic acid (80mg, 28.7% yield).

Example O: synthesis of Compound 102

Step 1: to a solution of compound 101-E (800mg, 1.76mmol) in DMF (15 mL) was added (S) -2- (((benzyloxy) carbonyl) amino) -6- ((tert-butoxycarbonyl) amino) hexanoic acid (735mg, 1.93mmol), 3- [ (E) -ethylazo ] -N, N-dimethyl-propan-1-amine hydrochloride (946.77mg, 5.27mmol), 1-hydroxybenzotriazole (711.94mg, 5.27mmol) and N, N-diisopropylethylamine (681mg, 5.27mmol). The mixture was stirred at 30 ℃ for 16h. TLC showed starting material depletion (50% ethyl acetate in petroleum ether, rf = 0.5). The mixture was poured into water (30 mL). The precipitate was filtered, washed with water, redissolved in methanol, and concentrated to give compound 102-a as a yellow solid (1200mg, 1.45mmol,83.5% yield).

Step 2: to a solution of compound 102-A (1200 mg, 1.47mmol) in methanol (15 mL) was added Pd/C (200.0 mg, 1.47mmol), and the mixture was stirred under hydrogen (50 psi), 30 ℃ for 16h. The catalyst was filtered off and the filtrate was concentrated to give compound 102-B as a white solid (900mg, 1.12mmol,81.6% yield). LCMS (5-95AB (u 1.5min): u 1500): t _R ＝0.782min,[M+H] ⁺ 684.4。

And step 3: a mixture of 4- (4-butylphenyl) benzoic acid (200mg, 0.79mmol) in thionyl chloride (5.0 mL) at 60 deg.CStirring for 16h. The solution was concentrated and dissolved in dichloromethane (2 mL). To a solution of compound 102-B (500mg, 0.73mmol) and triethylamine (74mg, 0.73mmol) in dichloromethane (15 mL) was added a solution of the above 4- (4-butylphenyl) benzoyl chloride in dichloromethane. The reaction mixture was stirred at 25 ℃ for 3h. LCMS showed complete depletion of all starting material. TLC (10% dichloromethane in methanol, rf = 0.4). The reaction was concentrated to dryness and the residue was purified by flash column chromatography (eluting with 5% dichloromethane in methanol). The desired fractions were concentrated to give compound 102-C as a white solid (650 mg,0.71mmol,96.6% yield). LCMS (5-95 AB/1.5 min): t _R ＝0.951min,[M+H] ⁺ 921.4. Alternatively, the conditions in example 4 can be used, using 4 '-butyl- [1,1' -biphenyl ]4-formic acid.

And 4, step 4: a mixture of aluminum chloride (2.8g, 21.19mmol) and 1-dodecanethiol (4.3g, 21.19mmol) in dichloromethane (12 mL) was stirred at 26 ℃ for 5min, then cooled to 0 ℃. Then, compound 102-C (650 mg, 0.71mmol) was slowly added. The solution was stirred at 26 ℃ for 2h. LCMS showed complete depletion of all starting material. The solution was quenched with 1N hydrochloric acid and filtered. The filter cake was dried to give crude compound 102-D as a white solid. LCMS (5-95 AB/1.5 min): t _R ＝0.828min,[M+H] ⁺ ＝778.4。

And 5: a solution of compound 331-D (500mg, 0.64mmol) and thionyl chloride (229mg, 1.93mmol) in methanol (10 mL) was stirred at 60 ℃ for 1h. LCMS showed complete depletion of all starting material. The solution was concentrated to give compound 102-E as a yellow solid (500mg, 0.63mmol,98.2% yield). LCMS (5-95 AB/1.5 min): t _R ＝0.856min,[M+H] ⁺ ＝792.8。

And 6: to a solution of compound 102-E (500mg, 0.63mmol) and sodium bicarbonate (10.6 mg, 0.13mmol) in 1, 4-dioxane (6 mL) and water (2 mL) was added di-tert-butyl dicarbonate (138mg, 0.63mmol). LCMS showed complete depletion of all starting material. TLC (5% dichloromethane in methanol, rf = 0.2). The reaction was concentrated to dryness and the residue was taken up in ethyl acetate (50 mL). It was mixed with water (20mL x 2) Brine (10 mL) was washed, dried (sodium sulfate), and concentrated. The crude product was purified by flash column chromatography (eluting with 5% dichloromethane in methanol). The desired fraction was concentrated in vacuo to afford compound 102-F as a white solid (500mg, 0.56mmol,88.8% yield). LCMS (5-95 AB/1.5 min): t _R ＝1.048min,[M+H] ⁺ ＝892.4。

Example P: synthesis of Compound 103

To compound 103-A (120mg, 0.13mmol) and Et at 0 deg.C ₃ To a solution of N (53. Mu.L, 0.38 mmol) in DCM (5 mL) was added trimethylsilyl isocyanate (44mg, 0.38mmol). The resulting mixture was allowed to warm to room temperature while stirring and stirred at the same temperature for 2h. The volatiles were removed and the residue was purified by preparative TLC to give compound 103 as a white solid (90mg, 72% yield). LCMS (methods 5-95AB, ESI) RT =0.759, [ M + H [ ]] ⁺ ＝991.7。

Example Q: synthesis of (S) -2- (((benzyloxy) carbonyl) amino) -4- (N-methyl-2-nitrophenylsulfonamide) butyric acid

Step 1: to a solution of (S) -4-amino-2- (((benzyloxy) carbonyl) amino) butyric acid (2000.0 mg, 7.93mmol) in N, N-dimethylformamide (50 mL) were added dropwise 2-nitrobenzenesulfonyl chloride (0.46mL, 23.78mmol) and triethylamine (4.42mL, 31.71mmol). The reaction mixture was stirred at 25 ℃ for 12h and filtered. To the filtrate was added water (50 mL), and the resulting precipitate was collected to give (S) -2- (((benzyloxy) carbonyl) amino) -4- (2-nitrophenylsulfonylamino) butyric acid (2000mg, 4.5723mmol,57.7% yield) as a white solid. LCMS (methods 5-95AB, ESI) RT =0.790min, [ M + H [ ] ] ⁺ ＝437.0。

And 2, step: to (S) -2- (((benzyloxy) carbonyl) amino) -4- (2-nitrophenylsulfonamido) butanoic acid(800.0 mg, 1.83mmol) to a solution in N, N-dimethylformamide (5 mL) was added iodomethane (4.59mL, 73.43mmol) and potassium carbonate (758.3mg, 5.49mmol) dropwise. The mixture was stirred at 25 ℃ for 14H, using H ₂ O (20 mL) was diluted and extracted with EtOAc (35mL x 3). The combined organic layers were washed with water (30mL. Times.4) and brine (40 mL) and washed with Na ₂ SO ₄ Dried and concentrated. The residue was purified by flash column chromatography (30% etoac in petroleum ether, rf = 0.3) to give methyl (S) -2- (((benzyloxy) carbonyl) amino) -4- (N-methyl-2-nitrophenylsulfonamido) butyrate (610mg, 71.7% yield) as a yellow oil. LCMS (methods 5-95AB, ESI) RT =0.813min, [ M + H [ ]] ⁺ ＝466.1。

And step 3: the NaOH hydrolysis of the ester yielded (S) -2- (((benzyloxy) carbonyl) amino) -4- (N-methyl-2-nitrophenylsulfonamido) butyric acid.

Example R: synthesis of (S) -2- (((benzyloxy) carbonyl) amino) -4- ((tert-butyldimethylsilyl) oxy) butyric acid

To a mixture of benzyl chloroformate (930.84mg, 5.46mmol) and sodium bicarbonate (705.25mg, 8.39mmol) in water (10 mL) was added (2S) -2-amino-4-hydroxy-butyric acid (500.0 mg, 4.2mmol), and stirred under nitrogen at 15 ℃ for 3 hours. The reaction mixture was washed with ethyl acetate (20mL × 3), acidified to pH 4 at 0 ℃ using 2N HCl (about 20 mL), and extracted with ethyl acetate (30mL × 3). The combined organic layers were dried over sodium sulfate and concentrated to give (2S) -2- (benzyloxycarbonylamino) -4-hydroxy-butanoic acid as a colorless oil (450mg, 1.7769mmol,42.3% yield). It was used in the next step without further purification.

To a mixture of (2S) -2- (benzyloxycarbonylamino) -4-hydroxy-butyric acid (450.0mg, 1.78mmol) and triethylamine (395.57mg, 3.91mmol) in N, N-dimethylformamide (8 mL) was added tert-butyldimethylchlorosilane (401.72mg, 2.67mmol) at 0 ℃ and stirred at 15 ℃ for 1 hour. The reaction mixture was diluted with water (30 mL) and sodium carbonate (5 g) was added.The resulting mixture was washed with ethyl acetate (15mL × 3). The aqueous phase was acidified to pH 4 using 2N HCl (ca. 20 mL) at 0 ℃ and extracted with ethyl acetate (30mL. Times.3). The combined organic layers were dried over sodium sulfate and concentrated to give (S) -2- (((benzyloxy) carbonyl) amino) -4- ((tert-butyldimethylsilyl) oxy) butanoic acid as a colorless oil (450mg, 1.2245mmol,68.9% yield). It was used in the next step without further purification. LCMS (methods 5-95AB, ESI): t _R ＝0.833min,[M+Na] ⁺ ＝389.9。

Example S: synthesis of (S) -2-decanamidopentanoic acid

To a stirred solution of decanoyl chloride (500mg, 2.6 mmol) in THF (5 mL) at 0 deg.C was added (S) -2-aminopentanoic acid (461mg, 3.9 mmol) and 2N NaOH (5.0 mL), and the resulting mixture was stirred at 0 deg.C for 1h. The pH of the mixture was adjusted to pH =2 using 1N HCl, which was extracted with EtOAc (20mL × 3). The combined organic layers were washed with brine (50mL. Times.2) and Na ₂ SO ₄ Dried and concentrated to give (S) -2-decanamidopentanoic acid as a white solid (630mg, 88.5% yield), which was used directly in the next step. LCMS (5-95AB, ESI): t _R ＝0.904,[M+H] ⁺ ＝272.0。

Example T: synthesis of Compound 104

Compound 104 was synthesized following a procedure analogous to that described for example C (compound 101-B) using (S) -2- ((tert-butoxycarbonyl) amino) -2- (4-hydroxyphenyl) acetic acid and methyl (S) -2-amino-2-cyclopropylacetate in step 1 to give the title compound as a brown solid. LCMS (ESI): [ M + H ]] ⁺ ＝354。

Example U: synthesis of Compound 105

Step 1: to a solution of compound 104 (1.16g, 2.48mmol) and triethylamine (0.86mL, 6.20mmol) in acetonitrile (25 mL) was added 4-nitrobenzenesulfonyl chloride (660mg, 2.98mmol) in portions, and the resulting reaction mixture was stirred at room temperature for 4h. The precipitate was collected by filtration, washed with a small amount of acetonitrile and dried under vacuum overnight to give 1.14g (70%) of (4S,7S,10S) -7-cyclopropyl-1 as an off-white solid ⁶ ,2 ⁶ -dimethoxy-10- ((4-nitrophenyl) sulfonamide) -6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylic acid methyl ester, which was used further without further purification. LCMS (ESI) [ < M + H ]] ⁺ ＝653。

Step 2: to (4S,7S,10S) -7-cyclopropyl-1 ⁶ ,2 ⁶ -dimethoxy-10- ((4-nitrophenyl) sulfonamide) -6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylate (1.14g, 1.75mmol) and K ₂ CO ₃ (1.93g, 14.0 mmol) in acetone (20 mL) was added methyl iodide (0.870mL, 14.0 mmol). The resulting reaction mixture was stirred at room temperature overnight. The mixture was filtered and evaporated in vacuo. The residue was diluted with water, extracted with isopropyl acetate (2x 100ml) and passed through Mg ₂ SO ₄ Drying, filtration, evaporation in vacuo and drying under vacuum gave 1.21g (100%) of (4S, 7S, 10S) -7-cyclopropyl-1 as an off-white solid ⁶ ,2 ⁶ -dimethoxy-10- ((N-methyl-4-nitrophenyl) sulfonamide) -6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylic acid methyl ester, which was used without further purification. LCMS (ESI): [ M + H ]] ⁺ ＝667。

And 3, step 3: to (4S,7S,10S) -7-cyclopropyl-1 ⁶ ,2 ⁶ To a solution of methyl-dimethoxy-10- ((N-methyl-4-nitrophenyl) sulfonamide) -6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylate (1.11g, 1.66mmol) in acetonitrile (22 mL) were added thioglycolic acid (6.6 equiv., 1.01g,11.0 mmol) and DBU (2.50mL, 16.6 mmol), and the resulting mixture was stirred at room temperature for 3h. The reaction mixture was evaporated in vacuo, diluted with isopropyl acetate (50 mL) and saturated Na HCO ₃ Washed with aqueous solution (50 mL). The aqueous layer was extracted again with iPrOAc (50 mL). The combined organics were washed with water and brine, over Mg ₂ SO ₄ Drying, filtration, evaporation in vacuo and drying under vacuum gave 776mg (96.8%) of compound 105 as an off-white solid. LCMS (ESI) [ M + H ]] ⁺ ＝482。

Example V: synthesis of Compounds 106-B1 and 106-B2

Step 1: compound 101-D (2.0 g, 3.65mmol) was added to a 1.25N HCl/MeOH solution (150 mL) and the mixture was stirred at 0 deg.C for 4h. Volatiles were removed to give the crude product as a white solid.

Step 2: the crude was dissolved in DCM (5 mL) and Boc was added to the mixture ₂ O (0.93g, 4.27mmol) and TEA (1.08g, 10.7 mmol). The resulting mixture was stirred at room temperature for 16h. The volatiles were removed and the residue was purified by silica gel flash column to give compounds 106-A1 and 106-A2 as a mixture of regioisomers as a white solid (1.8g, 76.4% yield). LCMS (5-95AB, ESI): t _R ＝0.880,[M+H] ⁺ =684.6. To a mixture of compounds 106-A1 and 106-A2 (1.8g, 2.72mmol) and tert-butyl (2-bromoethyl) carbamate (3.0g, 13.6mmol) in DMF (5 mL) was added K ₂ CO ₃ (3.8g, 27.2mmol), and the reaction mixture was stirred at room temperature for 3h. DCM (50 mL) was added to the reaction mixture, which was quenched with 2N HCl, saturated NaHCO ₃ And brine (20 mL each). Then the organic layer was passed over Na ₂ SO ₄ Drying, concentration and purification of the residue on silica gel flash column gave a mixture of regioisomers which was further purified by SFC (OD, 250mm x 30mm,5 um) to give compound 106-B1 (80mg, 3.6% yield) and compound 106-B2 (1.6 g,73.2% yield) as white solids.

Example 1: synthesis of Compound 201

Step 1: a solution of 1- (4-butylphenyl) ethan-1-one (500mg, 2.8mmol), DMF-DMA (406mg, 3.4mmol) and proline (32.66mg, 0.2800mmol) was stirred at 80 ℃ for 3h. The reaction was quenched with water (15 mL) and extracted with EtOAc (3X 20mL). The combined organic layers were washed with brine (50 mL) and Na ₂ SO ₄ Drying, concentration and purification of the crude product by silica gel chromatography eluting with 0-20% EtOAc in petroleum ether afforded 1- (4-butylphenyl) -3- (dimethylamino) prop-2-en-1-one (550mg, 84% yield) as a yellow solid.

Step 2: a solution of 1- (4-butylphenyl) -3- (dimethylamino) prop-2-en-1-one (400mg, 1.73mmol) and hydrazine monohydrate (90. Mu.L, 8.65 mmol) in EtOH (5 mL) was stirred at 90 ℃ for 2h. The reaction was partitioned between water and EtOAc (50 mL each). The organic layer was washed with Na ₂ SO ₄ Drying and concentration gave 3- (4-butylphenyl) -1H-pyrazole as a yellow oil (300mg, 87% yield), which was used directly in the next step.

And step 3: 3- (4-butylphenyl) -1H-pyrazole (240mg, 1.2mmol), methyl 4-bromo-2-methylbenzoate (412mg, 1.8mmol) and Pd ₂ (dba) ₃ Solutions of (27mg, 0.03mmol), t-BuXPhos (51mg, 0.12mmol) and NaOt-Bu (173mg, 1.8mmol) in toluene (3 mL) were dissolved in N ₂ Stirring at 80 deg.C for 7hr. The reaction was partitioned with water and EtOAc (50 mL each). The organic layer is coated with Na ₂ SO ₄ Drying, concentration and purification of the residue by HPLC gave 4- (3- (4-butylphenyl) -1H-pyrazol-1-yl) -2-methylbenzoic acid as a white solid (90mg, 22.5% yield). ¹ H NMR(400MHz,DMSO-d6):δ8.65(d,J＝5.6Hz,1H),7.98(d,J＝8.0Hz,1H),7.89-7.80(m,4H),7.28(d,J＝8.0Hz,2H),7.05(d,J＝5.6Hz,1H),2.63(s,3H),2.60(t,J＝7.2Hz,2H),1.62-1.55(m,2H),1.37-1.28(m,2H),0.91(t,J＝7.2Hz,3H)。

Compound 201 (formate) was prepared as a white solid from compound 101-K and 4- (3- (4-butylphenyl) -1H-pyrazol-1-yl) -2-methylbenzoic acid using a method similar to that described in example G. LCMS (methods 5-95AB, ESI): t _R ＝0.656min,[M+H] ⁺ ＝954.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.50(br s,2H),8.28(br s,1H),7.82-7.74(m,4H),7.54(d,J＝8.0Hz,1H),7.34(d,J＝8.0Hz,1H),7.27(d,J＝8Hz,2H),7.24-7.16(m,2H),7.10-7.05(m,1H),6.93-6.85(m,2H),6.77(s,1H),6.42(s,1H),5.21-5.14(m,1H),4.82-4.77(m,2H),4.28-4.10(m,4H),4.20(s,2H),3.30-3.07(m,8H),2.95(s,3H),2.67(t,J＝8Hz,2H),2.51(s,3H),2.36-2.24(m,1H),2.23-2.10(m,1H),1.70-1.60(m,2H),1.46-1.33(m,5H),0.97(t,J＝7.2Hz,3H)。

Example 2: synthesis of Compound 202

Compound 202 (formate) was prepared as a white solid from compound 101-K by using an analogous method to that described in example H. LCMS (methods 5-95AB, ESI): t _R ＝0.608min,[M+H] ⁺ ＝958.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.48(br s,2H),7.94(d,J＝8.4Hz,2H),7.86(d,J＝8.0Hz,2H),7.66-7.57(m,3H),7.36(d,J＝8.0Hz,1H),7.20(d,J＝8.4Hz,1H),7.11(d,J＝8.4Hz,1H),6.93(s,1H),6.85(s,1H),6.38(s,1H),5.21-5.18(m,1H),4.95-4.78(m,2H),4.30-4.10(m,4H),4.20(s,2H),3.50-3.18(m,8H),2.98(s,3H),2.55(s,3H),2.33-2.25(m,1H),2.25-2.16(m,1H),1.38(d,J＝6.8,3H)。

Example 3: synthesis of Compound 203

Compound 203 (formate) was prepared as a white solid from compound 101-K by using an analogous method to that described in example H. LCMS (method 5-95AB, ESI): t _R ＝0.735min,[M+H] ⁺ ＝888.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.51(br s,2H),7.58-7.35(m,7H),7.35-7.33(m,1H),7.23-7.18(m,2H),7.11-7.08(m,2H),6.88(br s,1H),6.38(s,1H),5.17-5.10(m,1H),4.85-4.80(m,2H),4.25-4.20(m,4H),4.22(s,2H),3.27-3.00(m,8H),2.95(s,3H),2.52(s,3H),2.29-2.16(m,2H),1.42(t,J＝7.2Hz,3H),1.39(s,9H)。

Example 4: synthesis of Compound 204

Compound 204 (formate) was prepared as a white solid from compound 101-K by using an analogous method to that described in example I. LCMS (methods 5-95AB, ESI): t _R ＝0.710min,[M+H] ⁺ ＝918.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.95(s,2H),8.50(br s,1H),7.65-7.58(m,2H),7.50(d,J＝8.0Hz,1H),7.33(d,J＝8.0Hz,1H),7.24-7.16(m,2H),7.07(d,J＝8.0Hz,1H),6.90(d,J＝2.4Hz,1H),6.69(s,1H),6.45(s,1H),5.22-5.16(m,1H),4.80-4.76(m,2H),4.30-4.18(m,4H),4.20(s,2H),3.27-3.06(m,8H),3.00(t,J＝7.6Hz,2H),2.98(s,3H),2.48(s,3H),2.35-2.24(m,1H),2.22-2.11(m,1H),1.91-1.81(m,2H),1.42-1.33(m,9H),0.93(t,J＝6.8Hz,3H)。

Example 5: synthesis of Compound 205

Step 1: mixing 6-bromo-2-methylnicotinic acid (140mg, 0.65mmol), 4-n-pentyl-phenylboronic acid (187mg, 0.97mmol), pd (dppf) Cl ₂ (95mg, 0.13mmol) and Cs ₂ CO ₃ (634mg, 1.94mmol) in toluene/H ₂ Solution in O (11mL, v/v = 10/1) in N ₂ And stirred at 110 ℃ for 16h. After filtration, the filtrate was taken up in EtOAc and H ₂ O (50 mL each). The organic layer was washed with brine (2 × 30 mL) and over Na ₂ SO ₄ Dried, concentrated, and the residue was purified by preparative TLC to give 2-methyl-6- (4-pentylphenyl) nicotinic acid as a colorless oil (120mg, 65% yield). ¹ H NMR(400MHz,CD ₃ Cl)δ8.36(d,J＝8.4Hz,1H),8.01(d,J＝8.4Hz,2H),7.66(d,J＝8.4Hz,1H),7.31(d,J＝8.4Hz,2H),2.96(s,3H),2.68(t,J＝8.0Hz,2H),1.66-1.34(m,6H),0.91(t,J＝6.0Hz,3H)。

Compound 205 (formate) is prepared by utilization and implementationAn analogous procedure to that described in example G was prepared from compound 101-K and 2-methyl-6- (4-pentylphenyl) nicotinic acid as a white solid. LCMS (methods 5-95AB, ESI): t _R ＝0.643min,[M+H] ⁺ ＝903.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.50(s,1H),7.80-7.65(m,3H),7.31(d,J＝8.4Hz,1H),7.31-7.21(m,2H),7.19-7.12(m,2H),6.92(s,1H),6.82(s,1H),6.39(s,1H),5.19-5.16(m,1H),4.90-4.79(m,2H),4.30-4.15(m,4H),4.20(s,2H),3.30-3.15(m,8H),2.96(s,3H),2.68(t,J＝7.6Hz,2H),2.65(s,3H),2.32-2.27(m,1H),2.20-2.13(m,1H),1.38-1.25(m,6H),0.93(t,J＝6.4Hz,3H)。

Example 6: synthesis of Compound 206

Compound 206 (formate) was prepared as a white solid from compound 101-K by using an analogous method to that described in example 5. LCMS (method 5-95AB, ESI): t _R ＝0.706min,[M+H] ⁺ ＝889.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.50(s,2H),7.92(d,J＝8.4Hz,2H),7.84(d,J＝8.0Hz,1H),7.73(d,J＝8.0Hz,1H),7.54(d,J＝8.4Hz,2H),7.36-7.28(m,1H),7.25-7.16(m,2H),7.10(d,J＝8.4Hz,1H),6.90(d,J＝2.0Hz,1H),6.77(s,1H),6.41(s,1H),5.19-5.16(m,1H),4.85-4.79(m,2H),4.24-4.15(m,4H),4.20(s,2H),3.17-3.08(m,8H),2.96(s,3H),2.68(s,3H),2.30-2.26(m,1H),2.18-2.12(m,1H),1.37(s,9H),1.36(t,J＝6.4Hz,3H)。

Example 7: synthesis of Compound 207

Compound 207 (formate) was prepared as a white solid from compound 101-K by using an analogous method to that described in example 5. LCMS (methods 5-95AB, ESI): t _R ＝0.707min,[M+H] ⁺ ＝889.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.49(br s,3H),7.88-7.82(m,3H),7.72(d,J＝8.4Hz,1H),7.31-7.29(m,3H),7.20-7.18(m,2H),7.11(d,J＝8.4Hz,1H),6.89(d,J＝2.0Hz,1H),6.74(s,1H),6.43(s,1H),5.17-5.15(m,1H),4.79-4.75(m,2H),4.30-4.15(m,4H),4.20(s,2H),3.34-3.10(m,8H),2.96(s,3H),2.69(t,J＝8.0Hz,2H),2.66(s,3H),2.40-2.25(m,1H),2.20-2.05(m,1H),1.55-1.50(m,2H),1.42-1.34(m,4H),0.96(t,J＝7.2Hz,3H)。

Example 8: synthesis of Compound 208

Compound 208 (formate) was prepared as a white solid from compound 101-K by using an analogous method to that described in example 5. LCMS (methods 5-95AB, ESI): t _R ＝0.690min,[M+H] ⁺ ＝875.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.42(s,1H),7.93(d,J＝8.0Hz,2H),7.86(d,J＝8.0Hz,1H),7.74(d,J＝8.0Hz,1H),7.33(d,J＝8.4Hz,2H),7.24(d,J＝8.4Hz,1H),7.18(d,J＝8.4Hz,1H),7.09(d,J＝8.4Hz,1H),6.91(s,1H),6.82(s,1H),6.37(s,1H),5.19-5.17(m,1H),4.98-4.78(m,2H),4.23-4.15(m,4H),4.19(s,2H),3.55-3.13(m,8H),2.95(s,3H),2.69(s,3H),2.67(t,J＝8.0Hz,2H),2.33-2.24(m,1H),2.24-2.08(m,1H),1.72-1.67(m,2H),1.39-1.33(m,2H),0.97(t,J＝7.6Hz,3H)。

Example 9: synthesis of Compound 209

Compound 209 (formate) was prepared as a white solid from compound 101-K by using a similar method to that described in example 5 and example I. LCMS (method 5-95AB, ESI): t _R ＝0.679min,[M+H] ⁺ ＝905.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ9.29(s,2H),7.89(s,2H),7.32(d,J＝7.6Hz,1H),7.25-7.11(m,2H),7.10-7.00(m,1H),6.88(s,1H),6.67(br s,1H),6.44(s,1H),5.20-5.16(m,1H),4.76-4.64(m,2H),4.40-4.11(m,6H),3.29-2.89(m,13H),2.64(s,3H),2.36-2.09(m,2H),1.90-1.84(m,2H),1.43-1.32(m,6H),0.93(t,J＝6.4Hz,3H)。

Example 10: synthesis of Compound 210

Step 1: a mixture of 4- (tert-butyl) -2-methylphenol (1.0 g, 6.1mmol), pyridine (0.96g, 12.2mmol) and trifluoromethanesulfonic anhydride (2.1g, 12.2mmol) in DCM (10 mL) was stirred at 20 ℃ for 2h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (2x 50mL) and over MgSO ₄ Drying and concentration gave 4- (tert-butyl) -2-methylphenyl triflate (1.5g, 83% yield) as a colorless oil.

Step 2: 4- (tert-butyl) -2-methylphenyl trifluoromethanesulfonate (1.0g, 3.4mmol), bis (pinacol) diboron (2.6g, 10.2mmol) and Pd (dppf) Cl ₂ A mixture of (247mg, 0.34mmol) and potassium acetate (1.7g, 17.0 mmol) in 1, 4-dioxane (10 mL) was stirred under nitrogen at 80 ℃ for 12h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3x 30mL). The combined organic layers were washed with brine (2x 50mL) and MgSO ₄ Dried and concentrated, and the residue was purified by preparative TLC (5% etoac in petroleum ether) to give 2- (4- (tert-butyl) -2-methylphenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan as a colorless oil (700mg, 76% yield). ¹ H NMR(400MHz,CDCl ₃ )δ7.72(d,J＝8.4Hz,1H),7.23-7.18(m,2H),2.50(s,3H),1.32(s,12H),1.30(s,9H)。

Compound 210 (formate salt) was prepared as a white solid from compound 101-K and 2- (4- (tert-butyl) -2-methylphenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan using an analogous method to that described in example 5. LCMS (methods 5-95AB, ESI): t _R ＝0.706min,[M+H] ⁺ ＝904.2； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.49(br s,4H),7.91(d,J＝8.0Hz,1H),7.41(d,J＝8.0Hz,1H),7.36–7.10(m,7H),6.90(s,1H),6.82(s,1H),6.37(s,1H),5.19-5.15(m,1H),4.90-4.78(m,2H),4.24-4.17(m,4H),4.19(s,2H),3.34-3.05(m,8H),2.96(s,3H),2.40-2.20(m,1H),2.32(s,3H),2.20-2.05(m,1H),1.36(s,9H),1.35(d,J＝7.2Hz,3H)。

Example 11: synthesis of Compound 211

Compound 211 (formate) was prepared as a white solid from compound 101-K by using a similar method as described in example 5. LCMS (method 5-95AB, ESI): t _R ＝0.705min,[M+H] ⁺ ＝941.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.04(d,J＝8.0Hz,2H),7.89(d,J＝8.0Hz,1H),7.79(d,J＝8.4Hz,1H),7.61(d,J＝8.0Hz,2H),7.37-7.28(m,1H),7.26-7.17(m,2H),7.10(d,J＝8.4Hz,1H),6.91(s,1H),6.81(s,1H),6.39(s,1H),5.20-5.15(m,1H),4.83-4.78(m,2H),4.28-4.17(m,4H),4.20(s,2H),3.37-3.08(m,8H),2.96(s,3H),2.70(s,3H),2.34-2.25(m,1H),2.20-2.12(m,1H),1.43(br s,2H),1.36(d,J＝6.8Hz,3H),1.17-1.11(br s,2H)。

Example 12: synthesis of Compound 212

Step 1: a mixture of 1- (4-bromophenyl) ethan-1-one (1.0g, 5.0mmol), methyl (triphenyl) phosphonium chloride (4.1g, 13mmol) and t-BuOK (1.5g, 13mmol) in THF (50 mL) was stirred at 20 ℃ for 3h. The volatiles were removed and the residue was redissolved in EtOAc (50 mL) and washed with brine (2x 50mL). The organic layer was MgSO ₄ Drying, concentration and purification of the residue by flash column chromatography eluting with 5% etoac in petroleum ether afforded 1-bromo-4- (prop-1-en-2-yl) benzene as a colourless oil (800mg, 81% yield).

Step 2: in N ₂ Et at 0 ℃ via syringe ₂ A solution of trifluoroacetic acid (1.54mL, 20.0 mmol) in DCM (10 mL) of Zn (1N, 3.5mL in toluene) was added dropwise and the mixture was stirred at the same temperature for 20min, followed by addition of a solution of 1-bromo-4- (prop-1-en-2-yl) benzene (346mg, 1.76mmol) in DCM (10 mL). After additional 20min of stirring, CH was added ₂ I ₂ (0.28mL，3.5mmol)，And the resulting mixture was stirred at 25 ℃ for 16h. The reaction was diluted with petroleum ether (30 mL) which was diluted with 1N aqueous HCl, saturated NaHCO ₃ And brine (20 mL each). The organic layer was MgSO ₄ Dried, concentrated, and the residue purified by HPLC to give 1-bromo-4- (1-methylcyclopropyl) benzene as a colorless oil (150mg, 40% yield).

Compound 212 (formate) was prepared as a white solid from 101-K and 1-bromo-4- (1-methylcyclopropyl) benzene using an analogous method to that described in example 10. LCMS (methods 5-95AB, ESI): t _R ＝0.689min,[M+H] ⁺ ＝887.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.46(br s,3H),7.92(d,J＝8.4Hz,2H),7.85(d,J＝8.4Hz,1H),7.73(d,J＝8.0Hz,1H),7.37(d,J＝8.0Hz,2H),7.31(d,J＝8.0Hz,1H),7.23(d,J＝8.0Hz,1H),7.18(d,J＝8.4Hz,1H),7.09(d,J＝8.4Hz,1H),6.90(s,1H),6.80(s,1H),6.38(s,1H),5.20-5.13(m,1H),4.85-4.79(m,2H),4.26-4.16(m,4H),4.19(s,2H),3.28-3.07(m,8H),2.95(s,3H),2.68(s,3H),2.33-2.23(m,1H),2.21-2.09(m,1H),1.45(s,3H),1.35(d,J＝7.2Hz,3H),0.92(s,2H),0.83(s,2H)。

Example 13: synthesis of Compound 213

Step 1: the compounds 6-bromo-2-methylnicotinic acid (100mg, 0.46mmol), 3-dimethyl-1-butyne (380mg, 4.6 mmol), cuI (17.6 mg, 0.09mmol), pd (dppf) Cl ₂ (32.5mg, 0.05mmol) in Et ₃ Mixture of N (10 mL) in N ₂ Stirred at 60 ℃ for 16h. The mixture was diluted with water (20 mL) and extracted with EtOAc (2X 20mL). The combined organic layers were washed with brine (2x 40mL). The organic layer was washed with Na ₂ SO ₄ Dried, concentrated, and the residue purified by preparative TLC (eluted with 10% meoh in DCM, R) _f = 0.4) to give 6- (3, 3-dimethylbut-1-yn-1-yl) -2-methylnicotinic acid as a yellow solid (60mg, 60% yield). LCMS (methods 5-95AB, ESI): t _R ＝0.642min,[M+H] ⁺ ＝217.8。

Compound 213 (formate) tongPrepared from compound 101-K and 6- (3, 3-dimethylbut-1-yn-1-yl) -2-methylnicotinic acid as white solids using a method analogous to that described in example G. LCMS (methods 5-95AB, ESI): t _R ＝0.616min,[M+H] ⁺ ＝837.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.50(br s,2H),7.78(d,J＝8.0Hz,1H),7.36(d,J＝8.0Hz,1H),7.28(d,J＝8.0Hz,1H),7.23(d,J＝8.0Hz,1H),7.18(d,J＝8.0Hz,1H),7.10(d,J＝8.0Hz,1H),6.89(s,1H),6.78(s,1H),6.40(s,1H),5.15-5.13(m,1H),4.85-4.78(m,2H),4.28-4.18(m,4H),4.20(s,2H),3.24-3.10(m,8H),2.94(s,3H),2.57(s,3H),1.36(s,9H),1.35(d,J＝6.8Hz,3H)。

Example 14: synthesis of Compound 214

Compound 214 (formate) was prepared as a white solid from compound 101-K by using an analogous method to that described in example 13. LCMS (method 5-95AB, ESI): t _R ＝0.689min,[M+H] ⁺ ＝863.9； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.46(br s,2H),7.78(d,J＝7.6Hz,1H),7.37(d,J＝7.6Hz,1H),7.33-7.27(m,1H),7.24(d,J＝4.8Hz,1H),7.17(d,J＝8.4Hz,1H),7.09(d,J＝8.4Hz,1H),6.89(d,J＝2.2Hz,1H),6.81(s,1H),6.36(s,1H),5.16-5.09(m,1H),4.80-4.71(m,2H),4.25-4.16(m,4H),4.19(s,2H),3.34-3.08(m,8H),2.93(s,3H),2.74-2.66(m,1H),2.57(s,3H),2.33-2.20(m,1H),2.18-2.06(m,1H),1.95-1.89(m,2H),1.79-1.76(m,2H),1.59-1.55(m,3H),1.45-1.37(m,3H),1.34(d,J＝7.2Hz,3H).

Example 15: synthesis of Compound 215

Starting from compound 101-K, a typical amide coupling (HATU/DIEA), suzuki coupling ester hydrolysis (LiOH, THF/H) similar to that described in examples G and H was applied ₂ O), amide coupling (HATU/DIEA) and Boc removal (TFA/HFIP) to give compound 215 (formate) as a white solid. LCMS (methods 5-95AB, ESI): t _R ＝0.702min,[M+H] ⁺ ＝889.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.58(s,1H),8.49(br s,3H),7.92-7.87(m,2H),7.78(s,1H),7.57-7.51(m,3H),7.32(d,J＝8.0Hz,1H),7.20(d,J＝8.0Hz,2H),7.08(d,J＝8.0Hz,1H),6.89(s,1H),6.43(s,1H),5.20-5.17(m,1H),4.82-4.79(m,2H),4.24-4.18(m,4H),4.20(s,2H),3.16-3.12(m,8H),2.95(s,3H),2.52(s,3H),2.29-2.17(m,2H),1.38(s,9H),1.36(d,J＝7.2Hz,3H)。

Example 16: synthesis of Compound 216

Compound 216 (formate salt) was prepared as a white solid by using a similar method as described in example 10 and example J starting from 5,6,7,8-tetrahydronaphthalen-2-ol and compound 101-K. LCMS (methods 5-95AB, ESI): t _R ＝0.709min,[M+H] ⁺ ＝888.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.77(s,1H),8.48(br s,2H),8.20-8.05(m,2H),7.40-7.30(m,1H),7.30-7.15(m,3H),7.15-7.05(m,1H),6.91(s,1H),6.80(s,1H),6.40(s,1H),5.25-5.15(m,1H),4.75-4.70(m,2H),4.25-4.15(m,4H),4.19(s,2H),3.25-3.05(m,8H),2.96(s,3H),2.87(br s,4H),2.75(s,3H),2.35-2.25(m,1H),2.25-2.10(m,1H),1.86(br s,4H),1.36(d,J＝6.8Hz,3H)。

Example 17: synthesis of Compound 217

Step 1: a mixture of cyclobutanecarboxaldehyde (202mg, 2.4 mmol) and 4-methylbenzenesulfonylhydrazide (448mg, 2.4 mmol) in 1, 4-dioxane (1 mL) was stirred at 50 ℃ for 1h. The volatiles were removed under reduced pressure to give N' - (cyclobutylmethylene) -4-methylbenzenesulfonylhydrazide (607 mg), which was used directly in the next step.

Step 2: n' - (cyclobutyl methylene) -4-methyl benzenesulfonyl hydrazide (600mg, 2.4mmol), 4-bromophenyl boric acid (716mg, 3.6mmol) and K ₂ CO ₃ (657mg, 4.8mmol) in 1, 4-dioxane (20 mL) was stirred at 110 ℃ for 16h. The reaction was diluted with water (10 mL) and extracted with EtOAc (3X 20mL). The combined organic layers were washed with brine (50 mL), mgSO ₄ Drying, concentration, and purification of the residue by silica gel column chromatography eluting with petroleum ether gave 1-bromo-4- (cyclobutylmethyl) benzene as a colorless oil (378mg, 71% yield).

Compound 217 (formate salt) was prepared as a white solid from 1-bromo-4- (cyclobutylmethyl) benzene and compound 101-K by using a method similar to that described in example 10 and example J. LCMS (method 5-95AB, ESI): t _R ＝0.640min,[M+H] ⁺ ＝902.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.77(s,2H),8.55(br s,2H),8.31(d,J＝8.4Hz,1H),7.32-7.28(m,3H),7.20-7.17(m,2H),7.07(d,J＝8.4Hz,1H),6.88(s,1H),6.76(s,1H),6.74(s,1H),5.18(t,J＝5.2Hz,1H),4.85-4.78(m,2H),4.21-4.15(m,4H),4.19(s,2H),3.14-3.00(m,8H),2.95(s,3H),2.78(d,J＝7.6Hz,2H),2.66(s,3H),2.20-2.10(m,1H),2.07-2.00(m,3H),1.95-1.78(m,4H),1.35(d,J＝6.8Hz,3H)。

Example 18: synthesis of Compound 218

Compound 218 (formate) was prepared as a white solid from compound 101-K by using an analogous method to that described in example 17. LCMS (methods 5-95AB, ESI): t _R ＝0.757min,[M+H] ⁺ ＝916.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.79(s,1H),8.48(br s,2H),8.36(d,J＝8.4Hz,2H),7.34-7.30(m,3H),7.25-7.17(m,2H),7.10(d,J＝8.4Hz,1H),6.91(d,J＝2.0Hz,1H),6.82(s,1H),6.39(s,1H),5.21-5.16(m,1H),4.72-4.68(m,2H),4.26-4.16(m,4H),4.20(s,2H),3.40-3.04(m,8H),2.96(s,3H),2.70-2.50(m,2H),2.40(s,6H),2.33-2.27(m,1H),2.20-2.12(m,2H),1.80-1.65(m,4H),1.61-1.53(m,2H),1.36(d,J＝6.8Hz,3H),1.30-1.22(m,2H)。

Example 19: synthesis of Compound 219

Compound 219 (formate salt) was prepared as a white solid from compound 101-K by using a similar method to that described in example 10 and example J. LCMS (method 5-95AB, ESI): t _R ＝0.714min,[M+H] ⁺ ＝942.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.82(s,1H),8.46(d,J＝8.0Hz,2H),7.63(d,J＝8.0Hz,2H),7.33(d,J＝8.4Hz,1H),7.22(m,2H),7.10(d,J＝8.4Hz,1H),6.91(d,J＝1.6Hz,1H),6.81(s,1H),6.40(s,1H),5.22-5.17(m,1H),4.75-4.71(m,2H),4.28-4.15(m,4H),4.20(s,2H),3.35-3.07(m,8H),2.96(s,3H),2.72(s,3H),2.33-2.27(m,1H),2.21-2.14(m,1H),1.43(br s,2H),1.36(d,J＝6.8Hz,3H),1.16(br s,2H)。

Example 20: synthesis of Compound 220

Compound 220 (formate) was prepared as a white solid from compound 101-K by using an analogous method to that described in example 17. LCMS (methods 5-95AB, ESI): t _R ＝0.632min,[M+H] ⁺ ＝904.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.77(s,1H),8.48(br s,2H),8.32(d,J＝8.0Hz,2H),7.40-7.30(m,3H),7.21(d,J＝8.0Hz,2H),7.09(d,J＝8.0Hz,1H),6.89(s,1H),6.75(s,1H),6.44(s,1H),5.20-5.15(m,1H),4.85-4.75(m,2H),4.35-4.15(m,4H),4.20(s,2H),3.40-3.05(m,8H),2.96(s,3H),2.72(t,J＝7.6Hz,2H),2.69(s,3H),2.35-2.25(m,1H),2.20-2.10(m,1H),1.70-1.50(m,3H),1.36(d,J＝6.4Hz,3H),0.98(d,J＝6.0Hz,6H)。

Example 21: synthesis of Compound 221

Step 1: 4-Bromomaphthalen-1-ol (2.0g, 9.0mmol), benzyl bromide (2.3g, 13.5mmol) and K ₂ CO ₃ (3.7 g, 27mmol) in DMF (1 mL)The mixture was stirred at 20 ℃ for 16h. The reaction was poured into water (50 mL) and extracted with EtOAc (3x 50mL). The combined organic layers were washed with brine (2x 100mL) and Na ₂ SO ₄ Drying, concentration, and purification of the residue by silica gel chromatography gave 1- (benzyloxy) -4-bromonaphthalene (2.0 g,71.2% yield) as a yellow oil. And 2, step: typical Suzuki (example H) and hydrogenation conditions (example D) were applied to 1- (benzyloxy) -4-bromonaphthalene to give 4-ethylnaphthalen-1-ol as a white solid.

Compound 221 (formate) was prepared as a white solid from compound 101-K and 4-ethylnaphthalen-1-ol using an analogous method to that described in example 10 and example J. LCMS (methods 5-95AB, ESI): t _R ＝0.701min,[M+H] ⁺ ＝912.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.93(s,1H),8.50(d,J＝8.4Hz,1H),8.23(d,J＝8.4Hz,1H),7.89(d,J＝8.0Hz,1H),7.63-7.53(m,3H),7.37-7.32(m,1H),7.25-7.16(m,2H),7.11(d,J＝8.0Hz,1H),6.92(s,1H),6.84(s,1H),6.42(s,1H),5.24-5.20(m,1H),4.83-4.80(m,2H),4.27-4.13(m,4H),4.19(s,2H),3.50-3.46(m,1H),3.29-3.07(m,9H),2.98(s,3H),2.77(s,3H),2.35-2.29(m,1H),2.21-2.16(m,1H),1.43(t,J＝7.2Hz,3H),1.36(d,J＝6.8Hz,3H)。

Example 22: synthesis of Compound 222

Alkylation (example 21), suzuki (example H) and hydrogenation (Pd/C, H) were carried out on 4-bromo-2-methylphenol ₂ Example D) conditions, 2-methyl-4-propylphenol was obtained as a colorless oil.

Compound 222 (formate) was prepared as a white solid from compound 101-K by using a similar method to that described in example 21 and example J. LCMS (method 5-95AB, ESI): t _R ＝0.680min,[M+H] ⁺ ＝890.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.82(s,1H),8.45(br s,3H),7.64(d,J＝7.2Hz,1H),7.32-7.25(m,1H),7.20-7.09(m,5H),6.89(s,1H),6.77(s,1H),6.42(s,1H),5.20-5.15(m,1H),4.85-4.78(m,2H),4.27-4.15(m,4H),4.20(s,2H),3.30-3.13(m,8H),2.96(s,3H),2.63(s,3H),2.62(t,J＝7.2Hz,2H),2.49(s,3H),2.40-2.25(m,1H),2.20-2.05(m,1H),1.71-1.66(m,2H),1.36(d,J＝6.8Hz,3H),0.97(t,J＝6.8Hz,3H)。

Example 23: synthesis of Compound 223

Compound 223 (formate) was prepared as a white solid from compound 101-K by using an analogous method to that described in example 22. LCMS (methods 5-95AB, ESI): t _R ＝0.714min,[M+H] ⁺ ＝904.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.82(s,1H),8.46(br s,2H),7.68(d,J＝7.6Hz,1H),7.32-7.25(m,1H),7.22-7.10(m,5H),6.90(s,1H),6.80(s,1H),6.39(s,1H),5.20-5.15(m,1H),4.85-4.78(m,2H),4.27-4.15(m,4H),4.20(s,2H),3.30-3.13(m,8H),2.95(s,3H),2.75-2.61(m,2H),2.69(s,3H),2.50(s,3H),2.40-2.25(m,1H),2.20-2.05(m,1H),1.66-1.62(m,2H),1.39-1.34(m,5H),0.96(t,J＝7.6Hz,3H)。

Example 24: synthesis of Compound 224

Compound 224 (formate) was prepared as a white solid from compound 101-K by using a similar method to that described in example 12 and example J. LCMS (methods 5-95AB, ESI): t _R ＝0.599min,[M+H] ⁺ ＝888.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.75(s,1H),8.50(br s,2H),8.28(d,J＝8.0Hz,2H),7.37-7.30(m,3H),7.21-7.19(m,2H),7.07(d,J＝8.0Hz,1H),6.88(s,1H),6.70(s,1H),6.48(s,1H),5.20-5.16(m,1H),4.85-4.78(m,2H),4.28-4.21(m,6H),3.31-3.13(m,8H),2.96(s,3H),2.67(s,3H),2.31-2.27(m,1H),2.19-2.16(m,1H),1.47(s,3H),1.35(d,J＝7.2Hz,1H),0.97-0.94(m,2H),0.86-0.83(m,2H)。

Example 25: synthesis of Compound 225

Compound 225 (formate) was prepared as a white solid from compound 101-K by using a similar method to that described in example 2 and example J. LCMS (method 5-95AB, ESI): t _R ＝0.607min,[M+H] ⁺ ＝960.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.87(s,1H),8.65(d,J＝8.4Hz,2H),8.50(br s,2H),7.98(d,J＝8.4Hz,2H),7.33-7.31(m,1H),7.24-7.18(m,2H),7.10(d,J＝8.4Hz,1H),6.91(s,1H),6.79(s,1H),6.41(s,1H),5.20-5.18(m,1H),4.80-4.78(m,2H),4.25-4.20(m,6H),3.48-3.44(m,1H),3.17-3.07(m,7H),2.97(s,3H),2.73(s,3H),2.30-2.28(m,1H),2.18-2.17(m,1H),1.36(d,J＝6.4Hz,3H)。

Example 26: synthesis of Compound 226

Step 1: a mixture of DMF-DMA (2.5g, 21mmol) and methyl acetoacetate (2.0g, 17mmol) was stirred at 100 ℃ for 2h. The reaction was concentrated to give methyl 2- ((dimethylamino) methylene) -3-oxobutanoate (2.8 g), which was used directly in the next step.

Step 2: a mixture of methyl 2- ((dimethylamino) methylene) -3-oxobutanoate (800mg, 4.7mmol), 4-bromobenzamidine hydrochloride (1.0g, 4.3mmol) and sodium ethoxide (293mg, 4.3mmol) in ethanol (15 mL) was stirred at 70 ℃ for 2h. The volatiles were removed and the residue was extracted with EtOAc (50 mL), which was washed with brine (2x 50mL). The organic layer was washed with Na ₂ SO ₄ Drying, concentration, and purification of the residue on silica gel column, eluting with 0-2% etoac in petroleum ether, afforded methyl 2- (4-bromophenyl) -4-methylpyrimidine-5-carboxylate as a white solid (700mg, 47% yield).

And step 3: starting from methyl 2- (4-bromophenyl) -4-methylpyrimidine-5-carboxylate, typical Suzuki and ester hydrolysis (NaOH, meOH) conditions were applied to give 4-methyl-2- (4-neopentylphenyl) pyrimidine-5-carboxylic acid as a white solid.

Compound 226 (formate) tolclovirPrepared as a white solid from compound 101-K and 4-methyl-2- (4-neopentylphenyl) pyrimidine-5-carboxylic acid in a similar manner as described in example G. LCMS (method 5-95AB, ESI): t _R ＝0.617min,[M+H] ⁺ ＝904.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.77(s,1H),8.47(br s,1H),8.30(d,J＝8.0Hz,2H),7.35-7.27(m,3H),7.24-7.17(m,2H),7.09(d,J＝8.4Hz,1H),6.89(d,J＝1.6Hz,1H),6.72(s,1H),6.47(s,1H),5.22-5.16(m,1H),4.82-4.75(m,2H),4.32-4.17(m,4H),4.19(s,2H),3.29-3.06(m,8H),2.97(s,3H),2.69(s,3H),2.61(s,2H),2.36-2.27(m,1H),2.23-2.14(m,1H),1.37(d,J＝6.8Hz,3H),0.97(s,9H)。

Example 27: synthesis of Compound 227

Step 1: typical Sonogashira conditions (example K) were applied to 2- (4-iodophenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan to give 4, 5-tetramethyl-2- (4- (pent-1-yn-1-yl) phenyl) -1,3, 2-dioxaborolan as a yellow oil.

Compound 227 (formate salt) was prepared as a white solid from compound 101-K and 4,4,5,5-tetramethyl-2- (4- (pent-1-yn-1-yl) phenyl) -1,3, 2-dioxaborolan using a method similar to that described in example J. LCMS (methods 5-95AB, ESI): t _R ＝0.613min,[M+H] ⁺ ＝900.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.78(s,1H),8.48(br s,2H),8.36(d,J＝8.0Hz,2H),7.48(d,J＝8.0Hz,2H),7.32(d,J＝8.4Hz,1H),7.20(d,J＝8.4Hz,2H),7.09(d,J＝8.4Hz,1H),6.89(s,1H),6.74(s,1H),6.45(s,1H),5.25-5.15(m,1H),4.80-4.75(m,2H),4.30-4.15(m,6H),3.40-3.35(m,1H),3.30-3.10(m,7H),2.96(s,3H),2.69(s,3H),2.44(t,J＝7.2Hz,2H),2.35-2.25(m,1H),2.25-2.15(m,1H),1.66(q,J＝6.8Hz,2H),1.36(d,J＝6.4Hz,3H),1.09(t,J＝7.6Hz,3H)。

Example 28: synthesis of Compound 228

Step 1: starting from ethyl 2-bromo-4-methylpyrimidine-5-carboxylate (described in example 26), a typical Sonogashira (example K) and ester hydrolysis (NaOH, meOH/H) was applied ₂ O, described in example H) to yield 2- (3, 3-dimethylbut-1-yn-1-yl) -4-methylpyrimidine-5-carboxylic acid as a yellow solid.

Compound 228 (formate) was prepared as a white solid from compound 101-K and 2- (3, 3-dimethylbut-1-yn-1-yl) -4-methylpyrimidine-5-carboxylic acid using an analogous method to that described in example G. LCMS (methods 5-95AB, ESI): t _R ＝0.542min,[M+H] ⁺ ＝838.3； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.68(s,1H),8.47(br s,3H),7.30(d,J＝8.4Hz,1H),7.24(d,J＝8.4Hz,1H),7.18(d,J＝8.4Hz,1H),7.09(d,J＝8.4Hz,1H),6.90(s,1H),6.81(s,1H),6.37(s,1H),5.16-5.12(m,1H),4.81-4.77(m,2H),4.26-4.16(m,4H),4.19(s,2H),3.48(br s,1H),3.21-3.09(m,7H),2.93(s,3H),2.61(s,3H),2.29-2.24(m,1H),2.16-2.11(m,1H),1.38(s,9H),1.36(t,J＝6.4Hz,3H)。

Example 29: synthesis of Compound 229

Compound 229 (formate) was prepared as a white solid from compound 101-K by using a similar method to that described in example 28. LCMS (method 0-30AB, ESI): t _R ＝0.999min,[M+H] ⁺ ＝824.3； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.68(s,1H),8.49(br.s.,1H),7.29(d,J＝8.4Hz,1H),7.24(d,J＝8.4Hz,1H),7.17(d,J＝8.4Hz,1H),7.08(d,J＝8.4Hz,1H),6.89(s,1H),6.80(s,1H),6.37(s,1H),5.14(t,J＝6.8Hz,1H),4.87-4.76(m,2H),4.25-4.16(m,4H),4.19(s,2H),3.40-3.30(m,1H),3.20-3.08(m,7H),2.93(s,3H),2.90-2.83(m,1H),2.60(s,3H),2.32-2.21(m,1H),2.18-2.08(m,1H),1.34(d,J＝6.8Hz,3H),1.31(d,J＝7.2Hz,6H)。

Example 30: synthesis of Compound 230

Compound 230 (formate) was prepared as a white solid from compound 101-K by using an analogous method to that described in example J. LCMS (methods 5-95AB, ESI): t _R ＝0.727min,[M+H] ⁺ ＝902.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.78(s,1H),8.40-8.33(m,2H),7.40(d,J＝8.0Hz,1H),7.37-7.31(m,1H),7.23-7.17(m,2H),7.14-7.08(m,2H),6.93(s,1H),6.84(s,1H),6.38(s,1H),5.20-5.16(m,1H),4.83-4.78(m,2H),4.38-4.16(m,6H),3.48-3.18(m,8H),2.96(s,3H),2.71(s,3H),2.40-2.30(m,1H),2.25-2.07(m,4H),1.94-1.61(m,8H),1.37(d,J＝6.8Hz,3H)。

Example 31: synthesis of Compound 231

Compound 231 (formate salt) was prepared from compound 101-K as a white solid by using a similar method to that described in example 17. LCMS (methods 5-95AB, ESI): t _R ＝0.649min,[M+H] ⁺ ＝918.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.81(s,1H),8.45(br s,1H),8.42(d,J＝8.0Hz,2H),7.43(d,J＝8.0Hz,2H),7.38-7.32(m,1H),7.28-7.19(m,2H),7.11(d,J＝8.4Hz,1H),6.93(s,1H),6.83(s,1H),6.41(s,1H),5.22-5.20(m,1H),4.84-4.80(m,2H),4.30-4.21(m,6H),4.11-4.08(m,2H),3.65-3.58(m,2H),3.25-3.11(m,8H),2.97(s,3H),2.73(s,3H),2.34-2.28(m,1H),2.23-2.14(m,1H),1.88-1.81(m,5H),1.39(t,J＝6.4Hz,3H)。

Example 32: synthesis of Compound 232

Step 1: starting from ethyl 2-bromo-4-methylpyrimidine-5-carboxylate (described in example 26), typical Suzuki (example H) and Sandmeyer conditions (example J) were applied to give ethyl 2 '-bromo-4-methyl- [2,5' -bipyrimidine ] -5-carboxylate as a white solid.

And 2, step: p-2 '-bromo-4-methyl- [2,5' -bipyrimidine]Application of typical ester hydrolysis conditions to Ethyl-5-carboxylate (LiOH, THF/H) ₂ O, example G) to give 2 '-bromo-4-methyl- [2,5' -bipyrimidine as a white solid]-5-carboxylic acid. LCMS (methods 5-95AB, ESI): t _R ＝0.671,[M+H] ⁺ ＝295.0。

And 3, step 3: from the compound 101-K and 2 '-bromo-4-methyl- [2,5' -bipyrimidine]5-Carboxylic acid, coupling using a typical amide analogous to that described in examples G and H (HATU/DIEA), suzuki, ester hydrolysis (LiOH, THF/H) ₂ O), amide coupling (HATU/DIEA) and Boc removal (TFA/HFIP) conditions to afford compound 232 (formate salt) as a white solid. LCMS (methods 5-95AB, ESI): t _R ＝0.753min,[M+H] ⁺ ＝968.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ9.66(s,2H),8.80(s,1H),8.54-8.36(m,5H),7.60(d,J＝7.6Hz,2H),7.33-7.22(m,2H),7.09-6.97(m,2H),6.85(s,1H),6.61(s,1H),6.48(s,1H),5.22-5.18(m,1H),4.85-4.74(m,2H),4.39-4.16(m,6H),3.28-3.05(m,8H),2.97(s,3H),2.68(s,3H),2.33-2.15(m,2H),1.39(s,9H),1.36(d,J＝6.8Hz,3H)。

Example 33: synthesis of Compound 233

Step 1: starting from ethyl 2- (4-bromophenyl) -4-methylpyrimidine-5-carboxylate (described in example 26), a typical Suzuki, hydrogenation (Pd/C, H) analogous to that described in examples G and H was applied ₂ ) And ester hydrolysis (NaOH, meOH/H) ₂ O) to yield 2- (4-cyclohexylphenyl) -4-methylpyrimidine-5-carboxylic acid as a white solid. LCMS (methods 5-95AB, ESI): t _R ＝0.901min,[M+H] ⁺ ＝296.9。

Compound 233 (formate) was prepared as a white solid from compound 101-K and 2- (4-cyclohexylphenyl) -4-methylpyrimidine-5-carboxylic acid using an analogous method to that described in example G. LCMS (methods 5-95AB, ESI): t _R ＝0.746min,[M+H] ⁺ ＝916.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.78(s,1H),8.37-8.30(m,3H),7.40-7.31(m,2H),7.25-7.20(m,2H),7.10(d,J＝8.4Hz,1H),6.92(s,1H),6.83(s,1H),6.38(s,1H),5.21-5.16(m,1H),4.84-4.80(m,2H),4.33-4.17(m,4H),4.20(s,2H),3.50-3.46(m,1H),3.27-3.10(m,7H),2.95(s,3H),2.71(s,3H),2.60-2.50(m,1H),2.34-2.29(m,1H),2.19-2.15(m,1H),1.92-1.87(m,4H),1.82-1.77(m,2H),1.55-1.45(m,4H),1.36(d,J＝7.2Hz,3H)。

Example 34: synthesis of Compound 234

Step 1: at-78 deg.C to TiCl ₄ Me was added to a solution of (3.2mL, 28.4 mmol) in DCM (10 mL) ₂ Zn (1N, 28.4mL in toluene), and the resulting orange-brown solution was stirred vigorously at the same temperature for 1h, followed by dropwise addition of a solution of 5-bromo-2, 3-dihydro-1-inden-1-one (1.0 g, 4.74mmol) in DCM (20 mL). The mixture was stirred at-78 ℃ for 2h; then brought to-10 ℃ and then saturated NH cooled with ice ₄ Aqueous Cl solution was quenched. The organic layer was separated and the aqueous layer was extracted with DCM (2X 40mL). The combined organic layers were washed with Na ₂ SO ₄ Drying, concentration and purification of the residue through a silica gel column eluting with petroleum ether gave 5-bromo-1, 1-dimethyl-2, 3-dihydro-1H-indene (450mg, 42% yield) as a yellow oil. ¹ H NMR(400MHz,CDCl ₃ )δ7.35(s,1H),7.20(d,J＝8.0Hz,1H),7.02(d,J＝8.0Hz,1H),2.90(t,J＝7.2Hz,2H),1.95(t,J＝7.2Hz,2H),1.27(s,6H)。

Compound 234 (formate salt) was prepared as a white solid from compound 101-K and 5-bromo-1, 1-dimethyl-2, 3-dihydro-1H-indene using a method analogous to that described in example 10 and example J. LCMS (methods 5-95AB, ESI): t _R ＝0.725min,[M+H] ⁺ ＝902.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.74(s,1H),8.52(br s,1H),8.18(d,J＝8.0Hz,1H),8.13(s,1H),7.31-7.21(m,3H),7.12-7.05(m,2H),6.85(s,1H),6.60(s,1H),6.54(s,1H),5.20-5.15(m,1H),4.82-4.69(m,2H),4.34-4.18(m,6H),3.23-3.12(m,8H),2.95(br s,5H),2.65(s,3H),2.20-2.17(m,2H),2.01(t,J＝6.8Hz,2H),1.36(d,J＝6.8Hz,3H),1.32(s,6H)。

Example 35: synthesis of Compound 235

Step 1: to a 0 ℃ solution of 4-bromo-2-chlorobenzonitrile (2.0 g,9.2 mmol) in THF (20 mL) was added HMDSLi (1N solution in THF, 13.9 mL) dropwise, and the reaction was stirred at 0 ℃ for 16h, followed by the addition of aqueous HCl (1N, 10 mL). The resulting precipitate was collected, washed with EtOAc, and dried under vacuum to give 4-bromo-2-chlorobenzamidine (4.0 g,93% yield).

Step 2:2- (4-butyl-2-chlorophenyl) -4-methylpyrimidine-5-carboxylic acid was prepared from 4-bromo-2-chlorobenzamidine as a white solid by a similar method to that described in example 26.

Compound 235 (formate) was prepared as a white solid by using an analogous method to that described in example G from compound 101-K and 2- (4-butyl-2-chlorophenyl) -4-methylpyrimidine-5-carboxylic acid. LCMS (method 5-95AB, ESI): t _R ＝0.713min,[M+H] ⁺ ＝924.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.86(s,1H),8.50(br s,1H),7.62(d,J＝8.4Hz,1H),7.40(s,1H),7.35-7.28(m,2H),7.25(d,J＝8.4Hz,1H),7.20(d,J＝8.8Hz,1H),7.10(d,J＝8.8Hz,1H),6.92(s,1H),6.82(s,1H),6.40(s,1H),5.23-5.16(m,1H),4.81-4.78(m,2H),4.27-4.17(m,4H),4.20(s,2H),3.36-3.13(m,8H),2.96(s,3H),2.74-2.69(m,2H),2.71(s,3H),2.34-2.27(m,1H),2.21-2.15(m,1H),1.71-1.62(m,2H),1.46-1.35(m,5H),0.98(t,J＝7.2Hz,3H)。

Example 36: synthesis of Compound 236

Compound 236 (formate) was prepared as a white solid from (4-bromophenyl) (phenyl) methanone and compound 101-K by using an analogous method to that described in example 34. LCMS (method 5-95AB, ESI): t _R ＝0.632min,[M+H] ⁺ ＝952.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.74(s,1H),8.49(br s,2H),8.27(d,J＝7.6Hz,2H),7.36(d,J＝8.4Hz,2H),7.32-7.10(m,8H),7.03(d,J＝8.4Hz,1H),6.86(s,1H),6.67(s,1H),6.47(s,1H),5.21-5.14(m,1H),4.79-4.75(m,2H),4.32-4.13(m,6H),3.25-3.07(m,8H),2.95(s,3H),2.66(s,3H),2.37-2.23(m,1H),2.21-2.08(m,1H),1.73(s,6H),1.35(d,J＝6.8Hz,3H)。

Example 37: synthesis of Compound 237

Compound 237 (formate) was prepared as a white solid from compound 101-K by using an analogous method to that described in example J. LCMS (methods 5-95AB, ESI): t _R ＝0.706min,[M+H] ⁺ ＝890.7； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.81(s,1H),8.50(s,1H),8.45(br s,1H),8.26(d,J＝8.0Hz,1H),7.61(d,J＝8.0Hz,1H),7.44(t,J＝8.0Hz,1H),7.37-7.30(m,1H),7.26-7.17(m,2H),7.09(d,J＝8.0Hz,1H),6.91(d,J＝2.0Hz,1H),6.82(s,1H),6.39(s,1H),5.23-5.16(m,1H),4.80-4.76(m,2H),4.29-4.15(m,6H),3.27-3.09(m,8H),2.96(s,3H),2.72(s,3H),2.35-2.26(m,1H),2.22-2.13(m,1H),1.40(s,9H),1.36(d,J＝6.5Hz,3H)。

Example 38: synthesis of Compound 238

Step 1: a mixture of ethyl 2- (4-bromophenyl) acetate (10.0g, 41mmol) and lithium diisopropylamide (2N in THF, 41mL) in anhydrous THF (60 mL) was stirred at-78 deg.C for 0.5h, followed by addition of cyano-ethyl formate (4.14mL, 45mmol). The resulting mixture was gradually warmed to 20 ℃ while stirring and stirred at the same temperature for 18h. The reaction was quenched with water (30 mL) and partitioned between 1N aqueous HCl (150 mL) and DCM (150 mL). The organic layer is coated with Na ₂ SO ₄ Dried and concentrated, and the residue was purified by silica gel chromatography, eluting with 0-20% etoac in petroleum ether, to give diethyl 2- (4-bromophenyl) malonate (8.5 g,66% yield).

And 2, step: a mixture of diethyl 2- (4-bromophenyl) malonate (10.0g, 32mmol) and NaH (60% dispersion in oil, 2.5g, 64mmol) in dry THF (80 mL) was stirred at 0 deg.C for 0.5h, followed by the addition of iodomethane (6.0mL, 96mmol). The resulting mixture was gradually warmed to 20 ℃ while stirring and stirred at the same temperature for 16h. The reaction was partitioned between 1N aqueous HCl (150 mL) and DCM (150 mL). The organic layer is coated with Na ₂ SO ₄ Dried and concentrated, and the residue was purified by silica gel chromatography, eluting with 0-20% etoac in petroleum ether, to give diethyl 2- (4-bromophenyl) -2-methylmalonate as a colorless oil (5.2g, 50% yield).

And step 3: diethyl 2- (4-bromophenyl) -2-methylmalonate (5.2g, 15.8mmol) and LiAlH ₄ (3.0 g, 79mmol) of the mixture was stirred at 0 ℃ for 5h. The mixture was quenched with water (20 mL) and partitioned between 1N aqueous HCl (100 mL) and DCM (150 mL). The organic layer was washed with Na ₂ SO ₄ Dried and concentrated, and the residue was purified by silica gel chromatography, eluting with EtOAc/petroleum ether (1.

And 4, step 4: a mixture of 2- (4-bromophenyl) -2-methylpropane-1, 3-diol (2.0g, 8.2mmol), triphenylphosphine (4.3g, 16.4mmol) and diisopropyl azodicarboxylate (3.2mL, 16.4 mmol) in toluene (20 mL) was heated at 140 ℃ for 1h under microwave irradiation. The volatiles were removed and the residue was purified by silica gel column, eluting with 10% EtOAc/petroleum ether, to give 3- (4-bromophenyl) -3-methyloxetane as a colorless oil (0.58g, 31% yield). ¹ H NMR(400MHz,CD ₃ Cl)δ7.48(d,J＝8.4Hz,2H),7.09(d,J＝8.4Hz,2H),4.92(d,J＝5.2Hz,2H),4.63(d,J＝5.2Hz,2H),1.71(s,3H)。

Compound 238 (formate) was prepared as a white solid from compound 101-K and 3- (4-bromophenyl) -3-methyloxetane using procedures analogous to those described in example 10 and example J. LCMS (method 5-95AB, ESI): t _R ＝0.618min,[M+H] ⁺ ＝904.7； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.80(s,1H),8.46(br s,3H),8.43(s,1H),7.38(d,J＝8.0Hz,2H),7.33(d,J＝8.4Hz,1H),7.23-7.19(m,2H),7.09(d,J＝8.4Hz),6.91(s,1H),6.77(s,1H),6.42(s,1H),5.20-5.16(m,1H),5.03-5.00(m,2H),4.83-4.80(m,2H),4.73-4.70(m,2H),4.30-4.20(m,6H),3.25-3.12(m,8H),2.96(s,3H),2.71(s,3H),2.30-2.16(m,2H),1.76(s,3H),1.36(d,J＝6.8Hz,3H)。

Example 39: synthesis of Compound 239

Compound 239 (formate) was prepared as a white solid from compound 101-K by using an analogous method to that described in example 17. LCMS (methods 5-95AB, ESI): t _R ＝0.790min,[M+H] ⁺ ＝968.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.78(s,1H),8.51(br s,3H),8.36(d,J＝8.0Hz,2H),7.52(d,J＝8.4Hz,2H),7.33(d,J＝8.0Hz,1H),7.23-7.17(m,2H),7.08(d,J＝8.4Hz,1H),6.89(s,1H),6.73(s,1H),6.46(s,1H),5.17-5.21(m,1H),4.81-4.79(m,2H),4.31-4.19(m,6H),3.10-3.22(m,8H),2.97(s,3H),2.69(s,3H),2.56(br s,2H),2.27-2.32(m,1H),2.19-2.16(m,1H),2.00-2.10(m,6H),1.78-1.94(m,6H),1.70-1.62(m,2H),1.36(d,J＝7.2Hz,3H)。

Example 40: synthesis of Compound 240

Compound 240 (formate) was prepared as a white solid from compound 101-K by using a similar method to that described in example 26. LCMS (methods 5-95AB, ESI): t _R ＝0.774min,[M+H] ⁺ ＝932.7； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.75(s,1H),8.48(br s,2H),8.29(d,J＝8.0Hz,2H),8.31(d,J＝8.0Hz,2H),7.24-7.13(m,2H),7.08(d,J＝8.0Hz,2H),6.88(s,1H),6.71(s,1H),6.47(s,1H),5.21-5.16(m,1H),4.82-4.75(m,2H),4.35-4.16(m,4H),4.21(s,2H),3.27-3.05(m,8H),2.96(s,3H),2.76-2.64(m,2H),2.67(s,3H),2.32-2.27(m,1H),2.21-2.14(m,1H),1.71-1.64(m,2H),1.45-1.25(m,11H),0.90(t,J＝6.8Hz 3H)。

Example 41: synthesis of Compound 241

Compound 241 (formate) was prepared as a white solid from compound 101-K by using a similar method as described in example J. LCMS (methods 5-95AB, ESI): t _R ＝0.731min,[M+H] ⁺ ＝920.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.72(s,1H),8.51(br s,2H),8.33(d,J＝8.4Hz,2H),7.31(d,J＝8.0Hz,1H),7.23-7.16(m,2H),7.08(d,J＝8.0Hz,1H),7.01(d,J＝8.4Hz,2H),6.88(s,1H),6.71(s,1H),6.48(s,1H),5.22-5.15(m,1H),4.85-4.79(m,2H),4.35-4.13(m,6H),4.07(t,J＝6.4Hz,2H),3.29-3.01(m,8H),2.96(s,3H),2.66(s,3H),2.35-2.24(m,1H),2.22-2.15(m,1H),1.88-1.78(m,2H),1.50-1.38(m,6H),1.35(d,J＝6.8Hz,3H),0.98(t,J＝7.2Hz,3H)。

Example 42: synthesis of Compound 242

Compound 242 (formate) was prepared as a white solid from compound 101-K by using an analogous method to that described in example J. LCMS (methods 5-95AB, ESI): t _R ＝0.713min,[M+H] ⁺ ＝920.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.80(s,1H),7.82(d,J＝8.8Hz,1H),7.36(d,J＝8.4Hz,1H),7.26(d,J＝8.4Hz,1H),7.20(d,J＝8.8Hz,1H),7.11(d,J＝8.8Hz,1H),6.92(s,1H),6.89-6.85(m,2H),6.83(s,1H),6.39(s,1H),5.21-5.16(m,1H),4.84-4.79(m,2H),4.34-4.18(m,6H),4.05(t,J＝6.4Hz,2H),3.37-3.11(m,8H),2.96(s,3H),2.70(s,3H),2.56(s,3H),2.32-2.27(m,1H),2.21-2.15(m,1H),1.82-1.75(m,2H),1.61-1.48(m,4H),1.36(d,J＝7.2Hz,3H),1.01(t,J＝7.6Hz,3H)。

Example 43: synthesis of Compound 243

Compound 243 (formate) was prepared as a white solid from compound 101-K by using a method analogous to that described in example J. LCMS (methods 5-95AB, ESI): t _R ＝0.731min,[M+H] ⁺ ＝934.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.75(s,1H),8.08(s,2H),7.33-7.28(m,1H),7.23-7.17(m,2H),7.11-7.05(m,1H),6.88(s,1H),6.73(s,1H),6.45(s,1H),5.20-5.14(m,1H),4.82-4.75(m,2H),4.29-4.17(m,6H),3.89-3.83(m,2H),3.25-3.10(m,8H),2.96(s,3H),2.67(s,3H),2.43(s,6H),2.33-2.10(m,2H),1.89-1.77(m,2H),1.66-1.54(m,2H),1.36(d,J＝6.8Hz,3H),1.04(t,J＝7.2Hz,3H)。

Example 44: synthesis of Compound 244

Step 1: 4-bromo-2-fluorophenol (1.0g, 5.2mmol), 1-bromobutane (1.1g, 7.8mmol) and Cs ₂ CO ₃ A mixture of (5.1 g,15.7 mmol) in DMF (20 mL) in N ₂ Stirred at 20 ℃ for 16h. The volatiles were removed and the residue was redissolved with EtOAc (100 mL) and washed with brine (2x 100mL). The organic layer was washed with Na ₂ SO ₄ Drying, concentration and purification of the residue through a silica gel column eluting with petroleum ether gave 4-bromo-1-butoxy-2-fluorobenzene as a yellow oil (1.1g, 85% yield).

Compound 244 (formate salt) was prepared as a white solid from compound 101-K and 4-bromo-1-butoxy-2-fluorobenzene using a similar method to that described in example 10 and example J. LCMS (method 5-95AB, ESI): t _R ＝0.720min,[M+H] ⁺ ＝924.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.72(s,1H),8.50(br s,1H),8.22(d,J＝8.4Hz,1H),8.07(d,J＝8.4Hz,1H),7.32(d,J＝8.4Hz,1H),7.25-7.15(m,3H),7.08(d,J＝8.4Hz,1H),6.88(s,1H),6.69(s,1H),6.47(s,1H),5.22-5.15(m,1H),4.82-4.77(m,2H),4.39-4.19(m,6H),4.16(t,J＝6.0Hz,2H),3.29-3.03(m,8H),2.96(s,3H),2.66(s,3H),2.31-2.28(m,1H),2.19-2.16(m,1H),1.90-1.79(m,2H),1.60-1.52(m,2H),1.36(d,J＝7.2Hz,3H),1.03(t,J＝7.2Hz,3H)。

Example 45: synthesis of Compound 245

Compound 245 (formate salt) was prepared as a white solid from compound 101-K and 1-bromo-4- (isopentyloxy) benzene using an analogous method to that described in example 244. LCMS (method 5-95AB, ESI): t _R ＝0.623min,[M+H] ⁺ ＝920.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.71(s,1H),8.51(br s,1H),8.28(br s,2H),7.32-7.30(m,1H),7.22-7.15(m,2H),7.09-7.07(m,1H),7.05-7.01(m,2H),6.87(s,1H),6.66(br s,1H),6.48(br s,1H),5.19-5.18(m,1H),4.85-4.78(m,2H),4.29-4.18(m,6H),4.11(t,J＝6.4Hz,2H),3.31-3.13(m,8H),2.96(s,3H),2.65(s,3H),2.28-2.17(m,1H),2.17-2.15(m,1H),1.90-1.86(m,1H),1.74-1.69(m,2H),1.36(d,J＝6.4Hz,3H),1.01(t,J＝6.4Hz,6H)。

Example 46: synthesis of Compound 246

Compound 246 (formate) was prepared as a white solid from compound 101-K by using an analogous method to that described in example J. LCMS (methods 5-95AB, ESI): t _R ＝0.556min,[M+H] ⁺ ＝892.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.70(s,1H),8.49(br s,1H),8.29(d,J＝8.8Hz,2H),7.35-7.28(m,1H),7.24-7.13(m,2H),7.08(d,J＝8.4Hz,1H),6.98(d,J＝8.8Hz,2H),6.87(d,J＝2.2Hz,1H),6.68(s,1H),6.48(s,1H),5.22-5.13(m,1H),4.80-4.71(m,2H),4.36-4.12(m,7H),3.26-3.07(m,8H),2.96(s,3H),2.65(s,3H),2.32-2.24(m,1H),2.22-2.13(m,1H),1.38-1.3(m,9H)。

Example 47: synthesis of Compound 247

Compound 247 (formate) was prepared as a white solid from compound 101-K by using an analogous method to that described in example J. LCMS (method 5-95AB, ESI): t _R ＝0.632min,[M+H] ⁺ ＝940.8； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.72(s,1H),8.50(br s,2H),8.40-8.30(m,2H),7.31(d,J＝8.8Hz,1H),7.25-7.10(m,3H),7.07(d,J＝8.8Hz,1H),6.86(s,1H),6.63(s,1H),6.51(s,1H),5.25-5.15(m,1H),4.80-4.75(m,2H),4.40-4.20(m,6H),4.17(t,J＝6.4Hz,2Hz),3.40-3.05(m,8H),2.96(s,3H),2.66(s,3H),2.35-2.25(m,1H),2.20-2.15(m,1H),1.90-1.80(m,2H),1.62-1.55(m,2H),1.36(d,J＝6.8Hz,3H),1.04(t,J＝7.6Hz,3H)。

Example 48: synthesis of Compound 248

Compound 248 (formate) was prepared as a white solid from compound 101-K by using an analogous method to that described in example J. LCMS (methods 5-95AB, ESI): t _R ＝0.634min,[M+H] ⁺ ＝934.7； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.74(s,1H),8.49(br s,2H),8.38(br s,2H),7.32(d,J＝8.4Hz,1H),7.23-7.17(m,2H),7.09(d,J＝8.4Hz,1H),7.05-6.99(m,2H),6.91(s,1H),6.78(br s,1H),6.42(br s,1H),5.20-5.14(m,1H),4.81-4.75(m,2H),4.25-4.16(m,6H),4.07(t,J＝6.4Hz,2H),3.48(br s,1H),3.27-3.07(m,7H),2.95(s,3H),2.68(s,3H),2.37-2.20(m,1H),2.20-2.07(m,1H),1.88-1.75(m,3H),1.51-1.49(m,2H),1.44-1.29(m,6H),0.94(t,J＝7.2Hz,3H)。

Example 49: synthesis of Compound 249

Step 1: a mixture of 1- (5-bromo-2-hydroxyphenyl) ethan-1-one (1.0 g, 4.65mmol) and pyrrolidine (0.78mL, 9.3 mmol) in toluene (8 mL) was stirred at 25 ℃ for 10min, followed by addition of acetone (3 mL). The resulting mixture was stirred at the same temperatureAnd (5) 16h. The volatiles were removed and the residue was taken up in EtOAc (50 mL), which was washed with brine (2x 50mL). The organic layer is coated with Na ₂ SO ₄ Drying, concentration, and purification of the residue through a silica gel column, eluting with 0-5% EtOAc in petroleum ether, afforded 6-bromo-2, 2-dimethylchroman-4-one as a yellow oil (850 mg,72% yield).

Step 2: a mixture of 6-bromo-2, 2-dimethylchroman-4-one (650mg, 2.55mmol) and triethylsilane (1.45g, 12.8mmol) in TFA (6 mL) was stirred at 0 ℃ for 12h. The volatiles were removed and the residue was taken up in EtOAc (50 mL) which was saturated NaHCO ₃ Aqueous and brine (50 mL each). The organic layer was washed with Na ₂ SO ₄ Drying, concentration, and the residue was purified by silica gel column, eluting with 5% etoac in 1-petroleum ether, to give 6-bromo-2, 2-dimethyl chroman as a colorless oil (490 mg,80% yield). ¹ H NMR(400MHz,CDCl ₃ )δ7.19-7.16(m,2H),6.66(d,J＝8.4Hz,1H),2.76(t,J＝6.8Hz,1H),1.79(t,J＝6.8Hz,1H),1.33(s,6H)。

Compound 249 (formate salt) was prepared as a white solid from compound 101-K and 6-bromo-2, 2-dimethyl chroman using a similar method to that described in example 10 and example J. LCMS (method 5-95AB, ESI): t _R ＝0.709min,[M+H] ⁺ ＝918.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.68(s,1H),8.46(br s,1H),8.12-8.06(m,2H),7.31(d,J＝8.0Hz,1H),7.22(d,J＝8.4Hz,1H),7.16(d,J＝8.0Hz,1H),7.08(d,J＝8.4Hz,1H),6.86(s,1H),6.79(d,J＝8.4Hz,1H),6.63(s,1H),6.52(s,1H),5.21-5.15(m,1H),4.81-4.70(m,2H),4.36-4.21(m,6H),3.29-3.15(m,8H),2.97(s,3H),2.88(d,J＝6.4Hz,2H),2.64(s,3H),2.35-2.25(m,1H),2.22-2.12(m,1H),1.89(t,J＝6.4Hz,2H),1.38(s,6H),1.36(d,J＝7.2Hz,3H)。

Example 50: synthesis of Compound 250

Step 1: typical Boc removal (TFA/DCM) conditions were applied to compound 250-1 (prepared following a similar procedure as described for compound 101-H) to afford compound 250-2.

Step 2: to (COCl) ₃ (916mg, 2.85mmol) in anhydrous diethyl ether (6 mL) was added 2- (triethylsilyl) -ethanol (1.0g, 8.46mmol) and pyridine (535mg, 6.77mmol), and the mixture was stirred at-30 ℃ for 4h. After filtration, the filtrate was evaporated under reduced pressure, and the residue was distilled to give 2- (trimethylsilyl) ethylchloroformate (1.0 g,65% yield).

And 3, step 3: a solution of 2- (trimethylsilyl) ethylchloroformate (580 mg, 3.21mmol) in 1, 4-dioxane (10 mL) was dissolved with saturated NaHCO ₃ The aqueous solution was treated until pH 7-8, followed by addition of compound 250-2 (400mg, 0.53mmol). The resulting mixture was stirred at 20 ℃ for 2h. The volatiles were removed and the residue was taken up in EtOAc (30 mL) which was washed with saturated brine (30 mL). The organic layer is coated with Na ₂ SO ₄ Dry, concentrate, and purify the residue by preparative TLC (DCM/MeOH =10, 1, rf = 0.4) to give compound 250-3 as a yellow solid (500mg, 79% yield). LCMS (methods 5-95AB, ESI): t _R ＝1.007min,[M+H] ⁺ ＝1180.7。

And 4, step 4: compound 250-4 compound 250-3 was prepared as a white solid by using a similar method to that described in example 10 and example J. LCMS (methods 5-95AB, ESI): t _R ＝1.048min,[M+H] ⁺ ＝1339.7。

And 5: a mixture of compound 250-4 (70mg, 0.05mmol) and tetraethylammonium fluoride (1N in THF, 0.26mL) in THF (3 mL) was stirred at 60 ℃ for 16h. The volatiles were removed and the residue was purified by HPLC eluting with 14-45% aqueous acetonitrile (0.225% formic acid) to give compound 250 (formate salt) as a white solid (31.7 mg,67% yield). LCMS (methods 5-95AB, ESI): t _R ＝0.694min,[M+Na] ⁺ ＝928.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.76(s,1H),8.43(br s,3H),8.35(d,J＝8.4Hz,2H),7.32(d,J＝8.4Hz,1H),7.23-7.17(m,2H),7.13-7.07(m,3H),6.89(s,1H),6.76(s,1H),6.42(s,1H),5.20-5.15(m,1H),4.85-4.75(m,2H),4.30-4.18(m,6H),3.28-3.11(m,8H),2.95(s,3H),2.68(s,3H),2.40-2.30(m,1H),2.20-2.14(m,1H),1.43(s,9H),1.36(d,J＝7.2Hz,3H)。

Example 51: synthesis of Compound 251

Compound 251 (formate) was prepared as a white solid from compound 101-K by using an analogous method to that described in example J. LCMS (method 5-95AB, ESI): t _R ＝0.663min,[M+H] ⁺ ＝892.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.78(s,1H),8.48(br s,1H),7.97-7.93(m,2H),7.38(d,J＝8.0Hz,1H),7.32(d,J＝8.0Hz,1H),7.20(d,J＝8.4Hz,2H),7.08(d,J＝8.4Hz,2H),6.89(s,1H),6.72(s,1H),6.46(s,1H),5.21-5.17(m,1H),4.83-4.80(m,2H),4.72-4.68(m,1H),4.31-4.20(m,6H),3.25-3.13(m,8H),2.96(s,3H),2.69(s,3H),2.21-2.18(m,1H),2.17-2.13(m,1H),1.38-1.35(m,9H)。

Example 52: synthesis of Compound 252

Compound 252 (formate) was prepared as a white solid from compound 101-K by using a similar method to that described in example 10 and example J. LCMS (method 5-95AB, ESI): t _R ＝0.619min,[M+H] ⁺ ＝920.3； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.75(s,1H),8.52(br s,2H),8.37(d,J＝8.4Hz,2H),7.34(d,J＝8.0Hz,1H),7.22(d,J＝8.4Hz,2H),7.11(d,J＝8.0Hz,1H),7.05(d,J＝8.0Hz,2H),6.91(d,J＝1.8Hz,1H),6.76(s,1H),6.46(s,1H),5.23-5.16(m,1H),4.85-4.78(m,2H),4.32-4.19(m,6H),3.75(s,2H),3.28-3.12(m,8H),2.97(s,3H),2.69(s,3H),2.36-2.27(m,1H),2.23-2.11(m,1H),1.38(d,J＝6.8Hz,3H),1.10(s,9H)。

Example 53: synthesis of Compound 253

Step 1: a mixture of urea (0.52g, 8.6 mmol), acetaldehyde (0.49mL, 8.6 mmol), methyl 3-oxobutyrate (1.0 g,8.6 mmol) and glacial acetic acid (1 drop) in methanol (2 mL) was stirred at 90 ℃ for 16h. Water (10 mL) was added to the reaction mixture, followed by filtration; the filter cake was then washed with water and air dried to give methyl 4, 6-dimethyl-2-oxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxylate as a pale yellow solid (900mg, 56.7% yield).

And 2, step: adding methyl 4, 6-dimethyl-2-oxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxylate (900mg, 4.9 mmol) portionwise within 3min to ice-cold 50% HNO ₃ In solution (4.0 mL). The reaction mixture was stirred at 0 ℃ for 10min. The mixture was poured into ice water (20 mL) and washed with solid K ₂ CO ₃ Neutralized and the resulting mixture was extracted with ethyl acetate (10 mL). The aqueous layer was reused with CHCl ₃ (40mL. Times.2). The organic layers were combined and washed with Na ₂ SO ₄ Drying and concentration gave methyl 2-hydroxy-4, 6-dimethylpyrimidine-5-carboxylate as a pale yellow solid (500mg, 2.7mmol,56.1% yield).

And step 3: 2-hydroxy-4, 6-dimethylpyrimidine-5-carboxylic acid methyl ester, POCl ₃ A mixture of (6.2 mL,66.5 mmol) and DIPEA (1.28g, 9.9 mmol) was stirred at 110 ℃ for 3h. The mixture was evaporated in vacuo, diluted with ethyl acetate (40 mL) and saturated NaHCO ₃ Washed with aqueous solution (25 mL), brine (30 mL), and Na ₂ SO ₄ Dried and evaporated in vacuo. The residue was purified by silica gel chromatography (0-30% ethyl acetate in petroleum ether) to give methyl 2-chloro-4, 6-dimethylpyrimidine-5-carboxylate as a white solid (350mg, 1.7mmol,63.6% yield). ¹ H NMR(400MHz,CDCl3)δ3.98(s,3H),2.55(s,6H)。

And 4, step 4: methyl 2-chloro-4, 6-dimethylpyrimidine-5-carboxylate (4.5g, 22.4mmol), 4-tert-butylboronic acid (4.8g, 26.9mmol), pd (dppf) Cl ₂ (1.6 g, 2.24mmol) and Na ₂ CO ₃ (4.8g, 44.9mmol) in dioxane/water (110mL, v/v = 10/1) in N ₂ And stirred at 100 ℃ for 16h. The mixture was diluted with water (150 mL) and extracted with EtOAc (200mL x 3). The combined organic layers were washed with brine (300mL. Times.2) and Na ₂ SO ₄ Drying, concentrating, and passing through silica gelChromatography purification, eluting with 0-5% EtOAc in petroleum ether, afforded methyl 2- (4- (tert-butyl) phenyl) -4, 6-dimethylpyrimidine-5-carboxylate as a white solid (6.2g, 93% yield). LCMS (methods 5-95AB, ESI): t _R ＝1.075min,[M+H] ⁺ ＝299.1。

And 5: a mixture of methyl 2- (4- (tert-butyl) phenyl) -4, 6-dimethylpyrimidine-5-carboxylate (6.2g, 20.8mmol) and NaOH (1.7g, 41.6 mmol) in MeOH/water (80ml, v/v = 1) was stirred at 90 ℃ for 4h. Volatiles were removed under reduced pressure and the residue was acidified to pH = 4-5 with 1N HCl, followed by extraction with EtOAc (100mL x 2). The combined organic layers were washed with brine (100mL. Times.2) and Na ₂ SO ₄ Drying and concentration gave 2- (4- (tert-butyl) phenyl) -4, 6-dimethylpyrimidine-5-carboxylic acid as a white solid (5.8g, 98% yield). LCMS (method 5-95AB, ESI): t _R ＝0.936min,[M+H] ⁺ ＝285.0； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.39(d,J＝8.4Hz,2H),7.52(d,J＝8.4Hz,2H),2.75(s,6H),1.37(s,9H)。

Compound 253 (formate salt) was prepared as a white solid from compound 101-K and 2- (4- (tert-butyl) phenyl) -4, 6-dimethylpyrimidine-5-carboxylic acid using an analogous method to that described in example J. LCMS (methods 5-95AB, ESI): t _R ＝0.715min,[M+H] ⁺ ＝904.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.48(br s,1H),8.34(d,J＝8.0Hz,2H),7.55(d,J＝8.0Hz,2H),7.24-7.15(m,2H),7.04(d,J＝8.0Hz,1H),6.95-6.90(m,1H),6.83(s,1H),6.73(s,1H),6.47(s,1H),5.28-5.23(m,1H),4.83-4.80(m,2H),4.54-4.45(m,2H),4.32-4.23(m,4H),3.42-3.38(m,1H),3.27-3.12(m,7H),3.05(s,3H),2.57(s,6H),2.38-2.26(m,1H),2.25-2.13(m,1H),1.39(s,3H),1.35(t,J＝7.2Hz,3H)。

Example 54: synthesis of Compound 254

Compound 254 (formate) was prepared as a white solid from compound 106-B2 by using an analogous method to that described in examples 53 and V. LCMS (method 5-95AB, ESI): t _R ＝0.776min,[M+H] ⁺ ＝861.5； ¹ H NMR(500MHz,DMSO-d6)δ9.17(d,J＝7.3Hz,1H),8.98(d,J＝7.7Hz,1H),8.71(t,J＝5.5Hz,1H),8.44(d,J＝9.0Hz,1H),8.36–8.29(m,2H),7.59–7.52(m,2H),7.19–7.04(m,3H),6.90–6.80(m,2H),6.71(s,1H),6.42(s,1H),5.09–5.01(m,1H),4.80–4.66(m,2H),4.29–4.15(m,4H),3.19–3.09(m,3H),3.02–2.88(m,6H),2.50(s,6H),2.14–2.03(m,1H),2.02–1.91(m,1H),1.35(s,9H),1.21(d,J＝6.6Hz,3H)。

Example 55: synthesis of Compound 255

Compound 255 (formate) was prepared as a white solid from compound 101-K by using a similar method to that described in example 53. LCMS (methods 5-95AB, ESI): t _R ＝0.715min,[M+H] ⁺ ＝904.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.44(br s,2H),8.33(d,J＝7.6Hz,2H),7.35-7.27(m,3H),7.26-7.18(m,2H),7.10(d,J＝8.4Hz,1H),6.92(s,1H),6.83(s,1H),6.42(s,1H),5.24-5.20(m,1H),4.85-4.75(m,2H),4.30-4.16(m,6H),3.49-3.47(m,1H),3.26-3.10(m,6H),3.01(s,3H),2.69(t,J＝7.6Hz,2H),2.57(s,6H),2.32-2.24(m,1H),2.20-2.12(m,1H),1.69-1.63(m,2H),1.43-1.38(m,2H),1.36(d,J＝6.8Hz,3H),0.97(t,J＝7.6Hz,3H)。

Example 56: synthesis of Compound 256

Step 1: starting from methyl 2-chloro-4, 6-dimethylpyrimidine-5-carboxylate (described in example 53), typical Suzuki, sonogashira, hydrogenations (Pd/C, H) analogous to those described in examples D, H and K were applied ₂ ) And ester hydrolysis (NaOH, meOH/H) ₂ O) to yield 2- (4-heptylphenyl) -4, 6-dimethylpyrimidine-5-carboxylic acid as a white solid.

Compound 256 (formate) was prepared from compound 101-K and 2- (4-heptylphenyl) by using an analogous method to that described in example G) 4, 6-dimethylpyrimidine-5-carboxylic acid was prepared as a white solid. LCMS (method 5-95AB, ESI): t _R ＝0.652min,[M+H] ⁺ ＝946.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.48(br s,2H),8.24-8.18(m,2H),7.31-7.22(m,4H),7.12-7.06(m,2H),6.88(s,1H),6.66(s,1H),6.53(s,1H),5.25-5.21(m,1H),4.85-4.77(m,2H),4.34(s,2H),4.30-4.22(m,4H),3.27-3.16(m,4H),3.18-3.05(m,4H),3.02(s,3H),2.69(t,J＝7.6Hz,2H),2.50(s,6H),2.32-2.26(m,1H),2.20-2.14(m,1H),1.70-1.61(m,2H),1.42-1.28(m,11H),0.91(t,J＝6.8Hz,3H)。

Example 57: synthesis of Compound 257

Compound 257 (formate) was prepared from compound 101-K by using an analogous method to that described in example 53 as a white solid. LCMS (method 5-95AB, ESI): t _R ＝0.737min,[M+Na] ⁺ ＝942.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.50(br s,1H),8.40(d,J＝8.0Hz,2H),7.68(d,J＝8.0Hz,2H),7.31(d,J＝8.0Hz,1H),7.30-7.15(m,2H),7.11(d,J＝8.0Hz,1H),6.94(d,J＝2.0Hz,1H),6.83(s,1H),6.45(s,1H),5.30-5.20(m,1H),4.80-4.70(m,2H),4.30-4.10(m,6H),3.25-3.10(m,8H),3.03(s,3H),2.59(s,6H),2.35-2.25(m,1H),2.25-2.10(m,1H),1.38(d,J＝7.2Hz,3H),0.33(s,9H)。

Example 58: synthesis of Compound 258

Compound 258 (formate) was prepared as a white solid from compound 101-K by using an analogous method to that described in example 53. LCMS (method 5-95AB, ESI): t _R ＝0.733min,[M+H] ⁺ ＝905.0； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.50(br s,1H),8.28(d,J＝8.0Hz,2H),7.35-7.25(m,3H),7.25-7.15(m,2H),7.09(d,J＝8.4Hz,1H),6.90(s,1H),6.75(brs,1H),6.48(s,1H),5.35-5.20(m,1H),4.80-4.70(m,2H),4.40-4.10(m,6H),3.30-3.05(m,8H),3.01(s,3H),2.60-2.45(m,8H),2.35-2.25(m,1H),2.25-2.10(m,1H),2.00-1.90(m,1H),1.36(d,J＝7.2Hz,3H),0.96(t,J＝6.8Hz,6H)。

Example 59: synthesis of Compound 259

Compound 259 (formate) was prepared as a white solid from compound 101-K by using an analogous method to that described in example 53. LCMS (methods 5-95AB, ESI): t _R ＝0.621min,[M+H] ⁺ ＝902.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.51(brs,2H),8.04(brs,2H),7.45-7.35(m,1H),7.30-7.05(m,5H),6.89(s,1H),6.72(s,1H),6.49(s,1H),5.30-5.20(m,1H),4.85-4.75(m,2H),4.35-4.10(m,6H),3.35-3.05(m,8H),3.01(s,3H),2.84(brs,4H),2.52(s,6H),2.30-2.20(m,1H),2.20-2.10(m,1H),1.86(brs,4H),1.35(d,J＝7.2Hz,3H)。

Example 60: synthesis of Compound 260

Compound 260 (formate) was prepared as a white solid from compound 101-K by using an analogous method to that described in example 53. LCMS (method 5-95AB, ESI): t _R ＝0.682min,[M+H] ⁺ ＝876.7； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.49(br s,2H),8.35-8.15(m,2H),7.40-7.30(m,3H),7.30-7.15(m,2H),7.09(d,J＝8.4Hz,1H),6.89(s,1H),6.73(s,1H),6.48(s,1H),5.35-5.20(m,1H),4.85-4.75(m,2H),4.35-4.10(m,6H),3.30-3.05(m,8H),3.01(s,3H),2.74(q,J＝7.2Hz,2H),2.53(s,6H),2.35-2.25(m,1H),2.25-2.05(m,1H),1.36(d,J＝6.4Hz,3H),1.30(t,J＝7.2Hz,3H)。

Example 61: synthesis of Compound 261

Compound 261 (formate) was prepared as a white solid from compound 101-K by using a similar method to that described in examples 53 and 10. LCMS (methods 5-95AB, ESI): t _R ＝0.735min,[M+H] ⁺ ＝918.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.42(br s,2H),8.33(d,J＝8.4Hz,2H),7.48(d,J＝8.4Hz,2H),7.30(d,J＝8.0Hz,1H),7.20(d,J＝8.0Hz,2H),7.10(d,J＝8.0Hz,1H),6.92(s,1H),6.79(s,1H),6.44(s,1H),5.30-5.20(m,1H),4.85-4.75(m,2H),4.35-4.15(m,6H),3.30-3.05(m,8H),3.01(s,3H),2.56(s,6H),2.35-2.25(m,1H),2.25-2.10(m,1H),1.78(q,J＝7.2Hz,2H),1.40-1.35(m,9H),0.72(t,J＝6.8Hz,3H)。

Example 62: synthesis of Compound 262

Compound 262 (formate salt) was prepared as a white solid from compound 101-K by using an analogous method to that described in examples 53 and 17. LCMS (methods 5-95AB, ESI): t _R ＝0.775min,[M+H] ⁺ ＝918.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.45(br s,1H),8.22(d,J＝8.0Hz,2H),7.35-7.15(m,4H),7.15-7.05(m,2H),6.88(s,1H),6.66(s,1H),6.52(s,1H),5.30-5.20(m,1H),4.85-4.70(m,2H),4.40-4.15(m,6H),3.40-3.35(m,1H),3.30-3.20(m,3H),3.15-2.95(m,7H),2.71(t,J＝8.0Hz,2H),2.50(s,6H),2.35-2.25(m,1H),2.25-2.15(m,1H),1.65-1.50(m,3H),1.36(d,J＝6.8Hz,3H),0.98(t,J＝5.6Hz,6H)。

Example 63: synthesis of Compound 263

Compound 263 (formate) was prepared as a white solid from compound 101-K by using procedures analogous to those described in examples 10 and 53. LCMS (methods 5-95AB, ESI): t _R ＝0.711min,[M+H] ⁺ ＝904.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.48(br s,1H),8.14(d,J＝7.6Hz,1H),7.58(d,J＝8.0Hz,1H),7.42-7.28(m,3H),7.25-7.16(m,2H),7.10(d,J＝8.4Hz,1H),6.90(s,1H),6.73(s,1H),6.48(s,1H),5.27-5.23(m,1H),4.82-4.76(m,2H),4.36-4.17(m,6H),3.29-3.09(m,8H),3.02(s,3H),2.55(s,6H),2.34-2.26(m,1H),2.22-2.14(m,1H),1.40(s,9H),1.36(d,J＝6.4Hz,3H)。

Example 64: synthesis of Compound 264

Step 1: a mixture of 2- (4-bromophenyl) acetonitrile (3.0 g,15.3 mmol) and NaH (60% in oil, 1.84g,45.9 mmol) in THF (100 mL) was stirred at 0 deg.C for 1h, followed by dropwise addition of iodomethane (9.5 g,67.2 mmol). The resulting mixture was stirred at 20 ℃ for 16h. The reaction mixture was washed with saturated NH ₄ Aqueous Cl (50 mL) was quenched and extracted with EtOAc (3x 50ml). The combined organic layers were washed with brine (2x 100mL) and Na ₂ SO ₄ Drying, concentration in vacuo, and purification of the residue by silica gel chromatography, eluting with 0-5% etoac in petroleum ether, afforded 2- (4-bromophenyl) -2-methylpropanenitrile (3.3g, 96% yield) as a pale yellow solid. ¹ H NMR(400MHz,CDCl ₃ )δ7.23(d,J＝8.0Hz,2H),7.36(d,J＝8.0Hz,2H),1.72(s,6H)。

Compound 264 (formate) was prepared as a white solid from compound 101-K and 2- (4-bromophenyl) -2-methylpropanenitrile using an analogous method to that described in examples 10 and 53. LCMS (method 0-30AB, ESI): t _R ＝1.153min,[M+H] ⁺ ＝915.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.50(br s,2H),8.32(d,J＝8.0Hz,2H),7.58(d,J＝8.0Hz,2H),7.27(brs,2H),7.10-7.01(m,2H),6.84(s,1H),6.60(brs,1H),6.49(brs,1H),5.35-5.29(m,1H),4.82-4.72(m,2H),4.40(s,2H),4.30-4.22(m,4H),3.29-3.21(m,4H),3.14(t,J＝7.7Hz,2H),3.02(s,3H),3.01-2.90(m,2H),2.46(s,6H),2.32-2.26(m,1H),2.20-2.13(m,1H),1.79(s,6H),1.35(d,J＝6.6Hz,3H)。

Example 65: synthesis of Compound 265

Compound 265 (formate) was prepared as a white solid from compound 101-K by using an analogous method to that described in examples 10 and 53. LCMS (methods 5-95AB, ESI): t _R ＝0.671min,[M+Na] ⁺ ＝896.8； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.58(br s,2H),8.31(d,J＝8.0Hz,2H),7.53(d,J＝8.0Hz,2H),7.31-7.21(m,2H),7.16-7.08(m,2H),6.90-6.78(m,2H),6.67(s,1H),6.51(s,1H),5.92(d,J＝17.6Hz,1H),5.36(d,J＝10.6Hz,1H),5.00-4.70(m,3H),4.34-4.26(m,4H),4.22(s,2H),3.27-3.23(m,4H),3.18-3.05(m,4H),3.02(s,3H),2.52(s,6H),2.30-2.28(m,1H),2.20-2.13(m,1H),1.36(d,J＝6.0Hz,3H)。

Example 66: synthesis of Compound 266

Step 1: 1- (4-bromophenyl) ethan-1-one was subjected to similar conditions as described in example 12 to give 1-bromo-4- (prop-1-en-2-yl) benzene as a colorless oil. ¹ H NMR(400MHz,CDCl ₃ )δ＝7.45(d,J＝8.4Hz,1H),7.34(d,J＝8.4Hz,1H),5.38(s,1H),5.12(s,1H),2.14(s,3H)。

Compound 266 (formate) was prepared as a white solid from compound 101-K and 1-bromo-4- (prop-1-en-2-yl) benzene using an analogous method to that described in examples 10 and 53. LCMS (methods 5-95AB, ESI): t _R ＝0.704min,[M+H] ⁺ ＝888.8； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.47(br s,1H),8.37(d,J＝8.0Hz,2H),7.61(d,J＝8.0Hz,2H),7.32-7.27(m,1H),7.23-7.16(m,2H),7.09(d,J＝8.0Hz,1H),6.90(brs,1H),6.76(brs,1H),6.44(s,1H),5.51(s,1H),5.25-5.20(m,1H),4.95-4.76(m,3H),4.30-4.16(m,6H),3.27-3.05(m,8H),3.00(s,3H),2.55(s,6H),2.29-2.24(m,1H),2.20(s,3H),2.18-2.12(m,1H),1.35(d,J＝7.2Hz,3H)。

Example 67: synthesis of Compound 267

Step 1: a mixture of 2- (4-bromophenyl) propan-2-ol (300mg, 1.39mmol) and NaH (60% in oil, 62mg, 1.53mmol) in THF (5 mL) was stirred at 0 deg.C for 1h, followed by the addition of iodomethane (3.8g, 27mmol). The resulting mixture was stirred at 15 ℃ for 5h. The reaction was diluted with water (30 mL) and extracted with EtOAc (3x 30mL). The combined organic layers were washed with brine (50 mL) and Na ₂ SO ₄ Dried and concentrated to give 1-bromo-4- (2-methoxyprop-2-yl) benzene (300 mg) as a colorless oil, which was used directly in the next step without further purification. ¹ H NMR(400MHz,CDCl ₃ )δ7.47(d,J＝8.4Hz,2H),7.28(d,J＝8.4Hz,2H),3.05(s,3H),1.50(s,6H)。

Compound 267 (formate salt) was prepared as a white solid from compound 101-K and 1-bromo-4- (2-methoxypropan-2-yl) benzene using an analogous method to that described in examples 10 and 53. LCMS (method 5-95AB, ESI): t _R ＝0.664min,[M+H] ⁺ ＝920.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.46(br s,2H),8.37(d,J＝8.0Hz,2H),7.53(d,J＝8.0Hz,2H),7.30(d,J＝8.4Hz,1H),7.22-7.17(m,2H),7.10(d,J＝8.4Hz,1H),6.90(s,1H),6.74(s,1H),6.46(s,1H),5.25-5.23(m,1H),4.80-4.76(m,1H),4.45-4.15(m,7H),3.26-3.05(m,11H),3.01(s,3H),2.54(s,6H),2.40-2.20(m,1H),2.15-2.05(m,1H),1.56(s,6H),1.35(d,J＝6.4Hz,3H)。

Example 68: synthesis of Compound 268

Step 1: starting from (3, 4-dichlorophenyl) boronic acid, similar Suzuki coupling and ester hydrolysis as described in example H (NaOH, meOH/H) were applied in succession ₂ O) to yield 2- (3, 4-dibutylphenyl) -4, 6-dimethylpyrimidine-5-carboxylic acid as a white solid.

Compound 268 (formate) was prepared as a white solid from compound 101-K and 2- (3, 4-dibutylphenyl) -4, 6-dimethylpyrimidine-5-carboxylic acid using an analogous method to that described in example G. LCMS (methods 5-95AB, ESI)):t _R ＝0.687min,[M+H] ⁺ ＝960.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.47(br s,3H),8.19(s,1H),8.09(d,J＝8.4Hz,1H),7.32-7.16(m,4H),7.09(d,J＝8.4Hz,1H),6.90(s,1H),6.77(s,1H),6.45(s,1H),5.26-5.20(m,1H),4.83-4.77(m,2H),4.33-4.15(m,6H),3.27-3.06(m,8H),3.00(s,3H),2.78-2.66(m,4H),2.54(s,6H),2.31-2.25(m,1H),2.19-2.13(m,1H),1.68-1.56(m,4H),1.52-1.41(m,4H),1.35(d,J＝7.2Hz,3H),0.99(t,J＝7.6Hz,6H)。

Example 69: synthesis of Compound 269

Compound 269 (formate) was prepared from compound 101-K as a white solid by using an analogous method to that described in examples 53 and 34. LCMS (method 5-95AB, ESI): t _R ＝0.723min,[M+H] ⁺ ＝916.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.44(br s,3H),8.13-8.02(m,2H),7.27-7.18(m,4H),7.08(b rs,2H),6.85(s,1H),6.60(br s,1H),5.32-5.28(m,1H),4.80-4.76(m,2H),4.40(s,2H),4.35-4.24(m,4H),3.40-3.33(m,1H),3.28-3.23(m,2H),3.14(t,J＝7.6Hz,3H),3.06-2.89(m,8H),2.46(s,6H),2.34-2.24(m,1H),2.21-2.11(m,1H),2.00(t,J＝7.6Hz,3H),1.35(d,J＝6.4Hz,3H),1.31(s,6H)。

Example 70: synthesis of Compound 270

Step 1: starting from 6-methoxy-3, 4-dihydronaphthalen-1 (2H) -one, applying dimethylation and demethylation conditions (as described in examples 34 and 98) gives 5, 5-dimethyl-5, 6,7, 8-tetrahydronaphthalen-2-ol as a yellow oil.

Compound 270 (formate) was prepared as a white solid from compound 101-K and 5, 5-dimethyl-5, 6,7, 8-tetrahydronaphthalen-2-ol using an analogous method to that described in examples 10 and 53. LCMS (method 5-95AB, ESI): t _R ＝0.741min,[M+H] ⁺ ＝930.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.51(br s,3H),8.03-7.95(m,2H),7.42(d,J＝8.0Hz,1H),7.28(br s,2H),7.10-7.02(m,2H),6.86(s,1H),6.63(br s,1H),5.31(br s,1H),4.80-4.78(m,2H),4.39(br s,2H),4.27(br s,4H),3.25-3.14(m,6H),3.10-2.95(m,2H),3.04(s,3H),2.87-2.79(m,2H),2.47(s,6H),2.32-2.17(m,2H),2.31-2.17(m,2H),1.89-1.88(m,2H),1.77-1.76(m,2H),1.40-1.35(m,9H)。

Example 71: synthesis of Compound 271

Step 1: after similar dimethylation conditions as described in example 34, 7-bromochroman-4-one was converted to 7-bromo-4, 4-dimethylchroman. ¹ H NMR(400MHz,CDCl ₃ )δ7.11(d,J＝8.0Hz,1H),7.00-6.95(m,2H),4.18(t,J＝5.2Hz,2H),1.82(t,J＝5.2Hz,2H),1.31(s,6H)。

Compound 271 (formate) was prepared as a white solid from compound 101-K and 7-bromo-4, 4-dimethyl chroman using an analogous method to that described in examples 10 and 53. LCMS (method 5-95AB, ESI): t _R ＝0.690min,[M+H] ⁺ ＝932.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.50(br s,2H),7.84(d,J＝8.0Hz,1H),7.40-7.22(m,4H),7.02(d,J＝8.0Hz,1H),6.86-6.70(m,3H),5.37-5.33(m,1H),4.85-4.72(m,2H),4.54-4.45(m,2H),4.25-4.15(m,6H),3.45-3.41(m,3H),3.28-3.24(m,3H),3.16-3.12(m,2H),3.02(s,3H),2.85-2.77(m,1H),2.37-2.31(m,5H),2.17-2.12(m,2H),1.93-1.89(m,2H),1.43-1.34(m,9H)。

Example 72: synthesis of Compound 272

Compound 272 (formate) was prepared as a white solid from compound 101-K by using a similar method to that described in example 66. LCMS (methods 5-95AB, ESI): t _R ＝0.739min,[M+H] ⁺ ＝916.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.45(br s,2H),8.28(d,J＝8.0Hz,2H),7.29(d,J＝8.0Hz,1H),7.24-7.15(m,4H),7.09(d,J＝8.4Hz,1H),6.89(s,1H),6.69(s,1H),6.50(s,1H),5.26-5.23(m,1H),4.81-4.76(m,2H),4.32-4.17(m,6H),3.31-3.12(m,8H),3.01(s,3H),2.52(s,6H),2.32-2.13(m,2H),2.00(s,3H),1.86(s,3H),1.63(s,3H),1.36(d,J＝6.4Hz,3H)。

Example 73: synthesis of Compound 273

Compound 273 (formate) was prepared from compound 101-K as a white solid by using a similar method to that described in example 66. LCMS (method 5-95AB, ESI): t _R ＝0.724min,[M+H] ⁺ ＝902.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.49(br s,3H),8.19(d,J＝7.2Hz,2H),7.30-7.20(m,4H),7.08(brs,2H),6.86(s,1H),6.61(s,1H),6.55(s,1H),6.35(s,1H),5.35-5.25(m,1H),4.85-4.75(m,2H),4.40-4.20(m,8H),3.28-3.24(m,2H),3.17-3.13(m,2H),3.05-2.95(m,2H),3.01(s,3H),2.46(s,6H),2.35-2.25(m,1H),2.20-2.10(m,1H),1.96(s,3H),1.94(s,3H),1.35(d,J＝6.8Hz,3H)。

Example 74: synthesis of Compound 274

Compound 274 (formate) was prepared from compound 101-K as a white solid by using a similar method to that described in example 66. LCMS (method 5-95AB, ESI): t _R ＝0.682min,[M+H] ⁺ ＝928.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.49(br s,3H),8.26(d,J＝8.0Hz,2H),7.39(d,J＝8.0Hz,2H),7.29(d,J＝8.0Hz,1H),7.24(d,J＝8.0Hz,1H),7.14-7.09(m,2H),6.89(s,1H),6.66(s,1H),6.54(s,1H),6.45(s,1H),5.29-5.26(m,1H),4.79-4.60(m,2H),4.34-4.23(m,6H),3.27-3.00(m,8H),3.02(s,3H),2.67-2.61(m,2H),2.56-2.49(m,6H),2.52(s,2H),2.33-2.28(m,1H),2.20-2.16(m,1H),1.90-1.83(m,2H),1.75-1.71(m,2H),1.36(d,J＝7.2Hz,3H)。

Example 75: synthesis of Compound 275

Step 1: starting from methyl 2- (4- (cyclopentylidenemethyl) phenyl) -4, 6-dimethylpyrimidine-5-carboxylate (as described in example 74), a typical hydrogenation (Pd/C, H) was applied ₂ Example D) and ester hydrolysis (NaOH, meOH/H) ₂ O, example H) to give 2- (4- (cyclopentylmethyl) phenyl) -4, 6-dimethylpyrimidine-5-carboxylic acid as a white solid. LCMS (methods 5-95AB, ESI): t _R ＝1.015min,[M+H] ⁺ ＝311.0。

Compound 275 (formate) was prepared as a white solid from compound 101-K and 2- (4- (cyclopentylmethyl) phenyl) -4, 6-dimethylpyrimidine-5-carboxylic acid using an analogous method to that described in example G. LCMS (methods 5-95AB, ESI): t _R ＝0.747min,[M+H] ⁺ ＝930.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.53(br s,3H),8.17(d,J＝8.0Hz,2H),7.30-7.22(m,4H),7.13-7.07(m,2H),6.87(s,1H),6.64(s,1H),6.55(br s,1H),5.34-5.30(m,1H),4.82-4.77(m,2H),4.38-4.26(m,6H),3.29-3.14(m,8H),3.04(s,3H),2.71(d,J＝7.6Hz,2H),2.47(s,6H),2.34-2.29(m,1H),2.19-2.18(m,1H),1.76-1.60(m,7H),1.37(d,J＝7.2Hz,3H),1.33-1.26(m,2H)。

Example 76: synthesis of Compound 276

Step 1: 4-methyl-N' - (pent-3-ylidene) benzenesulfonylhydrazide (1.0 g,3.9 mmol), 1- (bromomethyl) -4-chlorobenzene (88mg, 4.3 mmol), and Pd ₂ (dba) ₃ A mixture of (90mg, 0.10 mmol), tris (2-furyl) phosphine (183mg, 0.79mmol) and t-BuOLi (944mg, 11.8 mmol) in toluene (40 mL) was stirred under nitrogen at 80 ℃ for 16h. The volatiles were removed under reduced pressure and the residue was taken up in EtOAc (100 mL) which was washed with brine (100 mL). The organic layer was MgSO ₄ Drying, concentrating, and purifying the residue by silica gel chromatography on silica gel with stone5% in oil ether eluted with EtOAc to give 1-chloro-4- (2-ethylbut-1-en-1-yl) benzene as a colorless oil (200mg, 26% yield). ¹ H NMR(CDCl ₃ ,400MHz):7.28(d,J＝8.4Hz,2H),7.14(d,J＝8.4Hz,2H),6.18(s,1H),2.24-2.14(m,4H),1.14-1.05(m,6H)。

And 2, step: 1-chloro-4- (2-ethylbut-1-en-1-yl) benzene (500mg, 2.6mmol), bis (pinacol) diboron (783mg, 3.1mmol), pd ₂ (dba) ₃ A mixture of (118mg, 0.13mmol), tricyclohexylphosphine (86mg, 0.31mmol) and potassium acetate (755mg, 7.7mmol) in 1, 4-dioxane (20 mL) was stirred under nitrogen at 100 ℃ for 16h. The volatiles were removed under reduced pressure and the residue was purified by silica gel chromatography eluting with 0-1% EtOAc in petroleum ether to give 2- (4- (2-ethylbut-1-en-1-yl) phenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan as a green oil (400mg, 54% yield).

Compound 276 (formate salt) was prepared as a white solid from compound 101-K and 2- (4- (2-ethylbut-1-en-1-yl) phenyl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan using an analogous method to that described in example 53. LCMS (method 5-95AB, ESI): t _R ＝0.641min,[M+H] ⁺ ＝930.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.51(s,2H),8.20(d,J＝8.0Hz,2H),7.31-7.22(m,4H),7.08(br s,2H),6.86(s,1H),6.66-6.51(m,2H),6.32(s,1H),5.33-5.26(m,1H),4.87-4.72(m,2H),4.32(s,2H),4.29-4.20(m,4H),3.29-3.20(m,4H),3.18-3.12(s,2H),3.08-2.98(m,5H),2.47(s,6H),2.40-2.24(m,5H),2.22-2.12(m,1H),1.35(d,J＝6.4Hz,3H),1.20-1.10(m,6H)。

Example 77: synthesis of Compound 277

Step 1: starting from methyl 2- (4- (2-ethylbut-1-en-1-yl) phenyl) -4, 6-dimethylpyrimidine-5-carboxylate (prepared as described in example 76), a typical hydrogenation (Pd/C, H) was applied ₂ Example D) and ester hydrolysis (NaOH, meOH/H) ₂ O, example H) to give 2- (4- (2-ethylbutane) as a white solidYl) phenyl) -4, 6-dimethylpyrimidine-5-carboxylic acid.

Compound 277 (formate) was prepared as a white solid from compound 101-K and 2- (4- (2-ethylbutyl) phenyl) -4, 6-dimethylpyrimidine-5-carboxylic acid using an analogous method to that described in example G. LCMS (methods 5-95AB, ESI): t _R ＝0.767min,[M+H] ⁺ ＝932.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.49(br s,2H),8.20(d,J＝8.0Hz,2H),7.32-7.18(m,4H),7.15-7.04(m,2H),6.86(s,1H),6.62(s,1H),6.53(s,1H),5.30-5.23(m,1H),4.78-4.55(m,2H),4.34(s,2H),4.27-4.16(m,4H),3.28-3.19(m,4H),3.13-3.05(m,4H),3.01(s,3H),2.62(d,J＝7.2Hz,2H),2.49(s,6H),2.35-2.23(m,1H),2.20-2.12(m,1H),1.64-1.53(m,1H),1.39-1.31(m,7H),0.93(t,J＝7.2Hz,6H)。

Example 78: synthesis of Compound 278

Compound 278 (formate) was prepared from compounds 101-K as white solid 6 by using an analogous method to that described in example 5. LCMS (methods 5-95AB, ESI): t _R ＝0.631min,[M+H] ⁺ ＝916.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.14-8.10(m,2H),7.48-7.40(m,2H),7.26(br s,2H),7.07-7.00(m,2H),6.83(s,1H),6.66(s,1H),6.50-6.38(m,3H),5.34-5.30(m,1H),4.79-4.74(m,2H),4.30-4.20(m,6H),3.31-3.14(m,6H),2.91(s,3H),2.90-2.80(m,2H),2.45(s,6H),2.28-2.21(m,4H),1.60-1.51(m,2H),1.36(d,J＝6.8Hz,3H),1.01(t,J＝7.6Hz,3H)。

Example 79: synthesis of compound 279

Step 1: typical Wittig reaction conditions were applied to 4-bromobenzaldehyde (as described in example 12) to give (E) -1-bromo-4- (but-1-en-1-yl) benzene as a colorless oil.

Compound 279 (formate) by use of an analogous method to that described in example 53The procedure was prepared from compound 101-K and (E) -1-bromo-4- (but-1-en-1-yl) benzene as a white solid. LCMS (methods 5-95AB, ESI): t _R ＝0.714min,[M+H] ⁺ ＝902.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.46(br s,1H),8.25-8.21(m,2H),7.45-7.05(m,7H),6.88(brs,1H),6.50-6.40(m,3H),5.79-5.73(m,1H),5.27-5.22(m,1H),4.81-4.75(m,2H),4.32-4.20(m,6H),3.24-3.11(m,6H),3.05-2.96(m,5H),2.52(s,6H),2.41-2.27(m,3H),2.20-2.13(m,1H),1.36(d,J＝6.8Hz,3H),1.10(t,J＝7.6Hz,3H)

Example 80: synthesis of Compound 280

Compound 280 (formate) was prepared as a white solid from compound 101-K by using a similar method as described in examples 12 and 53. LCMS (method 5-95AB, ESI): t _R ＝0.586min,[M+H] ⁺ ＝902.3； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.50(br s,1H),8.35-8.20(m,2H),7.36-7.28(m,3H),7.21(d,J＝8.4Hz,2H),7.09(d,J＝8.4Hz,1H),6.90(br s,1H),6.76(br s,1H),6.46(s,1H),5.26-5.20(m,1H),4.79-4.70(m,2H),4.35-4.19(m,4H),4.21(s,2H),3.26-3.18(m,4H),3.16-3.09(m,4H),3.01(s,3H),2.54(s,6H),2.32-2.25(m,1H),2.20-2.13(m,1H),1.47(s,3H),1.36(d,J＝6.6Hz,3H),0.94(br s,2H),0.84(br s,2H)。

Example 81: synthesis of Compound 281

Compound 281 (formate salt) was prepared as a white solid from compound 101-K by using a similar method to that described in examples 12 and 53. LCMS (method 5-95AB, ESI): t _R ＝0.721min,[M+H] ⁺ ＝916.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.50(br s,2H),8.20(d,J＝8.0Hz,2H),7.35(d,J＝8.0Hz,2H),7.30-7.20(m,2H),7.08(br s,2H),6.86(s,1H),6.57(br s,1H),5.35-5.25(m,1H),4.85-4.75(m,2H),4.40-4.20(m,6H),3.30-3.20(m,4H),3.16-3.12(m,2H),3.05-2.95(m,5H),2.48(s,6H),2.35-2.25(m,1H),2.20-2.10(m,1H),1.68(q,J＝7.2Hz,2H),1.35(d,J＝6.8Hz,3H),0.92(t,J＝6.8Hz,3H),0.84(br s,2H),0.78(br s,2H)。

Example 82: synthesis of Compound 282

Compound 282 (formate) was prepared as a white solid from compound 101-K by using an analogous method to that described in examples 12 and 53. LCMS (method 5-95AB, ESI): t _R ＝0.753min,[M+H] ⁺ ＝930.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.51(br s,2H),8.22(d,J＝8.0Hz,2H),7.38(d,J＝8.0Hz,2H),7.31-7.25(m,2H),7.10(br s,2H),6.88(s,1H),6.62(s,1H),6.58(s,1H),5.32-5.28(m,1H),4.82-4.77(m,3H),4.36(s,2H),4.30-4.21(m,4H),3.32-3.10(m,8H),3.04(s,3H),2.50(s,6H),2.35-2.15(m,2H),1.67-1.63(m,2H),1.41-1.31(m,5H),0.92(t,J＝6.8Hz,3H),0.88-0.84(m,2H),0.80-0.76(m,2H)。

Example 83: synthesis of Compound 283

Compound 283 (formate) was prepared as a white solid from compound 101-K by using an analogous method to that described in examples 12 and 53. LCMS (method 5-95AB, ESI): t _R ＝0.775min,[M+H] ⁺ ＝944.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.46(brs,3H),8.31(d,J＝8.0Hz,2H),7.40(d,J＝8.0Hz,2H),7.30(d,J＝8.0Hz,1H),7.20(d,J＝8.0Hz,2H),7.10(d,J＝8.4Hz,1H),6.91(s,1H),6.80(brs,1H),6.44(s,1H),5.25-5.21(m,1H),4.89-4.80(m,2H),4.30-4.18(m,6H),3.25-3.09(m,8H),3.01(s,3H),2.56(s,6H),2.31-2.26(m,1H),2.19-2.14(m,1H),1.65(brs,3H),1.39-1.26(m,7H),0.91-0.80(m,5H),0.79-0.72(m.,2H)。

Example 84: synthesis of Compound 284

Step 1: starting from 5-bromo-2, 3-dihydro-1H-inden-1-one, the 5 '-bromo-2', 3 '-dihydrospiro [ cyclopropane-1, 1' -indene ] was obtained as a yellow oil using Wittig and cyclopropanation (as described in example 12) conditions ]。 ¹ H NMR(400MHz,CDCl ₃ )δ7.32(d,J＝1.6Hz,1H),7.23(dd,J＝8.0,1.6Hz,1H),6.53(d,J＝8.0Hz,1H),3.03(t,J＝7.2Hz,2H),2.13(t,J＝7.2Hz,2H),0.97-0.93(m,2H),0.89-0.87(m,2H)。

Compound 284 (formate) was synthesized from compound 101-K and 5 '-bromo-2', 3 '-dihydrospiro [ cyclopropane-1, 1' -indene ] by using a similar method to that described in example 53]Prepared as a white solid. LCMS (method 5-95AB, ESI): t _R ＝0.711min,[M+Na] ⁺ ＝936.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.49(brs,2H),8.15-8.02(m,2H),7.31-7.21(m,2H),7.16-7.07(m,2H),6.90-6.81(m,1H),6.77(d,J＝8.0Hz,1H),6.70-6.47(m,2H),5.28-5.25(m,1H),4.84-4.75(m,2H),4.35(s,2H),4.29-4.19(m,4H),3.29-3.19(m,4H),3.18-2.97(m,9H),2.48(s,6H),2.34-2.25(m,1H),2.28-2.11(m,3H),1.36(d,J＝6.8Hz,3H),1.04-0.95(m,4H)。

Example 85: synthesis of Compound 285

Step 1: starting from 7-bromochroman-4-one, the application of Wittig and cyclopropanation conditions (as described in example 12) gives 7-bromospiro [ chroman-4, 1' -cyclopropane as a yellow oil]。 ¹ H NMR(400MHz,CDCl ₃ )δ6.96(d,J＝8.0Hz,1H),6.95(s,1H),6.51(d,J＝8.0Hz,2H),4.28(t,J＝5.2Hz,2H),1.85(t,J＝5.2Hz,2H),1.03(t,J＝4.4Hz,2H),0.86(t,J＝4.4Hz,2H)。

Compound 285 (formate salt) was synthesized from compound 101-K and 7-bromospiro [ chroman-4, 1' -cyclopropane using a similar procedure as described in example 53]Prepared as a white solid. LCMS (methods 5-95AB, ESI): t _R ＝0.683min,[M+H] ⁺ ＝930.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.51(br s,2H),7.80(br s,1H),7.53-7.41(m,1H),7.31-7.20(m,2H),7.15-6.89(m,3H),6.85-6.72(m,2H),6.67(s,1H),5.32-5.21(m,1H),4.80-4.70(m,2H),4.37-4.25(m,8H),3.46-3.35(m,2H),3.27-3.20(m,4H),3.18-3.10(m,2H),3.02(s,3H),2.96-2.85(m,2H),2.38(s,6H),2.30-2.25(m,1H),2.19-2.10(m,1H),1.96-1.87(m,2H),1.35(d,J＝6.2Hz,3H),1.20-1.12(m,2H),1.00-0.91(m,2H)。

Example 86: synthesis of Compound 286

Step 1: to a mixture of cyclopentanecarbonyl chloride (2.0 g, 15mmol) and bromo-benzene (7.1g, 45mmol) was slowly added AlCl at 0 deg.C ₃ (3.0 g,22.5 mmol), and the mixture was stirred at 20 ℃ for 3h. The mixture is saturated with NH ₄ Aqueous Cl (20 mL) was quenched and extracted with EtOAc (3x 30mL). The combined organic layers were washed with brine (100 mL) and Na ₂ SO ₄ Drying, concentration, and the residue was purified by silica gel chromatography eluting with 0-5% etoac in petroleum ether to give (4-bromophenyl) (cyclopentyl) methanone as a yellow oil (1.56g, 41% yield).

Step 2: starting from (4-bromophenyl) (cyclopentyl) methanone, wittig and cyclopropanation conditions (as described in example 12) were applied to give 1-bromo-4- (1-cyclopentylcyclopropyl) benzene as a yellow oil. ¹ H NMR(400MHz,CDCl ₃ )δ7.39(d,J＝8.0Hz,2H),7.19(d,J＝8.0Hz,2H),1.80-1.75(m,1H),1.63-1.60(m,2H),1.50-1.45(m,4H),1.12-1.07(m,2H),0.71(br s,2H),0.67(br s,2H)。

Compound 286 (formate) was prepared as a white solid from compound 101-K and 1-bromo-4- (1-cyclopentylcyclopropyl) benzene using an analogous method to that described in example 53. LCMS (methods 5-95AB, ESI): t _R ＝0.769min,[M+H] ⁺ ＝956.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.47(br s,2H),8.20(br s,2H),7.39(d,J＝7.6Hz,2H),7.26(brs,2H),7.09(brs,2H),6.87(s,1H),6.64(s,1H),6.50(s,1H),5.32-5.24(m,1H),4.80-4.72(m,2H),4.36(s,2H),4.29-4.17(m,4H),3.29-3.08(m,8H),3.02(s,3H),2.49(s,6H),2.33-2.22(m,1H),2.21-2.12(m,1H),1.97-1.88(m,1H),1.74-1.62(m,2H),1.51(brs,4H),1.36(d,J＝6Hz,3H),1.22(br s,2H),0.81(br s,2H),0.75(br s,2H)。

Example 87: synthesis of Compound 287

Step 1: a mixture of Zn (684mg, 10.5 mmol), 1- (bromomethyl) -4- (tert-butyl) benzene (792mg, 3.5 mmol), and iodine (100 mg) in DMF (3 mL) was stirred under nitrogen at 25 deg.C for 1h, followed by addition of methyl 2-chloro-4, 6-dimethylpyrimidine-5-carboxylate (described in example 53) (350mg, 1.75mmol), 2-dicyclohexylphosphino-2 ',6' -dimethoxybiphenyl (36mg, 0.09mmol), and Pd ₂ (dba) ₃ (40mg, 0.04mmol). The resulting mixture was stirred under nitrogen at 60 ℃ for a further 3h. The reaction mixture was diluted with EtOAc (50 mL) and washed with brine (50 mL). The organic layer was washed with Na ₂ SO ₄ Drying, concentration and chromatography of the residue on silica gel eluting with 20% EtOAc in petroleum ether afforded methyl 2- (4- (tert-butyl) benzyl) -4, 6-dimethylpyrimidine-5-carboxylate as a colorless oil (350mg, 51% yield). ¹ H NMR(400MHz,CDCl ₃ )δ7.32(br s,4H),4.18(s,2H),3.94(s,3H),2.51(s,6H),1.30(s,9H)。

Step 2: typical ester hydrolysis conditions as described in example H (NaOH, meOH/H) were applied to methyl 2- (4- (tert-butyl) benzyl) -4, 6-dimethylpyrimidine-5-carboxylate ₂ O) to give 2- (4- (tert-butyl) benzyl) -4, 6-dimethylpyrimidine-5-carboxylic acid as a white solid.

Compound 287 (formate) was prepared as a white solid from compound 101-K and 2- (4- (tert-butyl) benzyl) -4, 6-dimethylpyrimidine-5-carboxylic acid using an analogous method to that described in example G. LCMS (methods 5-95AB, ESI): t _R ＝0.694min,[M+H] ⁺ ＝918.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.46(brs,3H),7.31-7.18(m,7H),7.11(d,J＝8.8Hz,1H),6.90(d,J＝2.0Hz,1H),6.80(s,1H),6.38(s,1H),5.17-5.15(m,1H),4.83-4.77(m,2H),4.26-4.13(m,8H),3.34-3.05(m,8H),2.97(s,3H),2.49(s,6H),2.25-2.15(m,1H),2.15-2.01(m,1H),1.34(d,J＝6.4Hz,3H),1.29

(s,9H)。

Example 88: synthesis of Compound 288

Step 1: 2- [ (4-tert-butylphenyl) methyl group]A mixture of-4, 6-dimethyl-pyrimidine-5-carboxylic acid methyl ester (described in example 87) (150.0mg, 0.4800mmol) and NaH (28.8mg, 1.2mmol) in DMF (5 mL) was stirred at 0 ℃ for 2h, followed by addition of methyl iodide (2.6g, 18.3mmol). The resulting mixture was stirred at 20 ℃ for 5h. The reaction was diluted with water (30 mL), which was extracted with EtOAc (30mL × 3). The combined organic layers were washed with brine (50mL. Times.2) over MgSO ₄ Drying, concentration, and purification of the residue by preparative TLC (eluent: 10% etoac in petroleum ether, rf = 0.5) gave 2- [1- (4-tert-butylphenyl) -1-methyl-ethyl ] as a colorless oil]4, 6-dimethyl-pyrimidine-5-carboxylic acid methyl ester (40mg, 24.5% yield). LCMS (method 5-95AB, ESI): t _R ＝1.050min,[M+H] ⁺ ＝341.3。

Step 2: from 2- [1- (4-tert-butylphenyl) -1-methyl-ethyl]Starting from methyl-4, 6-dimethyl-pyrimidine-5-carboxylate (40mg, 0.12mmol), ester hydrolysis conditions (NaOH, meOH/H) were applied ₂ O, described in example H) to give 2- (2- (4- (tert-butyl) phenyl) propan-2-yl) -4, 6-dimethylpyrimidine-5-carboxylic acid as a white solid (38mg, 99% yield).

Compound 288 (formate) was prepared as a white solid by using a method analogous to that described in example G from compound 101-K and 2- (2- (4- (tert-butyl) phenyl) propan-2-yl) -4, 6-dimethylpyrimidine-5-carboxylic acid. LCMS (methods 5-95AB, ESI): t _R ＝0.755min,[M+H] ⁺ ＝946.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.47(brs,4H),7.40-7.20(m,6H),7.17(d,J＝8.4Hz,1H),7.10(d,J＝8.4Hz,1H),6.90(d,J＝2.0Hz,1H),6.82(s,1H),6.37(s,1H),5.17-5.15(m,1H),4.80-4.77(m,1H),4.40-4.10(m,7H),3.34-3.00(m,8H),2.97(s,3H),2.80-2.70(m,3H),2.48(s,3H),2.25-2.15(m,1H),2.15-2.00(m,1H),1.70(d,J＝7.2Hz,3H),1.34-1.25(m,15H)。

Example 89: synthesis of Compound 289

Step 1: methyl 2- (4- (tert-butyl) benzyl) -4, 6-dimethylpyrimidine-5-carboxylate (prepared as described in example 88) (250mg, 0.80mmol) and CrO ₃ A mixture of (240mg, 2.4 mmol) in acetic acid (5 mL) was stirred at 30 ℃ for 6h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3x 30mL). The combined organic layers were washed with brine (2x 50mL) and over MgSO ₄ Dried, concentrated, and the residue was purified by preparative TLC (eluted with 20% etoac in petroleum ether) to give methyl 2- (4- (tert-butyl) benzoyl) -4, 6-dimethylpyrimidine-5-carboxylate as a white solid (150mg, 57% yield). LCMS (method 5-95AB, ESI): t _R ＝0.932min,[M+H] ⁺ ＝326.9。

Step 2: a mixture of methyl 2- (4- (tert-butyl) benzoyl) -4, 6-dimethylpyrimidine-5-carboxylate (120mg, 0.37mmol) and diethylaminosulfur trifluoride (2 mL) was stirred at 50 ℃ for 2h. The reaction was diluted with water (30 mL) and extracted with EtOAc (3x 30mL). The combined organic layers were washed with brine (2x 50mL) and over MgSO ₄ Drying, concentration, and purification of the residue by preparative TLC (eluting with 20% etoac in petroleum ether) afforded methyl 2- ((4- (tert-butyl) phenyl) difluoromethyl) -4, 6-dimethylpyrimidine-5-carboxylate as a white solid (80mg, 62% yield).

And 3, step 3: typical ester hydrolysis conditions (NaOH, meOH/H) were applied to methyl 2- ((4- (tert-butyl) phenyl) difluoromethyl) -4, 6-dimethylpyrimidine-5-carboxylate ₂ O, as described in example H) to give 2- ((4- (tert-butyl) phenyl) difluoromethyl) -4, 6-dimethylpyrimidine-5-carboxylic acid as a white solid. LCMS (methods 5-95AB, ESI): t _R ＝0.899min,[M+H] ⁺ ＝334.9。

Compound 289 (formate) was prepared by combining the compounds using a similar procedure as described in example GThe substance 101-K and 2- ((4- (tert-butyl) phenyl) difluoromethyl) -4, 6-dimethylpyrimidine-5-carboxylic acid were prepared as white solids. LCMS (methods 5-95AB, ESI): t _R ＝0.748min,[M+H] ⁺ ＝954.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.51(brs,2H),7.54(d,J＝8.0Hz,2H),7.48(d,J＝8.0Hz,2H),7.30-7.20(m,2H),7.17(d,J＝8.0Hz,1H),7.09(d,J＝8.0Hz,1H),6.90(s,1H),6.83(s,1H),6.38(s,1H),5.20-5.15(m,1H),4.79-4.75(m,1H),4.25-4.15(m,7H),3.35-3.32(m,1H),3.20-3.05(m,7H),2.97(s,3H),2.56(s,6H),2.30-2.20(m,1H),2.15-2.05(m,1H),1.36(d,J＝7.2Hz,3H),1.32(s,9H)。

Example 90: synthesis of Compound 290

Step 1: to the LDA solution (2N in THF, 35mL) was added 4-bromo-2-methylbenzoic acid (5.0 g, 23.2mmol) over 15min, and the reaction was stirred at-40 ℃ for 30min. After warming to 15 ℃ HCHO (2.7g, 93mmol) was added while maintaining the internal temperature (ice water bath) below 18 ℃. The resulting mixture was stirred at 15 ℃ for 2h, then cooled to 0 ℃, followed by addition of 3N aqueous HCl until pH <3. The mixture was then extracted with EtOAc (2x 100mL) and the combined organic layers were concentrated to approximately 50mL and added to15 ion exchange resin (1.5 g) and the mixture was stirred at 48 ℃ for 14h. The volatiles were removed and the residue was purified by silica gel column, eluting with 20-30% etoac in petroleum ether, to give 6-bromoisochroman-1-one as a pale yellow solid (1.5 g,28% yield). ¹ H NMR(400MHz,CDCl ₃ )δ7.97(d,J＝8.5Hz,1H),7.55(d,J＝8.5Hz,1H),7.46(s,1H),4.55(t,J＝6.0Hz,2H),3.06(t,J＝6.0Hz,2H)。

Step 2: to a solution of 6-bromoisochroman-1-one (800mg, 3.5 mmol) in THF (10 mL) at-78 deg.C was added MeMgBr (Et) ₂ 3N solution in O, 8.2 mL). The mixture was stirred at the same temperature for 0.5h; then the temperature is raised to 2 ℃ while stirringStirring for 1h at 0 ℃. The reaction was poured into cold saturated NH ₄ Aqueous Cl (50 mL), which was extracted with EtOAc (2x 50mL). The combined organic layers were washed with Na ₂ SO ₄ Drying, evaporation in vacuo, and chromatography of the residue on silica gel, eluting with 50-60% EtOAc in petroleum ether, afforded 6-bromo-1, 1-dimethylisochroman as a white solid (600mg, 71% yield).

Compound 290 (formate salt) was prepared as a white solid from compound 101-K and 6-bromo-1, 1-dimethylisochroman using an analogous method to that described in example 53. LCMS (methods 5-95AB, ESI): t _R ＝0.532min,[M+H] ⁺ ＝932.3； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.50(br s,1H),8.10-7.95(m,2H),7.33-7.18(m,3H),7.13-6.95(m,2H),6.83(s,1H),6.63(s,1H),6.48(s,1H),5.35-5.25(m,1H),4.82-4.70(m,2H),4.48-4.30(m,4H),4.25(s,2H),3.98(t,J＝5.6Hz,2H),3.30-3.28(m,2H),3.24(brs,2H),3.14(t,J＝8.0Hz,2H),3.02(s,3H),2.97-2.62(m,4H),2.44(s,6H),2.33-2.16(m,2H),1.57(s,6H),1.35(d,J＝6.8Hz,3H)。

Example 91: synthesis of Compound 291

Compound 291 (formate) was prepared as a white solid from compound 101-K by using an analogous method to that described in example 53. LCMS (method 5-95AB, ESI): t _R ＝0.674min,[M+H] ⁺ ＝918.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.53(brs,2H),8.10-8.04(m,3H),7.25-7.21(m,2H),7.06(d,J＝7.6Hz,2H),6.82(s,1H),6.68(brs,2H),5.31-5.27(m,2H),4.80-4.75(m,3H),4.26-4.17(m,6H),3.31-3.25(m,1H),3.17-3.13(m,7H),3.09(s,3H),2.39(s,6H),2.23-2.15(m,1H),2.12-2.05(m,1H),1.51(s,6H),1.34(d,J＝6.8Hz,3H)。

Example 92: synthesis of Compound 292

Step 1: typical alkylation (NaH, meI) conditions were applied to 1-bromo-4- (isocyanomethyl) benzene (as described in example 88) to give 1-bromo-4- (2-isocyanoprop-2-yl) benzene as a yellow oil.

Step 2: 1-bromo-4- (2-isocyanoprop-2-yl) benzene (1.77g, 7.9mmol) and NaOH (948mg, 23.7mmol) were placed in EtOH/H ₂ The mixture in O (40ml, v/v = 1/1) was stirred at 100 ℃ for 16h. The volatiles were removed and the residue was treated with 1N aqueous HCl until pH =4, then extracted with EtOAc (3x 30mL). The combined organic layers were washed with brine (2x 80mL) and over Na ₂ SO ₄ Drying and evaporation in vacuo gave 2- (4-bromophenyl) -2-methylpropionic acid as a yellow solid (1.9g, 99% yield).

And step 3: 2- (4-bromophenyl) -2-methylpropanoic acid (1.0g, 4.1mmol), phI (OAc) ₂ (2.0g，6.2mmol)、Pd(OAc) ₂ (46mg, 0.21mmol), 2-acetamidoacetic acid (144mg, 1.2mmol) and K ₂ CO ₃ A mixture of (807 mg, 8.2mmol) in tert-butanol (10 mL) was stirred under nitrogen at 100 ℃ for 20h. The volatiles were removed and the residue was purified by silica gel chromatography eluting with 0-10% etoac in petroleum ether to give 6-bromo-3, 3-dimethylbenzofuran-2 (3H) -one as an off-white solid (260mg, 26% yield). ¹ H NMR(400MHz,MeOH-d4)δ7.37(s,1H),7.36(d,J＝7.6Hz,1H),7.28(d,J＝7.6Hz,1H),1.47(s,6H)。

And 4, step 4: to a solution of lithium aluminium hydride (49mg, 1.29mmol) in THF (10 mL) at 0 deg.C was added 6-bromo-3, 3-dimethylbenzofuran-2 (3H) -one (260mg, 1.1mmol) and the mixture was stirred at 25 deg.C for 2H. With saturated NH ₄ The reaction was quenched with aqueous Cl (20 mL) and extracted with EtOAc (2X 25mL). The combined organic layers were washed with brine (50 mL), concentrated, and the residue was purified by preparative TLC eluting with 30% ethyl acetate in petroleum ether, R _f = 0.5) to give 6-bromo-3, 3-dimethyl-2, 3-dihydrobenzofuran as an off-white solid (180mg, 74% yield).

Compound 292 (formate salt) was prepared as a white solid by using a method analogous to that described in example 53 from compound 101-K and 6-bromo-3, 3-dimethyl-2, 3-dihydrobenzofuran. LCMS (method 5-95AB, ESI): t _R ＝0.688min,[M+H] ⁺ ＝918.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.53(br s,2H),7.92(d,J＝8.0Hz,1H),7.49-7.38(m,1H),7.32-7.26(m,1H),7.24-7.19(m,1H),7.17(d,J＝8.0Hz,1H),7.00-6.93(m,1H),6.89-6.66(m,3H),6.13(brs,1H),5.39-5.31(m,1H),4.80-4.70(m,2H),4.51-4.33(m,2H),4.33-4.16(m,6H),3.40-3.33(m,2H),3.20-3.05(m,4H),3.02(s,3H),2.88-2.67(m,2H),2.31(s,6H),2.23-1.98(m,2H),1.43-1.30(m,9H)。

Example 93: synthesis of Compound 293

Step 1: methyl 2-chloro-4, 6-dimethylpyrimidine-5-carboxylate (described in example 53) (200mg, 1.00mmol), 5-chloro-2- (tributylstannyl) pyridine (400mg, 0.99mmol) and Pd (PPh) ₃ ) ₄ A mixture (115mg, 0.10 mmol) in toluene (6 mL) was stirred under nitrogen at 110 ℃ for 16h. The volatiles were removed and the residue was purified by silica gel chromatography eluting with 0-50% etoac in petroleum ether to give methyl 2- (5-chloropyridin-2-yl) -4, 6-dimethylpyrimidine-5-carboxylate as a white solid (140mg, 51% yield).

And 2, step: starting from methyl 2- (5-chloropyridin-2-yl) -4, 6-dimethylpyrimidine-5-carboxylate, typical Suzuki coupling and ester hydrolysis conditions as described in example H were applied to give 2- (5-butylpyridin-2-yl) -4, 6-dimethylpyrimidine-5-carboxylic acid as a white solid.

Compound 293 (formate) was prepared as a white solid from compound 101-K and 2- (5-butylpyridin-2-yl) -4, 6-dimethylpyrimidine-5-carboxylic acid using an analogous method to that described in example G. LCMS (method 5-95AB, ESI): t _R ＝0.636min,[M+H] ⁺ ＝905.8； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.85(br s,1H),8.42(d,J＝8.0Hz,2H),7.76-7.72(m,1H),7.29(d,J＝8.0Hz,1H),7.24-7.20(m,1H),6.86-6.59(m,4H),5.45-5.36(m,1H),4.79-4.70(m,2H),4.67-4.41(m,2H),4.31-4.15(m,4H),3.59-3.34(m,4H),3.30-3.03(m,4H),3.01(s,3H),2.76(t,J＝7.6Hz,2H),2.37(s,6H),2.27-2.00(m,2H),1.79-1.67(m,2H),1.55-1.44(m,2H),1.36(d,J＝6.8Hz,3H),1.04(t,J＝7.2Hz,3H)。

Example 94: synthesis of Compound 294

Step 1: starting from 1- (4-bromophenyl) butan-1-one, typical Suzuki boronation (borylation), suzuki, difluorination (di-fluorination) (described in example 89) and ester hydrolysis (NaOH, meOH/H) ₂ O) to yield 2- (4- (1, 1-difluorobutyl) phenyl) -4, 6-dimethylpyrimidine-5-carboxylic acid as a white solid. LCMS (methods 5-95AB, ESI): t _R ＝0.844min,[M+H] ⁺ ＝320.9。

Compound 294 (formate) was prepared as a white solid by using a method analogous to that described in example G from compound 101-K and 2- (4- (1, 1-difluorobutyl) phenyl) -4, 6-dimethylpyrimidine-5-carboxylic acid. LCMS (methods 5-95AB, ESI): t _R ＝0.725min,[M+H] ⁺ ＝940.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.37(d,J＝8.0Hz,2H),7.55(d,J＝8.0Hz,2H),7.32-7.22(m,2H),7.08(brs,2H),6.86(s,1H),6.56(brs,2H),5.31-5.25(m,1H),4.82-4.75(m,2H),4.44-4.20(m,6H),3.38-3.32(m,3H),3.18-3.13(m,3H),3.07-2.96(m,5H),2.49(s,6H),2.35-2.09(m,4H),1.52-1.42(m,2H),1.35(d,J＝6.8Hz,3H),0.98(t,J＝7.2Hz,3H)。

Example 95: synthesis of Compound 295

Step 1: to a solution of 4- (tert-butyl) cyclohex-1-one (1.54g, 10mmol) in THF (20 mL) at-78 deg.C was added LDA (2N in THF, 5.5 mL) dropwise, and the mixture was stirred at the same temperature for 2h, followed by the addition of PhNTf ₂ (3.9g, 11mmol). The resulting mixture was stirred at 20 ℃ for 12h. The reaction was diluted with EtOAc (60 mL), which was washed with brine (2x 50mL). The organic layer was washed with Na ₂ SO ₄ Drying, concentrating, and purifying the residue by silica gel chromatography with petroleum ether5% EtOAc elution gave 4- (tert-butyl) cyclohex-1-en-1-yl trifluoromethanesulfonate as a colorless oil (800mg, 28% yield). ¹ H NMR(400MHz,MeOH-d4):δ5.74(t,J＝2.8Hz,1H),2.40-2.10(m,3H),2.00-1.85(m,2H),1.40-1.20(m,2H),0.87(s,9H)。

Compound 295 (formate salt) was prepared as a white solid from compound 101-K and 4- (tert-butyl) cyclohex-1-en-1-yl triflate using an analogous method to that described in examples 53 and 10. LCMS (method 5-95AB, ESI): t _R ＝0.740min,[M+H] ⁺ ＝908.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.56(br s,3H),7.30-7.15(m,4H),7.12-7.05(m,1H),6.85(brs,1H),6.68(brs,1H),6.45(brs,1H),5.20-5.10(m,1H),4.79-4.75(m,2H),4.40-4.10(m,6H),3.33-3.05(m,8H),2.98(s,3H),2.90-2.60(m,1H),2.44(s,6H),2.40-1.90(m,7H),1.36(d,J＝6.8Hz,3H),1.23-1.05(m,1H),0.98(s,9H)。

Example 96: synthesis of Compound 296

Step 1: a mixture of 2- (4-tert-butylcyclohexen-1-yl) -4, 6-dimethyl-pyrimidine-5-carboxylate (as described in example 95) (250mg, 0.83mmol) and 10% Pd/C (88mg, 0.08mmol) in MeOH (100 mL) in H ₂ And stirred for 5h at 15 ℃. The volatiles were removed and the residue was purified and the cis and trans stereoisomers (10% etoac in petroleum ether, rf = 0.7) were separated by preparative TLC to give methyl (cis) -2- (4-tert-butylcyclohexyl) -4, 6-dimethyl-pyrimidine-5-carboxylate (70mg, 28% yield) and methyl (trans) -2- (4-tert-butylcyclohexyl) -4, 6-dimethyl-pyrimidine-5-carboxylate (100mg, 40% yield) as white solids.

Step 2: starting from (trans) -2- (4-tert-butylcyclohexyl) -4, 6-dimethyl-pyrimidine-5-carboxylic acid methyl ester (70mg, 0.23mmol), typical ester hydrolysis conditions (NaOH, meOH/H) were applied ₂ O) to give (trans) -4-tert-butylcyclohexyl) -4, 6-dimethylpyrimidine-5-carboxylic acid as a white solid (65mg, 97% yield).

Compound 296 (formate) tongPrepared as a white solid from compound 101-K and (trans) -4-tert-butylcyclohexyl) -4, 6-dimethylpyrimidine-5-carboxylic acid by using an analogous method to that described in example 53. LCMS (methods 5-95AB, ESI): t _R ＝0.740min,[M+H] ⁺ ＝910.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.56(br s,3H),7.29-7.26(m,2H),7.19(d,J＝8.4Hz,1H),7.10(d,J＝8.4Hz,1H),6.90(d,J＝2.0Hz,1H),6.82(s,1H),6.38(s,1H),5.20-5.15(m,1H),4.79-4.75(m,2H),4.40-4.10(m,6H),3.33-3.05(m,8H),2.97(s,3H),2.75-2.65(m,1H),2.49(s,6H),2.30-2.05(m,2H),2.00-1.85(m,4H),1.70-1.55(m,2H),1.35(d,J＝6.8Hz,3H),1.25-1.05(m,3H),0.91(s,9H)。

Example 97: synthesis of Compound 297

Compound 297 (formate salt) was prepared as a white solid from compound 101-K and (cis) -2- (4-tert-butylcyclohexyl) -4, 6-dimethyl-pyrimidine-5-carboxylic acid methyl ester using a similar method to that described in example 96. LCMS (method 5-95AB, ESI): t _R ＝0.740min,[M+H] ⁺ ＝910.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.50(br s,2H),7.28-7.26(m,2H),7.18(d,J＝8.4Hz,1H),7.09(d,J＝8.8Hz,1H),,6.90(d,J＝2.0Hz,1H),6.82(d,J＝2.0Hz,1H),6.39(s,1H),5.20-5.15(m,1H),4.79-4.75(m,2H),4.40-4.10(m,6H),3.25-3.05(m,8H),2.98(s,3H),2.55(s,6H),2.55-2.40(m,2H),2.30-2.00(m,2H),1.75-1.60(m,2H),1.60-1.50(m,2H),1.40-1.20(m,3H),1.38(d,J＝6.8Hz,3H),1.20-1.05(m,1H),0.81(s,9H)。

Example 98: synthesis of Compound 298

Step 1: to a solution of 3- (tert-butyl) phenol (1.5g, 10mmol) in DCM (20 mL) was added a solution of bromine (0.51mL, 10mmol) in DCM (5 mL) over 15min while keeping the reaction temperature below 35 ℃. Then, while stirring, using 5% Na ₂ S ₂ SO ₃ The reaction was quenched with aqueous solution (15 mL). The organic layer was separated, washed with brine (50 mL), and Na ₂ SO ₄ Drying, concentration, and the residue was purified by flash chromatography on silica gel, eluting with 0-5% etoac in petroleum ether, to give 2-bromo-5- (tert-butyl) phenol as a colorless oil (1.6 g,70% yield). ¹ H NMR(400MHz,CDCl ₃ )δ7.37(d,J＝8.0Hz,1H),7.07(s,1H),6.85(d,J＝8.0Hz,1H),5.44(s,1H),1.30(s,9H)。

Step 2: starting from 2-bromo-5- (tert-butyl) phenol, typical alkylation (as described in example 21), suzuki boronation and Suzuki coupling conditions (as described in example 10) were applied to give methyl 2- (4- (tert-butyl) -2-methoxyphenyl) -4, 6-dimethylpyrimidine-5-carboxylate as a yellow oil. LCMS (ESI): [ M + H ]] ⁺ ＝329.0。

And step 3: to a solution of 2- (4- (tert-butyl) -2-methoxyphenyl) -4, 6-dimethylpyrimidine-5-carboxylate (150mg, 0.46mmol) in DCM (10 mL) was added BBr ₃ (87. Mu.L, 0.91 mmol) and the mixture was stirred at 0 ℃ for 12h. By 5% of Na ₂ S ₂ SO ₃ The reaction was quenched with aqueous solution (10 mL), the organic layer was separated, washed with brine (50 mL), and Na ₂ SO ₄ Drying, concentration and purification of the residue by HPLC gave 2- (4- (tert-butyl) -2-hydroxyphenyl) -4, 6-dimethylpyrimidine-5-carboxylic acid as a yellow solid (50mg, 36.4% yield). LCMS (ESI): [ M + H ]] ⁺ ＝300.9。

Compound 298 (formate) was prepared as a white solid by using a method analogous to that described in example G from compound 101-K and 2- (4- (tert-butyl) -2-hydroxyphenyl) -4, 6-dimethylpyrimidine-5-carboxylic acid. LCMS (method 5-95AB, ESI): t _R ＝0.730min,[M+H] ⁺ ＝920.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.50(br s,3H),8.34(d,J＝8.4Hz,2H),7.30-7.25(m,2H),7.02-6.98(m,2H),6.82(s,1H),6.69(brs,1H),5.35-5.31(m,1H),4.85-4.78(m,2H),4.32-4.12(m,6H),3.38-3.34(m,2H),3.16-3.12(m,4H),3.02(s,3H),3.00-2.90(m,2H),2.43(s,6H),2.31-2.10(m,2H),1.40-1.35(m,12H)。

Example 99: synthesis of Compound 299

Step 1: a mixture of 4- (tert-butyl) phenol (2.0 g, 13mmol) and Selectfluor (5.2 g, 14.6mmol) in MeOH (25 mL) was stirred at 85 deg.C for 4h. The volatiles were removed and the residue was taken up in EtOAc (50 mL), which was washed with brine (2x 50mL). The organic layer was washed with Na ₂ SO ₄ Drying, concentration, and purification of the residue by silica gel chromatography, eluting with 0-10% EtOAc in petroleum ether, afforded 4- (tert-butyl) -2-fluorophenol (900mg, 40% yield). ¹ H NMR(400MHz,CDCl ₃ )δ7.12-7.00(m,2H),6.96-6.89(m,1H),5.04(s,1H),1.29(s,9H)。

Compound 299 (formate) was prepared as a white solid from compound 101-K and 4- (tert-butyl) -2-fluorophenol using a similar method to that described in examples 10 and 53. LCMS (methods 5-95AB, ESI): t _R ＝0.711min,[M+H] ⁺ ＝922.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.51(br s,3H),7.85-7.82(m,1H),7.36-7.05(m,6H),6.88(s,1H),6.68(s,1H),6.51(s,1H),5.30-5.24(m,1H),4.80-4.70(m,2H),4.30-4.20(m,6H),3.32-3.00(m,8H),2.95(s,3H),2.56(s,6H),2.35-2.25(m,1H),2.25-2.15(m,1H),1.38(s,9H),1.36(d,J＝6.4Hz,3H)。

Example 100: synthesis of Compound 300

Compound 300 (formate) was prepared as a white solid from compound 101-K by using a similar method to that described in example 56. LCMS (methods 5-95AB, ESI): t _R ＝0.683min,[M+H] ⁺ ＝888.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.52(br s,1H),8.10(d,J＝7.6Hz,2H),7.26(brs,2H),7.15-7.01(m,4H),6.84(s,1H),6.62(s,1H),6.51(s,1H),5.33-5.27(m,1H),4.80-4.72(m,1H),4.36(brs,3H),4.27-4.23(m,4H),3.29-3.26(m,2H),3.22-3.06(m,6H),3.02(s,3H),2.99-2.90(m,2H),2.43(s,6H),2.33-2.23(m,1H),2.21-2.10(m,1H),2.03-1.93(m,1H),1.35(d,J＝6.8Hz,3H),1.10-1.03(m,2H),0.81-0.75(m,2H)。

Example 101: synthesis of Compound 301

Compound 301 (formate) was prepared as a white solid from compound 101-K by using a similar method to that described in example 56. LCMS (methods 5-95AB, ESI): t _R ＝0.709min,[M+H] ⁺ ＝902.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.53(br s,1H),8.15(d,J＝7.8Hz,2H),7.28-7.23(m,4H),7.07-6.95(m,2H),6.83(s,1H),6.67(s,1H),6.46(s,1H),5.33-5.29(m,1H),4.79-4.74(m,2H),4.32-4.19(m,6H),3.68-3.58(m,1H),3.22-3.06(m,7H),3.02(s,3H),2.47-2.38(m,2H),2.42(s,6H),2.32-2.04(m,6H),1.97-1.88(m,1H),1.34(d,J＝6.8Hz,3H)。

Example 102: synthesis of Compound 302

Step 1: methyl 2- (4-chlorophenyl) -4, 6-dimethylpyrimidine-5-carboxylate (100mg, 0.36mmol, described in example 56), 2- (cyclopent-1-en-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (91mg, 0.47mmol), pd ₂ (dba) ₃ (8.3mg, 0.01mmol), S-phos (7.4mg, 0.02mmol) and K ₃ PO ₄ (230mg, 1.1mmol) in 1, 4-dioxane/H ₂ Solution in O (6 mL, v/v = 5/1) in N ₂ Stirred at 110 ℃ for 16h. After filtration, the volatiles were removed under reduced pressure and the residue was purified by preparative TLC (eluent: etOAc: petroleum ether =1 = 10) to give methyl 2- (4- (cyclopent-1-en-1-yl) phenyl) -4, 6-dimethylpyrimidine-5-carboxylate (110mg, 99% yield) as a white solid. LCMS (method 5-95AB, ESI): t _R ＝0.969min,[M+H] ⁺ ＝309.3。

Step 2: starting from methyl 2- (4- (cyclopent-1-en-1-yl) phenyl) -4, 6-dimethylpyrimidine-5-carboxylate, hydrogenation (as described in example D) and ester water were appliedConditions were resolved (as described in example H) to give 2- (4-cyclopentylphenyl) -4, 6-dimethylpyrimidine-5-carboxylic acid as a white solid. LCMS (method 5-95AB, ESI): t _R ＝0.986min,[M+H] ⁺ ＝297.0

Compound 302 (formate) was prepared as a white solid from compound 101-K and 2- (4-cyclopentylphenyl) -4, 6-dimethylpyrimidine-5-carboxylic acid using an analogous method to that described in example G. LCMS (method 5-95AB, ESI): t _R ＝0.727min,[M+H] ⁺ ＝916.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.50(br s,2H),8.34-8.30(m,2H),7.40(d,J＝8.8Hz,2H),7.37-7.29(m,2H),7.22(d,J＝8.8Hz,2H),7.13-7.08(m,2H),6.51(brs,1H),5.28-5.22(m,1H),4.85-4.75(m,2H),4.35-4.23(m,6H),3.26-3.00(m,8H),3.01(s,3H),2.57(s,6H),2.33-2.13(m,4H),1.95-1.62(m,7H),1.36(d,J＝6.8Hz,3H)。

Example 103: synthesis of Compound 303

Compound 303 (formate) was prepared as a white solid from compound 101-K by using an analogous method to that described in example 302. LCMS (method 5-95AB, ESI): t _R ＝0.610min,[M+H] ⁺ ＝928.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.47(b rs,2H),8.37-8.31(m,2H),7.52(d,J＝8.0Hz,2H),7.33-7.17(m,3H),7.16-7.01(m,2H),6.79(s,1H),6.50(s,1H),6.29(s,1H),5.29-5.18(m,1H),4.83-4.75(m,2H),4.25-4.10(m,4H),4.20(s,2H),3.56-3.36(m,1H),3.29-2.99(m,10H),2.55(s,6H),2.51-2.45(m,2H),2.36-2.24(m,3H),2.22-2.11(m,1H),1.90-1.80(m,2H),1.75-1.65(m,2H),1.44-1.35(m,3H)。

Example 104: synthesis of Compound 304

Compound 304 (formate) was prepared as a white solid from compound 101-K by using a similar method to that described in example 302. LCMS (methods 5-95ABSI):t _R ＝0.610min,[M+H] ⁺ ＝928.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.54(br s,1H),8.34-8.30(m,2H),7.38-7.15(m,5H),7.14-7.03(m,2H),6.92(s,0.5H),6.79(s,0.5H),6.50(s,0.5H),6.41(s,0.5H),5.26-5.19(m,1H),4.85-4.78(m,2H),4.25-4.17(m,4H),4.20(s,2H),3.30-2.97(m,11H),2.66-2.60(m,1H),2.57(s,6H),2.36-2.24(m,1H),2.21-2.09(m,1H),1.96-1.77(m,5H),1.55-1.42(m,5H),1.36(d,J＝6.8Hz,3H)。

Example 105: synthesis of Compound 305

Step 1: cycloheptene (155mg, 1.6 mmol), 1- (benzyloxy) -4-iodobenzene (200mg, 0.64mmol), pd (OAc) ₂ (3.6 mg, 0.02mmol), P (tolyl) ₃ (9.8mg，0.03mmol)、(t-Bu) ₄ NBr (208mg, 0.64mmol) and K ₂ CO ₃ A mixture of (224mg, 1.6 mmol) in DMF (10 mL) was stirred at 110 ℃ for 16h. The volatiles were removed and the residue was taken up in EtOAc (50 mL), which was washed with brine (2x 50mL). The organic layer was MgSO ₄ Dried, concentrated, and the residue was purified by preparative TLC (eluting with 1% etoac in petroleum ether) to give 1- (4- (benzyloxy) phenyl) cyclohept-1-ene as a colorless oil (100mg, 56% yield).

Step 2: typical hydrogenation conditions (Pd/C, H) were applied to 1- (4- (benzyloxy) phenyl) cyclohept-1-ene ₂ As described in example D) to give 4-cycloheptylphenol as a white solid.

Compound 305 (formate salt) was prepared as a white solid from compound 101-K and 4-cycloheptylphenol using procedures analogous to those described in examples 53 and 10. LCMS (methods 5-95AB, ESI): t _R ＝0.765min,[M+H] ⁺ ＝944.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.54(brs,2H),8.21-8.17(m,2H),7.30-7.18(m,4H),7.05(brs,2H),6.84(s,1H),6.65-6.55(m,2H),5.30-5.22(m,1H),4.83-4.79(m,2H),4.33-4.11(m,6H),3.17-3.04(m,6H),3.04-2.85(m,5H),2.80-2.70(m,1H),2.46(s,6H),2.30-2.20(m,1H),2.16-2.03(m,1H),1.98-1.82(m,4H),1.80-1.60(m,8H),1.35(d,J＝6.8Hz,3H)。

Example 106: synthesis of Compound 306

Compound 306 (formate) was prepared as a white solid from compound 101-K by using an analogous method to that described in examples 53 and 27. LCMS (method 5-95AB, ESI): t _R ＝0.535min,[M+H] ⁺ ＝852.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.50(brs,1H),7.30-7.22(m,2H),7.20(d,J＝8.0Hz,2H),7.11(d,J＝8.0Hz,1H),6.89(d,J＝1.6Hz,1H),6.76(s,1H),6.44(s,1H),5.25-5.15(m,1H),4.85-4.70(m,2H),4.35-4.15(m,6H),3.40-3.12(m,8H),2.99(s,3H),2.47(s,6H),2.35-2.15(m,2H),1.41(s,9H),1.36(d,J＝7.2Hz,3H)。

Example 107: synthesis of Compound 307

Compound 307 (formate) was prepared as a white solid from compound 101-K by using an analogous method to that described in examples 53 and 27. LCMS (method 5-95AB, ESI): t _R ＝0.701min,[M+H] ⁺ ＝900.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.45(brs,2H),7.56(d,J＝8.0Hz,2H),7.32-7.19(m,5H),7.08(d,J＝8.0Hz,1H),6.89(d,J＝2.4Hz,1H),6.75(s,1H),6.45(s,1H),5.23-5.20(m,1H),4.80-4.78(m,2H),4.29(s,2H),4.24-4.20(brs,4H),3.36-3.34(m,1H),3.25-3.09(m,7H),2.99(s,3H),2.70(q,J＝7.6Hz,2H),2.50(s,6H),2.29-2.14(m,2H),1.35(d,J＝6.8Hz,3H),1.26(t,J＝7.6Hz,3H)。

Example 108: synthesis of Compound 308

Compound 308 (formate) was prepared by using a similar procedure as described in examples 53 and 27Compound 101-K was prepared as a white solid. LCMS (method 5-95AB, ESI): t _R ＝0.747min,[M+H] ⁺ ＝928.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.47(brs,3H),7.56(d,J＝8.0Hz,2H),7.31-7.27(m,3H),7.24-7.19(m,2H),7.08(d,J＝8.0Hz,1H),6.89(s,1H),6.75(s,1H),6.46(s,1H),5.24-5.20(m,1H),4.81-4.77(m,2H),4.30(s,2H),4.21(brs,4H),3.36-3.21(m,8H),3.13(s,3H),2.69(t,J＝7.2Hz,2H),2.50(s,6H),2.31-2.11(m,2H),1.68-1.60(m,2H),1.43-1.35(m,5H),0.97(t,J＝7.2Hz,3H)。

Example 109: synthesis of Compound 309

Compound 309 (formate) was prepared as a white solid from compound 101-K by using an analogous method to that described in examples 53 and 27. LCMS (methods 5-95AB, ESI): t _R ＝0.638min,[M+H] ⁺ ＝872.7； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.48(brs,2H),7.63(d,J＝8.0Hz,2H),7.53-7.45(m,3H),7.28-7.18(m,3H),7.05(d,J＝8.0Hz,1H),6.86(s,1H),6.64(s,1H),6.51(s,1H),5.26-5.23(m,1H),4.81-4.76(m,2H),4.35(s,2H),4.22(brs,4H),3.38-3.22(m,5H),3.14-3.07(m,3H),2.99(s,3H),2.47(s,6H),2.31-2.12(m,2H),1.35(d,J＝6.8Hz,3H)。

Example 110: synthesis of Compound 310

Step 1: typical Sonogoshira conditions were applied to 1-bromo-4-vinylbenzene (as described in example 13) to give trimethyl ((4-vinylphenyl) ethynyl) silane as a yellow oil. Step 2: trimethyl ((4-vinylphenyl) ethynyl) silane (200mg, 1.0 mmol) and K were reacted ₂ CO ₃ A mixture of (345mg, 2.5mmol) in MeOH (10 mL) was stirred at 25 ℃ for 3h. The volatiles were removed and the residue was purified by silica gel chromatography eluting with 0-1% EtOAc in petroleum ether to give 1-ethynyl as a yellow oil -4-vinylbenzene (60mg, 47% yield).

Compound 310 (formate salt) was prepared as a white solid from compound 101-K and 1-ethynyl-4-vinylbenzene using an analogous method to that described in examples 53 and 27. LCMS (method 5-95AB, ESI): t _R ＝0.692min,[M+H] ⁺ ＝898.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.14(brs,3H),7.63(d,J＝8.4Hz,2H),7.54(d,J＝8.4Hz,2H),7.30-7.09(m,4H),6.93(s,1H),6.84-6.75(m,2H),6.42(s,1H),5.93(d,J＝17.6Hz,1H),5.38(d,J＝11.2Hz,1H),5.23-5.19(m,1H),4.81-4.77(m,2H),4.34-4.22(m,4H),4.20(s,2H),3.49-3.46(m,1H),3.20-3.09(m,7H),3.01(s,3H),2.54(s,6H),2.30-2.24(m,1H),2.22-2.13(m,1H),1.36(d,J＝7.2Hz,3H)。

Example 111: synthesis of Compound 311

Compound 311 (formate) was prepared as a white solid from compound 101-K by using a similar method to that described in example 110. LCMS (method 5-95AB, ESI): t _R ＝0.741min,[M+H] ⁺ ＝928.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.49(brs,2H),7.59(d,J＝8.0Hz,2H),7.50(d,J＝8.0Hz,2H),7.32-7.17(m,3H),7.10(d,J＝8.4Hz,1H),6.92(brs,1H),6.84-6.80(m,1H),6.24(s,1H),5.38-5.34(m,1H),4.83-4.76(m,2H),4.28-4.18(m,4H),4.20(s,2H),3.38-3.08(m,8H),3.01(s,3H),2.52(s,6H),2.28-2.23(s,1H),2.20-2.16(m,2H),1.35(s,9H),1.33(d,J＝6.8Hz,3H)。

Example 112: synthesis of Compound 312

Step 1: typical Wittig conditions were applied to 1- (4-bromophenyl) ethan-1-one (as described in example 12) to give 1-bromo-4- (3-methylbut-2-en-2-yl) benzene as a colorless oil.

Compound 312 (formate) by Using an analogous procedure to that described in example 110The process was prepared from compound 101-K and 1-bromo-4- (3-methylbut-2-en-2-yl) benzene as a white solid. LCMS (method 5-95AB, ESI): t _R ＝0.752min,[M+H] ⁺ ＝940.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.49(brs,2H),7.61(d,J＝8.0Hz,2H),7.31-7.18(m,5H),7.09(d,J＝8.4Hz,1H),6.91(d,J＝8.4Hz,1H),6.83(s,1H),6.42(s,1H),5.23-5.19(m,1H),4.83-4.78(m,2H),4.25-4.19(m,4H),4.20(s,2H),3.48-3.45(m,1H),3.20-3.08(m,7H),3.00(s,3H),2.54(s,6H),2.29-2.24(m,1H),2.20-2.12(m,1H),1.98(s,3H),1.85(s,3H),1.61(s,3H),1.36(d,J＝6.4Hz,3H)。

Example 113: synthesis of Compound 313

Step 1: typical Wittig conditions were applied to 4-bromobenzaldehyde (as described in example 12) to give 1-bromo-4- (3-methylbut-2-en-2-yl) benzene as a colorless oil. ¹ H NMR(400MHz,CDCl ₃ )δ7.44(d,J＝8.0Hz,2H),7.10(d,J＝8.0Hz,2H),1.90(s,3H),1.85(s,3H)。

Compound 313 (formate) was prepared as a white solid from compound 101-K and 1-bromo-4- (3-methylbut-2-en-2-yl) benzene using a method analogous to that described in example 110. LCMS (methods 5-95AB, ESI): t _R ＝0.728min,[M+H] ⁺ ＝926.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.45(brs,1H),7.60(d,J＝8.0Hz,2H),7.36-7.17(m,5H),7.09(d,J＝8.4Hz,1H),6.91(brs,1H),6.79(brs,1H),6.43(s,1H),6.32(s,1H),5.24-5.18(m,1H),4.83-4.78(m,2H),4.34-4.17(m,6H),3.49-3.46(m,1H),3.26-3.07(m,7H),3.00(s,3H),2.52(s,6H),2.32-2.24(m,1H),2.19-2.14(m,1H),1.95(s,3H),1.91(s,3H),1.36(d,J＝6.8Hz,3H)。

Example 114: synthesis of Compound 314

Step 1: applying a typical Wittig strip to 1- (4-bromophenyl) ethan-1-oneThis was worked up (as described in example 12) to give 1-bromo-4- (prop-1-en-2-yl) benzene as a colorless oil. ¹ H NMR(400MHz,CDCl ₃ )δ7.45(d,J＝8.4Hz,2H),7.33(d,J＝8.4Hz,2H),5.36(s,1H),5.11(s,1H),2.13(s,3H)。

Compound 314 (formate salt) was prepared as a white solid from compound 101-K and 1-bromo-4- (prop-1-en-2-yl) benzene using an analogous method to that described in example 110. LCMS (method 5-95AB, ESI): t _R ＝0.730min,[M+H] ⁺ ＝912.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ7.65-7.57(m,3H),7.39-7.05(m,5H),6.93(brs,1H),6.84(brs,1H),6.42(brs,1H),5.51(s,1H),5.23-5.19(m,1H),4.82-4.77(m,2H),4.35-4.18(s,6H),3.48-3.35(m,3H),3.28-3.07(m,5H),3.00(s,3H),2.54(s,3H),2.23-2.12(m,9H),1.36(d,J＝6.4Hz,3H)。

Example 115: synthesis of Compound 315

Step 1: a mixture of methyl 2-chloro-4, 6-dimethylpyrimidine-5-carboxylate (described in example 53) (150mg, 0.75mmol) and 4- (tert-butyl) piperidine (158mg, 1.1 mmol) in EtOH (10 mL) was stirred at 80 ℃ for 2h. Volatiles were removed and the residue was purified by preparative TLC (20% EtOAc in petroleum ether _f = 0.6) to give methyl 2- (4- (tert-butyl) piperidin-1-yl) -4, 6-dimethylpyrimidine-5-carboxylate as a yellow oil (140mg, 61% yield). LCMS (methods 5-95AB, ESI): t _R ＝0.987min,[M+H] ⁺ ＝306.0。

Step 2: typical ester hydrolysis conditions (NaOH, meOH/H) were applied to methyl 2- (4- (tert-butyl) piperidin-1-yl) -4, 6-dimethylpyrimidine-5-carboxylate ₂ O, described in example H) to give 2- (4- (tert-butyl) piperidin-1-yl) -4, 6-dimethylpyrimidine-5-carboxylic acid as a white solid.

Compound 315 (formate) was prepared as a white solid from compound 101-K and 2- (4- (tert-butyl) piperidin-1-yl) -4, 6-dimethylpyrimidine-5-carboxylic acid using a method analogous to that described in example G. LCMS (method 5-95AB, ESI): t _R ＝0.713min,[M+H] ⁺ ＝911.8； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.49(brs,4H),7.25(d,J＝8.4Hz,2H),7.20(d,J＝8.4Hz,1H),7.11(d,J＝8.4Hz,1H),6.88(s,1H),6.72(s,1H),6.49(s,1H),5.20-5.15(m,1H),4.85-4.75(m,2H),4.35-4.20(m,6H),3.30-3.26(m,1H),3.26-3.20(m,4H),3.18-3.08(m,3H),2.98(s,3H),2.80-2.60(m,4H),2.27(s,6H),2.26-2.20(m,1H),2.18-2.10(m,1H),1.64-1.56(m,2H),1.36(d,J＝6.8Hz,3H),1.32-1.05(m,3H),0.89(s,9H)。

Example 116: synthesis of Compound 316

Compound 316 (formate) was prepared as a white solid from compound 101-K by using a similar method to that described in example 315. LCMS (methods 5-95AB, ESI): t _R ＝0.532min,[M+H] ⁺ ＝883.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.45(brs,2H),7.26(d,J＝8.4Hz,2H),7.19(d,J＝8.4Hz,1H),7.11(d,J＝8.4Hz,1H),6.89(s,1H),6.77(s,1H),6.43(s,1H),5.17-5.10(m,1H),4.80-5.75(m,2H),4.30-4.19(m,4H),4.21(s,2H),4.07-4.04(m,2H),3.90-3.88(m,2H),3.25-3.20(m,4H),3.19-3.07(m,4H),2.97(s,3H),2.62-2.60(m,1H),2.31(s,6H),2.27-2.22(m,1H),2.16-2.10(m,1H),1.35(d,J＝7.2Hz,3H),0.94(s,9H)。

Example 117: synthesis of Compound 317

Step 1: starting from methyl 2-chloro-4, 6-dimethylpyrimidine-5-carboxylate as described in example 53, typical S is used _N Ar (as described in example 315), alkylation (as described in example 38) and ester hydrolysis (as described in example H) conditions yielded 4, 6-dimethyl-2- (4- (pentyloxy) piperidin-1-yl) pyrimidine-5-carboxylic acid as a white solid.

Compound 317 (formate salt) was prepared from compound 101-K and 4, 6-dimethyl-2- (4- (pentyloxy) piperazine using an analogous method to that described in example GPyridin-1-yl) pyrimidine-5-carboxylic acid was prepared as a white solid. LCMS (methods 5-95AB, ESI): t _R ＝0.592min,[M+H] ⁺ ＝941.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.36(brs,4H),7.26-7.20(m,3H),7.11(d,J＝8.0,1H),6.88(brs,1H),6.73(s,1H),6.47(s,1H),5.19-5.16(m,1H),4.85-4.78(m,2H),4.31-4.21(m,8H),3.55-3.50(m,3H),3.25-3.09(m,8H),2.97(s,3H),2.26(s,6H),2.24-2.11(m,3H),1.88-1.85(m,2H),1.58-1.56(m,2H),1.43-1.34(m,11H),0.93(s,3H)。

Example 118: synthesis of Compound 318

Step 1: 1-bromo-4- (tert-butyl) benzene (550mg, 2.6 mmol), piperazine-1-carboxylic acid tert-butyl ester (577mg, 3.1mmol), pd (OAc) ₂ (23mg, 0.10mmol), BINAP (1.6g, 2.6mmol) and Cs ₂ CO ₃ A mixture of (1.23g, 3.9 mmol) in toluene (10 mL) was stirred at 90 ℃ for 16h. The volatiles were removed and the residue was redissolved with EtOAc (50 mL), which was washed with brine (50 mL). The organic layer is coated with Na ₂ SO ₄ Drying, concentration, and purification of the residue by silica gel chromatography, eluting with 5% etoac in petroleum ether, afforded tert-butyl 4- (4- (tert-butyl) phenyl) piperazine-1-carboxylate as a yellow solid (300mg, 37% yield). LCMS (method 5-95AB, ESI): t _R ＝0.872min,[M+H] ⁺ ＝318.9。

And 2, step: a solution of tert-butyl 4- (4-tert-butylphenyl) piperazine-1-carboxylate (300mg, 0.94mmol) in 20% TFA in DCM (15 mL) was stirred at 20 ℃ for 16h. The volatiles were removed under reduced pressure and the residue was taken up with saturated NaHCO ₃ Treating the aqueous solution until pH>7, which was then extracted with EtOAc (20mL. Times.3). The combined organic layers were washed with brine (50 mL) and Na ₂ SO ₄ Drying and concentration gave 1- (4-tert-butylphenyl) piperazine as a yellow solid (200mg, 97% yield).

Compound 318 (formate) was prepared as a white solid from compound 101-K and 1- (4- (tert-butyl) phenyl) piperazine using an analogous method to that described in example 315.LCMS (methods 5-95AB, ESI): t _R ＝0.724min,[M+H] ⁺ ＝988.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.49(br s,2H),7.31(d,J＝8.4Hz,2H),7.28-7.18(m,3H),7.10(d,J＝8.4Hz,1H),6.96(d,J＝8.4Hz,2H),6.88(s,1H),6.71(s,1H),6.48(s,1H),5.20-5.16(m,1H),4.81-4.77(m,2H),4.30(s,2H),4.22(brs,4H),3.93(brs,4H),3.28-3.05(m,8H),2.98(s,3H),2.29(s,6H),2.20-2.12(m,1H),2.09-2.02(m,1H),1.36(d,J＝6.8Hz,3H),1.30(s,9H)。

Example 119: synthesis of Compound 319

Step 1: starting from 4- (tert-butyl) pyridin-2 (1H) -one and methyl 2-chloro-4, 6-dimethylpyrimidine-5-carboxylate (described in example 53), typical alkylation (as described in example 315) and ester hydrolysis (described in example H) conditions were applied to give 2- (4- (tert-butyl) -2-oxopyridin-1 (2H) -yl) -4, 6-dimethylpyrimidine-5-carboxylic acid as a white solid. LCMS (methods 5-95AB, ESI): t _R ＝0.378min,[M+H] ⁺ ＝302.1。

Compound 319 (formate) was prepared as a white solid from compound 101-K and 2- (4- (tert-butyl) -2-oxopyridin-1 (2H) -yl) -4, 6-dimethylpyrimidine-5-carboxylic acid using a method analogous to that described in example G. LCMS (method 5-95AB, ESI): t _R ＝0.644min,[M+H] ⁺ ＝921.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.48(brs,3H),7.68(d,J＝8.0Hz,1H),7.29(d,J＝8.0Hz,1H),7.26-7.17(m,2H),7.10(d,J＝8.0Hz,1H),6.92(s,1H),6.78(s,1H),6.63(d,J＝8.0Hz,1H),6.57(s,1H),6.45(s,1H),5.26-5.23(m,1H),4.81-4.74(m,2H),4.30-4.19(m,6H),3.22-3.10(m,8H),3.01(s,3H),2.55(s,6H),2.35-2.25(m,1H),2.22-2.12(m,1H),1.36(d,J＝6.8Hz,3H),1.33(s,9H)。

Example 120: synthesis of Compound 320

Step 1: methyl 2- (4-chlorophenyl) -4, 6-dimethylpyrimidine-5-carboxylate (120mg, 0.43mmol), 4- (tert-butyl) piperidine (780mg, 0.56mmol), pd ₂ (dba) ₃ A mixture of (20mg, 0.02mmol), 2-dicyclohexylphosphino-2 ',6' -dimethoxybiphenyl (18mg, 0.04mmol) and t-BuONa (62.5mg, 0.65mmol) in toluene (8 mL) in N ₂ Stirring at 100 ℃ for 24h. The volatiles were removed under reduced pressure and the residue was purified by preparative TLC (eluting with 20% etoac in petroleum ether) to give methyl 2- (4- (4- (tert-butyl) piperidin-1-yl) phenyl) -4, 6-dimethylpyrimidine-5-carboxylate as a yellow solid (80mg, 48% yield).

Step 2: typical ester hydrolysis conditions (NaOH, meOH/H) as described in example H were applied to methyl 2- (4- (4- (tert-butyl) piperidin-1-yl) phenyl) -4, 6-dimethylpyrimidine-5-carboxylate ₂ O) to give 2- (4- (4- (tert-butyl) piperidin-1-yl) phenyl) -4, 6-dimethylpyrimidine-5-carboxylic acid as a white solid.

Compound 320 (formate) was prepared as a white solid from compound 101-K and 2- (4- (4- (tert-butyl) piperidin-1-yl) phenyl) -4, 6-dimethylpyrimidine-5-carboxylic acid using an analogous method to that described in example G. LCMS (methods 5-95AB, ESI): t _R ＝0.924min,[M+H] ⁺ ＝987.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.50(brs,2H),8.18-8.14(m,2H),7.31-7.26(m,1H),7.25-7.20(m,1H),7.18-7.07(m,2H),6.98(d,J＝8.4Hz,2H),6.88(brs,1H),6.66(brs,1H),6.54(s,1H),5.28-5.21(m,1H),4.83-4.75(m,2H),4.35-4.19(m,4H),4.23(s,2H),4.03-3.93(m,2H),3.29-3.07(m,8H),3.01(s,3H),2.80-2.69(m,2H),2.47(s,6H),2.32-2.21(m,1H),2.19-2.10(m,1H),1.89-1.81(m,,2H),1.50-1.40(m,2H),1.35(d,J＝6.8Hz,3H),1.30-1.25(m,1H),0.93(s,9H)。

Example 121: synthesis of Compound 321

Compound 321 (formate) was prepared as a white solid from compound 101-K by using an analogous method to that described in example 120. LCMS (method 5-95AB, ESI): t _R ＝0.690min,[M+H] ⁺ ＝917.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.51(brs,3H),8.20-8.10(m,2H),7.30-7.15(m,3H),7.09(d,J＝8.4Hz,1H),6.88(s,1H),6.69(s,1H),6.60(d,J＝8.4Hz,2H),6.52(s,1H),5.30-5.20(m,1H),4.85-4.75(m,2H),4.30-4.15(m,6H),3.45-3.35(m,5H),3.26-3.05(m,7H),3.01(s,3H),2.46(s,6H),2.30-2.25(m,1H),2.20-2.05(m,5H),1.35(d,J＝6.4Hz,3H)。

Example 122: synthesis of Compound 322

Compound 322 (formate) was prepared as a white solid from compound 101-K by using a similar method to that described in example 120. LCMS (methods 5-95AB, ESI): t _R ＝0.693min,[M+H] ⁺ ＝967.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.49(brs,1H),8.24(d,J＝8.4Hz,2H),7.31-7.25(m,1H),7.24-7.13(m,2H),7.11-7.02(m,3H),6.88(s,1H),6.70(brs,1H),6.49(s,1H),5.26-5.21(m,1H),4.80-4.77(m,2H),4.32-4.16(m,4H),4.22(s,2H),3.56-3.51(m,4H),3.30-3.04(m,8H),3.00(s,3H),2.48(s,6H),2.35-2.02(m,6H),1.35(d,J＝6.4Hz,3H)。

Example 123: synthesis of Compound 323

Compound 323 (formate) was prepared as a white solid from compound 101-K by using a similar method to that described in example 120. LCMS (methods 5-95AB, ESI): t _R ＝0.651min,[M+H] ⁺ ＝903.3； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.09(brs,2H),7.34-7.06(m,5H),6.87(s,1H),6.65-6.38(m,5H),5.30-5.24(m,1H),4.84-4.81(m,2H),4.43-4.23(m,6H),4.04-3.94(m,4H),3.33-3.10(m,5H),3.02(brs,6H),2.43(s,6H),2.40-2.35(m,2H),2.32-2.11(m,2H),1.35(d,J＝6.8Hz,3H)。

Example 124: synthesis of Compound 324

Compound 324 (formate) was prepared as a white solid from compound 101-K by using an analogous method to that described in example 120. LCMS (methods 5-95AB, ESI): t _R ＝0.950min,[M+H] ⁺ ＝931.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.51(brs,2H),8.10(d,J＝8.4Hz,2H),7.26(brs,2H),7.09(brs,2H),6.94(d,J＝8.4Hz,2H),6.86(s,1H),6.61(brs,1H),6.57(brs,1H),5.31-5.27(m,1H)4.85-4.78(m,2H),4.35(s,2H),4.25(brs,4H),3.37-3.34(m,4H),3.28-3.10(m,6H),3.05-2.93(m,2H),3.02(s,3H),2.42(s,6H),2.34-2.23(m,1H),2.20-2.10(m,1H),1.76-1.66(m,6H),1.35(d,J＝6.8Hz,3H)。

Example 125: synthesis of Compound 325

Compound 325 (formate salt) was prepared as a white solid from compound 101-K by using a similar method to that described in example 120. LCMS (methods 5-95AB, ESI): t _R ＝0.719min,[M+H] ⁺ ＝945.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.50(brs,1H),8.02-7.98(m,2H),7.28-7.24(m,2H),7.13-6.99(m,2H),6.83(brs,1H),6.75-6.60(m,3H),6.50(brs,1H),5.35-5.25(m,1H),4.78-4.75(m,2H),4.27(s,2H),4.25-4.18(m,4H),3.62-3.58(m,4H),3.31-3.26(m,4H),3.25-3.21(m,2H),3.15-3.11(m,2H),3.02(s,3H),2.37(s,6H),2.30-2.25(m,1H),2.21-2.09(m,1H),1.86(brs,4H),1.61(brs,4H),1.34(d,J＝6.8Hz,3H)。

Example 126: synthesis of Compound 326

Compound 326 (formate) was prepared as a white solid from compound 101-K by using a similar method to that described in example 120. LCMS (method 5-95AB, ESI): t _R ＝0.615min,[M+H] ⁺ ＝959.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.23(brs,2H),8.22-8.18(m,2H),7.39-6.86(m,6H),6.79-6.59(m,2H),6.49(s,1H),5.29-5.11(m,1H),4.75-4.67(m,2H),4.39-4.04(m,6H),3.64-3.55(m,4H),3.30-2.83(m,11H),2.50(s,6H),2.35-2.06(m,2H),1.81(brs,4H),1.55(brs,4H),1.45-1.39(m,2H),1.36(t,J＝7.2Hz,3H)。

Example 127: synthesis of Compound 327

Compound 327 (formate) was prepared as a white solid from compound 101-K by using an analogous method to that described in example 120. LCMS (method 5-95AB, ESI): t _R ＝0.681min,[M+H] ⁺ ＝959.7； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.41(brs,2H),8.25(d,J＝8.0Hz,2H),7.30-7.10(m,4H),7.00(d,J＝8.4Hz,2H),6.91(s,1H),6.79(s,1H),6.44(s,1H),5.24-5.20(m,1H),4.85-4.75(m,2H),4.36-4.18(m,8H),3.90-3.82(m,2H),3.29-3.22(m,6H),3.16-3.11(m,2H),3.01(s,3H),2.52(s,6H),2.40-2.25(m,3H),2.20-2.10(m,1H),1.90-1.83(m,1H),1.80-1.72(m,2H),1.36(d,J＝6.4Hz,3H),0.98(d,J＝6.4Hz,6H),0.87-0.74(m,1H)。

Example 128: synthesis of Compound 328

Compound 328 (formate) was prepared as a white solid from compound 101-K by using an analogous method to that described in example 53. LCMS (method 5-95AB, ESI): t _R ＝0.667min,[M+H] ⁺ ＝934.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.15(d,J＝8.0Hz,2H),7.26(brs,2H),7.15-7.05(m,2H),6.94(d,J＝8.4Hz,2H),6.85(s,1H),6.62(s,1H),6.51(s,1H),5.35-5.25(m,1H),4.80-4.70(m,2H),4.27(s,2H),4.25-4.15(m,4H),4.06(t,J＝6.8Hz,2H),3.40-3.35(m,1H),3.30-2.85(m,10H),2.42(s,6H),2.35-2.25(m,1H),2.25-2.15(m,1H),1.85-1.75(m,2H),1.55-1.40(m,4H),1.35(d,J＝6.4Hz,3H),0.98(t,J＝7.2Hz,3H)。

Example 129: synthesis of Compound 329

Compound 329 (formate) was prepared as a white solid from compound 101-K by using an analogous method to that described in example 53. LCMS (methods 5-95AB, ESI): t _R ＝0.740min,[M+H] ⁺ ＝934.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.47(brs,1H),8.25-8.18(m,2H),7.28-7.22(m,2H),7.10(brs,2H),6.95(d,J＝8.4Hz,2H),6.86(brs,1H),6.57(brs,1H),5.29-5.25(m,1H),4.85-4.75(m,2H),4.38-4.22(m,6H),4.10(t,J＝6.8Hz,2H),3.27-3.05(m,8H),3.01(s,3H),2.48(s,6H),2.34-2.24(m,1H),2.21-2.10(m,1H),1.95-1.82(m,1H),1.75-1.63(m,2H),1.35(d,J＝6.8Hz,3H),1.00(d,J＝6.4Hz,6H)。

Example 130: synthesis of Compound 330

Compound 330 (formate) was prepared as a white solid from compound 101-K by using an analogous method to that described in example 53. LCMS (methods 5-95AB, ESI): t _R ＝0.698min,[M+H] ⁺ ＝906.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.49(brs,2H),8.18(d,J＝8.0Hz,2H),7.30-7.22(m,2H),7.09(brs,2H),6.95(d,J＝8.4Hz,2H),6.86(s,1H),6.60(brs,1H),6.56(brs,1H),5.35-5.25(m,1H),4.85-4.70(m,2H),4.37(s,2H),4.30-4.15(m,4H),4.03(t,J＝6.4Hz,2H),3.25-2.90(m,8H),3.02(s,3H),2.44(s,6H),2.35-2.20(m,1H),2.20-2.10(m,1H),1.90-1.80(m,2H),1.35(d,J＝6.8Hz,3H),1.09(t,J＝7.6Hz,3H)。

Example 131: synthesis of Compound 331

Compound 331 (formate) is obtained by reactingAn analogous procedure to that described in example 53 was prepared from compound 101-K as a white solid. LCMS (methods 5-95AB, ESI): t _R ＝0.724min,[M+H] ⁺ ＝920.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.50(brs,3H),8.13(d,J＝7.6Hz,2H),7.26(brs,2H),7.15-7.00(m,2H),6.93(d,J＝8.4Hz,2H),6.84(s,1H),6.65(s,1H),6.48(s,1H),5.35-5.25(m,1H),4.85-4.70(m,2H),4.28(s,3H),4.30-4.15(m,4H),4.07(t,J＝6.4Hz,2H),3.40-2.90(m,8H),3.02(s,3H),2.41(s,6H),2.35-2.25(m,1H),2.20-2.10(m,1H),1.85-1.75(m,2H),1.60-1.50(m,2H),1.35(d,J＝6.8Hz,3H),1.03(t,J＝6.8Hz,3H)。

Example 132: synthesis of Compound 332

Compound 332 (formate) was prepared as a white solid from compound 101-K by using a similar method to that described in example 53. LCMS (method 5-95AB, ESI): t _R ＝0.780min,[M+H] ⁺ ＝948.7； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.50(brs,3H),8.19(d,J＝8.0Hz,2H),7.26(brs,2H),7.09(brs,2H),6.95(d,J＝8.8Hz,2H),6.86(s,1H),6.60(brs,1H),6.56(brs,1H),5.32-5.25(m,1H),4.81-4.71(m,2H),4.37(s,2H),4.30-4.21(m,4H),4.06(t,J＝6.4Hz,2H),3.25-2.95(m,8H),3.02(s,3H),2.44(s,6H),2.30-2.15(m,2H),1.87-1.79(m,2H),1.57-1.48(m,2H),1.47-1.24(m,7H),0.95(t,J＝6.4Hz,3H)。

Example 133: synthesis of Compound 333

Compound 333 (formate) was prepared as a white solid from compound 101-K by using a similar method to that described in example 53. LCMS (methods 5-95AB, ESI): t _R ＝0.502min,[M+H] ⁺ ＝922.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.24(d,J＝8.0Hz,2H),7.29-7.20(m,2H),7.16-7.05(m,2H),6.99(d,J＝8.0Hz,2H),6.87(s,1H),6.62(s,1H),6.55(s,1H),5.31-5.24(m,1H),4.85-4.76(m,2H),4.40-4.17(m,8H),3.79(t,J＝4.0Hz,2H),3.46(s,3H),3.28-2.95(m,8H),3.01(s,3H),2.47(s,6H),2.34-2.25(m,1H),2.19-2.10(m,1H),1.35(t,J＝6.8Hz,2H)。

Example 134: synthesis of Compound 334

Compound 334 (formate) was prepared as a white solid from compound 101-K by using an analogous method to that described in example 53. LCMS (methods 5-95AB, ESI): t _R ＝0.640min,[M+H] ⁺ ＝906.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.49(brs,2H),7.90-7.75(m,2H),7.40-7.02(m,4H),6.95-6.80(m,2H),6.67(brs,1H),6.49(brs,1H),5.30-5.20(m,1H),4.79-4.75(m,1H),4.40-4.10(m,11H),3.25-3.10(m,8H),3.00(s,3H),2.47(s,6H),2.35-2.15(m,1H),2.15-2.05(m,1H),1.35(d,J＝6.8Hz,3H)。

Example 135: synthesis of Compound 335

Step 1: 4-bromophenol (500mg, 2.9mmol), bromocyclobutane (585mg, 4.4mmol) and K ₂ CO ₃ A mixture of (800mg, 5.8 mmol) in DMF (2 mL) was stirred at 80 deg.C for 16h. The volatiles were removed under reduced pressure and the residue was taken up in EtOAc (50 mL), which was washed with brine (50 mL). The organic layer was MgSO ₄ Dried, concentrated, and the residue purified by preparative TLC (eluted with 5% EtOAc in petroleum ether, R _f = 0.3) to give 1-bromo-4-cyclobutoxybenzene as a colorless oil (400mg, 61% yield). ¹ H NMR(400MHz,MeOH-d ₄ )δ7.35(d,J＝8.0Hz,2H),6.70(d,J＝8.0Hz,2H),4.65-4.55(m,1H),2.47-2.43(m,2H),2.19-2.13(m,2H),1.85-1.75(m,1H),1.70-1.60(m,1H)。

Compound 335 (formate) was prepared as a white solid from compound 101-K and 1-bromo-4-cyclobutoxybenzene using an analogous method to that described in example 53. LCMS (method 5-95AB, ESI): t _R ＝0.687min,[M+H] ⁺ ＝918.7； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.49(brs,2H),8.25(brs,2H),7.30-7.20(m,2H),7.17-7.06(m.,2H),6.88(brs,3H),6.67(brs,1H),6.52(s,1H),5.27-5.23(m,1H),4.84-4.73(m,3H),4.35-4.19(m,6H),3.25-3.00(m,11H),2.58-2.45(m,2H),2.49(s,6H),2.36-2.09(m,5H),1.96-1.86(m,1H),1.82-1.73(m,1H),1.35(d,J＝6.8Hz,3H)。

Example 136: synthesis of Compound 336

Compound 336 (formate) was prepared as a white solid from compound 101-K by using a similar method as described in example 135. LCMS (methods 5-95AB, ESI): t _R ＝0.714min,[M+H] ⁺ ＝932.3； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.50(brs,3H),8.14(d,J＝8.0Hz,2H),7.26(brs,2H),7.15-7.00(m,2H),6.90(d,J＝8.4Hz,2H),6.84(s,1H),6.63(s,1H),6.51(s,1H),5.35-5.25(m,1H),4.85-4.70(m,3H),4.39(s,2H),4.25-4.15(m,4H),3.40-3.10(m,5H),3.02(s,3H),3.00-2.85(m,2H),2.42(s,6H),2.35-2.20(m,1H),2.20-2.10(m,1H),2.10-1.95(m,2H),1.95-1.80(m,4H),1.80-1.65(m,2H),1.35(d,J＝6.8Hz,3H)。

Example 137: synthesis of Compound 337

Compound 337 (formate) was prepared as a white solid from compound 101-K by using a similar method as described in example 135. LCMS (methods 5-95AB, ESI): t _R ＝0.730min,[M+H] ⁺ ＝946.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.50(brs,3H),8.15(d,J＝8.0Hz,2H),7.26(brs,2H),7.10-7.00(m,2H),6.93(d,J＝8.4Hz,2H),6.84(s,1H),6.62(s,1H),6.52(s,1H),5.35-5.25(m,1H),4.85-4.70(m,2H),4.50-4.30(m,3H),4.25(brs,4H),3.40-3.10(m,5H),3.02(s,3H),3.00-2.85(m,2H),2.42(s,6H),2.35-2.20(m,1H),2.20-2.10(m,1H),2.10-2.00(m,2H),1.90-1.80(m,2H),1.70-1.40(m,6H),1.35(d,J＝6.8Hz,3H)。

Example 138: synthesis of Compound 338

Compound 338 (formate) was prepared as a white solid from compound 101-K by using a similar method to that described in example 135. LCMS (methods 5-95AB, ESI): t _R ＝0.767min,[M+H] ⁺ ＝948.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.49(brs,2H),8.29(d,J＝8.0Hz,2H),7.29(d,J＝8.0Hz,1H),7.24-7.13(m,2H),7.09(d,J＝8.0Hz,1H),6.99(d,J＝8.0Hz,2H),6.89(s,1H),6.70(s,1H),6.50(s,1H),5.27-5.23(m,1H),4.81-4.75(m,2H),4.29(s,2H),4.25-4.20(m,4H),4.14(t,J＝7.2Hz,2H),3.24-3.11(m,8H),3.01(s,3H),2.50(s,6H),2.34-2.22(m,1H),2.21-2.09(m,1H),1.77(t,J＝7.2Hz,2H),1.35(d,J＝6.4Hz,3H),1.04(s,9H)。

Example 139: synthesis of Compound 339

Compound 339 (formate) was prepared as a white solid from compound 101-K by using an analogous method to that described in example 135. LCMS (methods 5-95AB, ESI): t _R ＝0.612min,[M+H] ⁺ ＝934.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.51(brs,3H),8.24(d,J＝8.0Hz,1H),8.14(d,J＝8.0Hz,1H),7.28-7.24(m,2H),7.11-6.88(m,6H),6.67(s,0.5H),6.61(0.5H),5.34-5.29(m,1H),4.80-4.77(m,2H),4.37-4.22(m,7H),3.36-3.00(m,11H),2.50(s,3H),2.43(s,3H),2.34-2.18(m,2H),1.77-1.72(m,4H)1.45-1.35(m,3H),1.04-1.00(m,6H)。

Example 140: synthesis of Compound 340

Compound 340 (formate) was prepared from compound 101-K as a white solid by using a similar method to that described in example 135. LCMS (methods 5-95AB, ESI): t _R ＝0.618min,[M+H] ⁺ ＝960.3； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.52(brs,2H),8.11(d,J＝8.0Hz,2H),7.26(brs,2H),7.07(d,J＝8.0Hz,1H),7.02-6.96(m,1H),6.86(d,J＝8.4Hz,2H),6.82(s,1H),6.67(s,1H),6.44(s,1H),5.33-5.30(m,1H),4.79-4.74(m,2H),4.63-4.56(m,1H),4.37(s,2H),4.26-4.23(m,4H),3.27-3.00(m,8H),3.02(s,3H),2.38(s,6H),2.32-2.26(m,1H),2.11-2.03(m,3H),1.88-1.77(m,5H),1.68-1.65(m,5H),1.57-1.53(m,2H),1.34(d,J＝6.4Hz,3H)。

Example 141: synthesis of Compound 341

Compound 341 (formate) was prepared as a white solid from compound 101-K by using a method analogous to that described in example 135. LCMS (methods 5-95AB, ESI): t _R ＝0.789min,[M+H] ⁺ ＝962.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.51(brs,2H),8.22(d,J＝8.0Hz,1H),7.30-7.20(m,2H),7.13-7.04(m,2H),6.94(d,J＝8.4Hz,2H),6.87(s,1H),6.61(brs,1H),6.56(brs,1H),5.30-5.24(m,1H),4.85-4.73(m,2H),4.49-4.44(m,1H),4.31(s,2H),4.26-4.21(m,4H),3.31-2.95(m,8H),3.01(s,3H),2.46(s,6H),2.31-2.26(m,1H),2.15-2.05(m,1H),1.77-1.64(m,4H),1.56-1.40(m,4H),1.35(d,J＝6.4Hz,3H),0.96(t,J＝7.6Hz,6H)。

Example 142: synthesis of Compound 342

Compound 342 (formate) was prepared as a white solid from compound 101-K by using a similar method as described in example 50. LCMS (method 5-95AB, ESI): t _R ＝0.707min,[M+H] ⁺ ＝920.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.17(d,J＝8.0Hz,2H),7.25(brs,2H),7.11-6.99(m,4H),6.84(s,1H),6.64(s,1H),6.52(s,1H),5.36-5.23(m,1H),4.84-4.74(m,2H),4.36(s,2H),4.28-4.15(m,4H),3.26-3.10(m,6H),3.10-2.89(m,2H),3.02(s,3H),2.44(s,6H),2.34-2.22(m,1H),2.18-2.09(m,1H),1.43(s,9H),1.35(d,J＝7.2Hz,3H)。

Example 143: synthesis of Compound 343

Compound 343 (formate) was prepared as a white solid from compound 101-K by using a similar method to that described in example 50. LCMS (methods 5-95AB, ESI): t _R ＝0.706min,[M+H] ⁺ ＝934.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.52(brs,3H),8.35-8.29(m,3H),7.49-7.43(m,4H),7.30-7.27(m,1H),7.11(brs,1H),6.91(s,1H),6.54(s,1H),4.82-4.80(m,2H),4.58(brs,4H),4.24(brs,5H),3.21-3.13(m,8H),3.04(s,3H),2.54(s,6H),2.30-2.10(m,2H),1.37(d,J＝6.8Hz,3H),1.35(s,9H)。

Example 144: synthesis of Compound 344

Step 1: starting from 1-fluoro-4-nitrobenzene, typical alkylation (using NaH as described in example 38), hydrogenation (using Pd/C and H as described in example E) were applied ₂ ) And sandmeyer (as described in example J) conditions, 1-bromo-4- (1-methylcyclopropoxy) benzene was obtained as a yellow solid.

Compound 344 (formate) was prepared as a white solid from compound 101-K and 1-bromo-4- (1-methylcyclopropoxy) benzene using an analogous method to that described in example 53. LCMS (methods 5-95AB, ESI): t _R ＝0.709min,[M+H] ⁺ ＝918.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.46(brs,2H),8.27(d,J＝7.6Hz,2H),7.31-7.21(m,2H),7.20-7.12(m,1H),7.11-7.04(m,3H),6.88(s,1H),6.68(s,1H),6.52(s,1H),5.30-6.22(m,1H),4.81-4.74(m,2H),4.37-4.17(m,6H),3.29-3.20(m,5H),3.17-3.08(m,3H),3.02(s,3H),2.49(s,6H),2.34-2.24(m,1H),2.21-2.11(m,1H),1.59(s,3H),1.36(d,J＝6.8Hz,3H),1.02-0.95(m,2H),0.84-0.76(m,2H)。

Example 145: synthesis of Compound 345

Step 1: to a stirred mixture of methyl propionate (5.0g, 56.8mmol) and Ti (i-PrO) over a period of 1h ₄ (1.6 g,5.7 mmol) in Et ₂ EtMgBr (Et) was added to a solution of O (80 mL) ₂ 3N in O, 41.6 mL), and the mixture was stirred for another 10min. Then pouring the mixture into the flask while keeping the temperature below 5 ℃ to 10% ₂ SO ₄ Aqueous solution (100 mL). With Et ₂ The resulting mixture was extracted with O (3x 100mL). The combined organic layers were washed with brine (50 mL) and Na ₂ SO ₄ Drying and concentration gave 1-ethylcyclopropan-1-ol as a yellow oil (4.5g, 92% yield). ¹ H NMR(400MHz,CDCl ₃ )δ1.56(q,J＝7.2Hz,2H),1.00(t,J＝7.2Hz,3H),0.70(t,J＝5.6Hz,2H),0.42(t,J＝5.6Hz 2H)。

Compound 345 (formate) was prepared as a white solid from compound 101-K and 1-ethylcyclopropan-1-ol using an analogous method to that described in example 144. LCMS (methods 5-95AB, ESI): t _R ＝0.602min,[M+H] ⁺ ＝932.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.45(brs,2H),8.23(d,J＝8.0Hz,2H),7.28(brs,2H),7.16-7.03(m,4H),6.89(s,1H),6.62(brs,1H),6.58(brs,1H),5.30-5.28(m,1H),4.84-4.79(m,2H),4.40(s,2H),4.35-4.23(m,4H),3.32-3.28(m,4H),3.04(brs,7H),2.49(s,6H),2.34-2.25(m,1H),2.24-2.13(m,1H),1.87(q,J＝6.8Hz,2H),1.37(d,J＝6.4Hz,3H),1.07(t,J＝6.8Hz,3H),1.01-0.95(m,2H),0.86-0.81(m,2H)。

Example 146: synthesis of Compound 346

Compound 346 (formate) can be obtained byPrepared from compounds 101-K as white solids in analogy to the procedure described in example 145. LCMS (methods 5-95AB, ESI): t _R ＝0.731min,[M+H] ⁺ ＝946.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.52(brs,2H),8.17(d,J＝7.6Hz,2H),7.25(brs,2H),7.12-6.97(m,4H),6.83(s,1H),6.64(s,1H),6.50(s,1H),5.29-5.26(m,1H),4.84-4.75(m,2H),4.37-4.17(m,6H),3.25-2.95(m,8H),3.02(s,3H),2.42(s,6H),2.30-2.23(m,1H),2.14-2.11(m,1H),1.86-1.74(m,2H),1.60-1.50(m,2H),1.35(d,J＝6.8Hz,3H),1.03-0.88(m,5H),0.84-0.80(m,2H)。

Example 147: synthesis of Compound 347

Compound 347 (formate) was prepared from compound 101-K as a white solid by using an analogous method to that described in example 145. LCMS (method 5-95AB, ESI): t _R ＝0.745min,[M+H] ⁺ ＝960.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.51(brs,1H),8.19(d,J＝7.6Hz,2H),7.23(d,J＝8.0Hz,2H),7.11-6.97(m,4H),6.85(s,1H),6.58(brs,2H),5.30-5.26(m,1H),4.83-4.72(m,2H),4.24(s,2H),4.20-4.10(m,4H),3.30-3.08(m,8H),3.01(s,3H),2.43(s,6H),2.32-2.22(m,1H),2.20-2.10(m,1H),1.89-1.76(m,2H),1.51-1.45(m,2H),1.43-1.30(m,5H),1.00-0.85(m,5H),0.85-0.78(m,2H)。

Example 148: synthesis of Compound 348

Step 1: typical Suzuki conditions as described in example H were applied to (4-hydroxyphenyl) boronic acid and methyl 2-chloro-4, 6-dimethylpyrimidine-5-carboxylate (described in example 53) to give methyl 2- (4-hydroxyphenyl) -4, 6-dimethylpyrimidine-5-carboxylate as a white solid. ¹ H NMR(400MHz,CDCl ₃ )δ8.39(d,J＝8.8Hz,2H),6.91(d,J＝8.8Hz,2H),5.11(s,1H),3.95(s,3H),2.58(s,6H)。

Step 2: at 0 ℃ in the direction ofMethyl 2- (4-hydroxyphenyl) -4, 6-dimethylpyrimidine-5-carboxylate (50mg, 0.19mmol), 4-dimethylcyclohexan-1-ol (62mg, 0.48mmol) and PPh ₃ (127mg, 0.48mmol) in toluene (5 mL) was added dropwise diisopropyl azodicarboxylate (98mg, 0.48mmol) and the resulting mixture was stirred at 80 ℃ for 2h. The volatiles were removed under reduced pressure and the residue was purified by preparative TLC (eluting with 30% etoac in petroleum ether) to give methyl 2- (4- ((4, 4-dimethylcyclohexyl) oxy) phenyl) -4, 6-dimethylpyrimidine-5-carboxylate as a white solid (50mg, 70% yield).

And 3, step 3: typical ester hydrolysis conditions (NaOH, meOH/H) were applied to methyl 2- (4- ((4, 4-dimethylcyclohexyl) oxy) phenyl) -4, 6-dimethylpyrimidine-5-carboxylate ₂ O, as described in example H) to give 2- (4- ((4, 4-dimethylcyclohexyl) oxy) phenyl) -4, 6-dimethylpyrimidine-5-carboxylic acid as a white solid. LCMS (method 5-95AB, ESI): t _R ＝1.022min,[M+H] ⁺ ＝355.0。

Compound 348 (formate) was prepared as a white solid by using a method analogous to that described in example G from compound 101-K and 2- (4- ((4, 4-dimethylcyclohexyl) oxy) phenyl) -4, 6-dimethylpyrimidine-5-carboxylic acid. LCMS (methods 5-95AB, ESI): t _R ＝0.740min,[M+H] ⁺ ＝974.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.51(brs,1H),8.25(d,J＝8.0Hz,2H),7.30-7.15(m,2H),7.14-7.05(m,2H),6.96(d,J＝8.4Hz,2H),6.87(s,1H),6.64(s,1H),6.52(s,1H),5.26-5.23(m,1H),4.85-4.75(m,2H),4.45-4.40(m,1H),4.30-4.10(m,6H),3.30-2.95(m,8H),3.00(s,3H),2.47(s,6H),2.25-2.15(m,1H),2.15-2.00(m,1H),1.95-1.85(m,2H),1.75-1.60(m,2H),1.59-1.45(m,2H),1.40-1.25(m,5H),1.01(s,3H),0.99(s,3H)。

Example 149: synthesis of Compound 349

Step 1: 2, 3-dihydro-1H-inden-2-ol (100mg, 0.75mmol) and PtO ₂ (30.0 mg, 0.75mmol) of the mixture in MeOH/AcOH (11mL, v/v = 10/1) in H ₂ (15 psi) atStirring for 16h. After filtration, the volatiles were removed under reduced pressure and the residue was purified by silica gel chromatography, eluting with 15% etoac in petroleum ether, to give (cis) -octahydro-1H-inden-2-ol as a colorless oil (20mg, 19% yield). ¹ H NMR(400MHz,CDCl ₃ )δ4.41-4.35(m,1H),2.10-1.98(m,2H),1.95-1.80(m,2H),1.55-1.45(m,6H),1.38-1.22(m,3H),0.90-0.80(m,1H)。

Compound 349 (formate salt, mixture of diastereomers) was prepared as a white solid by using a similar method to that described in example 148 using 101-K and (cis) -octahydro-1H-inden-2-ol. LCMS (method 5-95AB, ESI): t _R ＝0.750min,[M+H] ⁺ ＝986.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.51(brs,3H),8.30(d,J＝8.4Hz,2H),7.27(d,J＝8.4Hz,1H),7.19(d,J＝8.4Hz,2H),7.08(d,J＝8.4Hz,1H),7.00-6.80(m,3H),6.74(s,1H),6.46(s,1H),5.26-5.20(m,1H),5.00-4.75(m,3H),4.21(s,2H),4.20-4.16(m,4H),3.34-3.05(m,8H),3.00(s,3H),2.51(s,6H),2.40-2.05(m,7H),1.85-1.75(m,2H),1.70-1.45(m,4H),1.40-1.30(m,6H)。

Example 150: synthesis of Compound 350

Compound 350 (formate) was prepared as a white solid from compound 101-K by using a similar method to that described in example 148. LCMS (method 5-95AB, ESI): t _R ＝0.750min,[M+H] ⁺ ＝958.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.49(brs,3H),8.20(d,J＝8.0Hz,2H),7.28-7.22(m,2H),7.09-7.07(m,2H),6.90-6.86(m,3H),6.60(brs,1H),6.55(brs,1H),5.28-5.25(m,1H),4.85-4.77(m,2H),4.32-4.30(m,3H),4.25-4.19(m,4H),3.25-3.05(m,8H),3.01(s,1H),2.45(s,6H),2.31-2.12(m,2H),1.89-1.84(m,1H),1.70-1.57(m,5H),1.35(d,J＝6.4Hz,3H),1.26-1.22(m,4H)。

Example 151: synthesis of Compound 351

Step 1: (4-butoxy-2, 3,5, 6-tetrafluorophenyl) boronic acid (146mg, 0.55mmol), ethyl 2-chloro-4, 6-dimethylpyrimidine-5-carboxylate (100mg, 0.50mmol), pd ₂ (dba) ₃ (23mg，0.02mmol)、P(t-Bu) ₃ (15mg，0.07mmol)、Ag ₂ A mixture of O (139mg, 0.6mmol) and CsF (189mg, 1.25mmol) in toluene (5 mL) was N ₂ Stirring at 100 ℃ for 20h. Volatiles were removed under reduced pressure and the residue was purified by preparative TLC (eluted with 10% EtOAc in petroleum ether, R _f = 0.4) to give methyl 2- (4-butoxy-2,3,5, 6-tetrafluorophenyl) -4, 6-dimethylpyrimidine-5-carboxylate as a colorless oil (50mg, 26% yield). LCMS (ESI) [ < M + H ]] ⁺ ＝387.1。

Step 2: typical ester hydrolysis conditions (NaOH, meOH/H) were applied to methyl 2- (4-butoxy-2, 3,5, 6-tetrafluorophenyl) -4, 6-dimethylpyrimidine-5-carboxylate ₂ O, example H) to give 2- (4-butoxy-2, 3,5, 6-tetrafluorophenyl) -4, 6-dimethylpyrimidine-5-carboxylic acid as a white solid.

Compound 351 (formate) was prepared as a white solid from compound 101-K and 2- (4-butoxy-2, 3,5, 6-tetrafluorophenyl) -4, 6-dimethylpyrimidine-5-carboxylic acid using a method analogous to that described in example G. LCMS (method 5-95AB, ESI): t _R ＝0.619min,[M+H] ⁺ ＝992.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.50(brs,1H),7.34-7.28(m,1H),7.27-7.22(m,1H),7.19(d,J＝8.4Hz,1H),7.10(d,J＝8.4Hz,1H),6.92(d,J＝2.4Hz,1H),6.84(d,J＝2.4Hz,1H),6.41(s,1H),5.24-5.18(m,1H),4.82-4.80(m,2H),4.36(t,J＝6.4Hz,2H),4.26-4.17(m,6H),3.36-3.37(m,1H),3.21-3.10(m,7H),3.01(s,3H),2.61(s,6H),2.34-2.24(m,1H),2.21-2.11(m,1H),1.85-1.76(m,2H),1.61-1.51(m,2H),1.36(d,J＝7.0Hz,3H),1.02(t,J＝7.4Hz,3H)。

Example 152: synthesis of Compound 352

Step 1: 4-bromobenzenethiol (300mg, 1.6 mmol) and 1-bromopentane(1.2g, 8.0mmol) and K ₂ CO ₃ A mixture of (658mg, 4.8mmol) in DMF (7 mL) was stirred at 80 ℃ for 16h. The reaction was poured into water (20 mL), which was extracted with EtOAc (3x 30mL). The combined organic layers were washed with brine (2x 50mL) and Na ₂ SO ₄ Drying, concentration, and purification of the residue by silica gel chromatography, eluting with 5% EtOAc in petroleum ether, afforded (4-bromophenyl) (pentyl) sulfane as a colorless oil (300mg, 73% yield).

Compound 352 (formate) was prepared as a white solid from compound 101-K and (4-bromophenyl) (pentyl) sulfane using an analogous method to that described in example 53. LCMS (methods 5-95AB, ESI): t _R ＝0.760min,[M+H] ⁺ ＝950.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.50(brs,3H),8.31(d,J＝8.0Hz,2H),7.38(d,J＝8.4Hz,2H),7.27(d,J＝2.0Hz,1H),7.20(d,J＝8.4Hz,2H),7.09(d,J＝8.4Hz,1H),6.90(s,1H),6.89(s,1H),6.45(s,1H),5.24-5.20(m,1H),4.86-4.75(m,1H),4.24-4.15(m,7H),3.20-2.95(m,13H),2.53(s,6H),2.25-2.15(m,1H),2.15-2.05(m,1H),1.75-1.60(m,2H),1.50-1.25(m,7H),0.93(t,J＝7.2Hz,3H)。

Example 153: synthesis of Compound 353

Step 1: methyl 2-chloro-4, 6-dimethylpyrimidine-5-carboxylate (described in example 53) (100mg, 0.50mmol), 4-tert-butylphenol (97mg, 0.65mmol) and K ₂ CO ₃ A mixture of (207mg, 1.5 mmol) in DMF (3 mL) was stirred at 100 ℃ for 4h. The volatiles were removed under reduced pressure and the residue was taken up in EtOAc (30 mL), which was washed with brine (2x 30mL). The organic layer is coated with Na ₂ SO ₄ Dried, concentrated, and the residue purified by reverse phase HPLC to give methyl 2- (4- (tert-butyl) phenoxy) -4, 6-dimethylpyrimidine-5-carboxylate as a white solid (73mg, 47% yield). LCMS (methods 5-95AB, ESI): t _R ＝0.953min,[M+H] ⁺ ＝314.9。

And 2, step: p-2- (4- (tert-butyl) phenoxy) -4, 6-dimethylpyrimidine-5-carboxylic acid methyl esterTypical ester hydrolysis conditions (NaOH, meOH/H) were applied ₂ O, described in example H) to give 2- (4- (tert-butyl) phenoxy) -4, 6-dimethylpyrimidine-5-carboxylic acid as a white solid.

Compound 353 (formate) was prepared as a white solid by using an analogous method to that described in example G from compound 101-K and 2- (4- (tert-butyl) phenoxy) -4, 6-dimethylpyrimidine-5-carboxylic acid. LCMS (methods 5-95AB, ESI): t _R ＝0.721min,[M+H] ⁺ ＝920.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.48(brs,2H),7.46(d,J＝8.8Hz,2H),7.26-7.14(m,3H),7.11-7.03(m,3H),6.89(s,1H),6.79(s,1H),6.40(s,1H),5.20-5.14(m,1H),4.79-4.62(m,2H),4.29-4.18(m,6H),3.40-3.35(m,1H),3.21-3.08(m,7H),2.97(s,3H),2.41(s,6H),2.30-2.10(m,2H),1.36(s,9H),1.35(d,J＝6.8Hz,3H)。

Example 154: synthesis of Compound 354

Compound 354 (formate) was prepared from compound 101-K as a white solid by using a method analogous to that described in example 153. LCMS (method 5-95AB, ESI): t _R ＝0.738min,[M+H] ⁺ ＝920.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.51(brs,2H),7.26-7.21(m,4H),7.18(d,J＝8.4Hz,1H),7.10(d,J＝8.4Hz,1H),7.01(d,J＝8.4Hz,2H),6.88(d,J＝2.4Hz,1H),6.75(s,1H),6.44(s,1H),5.20-5.17(m,1H),4.82-4.77(m,2H),4.25-4.18(m,6H),3.40-3.35(m,1H),3.18-3.00(m,7H),2.98(s,3H),2.66(t,J＝8.4Hz,2H),2.40(s,6H),2.30-2.21(m,1H),2.18-2.08(m,1H),1.67-1.61(m,2H),1.49-1.30(m,5H),0.97(t,J＝7.5Hz,3H)。

Example 155: synthesis of Compound 355

Step 1: typical Suzuki conditions as described in example H were applied to 1, 2-dibromo-4-methoxybenzene to give 1, 2-dibutyl-4-methoxybenzene as a colorless oil.

And 2, step: to a solution of 1, 2-dibutyl-4-methoxybenzene (410mg, 1.9 mmol) in DCM (20 mL) at 0 deg.C was added BBr ₃ (0.54mL, 5.6 mmol) and the mixture was stirred at 15 ℃ for 16h. The reaction was quenched with MeOH (20 mL), the volatiles were removed under reduced pressure, and the residue was purified by silica gel chromatography, eluting with 0-20% EtOAc in petroleum ether, to give 3, 4-dibutylphenol as a brown oil (370mg, 96% yield). ¹ H NMR(400MHz,MeOH-d4):δ6.91(d,J＝8.4Hz,1H),6.56(d,J＝2.8Hz,1H),6.55-6.50(m,1H),2.60-2.45(m,4H),1.60-1.45(m,4H),1.45-1.30(m,4H),1.00-0.92(m,6H)。

Compound 355 (formate) was prepared as a white solid from compound 101-K and 3, 4-dibutylphenol using a method similar to that described in example 153. LCMS (methods 5-95AB, ESI): t _R ＝0.791min,[M+H] ⁺ ＝976.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.50(brs,1H),7.32-7.26(m,2H),7.21-7.15(m,2H),7.11-7.04(m,3H),6.93-6.88(m,2H),6.46(s,1H),5.20-5.15(m,1H),4.85-4.75(m,2H),4.23-4.12(m,6H),3.18-2.99(m,11H),2.66(t,J＝7.6Hz,4H),2.44(s,6H),2.30-2.23(m,1H),2.16-2.10(m,1H),1.65-1.55(m,4H),1.49-1.38(m,7H),0.97(t,J＝7.6Hz,6H)。

Example 156: synthesis of Compound 356

Step 1: typical alkylation conditions were applied to 4- (benzyloxy) phenol (as described in example 21) to give 1- (benzyloxy) -4- (3-bromopropoxy) benzene as a colorless oil.

And 2, step: to a solution of 1- (benzyloxy) -4- (3-bromopropoxy) benzene (1.5 g, 4.67mmol) and CuI (231mg, 2.33mmol) in THF (50 mL) was added t-BuMgCl (Et) ₂ 2n in O, 23.4 ml) and the mixture was stirred at 25 ℃ for 4h. With saturated NH ₄ The reaction was quenched with aqueous Cl (30 mL) and the resulting mixture was extracted with EtOAc (3X 30mL). The combined organic layers were washed with brine (2x 100mL) and Na ₂ SO ₄ Drying, concentrating, and collecting the residueThe residue was purified by reverse phase HPLC (acetonitrile 60-98%/0.225% aqueous formic acid) to give 1- (benzyloxy) -4- ((4, 4-dimethylpentyl) oxy) benzene as a white solid. ¹ H NMR(400MHz,CDCl ₃ )δ7.35-7.21(m,5H),6.90(d,J＝8.8Hz,2H),6.83(d,J＝8.8Hz,2H),5.01(s,2H),3.88(t,J＝6.4Hz,2H),1.76-1.70(m,2H),1.30-1.20(m,2H),0.91(s,9H)。

And 3, step 3: typical hydrogenation conditions as described in example D were applied to 1- (benzyloxy) -4- ((4, 4-dimethylpentyl) oxy) benzene to give 4- ((4, 4-dimethylpentyl) oxy) phenol as a colorless oil.

Compound 356 (formate) was prepared as a white solid from compound 101-K and 4- ((4, 4-dimethylpentyl) oxy) phenol by using an analogous method to that described in examples 10 and 53. LCMS (methods 5-95AB, ESI): t _R ＝0.766min,[M+H] ⁺ ＝962.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.52(brs,1H),8.23(d,J＝7.6Hz,2H),7.26-7.21(m,2H),7.12-7.08(m,2H),6.96(d,J＝8.4Hz,2H),6.86(d,J＝2.4Hz,1H),6.62(brs,1H),6.54(brs,1H),5.28-5.25(m,1H),4.80-4.75(m,1H),4.60-4.45(m,1H),4.40-4.10(m,6H),4.03(t,J＝6.4Hz,2H),3.33-3.15(m,4H),3.15-2.90(m,7H),2.46(s,6H),2.40-2.20(m,1H),2.20-2.05(m,1H),1.84-1.76(m,2H),1.42-1.33(m,5H),0.96(s,9H)。

Example 157: synthesis of Compound 357

Compound 357 (formate) was prepared as a white solid from compound 101-K by using a similar method to that described in example 156. LCMS (methods 5-95AB, ESI): t _R ＝0.780min,[M+H] ⁺ ＝976.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.52(brs,1H),8.27-8.22(m,2H),7.25-7.18(m,2H),7.14-7.05(m,2H),7.04-6.95(m,2H),6.86(s,1H),6.65(brs,1H),6.53(brs,1H),5.27-5.24(m,1H),4.85-4.75(m,2H),4.35-4.20(m,6H),4.07(t,J＝7.2Hz,2H),3.20-2.90(m,11H),2.47(s,6H),2.25-2.15(m,1H),2.14-2.05(m,1H),1.81-1.70(m,2H),1.50-1.40(m,2H),1.36(d,J＝7.2Hz,3H),1.30-1.20(m,2H),0.94(s,9H)。

Example 158: synthesis of Compound 358

Step 1: to a solution of (E) -ethyl 3-aminobut-2-enoate (17.0 g, 132mmol) in toluene (100 mL) was added HCl (4N in dioxane, 66mL) and the mixture was stirred at reflux for 16h. After filtration, the filtrate was concentrated and the residue was purified by silica gel chromatography, eluting with 5% MeOH/EtOAc, to give ethyl 2, 4-dimethyl-6-oxo-1, 6-dihydropyridine-3-carboxylate (5.0 g,20% yield) as a white solid. ¹ H NMR(400MHz,CDCl ₃ )δ6.25(s,1H),4.33(q,J＝7.2Hz,2H),2.52(s,3H),2.29(s,3H),1.36(t,J＝7.2Hz,3H)。

Step 2: to a solution of ethyl 2, 4-dimethyl-6-oxo-1, 6-dihydropyridine-3-carboxylate (2.0 g, 10.2mmol) in toluene (100 mL) was added SOCl ₂ (3.66g, 30.7 mmol) and DMF (1.12g, 15.4 mmol) and the mixture was stirred at 80 ℃ for 12h. The reaction mixture was diluted with water (50 mL), which was extracted with EtOAc (3x 50mL). The combined organic portions were washed with brine (2x 100mL) and MgSO ₄ Drying, concentration, and the residue was purified by silica gel chromatography eluting with 10% etoac in petroleum ether to give ethyl 6-chloro-2, 4-dimethylnicotinate as a brown oil (2.0 g,91% yield). LCMS (methods 5-95AB, ESI): t _R ＝0.816min,[M+H] ⁺ ＝213.8。

Compound 358 (formate) was prepared as a white solid by using a similar method to that described in example 53 from compound 101-K and ethyl 6-chloro-2, 4-dimethylnicotinate. LCMS (methods 5-95AB, ESI): t _R ＝0.670min,[M+H] ⁺ ＝903.8； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.46(brs,3H),7.80-7.74(m,2H),7.51-7.47(m,3H),7.29-7.22(m,2H),7.20-7.05(m,2H),6.87(s,1H),6.56(brs,2H),5.30-5.26(m,1H),4.86-4.77(m,1H),4.45-4.15(m,7H),3.34-3.10(m,8H),3.03(s,3H),2.50(s,3H),2.40-2.10(m,5H),1.37(s,9H),1.35(d,J＝6.8Hz,3H)。

Example 159: synthesis of Compound 359

Compound 359 (formate) was prepared as a white solid from compound 101-K by using a similar method to that described in example 158. LCMS (method 5-95AB, ESI): t _R ＝0.705min,[M+H] ⁺ ＝933.7； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.46(brs,2H),7.60(brs,2H),7.41(brs,1H),7.29-7.20(m,2H),7.15-7.01(m,2H),6.94(d,J＝8.4Hz,2H),6.81(s,1H),6.75(s,1H),6.37(s,1H),5.34(brs,1H),4.79-4.74(m,1H),4.55-4.30(m,2H),4.30-4.10(m,5H),3.68(s,2H),3.44-3.34(m,1H),3.31-3.05(m,5H),3.04(s,3H),3.00-2.85(m,2H),2.50-2.00(m,8H),1.37(d,J＝6.8Hz,3H),1.07(s,9H)。

Example 160: synthesis of Compound 360

Compound 360 (formate) was prepared as a white solid from compound 101-K by using a similar method to that described in example 158. LCMS (method 5-95AB, ESI): t _R ＝0.515min,[M+H] ⁺ ＝905.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.47(brs,3H),7.61(brs,2H),7.38(brs,1H),7.27-7.23(m,2H),7.11-7.05(m,2H),6.91(d,J＝8.4Hz,2H),6.82(s,1H),6.69(s,1H),6.37(s,1H),5.40-5.30(m,1H),4.76-4.65(m,2H),4.55-4.31(m,2H),4.30-4.10(m,5H),3.34-3.11(m,6H),3.03(s,3H),3.01-2.85(m,2H),2.50-2.00(m,8H),1.35(d,J＝6.0Hz,6H),1.34(d,J＝6.4Hz,3H)。

Example 161: synthesis of Compound 361

Compound 361 (formate) was prepared as a white solid from compound 101-K by using an analogous method to that described in example 158. LCMS (methods 5-95AB, ESI): t _R ＝0.688min,[M+H] ⁺ ＝915.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.43(brs,2H),7.63-7.15(m,6H),7.12(brs,2H),6.86(s,1H),6.59(brs,1H),5.33-5.27(m,1H),4.79-4.76(m,2H),4.44-4.20(m,6H),3.31-3.12(m,8H),3.04(s,3H),2.95(t,J＝6.8Hz,2H),2.48(s,3H),2.30(s,3H),2.28-2.14(m,2H),1.99(t,J＝6.8Hz,2H),1.37(d,J＝6.4Hz,3H),1.36(s,6H)。

Example 162: synthesis of Compound 362

Compound 362 (formate) was prepared as a white solid from compound 101-K by using a similar method to that described in example 158. LCMS (methods 5-95AB, ESI): t _R ＝0.700min,[M+H] ⁺ ＝933.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.50(brs,2H),7.94-7.86(m,2H),7.50(brs,1H),7.32-7.15(m,3H),7.10(d,J＝8.4Hz,1H),7.04-6.98(m,2H),6.92(d,J＝2.0Hz,1H),6.86-6.81(m,1H),6.57(s,1H),5.37-5.30(m,1H),4.82-4.73(m,2H),4.26-4.17(m,6H),4.03(t,J＝6.4Hz,2H),3.22-3.09(m,8H),3.02(s,3H),2.56(s,3H),2.43(s,3H),2.31-2.25(m,1H),2.17-2.11(m,1H),1.84-1.78(m,2H),1.54-1.38(m,4H),1.32(d,J＝6.8Hz,3H),0.97(t,J＝6.8Hz,3H)。

Example 163: synthesis of Compound 363

Compound 363 (formate) was prepared from compound 101-K as a white solid by using a similar method to that described in example 158. LCMS (methods 5-95AB, ESI): t _R ＝0.700min,[M+H] ⁺ ＝921.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.50(s,1H),7.75-7.64(m,1H),7.50(s,1H),7.36-7.05(m,5H),6.88(s,1H),6.64(brs,1H),6.54(brs,1H),5.30-5.25(m,1H),4.80-4.72(m,2H),4.39-4.16(m,6H),3.28-3.06(m,8H),3.03(s,3H),2.52(s,3H),2.34(s,3H),2.31-2.12(m,2H),1.38(s,9H),1.36(d,J＝6.8Hz,3H)。

Example 164: synthesis of Compound 364

Compound 364 (formate) was prepared as a white solid from compound 101-K by using a similar method to that described in example 158. LCMS (methods 5-95AB, ESI): t _R ＝0.690min,[M+H] ⁺ ＝945.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.47(brs,3H),7.78(brs,2H),7.45(brs,1H),7.27-7.08(m,4H),6.98(d,J＝8.4Hz,2H),6.87(s,1H),6.65(brs,1H),6.52(brs,1H),5.30-5.20(m,1H),4.85-4.75(m,2H),4.50-4.15(m,7H),3.25-3.10(m,8H),3.02(s,3H),2.51(s,3H),2.40-2.05(m,7H),2.05-1.95(m,2H),1.90-1.75(m,2H),1.70-1.40(m,6H),1.36(d,J＝7.2Hz,3H)。

Example 165: synthesis of Compound 365

Step 1: 5-chloro-2- (tributylstannyl) pyridine (400mg, 0.99mmol), 6-chloro-2, 4-dimethyl-pyridine-3-carboxylic acid ethyl ester (234mg, 1.09mmol) and Pd (PPh) ₃ ) ₄ A solution of (115mg, 0.10 mmol) in toluene (10 mL) was stirred at 110 ℃ for 8h. After filtration, the volatiles were removed under reduced pressure and the residue was purified by silica gel chromatography eluting with 0-5% etoac in petroleum ether to give ethyl 6- (5-chloro-2-pyridinyl) -2, 4-dimethyl-pyridine-3-carboxylate as a white solid (120mg, 42% yield). ¹ H NMR(400MHz,CDCl ₃ )δ8.62(s,1H),8.42(d,J＝8.6Hz,1H),8.08(s,1H),7.81-7.75(m,1H),4.42(q,J＝7.2Hz,2H),2.63(s,3H),2.43(s,3H),1.43(t,J＝7.2Hz,3H)。

Step 2: starting from ethyl 6- (5-chloro-2-pyridyl) -2, 4-dimethyl-pyridine-3-carboxylate, typical Suzuki and ester hydrolysis conditions were applied (as described in example 10) to give 5 '-butyl-4, 6-dimethyl- [2,2' -bipyridine ] -5-carboxylic acid as a colorless oil.

Compound 365 (formate) is prepared by utilization and implementationAn analogous procedure is described in example G starting from compound 101-K and 5 '-butyl-4, 6-dimethyl- [2,2' -bipyridine]-5-carboxylic acid was prepared as a white solid. LCMS (methods 5-95AB, ESI): t _R ＝0.536min,[M+H] ⁺ ＝904.3； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.60(brs,1H),8.38(brs,1H),8.12(brs,1H),7.85-7.61(m,2H),7.32-7.21(m,2H),6.92(brs,1H),6.80(brs,1H),6.66(brs,1H),6.25(brs,1H),5.40-5.29(m,1H),4.90-4.83(m,1H),4.79-4.71(m,1H),4.46(brs,2H),4.29-4.20(m,4H),3.48-3.39(m,1H),3.33--3.10(m,7H),3.03(s,3H),2.74(t,J＝7.6Hz,2H),2.51-2.38(m,2H),2.34-2.09(m,4H),1.75-1.67(m,2H),1.49-1.42(m,2H),1.36(d,J＝6.8Hz,3H),1.02(t,J＝7.6Hz,3H)。

Example 166: synthesis of Compound 366

Compound 366 (trifluoroacetate salt) was prepared as a white solid from compound 101-K by using an analogous method to that described in example 158. LCMS (methods 5-95AB, ESI): t _R ＝0.704min,[M+H] ⁺ ＝903.3； ¹ H NMR(400MHz,MeOH-d ₄ )δ7.70-7.64(m,2H),7.46-7.42(m,1H),7.30-7.22(m,4H),7.20-7.01(m,2H),6.86(s,1H),6.70(brs,1H),6.48(brs,1H),5.38-5.32(m,1H),4.80-4.74(m,1H),4.49-4.15(m,7H),3.26-2.87(m,8H),3.05(s,3H),2.70(t,J＝7.6Hz,2H),2.51(s,3H),2.36-2.12(m,5H),1.71-1.63(m,2H),1.45-1.36(m,2H),1.38(d,J＝6.8Hz,3H),1.00(t,J＝7.2Hz,3H)。

Example 167: synthesis of Compound 367

Compound 367 (formate) was prepared from compound 101-K as a white solid by using a similar method to that described in example 151. LCMS (methods 5-95AB, ESI): t _R ＝0.740min,[M+H] ⁺ ＝991.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.50(brs,1H),7.41(s,1H),7.34-7.22(m,2H),7.19(d,J＝8.4Hz,1H),7.10(d,J＝8.4Hz,1H),6.92(d,J＝2.0Hz,1H),6.83(d,J＝2.0Hz,1H),6.41(s,1H),5.23-5.20(m,1H),4.85-4.77(m,2H),4.34(t,J＝6.4Hz,2H),4.28-4.16(m,6H),3.23-3.09(m,8H),3.01(s,3H),2.60(s,3H),2.45(s,3H),2.33-2.23(m,1H),2.21-2.11(m,1H),1.84-1.76(m,2H),1.61-1.51(m,2H),1.36(d,J＝6.6Hz,3H),1.02(t,J＝7.4Hz,3H)。

Example 168: synthesis of Compound 368

Step 1: to a stirred solution of 1-bromo-4- (tert-butyl) benzene (3.0 g, 14mmol) in concentrated sulfuric acid (12 mL) was added dropwise HNO at 0 deg.C ₃ (0.69mL, 15.5 mmol). The mixture was stirred at 0 ℃ for 1h. The volatiles were removed under reduced pressure and the residue was taken up in EtOAc (50 mL) which was saturated Na ₂ CO ₃ Aqueous solution and brine (50 mL each). The organic layer was MgSO ₄ Drying, concentration and chromatography of the residue on silica gel eluting with petroleum ether gave 1-bromo-4- (tert-butyl) -2-nitrobenzene as a colourless oil (1.7g, 47% yield).

Compound 368 (formate salt) was prepared as a white solid from compound 101-K and 1-bromo-4- (tert-butyl) -2-nitrobenzene using an analogous method to that described in example 158. LCMS (methods 5-95AB, ESI): t _R ＝0.712min,[M+H] ⁺ ＝948.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.48(brs,1H),7.97(d,J＝2.0Hz,1H),7.81(d,J＝8.0Hz,1H),7.54(d,J＝8.0Hz,1H),7.34(s,1H),7.31-7.15(m,3H),7.10(d,J＝8.4Hz,1H),6.90(d,J＝2.4Hz,1H),6.79(s,1H),6.42(s,1H),5.24-5.20(m,1H),4.79-4.73(m,2H),4.29-4.15(m,6H),3.29-3.03(m,8H),3.00(s,3H),2.49(s,3H),2.41(s,3H),2.33-2.22(m,1H),2.21-2.10(m,1H),1.41(s,9H),1.35(d,J＝6.8Hz,3H)。

Example 169: synthesis of Compound 369

Compound 369 (formate salt) was prepared from compounds 101-K as a white solid by using a similar method to that described in example 168. LCMS (methods 5-95AB, ESI): t _R ＝0.664min,[M+H] ⁺ ＝918.3； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.49(brs,1H),7.41-7.15(m,5H),7.09(d,J＝8.4Hz,1H),6.89(brs,2H),6.80(brs,1H),6.78(brs,1H),6.49(s,1H),5.29-5.24(m,1H),4.84-4.75(m,2H),4.37-4.17(m,6H),3.31-3.11(m,8H),3.01(s,3H),2.54(s,3H),2.31-2.23(m,4H),2.18-2.13(m,1H),1.36(d,J＝6.8Hz,3H),1.33(s,9H)。

Example 170: synthesis of Compound 370

Compound 370 (formate) was prepared as a white solid from compound 101-K by using an analogous method to that described in example H. LCMS (method 5-95AB, ESI): t _R ＝0.747min,[M+H] ⁺ ＝902.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.53(brs,2H),7.50-7.40(m,4H),7.31-7.15(m,5H),7.06(d,J＝8.4Hz,1H),6.89(d,J＝2.0Hz,1H),6.67(s,1H),6.51(s,1H),5.28-5.25(m,1H),4.80-4.78(m,2H),4.26-4.17(m,6H),3.22-3.07(m,8H),3.02(s,3H),2.35-2.25(m,1H),2.31(s,6H),2.20-2.11(m,1H),1.37(d,J＝6.8Hz,3H),1.36(s,9H)。

Example 171: synthesis of Compound 371

Compound 371 (formate) was prepared from compound 101-K as a white solid by using a similar method to that described in example H. LCMS (methods 5-95AB, ESI): t _R ＝0.747min,[M+H] ⁺ ＝908.3； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.50(brs,2H),7.75(s,1H),7.66-7.52(m,6H),7.34-7.22(m,2H),7.18(d,J＝8.4Hz,1H),7.09(d,J＝8.4Hz,1H),6.91(s,1H),6.82(s,1H),6.34(s,1H),5.23-5.19(m,1H),4.79-4.73(m,2H),4.29-4.16(m,6H),3.23-3.07(m,8H),2.95(s,3H),2.34-2.29(m,1H),2.19-2.14(m,1H),1.37(d,J＝6.8Hz,3H),1.36(s,9H)。

Example 172: synthesis of Compound 372

Compound 372 (formate) was prepared as a white solid from compound 101-K by using an analogous method to that described in example H. LCMS (methods 5-95AB, ESI): t _R ＝0.726min,[M+H] ⁺ ＝889.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.50(brs,3H),7.59-7.54(m,3H),7.50-7.47(m,2H),7.36-7.33(m,1H),7.26-7.22(m,1H),7.16(d,J＝8.6Hz,1H),7.09(d,J＝8.6Hz,1H),7.04(d,J＝2.0Hz,1H),6.94-6.89(m,2H),6.82(d,J＝2.0Hz,1H),6.34(s,1H),5.16-5.12(m,1H),4.83-4.80(m,2H),4.22-4.17(m,6H),3.18-3.09(m,8H),2.87(s,3H),2.35-2.26(m,1H),2.20-2.12(m,1H),1.36(s,9H),1.35(d,J＝6.8Hz,3H)。

Example 173: synthesis of Compound 373

Step 1: to a stirred 0 ℃ mixture of 4-bromo-2-methylphenol (4.0 g,21.4 mmol) in acetic acid (22 mL) was added fuming HNO over 30min ₃ (1.25mL, 27.8 mmol) and the mixture was stirred at 0 ℃ for a further 15min. The reaction was poured into ice water (80 mL) and the resulting precipitate was collected by filtration, redissolved with DCM (100 mL) and Na ₂ SO ₄ Drying, concentration, and the residue was purified by silica gel chromatography eluting with 0-1% etoac in petroleum ether to give 4-bromo-2-methyl-6-nitrophenol as a yellow solid (2.9g, 58% yield).

Step 2: starting from 4-bromo-2-methyl-6-nitrophenol, typical Suzuki and triflation (triflation) as described in example 10 and Stille (as described in example 165) conditions were applied to give 4'- (tert-butyl) -3-methyl-5-nitro-4-vinyl-1, 1' -biphenyl as a yellow oil.

Step (ii) of3: 4'- (tert-butyl) -3-methyl-5-nitro-4-vinyl-1, 1' -biphenyl (100mg, 0.34mmol), osO ₄ (2.5 wt% in t-BuOH, 500 mg), naIO ₄ (362mg, 1.7 mmol) and 0.2M phosphate buffer (pH 7.2, 0.2mL) in acetonitrile/H ₂ The mixture in O (7.5ml, v/v = 2/1) was stirred at 25 ℃ for 24h. The reaction was diluted with water (20 mL) and extracted with EtOAc (2X 20mL). The combined organic layers were washed with Na ₂ SO ₄ Drying, concentrating, and purifying the residue by preparative TLC to give 4'- (tert-butyl) -3-methyl-5-nitro- [1,1' -biphenyl as a white solid]-4-Formaldehyde (40mg, 40% yield). ¹ H NMR(400MHz,CDCl ₃ )δ10.36(s,1H),8.14(s,1H),7.77(s,1H),7.60-7.50(m,4H),2.60(s,3H),1.38(s,9H)。

And 4, step 4: 4'- (tert-butyl) -3-methyl-5-nitro- [1,1' -biphenyl]-4-Formaldehyde (40mg, 0.14mmol), H ₂ O ₂ (35% aqueous solution, 75. Mu.L), naClO ₂ (25mg, 0.27mmol) and KH ₂ PO ₄ (3mg, 0.02mmol) in acetonitrile/H ₂ The mixture in O (6 ml, v/v = 5/1) was stirred at 25 ℃ for 24h. Then Na was added ₂ S ₂ O ₃ (50 mg) to quench excess H ₂ O ₂ . The mixture was partitioned between brine and EtOAc (20 mL each) and the organic layer was passed over Na ₂ SO ₄ Drying and concentrating to obtain 4'- (tert-butyl) -3-methyl-5-nitro- [1,1' -biphenyl ] as white solid]4-carboxylic acid (35mg, 83% yield).

Compound 373 (formate salt) was prepared from compound 101-K and 4'- (tert-butyl) -3-methyl-5-nitro- [1,1' -biphenyl ] using a method analogous to that described in example G]-4-carboxylic acid was prepared as a white solid. LCMS (method 5-95AB, ESI): t _R ＝0.742min,[M+H] ⁺ ＝903.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.51(brs,1H),7.41(brs,4H),7.31(d,J＝7.6Hz,1H),7.24-7.12(m,2H),7.08(d,J＝8.0Hz,1H),6.89(d,J＝7.6Hz,2H),6.73(brs,1H),6.70(brs,1H),6.53(s,1H),5.20-5.17(m,1H),4.80-4.78(m,1H),4.67-4.61(m,1H),4.30-4.15(m,6H),3.23-3.11(m,8H),3.00(s,3H),2.33-2.05(m,2H),2.21(s,3H),1.36(brs,12H)。

Example 174: synthesis of Compound 374

Step 1: methyl 4-bromo-2, 3-dimethylbenzoate (150mg, 0.62mmol), 4- (tert-butyl) phenol (139mg, 0.93mmol), pd (OAc) ₂ (7.0mg, 0.03mmol), 2-di-t-butylphosphino-2 ',4',6' -triisopropylbiphenyl (26mg, 0.06mmol), and K ₃ PO ₄ (330mg, 1.85mmol) of a mixture in toluene (8 mL) in N ₂ Stirred at 100 ℃ for 16h. The volatiles were removed under reduced pressure and the residue was purified by silica gel chromatography, eluting with 0-30% EtOAc in petroleum ether, to give methyl 4- (4- (tert-butyl) phenoxy) -2, 3-dimethylbenzoate as a pale yellow oil (180mg, 93% yield).

Step 2: typical ester hydrolysis conditions (NaOH, meOH/H) were applied to methyl 4- (4- (tert-butyl) phenoxy) -2, 3-dimethylbenzoate ₂ O, as described in example H) to give 4- (4- (tert-butyl) phenoxy) -2, 3-dimethylbenzoic acid as a white solid. LCMS (methods 5-95AB, ESI): t _R ＝0.990min,[M+H] ⁺ ＝299.0。

Compound 374 (formate) was prepared as a white solid by using a method analogous to that described in example G from compound 101-K and 4- (4- (tert-butyl) phenoxy) -2, 3-dimethylbenzoic acid. LCMS (methods 5-95AB, ESI): t _R ＝0.765min,[M+H] ⁺ ＝918.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.50(brs,2H),7.38(d,J＝8.0Hz,2H),7.35-7.16(m,4H),7.10(d,J＝8.0Hz,1H),6.90(d,J＝8.0Hz,1H),6.85-6.81(m,3H),6.75(d,J＝8.0Hz,1H),6.35(s,1H),5.15-5.12(m,1H),4.83-4.78(m,2H),4.26-4.18(m,6H),3.27-3.03(m,8H),2.94(s,3H),2.38(s,3H),2.30-2.20(m,1H),2.24(s,3H),2.18-2.09(m,1H),1.35(d,J＝7.2Hz,3H),1.32(s,9H)。

Example 175: synthesis of Compound 375

Compound 375 (Formate) was prepared as a white solid from compound 101-K by using a method similar to that described in example 174. LCMS (methods 5-95AB, ESI): t _R ＝0.621min,[M+H] ⁺ ＝918.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.51(brs,1H),7.43(d,J＝8.8Hz,2H),7.31-7.25(m,2H),7.19(d,J＝8.4Hz,1H),7.12(d,J＝8.4Hz,1H),6.96-6.91(m,3H),6.84(s,1H),6.70(brs,2H),6.39(s,1H),5.20-5.18(m,1H),4.83-4.75(m,2H),4.29-4.18(m,6H),3.39-3.35(m,1H),3.26-3.10(m,7H),3.01(s,3H),2.35-2.25(m,1H),2.31(s,6H),2.19-2.10(m,1H),1.37(d,J＝6.8Hz,3H),1.36(s,9H)。

Example 176: synthesis of Compound 376

Compound 376 (formate) was prepared as a white solid from compound 101-K by using a similar method to that described in example 174. LCMS (methods 5-95AB, ESI): t _R ＝0.621min,[M+H] ⁺ ＝924.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.49(brs,2H),7.50-7.46(m,3H),7.29(d,J＝8.4Hz,1H),7.23(d,J＝8.4Hz,1H),7.16(d,J＝8.4Hz,1H),7.09(d,J＝8.4Hz,1H),7.02-6.95(m,4H),6.89(s,1H),6.81(s,1H),6.31(s,1H),5.19-5.13(m,1H),4.80-4.73(m,2H),4.25-4.15(m,6H),3.36-3.32(m,1H),3.21-3.07(m,7H),2.91(s,3H),2.34-2.23(m,1H),2.17-2.08(m,1H),1.35(brs,12H)。

Example 177: synthesis of Compound 377

Compound 377 (formate) was prepared from compound 101-K as a white solid by using a method analogous to that described in example 174. LCMS (methods 5-95AB, ESI): t _R ＝0.760min,[M+H] ⁺ ＝924.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.51(brs,1H),7.48(d,J＝8.4Hz,1H),7.30-7.22(m,3H),7.15(d,J＝8.4Hz,1H),7.10-6.94(m,6H),6.81(s,1H),6.38(s,1H),6.31(s,1H),5.18-5.13(m,1H),4.79-4.73(m,2H),4.24-4.16(m,6H),3.45-3.40(m,1H),3.18-3.06(m,7H),2.93-2.88(m,3H),2.62(t,J＝6.8Hz,2H),2.33-2.22(m,1H),2.17-2.07(m,1H),1.61-1.58(m,2H),1.43-1.33(m,5H),0.96(t,J＝7.6Hz,3H)。

Example 178: synthesis of Compound 378

Compound 378 (formate salt) was prepared from compound 101-K as a white solid by using a similar method to that described in example 174. LCMS (methods 5-95AB, ESI): t _R ＝0.825min,[M+H] ⁺ ＝979.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.50(brs,3H),7.49(d,J＝8.4Hz,1H),7.30-6.80(m,11H),6.32(s,1H),5.20-5.15(m,1H),4.85-4.75(m,2H),4.25-4.15(m,4H),4.20(s,2H),3.26-3.00(m,8H),2.92(s,3H),2.65-2.55(m,4H),2.32-2.20(m,1H),2.20-2.09(m,1H),1.60-1.50(m,4H),1.50-1.25(m,7H),1.00-0.90(m,6H)。

Example 179: synthesis of Compound 379

Compound 379 (formate) was prepared as a white solid from compound 101-K by using a similar method to that described in example 53. LCMS (method 5-95AB, ESI): t _R ＝0.730min,[M+H] ⁺ ＝914.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.50(brs,2H),7.78(d,J＝8.0Hz,1H),7.39(d,J＝8.8Hz,1H),7.23(d,J＝8.8Hz,1H),7.15(d,J＝8.4Hz,1H),7.08(d,J＝8.4Hz,1H),6.90-6.80(m,4H),6.38(s,1H),5.11-5.09(m,2H),4.51-4.47(m,2H),4.38-4.34(m,1H),4.28-4.24(m,4H),4.20(s,2H),3.40-3.35(m,1H),3.22-3.09(m,7H),2.87(s,3H),2.67(t,J＝6.4Hz,2H),2.32-2.26(m,2H),1.68-1.58(m,3H),1.39-1.26(m,10H),0.90(t,J＝6.6Hz,3H)。

Example 180: synthesis of Compound 380

Step 1: starting from 1-bromo-4- (hexyloxy) benzene, typical Sonogoshira and trimethylsilyl removal conditions were applied (as described in example 110) to give 1-ethynyl-4- (hexyloxy) benzene as a yellow oil.

And 2, step: methyl 4-formylbenzoate (4.0g, 24.4mmol), hydroxyamino hydrochloride (3.4g, 48.8mmol) and sodium acetate (4.0g, 48.8mmol) in MeOH/H ₂ The mixture in O (21ml, v/v = 20/1) was stirred at 25 ℃ for 3h. Volatiles were removed under reduced pressure and the residue was taken up in H ₂ Partition between O (100 mL) and EtOAc (100 mL). The organic layer was washed with Na ₂ SO ₄ Drying, concentration, and the residue was purified by silica gel chromatography eluting with 0-30% etoac in petroleum ether to give methyl (E) -4- ((hydroxyimino) methyl) benzoate as a white solid (2g, 46% yield).

And step 3: a mixture of methyl (E) -4- ((hydroxyimino) methyl) benzoate (1.0g, 5.6 mmol) and N-chlorosuccinimide (1.1g, 8.4 mmol) in DMF (10 mL) was stirred at 25 ℃ for 4h. The volatiles were removed and the residue was purified by silica gel chromatography eluting with 0-20% etoac in petroleum ether to give methyl (Z) -4- (chloro (hydroxyimino) methyl) benzoate as a white solid (966 mg,81% yield).

And 4, step 4: methyl 1-ethynyl-4- (hexyloxy) benzene (from step 1) (320mg, 1.6 mmol), (Z) -4- (chloro (hydroxyimino) methyl) benzoate (405mg, 1.9mmol), KHCO ₃ (681mg，6.8mmol)、CuSO ₄ A mixture of (8mg, 0.03mmol) and sodium ascorbate (3.1mg, 0.02mmol) in 2-methyl-2-propanol (8 mL) was stirred at 45 ℃ for 1h. Subjecting the reaction mixture to hydrogenation with H ₂ O (20 mL) diluted, which was extracted with EtOAc (2X 30mL). The combined organic layers were washed with Na ₂ SO ₄ Drying, concentration and purification of the residue by silica gel chromatography eluting with 0-60% dcm in petroleum ether gave methyl 4- (5- (4- (hexyloxy) phenyl) isoxazol-3-yl) benzoate as a white solid (120mg, 20% yield). ¹ H NMR(400MHz,CDCl ₃ )δ8.16(d,J＝8.4Hz,2H),7.95(d,J＝8.4Hz,2H),7.78(d,J＝8.4Hz,2H),7.01(d,J＝8.4Hz,2H),6.75(s,1H),4.03(t,J＝6.4Hz,2H),3.97(s,3H),1.86-1.79(m,2H),1.49-1.26(m,6H),0.93(t,J＝6.4Hz,3H)。

And 5: typical ester hydrolysis conditions (NaOH, meOH/H) were applied to methyl 4- (5- (4- (hexyloxy) phenyl) isoxazol-3-yl) benzoate ₂ O, as described in example H) to give 4- (5- (4- (hexyloxy) phenyl) isoxazol-3-yl) benzoic acid as a white solid.

Compound 380 (formate) was prepared as a white solid by using a method analogous to that described in example G from compound 101-K and 4- (5- (4- (hexyloxy) phenyl) isoxazol-3-yl) benzoic acid. LCMS (method 5-95AB, ESI): t _R ＝0.793min,[M+H] ⁺ ＝985.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.49(brs,2H),8.10-7.98(m,4H),7.85(d,J＝8.4Hz,2H),7.33(d,J＝8.4Hz,1H),7.23(d,J＝8.4Hz,1H),7.16(d,J＝8.4Hz,2H),7.10-7.07(m,3H),6.89(brs,1H),6.80(s,1H),6.37(s,1H),5.21-5.15(m,1H),4.85-4.75(m,2H),4.33-4.15(m,6H),4.07(t,J＝6.0Hz,2H),3.29-2.97(m,8H),2.89(s,3H),2.38-2.29(m,1H),2.24-2.17(m,1H),1.86-1.78(m,2H),1.56-1.32(m,9H),0.94(t,J＝6.4Hz,3H)。

Examples 181 and 182: synthesis of Compounds 381 and 382

Step 1: ethyl 4-methyloxazole-5-carboxylate (600mg, 4.25mmol), 1-bromo-4-iodobenzene (1.44g, 5.10mmol), pd (dppf) Cl ₂ (158mg，0.21mmol)、PPh ₃ (112mg, 0.43mmol) and Ag ₂ CO ₃ (2.34g, 8.50mmol) in H ₂ Mixture in O (20 mL) in N ₂ And stirred at 70 ℃ for 16h. The reaction mixture was extracted with DCM (3x 20mL). The combined organic layers were washed with Na ₂ SO ₄ Drying, concentration, and purification of the residue by silica gel chromatography, eluting with 0-10% etoa in petroleum ether, gave ethyl 2- (4-bromophenyl) -4-methyloxazole-5-carboxylate as a white solid (1.0 g,80% yield). ¹ H NMR(400MHz,CDCl ₃ )δ7.99(d,J＝8.4Hz,2H),7.62(d,J＝8.4Hz,2H),4.42(q,J＝7.2Hz,2H),2.54(s,3H),1.42(t,J＝7.2Hz,3H)。

And 2, step: starting from ethyl 2- (4-bromophenyl) -4-methyloxazole-5-carboxylate, typical Suzuki and ester hydrolysis conditions as described in example H were applied to give 4-methyl-2- (4-pentylphenyl) oxazole-5-carboxylic acid as a white solid.

The title compound (formate) was prepared as a white solid by using a method similar to that described in example G using 101-K and 4-methyl-2- (4-pentylphenyl) oxazole-5-carboxylic acid and the two epimers were separated under chiral HPLC conditions.

Compound 381: LCMS (methods 5-95AB, ESI): t _R ＝0.738min,[M+H] ⁺ ＝893.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.47(brs,3H),8.09(d,J＝8.4Hz,2H),7.40(d,J＝8.4Hz,2H),7.31(d,J＝8.4Hz,1H),7.24(d,J＝8.4Hz,1H),7.13-7.07(m,2H),6.89(s,1H),6.81(s,1H),6.31(s,1H),5.17-5.11(m,2H),4.54-4.50(m,1H),4.28-4.14(m,4H),4.19(s,2H),3.26-3.04(m,8H),2.88(s,3H),2.71(t,J＝8.0Hz,2H),2.54(s,3H),2.37-2.31(m,1H),2.21-2.16(m,1H),1.73-1.63(m,3H),1.40-1.29(m,6H),0.92(t,J＝6.8Hz,3H)。

Compound 382: LCMS (methods 5-95AB, ESI): t _R ＝0.747min,[M+H] ⁺ ＝893.8； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.49(brs,2H),8.08(d,J＝8.4Hz,2H),7.37(d,J＝8.4Hz,2H),7.30(d,J＝8.4Hz,1H),7.23(d,J＝8.4Hz,1H),7.18(d,J＝8.4Hz,1H),7.08(d,J＝8.4Hz,1H),6.89(s,1H),6.80(s,1H),6.30(s,1H),5.28-5.22(m,2H),4.59-4.57(m,1H),4.28-4.15(m,4H),4.18(s,2H),3.27-3.05(m,8H),2.88(s,3H),2.74-2.69(m,2H),2.51(s,3H),2.30-2.28(m,1H),2.18-2.17(m,1H),1.71-1.63(m,3H),1.43-1.34(m,6H),0.91(t,J＝6.6Hz,3H)。

Example 183: synthesis of Compound 383

Step 1: 2-oxo-1, 2-dihydropyridine-4-carboxylic acid (1.5g, 10.8mmol) and SOCl ₂ A mixture of (3.1mL, 43.2mmol) in MeOH (30 mL) was stirred at 80 deg.C for 3h. The volatiles were removed under reduced pressure and the residue was taken up in EtOAc (50 mL) which was saturated Na ₂ CO ₃ Washed with aqueous solution (2x 30mL). The organic layer was washed with Na ₂ SO ₄ Dried and concentrated to give methyl 2-oxo-1, 2-dihydropyridine-4-carboxylate (540mg, 33% yield) as a white solid.

And 2, step: a mixture of methyl 2-oxo-1, 2-dihydropyridine-4-carboxylate (540mg, 3.5 mmol), cu (OAc) 2 (128mg, 0.71mmol) and (4- (tert-butyl) phenyl) boronic acid (816mg, 4.6 mmol) in DCM (20 mL) and pyridine (2 mL) was stirred at 25 ℃ for 24h. The volatiles were removed under reduced pressure and the residue was taken up in EtOAc (50 mL) which was washed with brine (2x 50mL). The organic layer was washed with Na ₂ SO ₄ Drying, concentration, and the residue was purified by silica gel chromatography, eluting with 0-5% meoh in DCM, to give methyl 1- (4- (tert-butyl) phenyl) -2-oxo-1, 2-dihydropyridine-4-carboxylate (440mg, 44% yield) as a brown solid. LCMS (methods 5-95AB, ESI): t _R ＝0.863min,[M+H] ⁺ ＝285.9。

And step 3: typical ester hydrolysis conditions (NaOH, meOH/H) were applied to methyl 1- (4- (tert-butyl) phenyl) -2-oxo-1, 2-dihydropyridine-4-carboxylate ₂ O, as described in example H), to give 1- (4- (tert-butyl) phenyl) -2-oxo-1, 2-dihydropyridine-4-carboxylic acid as a yellow solid.

Compound 383 (formate) was prepared as a white solid by using a method analogous to that described in example G from compound 101-K and 1- (4- (tert-butyl) phenyl) -2-oxo-1, 2-dihydropyridine-4-carboxylic acid. LCMS (method 5-95AB, ESI): t _R ＝0.676min,[M+H] ⁺ ＝891.8； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.49(brs,1H),7.67(d,J＝8.4Hz,1H),7.56(d,J＝8.4Hz,2H),7.30-7.19(m,3H),7.18-7.10(m,3H),6.99(brs,1H),6.85(brs,2H),6.68(brs,1H),5.11-5.02(m,1H),4.85-4.78(m,2H),4.37-4.18(m,6H),3.29-3.08(m,8H),2.92(s,3H),2.34-2.19(m,2H),1.38(brs,12H)。

Example 184: synthesis of Compound 384

Compound 384 (formate) was prepared as a white solid from compound 101-K by using an analogous method to that described in example 183. LCMS (method 5-95AB, ESI): t _R ＝0.698min,[M+H] ⁺ ＝892.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.51(brs,2H),8.27(s,1H),7.55-7.48(m,3H),7.35-7.19(m,5H),7.16(d,J＝8.4Hz,1H),6.86(d,J＝2.0Hz,1H),6.72(s,1H),6.62(brs,1H),5.17-5.07(m,1H),4.85-4.75(m,2H),4.40-4.20(m,4H),4.23(s,2H),3.25-3.09(m,8H),2.95(s,3H),2.37-2.18(m,2H),1.40(brs,12H)。

Example 185: synthesis of Compound 385

Step 1: to a solution of methyl 3-oxobutanoate (5.0 g, 43mmol) and DBU (9.8 g, 65mmol) in acetonitrile (40 mL) was added 4-acetamidobenzenesulfonyl azide (15.5 g, 65mmol) at 0 deg.C, and the mixture was stirred at 20 deg.C for 1h. After filtration, the filtrate was concentrated and the residue was taken up in saturated NaHCO ₃ The aqueous solution was partitioned with EtOAc (50 mL each). The organic layer was washed with Na ₂ SO ₄ Dried, concentrated, and the residue was purified by silica gel chromatography eluting with 4% etoac in petroleum ether to give methyl 2-diazo-3-oxobutanoate as a colorless oil (2.4 g,39% yield).

And 2, step: 4- (tert-butyl) benzoylhydrazine (425mg, 2.2mmol) and Cu (OAc) in 1, 2-dichloroethane (2 mL) ₂ (128mg, 0.70mmol) and NH ₄ A sealed tube of OAc (542mg, 7.0 mmol) was heated at 80 ℃ for 10min under microwave irradiation. The mixture was filtered through silica gel, washed with 50% EtOAc in petroleum ether, and concentrated. Methyl 2-diazo-3-oxobutanoate (200mg, 1.4 mmol) and AcOH (2 mL) were added to the residue and the resulting mixture was heated under microwave irradiation at 110 ℃ for 5min. The volatiles were removed under reduced pressure and the residue was redissolved with EtOAc (50 mL) which was saturated NaHCO ₃ Aqueous solution and brine (50 mL each). The organic layer was washed with Na ₂ SO ₄ Drying, concentrating, and purifying the residue by silica gel chromatographyElution with 5-20% EtOAc in petroleum ether afforded methyl 3- (4- (tert-butyl) phenyl) -5-methyl-1, 2, 4-triazine-6-carboxylate as a yellow solid (20mg, 5% yield). ¹ H NMR(400MHz,CDCl ₃ )δ8.53(d,J＝8.4Hz,2H),7.57(d,J＝8.4Hz,2H),4.08(s,3H),2.88(s,3H),1.38(s,9H)。

And 3, step 3: typical ester hydrolysis conditions (NaOH, meOH/H) were applied to methyl 3- (4- (tert-butyl) phenyl) -5-methyl-1, 2, 4-triazine-6-carboxylate ₂ O, described in example H) to give 3- (4- (tert-butyl) phenyl) -5-methyl-1, 2, 4-triazine-6-carboxylic acid as a yellow solid. LCMS (methods 5-95AB, ESI): t _R ＝0.875min,[M+H] ⁺ ＝271.9。

Compound 385 (formate salt) was prepared as a white solid from compound 101-K and 3- (4- (tert-butyl) phenyl) -5-methyl-1, 2, 4-triazine-6-carboxylic acid using an analogous method to that described in example G. LCMS (methods 5-95AB, ESI): t _R ＝0.720min,[M+H] ⁺ ＝891.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.52-8.44(m,4H),7.63(d,J＝8.4Hz,2H),7.32(d,J＝8.4Hz,1H),7.23(d,J＝8.0Hz,1H),7.15(d,J＝8.0Hz,1H),7.08(d,J＝8.0Hz,1H),6.89(s,1H),6.79(s,1H),6.37(s,1H),5.25-5.21(m,1H),4.82-4.75(m,2H),4.22-4.15(m,6H),3.20-3.09(m,7H),2.95(s,3H),2.89(s,3H),2.37-2.17(m,2H),1.39(s,9H),1.36(d,J＝6.4Hz,3H)。

Example 186: synthesis of Compound 386

Step 1: to a 0 ℃ solution of 1-bromo-4- (tert-butyl) benzene (3.0 g,14.1 mmol) in THF (20 mL) were added Mg (741mg, 28.2mmol) and I ₂ (357mg, 1.41mmol). The mixture was gradually warmed to 75 ℃ while stirring, and then stirred at that temperature for 3h. The above mixture was then added dropwise to a-78 ℃ solution of dimethyl oxalate in THF (20 mL), and the resulting mixture was stirred at the same temperature for 1h, then gradually warmed to 20 ℃ while stirring, and stirred for another 12h. With saturated NH ₄ The reaction was quenched with aqueous Cl (20 mL) and extracted with EtOAc (3X 30mL).The combined organic layers were washed with brine (30 mL) and Na ₂ SO ₄ Drying, concentration, and the residue was purified by silica gel chromatography eluting with 0-5% etoac in petroleum ether to give methyl 2- (4- (tert-butyl) phenyl) -2-oxoacetate (900mg, 48% yield). ¹ H NMR(400MHz,CDCl ₃ )δ7.96(d,J＝8.4Hz,2H),7.54(d,J＝8.4Hz,2H),3.98(s,3H),1.36(s,9H)。

And 2, step: a mixture of methyl 2- (4- (tert-butyl) phenyl) -2-oxoacetate (900mg, 4.1mmol), methyl 2, 3-diaminopropionate (1.45g, 12.3mmol) and NaOMe (1.1g, 20.5mmol) in MeOH (30 mL) was stirred at 70 ℃ for 12h. The volatiles were removed and the residue was purified by reverse phase HPLC to give methyl 5- (4- (tert-butyl) phenyl) -6-oxo-1, 6-dihydropyrazine-2-carboxylate as a yellow solid (80mg, 6.8% yield). ¹ H NMR(400MHz,CDCl ₃ )δ8.28(d,J＝8.4Hz,2H),8.13(s,1H),7.50(d,J＝8.4Hz,2H),3.97(s,3H),1.36(s,9H)。

And 3, step 3: starting from methyl 5- (4- (tert-butyl) phenyl) -6-oxo-1, 6-dihydropyrazine-2-carboxylate, typical alkylation (as described in example 21) and ester hydrolysis conditions (as described in example H) were applied to give 5- (4- (tert-butyl) phenyl) -1-methyl-6-oxo-1, 6-dihydropyrazine-2-carboxylic acid as a yellow solid.

Compound 386 (formate) was prepared as a white solid by using a method analogous to that described in example G from compound 101-K and 5- (4- (tert-butyl) phenyl) -1-methyl-6-oxo-1, 6-dihydropyrazine-2-carboxylic acid. LCMS (method 5-95AB, ESI): t _R ＝0.716min,[M+H] ⁺ ＝906.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.49(brs,2H),8.38-8.34(m,3H),7.56-7.52(m,2H),7.30-7.22(m,2H),7.09-7.04(m,2H),6.88(s,1H),6.81(s,1H),6.33(s,1H),5.20-5.16(m,1H),4.81-4.77(m,2H),4.22-4.16(m,6H),3.69(s,3H),3.40-3.35(m,1H),3.18-3.06(m,7H),2.88(s,3H),2.36-2.33(m,1H),2.14-2.10(m,1H),1.39(s,9H),1.36(d,J＝6.8Hz,3H)。

Example 187: synthesis of Compound 387

Step 1: typical Chan-Lam conditions were applied to 4, 5-dichloropyridazin-3 (2H) -one (as described in example 183) to give 2- (4- (tert-butyl) phenyl) -4, 5-dichloropyridazin-3 (2H) -one as a white solid.

Step 2: to a solution of 2- (4- (tert-butyl) phenyl) -4, 5-dichloropyridazin-3 (2H) -one (1.0g, 3.4 mmol) in THF (30 mL) at 0 deg.C was added MeMgBr (in Et) dropwise ₂ 3N in O, 9.0 mL), and the reaction was stirred at the same temperature for 2h. With saturated NH ₄ The reaction was quenched with aqueous Cl (40 mL) and extracted with EtOAc (3X 40mL). The combined organic layers were washed with brine (100 mL) and Na ₂ SO ₄ Drying, concentration and purification of the residue by silica gel chromatography eluting with 25% etoac in petroleum ether gave 2- (4- (tert-butyl) phenyl) -5-chloro-4-methylpyridazin-3 (2H) -one as an off-white solid (350mg, 38% yield). ¹ H NMR(400MHz,CDCl ₃ )δ8.01(s,1H),7.56(d,J＝7.6Hz,2H),7.25(d,J＝7.6Hz,2H),2.39(s,3H),1.38(s,9H)。

And step 3:1- (4- (tert-butyl) phenyl) -5-methyl-6-oxo-1, 6-dihydropyridazin-4-carboxylic acid was prepared as a white solid by using a method similar to that described in example 173 from 2- (4- (tert-butyl) phenyl) -5-chloro-4-methylpyridazin-3 (2H) -one. LCMS (method 5-95AB, ESI): t _R ＝0.886,[M+H] ⁺ ＝286.9

Compound 387 (formate) was prepared as a white solid by using a method analogous to that described in example G from compound 101-K and 1- (4- (tert-butyl) phenyl) -5-methyl-6-oxo-1, 6-dihydropyridazine-4-carboxylic acid. LCMS (methods 5-95AB, ESI): t _R ＝0.695min,[M+H] ⁺ ＝906.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.46(brs,2H),8.08(s,1H),7.64(d,J＝8.4Hz,2H),7.36(d,J＝8.4Hz,2H),7.30-7.21(m,2H),7.15-7.04(m,2H),6.88(s,1H),6.80(s,1H),6.30(s,1H),5.20-5.15(m,1H),4.78-4.74(m,2H),4.24-4.18(m,4H),4.20(s,2H),3.40-3.35(m,1H),3.20-3.11(m,7H),2.90(s,3H),2.44(s,3H),2.31-2.26(m,1H),2.15-2.08(m,1H),1.40(s,9H),1.36(d,J＝6.4Hz,3H)。

Example 188: synthesis of Compound 388

Compound 388 (formate) was prepared from 101-K as a white solid by using a similar method as described in example L and example 4. LCMS (methods 5-95AB, ESI): t _R ＝0.788min,[M+H] ⁺ ＝955.7； ¹ H NMR(400MHz,MeOH-d ₄ )δ9.04(s,2H),8.50(brs,3H),8.07(s,1H),7.98(d,J＝8.0Hz,1H),7.79(d,J＝8.0Hz,1H),7.33-7.07(m,5H),6.90(s,1H),6.80(s,1H),6.36(s,1H),5.22-5.18(m,1H),4.85-4.78(m,2H),4.23-4.19(m,7H),3.47-3.40(m,1H),3.25-3.05(m,7H),3.01(t,J＝7.6Hz,2H),2.93(s,3H),2.40-2.25(m,1H),2.20-2.05(m,1H),1.88-1.84(m,2H),1.50-1.25(m,9H),0.92(t,J＝6.4Hz,3H)。

Example 189: synthesis of Compound 389

Step 1: mixing ethyl piperidine-4-carboxylate (200mg, 1.27mmol), 1-bromo-4- (tert-butyl) benzene (407mg, 1.91mmol), dichloro [1, 3-bis (2, 6-di-3-pentylphenyl) imidazol-2-ylidene ] ate]A mixture of (3-Chloropyridinyl) palladium (II) (50mg, 0.06mmol) and t-BuOK (357mg, 3.18mmol) in 1, 4-dioxane (5 mL) in N ₂ Stirred at 110 ℃ for 16h. The volatiles were removed under reduced pressure and the residue was purified by reverse phase HPLC eluting with acetonitrile 17-47%/0.225% aqueous formic acid to give 1- (4- (tert-butyl) phenyl) piperidine-4-carboxylic acid as a white solid (15mg, 4.5% yield). LCMS (methods 5-95AB, ESI): t _R ＝0.723min,[M+H] ⁺ ＝262.2。

Compound 389 (formate) was prepared as a white solid from compound 101-K and 1- (4- (tert-butyl) phenyl) piperidine-4-carboxylic acid using an analogous method to that described in example G. LCMS (methods 5-95AB, ESI): t _R ＝0.643min,[M+H] ⁺ ＝881.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.37(brs,3H),7.29-7.22(m,4H),7.15-6.99(m,3H),6.95-6.92(m,2H),6.86-6.77(m,1H),6.36-6.29(m,1H),4.96-4.95(m,1H),4.80-4.76(m,2H),4.26-4.08(m,6H),3.70-3.64(m,2H),3.33-3.32(m,1H),3.21-3.04(m,7H),2.86-2.83(m,3H),2.73-2.69(m,2H),2.47-2.43(m,1H),2.21-2.17(m,1H),2.05-2.02(m,1H),2.00-1.82(m,4H),1.44-1.35(m,3H),1.28(s,9H)。

Example 190: synthesis of Compound 390

Step 1:4- (4- (tert-butyl) phenyl) piperidine was prepared as a white solid from tert-butyl 4-oxopiperidine-1-carboxylate by using a method analogous to that described in example 17. LCMS (methods 5-95AB, ESI): t _R ＝0.731,[M+H] ⁺ ＝218.2。

And 2, step: a mixture of compound 101-K (100mg, 0.11mmol) and CDI (19mg, 0.11mmol) in DCM (2 mL) was stirred at 20 deg.C for 16h, followed by the addition of 4- (4- (tert-butyl) phenyl) piperidine (47mg, 0.22mmol). The resulting mixture was stirred for a further 24h. The reaction mixture was diluted with DCM (30 mL) and washed with brine (2x 30mL). The organic layer was washed with Na ₂ SO ₄ Drying, concentration, and purification of the residue by preparative TLC gave compound 390-1 as a white solid (50mg, 40% yield). LCMS (methods 5-95AB, ESI): t _R ＝1.061,[M+H] ⁺ ＝1157.9

Compound 390 (formate) was prepared as a white solid from compound 390-1 by using an analogous method to that described in example G. LCMS (methods 5-95AB, ESI): t _R ＝0.725min,[M+H] ⁺ ＝881.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ7.37-7.33(m,3H),7.19-7.15(m,3H),7.11-7.06(m,2H),6.89(s,1H),6.82(s,1H),6.31(s,1H),4.82-4.75(m,1H),4.23-4.19(m,8H),3.26-3.17(m,4H),3.14-3.05(m,4H),2.98-2.91(m,4H),2.88(s,3H),2.77-2.71(m,2H),2.18-2.16(m,1H),1.89-1.86(m,2H),1.66-1.60(m,2H),1.43-1.34(m,3H),1.30(s,9H)。

Examples 191 and 192: synthesis of Compounds 391 and 392

Step 1: starting from methyl 4-oxocyclohexane-1-carboxylate, methyl (trans) -4- (4- (tert-butyl) phenyl) cyclohexane-1-carboxylate and methyl (cis) -4- (4- (tert-butyl) phenyl) cyclohexane-1-carboxylate were obtained after preparative TLC separation using a similar method as described in example 17.

Methyl (trans) -4- (4- (tert-butyl) phenyl) cyclohexane-1-carboxylate: ¹ H NMR(400MHz,CDCl ₃ )δ7.33(d,J＝8.2Hz,2H),7.15(d,J＝8.2Hz,2H),3.70(s,3H),2.54-2.48(m,1H),2.40-2.34(m,1H),2.14-2.08(m,2H),2.03-1.96(m,2H),1.66-1.57(m,2H),1.54-1.43(m,2H),1.32(s,9H)。

methyl (cis) -4- (4- (tert-butyl) phenyl) cyclohexane-1-carboxylate: ¹ H NMR(400MHz,CDCl ₃ )δ7.31(d,J＝8.4Hz,2H),7.14(d,J＝8.4Hz,2H),3.73(s,3H),2.72(brs,1H),2.58-2.49(m,1H),2.29-2.22(m,2H),1.84-1.76(m,2H),1.70-1.62(m,4H),1.32(s,9H)。

compound 391 (formate) and compound 392 (formate) were each prepared as a white solid from 101-K and (trans) -methyl 4- (4- (tert-butyl) phenyl) cyclohexane-1-carboxylate or (cis) -methyl 4- (4- (tert-butyl) phenyl) cyclohexane-1-carboxylate, respectively, using procedures analogous to those described in example G.

Compound 391: LCMS (method 5-95AB, ESI): t _R ＝0.730min,[M+H] ⁺ ＝880.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ7.32-7.28(m,3H),7.27-7.22(m,1H),7.21-7.16(m,1H),7.16-7.10(m,3H),6.90(brs,1H),6.82(brs,1H),6.32(s,1H),4.85-4.75(m,3H),4.33-4.12(m,6H),3.26-2.96(m,8H),2.83(s,3H),2.54-2.35(m,3H),2.22-2.16(m,1H),2.08-2.01(m,1H),1.98-1.90(m,4H),1.73-1.49(m,5H),1.36(t,J＝6.8Hz,2H),1.30(s,9H)。

Compound 392: LCMS (methods 5-95AB, ESI): t _R ＝0.738min,[M+H] ⁺ ＝880.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.49(brs,2H),7.34-7.28(m,3H),7.27-7.21(m,1H),7.19-7.13(m,3H),7.09(d,J＝8.4Hz,1H),6.89(d,J＝2.0Hz,1H),6.82(d,J＝2.0Hz,1H),6.29(s,1H),4.98-4.95(m,1H),4.81-4.76(m,2H),4.28-4.16(m,6H),3.30-3.09(m,6H),3.07-2.98(m,2H),2.85(s,3H),2.67-2.61(m,2H),2.29-2.13(m,1H),2.10-1.88(m,5H),1.76-1.73(m,4H),1.35(d,J＝6.8Hz,3H),1.29(s,9H)。

Example 193: synthesis of Compound 393

Step 1: mixing 4-chloropyridine-2-amine (500mg, 3.9mmol), methyl 3-oxobutanoate (542mg, 4.7mmol) and PhI (OAc) ₂ (1.5g, 4.7mmol) and BF ₃ ·Et ₂ A mixture of O (0.1mL, 0.78mmol) in toluene (20 mL) was stirred at 110 ℃ for 24h. Volatiles were removed under reduced pressure and the residue was taken up in EtOAc and H ₂ Partition between O (50 mL each). The organic layer was washed with Na ₂ SO ₄ Drying, concentrating, and purifying the residue by silica gel chromatography, eluting with 20% EtOAc in petroleum ether to give 7-chloro-2-methylimidazo [1,2-a ] as a white solid]Pyridine-3-carboxylic acid methyl ester (280mg, 32% yield). ¹ H NMR(400MHz,CDCl ₃ )δ9.22(d,J＝8.8Hz,1H),7.59(d,J＝2.4Hz,1H),6.95(dd,J＝8.8,2.4Hz,1H),3.95(s,1H),2.69(s,1H)。

And 2, step: from 7-chloro-2-methylimidazo [1,2-a ] ]Starting with pyridine-3-carboxylic acid methyl ester, typical Suzuki and ester hydrolysis conditions similar to those described in example H were applied to give 7- (4- (tert-butyl) phenyl) -2-methylimidazo [1,2-a ] as a white solid]Pyridine-3-carboxylic acid. LCMS (methods 5-95AB, ESI): t _R ＝0.786,[M+H] ⁺ ＝308.9

Compound 393 (formate) was synthesized from compound 101-K and 7- (4- (tert-butyl) phenyl) -2-methylimidazo [1,2-a ] using an analogous method to that described in example G]Pyridine-3-carboxylic acid was prepared as a white solid. LCMS (method 5-95AB, ESI): t _R ＝0.704min,[M+H] ⁺ ＝928.7； ¹ H NMR(400MHz,MeOH-d ₄ )δ9.19(d,J＝8.0Hz,1H),7.77(d,J＝8.0Hz,1H),7.72(d,J＝8.0Hz,2H),7.56(d,J＝8.0Hz,2H),7.43(d,J＝8.0Hz,1H),7.31(d,J＝8.0Hz,1H),7.24(d,J＝8.4Hz,1H),7.16(d,J＝8.4Hz,1H),7.08(d,J＝8.0Hz,1H),6.90(d,J＝2.0Hz,1H),6.81(brs,1H),6.37(s,1H),5.28-5.25(m,1H),4.81-4.75(m,2H),4.22-4.15(m,6H),3.34-3.10(m,8H),2.93(s,3H),2.70(s,3H),2.38-2.30(m,1H),2.19-2.13(m,1H),1.36(brs,12H)。

Example 194: synthesis of Compound 394

Compound 394 (formate) was prepared from compound 101-K as a white solid by using an analogous method to that described in example H. LCMS (method 5-95AB, ESI): t _R ＝0.692min,[M+H] ⁺ ＝891.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.48(brs,2H),8.39(s,1H),7.91(d,J＝8.4Hz,1H),7.79(s,1H),7.53(d,J＝8.4Hz,1H),7.34(d,J＝8.4Hz,1H),7.24(d,J＝8.4Hz,1H),7.19(d,J＝8.4Hz,1H),7.10(d,J＝8.4Hz,1H),6.92(d,J＝2.2Hz,1H),6.81(s,1H),6.40(s,1H),5.24-5.17(m,1H),4.84-4.77(m,2H),4.31-4.14(m,6H),3.40-3.35(m,1H),3.27-3.08(m,7H),2.99(s,3H),2.87(t,J＝7.5Hz,3H),2.78(s,3H),2.34-2.29(m,1H),2.23-2.14(m,1H),1.81-1.71(m,2H),1.51-1.26(m,9H),0.91(t,J＝6.8Hz,3H)。

Example 195: synthesis of Compound 395

Compound 395 (formate) was prepared as a white solid from compound 101-K by using an analogous method to that described in example H. LCMS (methods 5-95AB, ESI): t _R ＝0.693min,[M+H] ⁺ ＝891.8； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.49(brs,2H),8.38(s,1H),7.92(d,J＝8.4Hz,1H),7.77(s,1H),7.71(d,J＝8.8Hz,1H),7.34(d,J＝8.4Hz,1H),7.24(d,J＝8.4Hz,1H),7.19(d,J＝8.4Hz,1H),7.10(d,J＝8.8Hz,1H),6.92(d,J＝2.0Hz,1H),6.81(s,1H),6.41(s,1H),5.23-5.17(m,1H),4.84-4.77(m,2H),4.35-4.21(m,4H),4.20(s,2H),3.40-3.35(m,1H),3.27-3.12(m,7H),2.99(s,3H),2.85(t,J＝7.5Hz,3H),2.77(s,3H),2.35-2.27(m,1H),2.24-2.16(m,1H),1.79-1.71(m,2H),1.45-1.30(m,9H),0.91(t,J＝6.8Hz,3H)。

Example 196: synthesis of Compound 396

Step 1: 5-hydroxy-2-nitrobenzaldehyde (1.5g, 9.0mmol), ethyl acetoacetate (1.17g, 9.0mmol) and ZnCl ₂ (6.1g, 45mmol) and SnCl ₂ (8.5g, 45mmol) of a mixture in EtOH (30 mL) in N ₂ Stirred at 70 ℃ for 3h. The volatiles were removed under reduced pressure and the residue was taken up in EtOAc (50 mL) which was washed with brine (2x 50mL). The organic layer was washed with Na ₂ SO ₄ Drying, concentration, and the residue was purified by silica gel chromatography, eluting with 0-10% meoh in DCM, to give ethyl 6-hydroxy-2-methylquinoline-3-carboxylate (500mg, 24% yield) as a brown solid. ¹ H NMR(400MHz,MeOH-d4)9.44(s,1H),8.12(d,J＝9.2Hz,1H),7.80(dd,J＝9.2,2.4Hz,1H),7.60(d,J＝2.4Hz,1H),4.53(q,J＝7.2Hz,2H),3.19(s,3H),1.50(t,J＝7.2Hz,3H)。

Step 2: starting from 6-hydroxy-2-methylquinoline-3-carboxylic acid ethyl ester, typical alkylation (as described in example 21) and ester hydrolysis (NaOH, meOH/H) were applied ₂ O, described in example H) to yield 6- (hexyloxy) -2-methylquinoline-3-carboxylic acid as a white solid. LCMS (methods 5-95AB, ESI): t _R ＝0.798min,[M+H] ⁺ ＝287.9。

Compound 396 (formate) was prepared as a white solid from compound 101-K and 6- (hexyloxy) -2-methylquinoline-3-carboxylic acid using an analogous method to that described in example G. LCMS (method 5-95AB, ESI): t _R ＝0.706min,[M+H] ⁺ ＝907.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.45(brs,1H),8.32(s,1H),7.90(d,J＝8.4Hz,1H),7.47(d,J＝8.4Hz,1H),7.34-7.30(m,2H),7.23(d,J＝8.0Hz,1H),7.17(d,J＝8.0Hz,1H),7.09(d,J＝8.0Hz,1H),6.91(s,1H),6.81(s,1H),6.39(s,1H),5.21-5.18(m,1H),4.81-4.77(m,2H),4.24-4.16(m,6H),4.12(t,J＝6.4Hz,2H),3.40-3.35(m,1H),3.20-3.10(m,7H),2.98(s,3H),2.73(s,3H),2.22-2.19(m,1H),2.18-2.10(m,1H),1.88-1.84(m,2H),1.55-1.53(m,2H),1.42-1.35(m,7H),0.94(t,J＝6.8Hz,3H)。

Example 197: synthesis of Compound 397

Compound 397 (formate) was prepared as a white solid from compound 101-K and ethyl 6-hydroxy-2-methylquinoline-3-carboxylate (described in example 396) by using a similar method to that described in example 174. LCMS (method 5-95AB, ESI): t _R ＝0.733min,[M+H] ⁺ ＝955.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.54(brs,2H),8.29(s,1H),7.99(d,J＝8.4Hz,1H),7.61-7.55(m,1H),7.49(d,J＝8.4Hz,2H),7.32(d,J＝2.4Hz,2H),7.24(d,J＝8.0Hz,1H),7.16(d,J＝8.0Hz,1H),7.12-7.04(m,3H),6.90(d,J＝2.0Hz,1H),6.80(s,1H),6.38(s,1H),5.21-5.15(m,1H),4.80-4.78(m,2H),4.28-4.16(m,6H),3.29-3.10(m,8H),2.97(s,3H),2.76(s,3H),2.34-2.10(m,2H),1.36(s,9H),1.34(d,J＝6.8Hz,3H)。

Example 198: synthesis of Compound 398

Step 1: 2, 5-dibromo-3-nitropyridine (3.0g, 10.6mmol) and SnCl ₂ A mixture of (10.1 g,53.2 mmol) and sodium acetate (8.7 g, 106mmol) in MeOH/THF (130ml, v/v = 2/1) was stirred at 0 ℃ for 5h. After filtration, the filtrate was concentrated and the residue was taken up in EtOAc and saturated NaHCO ₃ The aqueous solutions (100 mL each) were partitioned. The organic layer was washed with brine (2x 100mL) and Na ₂ SO ₄ Drying and concentration gave N- (2, 5-dibromopyridin-3-yl) hydroxylamine as a yellow solid (2.7 g), which was used directly in the next step.

Step 2: n- (2, 5-dibromopyridin-3-yl) hydroxylamine (3.6 g,13.4 mmol), (E) -2-methylbut-2-enoic acid ethyl ester (5.2g, 40.2mmol) and FeCl ₂ ·4H ₂ A mixture of O (0.27g, 1.34mmol) in 1, 4-dioxane (20 mL) was stirred at 70 ℃ for 6h. After filtration, the filtrate is concentrated to dryness and the residue is purified by chromatography on silica gel, washing with 0-10% EtOAc in petroleum etherEthyl 3- ((2, 5-dibromopyridin-3-yl) amino) -2-methylenebutanoate was obtained as a pale yellow oil (800mg, 16% yield).

And 3, step 3: ethyl 3- ((2, 5-dibromopyridin-3-yl) amino) -2-methylenebutanoate (800mg, 2.1mmol), tetrabutylammonium iodide (782mg, 2.1mmol), and Pd (OAc) ₂ (48mg, 0.21mmol) of a mixture in DMF (10 mL) in N ₂ Stirred at 90 ℃ for 72h. After filtration, the filtrate was concentrated and the residue was purified by silica gel chromatography eluting with 0-5% etoac in petroleum ether to give ethyl 7-bromo-2-methyl-1, 5-naphthyridine-3-carboxylate as a white solid (100mg, 16% yield).

Compound 398 (formate) was prepared as a white solid by using a method analogous to that described in example 194 from compound 101-K and ethyl 7-bromo-2-methyl-1, 5-naphthyridine-3-carboxylate. LCMS (methods 5-95AB, ESI): t _R ＝0.710min,[M+H] ⁺ ＝892.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.85(s,1H),8.50(brs,3H),8.39(s,1H),8.11(s,1H),7.32-7.01(m,4H),6.81(brs,1H),6.53(brs,2H),5.25-5.19(m,1H),4.81-4.75(m,2H),4.39-4.20(m,6H),3.30-3.06(m,8H),3.00(s,3H),2.90-2.87(m,2H),2.78(s,3H),2.34-2.22(m,2H),1.77-1.75(m,2H),1.50-1.31(m,9H),0.93(t,J＝6.8Hz,3H).

Example 199: synthesis of Compound 399

Step 1: typical Sonogoshira conditions as described in example K were applied to 4-chloro-2-iodoaniline to give 4-chloro-2- ((trimethylsilyl) ethynyl) aniline as a brown oil.

And 2, step: a mixture of 4-chloro-2- ((trimethylsilyl) ethynyl) aniline (420mg, 1.9mmol), ethyl acetoacetate (0.36mL, 2.8mmol) and p-toluenesulfonic acid (357mg, 1.9mmol) in EtOH (16 mL) was stirred at 85 ℃ for 16h. The volatiles were removed under reduced pressure and the residue was redissolved with EtOAc (20 mL) which was saturated NaHCO ₃ Aqueous solution and brine (20 mL each). The organic layer is coated with Na ₂ SO ₄ Drying, concentrating, and making into capsule,and the residue was purified by silica gel chromatography, eluting with 5% EtOAc in petroleum ether, to give ethyl 6-chloro-2, 4-dimethylquinoline-3-carboxylate as a white solid (90mg, 18% yield). ¹ H NMR(400MHz,CDCl ₃ )δ7.98(d,J＝2.0Hz,1H),7.96(d,J＝9.2Hz,1H),7.67(dd,J＝9.2,2.0Hz,1H),4.50(q,J＝7.2Hz,2H),2.70(s,3H),2.63(s,3H),1.46(t,J＝7.2Hz,3H)。

And step 3: starting from 6-chloro-2, 4-dimethylquinoline-3-carboxylic acid ethyl ester, typical Suzuki (Pd) was applied ₂ (dba) ₃ (NaOH, meOH/H) coupling and ester hydrolysis ₂ O, as described in example H) to give 6-hexyl-2, 4-dimethylquinoline-3-carboxylic acid as a yellow solid. LCMS (methods 5-95AB, ESI): t _R ＝0.659min,[M+H] ⁺ ＝285.9

Compound 399 (formate salt) was prepared as a white solid from compound 101-K and 6-hexyl-2, 4-dimethylquinoline-3-carboxylic acid using an analogous method to that described in example G. LCMS (method 5-95AB, ESI): t _R ＝0.707min,[M+H] ⁺ ＝905.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.50(brs,2H),7.88-7.85(m,2H),7.64(d,J＝8.4Hz,1H),7.30(d,J＝8.4Hz,1H),7.22-7.18(m,2H),7.08(d,J＝8.4Hz,1H),6.89(brs,1H),6.74(brs,1H),6.44(s,1H),5.27-5.23(m,1H),4.78-4.77(m,2H),4.25-4.18(m,6H),3.19-3.11(m,8H),3.02(s,3H),2.83(t,J＝7.6Hz,2H),2.69(s,3H),2.64(s,3H),2.27-2.17(m,2H),1.72-1.70(m,2H),1.40-1.20(m,9H),0.89(t,J＝6.8Hz,3H)。

Example 200: synthesis of Compound 400

Step 1: starting from 3-hydroxy-7-methoxy-2-naphthoic acid, typical methyl ester formation (described in example M), triflation, suzuki conditions (described in example 10) were applied to give methyl 7-methoxy-3-methyl-2-naphthoate as a white solid. LCMS (methods 5-95AB, ESI): t _R ＝0.813min,[M+H] ⁺ ＝230.9。

Step 2: from 7-methoxy-3-methyl-2-naphthalineStarting with methyl ester, demethylation, methyl ester formation (as described in example M), triflation and Suzuki coupling (as described in example 10) and ester hydrolysis conditions (as described in example H) were applied to give 7-hexyl-3-methyl-2-naphthoic acid as a white solid. LCMS (methods 5-95AB, ESI): t _R ＝0.944min,[M+H] ⁺ ＝270.9。

Compound 400 (trifluoroacetate salt) was prepared as a white solid from compound 101-K and 7-hexyl-3-methyl-2-naphthoic acid using an analogous method to that described in example G. LCMS (methods 5-95AB, ESI): t _R ＝0.693min,[M+H] ⁺ ＝890.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ7.94(s,1H),7.77(d,J＝8.4Hz,1H),7.75-7.65(m,2H),7.44(d,J＝8.4Hz,1H),7.36(d,J＝8.4Hz,1H),7.27(d,J＝8.4Hz,1H),7.20(d,J＝8.4Hz,1H),7.12(d,J＝8.4Hz,1H),6.94(d,J＝2.0Hz,1H),6.85(s,1H),6.39(s,1H),5.25-5.18(m,1H),4.83-4.75(m,2H),4.28-4.21(m,6H),3.40-3.35(m,1H),3.26-3.12(m,7H),3.00(s,3H),2.81(t,J＝8.0Hz,2H),2.57(s,3H),2.37-2.27(m,1H),2.25-2.14(m,1H),1.75-1.71(m,2H),1.45-1.20(m,11H),0.92(t,J＝7.2Hz,3H)。

Example 201: synthesis of Compound 401

Step 1: to a solution of 4- (tert-butyl) benzaldehyde (5.0 g,30.8 mmol) in THF (50 mL) at 0 deg.C was added ethynylmagnesium bromide (0.5N, 92.5mL in THF) dropwise, and the mixture was stirred at 20 deg.C for 4h. With saturated NH ₄ The reaction was quenched with aqueous Cl (30 mL), which was extracted with EtOAc (3x 30mL). The combined organic layers were washed with Na ₂ SO ₄ Drying, concentration, and the residue was purified by silica gel chromatography eluting with 0-5% etoac in petroleum ether to give 1- (4- (tert-butyl) phenyl) prop-2-yn-1-ol as a colorless oil (4.5 g,78% yield).

Step 2: a mixture of 1- (4- (tert-butyl) phenyl) prop-2-yn-1-ol (4.5g, 24mmol), 2-iodoxybenzoic acid (20g, 72mmol) in EtOAc (50 mL) was stirred at 80 ℃ for 4h. After filtration, the filtrate was evaporated in vacuo to give 1- (4- (tert-butyl) phenyl) prop-2-yn-1-one (4.2 g) as a yellow oil, which was used directly in the next step.

And 3, step 3: a mixture of 1- (4- (tert-butyl) phenyl) prop-2-yn-1-one (3.9g, 20.8mmol) and methyl (E) -3-aminobut-2-enoate (2.0g, 17.4mmol) in EtOH (30 mL) was stirred at 50 ℃ for 0.5h. After cooling to 0 deg.C, N-bromosuccinimide (3.7 g, 20.8mmol) was added to the above solution, and the resulting mixture was stirred at 0 deg.C for 0.5h. The volatiles were removed and the residue was redissolved with EtOAc (50 mL) and washed with brine (2x 50mL). Na for organic layer ₂ SO ₄ Dried, concentrated and the residue purified by reverse phase HPLC (solvent gradient: acetonitrile 45-95%/(0.225% formic acid) -water) to give methyl 5-bromo-6- (4- (tert-butyl) phenyl) -2-methylnicotinate as a yellow oil (3.2g, 51% yield). LCMS (methods 5-95AB, ESI): t _R ＝0.945min,[M+H] ⁺ ＝361.9。

And 4, step 4: typical ester hydrolysis conditions as described in example H were applied to methyl 5-bromo-6- (4- (tert-butyl) phenyl) -2-methylnicotinate to give 5-bromo-6- (4- (tert-butyl) phenyl) -2-methylnicotinic acid as a yellow solid.

Compound 401 (formate salt) was prepared as a white solid from compound 101-K and 5-bromo-6- (4- (tert-butyl) phenyl) -2-methylnicotinic acid using a method analogous to that described in example G. LCMS (methods 5-95AB, ESI): t _R ＝0.743min,[M+H] ⁺ ＝967.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.49(brs,3H),8.16(s,1H),7.65-7.50(m,4H),7.32(d,J＝8.4Hz,1H),7.25(d,J＝8.4Hz,1H),7.19(d,J＝8.4Hz,1H),7.10(d,J＝8.4Hz,1H),6.91(s,1H),6.83(s,1H),6.39(s,1H),5.20-5.10(m,1H),4.85-4.75(m,2H),4.25-4.15(m,6H),3.40-3.35(m,1H),3.20-3.10(m,7H),2.95(s,3H),2.62(s,3H),2.33-2.25(m,1H),2.20-2.10(m,1H),1.39(s,9H),1.36(d,J＝6.8Hz,3H)。

Example 202: synthesis of Compound 402

Step 1: starting from methyl 5-bromo-6- (4- (tert-butyl) phenyl) -2-methylnicotinate (described in example 201), typical Suzuki and ester hydrolysis conditions were applied (as described in example H) to give 6- (4- (tert-butyl) phenyl) -2, 5-dimethylnicotinic acid as a yellow solid.

Compound 402 (formate) was prepared as a white solid from compound 101-K and 6- (4- (tert-butyl) phenyl) -2, 5-dimethylnicotinic acid using an analogous method to that described in example G. LCMS (method 5-95AB, ESI): t _R ＝0.688min,[M+H] ⁺ ＝903.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.47(brs,2H),7.77(s,1H),7.56(d,J＝8.4Hz,2H),7.43(d,J＝8.4Hz,2H),7.31(d,J＝8.0Hz,1H),7.24(d,J＝8.0Hz,1H),7.18(d,J＝8.0Hz,1H),7.10(d,J＝8.8Hz,1H),6.92(brs,1H),6.83(s,1H),6.38(s,1H),5.20-5.15(m,1H),4.85-4.75(m,2H),4.25-4.15(m,6H),3.40-3.35(m,1H),3.25-3.10(m,7H),2.96(s,3H),2.60(s,3H),2.35(s,3H),2.33-2.25(m,1H),2.20-2.10(m,1H),1.40(s,9H),1.36(d,J＝7.2Hz,3H)。

Example 203: synthesis of Compound 403

Step 1: a mixture of methyl 5-bromo-6- (4- (tert-butyl) phenyl) -2-methylnicotinate (described in example 402) (400mg, 1.1 mmol), naOMe (90mg, 1.7 mmol) and CuBr (16mg, 0.11mmol) in NMP/MeOH (9mL, v/v = 8/1) was stirred in N ₂ Stirred at 110 ℃ for 20h. The volatiles were removed under reduced pressure and the residue was purified by reverse phase HPLC (acetonitrile 50-75%/0.2% aqueous formic acid) to give 6- (4- (tert-butyl) phenyl) -5-methoxy-2-methylnicotinic acid (22mg, 6% yield) as a white solid. LCMS (method 5-95AB, ESI): t _R ＝0.833min,[M+H] ⁺ ＝300.2。

Compound 403 (formate) was prepared as a white solid from compound 101-K and 6- (4- (tert-butyl) phenyl) -5-methoxy-2-methylnicotinic acid using an analogous method to that described in example G. LCMS (method 5-95AB, ESI): t _R ＝0.710min,[M+H] ⁺ ＝919.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.48(brs,2H),7.75(d,J＝8.4Hz,2H),7.54(s,1H),7.48(d,J＝8.4Hz,2H),7.32(d,J＝8.0Hz,1H),7.24(d,J＝8.0Hz,1H),7.17(d,J＝8.0Hz,1H),7.10(d,J＝8.0Hz,1H),6.91(d,J＝2.4Hz,1H),6.82(s,1H),6.38(s,1H),5.19-5.16(m,1H),4.81-4.78(m,2H),4.24-4.19(m,6H),3.92(s,3H),3.40-3.35(m,1H),3.20-3.10(m,7H),2.96(s,3H),2.58(s,3H),2.35-2.14(m,2H),1.37(s,9H),1.36(d,J＝6.0Hz,3H)。

Example 204: synthesis of Compound 404

Step 1: methyl 5-bromo-6- (4- (tert-butyl) phenyl) -2-methylnicotinate (described in example 402) (120mg, 0.33mmol), pd ₂ (dba) ₃ (6.1mg, 0.99mmol), t-BuXphos (11mg, 0.03mmol) and KOH (56mg, 0.99mmol) in 1, 4-dioxane/H ₂ Mixture in O (8mL, v/v = 4/1) at N ₂ And stirred at 100 ℃ for 12h. The volatiles were removed under reduced pressure and the residue was purified by reverse phase HPLC (acetonitrile 25-55%/0.2% aqueous formic acid) to give 6- (4- (tert-butyl) phenyl) -5-hydroxy-2-methylnicotinic acid (10mg, 11% yield) as a white solid. LCMS (method 5-95AB, ESI): t _R ＝0.634min,[M+H] ⁺ ＝286.4。

Compound 404 (formate) was prepared as a white solid from compound 101-K and 6- (4- (tert-butyl) phenyl) -5-hydroxy-2-methylnicotinic acid using an analogous method to that described in example G. LCMS (methods 5-95AB, ESI): t _R ＝0.692min,[M+H] ⁺ ＝905.9； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.49(brs,3H),7.84(d,J＝8.4Hz,2H),7.51(d,J＝8.4Hz,2H),7.35-7.29(m,2H),7.25(d,J＝8.0Hz,1H),7.18(d,J＝8.4Hz,1H),7.10(d,J＝8.4Hz,1H),6.91(d,J＝2.8Hz,1H),6.83(s,1H),6.38(s,1H),5.16-5.14(m,1H),4.62-4.54(m,2H),4.25-4.14(m,6H),3.50-3.47(m,1H),3.20-3.07(m,5H),2.96(s,3H),2.82-2.65(m,2H),2.56(s,3H),2.34-2.10(m,2H),1.38(s,9H),1.37(d,J＝7.2Hz,3H)。

Example 205: synthesis of Compound 405

Step 1: methyl 5-bromo-6- (4- (tert-butyl) phenyl) -2-methylnicotinate (described in example 402) (200mg, 0.53mmol), benzophenone imine (145mg, 0.80mmol), pd ₂ (dba) ₃ (49mg, 0.05mmol), xantphos (62mg, 0.11mmol) and Cs ₂ CO ₃ (346mg, 1.06mmol) of a mixture in toluene (2 mL) in N ₂ And stirred at 90 ℃ for 16h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3X 20mL). The combined organic layers were washed with brine (2x 50mL) and MgSO ₄ Drying, concentrating, and purifying the residue by preparative TLC (20% EtOAc in petroleum ether _f = 0.5). To the above separated material was added HCl solution (2N, 3 mL) and the mixture was stirred at 20 ℃ for 3h. The volatiles were removed and the residue was purified by preparative TLC to give methyl 5-amino-6- (4- (tert-butyl) phenyl) -2-methylnicotinate as a white solid (100mg, 78% yield). LCMS (method 5-95AB, ESI): t _R ＝0.757min,[M+H] ⁺ ＝298.9。

And 2, step: typical ester hydrolysis conditions (NaOH, meOH/H) were applied to methyl 5-amino-6- (4- (tert-butyl) phenyl) -2-methylnicotinate ₂ O, described in example H) to give 5-amino-6- (4- (tert-butyl) phenyl) -2-methylnicotinic acid as a white solid.

Compound 405 (formate) was prepared as a white solid from compound 101-K and 5-amino-6- (4- (tert-butyl) phenyl) -2-methylnicotinic acid using an analogous method to that described in example G. LCMS (methods 5-95AB, ESI): t _R ＝0.650min,[M+H] ⁺ ＝904.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.45(brs,2H),7.60-7.40(m,4H),7.35-7.15(m,4H),7.12(d,J＝8.4Hz,1H),6.87(s,1H),6.72(s,1H),6.45(s,1H),5.16-5.13(m,1H),4.85-4.75(m,2H),4.40-4.05(m,6H),3.40-3.35(m,1H),3.25-3.05(m,7H),2.97(s,3H),2.43(s,3H),2.35-2.10(m,2H),1.37(s,9H),1.36(d,J＝6.4Hz,3H)。

Example 206: synthesis of Compound 406

Step 1: 98% of methyl 5-amino-6- (4- (tert-butyl) phenyl) -2-methylnicotinate (described in example 205, 200mg, 0.67mmol) ₂ SO ₄ Aqueous solution and 50% of H ₂ O ₂ The mixture in aqueous solution (4 ml, v/v = 1/1) was stirred at 0 ℃ for 16h. The mixture was saturated with Na ₂ CO ₃ The solution was quenched until pH =7 and then extracted with EtOAc (3x 20mL). The combined organic layers were washed with brine (50 mL) and MgSO ₄ Dried, concentrated, and the residue purified by preparative TLC (10% EtOAc in petroleum ether) _f = 0.5) to give methyl 6- (4- (tert-butyl) phenyl) -2-methyl-5-nitronicotinate as a white solid (60mg, 27% yield). LCMS (methods 5-95AB, ESI): t _R ＝1.010min,[M+H] ⁺ ＝329.1。

Step 2: typical ester hydrolysis conditions (NaOH, meOH/H) were applied to methyl 6- (4- (tert-butyl) phenyl) -2-methyl-5-nitronicotinate ₂ O, as described in example H) to give 6- (4- (tert-butyl) phenyl) -2-methyl-5-nitronicotinic acid as a white solid.

Compound 406 (formate) was prepared as a white solid from compound 101-K and 6- (4- (tert-butyl) phenyl) -2-methyl-5-nitronicotinic acid using an analogous method to that described in example G. LCMS (method 5-95AB, ESI): t _R ＝0.730min,[M+H] ⁺ ＝934.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.32(s,1H),7.60-7.40(m,4H),7.24(d,J＝8.0Hz,1H),7.20(d,J＝8.0Hz,1H),7.17(d,J＝8.0Hz,1H),7.11(d,J＝8.4Hz,1H),6.92(d,J＝2.0Hz,1H),6.83(s,1H),6.38(s,1H),5.19-5.17(m,1H),4.79-4.75(m,2H),4.40-4.05(m,6H),3.30-3.05(m,8H),2.95(s,3H),2.75(s,3H),2.40-2.10(m,2H),1.38(s,9H),1.37(d,J＝7.2Hz,3H)。

Example 207: synthesis of Compound 407

Step 1: to the 5-amino-6- (4- (tert-butyl) group at 0 deg.C) Phenyl) -2-methylnicotinate methyl ester (described in example 205, 200mg, 0.67mmol) to a solution in 6M aqueous HCl (6 mL) NaNO was added dropwise ₂ (139mg, 2.0 mmol) of H ₂ O (2 mL) solution and the mixture was stirred at 15 ℃ for 3h, followed by addition of CuCl (398mg, 4.0mmol). The resulting mixture was stirred at 15 ℃ for 16h. Will react with H ₂ Diluted O (20 mL) and extracted with EtOAc (3X 20mL). The combined organic layers were washed with brine (2x 50mL) and over MgSO ₄ Drying, concentration, and purification of the residue by preparative TLC (30% etoac in petroleum ether) gave methyl 6- (4- (tert-butyl) phenyl) -5-chloro-2-methylnicotinate as a colorless oil (50mg, 24% yield). LCMS (methods 5-95AB, ESI): t _R ＝1.060min,[M+H] ⁺ ＝317.9。

And 2, step: typical ester hydrolysis conditions (NaOH, meOH/H) were applied to methyl 6- (4- (tert-butyl) phenyl) -5-chloro-2-methylnicotinate ₂ O, as described in example H) to give 6- (4- (tert-butyl) phenyl) -5-chloro-2-methylnicotinic acid as a white solid.

Compound 407 (formate) was prepared as a white solid by using an analogous method to that described in example G from compound 101-K and 6- (4- (tert-butyl) phenyl) -5-chloro-2-methylnicotinic acid. LCMS (methods 5-95AB, ESI): t _R ＝0.740min,[M+H] ⁺ ＝923.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.44(brs,1H),7.98(s,1H),7.64(d,J＝8.4Hz,2H),7.56(d,J＝8.4Hz,2H),7.32(d,J＝8.0Hz,1H),7.28-7.10(m,2H),7.11(d,J＝8.4Hz,1H),6.91(d,J＝2.4Hz,1H),6.83(s,1H),6.38(s,1H),5.17-5.15(m,1H),4.79-4.75(m,1H),4.40-4.10(m,7H),3.30-3.05(m,8H),2.95(s,3H),2.63(s,3H),2.35-2.05(m,2H),1.38(s,9H),1.35(d,J＝6.4Hz,3H)。

Example 208: synthesis of Compound 408

Step 1: methyl 5-amino-6- (4- (tert-butyl) phenyl) -2-methylnicotinate (50mg, 0.17mmol, described in example 205), naBH ₃ CN (53mg, 0.84mmol) and paraformaldehyde (50mg, 1.7mmol) inThe mixture in acetic acid (3 mL) was stirred at 20 ℃ for 10h. With saturated Na ₂ CO ₃ The aqueous solution was adjusted to pH 8 to quench the reaction, then extracted with EtOAc (2X 20mL). The combined organic layers were washed with Na ₂ SO ₄ Dried, concentrated, and the residue purified by preparative TLC (20% EtOAc in petroleum ether) _f = 0.5) to give methyl 6- (4- (tert-butyl) phenyl) -5- (dimethylamino) -2-methylnicotinate as a yellow solid (50mg, 91% yield).

And 2, step: typical ester hydrolysis conditions (NaOH, meOH/H) were applied to methyl 6- (4- (tert-butyl) phenyl) -5- (dimethylamino) -2-methylnicotinate ₂ O, as described in example H) to give 6- (4- (tert-butyl) phenyl) -5- (dimethylamino) -2-methylnicotinic acid as a white solid. LCMS (methods 5-95AB, ESI): t _R ＝0.787min,[M+H] ⁺ ＝313.4。

Compound 408 (formate) was prepared as a white solid from compound 101-K and 6- (4- (tert-butyl) phenyl) -5- (dimethylamino) -2-methylnicotinic acid using an analogous method to that described in example G. LCMS (methods 5-95AB, ESI): t _R ＝0.711min,[M+H] ⁺ ＝932.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.46(brs,3H),7.71(d,J＝8.4Hz,2H),7.54-7.48(m,3H),7.32(d,J＝8.0Hz,1H),7.26-7.15(m,2H),7.10(d,J＝8.4Hz,1H),6.92(d,J＝2.4Hz,1H),6.83(s,1H),6.34(s,1H),5.20-5.14(m,1H),4.82-4.78(m,2H),4.30-4.15(m,6H),3.36-3.10(m,8H),2.96(s,3H),2.60(s,6H),2.55(s,3H),2.32-2.27(m,1H),2.20-2.15(m,1H),1.38(s,9H),1.36(d,J＝6.0Hz,3H)。

Example 209: synthesis of Compound 409

Step 1: to a solution of methyl 5-amino-6- (4- (tert-butyl) phenyl) -2-methylnicotinate (described in example 205, 50mg, 0.17mmol) in DCM (2 mL) and pyridine (0.5 mL) was added 2-nitrobenzenesulfonyl chloride (111mg, 0.50mmol), and the mixture was stirred at 15 ℃ for 16h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2X 20mL). Combined organic matterThe layer was washed with brine (30 mL), mgSO ₄ Drying, concentrating, and purifying the residue by preparative TLC (20% EtOAc in petroleum ether _f = 0.5) to give methyl 6- (4- (tert-butyl) phenyl) -2-methyl-5- ((4-nitrophenyl) sulfonamide) nicotinate as a yellow solid (50mg, 62% yield). LCMS (method 5-95AB, ESI): t _R ＝0.963min,[M+H] ⁺ ＝484.1。

And 2, step: typical alkylation conditions were applied to methyl 6- (4- (tert-butyl) phenyl) -2-methyl-5- ((4-nitrophenyl) sulfonamide) nicotinate (as described in example 21) to give methyl 6- (4- (tert-butyl) phenyl) -2-methyl-5- ((N-methyl-4-nitrophenyl) sulfonamide) nicotinate as a yellow solid.

And 3, step 3: methyl 6- (4- (tert-butyl) phenyl) -2-methyl-5- ((N-methyl-4-nitrophenyl) sulfonamide) nicotinate (50mg, 0.10mmol) and K ₂ CO ₃ A mixture of (70mg, 0.50mmol) in DMF (3 mL) and thiophenol (4.2 mL) was stirred at 20 ℃ for 2h. The reaction was partitioned between EtOAc and brine (30 mL each); the organic layer is coated with Na ₂ SO ₄ Drying, concentration and purification of the residue by chromatography on silica gel eluting with 30% etoac in petroleum ether afforded methyl 6- (4- (tert-butyl) phenyl) -2-methyl-5- (methylamino) nicotinate as a colorless oil (25mg, 80% yield). LCMS (methods 5-95AB, ESI): t _R ＝0.688min,[M+H] ⁺ ＝313.4。

And 4, step 4: typical ester hydrolysis conditions (NaOH, meOH/H) were applied to methyl 6- (4- (tert-butyl) phenyl) -2-methyl-5- (methylamino) nicotinate ₂ O, as described in example H) to give 6- (4- (tert-butyl) phenyl) -2-methyl-5- (methylamino) nicotinic acid as a white solid.

Compound 409 (formate) was prepared as a white solid from compound 101-K and 6- (4- (tert-butyl) phenyl) -2-methyl-5- (methylamino) nicotinic acid using an analogous method to that described in example G. LCMS (method 5-95AB, ESI): t _R ＝0.650min,[M+H] ⁺ ＝918.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.52(brs,1H),7.58(d,J＝8.4Hz,2H),7.48(d,J＝8.0Hz,2H),7.35-7.16(m,3H),7.13-7.05(m,2H),6.91(s,1H),6.82(s,1H),6.36(s,1H),5.20-5.10(m,1H),4.79-4.75(m,1H),4.40-4.10(m,7H),3.40-3.35(m,1H),3.25-3.05(m,7H),2.95(s,3H),2.80(s,3H),2.47(s,3H),2.35-2.10(m,2H),1.42(s,9H),1.36(d,J＝7.2Hz,3H)。

Example 210: synthesis of Compound 410

Step 1: a mixture of methyl (Z) -2- ((dimethylamino) methylene) -3-oxobutanoate (6.7g, 36mmol), 2-cyanoacetamide (2.98g, 35mmol), acetic acid (5.3g, 88mmol) and sodium ethoxide (1.24g, 3.8mmol) in EtOH (60 mL) was stirred at 15 ℃ for 1h. Volatiles were removed and 1N aqueous HCl (50 mL) was added. Filtering the precipitate with H ₂ O and saturated NaHCO ₃ The solution was washed and dried in an oven to give ethyl 5-cyano-2-methyl-6-oxo-1, 6-dihydropyridine-3-carboxylate (4.5g, 62% yield) as a yellow solid. LCMS (methods 5-95AB, ESI): t _R ＝0.614min,[M+H] ⁺ ＝206.8。

Compound 410 (formate) was prepared as a white solid by using a method analogous to that described in example 158 from compound 101-K and ethyl 5-cyano-2-methyl-6-oxo-1, 6-dihydropyridine-3-carboxylate. LCMS (methods 5-95AB, ESI): t _R ＝0.605min,[M+H] ⁺ ＝914.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.48(brs,3H),8.23(s,1H),7.90(d,J＝8.4Hz,2H),7.62(d,J＝8.4Hz,2H),7.35(d,J＝8.4Hz,1H),7.24-7.20(m,2H),7.10(d,J＝8.4Hz,1H),6.92(d,J＝2.4Hz,1H),6.82(s,1H),6.41(s,1H),5.20-5.16(m,1H),4.80-4.78(m,2H),4.25-4.18(m,6H),3.40-3.35(m,1H),3.18-3.12(m,7H),2.96(s,3H),2.75(s,3H),2.31-2.28(m,1H),2.18-2.15(m,1H),1.40(s,9H),1.36(t,J＝6.8Hz,3H)。

Example 211: synthesis of Compound 411

4-amino-6- (4- (tert-butyl) phenyl) nicotinic acid was prepared by using a typical Suzuki procedure (as described in example H)) And example 205 from methyl 4, 6-dichloronicotinate as a white solid. LCMS (methods 5-95AB, ESI): t _R ＝0.744min,[M+H] ⁺ ＝270.9。

Compound 411 (formate) was prepared as a white solid from compound 101-K and 4-amino-6- (4- (tert-butyl) phenyl) nicotinic acid using an analogous method to that described in example 158. LCMS (method 5-95AB, ESI): t _R ＝0.570min,[M+H] ⁺ ＝890.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.58(brs,1H),7.79(d,J＝8.4Hz,2H),7.55(d,J＝8.4Hz,2H),7.34(d,J＝8.0Hz,1H),7.30-7.05(m,5H),6.89(s,1H),6.81(s,1H),6.34(s,1H),5.20-5.10(m,1H),4.79-4.75(m,1H),4.40-4.10(m,7H),3.25-3.05(m,8H),2.87(s,3H),2.35-2.20(m,1H),2.15-2.05(m,1H),1.37(s,9H),1.36(d,J＝7.2Hz,3H)。

Example 212: synthesis of Compound 412

Step 1: 2-amino-6-chloronicotinic acid (150mg, 0.87mmol) and TMSCHN ₂ A mixture of (2N solution in hexane, 0.87 mL) in toluene (10 mL) and methanol (2.5 mL) was stirred at 25 ℃ for 16h. The volatiles were removed under reduced pressure and the residue was partitioned between EtOAc and brine (50 mL each). The organic layer is coated with Na ₂ SO ₄ Dried and concentrated to give methyl 2-amino-6-chloronicotinate (156 mg) as a white solid, which was used directly in the next step.

Compound 412 (formate) was prepared as a white solid from compound 101-K and methyl 2-amino-6-chloronicotinate using an analogous method to that described in example 158. LCMS (method 5-95AB, ESI): t _R ＝0.689min,[M+H] ⁺ ＝890.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.46(brs,3H),8.03-7.98(m,1H),7.92-7.80(m,2H),7.49(d,J＝7.6Hz,2H),7.33-7.21(m,2H),7.16-7.05(m,3H),6.86(d,J＝1.6Hz,2H),6.78(s,1H),6.44(s,1H),5.12-5.09(m,1H),4.81-4.75(m,2H),4.24-4.14(m,6H),3.37-3.36(m,1H),3.20-3.11(m,7H),2.89(s,3H),2.34-2.16(m,2H),1.37(s,9H),1.36(d,J＝7.2Hz,3H)。

Example 213: synthesis of Compound 413

Compound 413 (formate) was prepared from 101-K as a white solid by using a similar method to that described in example 211. LCMS (methods 5-95AB, ESI): t _R ＝0.658min,[M+H] ⁺ ＝904.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.42(brs,1H),7.71(d,J＝8.0Hz,2H),7.63(d,J＝8.0Hz,2H),7.35(d,J＝8.4Hz,1H),7.25(d,J＝8.4Hz,1H),7.20(d,J＝8.4Hz,1H),7.11(d,J＝8.4Hz,1H),7.01(s,1H),6.92(d,J＝2.0Hz,1H),6.83(s,1H),6.43(s,1H),5.11-5.05(m,1H),4.83-4.75(m,2H),4.32-4.23(m,4H),4.20(s,2H),3.28-3.08(m,8H),2.98(s,3H),2.59(s,3H),2.30-2.10(m,2H),1.38(s,9H),1.36(d,J＝7.2Hz,3H)。

Example 214: synthesis of Compound 414

Step 1-1: 2-amino-6- (4- (tert-butyl) phenyl) -4-methylnicotinic acid was prepared as a white solid from 2, 6-dichloro-4-methylnicotinic acid by using a typical Suzuki procedure (as described in example H) and the methods described in examples 212 and 205. LCMS (method 5-95AB, ESI): t _R ＝0.665min,[M+H] ⁺ ＝284.9。

Compound 414 (formate) was prepared as a white solid by using a method analogous to that described in example G from compound 101-K and 2-amino-6- (4- (tert-butyl) phenyl) -4-methylnicotinic acid. LCMS (method 5-95AB, ESI): t _R ＝0.669min,[M+H] ⁺ ＝904.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.31(brs,2H),7.75(d,J＝8.4Hz,1H),7.65(d,J＝8.4Hz,1H),7.45-7.38(m,2H),7.30-7.14(m,3H),7.06-6.95(m,3H),6.85(s,0.5H),6.82(s,0.5H),6.55(s,0.5H),6.48(s,0.5H),5.10-5.06(m,1H),4.85-4.75(m,2H),4.33-4.16(m,6H),3.30-2.95(m,8H)2.97(s,3H),2.29-2.16(m,5H),1.39(s,9H),1.37(d,J＝7.2Hz,3H)。

Example 215: synthesis of Compound 415

Step 1: following a similar procedure to that described in example 212, step 1, 2-amino-6-chloronicotinic acid was converted to methyl 2-amino-6-chloronicotinate as a white solid.

Step 2: methyl 2-amino-6-chloronicotinate (300mg, 1.6 mmol) and HNO ₃ A mixture of (80. Mu.L, 1.9 mmol) in sulfuric acid (10 mL) was stirred at 0 ℃ for 1h. The volatiles were removed and the residue was taken up in EtOAc (50 mL), which was washed with brine (2x 50mL). The organic layer was MgSO ₄ Drying, concentration and purification of the residue by silica gel chromatography eluting with 10% etoac in petroleum ether gave methyl 2-amino-6-chloro-5-nitronicotinate as a colourless oil (150mg, 40% yield). LCMS (ESI) [ < M + H ]] ⁺ ＝232.0。

Compound 415 (formate) was prepared as a white solid from compound 101-K and methyl 2-amino-6-chloro-5-nitronicotinate using a method analogous to that described in example 158. LCMS (methods 5-95AB, ESI): t _R ＝0.728min,[M+H] ⁺ ＝935.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.47(brs,2H),7.54-7.47(m,3H),7.43-7.36(m,2H),7.31-7.17(m,3H),7.12(d,J＝8.4Hz,1H),6.94(s,1H),6.80(s,1H),6.39(brs,1H),5.17-5.13(m,1H),4.62-4.55(m,2H),4.28-4.18(m,6H),3.28-3.10(m,8H),2.91(s,3H),2.35-2.31(m,1H),2.26-2.18(m,1H),1.39(s,9H),1.38(t,J＝7.2Hz,3H)。

Example 216: synthesis of Compound 416

Compound 416 (formate) was prepared as a white solid by using a similar method to that described in example 215. LCMS (method 5-95AB, ESI): t _R ＝0.653min,[M+H] ⁺ ＝905.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.40(brs,2H),7.55-7.47(m,5H),7.32-7.15(m,3H),7.11(d,J＝8.8Hz,1H),6.86(s,1H),6.75(s,1H),6.47(brs,1H),5.08-5.03(m,1H),4.79-4.73(m,2H),4.35-4.14(m,6H),3.40-3.35(m,1H),3.23-3.00(m,7H),2.91(s,3H),2.36-2.13(m,2H),1.38(d,J＝7.2Hz,3H),1.37(s,9H)。

Example 217: synthesis of Compound 417

Compound 417 (formate) was prepared as a white solid from compound 101-K by using an analogous method to that described in example 26. LCMS (method 5-95AB, ESI): t _R ＝0.749min,[M+H] ⁺ ＝904.7； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.74(s,1H),8.49(brs,1H),8.34(d,J＝8.0Hz,2H),7.33-7.28(m,3H),7.22-7.18(m,2H),7.08(d,J＝8.0Hz,1H),6.89(d,J＝1.6Hz,1H),6.77(s,1H),6.42(s,1H),5.19-5.16(m,1H),4.80-4.78(m,2H),4.26-4.19(m,6H),3.26-2.95(m,13H),2.57(d,J＝6.4Hz,2H),2.34-2.25(m,1H),2.20-2.13(m,1H),1.97-1.90(m,1H),1.39-1.34(m,6H),0.94(d,J＝6.4Hz,6H)。

Example 218: synthesis of Compound 418

Step 1: starting from 4-bromobenzylnitrile, typical Suzuki and amidine formation conditions similar to those described in example 35 were applied to give 4-isobutylbenzamidine as a colorless oil. LCMS (methods 5-95AB, ESI): t _R ＝0.563min,[M+H] ⁺ ＝177.0。

Step 2: (E) Ethyl-2- ((dimethylamino) methylene) -4, 4-difluoro-3-oxobutanoate was prepared as a yellow oil by using a similar method to that described in example 26.

And step 3: a mixture of ethyl (E) -2- ((dimethylamino) methylene) -4, 4-difluoro-3-oxobutanoate (400mg, 1.8mmol), 4-isobutylbenzamidine (478mg, 2.7 mmol) and triethylamine (505. Mu.L, 3.6 mmol) in toluene (15 mL) was stirred at 110 ℃ for 1h. Removing the volatile matter and removingThe residue was purified by silica gel chromatography, eluting with 0-2% EtOAc in petroleum ether, to give ethyl 4- (difluoromethyl) -2- (4-isobutylphenyl) pyrimidine-5-carboxylate as a white solid (500mg, 83% yield). ¹ H NMR(400MHz,CDCl ₃ ):δ9.36(s,1H),8.49(d,J＝8.4Hz,2H),7.42(t,J＝54Hz,1H),7.29(d,J＝8.4Hz,2H),4.47(q,J＝6.8Hz,2H),2.57(d,J＝7.2Hz,2H),1.99-1.88(m,1H),1.45(t,J＝6.8Hz,3H),1.29(d,J＝6.4Hz,6H)。

And 4, step 4: typical ester hydrolysis conditions (NaOH, meOH/H) were applied to ethyl 4- (difluoromethyl) -2- (4-isobutylphenyl) pyrimidine-5-carboxylate ₂ O, as described in example H) to give 4- (difluoromethyl) -2- (4-isobutylphenyl) pyrimidine-5-carboxylic acid as a white solid.

Compound 418 (formate salt) was prepared as a white solid from compound 101-K and 4- (difluoromethyl) -2- (4-isobutylphenyl) pyrimidine-5-carboxylic acid using a method similar to that described in example G. LCMS (methods 5-95AB, ESI): t _R ＝0.762min,[M+H] ⁺ ＝926.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ9.09(s,1H),8.48-8.44(m,3H),7.37-7.34(m,3H),7.29-7.25(m,1H),7.21(d,J＝8.0Hz,1H),7.15-7.11(m,1H),6.93(d,J＝2.4Hz,1H),6.84(s,1H),6.40(s,1H),5.24-5.21(m,1H),4.83-4.80(m,1H),4.30-4.17(m,7H),3.38-3.35(m,1H),3.26-3.12(m,8H),2.97(s,3H),2.61(d,J＝8.0Hz,3H),2.34-2.18(m,1H),1.99-1.96(m,1H),1.38(d,J＝6.8Hz,3H),0.97(d,J＝6.8Hz,6H)。

Example 219: synthesis of Compound 419

Step 1: a mixture of 4- (tert-butyl) benzamidine (4.0g, 22.7mmol), diethyl 2- (ethoxymethylene) malonate (4.9g, 22.7mmol) and sodium ethoxide (1.7g, 25.0mmol) in EtOH (10 mL) was stirred at 60 ℃ for 1h. The volatiles were removed and the residue was taken up in EtOAc (100 mL), which was washed with brine (100 mL). The organic layer was MgSO ₄ Drying, concentrating, and purifying the residue by silica gel chromatography, eluting with 40% EtOAc in petroleum ether to obtain a white colored extractSolid ethyl 2- (4- (tert-butyl) phenyl) -6-oxo-1, 6-dihydropyrimidine-5-carboxylate (800mg, 12% yield). LCMS (methods 5-95AB, ESI): t _R ＝0.749min,[M+H] ⁺ ＝300.9。

And 2, step: typical ester hydrolysis conditions (NaOH, meOH/H) were applied to ethyl 2- (4- (tert-butyl) phenyl) -6-oxo-1, 6-dihydropyrimidine-5-carboxylate ₂ O, as described in example H) to give 2- (4- (tert-butyl) phenyl) -6-oxo-1, 6-dihydropyrimidine-5-carboxylic acid as a white solid.

Compound 419 (formate salt) was prepared as a white solid from compound 101-K and 2- (4- (tert-butyl) phenyl) -6-oxo-1, 6-dihydropyrimidine-5-carboxylic acid using a method analogous to that described in example G. LCMS (method 5-95AB, ESI): t _R ＝0.693min,[M+H] ⁺ ＝892.9； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.76(s,1H),8.50(brs,1H),8.07(d,J＝8.0Hz,2H),7.53(d,J＝8.0Hz,2H),7.30(d,J＝8.0Hz,1H),7.19(d,J＝8.0Hz,1H),7.14(d,J＝8.0Hz,1H),7.05(d,J＝8.0Hz,1H),6.86(brs,1H),6.78(s,1H),6.39(s,1H),5.21-5.17(m,1H),4.80-4.76(m,2H),4.21-4.16(m,6H),3.40-3.35(m,1H),3.15-3.10(m,7H),2.86(s,3H),2.33-2.28(m,1H),2.19-2.14(m,1H),1.37(s,9H),1.36(d,J＝7.2Hz,3H)。

Example 220: synthesis of Compound 420

Step 1: starting from compound 420-1 (as described in example 219), typical alkylation (as described in example 21) and Me were used ₃ Hydrolysis of the SnOH methyl ester (as described in example N) conditions gave compound 420-2 as a white solid.

Step 2: starting from compound 420-2, typical amide couplings (HATU/DIEA), ester hydrolysis (LiOH, THF/H) as described in example G were applied ₂ O) and Boc removal (TFA/HFIP) conditions to give a white solidCompound 420 (formate). LCMS (methods 5-95AB, ESI): t _R ＝0.722,[M+H] ⁺ ＝950.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.97(s,1H),8.43(brs,2H),8.35(d,J＝8.0Hz,2H),7.53(d,J＝8.0Hz,2H),7.41(d,J＝8.0Hz,1H),7.23(d,J＝8.4Hz,1H),7.16(d,J＝8.0Hz,1H),7.07(d,J＝8.4Hz,1H),6.87(s,1H),6.83(s,1H),6.47(s,1H),5.17-5.13(m,1H),4.82-4.71(m,4H),4.35-4.16(m,6H),3.29-3.08(m,8H),2.88(s,3H),2.45-2.30(m,1H),2.26-2.10(m,1H),1.36(s,9H),1.35(d,J＝7.2Hz,3H)。

Example 221: synthesis of Compound 421

Step 1:2- (4- (tert-butyl) phenyl) -4-chloro-6-methylpyrimidine-5-carboxylic acid ethyl ester by using a typical chlorination (POCl) ₃ ) Conditions (as described in example 53) and the method described in example 219 were prepared as a yellow solid. LCMS (methods 5-95AB, ESI): t _R ＝1.110min,[M+H] ⁺ ＝332.9。

Step 2: ethyl 2- (4- (tert-butyl) phenyl) -4-chloro-6-methylpyrimidine-5-carboxylate (100mg, 0.30mmol) and NaOH (60mg, 1.5mmol) were dissolved in THF/H ₂ The mixture in O (15ml, v/v = 2/1) was stirred at 20 ℃ for 1h. With saturated KHSO ₄ The reaction was adjusted to pH =4 with aqueous solution and then extracted with EtOAc (3x 20mL). The combined organic layers were washed with brine (50 mL) and Na ₂ SO ₄ Drying, concentration, and purification of the residue by reverse phase HPLC (acetonitrile 50-80%/0.05% aqueous hcl) gave 2- (4- (tert-butyl) phenyl) -4-chloro-6-methylpyrimidine-5-carboxylic acid as a white solid (60mg, 66% yield). LCMS (methods 5-95AB, ESI): t _R ＝0.965min,[M+H] ⁺ ＝304.9。

Compound 421 (trifluoroacetate salt) was prepared as a white solid by using a method analogous to that described in example G from compound 101-K and 2- (4- (tert-butyl) phenyl) -4-chloro-6-methylpyrimidine-5-carboxylic acid. LCMS (methods 5-95AB, ESI): t _R ＝0.727min,[M+H] ⁺ ＝924.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.35(d,J＝8.4Hz,2H),7.56(d,J＝8.4Hz,2H),7.35-7.15(m,3H),7.10(d,J＝8.0Hz,1H),6.91(s,1H),6.79(s,1H),6.39(s,1H),5.30-5.20(m,1H),4.80-4.75(m,2H),4.30-4.05(m,6H),3.25-3.10(m,8H),2.99(s,3H),2.59(s,3H),2.35-2.05(m,2H),1.38(s,9H),1.37(d,J＝6.8Hz,3H)。

Example 222: synthesis of Compound 422

Step 1: starting from ethyl 2- (4- (tert-butyl) phenyl) -4-chloro-6-methylpyrimidine-5-carboxylate (described in example 221), typical alkylation (as described in example 21) and ester hydrolysis conditions (NaOH, meOH/H) were applied ₂ O, described in example H) to give 2- (4- (tert-butyl) phenyl) -4-methoxy-6-methylpyrimidine-5-carboxylic acid as a white solid. LCMS (method 5-95AB, ESI): t _R ＝0.815min,[M+H] ⁺ ＝300.9。

Compound 422 (formate) was prepared as a white solid by using a method analogous to that described in example G from compound 101-K and 2- (4- (tert-butyl) phenyl) -4-methoxy-6-methylpyrimidine-5-carboxylic acid. LCMS (method 5-95AB, ESI): t _R ＝0.727min,[M+H] ⁺ ＝920.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.50(brs,2H),8.36(d,J＝8.4Hz,2H),7.54(d,J＝8.4Hz,2H),7.32-7.28(m,1H),7.16-7.26(m,2H),7.10(d,J＝8.4Hz,1H),6.92(d,J＝2.4Hz,1H),6.81(s,1H),6.36(s,1H),5.23-5.20(m,1H),4.84-4.78(m,2H),4.30-4.10(m,6H),4.11(s,3H),3.25-3.09(m,8H),2.96(s,3H),2.51(s,3H),2.30-2.20(m,1H),2.20-2.09(m,1H),1.38(s,9H),1.37(d,J＝6.8Hz,3H)。

Example 223: synthesis of Compound 423

Step 1: typical ester hydrolysis conditions (NaOH, meOH/H) were applied to ethyl 2- (4- (tert-butyl) phenyl) -4-chloro-6-methylpyrimidine-5-carboxylate (described in example 221) ₂ O, as described in example H) to give2- (4- (tert-butyl) phenyl) -4-hydroxy-6-methylpyrimidine-5-carboxylic acid as a white solid. LCMS (method 5-95AB, ESI): t _R ＝0.788min,[M+H] ⁺ ＝286.9。

Compound 423 (formate) was prepared as a white solid from compound 101-K and 2- (4- (tert-butyl) phenyl) -4-hydroxy-6-methylpyrimidine-5-carboxylic acid using an analogous method to that described in example G. LCMS (method 5-95AB, ESI): t _R ＝0.690min,[M+H] ⁺ ＝906.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.44(brs,1H),7.98(d,J＝8.0Hz,2H),7.59(d,J＝8.0Hz,2H),7.31(d,J＝8.4Hz,1H),7.18(d,J＝8.8Hz,2H),7.08(d,J＝8.0Hz,1H),6.86(s,1H),6.75(s,1H),6.38(s,1H),5.20-5.10(m,1H),4.79-4.75(m,1H),4.40-4.10(m,7H),3.25-3.05(m,8H),2.91(s,3H),2.57(s,3H),2.35-2.20(m,1H),2.15-2.05(m,1H),1.38(s,9H),1.37(d,J＝6.8Hz,3H)。

Example 224: synthesis of Compound 424

Step 1: ethyl 2- (4- (tert-butyl) phenyl) -4-chloro-6-methylpyrimidine-5-carboxylate (described in example 221, 40mg, 0.12mmol), me ₂ NH(33mg，H ₂ 33% w/w,0.24 mmol) in O and DIEA (31mg, 0.24mmol) in DMF (5 mL) was stirred at 70 ℃ for 3h. The volatiles were removed and the residue was taken up in EtOAc (20 mL) which was washed with brine (2X 20mL). The organic layer was MgSO ₄ Dried, concentrated, and the residue purified by preparative TLC (30% EtOAc in petroleum ether) _f = 0.5) to give ethyl 2- (4- (tert-butyl) phenyl) -4- (dimethylamino) -6-methylpyrimidine-5-carboxylate as a white solid (30mg, 73% yield). LCMS (methods 5-95AB, ESI): t _R ＝0.811min,[M+H] ⁺ ＝342.0。

Step 2: typical ester hydrolysis conditions (NaOH, meOH/H) were applied to ethyl 2- (4- (tert-butyl) phenyl) -4- (dimethylamino) -6-methylpyrimidine-5-carboxylate ₂ O, as described in example H) to give 2- (4- (tert-butyl) phenyl) -4- (dimethylamino) -6-methylpyrimidine-5-carbox-yl as a white solidAnd (3) acid. LCMS (methods 5-95AB, ESI): t _R ＝0.769min,[M+H] ⁺ ＝313.9。

Compound 424 (formate) was prepared as a white solid by using a method analogous to that described in example G from compound 101-K and 2- (4- (tert-butyl) phenyl) -4- (dimethylamino) -6-methylpyrimidine-5-carboxylic acid. LCMS (methods 5-95AB, ESI): t _R ＝0.690min,[M+H] ⁺ ＝933.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.50(brs,2H),8.23(d,J＝8.4Hz,2H),7.50(d,J＝8.4Hz,2H),7.25-7.07(m,3H),7.09(d,J＝8.4Hz,1H),6.90(d,J＝2.4Hz,1H),6.79(s,1H),6.43(s,1H),5.19-5.16(m,1H),4.86-4.77(m,2H),4.30-4.10(m,6H),3.40-3.32(m,1H),3.24(s,6H),3.23-3.13(m,7H),3.00(s,3H),2.44(s,3H),2.25-2.15(m,1H),2.15-2.05(m,1H),1.41(s,9H),1.37(d,J＝7.2Hz,3H)。

Example 225: synthesis of Compound 425

Compound 425 (formate) was prepared as a white solid from compound 101-K by using a similar method to that described in example 224. LCMS (methods 5-95AB, ESI): t _R ＝0.690min,[M+H] ⁺ ＝919.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.48(brs,2H),8.27(d,J＝8.4Hz,2H),7.52(d,J＝8.4Hz,2H),7.33(d,J＝8.0Hz,1H),7.19(d,J＝8.0Hz,1H),7.10(d,J＝8.4Hz,1H),6.91(d,J＝2.4Hz,1H),6.83(s,1H),6.45(s,1H),5.09-5.07(m,1H),4.85-4.75(m,2H),4.30-4.05(m,6H),3.30-3.05(m,11H),2.97(s,3H),2.43(s,3H),2.30-2.05(m,2H),1.37(brs,12H)。

Example 226: synthesis of Compound 426

Compound 226 (trifluoroacetate salt) was prepared from compound 101-K as a white solid using an analogous method to that described in example 224. LCMS (methods 5-95AB, ESI): t _R ＝0.660min,[M+H] ⁺ ＝905.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.20(d,J＝8.4Hz,2H),7.50(d,J＝8.4Hz,2H),7.33(d,J＝8.8Hz,1H),7.25-7.15(m,2H),7.09(d,J＝8.8Hz,1H),6.90(d,J＝2.4Hz,1H),6.81(s,1H),6.44(s,1H),5.15-5.10(m,1H),4.85-4.75(m,2H),4.30-4.10(m,6H),3.40-3.35(m,1H),3.25-3.05(m,7H),2.97(s,3H),2.45(s,3H),2.25-2.05(m,2H),1.41(s,9H),1.36(d,J＝7.2Hz,3H)。

Example 227: synthesis of Compound 427

Step 1: typical alkylation conditions were applied to 4-hydroxybenzonitrile (as described in example 21) to give 4- (3, 3-dimethylbutoxy) benzonitrile as a colorless oil. ¹ H NMR(400MHz,CDCl ₃ )δ7.55(d,J＝8.8Hz,2H),6.93(d,J＝8.8Hz,2H),4.06(t,J＝7.2Hz,2H),1.74(t,J＝7.2Hz,2H),0.99(s,3H)。

Compound 427 (formate) was prepared as a white solid from compound 101-K and 4- (3, 3-dimethylbutoxy) benzonitrile using a similar method to that described in examples 35, 221 and 226. LCMS (method 5-95AB, ESI): t _R ＝0.711min,[M+H] ⁺ ＝949.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.45(brs,1H),8.24-8.13(m,2H),7.35-7.29(m,1H),7.24-7.17(m,2H),7.10(d,J＝8.4Hz,1H),7.00-6.93(m,2H),6.89(s,1H),6.76(brs,1H),6.51(br s,1H),5.10-5.05(m,1H),4.86-4.78(m,2H),4.30-4.16(m,6H),4.12(t,J＝7.2Hz,2H),3.28-3.24(m,4H),3.17-3.00(m,4H),2.95(s,3H),2.45-2.37(m,3H),2.29-2.10(m,2H),1.75(t,J＝7.2Hz,2H),1.47-1.32(m,3H),1.03(s,9H)。

Example 228: synthesis of Compound 428

Step 1: a solution of ethyl 2- (4- (tert-butyl) phenyl) -4-chloro-6-methylpyrimidine-5-carboxylate (described in example 221, 500mg,1.5 mmol), naI (4.5 g, 30mmol) and TFA (856 mg,7.5 mmol) in 2-butanone (3 mL)The mixture was stirred at 60 ℃ for 2h. The volatiles were removed and the residue was taken up in EtOAc (50 mL), which was washed with brine (2x 50mL). The organic layer was MgSO ₄ Drying, concentration and chromatography of the residue on silica gel eluting with 20% etoac in petroleum ether afforded ethyl 2- (4- (tert-butyl) phenyl) -4-iodo-6-methylpyrimidine-5-carboxylate as a colourless oil (400mg, 63% yield). LCMS (methods 5-95AB, ESI): t _R ＝1.160min,[M+H] ⁺ ＝424.9。

Step 2: a mixture of ethyl 2- (4- (tert-butyl) phenyl) -4-iodo-6-methylpyrimidine-5-carboxylate (50mg, 0.12mmol), methyl 2, 2-difluoro-2- (fluorosulfonyl) acetate (57mg, 0.30mmol), and CuI (34mg, 0.18mmol) in DMF (2 mL) was stirred at 80 ℃ for 15h. The volatiles were removed and the residue was taken up in EtOAc (20 mL), which was washed with brine (2x 20mL). The organic layer was MgSO ₄ Dried, concentrated, and the residue purified by preparative TLC (20% EtOAc in petroleum ether) _f = 0.6) to give ethyl 2- (4- (tert-butyl) phenyl) -4-methyl-6- (trifluoromethyl) pyrimidine-5-carboxylate as a colourless oil (25mg, 58% yield). LCMS (methods 5-95AB, ESI): t _R ＝1.150min,[M+H] ⁺ ＝367.0。

And step 3: typical ester hydrolysis conditions (NaOH, meOH/H) were applied to ethyl 2- (4- (tert-butyl) phenyl) -4-methyl-6- (trifluoromethyl) pyrimidine-5-carboxylate ₂ O, described in example H) to give 2- (4- (tert-butyl) phenyl) -4-methyl-6- (trifluoromethyl) pyrimidine-5-carboxylic acid as a white solid. LCMS (method 5-95AB, ESI): t _R ＝1.020min,[M+H] ⁺ ＝339.0。

Compound 428 (formate salt) was prepared as a white solid by using a method analogous to that described in example G from compound 101-K and 2- (4- (tert-butyl) phenyl) -4-methyl-6- (trifluoromethyl) pyrimidine-5-carboxylic acid. LCMS (method 5-95AB, ESI): t _R ＝0.750min,[M+H] ⁺ ＝958.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.42(d,J＝8.4Hz,2H),7.58(d,J＝8.4Hz,2H),7.30-7.19(m,3H),7.10(d,J＝8.0Hz,1H),6.90(s,1H),6.79(s,1H),6.40(s,1H),5.26-5.23(m,1H),4.80-4.75(m,1H),4.35-4.10(m,7H),3.33-3.09(m,8H),3.00(s,3H),2.40-2.20(m,1H),2.20-2.05(m,1H),1.39(s,9H),1.35(d,J＝6.8Hz,3H)。

Example 229: synthesis of Compound 429

Step 1: a solution of ethyl 2-cyano-3, 3-bis (methylthio) acrylate (900mg, 4.1mmol) and (4-methoxyphenyl) methylamine (682mg, 5.0 mmol) in EtOH (16 mL) was stirred at 60 ℃ for 2h. After the mixture was cooled to 0 ℃, 4- (tert-butyl) benzamidine (725mg, 4.1mmol) and triethylamine (1.71ml, 12.3mmol) were added. The resulting mixture was stirred at 60 ℃ for 22h. The volatiles were removed under reduced pressure and the residue was taken up in EtOAc (40 mL) which was washed with brine (40 mL). The organic layer was washed with Na ₂ SO ₄ Dried and the residue was purified by preparative reverse phase HPLC to give ethyl (E) -3- ((Z) - (amino (4- (tert-butyl) phenyl) methylene) amino) -2-cyano-3- ((4-methoxybenzyl) amino) acrylate as a white solid (220mg, 17.5% yield).

Step 2: a solution of ethyl (E) -3- ((Z) - (amino (4- (tert-butyl) phenyl) methylene) amino) -2-cyano-3- ((4-methoxybenzyl) amino) acrylate (250mg, 0.58mmol) and p-TsOH (5.0 mg, 0.03mmol) in toluene (8 mL) was dissolved in N ₂ Stirred at 110 ℃ for 3 days. The volatiles were removed under reduced pressure and the residue was taken up in EtOAc (40 mL) which was washed with brine (40 mL). The organic layer was washed with Na ₂ SO ₄ The residue was dried and purified by preparative TLC (eluent: etOAc: petroleum ether =1, rf = 0.5) to give ethyl 4-amino-2- (4- (tert-butyl) phenyl) -6- ((4-methoxybenzyl) amino) pyrimidine-5-carboxylate as a white solid (130mg, 52% yield). LCMS (methods 5-95AB, ESI): t _R ＝0.809min,[M+H] ⁺ ＝435.1。

And step 3: ethyl 4-amino-2- (4- (tert-butyl) phenyl) -6- ((4-methoxybenzyl) amino) pyrimidine-5-carboxylate (120mg, 0.28mmol) and (NH) ₄ ) ₂ Ce(NO ₃ ) ₆ (454mg, 0.83mmol) in MeCN/H ₂ The solution in O (0.4 ml, v/v = 1/1) was stirred at 0 ℃ for 30min. The reaction was saturated with Na ₂ CO ₃ Washed (15 mL) and extracted with EtOAc (3x 15mL). The combined organic layers were concentrated and the residue was purified by preparative TLC (EtOAc: petroleum ether =1, 3) to give 4, 6-diamino-2- (4- (tert-butyl) phenyl) pyrimidine-5-carboxylic acid ethyl ester (15mg, 17% yield). And 4, step 4: typical ester hydrolysis conditions (NaOH, meOH/H) were applied to ethyl 4, 6-diamino-2- (4- (tert-butyl) phenyl) pyrimidine-5-carboxylate ₂ O, described in example H) to give 4, 6-diamino-2- (4- (tert-butyl) phenyl) pyrimidine-5-carboxylic acid as a white solid. LCMS (method 5-95AB, ESI): t _R ＝0.902min,[M+H] ⁺ ＝286.9。

Compound 429 (formate) was prepared as a white solid by using an analogous method to that described in example G from compound 101-K and 2- (4- (tert-butyl) phenyl) -4-methyl-6- (trifluoromethyl) pyrimidine-5-carboxylic acid. LCMS (methods 5-95AB, ESI): t _R ＝0.676min,[M+H] ⁺ ＝906.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.34(brs,1H),8.14(d,J＝8.8Hz,1H),8.07(d,J＝8.0Hz,1H),7.47(t,J＝8.8Hz,2H),7.34-7.28(m,2H),7.21-7.18(m,2H),7.11-7.06(m,2H),6.89-6.77(m,1H),6.51-6.48(m,1H),5.17-5.10(m,1H),4.80-4.72(m,2H),4.30-4.05(m,4H),4.17(s,2H),3.28-2.90(m,11H),2.26-2.18(m,1H),2.16-2.10(m,1H),1.42(s,9H),1.41(d,J＝6.8Hz,3H)。

Example 230: synthesis of Compound 430

Compound 430 (trifluoroacetate salt) was prepared as a white solid by using procedures analogous to those described in example 5 and example O. LCMS (method 5-95AB, ESI): t _R ＝0.791min,[M+H] ⁺ ＝803.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ7.86(d,J＝8.0Hz,2H),7.74(d,J＝8.0Hz,1H),7.67(d,J＝8.0Hz,1H),7.27(d,J＝8.0Hz,2H),7.16(d,J＝8.0Hz,1H),7.08-6.91(m,4H),6.91(s,1H),6.86(s,1H),6.47(s,1H),5.20-5.15(m,1H),4.68-4.57(m,2H),4.20(s,2H),3.17-3.05(m,4H),2.93(s,3H),2.68(s,3H),2.55(d,J＝6.8Hz,2H),2.33-2.24(m,1H),2.20-2.11(m,1H),1.96-1.87(m,1H),1.36(d,J＝6.4Hz,3H),0.94(d,J＝6.4Hz,6H)。

Example 231: synthesis of Compound 431

Compound 431 (formate) was prepared as a white solid by using a similar method to that described in example J and example O. LCMS (method 5-95AB, ESI): t _R ＝0.814min,[M+H] ⁺ ＝804.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.80(s,1H),8.50(br s,1H),8.23(d,J＝8.0Hz,2H),8.51(d,J＝8.0Hz,2H),7.20-7.02(m,3H),6.99(d,J＝8.0Hz,1H),6.93(s,1H),6.86(s,1H),6.75(s,1H),5.21-5.15(m,1H),4.83-4.77(m,1H),4.60-4.54(m,1H),4.27(s,2H),3.20-2.85(m,4H),2.96(s,3H),2.55(s,3H),2.32-2.19(m,2H),1.45(s,9H),1.39(d,J＝6.8Hz,3H)。

Example 232: synthesis of Compound 432

Compound 432 (trifluoroacetate salt) was prepared as a white solid by using a similar method as described in example O. LCMS (methods 5-95AB, ESI): t _R ＝0.833min,[M+H] ⁺ ＝818.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.80(s,1H),8.28(d,J＝7.6Hz,2H),7.31(d,J＝7.6Hz,2H),7.13(d,J＝7.6Hz,1H),7.05-6.90(m,3H),6.87-6.78(m,2H),6.53(s,1H),5.19-5.11(m,1H),4.70-4.50(m,2H),4.23(s,2H),3.20-3.09(m,2H),3.07-2.99(m,2H),2.95(s,3H),2.73-2.65(m,2H),2.62(s,3H),2.29-2.20(m,1H),2.18-2.12(m,1H),1.72-1.59(m,2H),1.39-1.29(m,7H),0.94(br s,3H)。

Example 233: synthesis of Compound 433

Compound 433 (formate) was prepared as a white solid by using a similar method to that described in example J and example O. LCMS (methods 5-95AB, ESI): t _R ＝0.731min,[M+H] ⁺ ＝918.8； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.79(s,1H),8.52(br s,2H),8.37(d,J＝8.8Hz,2H),7.55(d,J＝8.0Hz,2H),7.31-7.28(m,1H),7.20-7.17(m,2H),7.13(d,J＝8.8Hz,1H),7.02(d,J＝8.0Hz,1H),6.84(d,J＝3.2Hz,1H),6.73(s,1H),6.38(s,1H),5.19-5.16(m,1H),4.82-4.75(m,2H),4.26-4.02(m,4H),4.20(s,2H),3.40-3.30(m,1H),3.14-3.06(m,3H),2.99-2.93(m,4H),2.97(s,3H),2.69(s,3H),2.31-2.00(m,4H),1.38(s,9H),1.35(d,J＝7.2Hz,3H).

Example 234: synthesis of Compound 434

Compound 434 (formate) was prepared as a white solid by using a similar method to that described in example 53 and example O. LCMS (methods 5-95AB, ESI): t _R ＝0.602min,[M+H] ⁺ ＝932.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.51(br s,2H),8.27(d,J＝8.8Hz,2H),7.50(d,J＝8.8Hz,2H),7.26(d,J＝8.4Hz,1H),7.15(d,J＝8.8Hz,2H),7.02(d,J＝8.4Hz,1H),6.82(s,1H),6.63(s,1H),6.48(s,1H),5.27-5.23(m,1H),4.77-4.74(m,2H),4.28-4.04(m,4H),4.22(s,2H),3.12(t,J＝7.9Hz,2H),3.08-2.97(m,6H),3.03(s,3H),2.52(s,6H),2.32-2.24(m,1H),2.19-2.03(m,4H),1.38(s,9H),1.34(d,J＝6.8Hz,3H)。

Example 235: synthesis of Compound 435

Compound 435 (formate) was prepared as a white solid by using a similar method to that described in example 128 and example O. LCMS (methods 5-95AB, ESI): t _R ＝0.626min,[M+H] ⁺ ＝962.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.51(br s,2H),8.25(d,J＝8.4Hz,2H),7.28-7.24(m,1H),7.16(d,J＝8.4Hz,1H),7.10(br s,1H),7.03(d,J＝8.4Hz,1H),6.96(d,J＝8.4Hz,2H),6.82(s,1H),6.58(s,1H),6.53(s,1H),5.30-5.23(m,1H),4.81-4.75(m,2H),4.32-4.19(m,4H),4.08-4.04(m,4H),3.13(t,J＝7.6Hz,2H),3.11-2.92(m,6H),3.03(s,3H),2.47(s,6H),2.31-2.23(m,1H),2.19-2.16(m,1H),2.14-1.99(m,4H),1.87-1.78(m,2H),1.53-1.41(m,4H),1.34(d,J＝6.8Hz,3H),0.98(t,J＝7.2Hz,3H)。

Example 236: synthesis of Compound 436

Compound 436 (formate) was prepared as a white solid by using a similar method to that described in example 226 and example O. LCMS (methods 5-95AB, ESI): t _R ＝0.722min,[M+H] ⁺ ＝977.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.46(br s,1H),8.24(d,J＝8.8Hz,2H),7.32-7.29(m,1H),7.21(d,J＝8.4Hz,1H),7.12(d,J＝8.8Hz,1H),7.03(d,J＝8.4Hz,1H),6.98(d,J＝8.8Hz,2H),6.85(s,1H),6.76(s,1H),6.42(s,1H),5.12-5.05(m,1H),4.79-4.75(m,2H),4.29-4.03(m,8H),3.40-3.30(m,2H),3.15-2.85(m,6H),2.94(s,3H),2.44(s,3H),2.30-1.98(m,2H),1.75(t,J＝7.2Hz,2H),1.40-1.30(m,4H),1.02(s,9H)。

Example 237: synthesis of Compound 437

Compound 437 (formate) was prepared as a white solid by using a similar method to that described in example 53 and example O. LCMS (method 5-95AB, ESI): t _R ＝0.724min,[M+H] ⁺ ＝960.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.53(br s,2H),8.23(d,J＝8.0Hz,2H),7.47(d,J＝8.0Hz,2H),7.23(d,J＝8.0Hz,1H),7.13(d,J＝8.0Hz,1H),7.00-6.97(m,2H),6.79(d,J＝2.4Hz,1H),6.56(s,1H),6.51(s,1H),5.30-5.27(m,1H),4.79-4.74(m,2H),4.21(s,2H),4.19-4.00(m,4H),3.11(t,J＝8.0Hz,2H),3.02(s,3H),2.97-2.84(m,6H),2.47(s,6H),2.32-2.23(m,1H),2.18-2.09(m,1H),1.88-1.72(m,8H),1.39(s,9H),1.34(d,J＝7.2Hz,3H)。

Example 238: synthesis of Compound 438

Step 1: to a solution of tert-butyl (S) -2-hydroxy-1-methylethylcarbamate (3.9g, 22.3mmol) and triethylamine (5.6g, 55.6mmol) in DCM (30 mL) at 0 deg.C was added methanesulfonyl chloride (3.77g, 32.9mmol) dropwise. The resulting mixture was gradually warmed while stirring and stirred at 20 ℃ for 6h. The reaction was diluted with DCM (40 mL) and saturated NaHCO ₃ Aqueous and brine (40 mL each). The organic layer was washed with Na ₂ SO ₄ Drying, concentration, and the residue was purified on silica gel column, eluting with 0-20% etoac in petroleum ether, to give (S) -2- (tert-butoxycarbonylamino) propyl methanesulfonate as a white solid (3.0 g,53% yield).

Step 2: a solution of (S) -2- (tert-butoxycarbonylamino) propyl methanesulfonate (3.0 g,11.8 mmol) and LiBr (4.1g, 47.4 mmol) in acetone (10 mL) was stirred at 25 ℃ for 16h. The reaction was diluted with EtOAc (40 mL) and saturated NaHCO ₃ Aqueous solution and brine (40 mL each). The organic layer was washed with Na ₂ SO ₄ Drying, concentration, and purification of the residue on silica gel column, eluting with 0-20% etoac in petroleum ether, afforded N- (S) -2-bromo-1-methyl-ethylcarbamic acid tert-butyl ester as a white solid (1.8g, 64% yield).

Compound 438 (formate salt) was prepared as a white solid from tert-butyl N- (S) -2-bromo-1-methyl-ethylcarbamate using an analogous method to that described in example J and example O. LCMS (methods 5-95AB, ESI): t _R ＝0.733min,[M+H] ⁺ ＝918.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.72(s,1H),8.49(br s,3H),8.24(d,J＝8.4Hz,2H),7.52(d,J＝8.4Hz,2H),7.32(d,J＝8.4Hz,1H),7.24(d,J＝8.4Hz,1H),7.15-7.05(m,2H),6.84(s,1H),6.58(br s,2H),5.25-5.15(m,1H),4.80-4.65(m,2H),4.25-4.00(m,4H),4.20(s,2H),3.65-3.45(m,2H),3.20-3.00(m,4H),2.97(s,3H),2.65(s,3H),2.35-2.15(m,2H),1.39(s,9H),1.36(d,J＝7.2Hz,3H),1.34(d,J＝7.2Hz,3H),1.23(d,J＝6.4Hz,3H)。

Example 239: synthesis of Compound 439

Step 1: a mixture of compound 101-E (300mg, 0.53mmol), 2- (bromomethyl) oxirane (732mg, 5.3mmol) and K ₂ CO ₃ A mixture of (738mg, 5.3mmol) in DMF (10 mL) was stirred at 50 ℃ for 4h. The reaction was taken up in EtOAc (100 mL) and washed with brine (3X 100mL). The organic layer was washed with Na ₂ SO ₄ Drying, concentration and purification of the residue by preparative reverse phase HPLC (water (0.225% formic acid) -acetonitrile) gave compound 439-1 (200mg, 56% yield) as a white solid. LCMS (method 5-95AB, ESI): t _R ＝0.868min,[M+H] ⁺ ＝674.3。

And 2, step: compound 439-1 (300mg, 0.45mmol), sodium azide (675mg, 10.3mmol) and CeCl ₃ A solution of (56mg, 0.22mmol) in acetonitrile (9 mL) was stirred at 75 ℃ for 12h. The reaction mixture was taken up in EtOAc (50 mL) which was saturated Na ₂ CO ₃ Aqueous (30 mL) wash. The organic layer is coated with Na ₂ SO ₄ Dry, concentrate, and purify the residue by preparative TLC (eluting with 10% meoh in DCM, rf = 0.4) to give compound 439-2 as a white solid (175mg, 48% yield). LCMS (methods 5-95AB, ESI): t _R ＝0.883min,[M+H] ⁺ ＝760.2。

And 3, step 3: a mixture of 439-2 (175mg, 0.23mmol) and PPh ₃ (104mg, 0.39mmol) in THF/H ₂ The solution in O (11ml, v/v = 10/1) was stirred at 50 ℃ for 12h. The reaction mixture was taken up in EtOAc (50 mL) which was saturated Na ₂ CO ₃ Aqueous (30 mL) wash. The organic layer was washed with Na ₂ SO ₄ Dry, concentrate, and purify the residue by preparative TLC (eluting with 10% meoh in DCM, rf = 0.5) to give compound 439-3 as a white solid (165mg, 99% yield). LCMS (methods 5-95AB, ESI): t _R ＝0.694min,[M+H] ⁺ ＝708.3。

And 4, step 4: mixing 439-3 (165mg, 0.23mmol) and Boc ₂ A solution of O (109mg, 0.50mmol) and triethylamine (60mg, 0.59mmol) in DCM (5 mL) was stirred at 20 deg.C for 12h. The volatiles were removed under reduced pressure and the residue was taken up in EtOAc (30 mL), which was washed with brine (2x 30mL). The organic layer was washed with Na ₂ SO ₄ Dry, concentrate, and then purify the residue by preparative TLC (eluting with 10% meoh in DCM, rf = 0.3) to give compound 439-4 as a white solid (150mg, 70% yield). LCMS (methods 5-95AB, ESI): t _R ＝0.908min,[M+Na] ⁺ ＝930.5。

Compound 439 (formate) was prepared from compound 439-4 as a white solid by using a similar method to that described in example 53. LCMS (methods 5-95AB, ESI): t _R ＝0.720min,[M+H] ⁺ ＝964.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.53(br s,2H),8.20(d,J＝8.0Hz,2H),7.47(d,J＝8.0Hz,2H),7.28-7.20(m,2H),7.02(d,J＝8.0Hz,2H),6.80(s,1H),6.61(s,1H),6.49(s,1H),5.36-5.20(m,1H),4.82-4.60(m,2H),4.30-3.90(m,6H),4.20(s,2H),3.20-2.60(m,11H),2.46(s,6H),2.35-2.23(m,1H),2.18-2.10(m,1H),1.39(s,9H),1.34(d,J＝6.8Hz,3H)。

Example 240: synthesis of Compound 440

Step 1: mixing compound 101-E (300mg, 0.53mmol), 3-bromo-2- (bromoethyl) -1-propene (0.31mL, 2.7 mmol) and K ₂ CO ₃ A mixture of (369mg, 2.7 mmol) in DMF (5 mL) was stirred at 25 ℃ for 3h. The reaction was taken up in EtOAc (30 mL) and washed with brine (2X 30mL). The organic layer is coated with Na ₂ SO ₄ Dry, concentrate, and purify the residue by preparative TLC (eluting with 2% meoh in DCM, rf = 0.3) to give compound 440-1 as a white solid (300mg, 92% yield). LCMS (methods 5-95AB, ESI): t _R ＝0.906min,[M+H] ⁺ ＝614.1。

Step 2: a solution of compound 440-1 (150mg, 0.24mmol) and m-CPBA (422mg, 2.4mmol) in DCM (20 mL) was stirred at 0 ℃ for 30min, then warmed while stirringTo 20 ℃ and stirred at the same temperature for 12h. The mixture was washed with saturated NaHCO ₃ Aqueous and brine (30 mL each). The organic layer was washed with Na ₂ SO ₄ Dry, concentrate, and purify the residue by preparative TLC (eluting with 3% meoh in DCM, rf = 0.3) to give compound 440-2 as a yellow solid (120mg, 78% yield). LCMS (methods 5-95AB, ESI): t _R ＝0.759min,[M+Na] ⁺ ＝652.1。

Compound 440 (trifluoroacetate salt) was prepared from compound 440-2 as a white solid by using a method analogous to that described in example 239. LCMS (method 5-95AB, ESI): t _R ＝0.751min,[M+H] ⁺ ＝903.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.32-8.20(m,2H),7.53-7.48(m,2H),7.45-7.10(m,4H),7.08(br s,1H),6.66(br s,1H),6.61(br s,1H),5.31-5.28(m,1H),4.85-4.75(m,2H),4.65-4.55(m,2H),4.49-4.45(m,3H),4.31-4.24(m,3H),3.15(t,J＝6.8Hz,2H),3.06-2.89(m,2H),2.99(s,3H),2.51(br s,6H),2.30-2.15(m,2H),1.40(s,9H),1.37(d,J＝6.8Hz,3H)。

Example 241: synthesis of Compound 441

Step 1: a solution of compound 101-F (200mg, 0.24mmol) in HFIP (5 mL) containing 5% TFA was stirred at 20 ℃ for 1h. The volatiles were removed under reduced pressure and the residue was added to 4-nitrophenyl (2- (trimethylsilyl) ethyl) carbonate (230mg, 0.81mmol) and Et ₃ A solution of N (352mg, 3.5 mmol) in DCM (20 mL). The resulting mixture was stirred at 20 ℃ for 16h. The reaction was quenched with water (30 mL) and the organic layer was washed with brine (30 mL) and Na ₂ SO ₄ Dry, concentrate, and purify the residue by preparative TLC (eluting with 10% meoh in DCM, rf = 0.3) to give compound 441-1 as a yellow solid (200mg, 92% yield). LCMS (methods 5-95AB, ESI): t _R ＝1.097min,[M+Na] ⁺ ＝958.5。

Step 2: compound 441-2 was synthesized from compound 44 by using a method similar to that described in example 53 1-1 was prepared as a white solid. LCMS (methods 5-95AB, ESI): t _R ＝1.204min,[M+H] ⁺ ＝1294.0。

And step 3: a solution of compound 441-2 (50mg, 0.04mmol) and tetrabutylammonium fluoride (69mg, 0.31mmol) in DMF (3 mL) was stirred at 50 ℃ for 1.5h. The reaction was diluted with EtOAc (50 mL), which was washed with brine (2x 50mL). The organic layer was washed with Na ₂ SO ₄ Drying and evaporation in vacuo gave compound 441-3 (38mg, 0.038mmol,98% yield) as a white solid, which was used directly in the next step. LCMS (methods 5-95AB, ESI): t _R ＝0.814min,[M+H] ⁺ ＝1004.7。

And 4, step 4: compounds 441-3 (38mg, 0.040mmol), N-methylpyrazole-1-carboxamidine (19mg, 0.15mmol) and Et ₃ A solution of N (57mg, 0.57mmol) in DCM (2 mL) was stirred at 20 ℃ for 2 days. The reaction was quenched with water (10 mL), which was extracted with EtOAc (3x 15mL). The combined organic layers were washed with brine (50 mL) and Na ₂ SO ₄ Dry, concentrate, and purify the residue by preparative TLC (eluting with 10% meoh in DCM, rf = 0.1) to give compound 441-4 as a white solid (20mg, 45% yield). LCMS (method 5-95AB, ESI): t _R ＝0.699min,[M+H] ⁺ ＝1116.6。

And 5: typical Boc removal conditions (TFA/HFIP, described in example G) were applied to compound 441-4 to give compound 440 (formate salt) as a white solid. LCMS (methods 5-95AB, ESI): t _R ＝0.723min,[M+H] ⁺ ＝1016.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.50(br s,1H),8.34(d,J＝8.4Hz,2H),7.55(d,J＝8.4Hz,2H),7.37-7.00(m,4H),6.89(s,1H),6.77(s,1H),6.43(s,1H),5.23-5.19(m,1H),4.85-4.76(m,2H),4.25-4.00(m,4H),4.21(s,2H),3.73-3.42(m,4H),3.27-2.95(m,7H),2.67(s,3H),2.62(s,6H),2.60(s,3H),2.34-2.10(m,2H),1.38(s,9H),1.31(d,J＝7.2Hz,3H)。

Example 242: synthesis of Compound 442

Step 1: compound 442-1 was prepared as a white solid using compound 101-G and using a method analogous to that described in example J. LCMS (methods 5-95AB, ESI): t _R ＝0.865min,[M+H] ⁺ ＝1113.9。

Step 2: compounds 442-1 (200mg, 0.17mmol) and (HCHO) _n (104mg, 3.45mmol), triethylamine (72. Mu.L, 0.52 mmol), acetic acid (60. Mu.L, 1.04 mmol) and NaBH ₃ CN (217mg, 3.45mmol) in MeOH/H ₂ The mixture in O (5.5ml, v/v = 10/1) was stirred at 15 ℃ for 32h. The volatiles were removed under reduced pressure and the residue was purified by preparative reverse phase HPLC (acetonitrile 20-50%/0.225% aqueous formic acid) to give compound 442-2 as a white solid (60mg, 30% yield). LCMS (methods 5-95AB, ESI): t _R ＝0.863min,[M+H] ⁺ ＝1168.8。

And 3, step 3: a solution of compound 442-2 (50mg, 0.04mmol) and quinuclidine (24mg, 0.21mmol) in DCM (5 mL) was stirred at 20 ℃ for 48h. The volatiles were removed under reduced pressure and the residue was purified by reverse phase HPLC (acetonitrile 0-40%/0.225% aqueous formic acid) to give compound 442 (formate salt) (9.5mg, 0.01mmol,23% yield) as a white solid. LCMS (methods 5-95AB, ESI): t _R ＝0.725min,[M+H] ⁺ ＝946.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.76(s,1H),8.52(br s.,1H),8.33(d,J＝8.4Hz,2H),7.53(d,J＝8.4Hz,2H),7.30-7.24(m,1H),7.18-7.08(m,2H),6.99(d,J＝8.4Hz,1H),6.80(d,J＝2.4Hz,1H),6.69(s,1H),6.41(s,1H),5.21-5.14(m,1H),4.82-4.72(m,2H),4.30-4.08(m,4H),4.22(s,2H),3.21-3.02(m,4H),2.91(s,3H),2.89-2.81(m,4H),2.66(s,3H),2.37(s,6H),2.27(s,6H),1.38(s,9H),1.34(d,J＝6.4Hz,3H)。

Example 243: synthesis of Compound 443

Step 1: to Cbz-Asp-OMeTypical amide coupling (HATU/DIEA) and ester hydrolysis (LiOH, THF/H) as described in examples E and G ₂ O) conditions to obtain N as a white solid ² - ((benzyloxy) carbonyl) -N ⁴ -methyl-L-asparagine. LCMS (method 5-95AB, ESI): t _R ＝0.567,[M+H] ⁺ ＝281.1

Compound 443 (trifluoroacetate salt) was prepared from compounds 101-G and N by using a similar procedure as described in example G ² - ((benzyloxy) carbonyl) -N ⁴ -methyl-L-asparagine was prepared as a white solid. LCMS (methods 5-95AB, ESI): t _R ＝0.815min,[M+H] ⁺ ＝896.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ7.25-7.01(m,7H),6.87(s,1H),6.80(s,1H),6.28(s,1H),4.95-4.75(m,3H),4.35-4.20(m,4H),4.18(s,2H),3.30-3.00(m,8H),2.79(d,J＝8.0Hz,3H),2.69(s,3H),2.62-2.59(m,2H),2.41(s,3H),1.60(br s,2H),1.45-1.29(m,13H),0.87(t,J＝6.8Hz,3H)。

Example 244: synthesis of Compound 444

Compound 444 (formate) was prepared from compounds 101-G as a white solid by using a similar method to that described in example 243. LCMS (methods 5-95AB, ESI): t _R ＝0.815min,[M+H] ⁺ ＝896.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.54(br s,1H),7.31-7.29(m,2H),7.22(d,J＝8.0Hz,1H),7.14(d,J＝8.0Hz,1H),7.08-7.04(m,3H),6.87(d,J＝2.4Hz,1H),6.72(s,1H),6.48(s,1H),5.08-5.04(m,1H),4.79-4.76(m,2H),4.19-4.12(m,6H),3.31-3.30(m,1H),3.15-3.06(m,4H),3.05(s,3H),3.01(s,3H),2.92(s,3H),2.65-2.51(m,3H),2.37(s,3H),2.24-2.17(m,1H),2.03-1.98(m,1H),1.60-1.58(m,2H),1.35-1.29(m,15H),0.89(t,J＝6.8Hz,3H)。

Example 245: synthesis of Compound 445

Compound 445 (formic acid)Salt) was prepared from compounds 101-G as a white solid using a method analogous to that described in example 243. LCMS (method 5-95AB, ESI): t _R ＝0.814min,[M+H] ⁺ ＝924.7； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.51(br s,1H),7.37(d,J＝8.0Hz,1H),7.31(d,J＝8.4Hz,1H),7.24(d,J＝8.0Hz,1H),7.16(d,J＝8.4Hz,1H),7.11-7.05(m,3H),6.89(s,1H),6.81(s,1H),6.44(s,1H),5.00-4.75(m,3H),4.25-4.15(m,4H),4.20(s,2H),3.21-3.18(m,6H),2.99(s,3H),2.61(t,J＝7.6Hz,2H),2.41-2.35(m,1H),2.04-1.92(m,1H),1.61(br s,2H),1.39-1.25(m,14H),1.09(t,J＝7.2Hz,3H),0.90(t,J＝6.8Hz,3H)。

Example 246: synthesis of Compound 446

Compound 446 (formate salt) was prepared as a white solid from compound 101-G by using a method analogous to that described in example 243. LCMS (methods 5-95AB, ESI): t _R ＝0.696min,[M+H] ⁺ ＝940.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.48(br s,2H),7.38(d,J＝7.5Hz,1H),7.31(d,J＝8.0Hz,1H),7.24(d,J＝7.5Hz,1H),7.15(d,J＝8.0Hz,1H),7.05-7.11(m,3H),6.89(br s,1H),6.81(br s,1H),6.40(s,1H),5.01-4.97(m,1H),4.80-4.75(m,2H),4.26-4.16(m,6H),3.57(t,J＝6.4Hz,2H),3.21-3.14(m,4H),2.98(s,3H),2.60(t,J＝6.4Hz,2H),2.45-2.37(s,5H),2.29-2.19(m,2H),2.05-1.93(m,2H),1.63-1.57(m,2H),1.44-1.22(m,15H),0.92-0.85(m,3H)。

Example 247: synthesis of Compound 447

Compound 447 (trifluoroacetate salt) was prepared from compounds 101-G as a white solid by using a similar method to that described in example 243. LCMS (method 5-95AB, ESI): t _R ＝0.782min,[M+Na] ⁺ ＝974.7； ¹ H NMR(400MHz,MeOH-d ₄ )δ7.30-7.24(m,2H),7.19(d,J＝8.0Hz,1H),7.10(d,J＝8.0Hz,1H),7.03-7.01(m,3H),6.82(s,1H),6.67(br s,1H),6.50(br s,1H),5.07-5.03(m,1H),4.78-4.73(m,2H),4.34-4.29(m,1H),4.23-4.19(m,3H),4.12-4.07(m,4H),4.00-3.95(m,1H),3.62-3.53(m,2H),3.13-3.06(m,1H),2.98-2.82(m,7H),2.53-2.51(m,3H),2.35(br s,3H),2.28-2.24(m,1H),2.15-2.00(m,1H),1.63-1.48(m,2H),1.34-1.23(m,15H),0.90(t,J＝6.4Hz,3H)。

Example 248: synthesis of Compound 448

Compound 448 (trifluoroacetate salt) was prepared from compounds 101-G as white solids by using a method analogous to that described in example 243. LCMS (methods 5-95AB, ESI): t _R ＝0.794min,[M+H] ⁺ ＝971.2； ¹ H NMR(400MHz,MeOH-d ₄ )δ7.33(d,J＝8.0Hz,1H),7.26(d,J＝8.0Hz,1H),7.20(d,J＝8.0Hz,1H),7.11(d,J＝8.0Hz,1H),7.04-7.02(m,3H),6.84-6.83(m,1H),6.69(s,1H),6.48(s,1H),5.04-5.01(m,1H),4.77-4.75(m,2H),4.19(s,2H),4.12-3.90(m,5H),3.63-3.59(m,3H),3.25-3.27(m,1H)3.14-3.07(m,1H),2.98-2.89(m,6H),2.55-2.41(m,4H),2.36(br s,3H),2.26-2.17(m,1H),2.03-2.02(m,1H),1.64-1.53(m,2H),1.36-1.29(m,15H),0.90(t,J＝6.8Hz,3H)。

Example 249: synthesis of Compound 449

Step 1: typical amide coupling conditions (HATU/DIEA, described in example E) were applied to compound 101-G (500mg, 0.70mmol) and (S) -4- ((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -2- (((benzyloxy) carbonyl) amino) butyric acid (332mg, 0.70mmol) to give compound 449-1 as a white solid (400mg, 49% yield). LCMS (method 5-95AB, ESI): t _R ＝1.039min,[M+H] ⁺ ＝1170.4。

And 2, step: a solution of compound 449-1 (150mg, 0.13mmol) and quinuclidine (43mg, 0.38mmol) in DCM (8 mL) was stirred at 25 ℃ for 24h. The volatiles were concentrated and the residue was purified by preparative TLC (eluting with 10% methanol in DCM, rf = 0.2) to give compound 449-2 as a white solid (90mg, 74.1% yield).

And 3, step 3: sulfuryl isocyanate chloride (sulfurocynato chloride) (1.41mL, 15.0 mmol) was added dropwise over 10min to a stirred solution of t-BuOH (1.86mL, 19.5 mmol) in DCM (12 mL) at 0 ℃. The reaction mixture was gradually warmed to 25 ℃ while stirring and stirred at the same temperature for 0.5h. The solvent was concentrated in vacuo to one third volume and the flask was placed back in the 0 ℃ bath where the product began to precipitate out of solution. After filtration, the product was washed with hexane and dried in an oven to give tert-butyl (chlorosulfonyl) carbamate as a colorless solid (1.8g, 55.6% yield). ¹ H NMR(400MHz,CDCl ₃ )δ8.45(br s,1H),1.56(s,9H)。

And 4, step 4: compound 449-2 (90mg, 0.09mmol), (chlorosulfonyl) carbamic acid tert-butyl ester (82mg, 0.38mmol) and Et ₃ A solution of N (53. Mu.L, 0.38 mmol) in DCM (5 mL) was stirred at 25 ℃ for 16hr. The volatiles were removed under reduced pressure and the residue was purified by preparative TLC (eluting with 5% methanol in DCM, rf = 0.5) to give compound 449-3 as a white solid (70mg, 65.4% yield). LCMS (methods 5-95AB, ESI): t _R ＝0.947min,[M-Boc+H] ⁺ ＝1027.1。

Compound 449 (formate) was prepared from compound 449-3 as a white solid by an analogous method to that described in example G. LCMS (method 5-95AB, ESI): t _R ＝0.710min,[M+H] ⁺ ＝948.1； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.49(br s,3H),7.36(d,J＝7.2Hz,1H),7.36-7.28(m,1H),7.28-7.20(m,1H),7.16(d,J＝8.8Hz,1H),7.12-7.02(m,3H),6.89(d,J＝2.4Hz,1H),6.80(d,J＝2.4Hz,1H),6.43(s,1H),5.14-5.07(m,1H),4.79-4.73(m,2H),4.29-4.11(m,6H),3.38-3.32(m,2H),3.26-3.08(m,6H),2.99(s,3H),2.64-2.55(m,2H),2.41(s,3H),2.22-2.10(m,2H),2.04-1.90(m,2H),1.65-1.56(m,2H),1.45-1.22(m,11H),0.90(t,J＝6.8Hz,3H)。

Example 250: synthesis of Compound 450

Step 1: (S) -5-amino-2- (((benzyloxy) carbonyl) amino) pentanoic acid (500mg, 1.88mmol), fmocosu (950mg, 2.82mmol) and Et ₃ A solution of N (0.52mL, 3.76mmol) in DCM/MeOH (20mL, v/v = 1/1) was stirred at 25 ℃ for 18h. Thereafter, the reaction mixture was washed with 1N KHSO ₄ The solution and brine (20 mL each) were washed, and the organic layer was washed with Na ₂ SO ₄ Dried, concentrated in vacuo, and the residue purified by silica gel chromatography, eluting with 5% meoh in DCM, to give (S) -5- ((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -2- (((benzyloxy) carbonyl) amino) pentanoic acid as a white solid (700mg, 76.3% yield). LCMS (methods 5-95AB, ESI): t _R ＝0.891min,[M+H] ⁺ ＝489.3。

Compound 450 (formate) was prepared as a white solid from compound 101-G and (S) -5- ((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -2- (((benzyloxy) carbonyl) amino) pentanoic acid using an analogous method to that described in example P. LCMS (methods 5-95AB, ESI): t _R ＝0.705min,[M+H] ⁺ ＝925.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.51(br s,2H),7.35-7.29(m,2H),7.28-7.20(m,2H),7.16(d,J＝8.4Hz,1H),7.11-7.04(m,3H),6.88(d,J＝2.2Hz,1H),6.80(d,J＝2.2Hz,1H),6.44(s,1H),4.79-4.73(m,3H),4.25-4.13(m,6H),3.26-3.08(m,8H),2.97(s,3H),2.60(t,J＝7.5Hz,2H),2.40(s,3H),1.98-1.88(m,2H),1.83-1.67(m,4H),1.63-1.58(m,2H),1.37-1.24(m,11H),0.90(t,J＝6.8Hz,3H)。

Example 251: synthesis of Compound 451

Compound 451 (formate) was prepared as a white solid from compounds 101-G by using an analogous method to that described in example P. LCMS (method 5-95AB, ESI): t _R ＝0.776min,[M+H] ⁺ ＝947.8； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.78(s,1H),8.50(br s,2H),8.22(d,J＝8.0Hz,2H),7.37-7.26(m,3H),7.20(d,J＝8.0Hz,1H),7.15-7.02(m,2H),6.85(s,1H),6.62(br s,2H),5.05-5.03(m,1H),4.77-4.73(m,2H),4.36-4.15(m,4H),4.29(s,2H),3.37-3.35(m,1H),3.30-3.05(m,7H),2.99(s,3H),2.70(t,J＝7.2Hz,2H),2.67(s,3H),2.16-2.10(m,1H),1.97-1.92(m,1H),1.75-1.60(m,3H),1.47-1.32(m,7H),0.93(t,J＝6.8Hz,3H)。

Example 252: synthesis of Compound 452

Compound 452 (formate) was prepared as a white solid from compound 101-G by using an analogous method to that described in example P. LCMS (method 5-95AB, ESI): t _R ＝0.750min,[M+H] ⁺ ＝933.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.78(s,1H),8.50(br s,2H),8.26(d,J＝8.0Hz,2H),7.52(d,J＝8.0Hz,2H),7.31(d,J＝8.0Hz,1H),7.21(d,J＝8.0Hz,1H),7.13-7.00(m,2H),6.85(s,1H),6.60(br s,2H),5.04-5.01(m,1H),4.77-4.73(m,2H),4.34-4.18(m,4H),4.22(s,2H),3.37-3.35(m,1H),3.27-3.05(m,7H),2.99(s,3H),2.67(s,3H),2.16-2.10(m,1H),1.97-1.94(m,1H),1.39(s,9H),1.35(d,J＝6.8Hz,3H)。

Example 253: synthesis of Compound 453

Compound 453 (formate) was prepared as a white solid from compound 101-G by using a similar method to that described in example 53 and example Q. LCMS (method 5-95AB, ESI): t _R ＝0.627min,[M+H] ⁺ ＝854.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.45(br s,5H),7.39(d,J＝8.0Hz,1H),7.32(d,J＝8.0Hz,1H),7.23(d,J＝8.0Hz,1H),7.17(d,J＝8.0Hz,1H),7.11-7.09(m,3H),6.89(s,1H),6.81(s,1H),6.26(s,1H),5.31-5.29(m,1H),4.80-4.76(m,2H),4.25-4.20(m,4H),4.19(s,2H),3.61-3.47(m,2H),3.25-3.17(m,6H),2.88(s,3H),2.75(s,3H),2.64-2.60(m,2H),2.42(s,3H),1.64-1.60(m,2H),1.34-1.29(m,11H),0.90(t,J＝7.0Hz,3H)。

Example 254: synthesis of Compound 454

Step 1: compound 454-1 was obtained as a white solid by a typical amide coupling (HATU/DIEA, described in example E) with compound 101G and N- (((9H-fluoren-9-yl) methoxy) carbonyl) -S-trityl-L-cysteine followed by Fmoc removal (using piperidine). LCMS (methods 5-95AB, ESI): t _R ＝0.793min,[M+H] ⁺ ＝1059.6

Compound 454 (formate) was prepared from compound 454-1 as a white solid by using an analogous method to that described in example G. LCMS (methods 5-95AB, ESI): t _R ＝0.805min,[M+H] ⁺ ＝857.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.49(br s,1H),7.45-7.00(m,7H),6.89(s,2H),6.81(s,1H),6.37(s,1H),5.15-5.05(m,1H),4.75-4.70(m,2H),4.30-4.05(m,6H),3.25-2.90(m,9H),2.82-2.70(m,2H),2.61(t,J＝6.4Hz,2H),2.41(s,3H),1.70-1.55(m,2H),1.40-1.20(m,11H),0.89(t,J＝6.8Hz,3H)。

Example 255: synthesis of Compound 455

To a solution of methyl (S) -2- (((benzyloxy) carbonyl) amino) -4-hydroxybutyrate (400mg, 1.16mmol) in DMF (5 mL) was added NaCN (62mg, 1.27mmol) at room temperature and the reaction mixture was allowed to warm to 75 ℃ while stirring and stirred at the same temperature for 2h. The volatiles were removed and the residue was taken up in EtOAc (40 mL) which was washed with brine (40 mL). The organic layer was washed with Na ₂ SO ₄ Dried, concentrated, and the residue was purified by preparative TLC to give methyl (S) -2- (((benzyloxy) carbonyl) amino) -4-cyanobutyrate as a colorless oil (210mg, 65.6% yield). LCMS (method 5-95AB, ESI): t _R ＝0.779,M+Na ⁺ ＝298.9。

Compound 455-diastereoisomeric mixture (formate) was prepared using the method described previously. LCMS (method 5-95AB, ESI): t _R ＝0.814,[M+H] ⁺ ＝830.4。

Compound 455 (formate) was isolated as a single unknown stereoisomer. LCMS (method 5-95AB, ESI): t _R ＝0.696min,[M+H] ⁺ ＝830.3； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.45(br s,1H),7.32-7.11(m,4H),6.91(s,1H),6.83(s,1H),6.27(s,1H),5.13-4.78(m,3H),4.27-4.20(m,4H),4.21(s,2H),3.23-3.19(m,4H),2.92(s,3H),2.70-2.53(m,3H),2.34-1.99(m,4H),1.70-1.64(m,2H),1.40-1.31(m,23H),0.90(t,J＝6.8Hz,3H)。

Example 256: synthesis of Compound 456

Compound 456 (trifluoroacetate salt) was prepared from compounds 101-G as white solids by using procedures analogous to those described in example G. LCMS (methods 5-95AB, ESI): t _R ＝0.760min,[M+H] ⁺ ＝854.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ7.40(d,J＝7.2Hz,1H),7.29-7.08(m,5H),6.90-6.80(m,3H),6.29(s,1H),4.85-4.76(m,3H),4.30-4.20(m,4H),4.18(s,2H),3.31-3.05(m,8H),2.92(s,3H),2.60(d,J＝7.6Hz,2H),2.42(s,3H),2.20-2.00(m,2H),1.60(t,J＝6.4Hz,2H),1.34-1.29(m,11H),0.89(t,J＝7.6Hz,3H)。

Example 257: synthesis of Compound 457

Compound 457 (formate) is prepared from compound 101-L as a white solid by using an analogous method to that described in example G. LCMS (methods 5-95AB, ESI): t _R ＝0.601min,[M+H] ⁺ ＝876.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.86(s,1H),8.45(br s,2H),8.37(d,J＝8.0Hz,2H),7.56(d,J＝8.0Hz,2H),7.33(d,J＝7.6Hz,1H),7.24-7.18(m,2H),7.09(d,J＝7.6Hz,1H),6.91(s,1H),6.79(s,1H),6.33(s,1H),5.35-5.34(m,1H),4.90-4.81(m,2H),4.28-4.20(m,6H),3.52-3.48(m,2H),3.48-3.31(m,7H),3.30-3.24(m,2H),2.91(s,3H),2.75(s,3H),1.39(s,9H),1.37(d,J＝6.8Hz,3H)。

Example 258: synthesis of Compound 458

Compound 458 (formate) was prepared as a white solid from compounds 101-G by using a similar method as described in example R. LCMS (methods 5-95AB, ESI): t _R ＝0.765min,[M+H] ⁺ ＝891.3； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.72(s,1H),8.53(br s,1H),8.18(d,J＝7.6Hz,2H),7.33-7.18(m,4H),7.05(d,J＝7.6Hz,2H),6.83(s,1H),6.74(s,1H),6.51(s,1H),5.23-5.18(m,1H),4.82-4.73(m,2H),4.35-4.18(m,6H),3.76(t,J＝5.2Hz,2H),3.25-3.00(m,6H),3.03(s,3H),2.63(s,3H),2.57(d,J＝6.8Hz,2H),2.22-2.10(m,1H),2.02-1.89(m,2H),1.35(d,J＝7.2Hz,3H),0.96(d,J＝5.6Hz,6H)。

Example 259: synthesis of Compound 459

Compound 459 (formate) was prepared as a white solid from compounds 101-G using an analogous method to that described in example R. LCMS (method 5-95AB, ESI): t _R ＝0.747min,[M+H] ⁺ ＝891.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.71(s,1H),8.53(br s,2H),8.21(d,J＝8.0Hz,2H),7.49(d,J＝8.0Hz,2H),7.31(d,J＝8.0Hz,1H),7.22(d,J＝8.0Hz,1H),7.05(d,J＝8.0Hz,2H),6.83(s,1H),6.73(s,1H),6.54(s,1H),5.21-5.15(m,1H),4.83-4.80(m,1H),4.74-4.69(m,1H),4.39-4.15(m,4H),4.22(s,2H),3.76(t,J＝5.6Hz,2H),3.35-2.90(m,6H),3.03(s,3H),2.64(s,3H),2.16-2.10(m,1H),2.06-1.90(m,1H),1.39(s,9H),1.37(d,J＝6.4Hz,3H)。

Example 260: synthesis of Compound 460

Step 1: starting from compound 460-1 (described in example 259), TBS deprotection, DMP oxidation and reductive amination were applied to give compound 460-2 as a white solid. LCMS (method 5-95AB, ESI): t _R ＝0.872min,[M+H] ⁺ ＝1096.6。

Compound 460 (formate) was prepared from compound 460-2 as a white solid by using a similar method to that described in example G. LCMS (method 5-95AB, ESI): t _R ＝0.633min,[M+H] ⁺ ＝920.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.69(s,1H),8.50(brs,3H),8.18(d,J＝7.6Hz,2H),7.50(d,J＝8.4Hz,2H),7.31-7.23(m,2H),7.04(brs,2H),6.81(s,1H),6.75(s,1H),6.46(s,1H),5.18-5.15(m,1H),4.85-4.75(m,2H),4.73-4.67(m,1H),4.40-4.15(m,3H),4.25(s,3H),3.54-3.48(m,1H),3.32-3.23(m,3H),3.13-2.90(m,4H),3.05(s,3H),2.63(s,3H),2.22-2.18(m,1H),2.01-1.97(m,1H),1.39(s,9H),1.36(d,J＝6.0Hz,3H)。

Example 261: synthesis of Compound 461

Step 1: a solution of 1- (tert-butyl) 2-methyl (2S, 4R) -4- (tosyloxy) pyrrolidine-1, 2-dicarboxylate (1.0g, 2.5mmol) and sodium cyanide (320mg, 6.53mmol) in DMSO (10 mL) was stirred at 80 ℃ for 5h. The reaction was diluted with EtOAc (120 mL) and washed with brine (60mL x 3). The organic layer was washed with Na ₂ SO ₄ Drying, concentration, and purification of the residue by chromatography on silica gel eluting with 10% EtOAc in petroleum ether afforded 1- (tert-butyl) 2-methyl (2S, 4S) -4-cyanopyrrolidine-1, 2-dicarboxylate (300mg, 47% yield) as a white solid.

Step 2: starting from 1- (tert-butyl) 2-methyl (2S, 4S) -4-cyanopyrrolidine-1, 2-dicarboxylate, typical Boc removal, cbz protection, ester hydrolysis and amide coupling with 101G (using and carrying out)Analogous procedure as described in examples 4 and 7) to give compound 461-1 as a white solid. LCMS (method 5-95AB, ESI): t _R ＝0.925min,[M+H-Boc] ⁺ ＝870.5。

And step 3: to a solution of compound 461-1 (155mg, 0.116mmol) and nickel (66.6mg, 1.13mmol) in THF (20 mL) was added a drop of ammonia and the mixture was taken up in H ₂ (15 psi), stirred at 20 ℃ for 12h. The reaction mixture was filtered and the filtrate was concentrated. The resulting residue was purified by preparative TLC (eluted with 10% meoh in DCM, rf = 0.15) to give compound 461-2 as a white solid (120mg, 77% yield). LCMS (methods 5-95AB, ESI): t _R ＝0.719min,[M+H] ⁺ ＝974.8。

Compound 461 (formate) was prepared as a white solid from compound 461-2 by using the methods previously described. LCMS (methods 5-95AB, ESI): t _R ＝0.717min,[M+H] ⁺ ＝866.7； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.45(s,2H),7.38(d,J＝8.0Hz,1H),7.27-7.08(m,6H),6.89(s,1H),6.84(s,1H),6.40(s,1H),5.11-5.08(m,1H),4.80-4.70(m,2H),4.23-4.15(m,4H),4.19(s,2H),3.62-3.58(m,1H),3.47(brs,1H),3.19-3.14(m,3H),3.05-2.98(m,4H),2.95(s,3H),2.74-2.68(m,2H),2.63-2.59(m,2H),2.37-2.32(m,1H),2.35(s,3H),1.81-1.78(m,1H),1.67-1.54(m,2H),1.36-1.33(m,9H),0.90(t,J＝5.2Hz,3H)。

Example 262: synthesis of Compound 462

Step 1: starting from (S) -3-amino-2- (((benzyloxy) carbonyl) amino) propionic acid, methyl ester formation (as described in example M), guanidine formation (as described in example 241) and ester hydrolysis (as described in example G), the (S) -2- (((benzyloxy) carbonyl) amino) -3- (2, 3-bis (tert-butoxycarbonyl) guanidino) propionic acid was obtained as a white solid. LCMS (methods 5-95AB, ESI): t _R ＝0.907min,[M+H] ⁺ ＝481.2。

Compound 462 (formate salt) was prepared from compound 101G and (S) -2- (((benzyloxy) carbonyl) amino) -3- (2, 3-bis (tert-butoxy) carbonyl) by using the methods previously describedCarbonyl) guanidino) propanoic acid was prepared as a white solid. LCMS (methods 5-95AB, ESI): t _R ＝0.602min,[M+H] ⁺ ＝918.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.77(s,1H),8.51(br s,1H),8.35(d,J＝8.0Hz,1H),7.55(d,J＝8.8Hz,1H),7.30(d,J＝8.0Hz,1H),7.22-7.16(m,2H),7.08(d,J＝8.8Hz,1H),6.89(d,J＝2.4Hz,1H),6.76(s,1H),6.40(s,1H),5.28(t,J＝6.4Hz,1H),4.82-4.75(m,2H),4.25-4.18(m,4H),4.20(s,2H),3.79-3.74(m,1H),3.66-3.61(m,1H),3.16-3.08(m,5H),2.93(s,3H),2.76-2.65(m,1H),2.68(s,3H),1.38(s,9H),1.37(d,J＝7.6Hz,3H)。

Example 263: synthesis of Compound 463

Compound 463 (formate) was prepared as a white solid by using a similar method as described in example S and example 7. LCMS (methods 5-95AB, ESI): t _R ＝0.576min,[M+Na] ⁺ ＝902.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.52(brs,2H),7.30-7.22(m,2H),7.15(d,J＝8.4Hz,1H),7.08(d,J＝8.4Hz,1H),6.87(s,1H),6.81(s,1H),6.26(s,1H),5.05-4.70(m,2H),4.40-4.30(m,1H),4.25-4.10(m,6H),3.85-3.70(m,2H),3.20–3.00(m,8H),2.81(s,3H),2.40-2.25(m,2H),2.25-2.13(m,1H),2.10-1.95(m,1H),1.70-1.55(m,2H),1.40-1.20(m,15H),0.90(t,J＝6.4Hz,3H)。

Example 264: synthesis of Compound 464

Compound 464 was prepared as a white solid by using a similar method to that described in example S and example 7. LCMS (methods 5-95AB, ESI): t _R ＝0.724min,[M+H] ⁺ ＝975.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.33(d,J＝8.4Hz,2H),7.54(d,J＝8.4Hz,2H),7.30(d,J＝7.2Hz,1H),7.24(d,J＝7.2Hz,1H),7.16(d,J＝8.4Hz,1H),7.09(d,J＝8.4Hz,1H),6.91(s,1H),6.89(s,1H),6.32(s,1H),5.10-4.81(m,3H),4.56(m,1H),4.24-4.18(brs,4H),4.20(s,2H),3.35-3.30(m,1H),3.21-3.07(m,7H),2.86(s,3H),2.58(s,6H),2.29-2.17(m,1H),2.13-2.01(m,1H),1.43(d,J＝7.0Hz,3H),1.44(s,9H),1.37(t,J＝7.2Hz,3H)。

Example 265: synthesis of Compound 465

Compound 465 is prepared using procedures analogous to those described in example S and example 7. LCMS (methods 5-95AB, ESI): t _R ＝0.625min,[M+H] ⁺ ＝991.8； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.34(d,J＝8.4Hz,2H),7.54(d,J＝8.8Hz,2H),7.34-7.22(m,2H),7.15(d,J＝8.4Hz,1H),7.12-7.07(m,1H),6.92(s,1H),6.84(s,1H),6.30(s,1H),5.15-4.59(m,4H),4.27-4.17(m,4H),4.19(s,2H),3.89(d,J＝6.0Hz,2H),3.26-3.01(m,8H),2.87(s,3H),2.60(s,6H),2.28-2.19(m,1H),2.14-2.05(m,1H),1.37(s,9H),1.36(t,J＝7.2Hz,3H)。

Example 266: synthesis of Compound 466

Compound 466 was prepared using a method analogous to that described in example S and example 7. LCMS (method 5-95AB, ESI): t _R ＝0.663min,[M+H] ⁺ ＝1047.8； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.50(brs,2H),8.33(d,J＝8.4Hz,2H),7.54(d,J＝8.4Hz,2H),7.32-7.19(m,2H),7.19-7.03(m,2H),6.90(s,1H),6.81(s,1H),6.32(s,1H),5.28-4.70(m,4H),4.25-4.08(m,4H),4.19(s,2H),3.75(d,J＝6.0Hz,2H),3.42-3.33(m,1H),3.29-3.09(m,10H),2.88(s,3H),2.59(s,6H),2.32-2.15(m,1H),2.14-2.00(m,1H),1.40(s,9H),1.37(t,J＝7.2Hz,3H),1.23(s,9H)。

Example 267: synthesis of compound 467

Compound 467 is prepared using procedures analogous to those described in example S and example 7. LCMS (method 5-95AB, ESI): t _R ＝0.716min,[M+H] ⁺ ＝991.8； ¹ H NMR(400MHz,MeOH-d ₄ )8.54(br s,1H),8.33(d,J＝8.4Hz,2H),7.54(d,J＝8.4Hz,2H),7.36-7.22(m,2H),7.13-7.04(m,2H),6.89(s,1H),6.81(s,1H),6.30(s,1H),5.14-4.66(m,4H),4.21-4.09(m,4H),4.19(s,2H),3.92(d,J＝6.0Hz,2H),3.24-3.07(m,8H),2.87(s,3H),2.53(s,6H),2.26-2.21(m,1H),2.10-2.01(m,1H),1.37-1.29(m,12H)。

Example 268: synthesis of Compound 468

Compound 468 was prepared using a method analogous to that described in example S and example 7. LCMS (method 5-95AB, ESI): t _R ＝0.766min,[M+H] ⁺ ＝1047.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.53(br s,1H),8.33(d,J＝8.4Hz,2H),7.52(d,J＝8.4Hz,2H),7.31-7.01(m,5H),6.85(s,1H),6.37(s,1H),5.10-4.71(m,4H),4.31-4.12(m,6H),3.80-3.74(m,2H),3.10-2.90(m,8H),2.86(s,3H),2.53(s,6H),2.23-2.18(m,1H),2.04-2.02(m,1H),1.42(t,J＝7.2Hz,3H),1.38(s,9H),1.24(s,9H)。

Example 269: synthesis of Compound 469

Compound 469 (formate) was prepared as a white solid by using a similar method to that described in example S and example 7. LCMS (methods 5-95AB, ESI): t _R ＝0.744min,[M+Na] ⁺ ＝1025.7； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.48(br s,1H),8.33(d,J＝8.4Hz,2H),7.53(d,J＝8.4Hz,2H),7.32-6.82(m,6H),6.30(s,1H),5.10-4.79(m,4H),4.25-4.18(m,6H),3.17-3.16(m,9H),2.93-2.87(m,2H),2.58(s,6H),2.24-2.00(m,2H),1.78-1.76(m,2H),1.52-1.37(m,14H),1.03(t,J＝5.2Hz,3H)。

Example 270: synthesis of Compound 470

Compound 470 (formate salt) was prepared as a white solid by using a similar method as described in example S and example 7. LCMS (methods 5-95AB, ESI): t _R ＝0.625min,[M+H] ⁺ ＝961.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.50(br s,2H),8.34(d,J＝8.4Hz,2H),7.55(d,J＝8.4Hz,2H),7.35-7.21(m,2H),7.17-7.06(m,2H),6.94(s,1H),6.75(s,1H),6.32(s,1H),5.11-4.80(m,4H),4.22-4.10(m,7H),3.51-3.32(m,1H),3.21-3.00(m,7H),2.88(s,3H),2.61(s,6H),2.32-2.18(m,1H),2.12-2.00(m,1H),1.42(s,9H),1.36(t,J＝6.4Hz,3H)。

Example 271: synthesis of Compound 471

Compound 471-1 was prepared as a white solid by using a method analogous to that described in example C, starting with (S) -2- ((tert-butoxycarbonyl) amino) -2- (4-hydroxyphenyl) acetic acid instead of (S) -2- ((tert-butoxycarbonyl) (methyl) amino) -2- (4-hydroxyphenyl) acetic acid. LCMS (methods 5-95AB, ESI): t _R ＝0.828min,[M+Na] ⁺ ＝564.2。

Compound 471-2 was prepared as a white solid from compound 471-1 using an analogous method to that described in example O. LCMS (method 5-95AB, ESI): t _R ＝0.699min,[M+H] ⁺ =716.3. Starting from compound 471-2, a typical Boc is applied ₂ O protection (Boc) ₂ O，Et ₃ N, as described in example 6), ester hydrolysis (LiOH, THF/H) ₂ O, as described in example G), amide coupling (HATU/DIEA, as described in example G) and Boc removal (TFA/HFIP, as described in example G) conditions to afford compound 471 (formate salt) as a white solid. LCMS (methods 5-95AB, ESI): t _R ＝0.691min,[M+H] ⁺ ＝741.1； ¹ H NMR(400MHz,DMSO-d ₆ )δ9.09(d,J＝8.4Hz,1H),8.85-8.70(m,2H),8.55(d,J＝7.2Hz,1H),8.31(s,1H),8.03(d,J＝8.0Hz,1H),7.30(d,J＝8.0Hz,1H),7.15-6.90(m,6H),6.63(t,J＝8.4Hz,2H),5.66(d,J＝8.0Hz,1H),4.90-4.80(m,1H),4.65-4.60(m,1H),4.60-4.50(m,1H),4.17(d,J＝5.2Hz,1H),3.00-2.85(m,4H),2.60-2.50(m,2H),2.32(s,3H),2.15-2.00(m,1H),2.00-1.90(m,1H),1.60-1.50(m,2H),1.30-1.15(m,9H),0.85(t,J＝6.8Hz,3H)。

Example 272: synthesis of Compound 472

Compound 472 (formate) was prepared as a white solid from compound 471-1 by using a similar method to that described in example D and example G. LCMS (method 5-95AB, ESI): t _R ＝0.719min,[M+H] ⁺ ＝876.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.84(s,1H),8.78(s,1H),8.45(br s,1H),8.38-8.36(m,2H),7.57-7.49(m,3H),7.31-7.06(m,2H),7.04-7.02(m,2H),6.83(br s,1H),5.86(s,1H),5.76(s,1H),4.75-4.70(m,2H),4.52-4.48(m,1H),4.24-4.15(m,6H),3.19-3.09(m,7H),2.72(s,2H),2.66(s,2H),2.25-2.00(m,2H),1.38(br s,12H)。

Example 273: synthesis of Compound 473

Step 1: to a solution of compound 471-1 (390mg, 0.88mmol) and 4-nitro-benzenesulfonyl chloride (255mg, 1.15mmol) in acetonitrile (5 mL) at 0 deg.C was added Et dropwise ₃ N (0.31mL, 2.21mmol). The mixture was stirred at the same temperature for 3h. The precipitate was collected and dried by oven to give compound 473-2 as a yellow solid (520mg, 94% yield).

And 2, step: to a solution of compound 473-2 (520mg, 0.83mmol) and ethyl iodide (650mg, 4.15mmol) in acetone (10 mL) at 0 ℃ was added K ₂ CO ₃ (573mg, 4.15mmol), and the mixture was gradually warmed to 25 ℃ while stirring and at the same temperature Stirred at room temperature for 14h. The volatiles were removed and the residue was redissolved with ethyl acetate (120 mL) and washed with brine (3x 50mL). The organic layer was washed with Na ₂ SO ₄ Drying, concentration and chromatography of the residue on silica gel eluting with 50% ethyl acetate in petroleum ether afforded compound 473-3 as a white solid (400mg, 73.6% yield).

And 3, step 3: a solution of compound 473-3 (400mg, 0.61mmol), mercaptoacetic acid (0.28mL, 4.03mmol) and DBU (0.92mL, 6.17mmol) in acetonitrile (5 mL) was stirred at 25 ℃ for 4h. The volatiles were removed under reduced pressure and the residue was redissolved with ethyl acetate (100 mL) and washed with brine (3x 50mL). The organic layer is coated with Na ₂ SO ₄ Drying, concentration and chromatography of the residue on silica gel eluting with 67% ethyl acetate in petroleum ether afforded compound 473-4 as a white solid (260mg, 91% yield). LCMS (method 5-95AB, ESI): t _R ＝0.698min,[M+H] ⁺ ＝470.5。

Starting from compound 473-4, compound 473 (formate) was prepared as a white solid by using a method analogous to that described in example 271. LCMS (method 5-95AB, ESI): t _R ＝0.811min,[M+H] ⁺ ＝768.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.50(br s,1H),7.33(d,J＝8.0Hz,1H),7.19(d,J＝8.0Hz,1H),7.08-7.00(m,4H),6.99(br s,1H),6.91(d,J＝8.0Hz,1H),6.84(d,J＝8.0Hz,1H),6.28(s,1H),5.14(m,1H),4.85-4.77(m,1H),4.60(br s,1H),4.18(s,2H),3.40-3.25(m,2H),3.16-3.08(m,4H),2.60(t,J＝7.6Hz,2H),2.40(s,3H),2.25-2.00(m,2H),1.60-1.50(m,3H),1.35-1.32(m,8H),0.97(t,J＝7.2Hz,3H),0.89(t,J＝6.8Hz,3H)。

Example 274: synthesis of Compound 474

Step 1: to a solution of compound 471-1 (480mg, 1.09mmol), tert-butyl (2-oxoethyl) carbamate (173mg, 1.2mmol) and acetic acid (0.3 mL) in MeOH (10 mL) was added NaBH ₃ CN (75mg, 1.2mmol), and dissolving the resulting solution in 2Stirring at 0 ℃ for 6h. The volatiles were removed under reduced pressure and the residue was redissolved with EtOAc (40 mL) and washed with brine (2x 40mL). The organic layer was MgSO ₄ Drying, concentration, and purification of the residue by preparative TLC (eluting with 50% etoac in petroleum ether, rf = 0.4) afforded compound 474-2 (440mg, 69% yield) as a white solid. LCMS (method 5-95AB, ESI): t _R ＝0.619min,[M+H] ⁺ ＝585.1。

Step 2: a solution of (S) -2- (((benzyloxy) carbonyl) amino) -4- ((tert-butoxycarbonyl) amino) butanoic acid (200mg, 0.57mmol), N-methylmorpholine (115mg, 1.14mmol) and isobutyl chloroformate (62mg, 0.45mmol) in THF (10 mL) was stirred at-10 deg.C for 1h, followed by addition of compound 474-2 (232mg, 0.40mmol). The resulting mixture was stirred at the same temperature for a further 1h. The volatiles were removed under reduced pressure and the residue was redissolved with EtOAc (30 mL) and washed with brine (2x 30mL). The organic layer was MgSO ₄ Drying, concentration, and purification of the residue by preparative TLC (eluting with 50% etoac in petroleum ether, rf = 0.3) gave compound 474-3 as a white solid (130mg, 25% yield). LCMS (methods 5-95AB, ESI): t _R ＝0.835min,[M+H] ⁺ ＝919.6。

Starting from compound 474-3, compound 474 (formate) was prepared as a white solid by using a similar method to that described in example 271. LCMS (methods 5-95AB, ESI): t _R ＝0.661min,[M+H] ⁺ ＝783.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.55(br s,2H),7.44(d,J＝7.2Hz,1H),7.33(d,J＝7.2Hz,1H),7.17(br s,1H),7.18-7.06(m,4H),6.96-6.81(m,1H),6.29(s,1H),5.99(s,1H),5.09(br s,1H),4.78-4.76(m,2H),4.17(d,J＝8.0Hz,2H),3.78-3.40(m,4H),3.35-3.02(m,4H),2.61(t,J＝7.2Hz,2H),2.47(s,3H),2.41-2.05(m,2H),1.64-1.60(m,2H),1.37-1.30(m,9H),0.91(t,J＝6.8Hz,3H)。

Example 275: synthesis of Compound 475

Compound 475 (formate) by utilization and implementationExample 274A white solid was prepared in a similar manner. LCMS (methods 5-95AB, ESI): t _R ＝0.814min,[M+H] ⁺ ＝784.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.54(br s,3H),7.33(d,J＝8.0Hz,1H),7.18-7.01(m,6H),6.87(d,J＝8.0Hz,1H),6.80(d,J＝8.0Hz,1H),6.15(s,1H),5.00-4.75(m,3H),4.18(s,2H),3.80-3.70(m,2H),3.30-3.10(m,3H),3.07-3.01(m,3H),2.63-2.59(m,2H),2.40(s,3H),2.30-2.15(m,1H),2.13-2.02(m,1H),1.70-1.50(m,3H),1.37-1.27(m,8H),0.90(t,J＝6.8Hz,3H)。

Example 276: synthesis of Compound 476

Compound 476 (formate salt) was prepared as a white solid by using a similar method as described in example 7. LCMS (method 5-95AB, ESI): t _R ＝0.718min,[M+H] ⁺ ＝876.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.72(s,1H),8.46(br s,2H),8.28(d,J＝8.0Hz,1H),7.52(d,J＝8.0Hz,1H),7.35-7.30(m,1H),7.25-7.20(m,1H),7.12(d,J＝8.4Hz,1H),7.06(d,J＝8.4Hz,1H),6.86(s,1H),6.64(s,1H),6.56(s,1H),5.22-5.18(m,1H),4.80-4.70(m,2H),4.67(d,J＝14.4Hz,1H),4.34-4.22(m,4H),4.20(s,2H),3.59-3.52(m,1H),3.31-3.25(m,4H),3.18-3.12(m,2H),3.00-2.95(m,1H),2.92(s,3H),2.66(s,3H),2.28-2.17(m,1H),2.15-2.01(m,1H),1.39(s,9H)。

Example 277: synthesis of Compound 477

Compound 477 (formate salt) was prepared as a white solid by using a similar method to that described in example 7. LCMS (method 5-95AB, ESI): t _R ＝0.722min,[M+H] ⁺ ＝906.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.72(s,1H),8.50(br s,3H),8.30(d,J＝7.6Hz,2H),7.53(d,J＝8.0Hz,2H),7.31(d,J＝7.6Hz,1H),7.22-7.14(m,2H),7.06(d,J＝8.0Hz,1H),6.79(s,1H),6.66(s,1H),6.50(s,1H),5.20-5.15(m,1H),4.81-4.75(m,2H),4.28-4.14(m,4H),4.19(s,2H),3.72(d,J＝7.2Hz,2H),3.43-3.38(m,2H),3.22-3.13(m,5H),3.05-3.01(m,1H),2.95(s,3H),2.67(s,3H),2.27-2.66(m,1H),2.18-2.16(m,1H),1.38(s,9H)。

Example 278: synthesis of Compound 478

Compound 478 (formate) was prepared from compound 105 (example U) using an analogous method to that described in example G (compound 101) to give a white solid. LCMS (ESI): [ M + H ]] ⁺ ＝880； ¹ H NMR (400 MHz, methanol-d) ₄ )δ7.34-7.32(m,2H),7.26(dd,J＝8.6,2.3Hz,1H),7.19(d,J＝8.6Hz,1H),7.16–7.08(m,3H),6.82(dd,J＝9.8,2.4Hz,2H),6.39(s,1H),5.15(dd,J＝7.9,5.5Hz,1H),4.98(dd,J＝11.5,3.2Hz,1H),4.29–4.19(m,7H),3.30(d,J＝3.3Hz,1H),3.24-3.17(m,5H),3.16–3.09(m,2H),2.93(s,2H),2.64(t,J＝7.6Hz,2H),2.44(s,3H),2.34–2.25(m,1H),2.19-2.10(m,1H),1.63(q,J＝7.3Hz,2H),1.39–1.28(m,9H),1.26-1.19(m,1H),0.96–0.88(m,3H),0.57–0.49(m,4H)。

Example 279: synthesis of Compound 479

Compound 479 (formate) was prepared using a similar method as described in example G (compound 101) to give a white solid. LCMS (ESI) [ < M + H ]] ⁺ ＝868； ¹ H NMR (400 MHz, methanol-d) ₄ )δ7.37–7.32(m,2H),7.27(dd,J＝8.6,2.4Hz,1H),7.20(d,J＝8.6Hz,1H),7.15–7.08(m,3H),6.88(dd,J＝17.2,2.4Hz,2H),6.34(s,1H),5.15(dd,J＝7.8,5.5Hz,1H),4.94(dd,J＝11.5,3.1Hz,1H),4.62(t,J＝7.4Hz,1H),4.31–4.19(m,6H),3.25(q,J＝4.9Hz,4H),3.16–3.09(m,2H),2.94(s,3H),2.64(t,J＝7.6Hz,2H),2.43(s,3H),2.34-2.23(m,1H),2.19–2.09(m,1H),1.88-1.78(m,1H),1.73-1.59(m,2H),1.38–1.29(m,10H),0.98(t,J＝7.4Hz,3H),0.95–0.89(m,2H)。

Example 280: synthesis of Compound 480

Compound 480 (formate) was prepared using a similar method as described in example 279 and example G (compound 101) to give a white solid. LCMS (ESI) [ < M + H ] ] ⁺ ＝854； ¹ H NMR (400 MHz, methanol-d) ₄ )δ7.46(dd,J＝18.2,7.7Hz,1H),7.36(dd,J＝22.5,7.7Hz,1H),7.29–7.20(m,1H),7.15–7.03(m,3H),6.99(d,J＝8.3Hz,1H),6.84–6.79(m,1H),5.87(s,1H),4.99–4.91(m,2H),4.69–4.61(m,1H),4.52(d,J＝11.0Hz,1H),4.21–3.99(m,6H),3.12–2.92(m,4H),2.61(td,J＝7.6,3.9Hz,3H),2.40(d,J＝22.7Hz,3H),1.80(dt,J＝12.5,6.5Hz,1H),1.64(d,J＝21.1Hz,3H),1.30(d,J＝13.8Hz,12H),0.97(t,J＝7.4Hz,3H),0.92–0.87(m,3H)。

Example 281: synthesis of Compound 481

Compound 481-1 was prepared as an off-white solid using (2s, 4r) -1-benzyloxycarbonyl-4- (tert-butoxycarbonylamino) pyrrolidine-2-carboxylic acid following the procedure for compound 101-I. LCMS (ESI) [ < M + H ]] ⁺ ＝926。

Compound 481 (formate) was prepared using a similar method as described in example G (compound 101) to give an off-white solid. LCMS (ESI) [ < M + H ]] ⁺ ＝852； ¹ H NMR (400 MHz, methanol-d) ₄ )δ7.42–7.36(m,1H),7.29–7.04(m,8H),6.87(dd,J＝21.4,2.5Hz,1H),6.39(d,J＝6.2Hz,1H),5.21(t,J＝7.2Hz,1H),4.80–4.72(m,1H),4.24–4.15(m,5H),3.84–3.78(m,1H),3.75–3.68(m,1H),3.25–3.19(m,1H),3.19–3.11(m,4H),2.95(d,J＝3.2Hz,3H),2.62(t,J＝7.6Hz,2H),2.39(s,2H),2.34(q,J＝5.4,4.6Hz,4H),1.62(dt,J＝14.9,8.1Hz,3H),1.38–1.28(m,10H),0.93–0.88(m,3H)。

Example 282: synthesis of Compound 482

Compound 482 (formate) was prepared as an off-white solid by using a similar method as described in example G (compound 101). LCMS (method A, ESI): t _R ＝3.519min,[M+H] ⁺ ＝860； ¹ H NMR (400 MHz, methanol-d) ₄ )δ7.40–7.34(m,1H),7.23(dd,J＝8.6,2.4Hz,1H),7.18(d,J＝8.4Hz,1H),7.09(d,J＝8.6Hz,1H),6.85(dd,J＝18.5,2.5Hz,2H),6.30(s,1H),5.02(dd,J＝7.9,5.8Hz,1H),4.88(d,J＝3.1Hz,1H),4.80–4.74(m,1H),4.26–4.18(m,6H),4.00–3.88(m,2H),3.58(dd,J＝10.1,4.1Hz,1H),3.22–3.16(m,4H),2.88(s,3H),2.44–2.37(m,2H),2.31–2.26(m,1H),1.65(q,J＝7.4Hz,2H),1.42–1.27(m,26H),0.93–0.87(m,3H)。

Example 283: synthesis of compound 483

Compound 483 (formate) was prepared as an off-white solid by using a similar method as described in example G (compound 101). LC-MS (method A, ESI) t _R ＝3.522min,[M+H] ⁺ ＝860； ¹ H NMR (400 MHz, methanol-d) ₄ )δ7.31(dd,J＝8.6,2.5Hz,1H),7.17(dd,J＝8.5,2.4Hz,1H),7.11(d,J＝8.6Hz,1H),7.02(d,J＝8.4Hz,1H),6.78(dd,J＝19.8,2.4Hz,2H),6.22(s,1H),4.99(dd,J＝8.3,5.2Hz,1H),4.81(s,1H),4.69(q,J＝6.7Hz,1H),4.24–4.10(m,6H),4.01–3.96(m,2H),3.63(q,J＝7.4Hz,1H),3.22–3.15(m,4H),3.11–3.01(m,1H),2.81(s,3H),2.38–2.26(m,4H),1.58(q,J＝7.3Hz,2H),1.36–1.19(m,24H),0.87–0.80(m,3H)。

Example 284: synthesis of Compound 484

Compound 484 (formate) by usePrepared as an off-white solid in analogy to the procedure described in example G (compound 101). LC-MS (method A, ESI) t _R ＝2.073min,[M+H] ⁺ ＝796； ¹ H NMR(400MHz,DMSO-d ₆ )δ9.04(d,J＝7.8Hz,1H),8.78(t,J＝5.7Hz,1H),8.73(d,J＝7.7Hz,1H),8.37(d,J＝9.0Hz,1H),7.66–7.58(m,2H),7.22–7.13(m,2H),7.06(dd,J＝27.1,8.6Hz,2H),6.71(d,J＝2.5Hz,2H),6.28(s,1H),4.97–4.90(m,1H),4.80–4.67(m,2H),4.17(d,J＝5.8Hz,2H),4.03–3.93(m,3H),3.18(d,J＝16.8Hz,2H),3.04–2.97(m,1H),2.88–2.72(m,10H),2.05–1.91(m,2H),1.80–1.71(m,4H),1.19(d,J＝6.7Hz,3H)。

Example 285: synthesis of Compound 485

Step 1: a solution of ethyl 3-oxopentanoate (1.00mL, 7.02mmol), triethyl orthoacetate (2.0mL, 11mmol), pyridine (57. Mu.L, 0.698 mmol), acetic acid (40. Mu.L, 0.697 mmol) and toluene (6.0mL, 56mmol) was heated in a sealed vial at 120 ℃ for 23h. The reaction mixture was evaporated under reduced pressure to give the crude product as an orange oil. The crude product was purified by flash chromatography on silica gel (40 g silica, solvent gradient: 0-50% ethyl acetate in heptane) to yield 254.2mg (17%) ethyl (Z) -2- (1-ethoxyethylidene) -3-oxopentanoate as an orange oil. LCMS (ESI) [ < M + H ] ] ⁺ ＝215.0。

Step 2: lithium bis (trimethylsilyl) amide (1 mol/L) in THF (110.0 mL,110.0 mmol) was added dropwise to a 0 ℃ solution of 4-tert-butyl benzonitrile (9.00mL, 53mmol) in diethyl ether (100mL, 960 mmol) over 30 minutes. The reaction was stirred at 0 ℃ for 2h and then warmed to room temperature. After an additional 6h, the reaction was cooled in an ice bath and quenched by the careful addition of hydrogen chloride (12 mol/L water) (20mL, 240mmol), diluted with water (50 mL), and then stirred for 10 min. Subjecting the obtained product toThe mixture was extracted with water (4x 50mL). The combined aqueous extracts were adjusted to pH 13 with aqueous sodium hydroxide (10 mol/L) (15mL, 150mmol) and then extracted with 10% isopropanol (4X50mL) in dichloromethane. The combined dichloromethane extracts were dried over magnesium sulfate and filtered. The filtered solid was stirred with 1. LCMS (ESI) [ < M + H ]] ⁺ ＝177.15； ¹ H NMR(400MHz,DMSO-d ₆ )δ7.68(d,J＝8.4Hz,2H),7.43(d,J＝8.2Hz,2H),6.98(br s,3H),1.29(s,9H)。

And step 3: a mixture of (2Z) -2- (1-ethoxyethylidene3-oxo-pentanoic acid ethyl ester (254.2mg, 1.186mmol), 4-tert-butyl-benzamidine (197.0 mg, 1.118mmol), sodium ethoxide (21 wt% solution in ethanol) (0.80mL, 2.1 mmol), and ethanol (1.5 mL, 26mmol) was heated in a sealed vial at 70 ℃ overnight. The reaction mixture was evaporated onto celite. The crude product was purified by flash chromatography on silica gel (12 g silica, solvent gradient: 0-50% ethyl acetate in heptane) to yield 80.2mg (22%) of ethyl 2- (4- (tert-butyl) phenyl) -4-ethyl-6-methylpyrimidine-5-carboxylate as a clear, colorless oil. LCMS (ESI): [ M + H ] ] ⁺ ＝327。

And 4, step 4: to a solution of ethyl 2- (4-tert-butylphenyl) -4-ethyl-6-methyl-pyrimidine-5-carboxylate (97mg, 0.2972mmol) in tetrahydrofuran (2.0mL, 25mmol) was added lithium hydroxide (1.0M in water) (0.30mL, 0.30mmol). The reaction mixture was stirred at room temperature for 3.5h. After addition of additional lithium hydroxide (1.0M in water) (0.90mL, 0.90mmol) and methanol (1 mL), the reaction mixture was heated at 50 ℃ overnight. The reaction mixture was diluted with dichloromethane, neutralized with a solution of hydrochloric acid (1 mol/L) in water (1.2 mL), and washed with brine. The aqueous layer was extracted with another portion of dichloromethane and the combined organic layers were dried over magnesium sulfate, filtered, and evaporated in vacuo to give 88.4mg (99.7%) of 2- (4- (tert-butyl) phenyl) -4-ethyl-6-methylpyrimidine-5-carboxylic acid, which was used without further purification. LCMS (ESI): [ M + H ]] ⁺ ＝299.15。

Compound 485 (TFA salt) was synthesized from 2- (4- (tert-butyl) phenyl using an analogous method to that described in example G (Compound 101)) -4-ethyl-6-methylpyrimidine-5-carboxylic acid and compound 101-K. LCMS (method A, ESI): t _R ＝2.971min,[M+H] ⁺ ＝918.5； ¹ H NMR(400MHz,DMSO-d ₆ )δ9.18(d,J＝7.3Hz,1H),8.96(d,J＝7.9Hz,1H),8.71(t,J＝5.7Hz,1H),8.37–8.29(m,3H),7.99–7.72(m,6H),7.56(d,J＝8.5Hz,2H),7.28–7.22(m,1H),7.21–7.07(m,3H),6.74(s,1H),6.45(s,1H),5.09–4.99(m,1H),4.82–4.66(m,2H),4.28–4.05(m,7H),3.21–2.98(m,11H),2.91(s,3H),2.77(q,J＝7.4Hz,2H),2.02(d,J＝39.8Hz,2H),1.34(s,9H),1.29(t,J＝7.5Hz,3H),1.21(d,J＝6.7Hz,3H)。

Example 286: synthesis of Compound 486

Compound 486 (TFA salt) was prepared from ethyl 3-oxohexanoate by using a method similar to that described in example 285. LCMS (method A, ESI): t _R ＝3.162min,[M+H] ⁺ ＝932.5； ¹ H NMR(400MHz,DMSO-d ₆ )δ9.18(d,J＝7.3Hz,1H),8.95(d,J＝7.9Hz,1H),8.71(t,J＝5.7Hz,1H),8.38–8.30(m,3H),7.93–7.76(m,10H),7.56(d,J＝8.5Hz,2H),7.26–7.08(m,3H),6.74(d,J＝2.4Hz,1H),6.47(s,1H),5.09–4.98(m,1H),4.81–4.67(m,2H),4.29–4.05(m,6H),3.28–2.93(m,6H),2.91(s,2H),2.79–2.63(m,2H),2.12–1.92(m,2H),1.78(q,J＝7.5Hz,2H),1.34(s,9H),1.21(d,J＝6.7Hz,2H),0.95(t,J＝7.3Hz,2H)。

Example 287: synthesis of Compound 487

Compound 487 (TFA salt) was prepared from ethyl 4-methyl-3-oxopentanoate using an analogous method to that described in example 285. LCMS (method A, ESI): t _R ＝3.260min,[M+H] ⁺ ＝932.5； ¹ H NMR(400MHz,DMSO-d ₆ )δ9.20(d,J＝7.3Hz,1H),8.95(d,J＝8.1Hz,1H),8.69(d,J＝5.8Hz,1H),8.38–8.29(m,3H),7.83(s,9H),7.57(d,J＝8.4Hz,2H),7.24(d,J＝8.6Hz,1H),7.20–7.06(m,3H),6.73(s,2H),6.46(s,1H),5.08–4.97(m,1H),4.80–4.65(m,2H),4.28–4.06(m,6H),3.25–2.97(m,8H),2.91(s,3H),2.13–1.92(m,2H),1.34(s,9H),1.29(d,J＝6.6Hz,6H),1.21(d,J＝6.7Hz,3H)。

Example 288: synthesis of Compound 488

Step 1: to 3-oxobicyclo [3.1.0]To a solution of hexane-6-carboxylic acid ethyl ester (519.9 mg, 3.091mmol) in ethanol (8.0 mL, 140mmol) was added 4-methylbenzenesulfonylhydrazide (596.9 mg, 3.109mmol). The reaction mixture was stirred at room temperature for 90min, then evaporated in vacuo to give 3- (2-tosylhydrazono) bicyclo [3.1.0]Hexane-6-carboxylic acid ethyl ester, which was used without further purification. LCMS (ESI) [ < M + H ]] ⁺ ＝337.05。

Step 2: the product obtained in step 1 was combined with (4-tert-butylphenyl) boronic acid (840.2mg, 4.720mmol), potassium carbonate (669mg, 4.8405mmol) and 1, 4-dioxane (12mL, 140mmol), and the mixture was heated at 100 ℃ for 2h. Additional (4-tert-butylphenyl) boronic acid (514.5mg, 2.890 mmol) and 1, 4-dioxane (10 mL) were added, and the reaction mixture was heated at 110 ℃ overnight. The reaction mixture was evaporated onto celite in vacuo. The crude product was purified by flash chromatography on silica gel (40 g silica, solvent gradient: 0-20% ethyl acetate in heptane) to give 249.5mg ethyl 3- (4- (tert-butyl) phenyl) bicyclo [3.1.0] hexane-6-carboxylate as a yellow oil (28% yield over 2 steps).

Compound 488 (TFA salt) was prepared from 3- (4- (tert-butyl) phenyl) bicyclo [3.1.0 ] by using an analogous method to that described in example 285]Hexane-6-carboxylic acid ethyl ester. LCMS (method A, ESI): t _R ＝2.997min,[M+H] ⁺ ＝879.5。

Example 289: synthesis of Compound 489

Step 1: to a solution of 4-tert-butylbenzoamidine (1.02g, 5.78mmol) in ethanol (29 mL) was added diethyl 2- (ethoxymethylene) malonate (1.25g, 5.78mmol), followed by sodium ethoxide (2.6M solution in ethanol, 2.4mL, 5.78mmol). The reaction was stirred under nitrogen at room temperature. After 1.5h the reaction was concentrated to give 2.29g of crude product, which was used without further purification.

Step 2: to a vial containing ethyl 2- (4-tert-butylphenyl) -6-oxo-1H-pyrimidine-5-carboxylate (1.20g, 4.0mmol) was added phosphoryl chloride (1.9mL, 20mmol). The reaction was heated to 60 ℃. After 1.5h, an additional 3 equivalents of phosphorus oxychloride (1.2 mL, 12mmol) was added. After 3h, the reaction was evaporated in vacuo and used directly in the next step.

And 3, step 3: to a solution of ethyl 2- (4-tert-butylphenyl) -4-chloro-pyrimidine-5-carboxylate (1.28g, 4 mmol) in THF (8 mL) was added a solution of methylamine (2M) in THF (8 mL, 16mmol). After stirring at room temperature for 2h, the reaction was concentrated, treated with water, and extracted with DCM (3 times). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated. Purification by flash chromatography on silica gel (solvent gradient: 0-40% isopropyl acetate/heptane, then 100% isopropyl acetate) gave the desired product as a white solid (0.754g, 60%). LCMS (ESI) [ M +1 ] ] ⁺ ＝314.2； ¹ H NMR(400MHz,DMSO-d ₆ )δ8.83(s,1H),8.38–8.31(m,2H),8.22(d,J＝5.2Hz,1H),7.54(d,J＝8.5Hz,2H),4.33(q,J＝7.1Hz,2H),3.11(d,J＝4.8Hz,3H),1.37–1.30(m,12H)。

And 4, step 4: to a solution of ethyl 2- (4-tert-butylphenyl) -4- (methylamino) pyrimidine-5-carboxylate (0.15g, 0.50mmol) in THF (2.7 mL) and methanol (0.8 mL) was added a solution of lithium hydroxide (1M) in water (1.5mL, 1.5mmol). The reaction was heated to 60 ℃. After stirring overnight, the reaction was evaporated in vacuo, treated with dilute HCl to reach pH-5-6, and extracted with ethyl acetate (3 times). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and evaporated in vacuo. The crude solid was dissolved in DCM and filtered through a celite pad, washing with 5% methanol/DCM. The filtrate was evaporated in vacuo to give the title compound (142 mg) as a white solid. LCMS (ESI) [ M +1 ]] ⁺ ＝286； ¹ H NMR(400MHz,DMSO-d ₆ )δ13.24(s,1H),8.77(s,1H),8.33(d,J＝8.3Hz,2H),7.52(d,J＝8.3Hz,2H),7.14(s,1H),3.09(d,J＝4.7Hz,3H),1.32(s,9H)。

And 5: compound 489 (TFA salt) was prepared from 2- (4- (tert-butyl) phenyl) -4- (methylamino) pyrimidine-5-carboxylic acid by the method described in example G (compound 101-K). LCMS (method A, ESI): t _R ＝2.82min,[M+H] ⁺ ＝906.4； ¹ H NMR(400MHz,DMSO-d ₆ )δ9.04(d,J＝7.8Hz,1H),8.95(d,J＝7.8Hz,1H),8.83(s,1H),8.71(t,J＝5.7Hz,1H),8.56(d,J＝5.5Hz,1H),8.39(d,J＝9.1Hz,1H),8.36–8.24(m,2H),7.94–7.68(m,10H),7.59–7.48(m,2H),7.30–7.20(m,2H),7.15(d,J＝8.7Hz,1H),7.08(t,J＝7.0Hz,1H),6.76–6.68(m,2H),6.32(s,1H),5.04–4.90(m,1H),4.83–4.64(m,2H),4.23–4.07(m,6H),3.17–2.99(m,10H),2.73(s,3H),2.11(s,2H),1.40–1.27(m,11H),1.22(d,J＝6.8Hz,3H)。

Example 290: synthesis of Compound 490

Compound 490 (TFA salt) was prepared as a white solid by using a method analogous to that described in example 289. LCMS (method A, ESI): t _R ＝2.66min,[M+H] ⁺ ＝920.5； ¹ H NMR(400MHz,DMSO-d ₆ )δ9.12(d,J＝7.3Hz,1H),8.95(d,J＝8.0Hz,1H),8.71(t,J＝5.6Hz,1H),8.39–8.23(m,4H),7.95–7.72(m,10H),7.56–7.49(m,2H),7.28–7.02(m,4H),6.73(d,J＝2.4Hz,2H),6.40(s,1H),4.91(q,J＝7.4Hz,1H),4.81–4.65(m,2H),4.26–4.06(m,6H),3.22–2.91(m,15H),2.85(s,2H),2.08–1.95(m,2H),1.33(s,9H),1.21(d,J＝6.7Hz,3H)。

Example 291: synthesis of Compound 491

Step 1: to 2- (4-tert-butylphenyl) -4-methyl-pyrimidine-5-carboxylic acid (as in example)69) (811mg, 3.0 mmol) and DCM (9 mL) were added DIPEA (1.57mL, 9mmol) followed by HATU (1.25g, 3.3 mmol). The reaction mixture was stirred at 20 ℃ for 5min, then [ (1S) -1- [ (tert-butoxycarbonylamino) methyl ] was added ]-2-methoxy-2-oxo-ethyl]Ammonium chloride (917mg, 3.6 mmol). The mixture was stirred at 20 ℃ for 18h, then diluted with DCM, washed with saturated aqueous ammonium chloride, brine, then Na ₂ SO ₄ Dried and the solvent removed. The residue was purified by silica gel chromatography (eluting with 40% ethyl acetate/cyclohexane) to give (2S) -3- (tert-butoxycarbonylamino) -2- [ [2- (4-tert-butylphenyl) -4-methyl-pyrimidine-5-carbonyl as a white foamy solid]Amino group]Methyl propionate (1.37g, 97%). LCMS (ESI): [ M + H ]] ⁺ ＝471。

Step 2: reacting (2S) -3- (tert-butoxycarbonylamino) -2- [ [2- (4-tert-butylphenyl) -4-methyl-pyrimidine-5-carbonyl]Amino group]Methyl propionate (1.37g, 2.91mmol) was dissolved in HCl-containing dioxane (4.0M, 5mL, 20mmol) and stirred at 20 ℃ for 5h. Removal of the solvent gave [ (2S) -2- [ [2- (4-tert-butylphenyl) -4-methyl-pyrimidine-5-carbonyl ] as an off-white solid]Amino group]-3-methoxy-3-oxo-propyl]Ammonium chloride 1.3g (109%). LCMS (ESI): [ M + H ]] ⁺ ＝371。

And step 3: to nitrogen at 0 deg.C [ (2S) -2- [ [2- (4-tert-butylphenyl) -4-methyl-pyrimidine-5-carbonyl]Amino group]-3-methoxy-3-oxo-propyl]To a solution of ammonium chloride (407mg, 1mmol) in DCM (4 mL) was added DIPEA (0.52mL, 3mmol) followed by dropwise addition of benzyl chloroformate (0.17mL, 1.1mmol). The mixture was stirred at 0 ℃ for 2h. The reaction was quenched with water, diluted with DCM and allowed to warm to 20 ℃. The phases were separated and the organic layer was washed with brine and over Na ₂ SO ₄ Dried and the solvent removed. The residue was purified by silica gel chromatography (eluting with 50% ethyl acetate/cyclohexane) to give (2S) -3- (benzyloxycarbonylamino) -2- [ [2- (4-tert-butylphenyl) -4-methyl-pyrimidine-5-carbonyl) as a white foam]Amino group]Methyl propionate (426mg, 84%). LCMS (ESI): [ M + H ]] ⁺ ＝505。

And 4, step 4: to (2S) -3- (benzyloxycarbonylamino) -2- [ [2- (4-tert-butylphenyl) -4-methyl-pyrimidine-5-carbonyl in THF (4 mL)]Amino group]Propionic acid methyl ester(423mg, 0.84mmol) was added with lithium hydroxide (1.0M aqueous solution, 1.0mL,1.0 mmol). The mixture was stirred at 20 ℃ for 2h. The solvent was removed and the residue was dissolved in water and acidified to about pH 2 with 1M aqueous HCl. The mixture was extracted twice with ethyl acetate and the combined organic layers were washed with brine, over Na ₂ SO ₄ Drying and removal of the solvent gave (2S) -3- (benzyloxycarbonylamino) -2- [ [2- (4-tert-butylphenyl) -4-methyl-pyrimidine-5-carbonyl as a white foam]Amino group]Propionic acid (416mg, 101%). LCMS (ESI) [ < M + H ]] ⁺ ＝491。

And 5: to compound 101-G (592mg, 0.83mmol) and (2S) -3- (benzyloxycarbonylamino) -2- [ [2- (4-tert-butylphenyl) -4-methyl-pyrimidine-5-carbonyl ] under nitrogen]Amino group]To a mixture of propionic acid (407mg, 0.83mmol) in THF (5.0 mL) was added sodium bicarbonate (279mg, 3.32mmol) followed by DEPBT (745mg, 2.49mmol). The mixture was stirred at 60 ℃ for 18h. The mixture was cooled to ambient temperature, diluted with ethyl acetate and the organic layer was washed successively with saturated aqueous sodium bicarbonate and brine, then over Na ₂ SO ₄ Dried and the solvent removed. The residue was purified by silica gel chromatography (solvent gradient: 50% to 100% ethyl acetate in cyclohexane) to give compound 491-1 (422mg, 43%) as a white glassy solid. LCMS (ESI) [ < M + H ]] ⁺ ＝1186。

Starting from compound 494-1 and (N-tert-butoxycarbonyl) glycine, using typical amide coupling (HATU/DIEA), hydrolysis and global Boc removal (TFA/HFIP) procedures (as described in examples 5 and 7) gave compound 491 (trifluoroacetate salt) as a white solid. LCMS (ESI): t _R ＝2.50min,[M+H] ⁺ ＝933.7。 ¹ H NMR(400MHz,DMSO-d ₆ )δ9.18(d,J＝8.2Hz,1H),8.99(d,J＝8.2Hz,1H),8.85(s,1H),8.76-8.70(m,1H),8.66-8.60(m,1H),8.40-8.31(m,3H),8.10-7.84(m,9H),7.58(d,J＝8.9Hz,2H),7.28-7.03(m,4H),6.73(s,2H),6.36(s,1H),5.10-5.02(m,1H),4.79-4.67(m,2H),4.27-4.07(m,6H),3.77-2.97(m,11H),2.86(s,2H),2.63(s,3H),1.33(s,9H),1.22(d,J＝7.4Hz,3H)。

Example 292: synthesis of Compound 492

Step 1: to a mixture of methyl 2- (benzyloxycarbonylamino) -2-dimethoxyphosphoryl-acetate (994mg, 3.0mmol) and tert-butyl N- (1, 1-dimethyl-2-oxo-ethyl) carbamate (562mg, 3.0mmol) in DCM (5.0 mL) was added 1, 8-diazabicyclo [5.4.0]Undecane (0.45mL, 3mmol). The mixture was stirred at 20 ℃ for 18h. The reaction mixture was diluted with DCM, washed successively with 1M aqueous HCl and brine, then over Na ₂ SO ₄ Dried and the solvent removed. The residue was purified by silica gel chromatography (eluting with 30% ethyl acetate/cyclohexane) to give (E) -2- (benzyloxycarbonylamino) -4- (tert-butoxycarbonylamino) -4-methyl-pent-2-enoic acid methyl ester (746 mg, 63%) as a colorless oil. LCMS (ESI) [ M + Na ] ] ⁺ ＝415。

Step 2: a solution of (E) -2- (benzyloxycarbonylamino) -4- (tert-butoxycarbonylamino) -4-methyl-pent-2-enoic acid methyl ester (740mg, 1.89mmol) in methanol (10 mL) was added to 1, 2-bis [ (2S, 5S) -2, 5-diethylphosphoryl chloride (diethylphosphoryl) in a glass-lined steel reactor]Benzene (1, 5-cyclooctadiene) rhodium (I) trifluoromethanesulfonate (136mg, 0.19mmol). The autoclave was flushed four times with nitrogen and then with hydrogen, the pressure was increased to 4.5atm, and the mixture was stirred for 18h. The pressure was released, the mixture was taken out of the reaction kettle, and the solvent was removed. The residue was purified by silica gel chromatography (eluting with 20% ethyl acetate/cyclohexane) to give (2S) -2- (benzyloxycarbonylamino) -4- (tert-butoxycarbonylamino) -4-methyl-pentanoic acid methyl ester as a white solid (425mg, 57%). LCMS (ESI) [ < M + H ]] ⁺ ＝395。

And step 3: to a solution of (2S) -2- (benzyloxycarbonylamino) -4- (tert-butoxycarbonylamino) -4-methyl-pentanoic acid methyl ester (412mg, 1.04mmol) in THF (5 mL) was added a LiOH solution (1.0M, 1.1mL, 1.1mmol). The mixture was stirred at 20 ℃ for 5h. The solvent was removed and the residue was dissolved in water, acidified with 1.0M aqueous HCl and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, over Na ₂ SO ₄ Drying and removing the solvent to give (2S) -2- (benzyloxycarbonylamino) -4- (tert-butoxy) as a white solidCarbonylamino) -4-methyl-pentanoic acid (390mg, 98%). LCMS (ESI) [ M-H ]] ⁺ ＝379。

Compound 101-G was coupled with (2S) -2- (benzyloxycarbonylamino) -4- (tert-butoxycarbonylamino) -4-methyl-pentanoic acid and hydrogenated as described in example E. Coupling the resulting compound with 2- (4-tert-butylphenyl) -4, 6-dimethyl-pyrimidine-5-carboxylic acid,

subsequent ester hydrolysis, coupling with aminoacetonitrile hydrochloride, and global deprotection using the procedure described in example G gave compound 492 (formate salt) as a white solid. LCMS (ESI): t _R ＝2.78min,[M+H] ⁺ ＝932.5。 ¹ H NMR(400MHz,DMSO-d ₆ )δ9.25(d,J＝7.6Hz,1H),8.96(d,J＝7.9Hz,1H),8.74-8.69(m,1H),8.39-8.29(m,3H),7.56(d,J＝8.3Hz,2H),7.30-7.06(m,5H),6.78-6.71(m,2H),6.46(s,1H),5.11-5.03(m,1H),4.79-4.64(m,2H),4.22-4.05(m,7H),3.25-3.01(m,6H),2.95(s,3H),2.25-2.17(m,1H),2.00-1.91(m,1H),1.33(s,15H),1.19(d,J＝6.9Hz,3H)。

Example 293: synthesis of Compound 493

Compound 493-1 was prepared as a white solid (373 mg) following an analogous procedure as described in example 291, using [ (1S) -3- (tert-butoxycarbonylamino) -1-methoxycarbonyl-propyl ] -n]Ammonium chloride instead of [ (1S) -1- [ (tert-butoxycarbonylamino) methyl group]-2-methoxy-2-oxo-ethyl]Ammonium chloride. LCMS (ESI): [ M + H ]] ⁺ ＝1066。

To compound 493-1 (373mg, 0.35mmol) in acetonitrile (3.0 mL) were added potassium carbonate (58mg, 0.42mmol) and 2-bromoacetamide (46mg, 0.33mmol). DMF (0.5 mL) was added to aid dissolution. The mixture was stirred at 20 ℃ for 18h, then potassium carbonate (58mg, 0.42mmol) and di-tert-butyl dicarbonate (92mg, 0.42mmol) were added. The reaction was stirred at 20 ℃ for 3h, then the resulting mixture was partitioned between ethyl acetate and water and the phases were separated. The organic layer was washed with brine, over Na ₂ SO ₄ Dried and the solvent removed. The residue was purified by silica gel chromatography(eluted with 7% MeOH/DCM) affording compound 493-2 as glass (295mg, 69%). LCMS (ESI) [ < M + H ]] ⁺ ＝1247。

Starting from compound 493-2, typical hydrolysis, amide coupling (HATU/DIEA) and global Boc removal (TFA/HFIP) procedures (as described in example G) were applied to give compound 493 (formate salt) as a white solid. LCMS (ESI): t _R ＝2.51min,[M+H] ⁺ ＝947.5。 ¹ H NMR(400MHz,DMSO-d ₆ )δ9.15(d,J＝7.2Hz,1H),8.97(d,J＝7.8Hz,2H),8.82(s,2H),8.73-8.67(m,2H),8.44-8.32(m,3H),8.02-7.66(m,4H),7.63-7.55(m,3H),7.30-7.00(m,5H),6.73(s,2H),6.38(s,1H),5.05-4.93(m,1H),4.80-4.67(m,2H),4.30-4.02(m,6H),3.21-2.94(m,8H),2.84(s,3H),2.65(s,3H),2.54(s,2H),1.34(s,9H),1.22(d,J＝7.0Hz,3H)。

Example 294: synthesis of Compound 494

Step 1: a mixture of compound 493-1 (340mg, 0.32mmol) and sodium formate (26mg, 0.38mmol) in ethyl formate (5 mL) was stirred at 50 ℃ for 5h. The mixture was partitioned between ethyl acetate and water and the phases were separated. The organic layer was washed with brine, over Na ₂ SO ₄ Dried and the solvent removed. The residue was purified by silica gel chromatography (solvent gradient: 0-10% MeOH/DCM) to give compound 494-1 as a white solid (273mg, 78%). LCMS (ESI): [ M + H ]] ⁺ ＝1095。

Starting from compound 494-1, typical hydrolysis, amide coupling (HATU/DIEA) and global Boc removal (TFA/HFIP) procedures (as described in examples E and G) were applied to give compound 494 (formate salt) as a white solid. LCMS (ESI): t _R ＝2.94min,[M+H] ⁺ ＝918.7。 ¹ H NMR(400MHz,DMSO-d ₆ )δ9.11-9.00(m,2H),8.84-8.77(m,2H),8.39-7.98(m,8H),7.60-7.55(m,2H),7.23-7.02(m,4H),6.76-6.66(m,2H),6.37(s,1H),4.89-4.67(m,4H),4.17(d,J＝6.9Hz,2H),4.10-4.01(m,4H),3.30-3.19(m,2H),3.17(s,1H),3.05-2.87(m,6H),2.83(s,2H),2.65(s,3H),2.03-1.74(m,2H),1.37(s,9H),1.19(d,J＝8.4Hz,3H)。

Example 295: synthesis of Compound 495

Step 1: to a solution of argon, methyl (S) -N-Z-aziridine-2-carboxylate (1.26mL, 6.38mmol) and tert-butyl N- (2-hydroxyoxyethyl) carbamate (3.45mL, 22.32mmol) in chloroform (45 mL) at 0 deg.C was added dropwise boron trifluoride diethyl etherate (0.81mL, 6.38mmol). The reaction mixture was allowed to reach ambient temperature within 30 min. With saturated NaHCO ₃ The reaction was quenched with aqueous solution (70 mL) and extracted with DCM. The organic extract was over MgSO ₄ Dried and the solvent removed. The crude residue was purified by silica gel chromatography (eluting with 50% ethyl acetate/cyclohexane) to give (2S) -2- (benzyloxycarbonylamino) -3- [2- (tert-butoxycarbonylamino) ethoxy ] ethyl acetate as a colorless oil]Methyl propionate (1.30g, 3.28mmol). LCMS (ESI) [ M + Na ]] ⁺ ＝419。

Step 2: to (2S) -2- (benzyloxycarbonylamino) -3- [2- (tert-butoxycarbonylamino) ethoxy group]To a solution of methyl propionate (1.3g, 3.28mmol) in THF (30 mL) was added lithium hydroxide (1.0M, 6.56mL, 6.56mmol), and the reaction mixture was stirred at 50 ℃ for 30min. The reaction was quenched with 1N aqueous HCl (8.0 mL), followed by water (50 mL), and the resulting mixture was extracted with DCM. The combined organic extracts were over MgSO ₄ Drying and removal of the solvent gave (2S) -2- (benzyloxycarbonylamino) -3- [2- (tert-butoxycarbonylamino) ethoxy ] as a colorless oil]Propionic acid (1.20g, 3.14mmol). LCMS (ESI): [ M + Na ]] ⁺ ＝405。

Reacting the compound 101-G with (2S) -2- (benzyloxycarbonylamino) -3- [2- (tert-butoxycarbonylamino) ethoxy]Propionic acid was coupled and hydrogenated as described in example E. The resulting compound was coupled with 2- (4-tert-butylphenyl) -4, 6-dimethyl-pyrimidine-5-carboxylic acid, followed by ester hydrolysis, coupling with aminoacetonitrile hydrochloride, and global deprotection using the procedure described in example G gave compound 495 (formate salt) as a white solid. LCMS (ESI): t _R ＝2.48min,[M+H] ⁺ ＝934.4。 ¹ H NMR(400MHz,DMSO-d ₆ )δ9.21-9.11(m,1H),8.96(d,J＝8.0Hz,1H),8.72(t,J＝5.4Hz,1H),8.41-8.29(m,3H),7.90-7.74(m,6H),7.55(d,J＝8.4Hz,2H),7.28-7.06(m,4H),6.73-6.69(m,1H),6.43(s,1H),5.20-5.12(m,1H),4.78-4.56(m,1H),4.28-4.07(m,6H),3.86-3.78(m,2H),3.74-3.61(m,6H),3.25-2.96(m,9H),2.91(s,3H),2.65(m,2H),2.46(d,J＝5.2Hz,1H),1.34(s,9H),1.24-1.18(m,3H)。

Example 296: synthesis of Compound 496

Step 1: to a solution of 4-bromophenol (1.0g, 5.78mmol) in DMF (10 mL) was added bromocyclohexane (1.8g, 11.0mmol) and K ₂ CO ₃ (2.4g, 17.4mmol) and the reaction stirred at 80 ℃ for 16h. The reaction mixture was poured into water (20 mL), which was extracted with EtOAc (50mL × 3). The combined organic layers were washed with brine (100mL. Times.2) and Na ₂ SO ₄ Dried and concentrated. The residue was purified by silica gel chromatography, eluting with petroleum ether, to give compound 496-1 (170.0 mg, 11%) as a colorless oil.

And 2, step: to a solution of compound 496-1 (170.0mg, 0.67mmol) in DMF (5 mL) was added bis (pinacol) diboron (254mg, 1.00mmol) and Pd (dppf) Cl ₂ (24.4 mg, 0.03mmol) and potassium acetate (196mg, 2.00mmol) and the resulting mixture was stirred under nitrogen at 80 ℃ for 3h. The reaction was poured into water (20 mL) and extracted with EtOAc (20mL. Times.3). The combined organic layers were washed with brine (50mL. Times.2) and Na ₂ SO ₄ Dried and concentrated. The residue was purified by silica gel chromatography (eluent: 8% EtOAc in petroleum ether) to give compound 496-2 as a yellow oil (140mg, 70% yield).

And 3, step 3: compound 496-2 (200mg, 0.66mmol) in 1, 4-dioxane (5 mL) and H ₂ In O (1 mL)The mixture was added with methyl 2-chloro-4, 6-dimethylpyrimidine-5-carboxylate (described in example 53) (199mg, 0.99mmol) and K ₂ CO ₃ (274mg, 2.0mmol) and Pd (dppf) Cl ₂ (48.4 mg, 0.07mmol) and the resulting mixture was stirred under nitrogen at 110 ℃ for 16h. After filtration, the filtrate is taken with H ₂ O (20 mL) diluted, it was extracted with EtOAc (20mL x 2). The combined organic layers were washed with water and brine (30 mL each) and Na ₂ SO ₄ Dried and concentrated. The residue was purified by preparative TLC (eluent: 10% EtOAC in petroleum ether) to give methyl 2- (4- (cyclohexyloxy) phenyl) -4, 6-dimethylpyrimidine-5-carboxylate as a white solid (110mg, 59% yield). LCMS (ESI): [ M + H ]] ⁺ ＝341.0。

And 4, step 4: to a solution of methyl 2- (4- (cyclohexyloxy) phenyl) -4, 6-dimethylpyrimidine-5-carboxylate (110mg, 0.32mmol) in methanol (10 mL) was added a 1.0M aqueous NaOH solution (1.62mL, 1.62mmol), and the mixture was stirred at 80 ℃ for 4h. With saturated KHSO ₄ The reaction mixture was adjusted to pH =4 with water, to which EtOAc (40 mL) was added. The organic layer was washed with brine (30mL x 2) and Na ₂ SO ₄ Drying and concentration gave compound 496-3 as a white solid (100mg, 95% yield), which was used directly in the next step.

Compound 496-4 was prepared from compound 101-G and (S) -2- (((benzyloxy) carbonyl) amino) -4- (((2- (trimethylsilyl) ethoxy) carbonyl) amino) butanoic acid using conditions analogous to those described for example E. LCMS (ESI): [ M + H ] ] ⁺ ＝958。

And 5: application of example E to compound 496-4 (3.37g, 3.52mmol) and compound 496-3 (1.26g, 3.87mmol) gave compound 496-5 (3.78g, 85%) as a white solid. LCMS (ESI) [ < M + H ]] ⁺ ＝1266。

Step 6 to a solution of 496-5 (3.05g, 2.41mmol) in THF (15 mL) was added a solution of tetrabutylammonium fluoride (1.0M, 3.6mL,3.6mmol in THF). The mixture was stirred at 50 ℃ for 18h. The mixture was cooled to room temperature and the solvent was removed. The residue was dissolved in ethyl acetate, washed with brine and Na ₂ SO ₄ Drying and removal of the solvent gave compound 496-6 (3.20 g) as an off-white solid118%). The residue was used without further purification. LCMS (ESI) [ < M + H ]] ⁺ ＝1122。

And 7: to compound 496-6 (280mg, 0.25mmol) in DCM (3 mL) at 0 deg.C was added DIPEA (0.07mL, 0.38mmol), followed by acetic anhydride (28mg, 0.28mmol). The mixture was stirred at 0 ℃ for 2h. The mixture was partitioned between DCM and water and the phases were separated. The organic layer was washed with brine, over Na ₂ SO ₄ Dried and the solvent removed. The residue was purified on a silica gel column (8% MeOH/DCM) to give compound 496-7 as a white solid (195mg, 67%). LCMS (ESI): [ M + H ]] ⁺ ＝1164。

And 8-9: starting from compound 496-7, using a typical hydrolysis, amide coupling (HATU/DIEA) and global Boc removal (TFA/HFIP) procedure (example G), compound 496 (trifluoroacetate salt) was obtained as a white solid. LCMS (ESI): t _R ＝3.18min,[M+H] ⁺ ＝988.4。 ¹ H NMR(400MHz,DMSO-d ₆ )δ9.05-8.96(m,2H),8.76(t,J＝5.8Hz,1H),8.37-8.28(m,5H),7.94(t,J＝5.8Hz,1H),7.28-6.93(m,7H),6.76-6.68(m,2H),6.39(s,1H),4.88-4.81(m,1H),4.78-4.67(m,2H),4.49-4.42(m,1H),4.19-4.15(m,2H),4.07-3.94(m,4H),3.23-3.14(m,3H),3.03-2.82(m,4H),2.84(s,3H),2.44(s,1H),1.99-1.92(m,2H),1.79(s,3H),1.77-1.69(m,3H),1.58-1.37(m,4H),1.33-1.23(m,1H),1.19(d,J＝7.2Hz,3H)。

Example 297: synthesis of Compound 497

Compound 497 (trifluoroacetate salt) is prepared as a white solid by using a similar method as described in example 296, using methanesulfonyl chloride instead of acetic anhydride in step 7. LCMS (ESI): t _R ＝3.30min,[M+H] ⁺ ＝1024.4。 ¹ H NMR(400MHz,DMSO-d ₆ )δ9.01-8.86(m,2H),8.67(t,J＝7.4Hz,1H),8.33-8.28(m,3H),7.30-7.02(m,9H),6.78-6.72(m,2H),6.42(s,1H),4.97-4.91(m,1H),4.77-4.69(m,2H),4.48-4.40(m,1H),4.28-4.03(m,7H),3.26-2.98(m,8H),2.90(s,3H),2.88(s,3H),2.00-1.91(m,3H),1.86-1.70(m,3H),1.59-1.51(m,1H),1.50-1.35(m,4H),1.33-1.24(m,1H),1.24(d,J＝6.6Hz,3H)。

Example 298: synthesis of Compound 498

Compound 498 (formate) is prepared as a white solid by using a similar method as described in example 296, using trimethyl isocyanate instead of acetic anhydride in step 7. LCMS (ESI): t _R ＝3.06min,[M+H] ⁺ ＝989.4。 ¹ H NMR(400MHz,DMSO-d ₆ )δ9.06-8.96(m,2H),8.78(t,J＝5.5Hz,1H),8.33-8.29(m,5H),7.21-7.18(m,1H),7.16-7.10(m,2H),7.07-7.02(m,4H),6.76-6.68(m,2H),6.39(s,1H),6.16-6.09(m,1H),5.51-5.39(m,2H),4.89-4.81(m,1H),4.78-4.67(m,2H),4.48-4.41(m,1H),4.22-4.14(m,2H),4.08-3.95(m,4H),3.21-2.85(m,7H),2.84(s,3H),2.45(s,1H),2.00-1.92(m,2H),1.92-1.84(m,1H),1.76-1.69(m,2H),1.58-1.51(m,1H),1.48-1.37(m,3H),1.33-1.24(m,1H),1.24(d,J＝6.4Hz,3H)。

Example 299: synthesis of Compound 499

Using the procedure in example 296, compound 499 (trifluoroacetate) was prepared as a white solid using trimethylsilyl isocyanate in place of acetic anhydride in step 7. LCMS (ESI): t _R ＝3.05min,[M+H] ⁺ ＝975.3。 ¹ H NMR(400MHz,DMSO-d ₆ )δ9.01-8.95(m,2H),8.70(t,J＝5.3Hz,1H),8.34-8.26(m,3H),7.88(br s,6H),7.28-7.03(m,6H),6.77-6.70(m,2H),6.41(s,1H),6.14-6.07(m,1H),5.78-5.64(m,2H),5.01-4.94(m,1H),4.79-4.66(m,2H),4.49-4.41(m,1H),4.28-4.08(m,7H),3.51-3.43(m,2H),3.24-3.00(m,8H),2.94(s,2H),2.47-2.44(m,1H),2.00-1.92(m,2H),1.77-1.69(m,2H),1.59-1.24(m,7H),1.21(d,J＝7.0Hz,3H)。

Example 300: synthesis of Compound 500

Compound 500 (trifluoroacetate) was prepared as a white solid using the procedure in example 296, using tert-butyl (chlorosulfonyl) carbamate (formed by mixing equimolar amounts of chlorosulfonyl isocyanate and tert-butanol in DCM) in place of acetic anhydride in step 7. LCMS (ESI): t _R ＝3.22min,[M+H] ⁺ ＝1025.4. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.01-8.95(m,2H),8.72-8.67(m,1H),8.34-8.25(m,3H),7.92-7.81(br s,6H),7.26-7.03(m,7H),6.75-6.68(m,3H),6.53(s,2H),6.45(s,1H),4.97-4.90(m,1H),4.79-4.69(m,2H),4.48-4.42(m,1H),4.25-4.10(m,6H),3.25-2.97(m,9H),2.89(s,3H),2.01-1.95(m,3H),1.83-1.69(m,3H),1.57-1.25(m,6H),1.21(d,J＝6.8Hz,3H)。

Example 301: synthesis of Compound 501

Compound 501 (formate) was prepared as a white solid using the procedure in example 296, trimethylsilyl isocyanate instead of acetic anhydride in step 7. LCMS (ESI): t _R ＝3.06min,[M+H] ⁺ ＝1003.5. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.11-8.99(m,2H),8.80(t,J＝5.6Hz,1H),8.35-8.28(m,4H),7.19-7.02(m,7H),6.76-6.70(m,2H),6.41(s,1H),6.05-5.96(m,1H),5.38(s,2H),4.86-4.68(m,4H),4.48-4.42(m,2H),4.21-4.13(m,2H),4.08-4.00(m,6H),3.22-3.07(m,2H),3.05-2.95(m,3H),2.86(s,6H),2.68-2.63(m,1H),2.48(s,4H),2.01-1.93(m,3H),1.80-1.70(m,3H),1.63-1.24(m,9H),1.20(d,J＝6.8Hz,3H)。

Example 302: synthesis of Compound 502

The method as described in example 296In a similar manner, compound 502 (trifluoroacetate salt) was prepared as a white solid in step 7 using tert-butyl (chlorosulfonyl) carbamate (formed by mixing equimolar amounts of chlorosulfonyl isocyanate and tert-butanol in DCM) in place of acetic anhydride. LCMS (ESI): t _R ＝3.09min,[M+H] ⁺ ＝1001.5. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.10-8.99(m,2H),8.80-8.74(m,1H),8.40(d,J＝8.8Hz,1H),8.35-8.29(m,4H),7.24-7.03(m,7H),6.74(dd,J＝1.6,13.2Hz,2H),6.65(s,3H),6.38(s,1H),5.13(dd,J＝7.6,13.6Hz,1H),4.77-4.70(m,2H),4.48-4.42(m,1H),4.21-4.15(m,2H),4.14-4.01(m,6H),3.18(d,J＝16.0Hz,2H),3.06-2.97(m,2H)2.95-2.91(m,6H),2.48(s,4H),2.46-2.43(m,1H),1.97(d,J＝6.4Hz,3H),1.78-1.73(m,3H),1.57-1.23(m,7H),1.20(d,J＝6.8Hz,3H)。

Example 303: synthesis of Compound 503

Compound 503 (trifluoroacetate salt) was prepared as a white solid using the procedure in example 296, using tert-butyl (chlorosulfonyl) carbamate (formed by mixing equimolar amounts of chlorosulfonyl isocyanate and tert-butanol in DCM) in place of acetic anhydride in step 7. LCMS (ESI): t _R ＝3.15min,[M+H] ⁺ ＝1039.6. ¹ H NMR(400MHz,DMSO-d ₆ )δ8.97(d,J＝6.8Hz,2H),8.70(t,J＝5.6Hz,1H),8.34-8.25(m,3H),7.94-7.88(m,6H),7.25-7.03(m,7H),6.73(t,J＝2.4Hz,2H),6.53-6.44(m,3H),4.82-4.69(m,3H),4.48-4.42(m,1H),4.25-4.11(m,6H),3.25-2.88(m,12H),2.49-2.43(m,4H),1.97-1.26(m,15H),1.22(d,J＝6.8Hz,3H)。

Example 304: synthesis of Compound 504

Step 1: a mixture of 496-6 (described in example 296) (280mg, 0.25mmol) and sodium formate (20.4 mg, 0.38mmol) in ethyl formate (4 mL) was subjected to 50 deg.CStirring for 18h. The mixture was partitioned between ethyl acetate and water and the phases were separated. The organic layer was washed with brine, over Na ₂ SO ₄ Dried and the solvent removed. The residue was purified by silica gel chromatography (eluting with 7% MeOH/DCM) to give compound 504-1 as a white solid (168mg, 58%). LCMS (ESI): [ M + H ] ] ⁺ ＝1150。

Starting from compound 504-1, typical hydrolysis, amide coupling (HATU/DIEA) and global Boc removal (TFA/HFIP) procedures (as described in examples 5 and 7) were applied to give compound 504 (formate salt) as a white solid. LCMS (ESI): t _R ＝3.70min,[M+H] ⁺ ＝974.3. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.05-8.97(m,2H),8.72-8.67(m,1H),8.38-8.00(m,6H),7.25-6.99(m,6H),6.80-6.67(m,2H),6.42(s,1H),4.89-4.82(m,1H),4.80-4.66(m,3H),4.49-4.40(m,2H),4.17(d,J＝5.7Hz,3H),4.13-4.00(m,6H),3.30-3.19(m,4H),3.05-2.90(m,6H),2.85(s,3H),2.68-2.63(m,1H),2.00-1.87(m,3H),1.82-1.68(m,3H),1.59-1.20(m,7H),1.19(d,J＝5.7Hz,3H)。

Example 305: synthesis of Compound 505

Compound 505 (formate) was prepared as a white solid from compound 101-G and compound 496-3 (described in example 296) by using a similar method to that described in example 7. LCMS (ESI): t _R ＝3.15min,[M+H] ⁺ ＝974.4. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.06-8.87(m,2H),8.74-8.63(m,1H),8.37-8.28(m,2H),8.25(s,1H),7.45-6.91(m,6H),6.88-6.66(m,2H),6.42(s,1H),4.96-4.58(m,3H),4.51-4.40(m,1H),4.17(d,J＝5.8Hz,2H),4.12-3.99(m,4H),3.25-3.09(m,1H),3.05-2.85(m,6H),2.34-2.22(m,2H),2.09-1.89(m,2H),1.84-1.67(m,2H),1.60-1.36(m,4H),1.35-1.17(m,4H)。

Example 306: synthesis of Compound 506

Step 1: after coupling of HATU with compound 101-G (357mg, 0.50mmol) and Fmoc-L-Asn (Trt) -OH (448mg, 0.75mmol), compound 506-1 (561mg, 87%) was obtained. LCMS (ESI) [ < M + H ]] ⁺ ＝1292。

And 2, step: to a solution of compound 506-1 (503mg, 0.389mmol) in DMF (3.0 mL) was added piperidine (0.385mL, 3.89mmol). The mixture was stirred at ambient temperature for 18h. The mixture was partitioned between ethyl acetate and water, and the organic layer was washed with brine, over Na ₂ SO ₄ Dried and the solvent removed. The crude residue was purified by silica gel chromatography (solvent gradient: 0-10% MeOH/DCM) to afford compound 506-2 as an off-white solid (300mg, 72%). LCMS (ESI) [ < M + H ]] ⁺ ＝1070。

Compound 506 (trifluoroacetate salt) was obtained as a white solid from compound 506-2 following typical amide coupling (HATU/DIEA), hydrolysis, amide coupling (HATU/DIEA) and global Boc/trityl removal (TFA/HFIP) procedures (as described in example G). LCMS (ESI): t _R ＝3.10min,[M+H] ⁺ ＝933.5. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.03(d,J＝7.7Hz,1H),8.50(d,J＝8.8Hz,1H),8.34-8.27(m,2H),7.84-7.76(m,1H),7.40(s,1H),7.10(s,1H),7.08-7.01(m,3H),6.99-6.90(m,2H),6.80-6.73(m,2H),6.31(s,1H),5.31-5.23(m,1H),4.68-4.58(m,2H),4.50-4.41(m,1H),4.08-3.96(m,4H),3.10-3.00(m,1H),2.95-2.83(m,5H),2.68-2.59(m,2H),2.42-2.38(m,1H),2.45(s,1H),2.01-1.90(m,2H),1.78-1.69(m,2H),1.59-1.22(m,6H),1.17(d,J＝6.5Hz,3H)。

Example 307: synthesis of Compound 507

Using an analogous method to that described in example R, (S) -2- (((benzyloxy) carbonyl) amino) -3- ((tert-butyldimethylsilyl) oxy) propionic acid, 2- [4- (cyclohexyloxy) phenyl]-4, 6-dimethyl-pyrimidine-5-carboxylic acid and compound 101-G, compound 507 prepared as a white solid and purified by chiral SFC. LCMS (ESI): t _R ＝3.06min,[M+H] ⁺ ＝960.3。 ¹ H NMR(400MHz,DMSO-d ₆ )δ9.08-8.93(m,2H),8.76-8.66(d,J＝7.1Hz,1H),8.36-8.25(m,2H),7.89(br s,6H),7.39-7.01(m,7H),6.78-6.68(m,2H),6.45(s,1H),5.03-4.93(m,1H),4.80-4.67(m,2H),4.50-4.40(m,1H),4.33-4.07(m,6H),3.82-3.74(m,1H),3.64-3.54(m,1H),3.24-2.97(m,6H),2.92(s,3H),2.69-2.62(m,1H),2.47(s,1H),2.43(s,1H),2.02-1.91(m,2H),1.79-1.68(m,2H),1.61-1.15(m,9H)。

Example 308: synthesis of Compound 508

Compound 508 was separated as the minor epimer from the synthesis of compound 507 by chiral SFC. LCMS (ESI): t _R ＝3.13min,[M+H] ⁺ ＝933.5. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.06(d,J＝7.1Hz,1H),8.66(t,J＝5.4Hz,1H),8.53(d,J＝9.0Hz,1H),8.74-8.49(m,2H),8.36-8.18(m,2H),7.86(br s,6H),7.32-7.22(m,1H),7.20-7.01(m,5H),6.94(s,1H),6.42(s,1H),5.04-4.93(m,1H),4.65-4.54(m,1H),4.50-4.40(m,1H),4.28-4.11(m,6H),3.97-3.86(m,1H),3.84-3.75(m,1H),3.65-3.56(m,1H),3.23-3.05(m,6H),3.01(s,3H),2.74-2.64(m,1H),2.41(s,1H),2.02-1.90(m,2H),1.80-1.68(m,2H),1.61-1.14(m,9H).

Example 309: synthesis of Compound 509

Using an analogous method to that described in example R, starting from (S) -2- (((benzyloxy) carbonyl) amino) -4- ((tert-butyldimethylsilyl) oxy) butanoic acid, 2- [4- (cyclohexyloxy) phenyl]4, 6-dimethyl-pyrimidine-5-carboxylic acid and Compounds 101-G Compound 509 (trifluoroacetate salt) was prepared as a white solid. LCMS (ESI): t _R ＝3.14min,[M+H] ⁺ ＝947.5。 ¹ H NMR(400MHz,DMSO-d ₆ )δ ¹ H NMR(400MHz,DMSO-d ₆ )δ8.98-8.95(m,2H),8.69(t,J＝4.5Hz,1H),8.33-8.23(m,3H),7.94-7.84(br s,6H),7.26-7.04(m,7H),6.76-6.70(m,2H),6.45(s,1H),5.18-4.97(m,2H),4.79-4.67(m,2H),4.49-4.42(m,2H),4.29-4.07(m,6H),3.56-3.50(m,2H),3.22-2.97(m,7H),2.89(s,3H),2.00-1.83(m,3H),1.79-1.69(m,3H),1.99-1.51(m,1H),1.50-1.35(m,4H),1.33-1.25(m,2H),1.21(d,J＝7.0Hz,3H)。

Example 310: synthesis of Compound 510

Step 1: to a mixture of compound 496-4 (described in example 296) (479mg, 0.50mmol) and (2S) -2- (9H-fluoren-9-ylmethoxycarbonylamino) butanoic acid (195mg, 0.60mmol) in DCM (7 mL) was added DIPEA (0.17mL, 1mmol) followed by HATU (247mg, 0.65mmol) in portions. The mixture was stirred at 20 ℃ for 16h. The mixture was diluted with DCM, washed with water, brine and then Na ₂ SO ₄ Dried and the solvent removed. The crude product was purified by silica gel chromatography (solvent gradient: 70-80% ethyl acetate/cyclohexane) to give compound 510-1 (435mg, 69%) as a colorless oil. LCMS (ESI): [ M + H ]] ⁺ ＝1265。

And 2, step: to compound 510-1 (432mg, 0.34mmol) in DMF (4 mL) was added piperidine (0.34mL, 3.41mmol) and the mixture was stirred at 20 ℃ for 16h. The mixture was diluted with water and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, over Na ₂ SO ₄ Dried and the solvent removed. The residue was purified by silica gel chromatography (solvent gradient: 7-10% MeOH/DCM) to give compound 510-2 as a white solid (313mg, 88%). LCMS (ESI): [ M + H ]] ⁺ ＝1044。

And 3, step 3: the procedure of example G was applied to compound 510-2 to give compound 510-3 (133 mg, 33% over 3 steps) as a colorless glass. LCMS (ESI) [ < M + H ]] ⁺ ＝1376。

And 4, step 4: to a solution of compound 510-3 (130mg, 0.09mmol) in THF (2 mL) was added a solution of tetrabutylammonium fluoride (1.0M, 0.14mL,0.14mmol in THF), and the mixture was stirred at 60 ℃ for 24 hours. The mixture is cooled to the ringAmbient temperature and the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and brine and the phases were separated. The organic layer was washed with Na ₂ SO ₄ Dried and the solvent removed. The general global Boc removal procedure of example G (TFA/HFIP) was applied to afford compound 510 (trifluoroacetate salt) as a white solid. LCMS (ESI): t _R ＝2.86min,[M+H] ⁺ ＝1032.2。 ¹ H NMR(400MHz,DMSO-d ₆ )δ8.97(d,J＝8.0Hz,1H),8.79(d,J＝6.4Hz,1H),8.73(t,J＝5.6Hz,1H),8.59(d,J＝8.4Hz,1H),8.38(d,J＝8.8Hz,1H),8.31(d,J＝8.8Hz,2H),7.99-7.89(m,6H),7.79(s,3H),7.33-7.02(m,7H),6.71(s,2H),6.30(s,1H),4.96-4.89(m,1H),4.78-4.67(m,2H),4.47-4.33(m,2H),4.24-4.10(m,5H),3.27-2.81(m,9H),2.74(s,3H),2.47(s,4H),2.06-1.84(m,4H),1.78-1.23(m,11H),1.21(d,J＝6.8Hz,3H),0.97(t,J＝7.2Hz,3H)。

Example 311: synthesis of Compound 511

Step 1 and step 2: the procedure of example G was applied to compound 496-4 (described in example 296) (1.20g, 0.95mmol) to give compound 511-1 as a white foam (898 mg, s% over 2 steps 73). LCMS (ESI): [ M + H ]] ⁺ ＝1266。

And 3, step 3: to a solution of compound 511-1 (895mg, 0.69mmol) in THF (5 mL) was added a tetrabutylammonium fluoride solution (1.0M, 1mL,1mmol in THF). The mixture was stirred at 20 ℃ for 16h, then the temperature was raised to 50 ℃ and stirred for a further 6h. The mixture was cooled to ambient temperature and the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and brine and the phases were separated. The organic layer was collected and passed over Na ₂ SO ₄ Drying and removal of the solvent gave compound 511-2 as a white solid (888mg, 112%). The material was used directly in the next step without further purification. LCMS (ESI) [ < M + H ]] ⁺ ＝1146。

And 4, step 5: from compounds 511-2 and 2- [ tert-butyl (dimethyl) silyl]Starting with oxyacetic acid, amide coupling (HATU/DIEA) and Global application example G Boc removal (TFA/HFIP) procedure afforded compound 511 (trifluoroacetate salt) as a white solid. LCMS (ESI): t _R ＝3.05min,[M+H] ⁺ ＝1004.8。 ¹ H NMR(400MHz,DMSO-d ₆ )δ9.01(d,J＝7Hz,1H),8.96(d,J＝7.0Hz,1H),8.69(t,J＝5.5Hz,1H),8.32(d,J＝8.7Hz,2H),8.27(d,J＝8.7Hz,1H),7.94-7.80(br s,6H),7.28-7.02(m,7H),6.73(dd,J＝2.0,10.7Hz,2H),6.43(s,1H),4.89-4.66(m,4H),4.49-4.41(m,2H),4.28-4.08(m,6H),3.78(s,2H),3.32-2.97(m,9H),2.85(s,3H),2.03-1.92(m,3H),1.82-1.69(m,3H),1.60-1.35(m,5H),1.35-1.24(m,2H),1.21(d,J＝7.0Hz,3H)。

Example 312: synthesis of Compound 512

Step 1: to a solution of 1, 1' -carbonylimidazole (55mg, 0.34mmol) in THF (2.0 mL) at 20 ℃ under nitrogen was added dropwise a solution of compound 511-2 (195mg, 0.17mmol) in THF (2.0 mL). The mixture was stirred at 20 ℃ for 1 hour, then O- (tert-butyldimethylsilyl) hydroxylamine (75mg, 0.51mmol) was added. The mixture was stirred at 20 ℃ for 18h. The temperature was raised to 50 ℃ and stirred for a further 4h. The mixture was cooled to ambient temperature, partitioned between ethyl acetate and water, and the phases were separated. The organic layer was washed with 0.1M aqueous HCl, brine, and Na ₂ SO ₄ Dried and the solvent removed under reduced pressure. The residue was used in the next step without further purification. LCMS (ESI): [ M + H ]] ⁺ ＝1206。

And 2, step: the global Boc removal (TFA/HFIP) procedure of example G was applied to afford compound 512 (trifluoroacetate salt) as a white solid. LCMS (ESI): t _R ＝3.20min,[M+H] ⁺ ＝1005.7。 ¹ H NMR(400MHz,DMSO-d ₆ )δ9.01-8.95(m,2H),8.70(t,J＝5.5Hz,1H),8.60-8.51(br s,2H),8.35-8.25(m,4H),7.97-7.83(br s,6H),7.28-7.01(m,7H),6.87(t,J＝5.5Hz,1H),6.75-6.71(br s,2H),6.44(s,1H),4.87-4.79(m,2H),4.79-4.67(m,2H),4.50-4.41(m,2H),4.29-4.08(m,6H),3.26-2.96(m,9H),2.86(s,3H),2.01-1.93(m,3H),1.80-1.69(m,3H),1.60-1.50(m,1H),1.50-1.35(m,4H),1.35-1.25(m,2H),1.21(d,J＝7.0Hz,3H)。

Example 313: synthesis of Compound 513

Compound 513 (formate) was prepared as a white solid from compound 101-K by using an analogous method to that described in example 53. LCMS (methods 5-95AB, ESI): t _R ＝0.754min,[M+H] ⁺ ＝918.8； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.46(br s,3H),8.28(d,J＝8.4Hz,2H),7.32-7.26(m,3H),7.20(d,J＝8.4Hz,2H),7.09(d,J＝8.4Hz,1H),6.90(s,1H),6.75(brs,1H),6.45(s,1H),5.25-5.21(m,1H),4.85-4.78(m,2H),4.29-4.19(m,6H),3.23-3.05(m,8H),3.00(s,3H),2.69(t,J＝7.6Hz,2H),2.53(s,6H),2.33-2.22(m,1H),2.20-2.10(m,1H),1.70-1.64(m,2H),1.38-1.33(m,7H),0.92(t,J＝6.8Hz,3H)。

Examples 314 to 358: synthesis of Compounds 514-558

The compounds in table 3 below were prepared by using a similar method to that previously described.

TABLE 3

Example 359 Synthesis of Compound 559

Step 1. (4S,7S,10S) -10- ((S) -4- ((tert-butoxycarbonyl) amino) -2- (2- (4- (tert-butyl) phenyl) -4, 6-dimethylpyrimidine-5-carboxamido) -N-methylbutanamide) -1 ⁶ - (2- ((tert-Butoxycarbonyl) amino) ethoxy) -2 ⁶ -hydroxy-7-methyl-2 ⁵ -nitro-6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylic acid methyl ester

To a mixture of compound 559-1 (77.4 mg, 0.0746mmol) and acetic acid (1.0 mL, 17mmol) was added nitric acid (11. Mu.L, 0.22 mmol). The reaction mixture was stirred at room temperature for 2h. The reaction mixture was evaporated under reduced pressure and the resulting residue was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and evaporated in vacuo. The crude product was purified by flash chromatography on silica gel (4 g silica, solvent gradient: 0-5% methanol in dichloromethane) to yield 63.1mg (78%) of the title compound. LCMS (ESI): [ M + H ]] ⁺ ＝1082.45。

Step 2. (4S,7S,10S) -2 ⁵ -amino-10- ((S) -4- ((tert-butoxycarbonyl) amino) -2- (2- (4- (tert-butyl) phenyl) -4, 6-dimethylpyrimidine-5-carboxamido) -N-methylbutanamido) -1 ⁶ - (2- ((tert-butoxycarbonyl) amino) ethoxy) -2 ⁶ -hydroxy radicalMethyl 7-methyl-6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylate

To (4S,7S,10S) -10- ((S) -4- ((tert-butoxycarbonyl) amino) -2- (2- (4- (tert-butyl) phenyl) -4, 6-dimethylpyrimidine-5-carboxamido) -N-methylbutanamido) -1 ⁶ - (2- ((tert-Butoxycarbonyl) amino) ethoxy) -2 ⁶ -hydroxy-7-methyl-2 ⁵ To a solution of-nitro-6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylic acid methyl ester (63.1mg, 0.0583mmol) in ethanol (2.0 mL) was added palladium (10 wt.%, on carbon) (6.5mg, 0.0061mmol). The reaction mixture was purged with nitrogen, then with hydrogen, and stirred at room temperature under a hydrogen balloon for 24h. The reaction mixture was filtered through celite, rinsed with methanol, and the filtrate evaporated in vacuo to give the title compound (57.7 mg, 94%). LCMS (ESI): [ M + H ]] ⁺ ＝1052.4。

Step 3. (4S,7S,10S) -2 ⁵ -acetamido-10- ((S) -4- ((tert-butoxycarbonyl) amino) -2- (2- (4- (tert-butyl) phenyl) -4, 6-dimethylpyrimidine-5-carboxamido) -N-methylbutanamido) -1 ⁶ - (2- ((tert-Butoxycarbonyl) amino) ethoxy) -2 ⁶ -hydroxy-7-methyl-6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylic acid methyl ester

To (4S,7S,10S) -2 ⁵ -amino-10- ((S) -4- ((tert-butoxycarbonyl) amino) -2- (2- (4- (tert-butyl) phenyl) -4, 6-dimethylpyrimidine-5-carboxamido) -N-methylbutanamido) -1 ⁶ - (2- ((tert-Butoxycarbonyl) amino) ethoxy) -2 ⁶ To a solution of methyl (57.7 mg, 0.0548mmol) of-hydroxy-7-methyl-6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylate in dichloromethane (1.5 mL) was added acetic anhydride (16. Mu.L, 0.169 mmol) and pyridine (27. Mu.L, 0.330 mmol). The reaction mixture was stirred at room temperature for 2h. The reaction mixture was evaporated onto celiteAnd the crude product was purified by flash chromatography on silica gel (4 g silica, solvent gradient: 0-5% methanol in DCM) to give 60.0mg (69%) of the title compound. LCMS (ESI): [ M + H ]] ⁺ ＝1094.5。

Step 4. (4S,7S,10S) -2 ⁵ -acetamido-10- ((S) -4- ((tert-butoxycarbonyl) amino) -2- (2- (4- (tert-butyl) phenyl) -4, 6-dimethylpyrimidine-5-carboxamido) -N-methylbutanamido) -1 ⁶ - (2- ((tert-butoxycarbonyl) amino) ethoxy) -2 ⁶ -hydroxy-7-methyl-6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylic acid

To (4S,7S,10S) -2 ⁵ -acetamido-10- ((S) -4- ((tert-butoxycarbonyl) amino) -2- (2- (4- (tert-butyl) phenyl) -4, 6-dimethylpyrimidine-5-carboxamido) -N-methylbutanamido) -1 ⁶ - (2- ((tert-butoxycarbonyl) amino) ethoxy) -2 ⁶ To a solution of methyl-hydroxy-7-methyl-6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylate (41.3mg, 0.0377mmol) in tetrahydrofuran (1.0 mL) were added water (0.20 mL) and lithium hydroxide (1.0M aqueous solution) (0.10mL, 0.10mmol). The reaction mixture was stirred at room temperature for 1h. The reaction mixture was evaporated in vacuo and used without further purification, assuming quantitative yield. LCMS (ESI) [ < M + H ]] ⁺ ＝1081.25。

Step 5. ((S) -4- (((3S, 6S, 9S) -1) ⁵ -acetamido-2 ⁶ - (2- ((tert-butoxycarbonyl) amino) ethoxy) -9- ((cyanomethyl) carbamoyl) -1 ⁶ -hydroxy-6-methyl-4, 7-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecan-3-yl) (methyl) amino) -3- (2- (4- (tert-butyl) phenyl) -4, 6-dimethylpyrimidine-5-carboxamido) -4-oxobutyl) carbamic acid tert-butyl ester

To (4S,7S,10S) -2 ⁵ -acetamido-10- ((S) -4- ((tert-butoxycarbonyl)Yl) amino) -2- (2- (4- (tert-butyl) phenyl) -4, 6-dimethylpyrimidine-5-carboxamido) -N-methylbutanamido) -1 ⁶ - (2- ((tert-Butoxycarbonyl) amino) ethoxy) -2 ⁶ To a mixture of-hydroxy-7-methyl-6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylic acid (0.0377mmol ), aminoacetonitrile hydrochloride (7.5mg, 0.081mmol), HATU (32.0mg, 0.0825mmol) and DMF (1.0 mL) was added N, N-diisopropylethylamine (33. Mu.L, 0.189 mmol). The reaction mixture was stirred at room temperature for 3h. To the reaction mixture were added 8.6mg of aminoacetonitrile hydrochloride, 50uL of N, N-diisopropylethylamine and 31.6mg of HATU. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with 2. The crude product was purified by flash chromatography on silica gel (4 g silica, solvent gradient: 0-10% methanol in dichloromethane) to yield 33.1mg (42%) of the title compound. LCMS (ESI) [ < M + H ] ] ⁺ ＝1118。

Step 6. (4S,7S,10S) -2 ⁵ -acetamido-10- ((S) -4-amino-2- (2- (4- (tert-butyl) phenyl) -4, 6-dimethylpyrimidine-5-carboxamido) -N-methylbutanamido) -1 ⁶ - (2-aminoethoxy) -N- (cyanomethyl) -2 ⁶ -hydroxy-7-methyl-6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxamide

To ((S) -4- (((3S, 6S, 9S) -1) ⁵ -acetamido-2 ⁶ - (2- ((tert-butoxycarbonyl) amino) ethoxy) -9- ((cyanomethyl) carbamoyl) -1 ⁶ To a solution of tert-butyl (33.1mg, 0.0296mmol) of-hydroxy-6-methyl-4, 7-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecan-3-yl) (methyl) amino) -3- (2- (4- (tert-butyl) phenyl) -4, 6-dimethylpyrimidine-5-carboxamido) -4-oxobutyl) carbamate (1, 3-hexafluoro-2-propanol (1.0 mL) was added trifluoroacetic acid (0.1mL, 1mmol). The reaction mixture was stirred at room temperature for 2h. The reaction mixture was evaporated in vacuo and azeotroped with diethyl ether (2 × 2 mL). The resulting residue was purified by reverse phase preparative HPLC and lyophilized to give 3.4mg (12%) of the title compound. LCMS (method A, ESI): t _R ＝4.443min,[M+H] ⁺ ＝918.4； ¹ H NMR(400MHz,DMSO-d ₆ )δ9.92(s,1H),9.20–9.07(m,2H),9.00(d,J＝7.9Hz,1H),8.73–8.65(m,1H),8.58–8.41(m,1H),8.36–8.28(m,3H),7.56(d,J＝8.5Hz,3H),7.22–7.12(m,3H),6.86–6.47(m,3H),6.43(s,1H),5.04(s,1H),4.84–4.63(m,2H),4.37–4.12(m,5H),3.20(d,J＝4.9Hz,3H),3.12(d,J＝3.5Hz,3H),2.95(d,J＝15.8Hz,6H),2.18–2.01(m,5H),1.33(d,J＝2.2Hz,12H),1.21(d,J＝6.9Hz,3H)。

Example 360 Synthesis of Compound 560

Step 1 methyl (S) -2- ((tert-butoxycarbonyl) amino) -3- (3-fluoro-4-hydroxy-5-iodophenyl) propanoate

To a solution of methyl (2S) -2- (tert-butoxycarbonylamino) -3- (3-fluoro-4-hydroxy-phenyl) propionate (1.4814g, 4.256mmol) in methanol (10.0 mL) were added silver sulfate (1.418g, 4.548mmol) and iodine (1.123g, 4.40mmol) in this order. The reaction mixture was stirred at room temperature for 2h. The reaction was quenched with sodium thiosulfate and extracted with ethyl acetate. The organic portion was dried over brine and magnesium sulfate, filtered, and evaporated in vacuo. The crude product was purified by flash chromatography on silica gel (40 g silica, solvent gradient: 0-100% ethyl acetate in dichloromethane) to yield 1.5246g (81%) of the title compound. LCMS (ESI) [ M + Na ] ] ⁺ ＝461.95。

Step 2 methyl (S) -3- (4- (benzyloxy) -3-fluoro-5-iodophenyl) -2- ((tert-butoxycarbonyl) amino) propanoate

To methyl (S) -2- ((tert-butoxycarbonyl) amino) -3- (3-fluoro-4-hydroxy-5-iodophenyl) propionate (1.5246g, 3.471mmol), potassium carbonate (962mg, 6.9604mmol) and N, N-dimethylformamide (12)mL) was added benzyl bromide (0.50mL, 4.2mmol). The reaction mixture was stirred at room temperature for 19h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered, and evaporated in vacuo. The crude product was purified by flash chromatography on silica gel (40 g silica, solvent gradient: 0-50% ethyl acetate in heptane) to yield 1.6527g (95%) of the title compound as a clear colorless gum. LCMS (ESI) [ M + Na ]] ⁺ ＝552.0。

Step 3 methyl (S) -3- (4- (benzyloxy) -3-fluoro-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -2- ((tert-butoxycarbonyl) amino) propanoate

Methyl (S) -3- (4- (benzyloxy) -3-fluoro-5-iodophenyl) -2- ((tert-butoxycarbonyl) amino) propanoate (1.6527g, 3.122mmol), bis (pinacol) diboron (1.3990g, 5.455mmol), potassium acetate (0.985g, 9.94mmol), dichloromethane complexed [1,1' -bis (diphenylphosphino) ferrocene ]A mixture of palladium (II) chloride (1) (0.289g, 0.354mmol) and dimethyl sulfoxide (10.0 mL) was heated at 70 ℃ under nitrogen for 16h. The reaction mixture was diluted with ethyl acetate, washed with water (2 ×), brine, dried over magnesium sulfate, filtered, and evaporated in vacuo. The crude product was purified by flash chromatography on silica gel (40 g silica, solvent gradient: 0-100% ethyl acetate in dichloromethane) to yield 0.9468g (57%) of the title compound. LCMS (ESI) [ M + H-Boc ]] ⁺ ＝430.15,[M+NH ₄ ] ⁺ ＝547.25。 ¹ H NMR(400MHz,DMSO-d ₆ )δ7.54–7.49(m,2H),7.41–7.22(m,6H),4.96(s,2H),4.15(td,J＝9.4,4.7Hz,1H),3.62(s,3H),2.99(dd,J＝13.7,4.7Hz,1H),2.82(dd,J＝13.8,10.4Hz,1H),1.32(s,9H),1.29(s,12H)。

Step 4 methyl (S) -2-amino-3- (4- (benzyloxy) -3-fluoro-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) propanoate

To a solution of methyl (S) -3- (4- (benzyloxy) -3-fluoro-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -2- ((tert-butoxycarbonyl) amino) propanoate (945mg, 1.785 mmol) in dichloromethane (8 mL) was added trifluoroacetic acid (1.0ml, 13mmol). The reaction mixture was stirred at room temperature. After 7h, the reaction mixture was evaporated in vacuo to give the title compound as a TFA salt, which was used without further purification. LCMS (ESI) [ < M + H ]] ⁺ ＝430。

Step 5. (5S, 8S, 11S) -11- (4- (benzyloxy) -3-fluoro-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) -5- (4- (2- ((tert-butoxycarbonyl) amino) ethoxy) -3-iodophenyl) -4, 8-dimethyl-3, 6, 9-trioxo-1-phenyl-2-oxa-4, 7, 10-triazadecane-12-oic acid methyl ester

To (2S) -2- [ [ (2S) -2- [ benzyloxycarbonyl (methyl) amino group]-2- [4- [2- (tert-butoxycarbonylamino) ethoxy]-3-iodo-phenyl]Acetyl group]Amino group]To a solution of propionic acid (1.011g, 1.542mmol) in THF (5 mL) was added 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine (365.9mg, 2.084mmol) and 4-methylmorpholine (0.90mL, 8.2mmol). After 20 minutes, a solution of methyl (S) -2-amino-3- (4- (benzyloxy) -3-fluoro-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) propanoate (1.785mmol ) in THF (5 mL) was added. The reaction mixture was stirred at room temperature for 16h. The reaction mixture was diluted with ethyl acetate, washed with water (2 ×), brine, dried over magnesium sulfate, filtered, and evaporated in vacuo. The crude product was purified by flash chromatography on silica gel (40 g silica, solvent gradient: 0-5% methanol in dichloromethane) to yield 1.412g (86%) of the title compound. LCMS (ESI) ([ M + H-tBu)] ⁺ ＝1011.20,[M+NH ₄ ] ⁺ ＝1084.30。

Step 6 (4S,7S,10S) -2 ⁶ - (benzyloxy) -10- (((benzyloxy) carbonyl) (methyl) amino) -1 ⁶ - (2- ((tert-Butoxycarbonyl) amino) ethoxy) -2 ⁵ -fluoro-7-methyl-6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylic acid methyl ester

To a mixture of (5S, 8S, 11S) -11- (4- (benzyloxy) -3-fluoro-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) -5- (4- (2- ((tert-butoxycarbonyl) amino) ethoxy) -3-iodophenyl) -4, 8-dimethyl-3, 6, 9-trioxo-1-phenyl-2-oxa-4, 7, 10-triazadecane-12-oic acid methyl ester (1.412g, 1.324mmol) and tripotassium phosphate (388mg, 4.0766mmol) in acetonitrile (60 mL) was added water (6.0 mL), followed by [1,1' -bis (diphenylphosphino) ferrocene complexed with dichloromethane ]Palladium (II) chloride (1) (169.0 mg,0.2070 mmol). The reaction mixture was heated at 70 ℃ for 90min under a nitrogen balloon. The reaction mixture was evaporated under reduced pressure to remove most of the acetonitrile. The residual material was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered and evaporated in vacuo. The crude product was purified by flash chromatography on silica gel (40 g silica, solvent gradient: 0-5% methanol in dichloromethane) to yield 335.0mg (31%) of the title compound. LCMS (ESI) [ < M + H ]] ⁺ ＝813.3。

Step 7. (4S,7S,10S) -1 ⁶ - (2- ((tert-Butoxycarbonyl) amino) ethoxy) -2 ⁵ -fluoro-2 ⁶ -hydroxy-7-methyl-10- (methylamino) -6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylic acid methyl ester

Mixing (4S,7S,10S) -2 ⁶ - (benzyloxy) -10- (((benzyloxy) carbonyl) (methyl) amino) -1 ⁶ - (2- ((tert-Butoxycarbonyl) amino) ethoxy) -2 ⁵ A suspension of-fluoro-7-methyl-6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylic acid methyl ester (335mg, 0.4121mmol) in ethanol (3 mL) was purged with nitrogen. Ammonium formate (411.1mg, 6.520mmol) and palladium hydroxide (20 wt.%, carbon-supported) (139.7 mg, 0.1990mmol) were added, and the reaction mixture was stirred at room temperatureHeating at 100 deg.C for 20 min under microwave radiation. 72.7mg of palladium hydroxide (20 wt.%, carbon supported) and 220.3mg of ammonium formate were added and the mixture was heated under microwave irradiation at 100 ℃ for 45 minutes. The reaction mixture was filtered through celite, rinsing with dichloromethane. The filtrate was further diluted with dichloromethane and washed with aqueous sodium bicarbonate to remove formate. The aqueous layer was extracted with an additional portion of DCM and the combined DCM portions were dried over brine and magnesium sulfate, filtered and evaporated in vacuo to give 261.8mg (quantitative) of the title compound which was used without further purification. LCMS (ESI) [ < M + H ] ] ⁺ ＝589.25。

Step 8. (4S, 7S, 10S) -10- ((S) -2- ((((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -4- ((tert-butoxycarbonyl) amino) -N-methylbutanamido) -1 ⁶ - (2- ((tert-butoxycarbonyl) amino) ethoxy) -2 ⁵ -fluoro-2 ⁶ -hydroxy-7-methyl-6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylic acid methyl ester

To a solution of (2S) -4- (tert-butoxycarbonylamino) -2- (9H-fluoren-9-ylmethoxycarbonylamino) butanoic acid (196.0 mg, 0.4449mmol) in THF (1.0 mL) were added 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine (117.1mg, 0.6670mmol) and 4-methylmorpholine (0.20mL, 1.8mmol). After 20 minutes, (4S,7S,10S) -1 was added ⁶ - (2- ((tert-butoxycarbonyl) amino) ethoxy) -2 ⁵ -fluoro-2 ⁶ -hydroxy-7-methyl-10- (methylamino) -6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylic acid methyl ester (261.8mg, 0.4003mmol) in THF (2 mL). The reaction mixture was stirred at room temperature for 2h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered, and evaporated in vacuo. The crude product was purified by flash chromatography on silica gel (12 g silica, solvent gradient: 0-100% ethyl acetate in dichloromethane) to yield 273.4mg (68%) of the title compound. LCMS (ESI) [ < M + H ] ] ⁺ ＝1011.40。

Step 9. (4S,7S,10S) -10- ((S) -2-amino-4- ((tert-butoxycarbonyl) amino) -N-methylbutanamideRadical) -1 ⁶ - (2- ((tert-butoxycarbonyl) amino) ethoxy) -2 ⁵ -fluoro-2 ⁶ -hydroxy-7-methyl-6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylic acid methyl ester

To (4S,7S,10S) -10- ((S) -2- (((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -4- ((tert-butoxycarbonyl) amino) -N-methylbutanamido) -1 ⁶ - (2- ((tert-butoxycarbonyl) amino) ethoxy) -2 ⁵ -fluoro-2 ⁶ To a solution of methyl-hydroxy-7-methyl-6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylate (273.4mg, 0.2704mmol) in THF (3.0 mL) was added tetrabutylammonium fluoride (1 mol/L in THF, 0.55mL, 0.55mmol). The reaction mixture was stirred at room temperature. After 4h, the reaction mixture was partitioned between heptane (50 mL) and water (50 mL) and 5mL of 10% aqueous citric acid was added. The organic layer was extracted again with 10% aqueous citric acid. The combined aqueous portions were adjusted to pH-8 with solid sodium bicarbonate and extracted with DCM (3x 50mL). The combined dichloromethane fractions were dried over magnesium sulfate, filtered, and evaporated in vacuo to give the title compound in quantitative yield, which was used without further purification. LCMS (ESI): [ M + H ]] ⁺ ＝789.40。

Step 10. (4S,7S,10S) -10- ((S) -4- ((tert-butoxycarbonyl) amino) -2- (2- (4- (tert-butyl) phenyl) -4, 6-dimethylpyrimidine-5-carboxamido) -N-methylbutanamido) -1 ⁶ - (2- ((tert-Butoxycarbonyl) amino) ethoxy) -2 ⁵ -fluoro-2 ⁶ -hydroxy-7-methyl-6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylic acid methyl ester

To a solution of 2- (4-tert-butylphenyl) -4, 6-dimethyl-pyrimidine-5-carboxylic acid (91.5mg, 0.322mmol) in tetrahydrofuran (2 mL) was added triethylamine (0.20mL, 1.4 mmol), followed by addition of thionyl chloride (42. Mu.L, 0.577 mmol). The reaction mixture was stirred at room temperatureFor 10 minutes, then evaporated in vacuo. The resulting residue was suspended in 2mL THF. Half of this THF solution (approximately 0.161 mmol) was added to 0 deg.C cooled (4S,7S,10S) -10- ((S) -2-amino-4- ((tert-butoxycarbonyl) amino) -N-methylbutanamido) -1 ⁶ - (2- ((tert-butoxycarbonyl) amino) ethoxy) -2 ⁵ -fluoro-2 ⁶ -hydroxy-7-methyl-6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylic acid methyl ester (0.135mmol ) and triethylamine (60.0. Mu.L, 0.426 mmol) in tetrahydrofuran (2 mL). The reaction mixture was stirred at 0 ℃ and the ice bath was slowly warmed to room temperature. After 3h, the reaction mixture was evaporated onto celite and the crude product was purified by flash chromatography on silica gel (12 g silica, solvent gradient: 0-5% methanol in dichloromethane) to give 99.6mg (70%) of the title compound. LCMS (ESI) [ < M + H ] ] ⁺ ＝1055.50

Step 11. (4S,7S,10S) -10- ((S) -4-amino-2- (2- (4- (tert-butyl) phenyl) -4, 6-dimethylpyrimidine-5-carboxamido) -N-methylbutanamido) -1 ⁶ - (2-aminoethoxy) -N- (cyanomethyl) -2 ⁵ -fluoro-2 ⁶ -hydroxy-7-methyl-6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxamide

Following a procedure analogous to that described in example 559, steps 4-6, starting from (4S, 7S, 10S) -10- ((S) -4- ((tert-butoxycarbonyl) amino) -2- (2- (4- (tert-butyl) phenyl) -4, 6-dimethylpyrimidine-5-carboxamide) -N-methylbutanamido) -1 ⁶ - (2- ((tert-butoxycarbonyl) amino) ethoxy) -2 ⁵ -fluoro-2 ⁶ -hydroxy-7-methyl-6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylic acid methyl ester the title compound was prepared as TFA salt. LCMS (method A, ESI): t _R ＝4.499min,[M+H] ⁺ ＝879.4； ¹ H NMR(400MHz,DMSO-d ₆ )δ9.17(d,J＝7.3Hz,1H),8.99(d,J＝7.9Hz,1H),8.70(t,J＝5.6Hz,1H),8.45(d,J＝9.0Hz,1H),8.37–8.30(m,2H),7.56(d,J＝8.6Hz,2H),7.22–7.07(m,3H),6.81(s,1H),6.52(s,1H),6.43(s,1H),5.04(q,J＝7.7Hz,1H),4.80-4.64(m,2H),4.33-4.21(m,2H),4.19–4.15(m,2H),3.46-3.38(m,2H),3.24-3.18(m,3H),3.17–3.07(m,1H),3.03–2.93(m,3H),2.91(s,3H),2.54(s,1H),2.47-2.44(m,1H),2.14–1.89(m,2H),1.34(s,11H),1.21(d,J＝6.7Hz,3H)。

Example 361: synthesis of Compound 561

Step 1: ((S) -2- ((tert-Butoxycarbonyl) (methyl) amino) -2- (4-methoxyphenyl) acetyl) -L-alanine methyl ester

To a solution of ((S) -2- ((tert-butoxycarbonyl) (methyl) amino) -2- (4-hydroxyphenyl) acetyl) -L-alanine methyl ester (13.8mmol, 5.54g) in acetone (10 mL) were added potassium carbonate (14.25mmol, 1.97g) and iodomethane (14.25mmol, 2.02g), and the reaction was stirred at room temperature overnight. The solvent was evaporated. EtOAc was added and the mixture was filtered. The filtrate was washed with water and brine, over Na ₂ SO ₄ Drying and concentration gave compound 561-1 (1.355g, 100%) as an oil, which was used as such. (MS + 1) m/z 381.1.

Step 2: ((S) -2- ((tert-Butoxycarbonyl) (methyl) amino) -2- (3-iodo-4-methoxyphenyl) acetyl) -L-alanine methyl ester

To a 0 ℃ solution of compound 561-1 (3.562mmol, 1.355g) in methanol (50 mL) was added silver sulfate (3.740mmol, 1.166g) and iodine (3.740mmol, 949mg) in this order. The reaction mixture was stirred at room temperature for 1h. A10% (w/w) sodium thiosulfate solution was added until the reaction became pale yellow. Most of the methanol was evaporated by rotary evaporation, then saturated sodium bicarbonate and ethyl acetate were added. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was purified on silica gel, eluting with 0-3% MeOH in DCM to afford compound 561-2 (1.393g, 77.2%). (MS + 1) m/z 507.1.

And step 3: ((S) -2- ((tert-Butoxycarbonyl) (methyl) amino) -2- (3-iodo-4-methoxyphenyl) acetyl) -L-alanine

To a solution of compound 561-2 (2.751mmol, 1.393g) in THF (16 mL) at 0 deg.C was added lithium hydroxide, 0.5M aqueous solution (2.751mmol, 5.50mL). The reaction was stirred at room temperature for 2h. The reaction mixture was cooled to 0 ℃ and adjusted to pH2-3 by addition of 0.5M HCl. Extraction with EtOAc, washing with brine, drying over MgSO4, and concentration in vacuo afforded crude compound 561-3 (1.353g, 99.9%) as a light tan solid, which was used without further purification. (MS + 1) m/z 493.0

And 4, step 4: (S) -2- ((tert-Butoxycarbonyl) amino) -3- (3, 5-diiodo-4-methoxyphenyl) propionic acid methyl ester

To a solution of methyl (S) -2- ((tert-butoxycarbonyl) amino) -3- (4-hydroxy-3, 5-diiodophenyl) propionate (1.10mmol, 5.471g) in acetone (50 mL) were added potassium carbonate (4.40mmol, 5.528g) and iodomethane (4.40mmol, 5.677g, 2.49mL), and the reaction was stirred at room temperature overnight. The solvent was evaporated. EtOAc was added and the mixture was filtered. The filtrate was washed with water and brine, over Na ₂ SO ₄ Dried and concentrated. The residue was purified on silica gel, eluted with 0-40% EtOAc in heptane to give compound 561-4 (95.321g, 94.82%) as a white foam. (MS + 1) m/z561.8

And 5: (S) -2- ((tert-Butoxycarbonyl) amino) -3- (3-hydroxy-5-iodo-4-methoxyphenyl) propionic acid methyl ester

A mixture of compound 561-4 (16.7 mmol, 9.40g) and trimethyl borate (83.7 mmol,8.7g, 9.53mL) in diethyl ether (100 mL) was cooled to-70 ℃. N-butyllithium (2.5 mol/L) in hexane (41.9 mmol,11.00g, 17mL) was added dropwise while maintaining the internal temperature below-65 ℃. The reaction mixture was allowed to warm to room temperature and stirred overnight.

The reaction mixture was cooled to 0 ℃ and treated with acetic acid (167mmol, 10.0g,9.6 mL) and hydrogen peroxide (30% w/w) in water (17.1 mL). The reaction mixture was stirred overnight and allowed to warm to room temperature. The reaction was quenched with saturated NH4Cl (aq) and extracted with isopropyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated. The residue was purified on silica gel, eluted with 0-50% EtOAc in heptane to afford compound 561-5 (2.45g, 32.5%) as a white foam. (MS + 1) m/z 452.3

Step 6: (S) -methyl 2- ((tert-butoxycarbonyl) amino) -3- (3-hydroxy-4-methoxy-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) propanoate

Compound 561-5 (4.63mmol, 2.09g), bis (pinacol) diboron (10.2mmol, 2.59g), potassium acetate (18.5mmol, 1.82g) and 1,1' -bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (0.463mmol, 386 mg) were suspended in anhydrous dimethyl sulfoxide (50 mL) (degassed by purging with nitrogen) and heated to 85 ℃ under nitrogen overnight. The reaction mixture was cooled to room temperature and then filtered through Celite. The filtrate was diluted with isopropyl 1 acetate and water and filtered through Celite. The layers were separated and the aqueous layer was extracted 3 times with isopropyl acetate. The combined organic layers were dried over MgSO4 and concentrated in vacuo. The dark brown residue was purified by flash chromatography (silica, 20-60% etoac in heptane) to yield compound 561-6 (1.743g, 83.4%) as a white solid. (MS + 1) m/z 452.1

And 7: (S) -2-amino-3- (3-hydroxy-4-methoxy-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) propanoic acid methyl ester

Compound 561-6 (1.405mmol, 634mg) in dichloromethane (4 mL) was cooled to 0 ℃ and treated with trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature for 2h. The mixture was concentrated. Et was added to the residue ₂ O, then concentrated. This process was repeated 2 more times. The residue was dried under high vacuum to give compound 561-7 (493.4 mg, 100.0%) which was used as such. (MS + 1) m/z 352.1

And 8: (6S, 9S, 12S) -12- (3-hydroxy-4-methoxy-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) -6- (3-iodo-4-methoxyphenyl) -2, 5, 9-tetramethyl-4, 7, 10-trioxo-3-oxa-5, 8, 11-triazatridecane-13-carboxylic acid methyl ester

To a solution of compound 561-7 (1.405mmol, 493.4mg) in acetonitrile (5 mL) and N, N-dimethylformamide (3 mL) was added 1-hydroxybenzotriazole hydrate (1.532mmol, 234.6mg), compound 561-3 (1.277mmol, 672mg), TEA (0.38mL, 0.38mmol), and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (3.192mmol, 611.9mg) at 0 ℃. The resulting mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with water, saturated NaHCO ₃ And brine, mgSO ₄ Drying and concentration under reduced pressure gave crude compound 561-8 as an off-white solid, which was used without further purification. (MS + 1) m/z 826.1

And step 9: (4S,7S,10S) -10- ((tert-butoxycarbonyl) (methyl) amino) -25-hydroxy-16, 26-dimethoxy-7-methyl-6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylic acid methyl ester

A mixture of compound 561-8 (2.000mmol, 1.651g), tripotassium phosphate (7.000mmol, 1.53g) and 1,1' -bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (0.2000mmol, 165mg) in degassed acetonitrile under nitrogen was heated at 65 ℃ for 2h. The reaction mixture was cooled to room temperature and washed with EtOAc and dilute NH ₄ And partitioning between Cl aqueous solutions. The aqueous phase was extracted twice with EtOAc. The combined organic layers were washed with water and brine, dried, and concentrated under reduced pressure. Purification by flash column chromatography (SiO 2; 0-100% EtOAc in DCM) gave compound 561-9 as an off-white solid (276 mg, 17.14%). (MS + 1) m/z 572.1

Step 10: (4S,7S,10S) -25- (2- (((benzyloxy) carbonyl) amino) ethoxy) -10- ((tert-butoxycarbonyl) (methyl) amino) -16, 26-dimethoxy-7-methyl-6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylic acid methyl ester

To a solution of compound 561-9 (0.249mmol, 142mg) and benzyl (2-bromoethyl) carbamate (0.746mmol, 203mg) in N, N-dimethylformamide (5 mL) was added cesium carbonate (1.243mmol, 405mg). The reaction mixture was stirred at room temperature overnight. The reaction was diluted with EtOAc and washed with water. The organic layer was washed with brine and concentrated. The residue was purified on silica gel, eluting with 0-2% MeOH in DCM to afford compounds 561-10 (124mg, 47.96%). (MS + 1) m/z 749.3

Step 11: (4S,7S,10S) -25- (2- (((benzyloxy) carbonyl) amino) ethoxy) -16, 26-dimethoxy-7-methyl-10- (methylamino) -6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylic acid methyl ester

10 (0.1416 mmol, 106mg) in dichloromethane (8 mL) was cooled to 0 ℃ and treated with trifluoroacetic acid (2 mL). The reaction mixture was stirred at room temperature for 1h. The mixture was concentrated. To the residueEt was added to the mixture ₂ O, then concentrated again. This process was repeated 2 more times. The residue was dried under high vacuum to give crude compound 561-11 (91.8 mg, 100%) which was used without further purification. (MS + 1) m/z 649.1

Step 12: (4S,7S,10S) -10- ((S) -4- (((benzyloxy) carbonyl) amino) -2- ((tert-butoxycarbonyl) amino) -N-methylbutanamido) -25- (2- (((benzyloxy) carbonyl) amino) ethoxy) -16, 26-dimethoxy-7-methyl-6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylic acid methyl ester

To a mixture of (2S) -4- (benzyloxycarbonylamino) -2- (tert-butoxycarbonylamino) butyric acid (0.2127mmol, 74.97mg) and compound 561-11 (0.1418mmol, 92mg) in N, N-dimethylformamide (5 mL) were added N, N-diisopropylethylamine (1.418mmol, 183mg, 0.247mL) and HATU (0.284mmol, 110mg). After stirring at room temperature for 15min, the reaction mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSO4, and concentrated. The residue was purified on silica gel, eluting with 0-5% MeOH in DCM to afford compounds 561-12 (128mg, 85.4%). (MS + 1) m/z 983.4

Step 13: (4S,7S,10S) -10- ((S) -2-amino-4- (((benzyloxy) carbonyl) amino) -N-methylbutanamido) -25- (2- (((benzyloxy) carbonyl) amino) ethoxy) -16, 26-dimethoxy-7-methyl-6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylic acid methyl ester

Compound 561-12 (0.2360mmol, 232mg) in dichloromethane (10 mL) was cooled to 0 ℃ and treated with trifluoroacetic acid (4 mL). The reaction mixture was stirred at room temperature for 0.5h, then concentrated. Et was added to the residue ₂ O, and concentrated again. This process was repeated 2 more times. The residue is dried under high vacuum to give compound 561-13, which continues without purificationThe preparation is used. (MS + 1) m/z 883.3

Step 14: (4S,7S, 10S) -10- ((S) -4- (((benzyloxy) carbonyl) amino) -2- (2- (4- (tert-butyl) phenyl) -4, 6-dimethylpyrimidine-5-carboxamido) -N-methylbutanamido) -25- (2- (((benzyloxy) carbonyl) amino) ethoxy) -16, 26-dimethoxy-7-methyl-6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylic acid methyl ester

To a mixture of 2- (4-tert-butylphenyl) -4, 6-dimethyl-pyrimidine-5-carboxylic acid (0.355mmol, 101mg) and compound 561-13 (0.237mmol, 209mg) in N, N-dimethylformamide (8 mL) were added N, N-diisopropylethylamine (2.367mmol, 306mg, 0.413ml) and HATU (0.473mmol, 1834mg). After stirring at room temperature for 15min, the reaction mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSO4, and concentrated. The residue was purified on silica gel, eluting with 0-10% MeOH in DCM to afford compounds 561-14 (138mg, 51%). (MS + 1) m/z 1149.5

Step 15: (4S,7S, 10S) -10- ((S) -4-amino-2- (2- (4- (tert-butyl) phenyl) -4, 6-dimethylpyrimidine-5-carboxamido) -N-methylbutanamido) -25- (2-aminoethoxy) -16, 26-dihydroxy-7-methyl-6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylic acid

Aluminum chloride (7.233mmol, 965mg) and 1-dodecanethiol (7.233mmol, 1.464mg, 1.73mL) in dichloromethane (15 mL) were stirred at room temperature for 0.5h. 14 (0.120mmol, 156mg) in dichloromethane (15 mL) was added gradually. The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was dried under high vacuum to give crude compound 561-15, which was used without further purification. (MS + 1) m/z 839.4

Step 16: (4S,7S, 10S) -10- ((S) -4-amino-2- (2- (4- (tert-butyl) phenyl) -4, 6-dimethylpyrimidine-5-carboxamido) -N-methylbutanamido) -25- (2-aminoethoxy) -16, 26-dihydroxy-7-methyl-6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylic acid methyl ester

To compound 561-15 (0.1204mmol, 101mg) in dry methanol (15 mL) was added thionyl chloride (1 mL). The reaction mixture was stirred at room temperature for 1h. The mixture was concentrated to provide crude compound 561-16, which was used without further purification.

And step 17: (4S,7S, 10S) -10- ((S) -4- ((tert-butoxycarbonyl) amino) -2- (2- (4- (tert-butyl) phenyl) -4, 6-dimethylpyrimidine-5-carboxamido) -N-methylbutanamido) -25- (2- ((tert-butoxycarbonyl) amino) ethoxy) -16, 26-dihydroxy-7-methyl-6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylic acid methyl ester

Acetone (15 mL) and 16 (0.1184mmol, 101mg) in water (5 mL) were treated with saturated aqueous K2CO3 to pH 9-10. Di-tert-butyl dicarbonate (1.184mmol, 266.4 mg) was then added and the reaction mixture was stirred at room temperature for 1h. The reaction mixture was extracted with EtOAc, and the organic layer was concentrated. The residue was purified on silica gel, eluted with 0-10% MeOH in DCM to afford compounds 561-17 (124.7 mg, 100.0%). (MS + 1) m/z 1053.6

Step 18: (4S,7S,10S) -10- ((S) -4- ((tert-butoxycarbonyl) amino) -2- (2- (4- (tert-butyl) phenyl) -4, 6-dimethylpyrimidine-5-carboxamido) -N-methylbutanamido) -25- (2- ((tert-butoxycarbonyl) amino) ethoxy) -16- ((tert-butoxycarbonyl) oxy) -26-hydroxy-7-methyl-6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylic acid methyl ester

A mixture of compounds 561-17 (0.1184mmol, 124.7mg), N-diisopropylethylamine (0.5920mmol, 76mg, 0.103mL) and di-tert-butyl dicarbonate (0.5920mmol, 133mg) in dichloromethane (20 mL) was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was purified on silica gel, eluting with 0-10% meoh in DCM, to give compounds 561-18 (117mg, 86%). (MS + 1) m/z 1154.2

Step 19: (4S,7S,10S) -10- ((S) -4- ((tert-butoxycarbonyl) amino) -2- (2- (4- (tert-butyl) phenyl) -4, 6-dimethylpyrimidine-5-carboxamido) -N-methylbutanamido) -25- (2- ((tert-butoxycarbonyl) amino) ethoxy) -16- ((tert-butoxycarbonyl) oxy) -26-hydroxy-7-methyl-6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylic acid

Compound 561-18 (0.101mmol, 116mg) was dissolved in 1, 4-dioxane (6 mL) and water (3 mL). Lithium hydroxide (0.5M, 0.304mmol, 0.61mL) was added dropwise at 0 deg.C, and the reaction mixture was stirred at room temperature for 1h. Water (6 mL) was added and the reaction mixture was acidified to pH 3 with 0.5M HCl. The resulting white precipitate was extracted with EtOAc, dried over MgSO4, filtered, and concentrated to give crude compounds 561-19 (106.8mg, 92.64%) as white solids, which were used as such. (MS + 1) m/z 1140.4

Step 20: (2- (((3S, 6S, 9S) -3- ((S) -4- ((tert-butoxycarbonyl) amino) -2- (2- (4- (tert-butyl) phenyl) -4, 6-dimethylpyrimidine-5-carboxamido) -N-methylbutanamido) -26- ((tert-butoxycarbonyl) oxy) -9- ((cyanomethyl) carbamoyl) -16-hydroxy-6-methyl-4, 7-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecan-15-yl) oxy) ethyl) carbamic acid tert-butyl ester

To the mixture of 561-19 (0.035mmol, 40mg), aminoacetonitrile hydrochloride (0.35mmol, 33mg)) To a mixture in N, N-dimethylformamide (5 mL) were added N, N-diisopropylethylamine (0.526 mmol,68mg, 0.092mL) and HATU (0.0526mmol, 21mg). The reaction was stirred at room temperature for 1h. The reaction mixture was diluted with EtOAc and washed with water. Na for organic layer ₂ SO ₄ Dried and concentrated. The residue was purified on silica gel, eluting with 0-10% MeOH in DCM to afford compounds 561-20 (17.1mg, 41.4%). (MS + 1) m/z 1177.8

Step 21: (4S,7S, 10S) -10- ((S) -4-amino-2- (2- (4- (tert-butyl) phenyl) -4, 6-dimethylpyrimidine-5-carboxamido) -N-methylbutanamido) -25- (2-aminoethoxy) -N- (cyanomethyl) -16, 26-dihydroxy-7-methyl-6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxamide

Trifluoroacetic acid (0.25 mL) and compound 561-20 (0.0145mmol, 17.1mg) in 1, 3-hexafluoro-2-propanol (4.75 mL) were stirred at room temperature for 1h. The reaction mixture was concentrated. Et was added to the residue ₂ O, and concentrating again; this process was repeated 2 more times. The residue was dried under high vacuum and then purified by reverse phase HPLC to give compound 561 (6 mg, 47.1%) as a white powder. (MS + 1) m/z 877.4

¹ H NMR (400 MHz, methanol-d 4) δ 8.34 (dd, J =8.7,2.2hz, 2h), 7.59-7.52 (m, 2H), 7.18 (dd, J =8.2,2.3hz, 1h), 7.07 (d, J =2.4hz, 1h), 7.01 (d, J =8.5hz, 1h), 6.90 (d, J =2.0hz, 1h), 6.43 (s, 1H), 5.26-5.19 (m, 2H), 4.28 (td, J =8.7,7.5,4.2hz, 2h), 4.20 (d, J =7.3hz, 1h), 3.46 (s, 1H), 3.41 (t, J =5.1hz, 3h), 3.15 (d, J =7.5hz, 3h), 3.04 (s, 1H), 2.99 (s, 3H), 2.30 (dq, J =14.2,7.2hz, 1h), 2.16 (dq, J =14.3,7.5hz, 1h), 1.38-1.33 (m, 9H).

Example 362: synthesis of Compound 562

Step 1: (S) -2-amino-3- (3-bromo-4-hydroxyphenyl) propionic acid methyl ester hydrochloride

To a solution of (2S) -2-amino-3- (3-bromo-4-hydroxy-phenyl) propionic acid (39.32mmol, 10.3g) in methanol (100 mL) at 0 deg.C was slowly added thionyl chloride (86.5mmol, 10,29g, 6.30mL). The resulting mixture was stirred at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was dried under high vacuum to give the title compound (12.21g, 100%) which was used without further purification. (MS + 1) m/z 272.0

Step 2: (S) -3- (3-bromo-4-hydroxyphenyl) -2- ((tert-butoxycarbonyl) amino) propionic acid methyl ester

To a mixture of methyl (S) -2-amino-3- (3-bromo-4-hydroxyphenyl) propionate hydrochloride (39.32mmol, 12.21g) in 1. The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched by addition of 1N HCl to pH 3-4. The aqueous layer was extracted twice with EtOAc (2X 100 mL) and the combined organic layers were washed with brine, na ₂ SO ₄ Dried and concentrated to give crude methyl (S) -3- (3-bromo-4-hydroxyphenyl) -2- ((tert-butoxycarbonyl) amino) propionate, which was used without further purification. (MS + 1) m/z 372.0

And step 3: (S) -3- (3-bromo-4-hydroxy-5-iodophenyl) -2- ((tert-butoxycarbonyl) amino) propionic acid methyl ester

To a solution of (S) -3- (3-bromo-4-hydroxyphenyl) -2- ((tert-butoxycarbonyl) amino) propionate (18.95mmol, 7.09g) in N, N-dimethylformamide (50 mL) was added N-iodosuccinimide (22.74mmol, 5.22g). The reaction was stirred at room temperature for 1h. The reaction mixture was partitioned between EtOAc and water. Organic layer with saturated NaHCO ₃ And washed with brine and Na ₂ SO ₄ DryingAnd concentrated. The residue was purified on silica gel, eluted with 15-30% EtOAc in heptane to give the title compound as a white solid (6.86g, 72.4%). (MS + 1) m/z 499.9

And 4, step 4: (S) -3- (3-bromo-5-iodo-4-methoxyphenyl) -2- ((tert-butoxycarbonyl) amino) propionic acid methyl ester

Methyl (S) -3- (3-bromo-4-hydroxy-5-iodophenyl) -2- ((tert-butoxycarbonyl) amino) propanoate (6.24mmol, 3.12g) was dissolved in acetone (50 mL) and treated sequentially with potassium carbonate (31.2mmol, 4.31g) and iodomethane (7.49mmol, 1.06g,0.466 mL). The solution was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was dissolved in EtOAc, which was washed with water and brine, over Na ₂ SO ₄ Dried and concentrated. The residue was purified by flash chromatography (0-40% etoac in heptane) to yield the title compound as a white foam (2.28g, 71.1%). (MS + 1) m/z 513.9

And 5: (S) -3- (3-bromo-5-hydroxy-4-methoxyphenyl) -2- ((tert-butoxycarbonyl) amino) propionic acid methyl ester

Bis (pinacol) diboron (8.046 mmol, 2.04g), (S) -methyl 3- (3-bromo-5-iodo-4-methoxyphenyl) -2- ((tert-butoxycarbonyl) amino) propanoate (5.364mmol, 2.76g), potassium acetate (13.41mmol, 1.32g) and 1,1' -bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (0.2682mmol, 223mg) were suspended in anhydrous dimethyl sulfoxide (50 mL) (degassed by purging with nitrogen) and heated to 65 ℃ under nitrogen overnight. The mixture was cooled to room temperature and filtered through Celite. The filtrate was diluted with 1. The layers were separated and the aqueous layer was extracted 3 times with EtOAc. The combined organic layers were dried over MgSO4 and concentrated in vacuo to give crude methyl (S) -3- (3-bromo-4-methoxy-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -2- ((tert-butoxycarbonyl) amino) propanoate as a dark brown gum which was used without further purification. (MS + 1) m/z 514.1

The above methyl (S) -3- (3-bromo-4-methoxy-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -2- ((tert-butoxycarbonyl) amino) propanoate (5.364mmol, 2.76g) was dissolved in methanol (24 mL) and hydrogen peroxide (30% aqueous solution) (8 mL) and stirred at room temperature for 1h. MeOH was removed under reduced pressure. To the residue was added EtOAc and brine. Separating the organic layer with Na ₂ SO ₄ Dried, filtered, and concentrated. The residue was purified on silica gel, eluting with 0-50% etoac in heptane, to give the title compound (1.15 g, 53% over 2 steps). (MS + 1) m/z 404.0

And 6: ((S) -2- (((benzyloxy) carbonyl) (methyl) amino) -2- (4-hydroxy-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) acetyl) -L-alanine tert-butyl ester

Bis (pinacol) diboron (19.22mmol, 4.88g), (tert-butyl 2S) -2- [ [ (2S) -2- [ benzyloxycarbonyl (methyl) amino ] -2- (4-hydroxy-3-iodo-phenyl) acetyl ] amino ] propanoate (12.01mmol, 6.827g), potassium acetate (36.03mmol, 3.536g) and 1,1' -bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (0.600600600mmol, 500mg) were suspended in anhydrous dimethyl sulfoxide (120 mL) (degassed by purging with nitrogen) and heated to 85 ℃ under nitrogen overnight. The reaction mixture was cooled to room temperature and then filtered through Celite. The filtrate was diluted with 1. The layers were separated and the aqueous layer was extracted 3 times with EtOAc. The combined organic layers were dried over MgSO4, concentrated in vacuo, and the residue was run through a flash silica column, eluting with 20-80% EtOAc in heptane to give the title compound (3.85g, 56.4%). (MS + 1) m/z 569.2

And 7: (S) -methyl 2- ((tert-butoxycarbonyl) amino) -3- (2 ', 5-dihydroxy-6-methoxy-5 ' - ((5S, 8S) -4,8, 11-tetramethyl-3, 6, 9-trioxo-1-phenyl-2, 10-dioxa-4, 7-diaza-dodec-5-yl) - [1,1' -biphenyl ] -3-yl) propionate

A mixture of ((S) -2- (((benzyloxy) carbonyl) (methyl) amino) -2- (4-hydroxy-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) acetyl) -L-alanine tert-butyl ester (3.42mmol, 1.94g), (S) -3- (3-bromo-5-hydroxy-4-methoxyphenyl) -2- ((tert-butoxycarbonyl) amino) propanoic acid methyl ester (2.85mmol, 1.92g), tripotassium phosphate (11.4 mmol,2.49g and chloro (crotyl) (tri-tert-butylphosphine) palladium (II) (0.285mmol, 120mg) in degassed acetonitrile (60 mL) and water (4 mL) was heated at 85 ℃ for 2h, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (0-50 EtOAc in DCM) to give the title compound (2.64g, 60.5 m. + 1) m/z 3.766)

And 8: ((S) -2- (5 '- ((S) -2-amino-3-methoxy-3-oxopropyl) -3', 6-dihydroxy-2 '-methoxy- [1,1' -biphenyl ] -3-yl) -2- (((benzyloxy) carbonyl) (methyl) amino) acetyl) -L-alanine

(S) -2- ((tert-Butoxycarbonyl) amino) -3- (2 ', 5-dihydroxy-6-methoxy-5 ' - ((5S, 8S) -4,8, 11-tetramethyl-3, 6, 9-trioxo-1-phenyl-2, 10-dioxa-4, 7-diaza-dodec-5-yl) - [1,1' -biphenyl ] in TFA (8 mL) and DCM (32 mL) ]Methyl-3-yl) propionate (1.72mmol, 2.64g) was stirred at room temperature overnight. The reaction mixture was concentrated. Et was added to the residue ₂ O and concentrated again and the process repeated twice more. The residue was dried under high vacuum to give the crude title compound (1.05g, 100%) which was used without further purification. (MS + 1) m/z 610.2

And step 9: (4S,7S,10S) -10- (((benzyloxy) carbonyl) (methyl) amino) -16, 25-dihydroxy-26-methoxy-7-methyl-6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylic acid methyl ester

To a solution of 50% (3.79mmol, 2.41g, 2.21mL) of 2,4, 6-tripropyl-1, 3,5,2,4, 6-trioxane-2, 4, 6-trioxide in DMF at room temperature and N, N-diisopropylethylamine (8.61mmol, 1.11g, 1.50mL) in N, N-dimethylformamide (42 mL) was added ((S) -2- (5 '- ((S) -2-amino-3-methoxy-3-oxopropyl) -3', 6-dihydroxy-2 '-methoxy- [1,1' -biphenyl ] -2, 6-trioxane-2, 4-trioxide]A solution of (E) -3-yl) -2- (((benzyloxy) carbonyl) (methyl) amino) acetyl) -L-alanine (1.72mmol, 1.05g) in N, N-dimethylformamide (43 mL). The resulting reaction mixture was stirred at room temperature for 1h. The reaction mixture was diluted with EtOAc and saturated NaHCO ₃ (aqueous solution) and brine wash. The organic layer was dried over MgSO4 and concentrated. The residue was purified on silica gel, eluting with 0-5% meoh in DCM, to give the title compound (747mg, 49.1%). (MS + 1) m/z 592.2

Step 10: (4S,7S, 10S) -10- (((benzyloxy) carbonyl) (methyl) amino) -16, 25-bis (2- ((tert-butoxycarbonyl) amino) ethoxy) -26-methoxy-7-methyl-6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylic acid methyl ester

To a solution of (4S,7S, 10S) -10- (((benzyloxy) carbonyl) (methyl) amino) -16, 25-dihydroxy-26-methoxy-7-methyl-6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylic acid methyl ester (0.322212mmol, 373.7mg) and N- (2-bromoethyl) carbamic acid tert-butyl ester (1.611mmol, 380mg) in N, N-dimethylformamide (10 mL) was added cesium carbonate (1.611mmol, 524.8mg). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and washed with water. The organic layer was washed with brine and concentrated. The residue was purified on silica gel, eluting with 0-5% meoh in DCM, to give the title compound (266mg, 48%). (MS + 1) m/z 878.0

Step 11: (4S,7S,10S) -16, 25-bis (2- ((tert-butoxycarbonyl) amino) ethoxy) -26-methoxy-7-methyl-10- (methylamino) -6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylic acid methyl ester

To a solution of (4S, 7S, 10S) -10- (((benzyloxy) carbonyl) (methyl) amino) -16, 25-bis (2- ((tert-butoxycarbonyl) amino) ethoxy) -26-methoxy-7-methyl-6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylic acid methyl ester (0.1545mmol, 266mg) in isopropanol (50 mL) was added 20 Pd (OH) ₂ (50 mg), and the reaction was placed under a hydrogen atmosphere. The reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered through Celite, and the filtrate was concentrated to give crude (4S, 7S, 10S) -16, 25-bis (2- ((tert-butoxycarbonyl) amino) ethoxy) -26-methoxy-7-methyl-10- (methylamino) -6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylic acid methyl ester (114.9mg, 100%) which was used without further purification. (MS + 1) m/z 744.0

Step 12: (4S, 7S, 10S) -10- ((S) -2- ((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -4- ((tert-butoxycarbonyl) amino) -N-methylbutanamide) -16, 25-bis (2- ((tert-butoxycarbonyl) amino) ethoxy) -26-methoxy-7-methyl-6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylic acid methyl ester

To a mixture of (2S) -4- (tert-butoxycarbonylamino) -2- (9H-fluoren-9-ylmethoxycarbonylamino) butanoic acid (0.232mmol, 102mg) and (4S, 7S, 10S) -16, 25-bis (2- ((tert-butoxycarbonyl) amino) ethoxy) -26-methoxy-7-methyl-10- (methylamino) -6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylic acid methyl ester (0.154mmol, 114mg) in N, N-dimethylformamide (5 mL) were added N, N-diisopropylethylamine (0.7724mmol, 99.8mg, 0.135mL) and HATU (0.3862mmol, 149.8mg). After stirring at room temperature for 0.5h, the reaction mixture was partitioned between EtOAc and water, washed with brine, and the organic layer was concentrated. The residue was purified on silica gel, eluting with 0-10% meoh in DCM, to give the title compound (286mg, 95%). (MS + 1) m/z 1167.4

Step 13: (4S,7S,10S) -10- ((S) -2-amino-4- ((tert-butoxycarbonyl) amino) -N-methylbutanamido) -16, 25-bis (2- ((tert-butoxycarbonyl) amino) ethoxy) -26-methoxy-7-methyl-6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylic acid methyl ester

A mixture of (4S, 7S, 10S) -10- ((S) -2- ((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -4- ((tert-butoxycarbonyl) amino) -N-methylbutanamido) -16, 25-bis (2- ((tert-butoxycarbonyl) amino) ethoxy) -26-methoxy-7-methyl-6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylic acid methyl ester (0.1471 mmol,286 mg) in 10% piperidine in DMF (10 mL) was stirred at room temperature for 10min, then concentrated and dried under high vacuum to give the crude title compound (138.9mg, 100%) which was used further without further purification. (MS + 1) m/z 944.6

Step 14: (4S,7S,10S) -10- ((S) -4- ((tert-butoxycarbonyl) amino) -2- (2- (4- (tert-butyl) phenyl) -4, 6-dimethylpyrimidine-5-carboxamido) -N-methylbutanamido) -16, 25-bis (2- ((tert-butoxycarbonyl) amino) ethoxy) -26-methoxy-7-methyl-6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylic acid methyl ester

To a solution of (4S,7S,10S) -10- ((S) -2-amino-4- ((tert-butoxycarbonyl) amino) -N-methylbutanamido) -16, 25-bis (2- ((tert-butoxycarbonyl) amino) ethoxy) -26-methoxy-7-methyl-6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylic acid methyl ester (0.1471mmol, 138.9mg) in N, N-dimethylformamide (5 mL) were added 2- (4-tert-butylphenyl) -4, 6-dimethyl-pyrimidine-5-carboxylic acid (0.1765mmol, 50.2mg), N-diisopropylethylamine (0.7356mmol, 95mg, 0.128mL) and HATU (0.2207mmol, 85.6mg). After stirring at room temperature for 0.5h, the reaction mixture was diluted with EtOAc and washed 3 times with water. The combined organic layers were concentrated and the residue was purified by silica gel chromatography eluting with 0-10% meoh in DCM to give the title compound (93mg, 52%). (MS + 1) m/z 1211.5

Step 15: (4S,7S, 10S) -10- ((S) -4-amino-2- (2- (4- (tert-butyl) phenyl) -4, 6-dimethylpyrimidine-5-carboxamido) -N-methylbutanamido) -16, 25-bis (2-aminoethoxy) -26-hydroxy-7-methyl-6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylic acid

Aluminum chloride (12.0mmol, 1.60g) and 1-dodecanethiol (12.0mmol, 2.43g, 2.88mL) in dichloromethane (10 mL) were stirred at room temperature for 0.5h, then added to a solution of (4S, 7S, 10S) -10- ((S) -4- ((tert-butoxycarbonyl) amino) -2- (2- (4- (tert-butyl) phenyl) -4, 6-dimethylpyrimidine-5-carboxamido) -N-methylbutanamido) -16, 25-bis (2- ((tert-butoxycarbonyl) amino) ethoxy) -26-methoxy-7-methyl-6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylic acid methyl ester (0.0732mmol, 148mg) in dichloromethane (10 mL) at room temperature. The resulting mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was dried under high vacuum to give the crude title compound, which was used without further purification. (MS + 1) m/z 883.4

Step 16: (4S,7S, 10S) -10- ((S) -4-amino-2- (2- (4- (tert-butyl) phenyl) -4, 6-dimethylpyrimidine-5-carboxamido) -N-methylbutanamide) -16, 25-bis (2-aminoethoxy) -26-hydroxy-7-methyl-6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylic acid methyl ester

To a solution of (4S,7S,10S) -10- ((S) -4-amino-2- (2- (4- (tert-butyl) phenyl) -4, 6-dimethylpyrimidine-5-carboxamido) -N-methylbutanamido) -16, 25-bis (2-aminoethoxy) -26-hydroxy-7-methyl-6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylic acid (0.07596mmol, 67mg) in anhydrous methanol (10 mL) was added thionyl chloride (15mmol, 1.80g, 1.1mL). The reaction mixture was stirred at room temperature for 1h. The mixture was concentrated to give the crude title compound, which was used in the next step without further purification. (MS + 1) m/z 896.8

And step 17: (4S,7S,10S) -10- ((S) -4- ((tert-butoxycarbonyl) amino) -2- (2- (4- (tert-butyl) phenyl) -4, 6-dimethylpyrimidine-5-carboxamido) -N-methylbutanamido) -16, 25-bis (2- ((tert-butoxycarbonyl) amino) ethoxy) -26-hydroxy-7-methyl-6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylic acid methyl ester

A mixture of (4S, 7S, 10S) -10- ((S) -4-amino-2- (2- (4- (tert-butyl) phenyl) -4, 6-dimethylpyrimidine-5-carboxamido) -N-methylbutanamido) -16, 25-bis (2-aminoethoxy) -26-hydroxy-7-methyl-6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylic acid methyl ester (0.07589NaHCO) suspended in acetone (10 mL) and water (5 mL) was taken up with a saturated mixture of ₃ The aqueous solution is treated to pH 9-10. A high excess of di-tert-butyl dicarbonate (1.518mmol, 341.5 mg) is then added and the reaction mixture is stirred at room temperature for 0.5h until complete conversion is observed. The reaction mixture was diluted with EtOAc and filtered through Celite. The organic layer was concentrated. The residue was purified on silica gel, eluting with 0-10% MeOH in DCM to give the title compound (51.3mg, 56.5%). (MS + 1) m/z 1196.8

Step 18: (4S, 7S, 10S) -10- ((S) -4- ((tert-butoxycarbonyl) amino) -2- (2- (4- (tert-butyl) phenyl) -4, 6-dimethylpyrimidine-5-carboxamido) -N-methylbutanamido) -16, 25-bis (2- ((tert-butoxycarbonyl) amino) ethoxy) -26-hydroxy-7-methyl-6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylic acid

(4S, 7S, 10S) -10- ((S) -4- ((tert-butoxycarbonyl) amino) -2- (2- (4- (tert-butyl) phenyl) -4, 6-dimethylpyrimidine-5-carboxamido) -N-methylbutanamido) -16, 25-bis (2- ((tert-butoxycarbonyl) amino) ethoxy) -26-hydroxy-7-methyl-6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylic acid methyl ester (0.0524mmol, 114mg) was dissolved in 1, 4-dioxane (3 mL) and water (1 mL), lithium hydroxide (0.5M, 0.26204mmol, 0.524mL) was added dropwise at 0 ℃, and the reaction mixture was stirred at room temperature for 0.5h. Water (3 mL) was added and the reaction mixture was acidified to pH 3-4 with 0.5M HCl. The resulting white precipitate was extracted with EtOAc, dried over MgSO4, filtered, and concentrated to give the crude title compound as a white solid (105mg, 93%), which was used in the next step without further purification. (MS + 1) m/z 1183.5

Step 19: t-butyl ((S) -4- (((3S, 6S, 9S) -15, 26-bis (2- ((t-butoxycarbonyl) amino) ethoxy) -9- ((cyanomethyl) carbamoyl) -16-hydroxy-6-methyl-4, 7-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecan-3-yl) (methyl) amino) -3- (2- (4- (t-butyl) phenyl) -4, 6-dimethylpyrimidine-5-carboxamido) -4-oxobutyl) carbamate

To a mixture of (4S,7S,10S) -10- ((S) -4- ((tert-butoxycarbonyl) amino) -2- (2- (4- (tert-butyl) phenyl) -4, 6-dimethylpyrimidine-5-carboxamido) -N-methylbutanamido) -16, 25-bis (2- ((tert-butoxycarbonyl) amino) ethoxy) -26-hydroxy-7-methyl-6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylic acid (0.037211mmol, 80mg) and aminoacetonitrile hydrochloride (0.1861mmol, 17.2mg) in N, N-dimethylformamide (5 mL) was added N, N-diisopropylethylamine (0.3712mmol, 48.1mg, 0.0649mL) and HATU (0.05582mmol, 21.7mg). The reaction was stirred at room temperature for 0.5h. The reaction mixture was diluted with EtOAc and washed with water. Na for organic layer ₂ SO ₄ Dried and concentrated. The residue is treatedPurification using silica gel chromatography, eluting with 0-10% meoh in DCM, gave the title compound (36mg, 63.4%). (MS + 1) m/z1221.8

Step 20: (4S,7S,10S) -10- ((S) -4-amino-2- (2- (4- (tert-butyl) phenyl) -4, 6-dimethylpyrimidine-5-carboxamido) -N-methylbutanamido) -16, 25-bis (2-aminoethoxy) -N- (cyanomethyl) -26-hydroxy-7-methyl-6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxamide

Tert-butyl ((S) -4- (((3S, 6S, 9S) -15, 26-bis (2- ((tert-butoxycarbonyl) amino) ethoxy) -9- ((cyanomethyl) carbamoyl) -16-hydroxy-6-methyl-4, 7-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecan-3-yl) (methyl) amino) -3- (2- (4- (tert-butyl) phenyl) -4, 6-dimethylpyrimidine-5-carboxamido) -4-oxobutyl) carbamate (0.0236mmol, 36mg) was dissolved in TFA (0.1 mL) and 1, 3-hexafluoro-2-propanol (4.9 mL) and stirred at room temperature for 1.5h. The reaction mixture was concentrated. Et was added to the residue ₂ O and concentrated again. This procedure was repeated two more times and the residue was purified by reverse phase HPLC to give the title compound as a white powder (23.4 mg, 92.1%). (MS + 1) m/z 921.4

¹ H NMR (400 MHz, methanol-d 4) δ 8.39-8.30 (m, 2H), 7.59-7.49 (m, 2H), 7.30 (dd, J =8.8,2.4hz, 1h), 7.17 (d, J =8.6hz, 1h), 6.96 (d, J =2.4hz, 1h), 6.87 (d, J =2.0hz, 1h), 6.47 (s, 1H), 6.42 (s, 1H), 5.22 (dd, J =7.5,6.0hz, 1h), 4.83 (d, J =19.6hz, 3H), 4.45-4.32 (m, 2H), 4.36-4.22 (m, 2H), 4.26-4.09 (m, 2H), 3.47-3.22 (m, 6H), 3.19-3.04 (m, 2H), 2.99 (s, 3H), 2.65 (s, 1H), 2.57 (s, 6H), 2.30 (dq, J =14.1,7.3hz, 1H), 2.16 (dq, J =14.7, 7.7 hz, 1H), 1.38 (s, 12H).

Example 363: synthesis of Compound 563

(4S, 7S, 10S) -10- ((S) -4- ((tert-butoxycarbonyl) amino) -2- (2- (4- (tert-butyl) phenyl) -4, 6-dimethylpyrimidine-5-carboxamido) -N-methylbutanamido) -16, 25-bis (2- ((tert-butoxycarbonyl) amino) ethoxy) -26-hydroxy-7-methyl-6, 9-dioxo-5, 8-diaza-1, 2 (1, 3) -diphenylcyclodecane-4-carboxylic acid (0.01269mmol, 25mg) was dissolved in TFA (0.1 mL) and 1, 3-hexafluoro-2-propanol (4.9 mL) and stirred at room temperature for 4h. The reaction mixture was concentrated, and the residue was purified by reverse phase HPLC to give the title compound as a white powder (12.4 mg, 98.1%). m/z 883.4

¹ H NMR (400 MHz, methanol-d 4) δ 8.39-8.30 (m, 2H), 7.59-7.49 (m, 2H), 7.29 (dd, J =8.9,2.5hz, 1h), 7.17 (d, J =8.6hz, 1h), 6.95 (s, 1H), 6.50 (s, 1H), 6.43 (s, 1H), 5.22 (t, J =6.8hz, 1h), 4.86 (s, 2H), 4.43-4.21 (m, 3H), 3.48-3.29 (m, 5H), 3.28 (dd, J =3.4,1.7hz, 2h), 3.20-3.03 (m, 2H), 3.00 (s, 3H), 2.65 (s, 1H), 2.57 (s, 5H), 2.30 (dq, J =14.1,7.5,7.1hz, 1h), 2.16 (dq, J =14.6,7.6hz, 1h), 1.38 (s, 9H), 1.43-1.26 (m, 4H).

Example 364: synthesis of Compound 564

Step 1: starting from 4-bromophenol and bromocycloheptane, S is applied _N 2 reaction conditions (described in example 44) and Suzuki boronation (described in example 10) to give 2- (4- (cycloheptyloxy) phenyl) -4,4, 5-tetramethyl-1, 3, 2-dioxaborolan as a colorless oil. ¹ H NMR(400MHz,CDCl ₃ )δ7.73(d,J＝8.8Hz,2H),6.86(d,J＝8.8Hz,2H),4.51-4.45(m,1H),2.05-1.98(m,2H),1.82-1.72(m,4H),1.60-1.57(m,4H),1.51-1.44(m,2H),1.34(s,12H)。

Tert-butyl (3-bromopropyl) carbamate and 4-amino-6- (4- (cycloheptyloxy) phenyl) -2-methylnicotinic acid were prepared as white solids by using a method similar to that described in example 213. LCMS (methods 5-95AB, ESI): t _R ＝0.791min,[M+H] ⁺ ＝341.0

Compound 564 (FA salt) was prepared as a white solid from 101E, tert-butyl (3-bromopropyl) carbamate, and 4-amino-6- (4- (cycloheptyloxy) phenyl) -2-methylnicotinic acid using an analogous method to that described in example 53. LCMS (methods 5-95AB, ESI): t _R ＝0.703min,[M/2+H] ⁺ ＝495.1； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.45(br s,1H),7.68-7.65(m,2H),7.28-7.16(m,2H),7.10-7.07(m,1H),7.03-6.95(m,4H),6.89-6.87(m,1H),6.81-6.72(m,1H),6.43-6.37(m,1H),5.07-5.02(m,1H),4.74-4.71(m,1H),4.59-4.53(m,1H),4.20-4.15(m,4H),4.08-4.02(m,2H),3.20-3.01(m,4H),2.98-2.93(m,7H),2.51(d,J＝3.2Hz,3H),2.21-2.09(m,2H),2.04-1.99(m,6H),1.82-1.70(m,4H),1.62-1.60(m,4H),1.52-1.51(m,2H),1.39-1.31(m,3H)。

Example 365: synthesis of Compound 565

Compound 565 (FA salt) was prepared as a white solid from 101E and bromocyclohexane by using a similar method to that described in example 364. LCMS (method 5-95AB, ESI): t _R ＝0.692min,[M+H] ⁺ ＝974.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.40(br s,1H),7.64(d,J＝8.0Hz,2H),7.26-7.14(m,2H),7.07-6.93(m,5H),6.89(br s,1H),6.78-6.70(m,1H),6.41-6.33(m,1H),5.02-4.99(m,1H),4.72-4.69(m,2H),4.41-4.36(m,1H),4.19-4.13(m,4H),4.04-4.00(m,2H),3.17-3.05(m,3H),2.99-2.90(m,7H),2.51(br s,3H),2.20(br s,1H),2.14-2.11(m,1H),1.98(br s,6H),1.75(br s,2H),1.54-1.20(m,9H)。

Example 366: synthesis of Compound 566

Step 1: at N ₂ To a solution of 4-hydroxybenzonitrile (5.00g, 43.8mmol), cycloheptanol (11.7g, 98.5mmol) and triphenylphosphine (27.6g, 105mmol) in toluene (50 mL) at 25 ℃ was added DIAD (21.3g, 105mmol). The reaction was stirred at 80 ℃ for 2h. The volatiles were removed and the residue was purified by chromatography on silica gel eluting with 0-5% etoac in petroleum ether to give 4- (cycloheptyloxy) benzonitrile (6.1 g,65% yield) as a white solid.

Step 2: to 4- (cycloheptyloxy) benzonitrile (3.8g, 17.6mmol) at 0 ℃ was added TH LiHMDS (1M in THF, 70.6 mL) was added to the F (40 mL) solution. The reaction was stirred at 25 ℃ for 40h. Thereafter, HCl (H) was added ₂ O4m,60ml), and the mixture was stirred for 10min, then adjusted to pH =12 with NaOH and extracted with DCM (100 mL). The organic layer was washed with Na ₂ SO ₄ Drying and concentration gave 4- (cycloheptyloxy) benzamidine as a brown oil (2.6 g,63% yield).

4-amino-2- (4- (cycloheptyloxy) phenyl) -6-methylpyrimidine-5-carboxylic acid was prepared as a white solid by using the similar methods as described in example 221 and example 213. LCMS (methods 5-95AB, ESI): t _R ＝0.671min,[M+H] ⁺ ＝342.5

Compound 566 (FA salt) was prepared as a white solid from 101E and 4-amino-2- (4- (cycloheptyloxy) phenyl) -6-methylpyrimidine-5-carboxylic acid using a method analogous to that described in example 364. LCMS (method 5-95AB, ESI): t _R ＝0.589min,[M+H] ⁺ ＝989.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.53(br s,1H),8.11(d,J＝8.0Hz,2H),7.28-7.06(m,4H),6.89(d,J＝8.0Hz,2H),6.83(s,1H),6.64-6.61(m,2H),4.79-4.67(m,3H),4.61-4.60(m,1H),4.39-4.09(m,6H),3.28-3.01(m,10H),2.31(s,3H),2.23-2.08(m,7H),1.88-1.80(m,5H),1.75-1.60(m,4H),1.58(s,2H),1.43-1.32(m,4H)。

Example 367: synthesis of Compound 567

Step 1: 101E (1.0 g, 1.78mmol) and K ₂ CO ₃ (4.4g, 32mmol) and [ (2R) -Oxiran-2-yl]A solution of methyl 3-nitrobenzenesulfonate (6.9g, 26.7mmol) in DMF (10 mL) was stirred at 50 ℃ for 24h. To the reaction mixture was added EtOAc (150 mL) which was washed with brine (150mL x 3) over Na ₂ SO ₄ Dried, concentrated, and the residue purified by column (2% meoh in DCM) to give compound 567-1 as a white solid (1.0 g,83% yield). LCMS (10-80AB (u) 7min, ESI): t _R ＝3.611min,[M+Na] ⁺ ＝696.1

Step 2: chemical combinationA solution of 567-1 (1.0 g, 1.48mmol) in acetonitrile (20 mL) and water (5 mL) was added CeCl ₃ (183mg, 0.74mmol) and NaN ₃ (1.45g, 22mmol) and the mixture was stirred at 75 ℃ for 24h. Water (100 mL) was added to the above solution, and the mixture was stirred for 5min. The resulting precipitate was collected for the next step. The filtrate was treated with aqueous HCl (1 mol/L) until pH =6, which was extracted with EtOAc (50mL × 2). The organic layers were combined and washed with Na ₂ SO ₄ Dried and concentrated. The resulting residue was taken up with the above precipitate in PPh in THF (20 mL) ₃ (2.0g，7.9mmol)、H ₂ O (0.3 mL) was treated at 50 ℃ for 15h. Volatiles were removed and the residue was taken up in SOCl in MeOH (6 mL) ₂ (230mg, 2mmol) was treated at 75 ℃ for 1h. After concentration in vacuo, the residue was dissolved in THF/H2O (20ml, v/v =7 ₃ (415mg, 4.9 mmol) and Boc ₂ O (925mg, 4.2mmol). The mixture was stirred at 30 ℃ for 2h. Water (50 mL) was added to the reaction mixture, which was extracted with EtOAc (100mL × 2). The combined organic layers were washed with Na ₂ SO ₄ Drying, concentrating, and purifying the residue through a column, eluting with 30% acetone in petroleum ether, to remove PPh ₃ O, then eluted with 70% etoac in petroleum ether to give compound 567-2 as a white solid (860 mg,67% yield). LCMS (methods 5-95AB, ESI): t _R ＝0.878min,[M+Na] ⁺ ＝930.2

Compound 567 (FA salt) was prepared from compound 567-2 as a white solid by using a method similar to that described in example 53. LCMS (methods 5-95AB, ESI): t _R ＝0.708min,[M+H] ⁺ ＝964.8； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.51(br s,1H),8.20(d,J＝8.0Hz,2H),7.47(d,J＝8.0Hz,2H),7.29-7.15(m,2H),7.02(s,1H),6.80(s,1H),6.59(s,1H),6.50(s,1H),5.36-5.23(m,1H),4.81-4.70(m,2H),4.32-4.04(m,7H),4.02-3.90(m,1H),3.20-3.04(m,4H),3.03-2.87(m,6H),2.46(s,6H),2.31-2.10(m,2H),1.38(s,9H),1.33(d,J＝6.4Hz,3H)。

Example 368: synthesis of Compound 568

Compound 568 (FA salt) was prepared as a white solid by using a method similar to that described in example 367 from 2- (4- (cyclohexyloxy) phenyl) -4, 6-dimethylpyrimidine-5-carboxylic acid (described in example 137). LCMS (methods 5-95AB, ESI): t _R ＝0.742min,[M/2+H] ⁺ ＝504.0； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.54(br s,1H),8.19-8.01(m,2H),7.22(br s,2H),7.08-6.85(m,4H),6.77(s,1H),6.71(s,1H),6.36(br s,1H),5.40-5.30(m,1H),4.82-4.68(m,2H),4.51-3.86(m,10H),3.28-2.64(m,10H),2.58-2.22(m,7H),2.21-2.08(m,1H),2.07-1.98(m,2H),1.90-1.79(m,2H),1.68-1.26(m,9H)。

Example 369: synthesis of Compound 569

Compound 569 (FA salt) was prepared as a white solid from 2- (4-isopropoxyphenyl) -4, 6-dimethylpyrimidine-5-carboxylic acid using a method analogous to that described in example 367. LCMS (method 5-95AB, ESI): t _R ＝0.679min,[M+H] ⁺ ＝966.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.54(br s,1H),8.10-8.04(m,2H),7.24(br s,2H),7.02(d,J＝8.8Hz,1H),6.94-6.87(m,3H),6.76(s,2H),6.30(s,1H),5.38-5.36(m,1H),4.77-4.69(m,2H),4.34-4.16(m,7H),3.98-3.95(m,1H),3.31-3.26(m,1H),3.16-3.06(m,4H),3.01(s,3H),2.95-2.92(m,2H),2.76-2.48(m,2H),2.35(s,6H),2.30-2.12(m,2H),1.38(d,J＝6.0Hz,6H),1.33(d,J＝6.8Hz,3H)。

Example 370: synthesis of Compound 570

Compound 570 (FA salt) was synthesized from 101E and [ (2S) -oxirane-2-yl ] by an analogous method to that described in example 367]Methyl 3-nitrobenzenesulfonate was prepared as a white solid. LCMS (methods 5-95AB, ESI): t _R ＝0.720min,[M+H] ⁺ ＝964.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.53(br s,1H),8.14(d,J＝8.0Hz,2H),7.45(d,J＝8.0Hz,2H),7.27-7.16(m,2H),7.06-6.92(m,2H),6.78(s,1H),6.67(s,1H),6.41(s,1H),5.41-5.18(m,1H),4.83-4.70(m,2H),4.41-3.90(m,9H),3.23-2.82(m,10H),2.43(s,6H),2.33-2.08(m,2H),1.39(s,9H),1.33(d,J＝6.4Hz,3H)。

Example 371: synthesis of Compound 571

Step 1: a solution of compound 571-1 (from example V (compound 106-B1), 300mg, 0.37mmol) in DCM (30 mL) containing 10% TFA was stirred at 25 ℃ for 5h. Volatiles were removed and the residue was redissolved in THF (12 mL) to which Boc was added ₂ O (93mg, 0.43mmol). To the resulting mixture was added saturated NaHCO ₃ Solution until pH =8 and the reaction was stirred at 25 ℃ for 2h. Water (30 mL) was added to the reaction, which was extracted with EtOAc (30mL x 3). The combined organic layers were washed with brine (50mL. Times.2), na ₂ SO ₄ Drying, concentration, and purification of the residue by preparative TLC (10% meoh in DCM, rf = 0.4) gave compound 571-2 as a white solid (251mg, 96% yield). LCMS (methods 5-95AB, ESI): t _R ＝0.907min,[M+Na] ⁺ ＝727.5

Compound 571 (FA salt) was prepared as a white solid from compound 571-2 by using a method analogous to that described in example 367. LCMS (method 10-80AB, ESI,7 min): t _R ＝1.756min,[M+H] ⁺ ＝935.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.52(br s,2H),8.28-8.14(m,2H),7.50-7.45(m,2H),7.32-7.18(m,2H),7.10-6.96(m,2H),6.83(s,1H),6.65-6.40(m,2H),5.30(m,1H),4.85-4.77(m,2H),4.46-4.29(m,3H),4.25-4.00(m,4H),3.30-3.26(m,2H),3.14(br s,3H),3.07-3.01(m,3H),3.00-2.86(m,3H),2.45(s,6H),2.35-2.23(m,1H),2.22-2.09(m,1H),1.39(s,9H),1.34(d,J＝6.0Hz,3H)。

Example 372: synthesis of Compound 572

Step 1: to 2- (trimethylsilyl) ethanol (7.0g, 60mmol) and Et ₃ To a solution of N (10g, 100mmol) in DCM (15 mL) was added 4-nitro-phenylchloroformate (10g, 50mmol), and the mixture was stirred at 30 ℃ for 1h. The reaction was quenched with water (50 mL) and then extracted with DCM (50mL × 3). The combined organic layers were washed with Na ₂ SO ₄ Drying, concentration, and the residue was purified by column eluting with 2% EtOAc in petroleum ether to give (4-nitrophenyl) 2-trimethylsilylethylcarbonate as a colorless oil (10g, 71% yield).

Step 2: to a solution of (4-nitrophenyl) 2-trimethylsilylethylcarbonate (5.0 g,17.6 mmol) in DMF (45 mL) at 25 deg.C were added (2S) -3-amino-2- (benzyloxycarbonylamino) propionic acid (3.5g, 14.7 mmol) and Et ₃ N (3.0 g,29.4 mmol), and the mixture was stirred at the same temperature for 3h. Volatiles were removed and the residue was taken up in DCM with H ₂ Partition between O (200 mL each). The organic layer was washed with brine (100mL. Times.2) and Na ₂ SO ₄ Dried, concentrated, and the residue was purified by silica gel column, eluting with 10% -30% meoh in DCM, to give (2S) -2- (benzyloxycarbonylamino) -3- (2-trimethylsilylethoxycarbonylamino) propionic acid as a white solid (3.4 g,61% yield).

Compound 572-1 was prepared as a white solid by using a method similar to that described in example 53. LCMS (methods 5-95AB, ESI): t _R ＝1.146min,[M+H] ⁺ ＝1235.4。

And step 3: to a solution of compound 572-1 (120mg, 0.097mmol) in DMF (2 mL) at 20 ℃ was added TBAF (1M in THF, 40. Mu.L) and the reaction was stirred at 50 ℃ for 2h. The mixture was diluted with water (20 mL), which was extracted with EtOAc (20mL × 2). The combined organic layers were washed with brine (40 mL) and Na ₂ SO ₄ Dried and concentrated to afford INT-A.

To another 0 ℃ solution of chlorosulfonyl isocyanate (17mg, 0.11mmol) in DCM (2 mL) was added t-BuOH (13. Mu.L, 0.11 mmol), and the mixture was stirred for 30min, followed by addition of pyridine (26. Mu.L, 0.22 mmol). The resulting mixture was stirred for 40min, during which time a precipitate formed, which was added via pipette to a mixture of INT-A and DIEA (40mg, 0.30mmol) in DCM (2 mL) at 0 ℃. The reaction was stirred at 0 ℃ for 0.5h. After that, the mixture was diluted with DCM (10 mL), which was washed with brine (10 mL). The organic layer was washed with Na ₂ SO ₄ Dried, concentrated, and the residue purified by preparative TLC (10% meoh in DCM) to give compound 572-2 (40mg, 33% yield)

Compound 572 (FA salt) was prepared from compound 572-2 as a white solid by using a method similar to that described in example 53. LCMS (methods 5-95AB, ESI): t _R ＝0.756min,[M+H] ⁺ ＝969.7； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.54(br s,2H),8.01(d,J＝8.0Hz,2H),7.37(d,J＝8.0Hz,2H),7.28-7.21(m,2H),7.05(d,J＝8.0Hz,1H),6.90-9.84(m,2H),6.76(s,1H),6.27(s,1H),5.51-5.47(m,1H),4.76-4.71(m,1H),4.43(s,1H),4.29-4.20(m,5H),4.09(s,1H),3.56-3.51(m,1H),3.40-3.34(m,2H),3.21(s,2H),3.09(s,3H),2.87-2.77(m,1H),2.61-2.53(m,1H),2.35(s,6H),1.39(s,9H),1.33(d,J＝6.4Hz,3H)。

Example 373: synthesis of Compound 573

Compound 573 (FA salt) was prepared as a white solid from 2- (4- (cyclohexyloxy) phenyl) -4, 6-dimethylpyrimidine-5-carboxylic acid (described in example 137) using an analogous method to that described in example 372. LCMS (method 5-95AB, ESI): t _R ＝0.801min,[M+H] ⁺ ＝997.4； ¹ H NMR(400MHz,DMSO-d ₆ )δ8.40(br s,3H),8.12(d,J＝8.0Hz,1H),7.28-7.15(m,2H),7.06-7.04(m,3H),7.00-6.94(m,2H),6.74-6.64(m,3H),5.76-5.72(m,1H),4.93-4.60(m,2H),4.45-4.35(m,2H),4.20-4.16(m,2H),4.05(s,5H),3.77(s,12H),2.97(m,4H),2.42(s,2H),1.94(s,2H),1.74-1.72(m,2H),1.56-1.36(m,6H),1.25-1.21(m,3H)。

Example 374: synthesis of Compound 574

Compound 574 (FA salt) was prepared as a white solid from (S) -4-amino-2- (((benzyloxy) carbonyl) amino) butanoic acid by using an analogous method to that described in example 372. LCMS (method 5-95AB, ESI): t _R ＝0.782min,[M+H] ⁺ ＝983.7； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.51(br s,1H),8.12-8.06(m,2H),7.43(d,J＝8.4Hz,2H),7.27-7.23(m,2H),7.07(d,J＝8.4Hz,1H),7.00-6.96(m,1H),6.83(s,1H),6.81(s,1H),6.40(s,1H),5.33-5.32(m,1H),4.90-4.85(m,1H),4.78-4.73(m,1H),4.45-4.41(m,2H),4.32-4.22(m,4H),3.35(m,3H),3.27-3.17(m,4H),3.07(m,3H),2.91(m,1H),2.43(s,6H),2.04-1.98(m,1H),2.07-1.95(m,1H),1.39(s,9H),1.34(d,J＝6.8Hz,3H)。

Example 375: synthesis of Compound 575

Compound 575 (FA salt) was prepared as a white solid from 101E and tert-butyl (3-bromopropyl) carbamate using an analogous method to that described in example 372. LCMS (method 5-95AB, ESI): t _R ＝0.772min,[M+H] ⁺ ＝997.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.42(br s,1H),7.99(d,J＝8.0Hz,2H),7.35(d,J＝8.4Hz,2H),7.27-7.12(m,2H),7.07-6.93(m,2H),6.87-6.75(m,1H),6.69(s,1H),6.19(br s,1H),5.58-5.48(m,1H),4.78-4.62(m,1H),4.50-4.15(m,5H),4.13-3.77(m,2H),3.60-3.47(m,1H),3.41-3.32(m,1H),3.28-3.16(m,2H),3.15-2.93(m,5H),2.83-2.68(m,1H),2.60-2.46(m,1H),2.31(s,6H),2.20-1.90(m,4H),1.39(s,9H),1.34(d,J＝6.8Hz,3H)。

Example 376: synthesis of Compound 576

Compound 576 (FA salt) was synthesized from 101E, (3-bromopropyl) by an analogous method to that described in example 372) Tert-butyl carbamate and 2- (4- (cyclohexyloxy) phenyl) -4, 6-dimethylpyrimidine-5-carboxylic acid (described in example 137) were prepared as white solids. LCMS (methods 5-95AB, ESI): t _R ＝0.771min,[M+H] ⁺ ＝1039.9； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.41(br s,3H),8.11(d,J＝6.4Hz,2H),7.22(br s,2H),7.11-6.95(m,3H),6.90(d,J＝8.4Hz,2H),6.77(s,1H),6.40(br s,1H),5.52-5.45(m,1H),4.84-4.74(m,2H),4.48-4.24(m,6H),4.13-4.05(m,1H),3.61-3.49(m,1H),3.42-3.35(m,1H),3.22-2.97(m,8H),2.96-2.85(m,1H),2.39(s,6H),2.22(br s,2H),2.09-2.02(m,4H),1.89-1.80(m,2H),1.69-1.44(m,6H),1.38(d,J＝6.8Hz,3H)。

Example 377: synthesis of Compound 577

Compound 577 (FA salt) was prepared as a white solid from compound 577-1 (synthesis described in example 367) by using a method similar to that described in example 372. LCMS (method 10-80AB, ESI,7 min): t _R ＝2.329min,[M+H] ⁺ ＝1029.4； ¹ H NMR(400M Hz,MeOH-d ₄ )δ8.54(br s,1H),7.98(d,J＝8.4Hz,2H),7.34(d,J＝8.4Hz,2H),7.27-7.09(m,2H),6.99(d,J＝8.8Hz,2H),6.87-6.75(m,1H),6.69(s,1H),6.16(br s,1H),5.52-5.95(m,1H),4.55-4.52(m,1H),4.45-4.10(m,8H),4.00-3.70(m,2H),3.60-3.45(m,1H),3.40-3.25(m,5H),3.17-3.08(m,2H),3.00-2.90(m,1H),2.81-2.65(m,1H),2.30(s,6H),1.40(s,9H),1.34(d,J＝6.4Hz,3H)。

Example 378: synthesis of Compound 578

Compound 578 (FA salt) was prepared as a white solid by using a method analogous to that described in example 372 from compound 578-1 (synthesis described in example 367) and 2- (4- (cyclohexyloxy) phenyl) -4, 6-dimethylpyrimidine-5-carboxylic acid (described in example 137). LCMS (method 5-95AB, ESI): t _R ＝0.776min,[M+H] ⁺ ＝1072.0； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.54(br s,1H),8.08-7.88(m,2H),7.29-7.11(m,2H),7.08-6.80(m,5H),6.72(s,1H),6.24(br s,1H),5.55-5.46(m,1H),4.83-4.62(m,2H),4.49-3.83(m,10H),3.59-3.48(m,1H),3.41-3.34(m,1H),3.30-3.18(m,1H),3.16-2.71(m,7H),2.54-2.15(m,6H),2.09-1.98(m,2H),1.90-1.80(m,2H),1.70-1.31(m,9H)。

Example 379: synthesis of Compound 579

Compound 579 (FA salt) was prepared as a white solid from compound 579-1 (synthesis described in example 367) and 2- (4-isopropoxyphenyl) -4, 6-dimethylpyrimidine-5-carboxylic acid using an analogous method to that described in example 372. LCMS (methods 5-95AB, ESI): t _R ＝0.582min,[M+H] ⁺ ＝1031.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.54(br s,1H),8.14-7.94(m,2H),7.26-7.16(m,2H),7.06-7.01(m,1H),7.01-6.90(m,2H),6.86(d,J＝8.4Hz,2H),6.75(br s,1H),6.34(s,1H),5.54-5.45(m,1H),4.78-4.67(m,2H),4.38-4.08(m,8H),4.00-3.92(m,1H),3.58-3.50(m,1H),3.41-3.33(m,2H),3.30-3.22(m,1H),3.14-2.99(m,5H),2.95-2.81(m,2H),2.34(s,6H),1.39(d,J＝5.6Hz,6H),1.37(d,J＝6.4Hz,3H)

Example 380: synthesis of Compound 580

Compound 580 (FA salt) was prepared as a white solid from (S) -4-amino-2- (((benzyloxy) carbonyl) amino) butanoic acid by using an analogous method to that described in example 377. LCMS (methods 5-95AB, ESI): t _R ＝0.776min,[M+H] ⁺ ＝1043.8； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.55(s,1H),8.08(d,J＝6.8Hz,2H),7.40(d,J＝8.0Hz,2H),7.26-7.14(m,2H),7.05-6.82(m,3H),6.75(s,1H),6.28(br s,1H),5.41-5.32(m,1H),4.77-4.67(m,1H),4.42-3.88(m,10H),3.28-3.15(m,3H),3.12-2.98(m,5H),2.95-2.74(m,2H),2.38(s,6H),2.26-2.15(m,1H),2.08-1.95(m,1H),1.39(s,9H),1.32(d,J＝6.8Hz,3H)。

Example 381: synthesis of Compound 581

Compound 581 (TFA salt) was synthesized from [ (2S) -oxiran-2-yl ] by using a similar procedure as described in example 377]Methyl 3-nitrobenzenesulfonate was prepared as a white solid. LCMS (methods 5-95AB, ESI): t _R ＝0.772min,[M+H] ⁺ ＝1029.3； ¹ H NMR(400MHz,MeOH-d ₄ )δ7.98(d,J＝8.0Hz,2H),7.36(d,J＝8.0Hz,2H),7.25(d,J＝8.8Hz,1H),7.16(d,J＝8.8Hz,1H),7.05-6.95(m,2H),6.89-6.79(m,1H),6.70(br s,1H),6.19(br s,1H),5.58-5.48(m,1H),4.83-4.61(m,2H),4.44-3.99(m,8H),3.59-3.48(m,1H),3.41-3.31(m,2H),3.29-3.14(m,2H),3.10(s,3H),3.08-3.02(m,1H),3.00-2.92(m,1H),2.82-2.69(m,1H),2.32(s,6H),1.40(s,9H),1.36(d,J＝7.2Hz,3H)。

Example 382: synthesis of Compound 582

Step 1: to a solution of compound 582-1 (from example V (compound 106-A2), 13.0g, 20mmol) in MeOH (100 mL) at 20 deg.C was added AgSO ₄ (4.35g, 14.0mmol) and I ₂ (5.57g, 22mmol) and the reaction mixture was stirred at 20 ℃ for 2h. After filtration, the filtrate was concentrated and the residue was purified by silica gel column eluting with 5% meoh in DCM. The resulting material was dissolved in DCM (130 mL), to which DIEA (6.5 g, 50mmol) and SEM-Cl (4.45mL, 25mmol) were added. The reaction was stirred at 25 ℃ for 4h. To the mixture was added DCM (300 mL) saturated with NH ₄ Cl solution and brine (250 mL each). The organic layer is coated with Na ₂ SO ₄ Drying, concentration, and purification of the residue through a silica gel column gave compound 582-2 as an off-white solid (15g, 83% yield). LCMS (methods 5-95AB, ESI): t _R ＝1.088min,[M+Na] ⁺ ＝930.0

Step 2: KOAc (7.57g, 77mmol), compound 582-2 (10.0 g, 11mmol), pin ₂ B ₂ (14.0g，55mmol)、Pd ₂ (dba) ₃ (504mg, 0.55mmol) and PCy ₃ (309mg, 1.1mmol) of a mixture in DMSO (150 mL) in N ₂ And stirred at 80 ℃ overnight. The mixture was diluted with EtOAc (500 mL) and it was diluted with saturated NaHCO ₃ The solution was washed with brine (500 mL each). The organic layer is coated with Na ₂ SO ₄ Dried, concentrated, and the residue was purified by silica gel column, eluting with 5% meoh in DCM. The resulting material was redissolved in MeOH (100 mL) to which H was added ₂ O ₂ (30% w/w,20 mL). The reaction was stirred at 30 ℃ for 6h. The mixture was diluted with EtOAc (200 mL), which was washed with water and brine (100 mL each). The organic layer is coated with Na ₂ SO ₄ Drying, concentration, and the residue was purified by silica gel column eluting with 5% meoh in DCM to give the desired product compound 582-3 as a white solid (7.2g, 9.0mmol,82% yield). LCMS (method 5-95AB, ESI): t _R ＝0.996min,[M+Na] ⁺ ＝820.0

And 3, step 3: the contents of compounds 582-3 (2.4g, 3.0mmol) and 10% in Pd/C (1.6g, 1.5mmol) in DMA (20 mL) in H ₂ (50 psi) and stirred at 50 ℃ for 20h. After filtration, cbzOSu (749mg, 3.0 mmol) was added to the filtrate, and the resulting mixture was stirred at 25 ℃ for 1h. After that, etOAc (120 mL) was added to the mixture, which was washed with brine (100mL x 3). The organic layer was washed with Na ₂ SO ₄ Drying, concentration, and the residue was purified by silica gel column, eluting with 50% etoac in petroleum ether, to give compound 582-4 as a white solid (1.9 g,90% yield). LCMS (methods 5-95AB, ESI): t _R ＝0.904min,[M+Na] ⁺ ＝730.2

Compound 582-4 was prepared as a white solid (SEM removed under methyl ester forming conditions) by using a similar method to that described in example 367. LCMS (methods 5-95AB, ESI): t _R ＝0.863min,[M+Na] ⁺ ＝946.3

Compound 582 (TFA salt) was prepared by using a method analogous to that described in example 377 (after each amide coupling step)Excess acylation on the unprotected phenol that occurred in the process, which could be converted back to the desired product by treatment with 3% ammonia in MeOH for 1 h). LCMS (method 10-80AB, ESI,7 min): t _R ＝2.331min,[M+H] ⁺ ＝1045.6；1H NMR(400MHz,DMSO-d6,T＝80℃)δ8.84-8.58(m,2H),8.52(br s,1H),8.32(d,J＝7.6Hz,2H),8.07(d,J＝8.4Hz,1H),7.54(d,J＝7.6Hz,2H),7.18(d,J＝8.4Hz,1H),7.02(d,J＝8.4Hz,1H),6.83(br s,1H),6.77(br s,1H),6.46(br s,1H),6.34(s,1H),5.20-5.09(m,1H),4.81-4.68(m,2H),4.22-4.06(m,8H),3.45-3.35(m,1H),3.26-3.15(m,2H),3.10-2.92(m,6H),2.88-2.72(m,2H),2.53(s,6H),1.35(s,9H),1.24(d,J＝6.0Hz,3H)

Example 383: synthesis of Compound 583

Compound 583 (TFA salt) was prepared from compound 582-4 (described in example 382) by using a method analogous to that described in example 53. LCMS (methods 5-95AB, ESI): t _R ＝0.706min,[M+H] ⁺ ＝920.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.35(d,J＝8.4Hz,2H),7.55(d,J＝8.4Hz,2H),7.23(d,J＝7.6Hz,1H),7.08(d,J＝8.0Hz,1H),6.91(s,1H),6.84(s,1H),6.58(s,1H),6.42(s,1H),5.25-5.15(m,1H),4.85-4.80(m,2H),4.48-4.15(m,6H),3.45-3.35(m,4H),3.27-3.07(m,4H),3.07-3.00(m,3H),2.59(s,6H),2.35-2.25(m,1H),2.25-2.15(m,1H),1.40(s,9H),1.38(d,J＝7.2Hz,3H)。

Example 384: synthesis of Compound 584

Compound 584 (TFA salt) was prepared from compound 582-4 (described in example 382) using an analogous method to that described in example 372. LCMS (methods 5-95AB, ESI): t _R ＝0.767min,[M+H] ⁺ ＝985.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.34-8.16(m,2H),7.54-7.26(m,2H),7.12-7.05(m,2H),6.85(s,1H),6.71-6.37(m,3H),5.33(m,1H),4.80-4.78(m,2H),4.38-4.20(m,6H),3.61-3.38(m,6H),3.20-2.90(m,2H),3.02(s,3H),2.53(s,6H),1.36(s,9H),1.27(d,J＝6.8Hz,3H)。

Example 385: synthesis of Compound 585

Compound 585 (FA salt) was prepared from compound 585-1 (from example V (Compound 106-A2), methyl iodide, and tert-butyl (2-bromoethyl) carbamate using an analogous method to that described in example 382 LCMS (method 5-95AB, ESI): t _R ＝0.758min,[M+Na] ⁺ ＝1021.1； ¹ H NMR(400MHz,DMSO-d ₄ )δ8.51(s,2H),8.32(d,J＝8.4Hz,2H),7.54(d,J＝8.4Hz,2H),7.09-7.00(m,3H),6.54(br s,1H),6.52(br s,1H),6.39(s,1H),5.24-5.08(m,1H),4.88-4.67(m,2H),4.39-4.20(m,7H),3.91(s,3H),3.68-3.31(m,6H),3.19(s,3H),2.94-2.79(m,2H),2.45(s,6H),1.36(s,9H),1.23(d,J＝6.8Hz,3H)。

Example 386: synthesis of Compound 586

Compound 586 (FA salt) was prepared from compound 586-1 (from example V (compound 106-A2), iodomethane, and (S) -3- (((benzyloxy) carbonyl) amino) -5- ((tert-butoxycarbonyl) amino) -2-oxopentanoic acid using an analogous method to that described in example 382 LCMS (method 5-95AB, ESI): t _R ＝0.749min,[M+Na] ⁺ ＝1016.3； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.50(br s,2H),8.29(d,J＝8.8Hz,2H),7.51(d,J＝8.8Hz,2H),7.06(d,J＝8.4Hz,2H),6.75(s,1H),6.58(s,1H),6.56(s,1H),5.23-5.21(m,1H),4.82-4.77(m,1H),4.26-4.04(m,8H),3.80(s,3H),3.29-3.00(m,8H),3.07(s,3H),2.55(s,6H),2.33-2.17(m,2H),1.40(s,9H),1.38(d,J＝7.2Hz,3H)。

Example 387: synthesis of Compound 587

Compound 587-2 was prepared from compound 587-1 ((from example V (compound 106-A2)), iodomethane, and tert-butyl (2-bromoethyl) carbamate using an analogous method to that described in example 382 LCMS (method 5-95AB, ESI): t _R ＝0.854min,[M+Na] ⁺ =847.2 compound 587 (FA salt) was prepared from compound 587-2 and (S) -3- (((benzyloxy) carbonyl) amino) -5- ((tert-butoxycarbonyl) amino) -2-oxopentanoic acid by using a method similar to that described in example 382. LCMS (methods 5-95AB, ESI): t _R ＝0.706min,[M+H] ⁺ ＝964.3； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.49(br s,2H),8.35(d,J＝8.4Hz,2H),7.54(d,J＝8.4Hz,2H),7.28-7.21(m,1H),7.08-6.96(m,2H),6.86(s,1H),6.62-6.55(m,1H),6.43(s,1H),5.20-5.09(m,1H),4.84-4.72(m,2H),4.38-4.02(m,7H),3.66(s,3H),3.37-3.31(m,3H),3.21-2.95(m,8H),2.59(s,6H),2.33-2.07(m,2H),1.38(s,9H),1.36(d,J＝6.8Hz,3H)。

Example 388: synthesis of Compound 588

Compound 588-2 was prepared from compound 588-1 ((from example V (compound 106-B1)) by using a method similar to that described in example 54 LCMS (method 5-95AB, ESI): t _R ＝1.042min,[M+Na] ⁺ ＝1059.1

Compound 588-3 was prepared from compound 588-2 and benzyl bromide (synthesis described in example 391) by using an analogous method to that described in example 382. LCMS (method 5-95AB, ESI): t _R ＝1.083min,[M+Na] ⁺ ＝1338.6

Compound 588-4 was prepared by hydrogenation of compound 588-3 (described in example 414). LCMS (methods 5-95AB, ESI): t _R ＝1.017min,[M+Na] ⁺ ＝1249.6

Compound 588 (a FA salt) was prepared by using procedures analogous to those described in example 382. LCMS (methods 5-95AB, ESI): t _R ＝0.704min,[M+H] ⁺ ＝950.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.50(br s,2H),8.31(d,J＝7.6Hz,2H),7.53(d,J＝8.0Hz,2H),7.16(s,1H),7.07(d,J＝8.8Hz,1H),6.83(s,1H),6.77(s,1H),6.54(s,2H),5.22-5.21(t,J＝6.4Hz,1H),4.81(q,J＝6.4Hz,1H),4.41-4.34(m,2H),4.25(s,3H),4.07-4.05(m,2H),3.43-3.34(m,2H),3.22-3.05(m,9H),2.56(s,6H),2.32-2.17(m,2H),1.40(s,9H),1.38(d,J＝6.8Hz,3H)。

Example 389: synthesis of Compound 589

Step 1: 2-aminoethanol (2.0 g,32.7 mmol) and Na were added at 20 deg.C ₂ CO ₃ (10.4g, 98.2mmol) in H ₂ To a solution in O (35 mL) was added FmocCl (9.3 g,36.0 mmol), and the mixture was stirred at the same temperature for 2h. The mixture was extracted with DCM (100mL x 3). The combined organic layers were washed with Na ₂ SO ₄ Drying, concentration, and the residue was purified by silica gel column eluting with 50% etoac in petroleum ether to give (9H-fluoren-9-yl) methyl (2-hydroxyethyl) carbamate as a white solid (5.6 g,60.4% yield).

And 2, step: a solution of (9H-fluoren-9-yl) methyl (2-hydroxyethyl) carbamate (1.0g, 3.5mmol) and 2-iodoxybenzoic acid (3.0g, 10.5mmol) in EtOAc (100 mL) was dissolved in N ₂ And stirred at 80 ℃ for 16h. After filtration, the filtrate was concentrated to give (9H-fluoren-9-yl) methyl (2-oxoethyl) carbamate (1.0 g, quantitative yield) as a white solid. ¹ H NMR(400MHz,CDCl ₃ )δ9.67(s,1H),7.78(d,J＝8.0Hz,2H),7.60(d,J＝8.0Hz,2H),7.43-7.39(m,2H),7.34-7.31(m,2H),5.50-5.44(m,1H),4.43(d,J＝6.8Hz,2H),4.24(t,J＝6.8Hz,1H),4.20-4.00(m,2H)。

And step 3: to a solution of compound 589-1 (synthesis described in example 388, 200mg, 0.19mmol) in HOAc (2 mL) at 0 deg.C was added fuming nitric acid (30. Mu.L). The mixture was gradually warmed to 25 ℃ while stirring and stirred at the same temperature for 3.5h. To the mixture was added saturated NaHCO ₃ Solution (40 mL),Boc ₂ O (84mg, 0.39mmol) and THF (12 mL), and the resulting mixture was stirred at 25 deg.C for 1.5h. The mixture was extracted with EtOAc (× 3 30mL). The combined organic layers were washed with brine (50mL. Times.2) and Na ₂ SO ₄ Drying, concentration, and purification of the residue on silica gel column, eluting with 5% meoh in DCM, gave compound 589-2 as a yellow solid (140mg, 67% yield). LCMS (methods 5-95AB, ESI): t _R ＝1.131min,[M+H] ⁺ ＝1082.7

And 4, step 4: the% of the solutions of compounds 589-2 (140mg, 0.13mmol) and 10% Pd/C (134mg, 0.13mmol) in ethanol (10 mL) in H ₂ (15 psi), stirred at 30 ℃ for 1h. After filtration, the filtrate was concentrated, and the residue was redissolved in MeOH (4 mL), to which was added (9H-fluoren-9-yl) methyl (2-oxoethyl) carbamate (43mg, 0.15mmol) and HOAc (50 μ L). The resulting mixture was stirred at 25 ℃ for 6h. Thereafter, etOAc (40 mL) was added to the mixture, which was washed with brine (50 mL) and Na ₂ SO ₄ Dried and concentrated. The residue was purified by preparative TLC, eluting with 7% meoh in DCM to give compound 589-3 as a white solid (140mg, 83% yield). LCMS (methods 5-95AB, ESI): t _R ＝1.136min,[M+H] ⁺ ＝1318.2

And 5: compound 589-3 (140mg, 0.11mmol) and TEAF.4H ₂ A solution of O (47mg, 0.21mmol) in DMF (2 mL) was stirred at 30 ℃ for 30min. EtOAc (30 mL) is added to the mixture, which is washed with brine (30 mL), over Na ₂ SO ₄ Dried and concentrated. The resulting residue was redissolved in THF (3 mL), to which was added Boc2O (24mg, 0.12mmol) and saturated NaHCO ₃ (2 mL). The resulting mixture was stirred at 25 ℃ for 1h. The reaction was partitioned between EtOAc and water (50 mL each), and the organic layer was washed with brine (40 mL) and Na ₂ SO ₄ Dried and concentrated. The residue was purified by preparative TLC eluting with 5% meoh in DCM to give compound 589-4 as a white solid (50mg, 38% yield). LCMS (method 5-95AB, ESI): t _R ＝1.052min,[M+H] ⁺ ＝1195.4

Compound 589 (TFA salt) was prepared by using a method analogous to that described in example 382. LCMS (Square solution)Method 5-95AB, ESI) t _R ＝0.733min,[M+H] ⁺ ＝919.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.29(d,J＝8.0Hz,2H),7.51(d,J＝8.8Hz,2H),7.18(d,J＝8.8Hz,1H),7.04(d,J＝8.8Hz,1H),6.91(s,1H),6.52(s,1H),6.41(s,1H),6.21(s,1H),5.15-5.12(m,1H),4.80-4.76(m,2H),4.31-4.26(m,2H),4.19(s,2H),3.45-3.43(m,2H),3.30-3.28(m,3H),3.15-3.09(m,5H),3.02(s,3H),2.55(s,6H),2.26-2.12(m,2H),1.36(s,9H),1.34(d,J＝6.8Hz,3H)。

Example 390: synthesis of Compound 590

2- (trimethylsilyl) ethyl (2-bromoethyl) carbamate was prepared from 2-bromoethylamine and 4-nitrophenyl (2- (trimethylsilyl) ethyl) carbonate (synthesis described in example 372) as a light yellow oil by applying the same method described in example 372.

Compound 590-2 was prepared from compound 590-1 ((from example V (compound 106-B1)) by an analogous method to that described in example 372 as a white solid LCMS (method 5-95AB, ESI): t _R ＝0.973min,[M+H] ⁺ ＝1124.1

Compound 590-3 was prepared as a white solid from compound 590-2 and benzyl bromide (synthesis described in example 391) using an analogous method to that described in example 382. LCMS (methods 5-95AB, ESI): t _R ＝1.224min,[M+H] ⁺ ＝1388.8

Compound 590-4 was prepared as a white solid from compound 590-3 and 2- (trimethylsilyl) ethyl (2-bromoethyl) carbamate using an analogous method to that described in example 395. LCMS (methods 5-95AB, ESI): t _R ＝1.252min,[M/2+H] ⁺ ＝837.9

Compound 590 (TFA salt) was prepared by using a method analogous to that described in example 388. LCMS (methods 5-95AB, ESI): t _R ＝0.769min,[M+H] ⁺ ＝1027.7； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.38-8.18(m,2H),7.57-7.43(m,2H),7.28-6.99(m,3H),6.86(br s,1H),6.71(br s,1H),6.52(s,1H),5.37-5.26(m,1H),4.83-4.56(m,2H),4.37(s,2H),4.30-4.02(m,3H),3.70-3.45(m,3H),3.43-3.32(m,2H),3.18-2.96(m,1H),3.08(s,3H),2.52(s,6H),1.40(s,9H),1.38(d,J＝6.8Hz,3H)。

Example 391: synthesis of compound 591

Step 1: a solution of NBS (634mg, 3.56mmol) and 101E (1.0 g, 1.78mmol) in DCM (5 mL) was stirred at 30 ℃ for 3h. Volatiles were removed and the residue was purified by silica gel column, eluting with 5% meoh in DCM. The resulting residue was redissolved in DMF (6 mL) and K was added thereto ₂ CO ₃ (1.15g, 8.34mmol) and methyl iodide (0.7mL, 11.3mmol). The reaction was stirred at 25 ℃ for 16h. EtOAc (60 mL) was added to the mixture, followed by filtration. The filtrate was washed with brine (50mL. Times.3) and Na ₂ SO ₄ Drying, concentration, and the residue was purified by silica gel column eluting with 40% etoac in petroleum ether to give compound 591-1 as a white solid (1.2g, 96% yield). LCMS (methods 5-95AB, ESI): t _R ＝1.023min,[M+H] ⁺ ＝746.0。

Compound 591 (TFA salt) was prepared from compound 591-1 and (S) -3- (((benzyloxy) carbonyl) amino) -5- ((tert-butoxycarbonyl) amino) -2-oxopentanoic acid using an analogous method to that described in example 382. LCMS (methods 5-95AB, ESI): t _R ＝0.696min,[M+H] ⁺ ＝1024.8； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.31(d,J＝8.4Hz,2H),7.51(d,J＝8.4Hz,2H),6.92(d,J＝7.6Hz,2H),6.52(s,1H),6.42(s,2H),5.20-5.10(m,1H),4.78-4.72(m,2H),4.28-4.16(m,8H),3.78-3.66(m,3H),3.30-3.20(m,3H),3.19-3.00(m,11H),2.56(s,6H),2.25-2.15(m,1H),2.15-2.05(m,1H),1.36(s,9H),1.33(d,J＝6.8Hz,3H)。

Example 392: synthesis of Compound 592

Compound 592 (FA salt) is prepared from compound 591-1 (the synthesis described in example 391) and tert-butyl (2-bromoethyl) carbamate using an analogous method to that described in example 391. LCMS (methods 5-95AB, ESI): t _R ＝0.703min,[M+Na] ⁺ ＝986.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.50(br s,3H),8.33(d,J＝8.8Hz,2H),7.52(d,J＝8.8Hz,2H),7.00(s,1H),6.96(s,1H),6.57(br s,1H),6.49(br s,1H),6.41(s,1H),5.14-5.11(m,1H),4.77-4.75(m,2H),4.32-4.19(m,6H),3.73(s,3H),3.69(s,3H),3.39-3.34(m,6H),3.14-3.05(m,2H),3.01(s,3H),2.57(s,6H),2.26-2.12(m,2H),1.36(s,9H),1.33(d,J＝6.8Hz,3H)。

Example 393: synthesis of Compound 593

Compound 593 (a FA salt) was prepared from compound 591-1 (the synthesis described in example 391) by using a method analogous to that described in example 391. LCMS (methods 5-95AB, ESI): t _R ＝0.736min,[M+H] ⁺ ＝1089.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.51(br s,1H),8.18-8.12(m,2H),7.44-7.38(m,2H),6.86(br s,1H),6.71(br s,2H),6.44(s,1H),6.14(s,1H),5.39-5.30(m,1H),4.79-4.67(m,2H),4.25-4.03(m,8H),4.02-3.88(m,4H),3.76(s,3H),3.59-3.50(m,1H),3.39-3.30(m,2H),3.29-3.20(m,2H),3.11-3.00(m,2H),3.05(s,3H),2.41(s,6H),1.36(s,9H),1.35(d,J＝6.4Hz,3H)

Example 394: synthesis of Compound 594

Compound 594-2 was prepared from compound 594-1 (from example V (compound 106-A2)) by using an analogous method to that described in example 395. LCMS (method 5-95AB, ESI): t _R ＝0.950min,[M+H] ⁺ ＝1067.5

Compound 594 (FA salt) by Using a method analogous to that described in example 382Prepared from compound 594-2 and tert-butyl (2-bromoethyl) carbamate. LCMS (method 5-95AB, ESI): t _R ＝0.729min,[M+H] ⁺ ＝950.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.56(br s,2H),8.35(d,J＝8.0Hz,2H),7.56(d,J＝8.0Hz,2H),7.29(d,J＝8.4Hz,1H),7.16(d,J＝8.4Hz,1H),6.95(d,J＝1.2Hz,1H),6.85(s,1H),6.46(s,1H),6.41(s,2H),5.26-5.22(m,1H),4.84-4.77(m,2H),4.30-4.10(m,7H),3.50-3.40(m,2H),3.25-3.05(m,6H),3.01(s,3H),2.58(s,6H),2.30-2.27(m,1H),2.18-2.14(m,1H),1.36(s,9H),1.34(d,J＝6.8Hz,3H)。

Example 395: synthesis of Compound 595

Step 1: a solution of compound 595-1 (from example V (compound 106-B2), 300mg, 0.37mmol) in HFIP (15 mL) containing 5% TFA was stirred at room temperature for 1h. The mixture was concentrated and the residue was redissolved in THF (8 mL) to which was added tert-butyl (((tert-butoxycarbonyl) amino) (1H-pyrazol-1-yl) methylene) carbamate (158mg, 0.51mmol). The resulting mixture was stirred at room temperature for a further 3h. Water (15 mL) was added to the reaction, which was extracted with EtOAc (15mL. Times.3). The combined organic layers were washed with brine (30 mL) and Na ₂ SO ₄ Dried, concentrated and purified by column (5% meoh/DCM) to give compound 595-2 as a white solid (280 mg, 97.5% yield over two steps). LCMS (methods 5-95AB, ESI): t _R ＝0.825min,[M+H] ⁺ ＝847.1

Step 2: to a solution of compound 595-2 (280mg, 0.33mmol) in DCM (15 mL) at room temperature was added Et ₃ N (100mg, 0.99mmol) and Boc ₂ O (2.16g, 9.92mmol), and the reaction was stirred at the same temperature for 72 hours. Water (15 mL) was added to the reaction, which was extracted with EtOAc (15mL. Times.3). The combined organic layers were washed with brine (30 mL) and Na ₂ SO ₄ Dried, concentrated, and purified by column (5% meoh/DCM) to give compound 595-3 as a white solid (300mg, 96% yield). LCMS (method 5-95AB, ESI): t _R ＝0.875min,[M+H] ⁺ ＝947.4

Compound 595 (TFA salt) was prepared as a white solid from compound 595-3 using an analogous method to that described in example 54. LCMS (methods 5-95AB, ESI): t _R ＝0.749min,[M+H] ⁺ ＝903.6； ¹ H NMR(400MHz,MeOH-d4)δ8.30(d,J＝8.4Hz,2H),7.51(d,J＝8.0Hz,2H),7.27(d,J＝8.4Hz,1H),7.17(d,J＝8.4Hz,1H),6.92-6.86(m,2H),6.85(d,J＝8.4Hz,1H),6.62(br s,1H),6.41(s,1H),5.35-5.26(m,1H),4.83-4.78(m,1H),4.62(br s,1H),4.42-4.32(m,2H),4.30-4.23(m,2H),3.74-3.61(m,2H),3.14(t,J＝8.0Hz,2H),3.05-2.72(m,5H),2.44(s,6H),2.29-2.10(m,2H),1.38(s,9H),1.34(d,J＝6.4Hz,3H)。

Example 396: synthesis of Compound 596

Compound 596-1 was prepared as a white solid from 101E and tert-butyl (3-bromopropyl) carbamate using a method similar to that described in example 54.

Compound 596 (FA salt) was prepared from compound 596-1 as a white solid by using a method analogous to that described in example 395. LCMS (methods 5-95AB, ESI): t _R ＝0.634min,[M+H] ⁺ ＝917.5； ¹ H NMR(400MHz,MeOH-d4)δ8.52(br s,1H),8.37-8.23(m,2H),7.57-7.46(m,2H),8.33-8.22(m,1H),7.20-6.89(m,3H),6.87-6.75(m,1H),6.62(br s,1H),6.50(s,1H),5.30-5.18(m,1H),4.83-4.79(m,2H),4.33-4.01(m,4H),3.54-3.35(m,2H),3.26-2.91(m,7H),2.56-2.49(s,6H),2.35-1.95(m,4H),1.42(s,9H),1.38(d,J＝6.8Hz,3H)。

Example 397: synthesis of Compound 597

Compound 597 (FA salt) was prepared as a white solid from compound 597-1 (a by-product of the synthesis of compound 596-1 in the synthesis of example 396) by using a similar method to that described in example 54. LCMS (methods 5-95ABSI):t _R ＝0.758min,[M+H] ⁺ ＝875.4； ¹ H NMR(400MHz,MeOH-d4)δ8.50(br s,2H),8.19(d,J＝8.0Hz,2H),7.47(d,J＝8.0Hz,2H),7.11-7.06(m,1H),7.05-6.95(m,3H),6.79(br s,1H),6.64(br s,1H),6.54(s,1H),5.35-5.29(m,1H),4.82-4.75(m,2H),4.35-4.25(m,3H),4.20-4.10(m,1H),3.27-3.10(m,5H),3.11(s,3H),3.05-2.90(m,1H),2.45(s,6H),2.35-2.25(m,1H),2.20-2.10(m,3H),1.39(s,9H),1.35(d,J＝7.2Hz,3H)。

Example 398: synthesis of Compound 598

Compound 598 (FA salt) was prepared as a white solid from 4, 6-dimethyl-2- (4- (pentyloxy) phenyl) pyrimidine-5-carboxylic acid (described in example 128) using a method similar to that described in example 396 and example 54. LCMS (methods 5-95AB, ESI): t _R ＝0.777min,[M+H] ⁺ ＝905.8； ¹ H NMR(400MHz,MeOH-d4)δ8.52(br s,2H),8.28(d,J＝8.4Hz,2H),7.60-7.25(m,2H),7.05-7.00(m,1H),6.98(d,J＝8.4Hz,2H),6.91(d,J＝2.4Hz,1H),6.83(br s,1H),6.62(br s,1H),6.51(s,1H),5.30-5.20(m,1H),4.82-4.75(m,2H),4.41-4.29(m,2H),4.22(s,2H),4.06(t,J＝6.4Hz,2H),3.27-2.95(m,9H),2.49(s,6H),2.35-2.24(m,1H),2.20-2.10(m,3H),1.90-1.80(m,2H),1.55-1.40(m,4H),1.35(d,J＝6.4Hz,3H),0.98(t,J＝6.8Hz,3H)。

Example 399: synthesis of Compound 599

Step 1: compound 599-1 (from example V (Compound 106-A2), 300mg, 0.45mmol), 1, 2-dibromoethane (852mg, 4.5mmol) and K ₂ CO ₃ A solution of (627mg, 4.5mmol) in DMF (10 mL) was stirred at 25 ℃ for 12h. The reaction was taken up in EtOAc (100 mL), which was washed with brine (50mL x3) and Na ₂ SO ₄ Dried, concentrated, and the residue purified by preparative TLC (10% me in DCM)OH) to yield compound 599-2 as a white solid (275mg, 79% yield).

Step 2: the compound 599-2 (275mg, 0.36mmol), methylamine (2M in THF, 1.8mL), K ₂ CO ₃ A solution of (494mg, 3.6 mmol) in DMF (10 mL) was stirred at 25 ℃ for 12h. The reaction mixture was taken up in EtOAc (100 ml), washed with brine (50mL × 2) and taken over Na ₂ SO ₄ Drying and concentrating. The residue was treated with 10% TFA/DCM (10 mL) for 1h. Volatiles were removed and the residue was purified by preparative TLC to give compound 599-3 as an off-white solid (160mg, 72% yield). LCMS (methods 5-95AB, ESI): t _R ＝0.745min,[M+H] ⁺ ＝619.6

The title compound (FA salt) was prepared from compound 599-3 as a white solid by using a method similar to that described in example 395. LCMS (methods 5-95AB, ESI): t _R ＝0.758min,[M+H] ⁺ ＝917.4； ¹ H NMR(400MHz,MeOH-d4)δ8.54(br s,1H),8.22(d,J＝8.0Hz,2H),7.50(d,J＝8.0Hz,2H),7.29-7.15(m,2H),6.96-6.80(m,3H),6.57(s,1H),6.53(s,1H),5.30-5.26(m,1H),4.81-4.60(m,2H),4.46-4.24(m,2H),4.24(s,2H),3.87-3.74(m,2H),3.15-2.89(m,10H),2.49(s,6H),2.30-2.12(m,2H),1.39(s,9H),1.36-1.20(m,3H)。

Example 400: synthesis of Compound 600

Step 1: compound 599-3 (synthesized as described in example 399, 210mg,0.3 mmol), boc ₂ O (273mg, 1.25mmol) and Et ₃ A solution of N (127mg, 1.25mmol) in DCM (20 mL) was stirred at 25 ℃ for 12h. The volatiles were removed and the residue was taken up in EtOAc (30 mL), which was washed with brine (30mL × 2). The organic layer is coated with Na ₂ SO ₄ Dry, concentrate, and purify the residue by preparative TLC (10% meoh in DCM) to give compound 600-2 as a white solid (143mg, 70% yield).

Compound 600 (FA salt) was prepared from Compound 600-2 by using a similar method to that described in example 54A white solid. LCMS (methods 5-95AB, ESI): t _R ＝0.740min,[M+H] ⁺ ＝875.4； ¹ H NMR(400MHz,MeOH-d4)δ8.52(br s,1H),8.10(d,J＝7.6Hz,2H),7.43(d,J＝7.6Hz,2H),7.30-7.19(m,2H),7.06-6.74(m,3H),6.73(br s,1H),6.32(s,1H),5.40-5.31(m,1H),4.82-4.65(m,2H),4.53(s,2H),4.35-4.18(m,2H),3.52-3.44(m,2H),3.14(t,J＝7.6Hz,2H),3.01(s,3H),2.95-2.84(m,1H),2.80(s,3H),2.66-2.52(m,1H),2.41(s,6H),2.31-2.13(m,1H),1.39(s,9H),1.34(d,J＝6.4Hz,3H)。

Example 401: synthesis of Compound 601

Compound 601 (FA salt) was prepared as a white solid from compound 601-1 (described in example 399) and tert-butyl (2-aminoethyl) carbamate using an analogous method to that described in example 399 and example 600. LCMS (methods 5-95AB, ESI): t _R ＝0.716min,[M+H] ⁺ ＝904.5； ¹ H NMR(400MHz,MeOH-d4)δ8.49(br s,1H),8.24(d,J＝8.0Hz,1H),8.10(d,J＝8.0Hz,1H),7.53-7.41(m,2H),7.26-7.15(m,2H),7.10-6.99(m,1H),6.85-6.74(m,2H),6.67(br s,1H),6.34(s,1H),5.33-5.23(m,1H),4.79-4.76(m,2H),4.38-4.30(m,2H),4.26-4.18(m,2H),3.17-3.03(m,5H),2.99-2.88(m,6H),2.51(s,3H),2.39(s,3H),2.30-2.13(m,2H),1.40(s,9H),1.37(d,J＝6.4Hz,3H)。

Example 402: synthesis of Compound 602

Compound 602 (FA salt) was prepared as a white solid from compound 602-1 (described in example 399) and tert-butyl (3-aminopropyl) carbamate using an analogous method to that described in example 399 and example 600. LCMS (method 10-80AB u 7min, ESI): t _R ＝2.087min,[M+H] ⁺ ＝918.6； ¹ H NMR(400MHz,MeOH-d4)8.57(br s,2H),8.13(d,J＝8.0Hz,2H),7.44(d,J＝8.0Hz,2H),7.28-7.19(m,2H),6.91-6.78(m,3H),6.64(br s,1H),6.38(s,1H),5.33-5.18(m,1H),4.82-4.50(m,2H),4.46(s,2H),4.31-4.17(m,2H),3.61-3.55(m,4H),3.26-3.08(m,4H),3.02(s,3H),2.92-2.51(m,2H),2.41(s,6H),2.33-2.05(m,2H),2.02-1.87(m,2H),1.39(s,9H),1.35(d,J＝6.8Hz,3H)。

Example 403: synthesis of Compound 603

Step 1: to a solution of 4-nitro-phenyl-chloroformate (3.0 g,14.9 mmol) and 2- (trimethylsilyl) ethanol (2.1 g,17.9 mmol) in DCM (15 mL) was added Et ₃ N (3.0 g,29.8 mmol), and the mixture was stirred at 30 ℃ for 1h. The reaction was quenched with water (15 mL) and extracted with DCM (30mL × 3). The combined organic layers were washed with brine (50mL. Times.2), na ₂ SO ₄ Drying, concentration, and the residue was purified by column on silica gel eluting with 5% EtOAc in petroleum ether to give (4-nitrophenyl) 2-trimethylsilylethyl carbonate (2.8g, 68% yield) as a colorless oil.

Step 2: a solution of compound 603-1 (from example V (compound 106-B2), 400mg, 0.50mmol) in HFIP (15 mL) containing 5% TFA was stirred at 30 ℃ for 1h. The reaction was concentrated and the residue was redissolved in DMF (15 mL) to which DIEA (577 mg,4.5 mmol) and (4-nitrophenyl) 2-trimethylsilylethylcarbonate (253mg, 0.89mmol) were added sequentially at 0 ℃. The resulting mixture was stirred at 30 ℃ for 16h. The reaction was quenched with water (30 mL) and extracted with EtOAc (30mL. Times.3). The combined organic layers were washed with brine (50mL × 2), concentrated, and the residue was purified by silica gel column, eluting with 0-5% meoh in DCM to give compound 603-2 as a white solid (310mg, 93% yield). LCMS (method 5-95AB, ESI): t _R ＝0.964min,[M+Na] ⁺ ＝771.3

And step 3: compound 603-3 (130 mg) was prepared as a white solid from compound 603-2 by using a method similar to that described in example 54. LCMS (methods 5-95AB, ESI): t _R ＝1.054min,[M+Na] ⁺ ＝1227.6

And 4, step 4: to a solution of compound 603-3 (110mg, 0.09mmol) in DMF (3 mL) was added TBAF (95mg, 0.36mmol), and the mixture was stirred at 50 ℃ for 3h. Water (15 mL) was added to the reaction, which was extracted with EtOAc (15mL. Times.3). The combined organic layers were washed with brine (50mL. Times.2), na ₂ SO ₄ Dried and concentrated. The residue was redissolved with acetonitrile (5 mL), to which were added ethyl acetimidate (24mg, 0.27mmol) and DIEA (58mg, 0.45mmol). The mixture was stirred at 25 ℃ for 2h. The reaction was concentrated to dryness, and the residue was taken up in EtOAc (30 mL), which was washed with brine (30 mL). The organic layer is coated with Na ₂ SO ₄ Dried and concentrated, and the resulting residue was treated with 5% TFA/HFIP (5 mL) at 25 ℃ for 3h. The reaction was concentrated, and the residue was purified by preparative HPLC (acetonitrile 10-35/0.225% aqueous fa) to give the title compound as a white solid (TFA salt, 13.6mg, 16% yield over three steps). LCMS (methods 5-95AB, ESI): t _R ＝0.764min,[M+H] ⁺ ＝902.4； ¹ HNMR(400MHz,MeOH-d4)δ8.24(d,J＝8.0Hz,1H),7.49(d,J＝8.0Hz,2H),7.33-7.15(m,2H),7.03-6.81(m,3H),6.60-6.50(m,2H),5.29-5.21(m,1H),4.82-4.75(m,2H),4.44-4.30(m,2H),4.23(s,2H),3.75-3.63(m,2H),3.21-2.82(m,7H),2.50(s,6H),2.31-2.05(m,2H),2.21(s,3H),1.38(s,9H),1.35(d,J＝6.8Hz,3H)。

Examples 404 and 405: synthesis of Compounds 604 and 605

Step 1: adding 101E (320mg, 0.58mmol) and K ₂ CO ₃ A mixture of (394mg, 2.85mmol) and tert-butyl 3-bromoazacyclobutane-1-carboxylate (672mg, 2.85mmol) in DMF (5 mL) was stirred at 50 ℃ for 5 days. The reaction mixture was taken up in EtOAc (50 mL), which was washed with saturated aqueous brine solution (30mL. Times.2) over Na ₂ SO ₄ Drying, concentration, and purification of the residue by HPLC (water (0.225% fa) -ACN) gave compound 604-1 as a white solid (120mg, 29% yield). LCMS (methods 5-95AB, ESI): t _R ＝0.895min,[M+Na] ⁺ ＝739.5

Both title compounds (TFA salts) were prepared as white solids from compound 604-1 by using a similar method to that described in example 395 and isolated in the last step by HPLC.

Compound 604: LCMS (method 5-95AB, ESI): t _R ＝0.753min,[M+H] ⁺ ＝873.9； ¹ H NMR (400 MHz, methanol-d 4) δ 8.25 (d, J =8.4hz, 2h), 7.49 (d, J =8.4hz, 2h), 7.13-6.96 (m, 3H), 6.80 (br s, 1H), 6.74 (d, J =8.4hz, 2h), 6.54 (br s, 1H), 5.31-5.10 (m, 2H), 4.80-4.78 (m, 2H), 4.50-4.35 (m, 2H), 4.26-4.18 (m, 3H), 4.08-4.00 (m, 1H), 3.35-3.33 (m, 1H), 3.11 (t, J =7.2hz, 2h), 3.05-2.98 (m, 4H), 2.49 (s, 6H), 2.30-2.11 (m, 605H), 3.9H, 39H, 8H, 6H, 8H, 7H, 8H: LCMS (method 5-95AB, ESI): t _R ＝0.740min,[M+H] ⁺ ＝873.4； ¹ H NMR(400MHz,MeOH-d4)δ8.55(br s,1H),8.26(d,J＝8.0Hz,2H),7.49(d,J＝8.0Hz,2H),7.25-7.22(m,1H),6.93-6.81(m,4H),6.54(br s,2H),5.32-5.24(m,2H),4.82-4.78(m,2H),4.47-4.44(m,2H),4.30-4.10(m,2H),4.24(s,2H),3.22-3.09(m,4H),3.00(s,3H),2.49(s,6H),2.34-2.10(m,2H),1.39(s,9H),1.35(d,J＝7.2Hz,3H)。

Examples 406 and 407: synthesis of Compounds 606 and 607

Both title compounds (FA salts) were prepared as white solids from 101E and tert-butyl (2-bromopropyl) carbamate by using a similar method to that described in example 404/405, and were isolated by HPLC in the last step.

Compound 606: LCMS (methods 5-95AB, ESI): t _R ＝0.751min,[M+H] ⁺ ＝875.5； ¹ H NMR(400MHz,MeOH-d4)δ8.54(br s,1H),8.12-8.06(m,2H),7.46-7.40(m,2H),7.25-7.20(m,1H),7.06-6.84(m,1H),6.79-6.74(m,3H),6.43(br s,1H),5.36-5.32(m,1H),4.80-4.75(m,4H),4.32-4.24(m,2H),3.28-3.00(m,8H),2.42-1.93(m,8H),1.52-1.26(m,15H)。

Compound 607: LCMS (methods 5-95AB, ESI): t _R ＝0.753min,[M+H] ⁺ ＝875.5； ¹ H NMR(400MHz,MeOH-d4)δ8.52(br s,1H),8.21-8.14(m,2H),7.46-7.40(m,2H),7.25-7.21(m,1H),7.06-7.01(m,1H),6.85-6.61(m,3H),6.43(br s,1H),5.35-5.28(m,1H),4.81-4.76(m,4H),4.30-4.24(m,2H),3.35-3.30(m,1H),3.18-2.93(m,7H),2.45-1.93(m,8H),1.48-1.32(m,15H)。

Examples 408 and 409: synthesis of Compounds 608 and 609

Both title compounds (FA salts) were prepared as white solids from 101E and tert-butyl 4-bromopiperidine-1-carboxylate using a similar method to that described in example 404/405, and were isolated in the last step by HPLC.

Compound 608: LCMS (methods 5-95AB, ESI): t _R ＝0.751min,[M+H] ⁺ ＝901.5； ¹ H NMR (400mhz, meoh-d 4) δ 8.50 (br s, 2H), 8.13 (d, J =8.0hz, 2H), 7.42 (d, J =8.0hz, 2H), 7.10-7.03 (m, 3H), 6.91 (br s, 1H), 6.80 (s, 1H), 6.78 (s, 1H), 6.43 (br s, 1H), 5.38-5.33 (m, 1H), 4.81-4.60 (m, 1H), 4.34-4.12 (m, 4H), 3.57-3.50 (m, 2H), 3.28-3.07 (m, 10H), 2.69-2.10 (m, 4H), 2.41 (s, 6H), 2.00-1.93 (m, 1H), 1.81-1.75 (m, 1H), 1.9.8H (m, 6H), 3.9H, 8H (m, 1H). Compound 609: LCMS (methods 5-95AB, ESI): t _R ＝0.748min,[M+H] ⁺ ＝901.5； ¹ H NMR(400MHz,MeOH-d4)8.54(br s,1H),8.15(d,J＝8.0Hz,2H),7.42(d,J＝8.0Hz,2H),7.28-7.19(m,2H),6.89(br s,1H),6.86-6.73(m,2H),6.64(br s,1H),6.38(s,1H),5.33-5.18(m,1H),4.82-4.50(m,2H),4.32-4.15(m,3H),3.61-3.55(m,1H),3.28-2.86(m,10H),2.41(s,6H),2.48-2.09(m,6H),1.38(s,9H),1.34(d,J＝6.8Hz,3H)。

Examples 410 and 411: synthesis of Compounds 610 and 611

Step 1: to (2, 2-dimethyl-1, 3-dioxan-5-yl) methanol (1.0g, 6.84mmol) and NaH (60% in oil, 0.41g, 10.3mmol) inTo a solution in THF (30 mL) was added BnBr (1.62mL, 13.7 mmol). The reaction was stirred at 20 ℃ for 16h. The reaction was taken up in EtOAc (50 mL), which was washed with brine (30mL. Times.2) and Na ₂ SO ₄ Drying, concentration, and the residue was purified by silica gel column, eluting with 10% EtOAc in petroleum ether, to give 5- (benzyloxymethyl) -2, 2-dimethyl-1, 3-dioxane as a colorless oil (1.6 g,99% yield).

Step 2: to a solution of 5- (benzyloxymethyl) -2, 2-dimethyl-1, 3-dioxane (1.5g, 6.35mmol) in MeOH (20 mL) was added TsOH (109mg, 0.63mmol). The reaction mixture was stirred at 20 ℃ for 1h. The reaction was taken up in EtOAc (50 mL), which was washed with brine (20mL. Times.3), and Na ₂ SO ₄ Drying, concentration, and the crude product was purified by silica gel column, eluting with 50% EtOAc in petroleum ether, to give 2- (benzyloxymethyl) propane-1, 3-diol as a colorless oil (1.0 g,80% yield).

And 3, step 3: 2- (benzyloxymethyl) propane-1, 3-diol (1.0 g, 5.1mmol) and Et ₃ A solution of N (2.86mL, 20.4mmol) in DCM (20 mL) was stirred at 0 ℃ for 30min, followed by the slow addition of MsCl (1.22mL, 15.7mmol). The mixture was stirred at 0 ℃ for a further 3h. After filtration, the filtrate was concentrated and the residue was purified by silica gel column, eluted with 10% etoac in petroleum ether to give [2- (benzyloxymethyl) -3-methylsulfonyloxy-propyl ] as a colorless oil ]Mesylate (1.5g, 84% yield). ¹ H NMR(400MHz,CDCl ₃ )δ7.35-7.27(m,5H),4.50(s,2H),4.36-4.29(m,4H),3.55(d,J＝6.0Hz,2H),2.99(s,6H),2.55-2.46(m,1H)。

And 4, step 4: coupling [2- (benzyloxymethyl) -3-methylsulfonyloxy-propyl ] group]Methanesulfonic acid ester (1.5g, 4.3mmol) and NaN ₃ A solution of (2.84g, 43.7 mmol) in DMF (20 mL) was stirred at 80 ℃ for 16h. After filtration, the filtrate was taken up in EtOAc (200 mL), which was washed with brine (100mL x 3) and Na ₂ SO ₄ Drying, concentrating, and purifying the residue by silica gel column, eluting with 7% MeOH in DCM to give [ 3-azido-2- (azidomethyl) propoxy ] as a colorless oil]Methylbenzene (1.0 g,95.4% yield).

Step (ii) of5: to [ 3-azido-2- (azidomethyl) propoxy group]Addition of 10% of Pd (OH) to a solution of methylbenzene (1.0g, 4.1mmol) in MeOH (20 mL) ₂ C (432mg, 0.41mmol). Reaction mixture is reacted in H ₂ (15 psi), stirred at 15 ℃ for 5h. The mixture was filtered and the filtrate was concentrated. The residue was redissolved in THF (10 mL) and Boc was added thereto ₂ O(4.04g，18.5mmol)、Et ₃ N (2.81g, 27.8 mmol) and DMAP (142mg, 1.2mmol). The reaction mixture was stirred at 20 ℃ for 16h. The reaction was then taken up in EtOAc (200 mL), washed with brine (100mL x 3) and Na ₂ SO ₄ Drying, concentrating, and purifying the residue through a silica gel column, eluting with 20% EtOAc in petroleum ether to give N- [2- (benzyloxymethyl) -3- (tert-butoxycarbonylamino) propyl ] as a colorless oil ]Tert-butyl carbamate (1.3g, 71% yield).

Step 6: to the residue N- [2- (benzyloxymethyl) -3- (tert-butoxycarbonylamino) propyl group]Add 10% Pd/C (351mg, 0.33mmol) to a solution of tert-butyl carbamate (1.3g, 3.3mmol) in MeOH (20 mL) and subject the reaction mixture to H ₂ (40 psi), stirred at 60 ℃ for 5h. The mixture was filtered and the filtrate was concentrated. The residue was redissolved in DCM and Et was added thereto at 0 deg.C ₃ N (740. Mu.L, 5.3 mmol) for 30min. MsCl (150. Mu.L, 2.0 mmol) in DCM (2 mL) was then added dropwise to the above solution and the resulting mixture was stirred at 0 ℃ for a further 3h. After filtration, the filtrate was concentrated to give [3- (tert-butoxycarbonylamino) -2- [ (tert-butoxycarbonylamino) methyl group as a colorless oil]Propyl radical]Mesylate (500 mg, quantitative yield) was used directly without further purification.

Both title compounds (FA salts) were prepared as white solids from 101E and [3- (tert-butoxycarbonylamino) -2- [ (tert-butoxycarbonylamino) methyl ] propyl ] methanesulfonate by using a similar method to that described in example 404/405 and isolated by HPLC in the last step.

Compound 610: LCMS (method 5-95AB, ESI): t _R ＝0.743min,[M+H] ⁺ ＝904.4； ¹ H NMR(400MHz,MeOH-d4)δ8.48(br s,2H),8.35(d,J＝8.0Hz,2H),7.56(d,J＝8.0Hz,2H),7.35-6.90(m,4H),6.89-6.75(m,2H),6.43(s,1H),5.26-5.25(m,1H),4.80-4.70(m,2H),4.60-4.25(m,2H),4.22(s,2H),3.50-3.40(m,1H),3.25-2.95(m,10H),2.57(s,6H),2.45-2.35(m,1H),2.30-2.20(m,1H),2.19-2.10(m,1H),1.40(s,9H),1.37(d,J＝6.8Hz,3H)。

Compound 611: LCMS (method 5-95AB, ESI): t _R ＝0.740min,[M+H] ⁺ ＝905.0； ¹ H NMR(400MHz,MeOH-d4)δ8.57(br s,1H),8.40-8.20(m,2H),7.56-7.54(m,2H),7.35-7.00(m,3H),6.98-6.75(m,2H),6.69(br s,1H),6.47(s,1H),5.30-5.15(m,1H),4.80-4.70(m,2H),4.41-4.31(m,2H),4.22(s,2H),3.50-3.40(m,1H),3.25-3.04(m,7H),3.05(s,3H),2.57(s,6H),2.45-2.35(m,1H),2.30-2.20(m,1H),2.19-2.10(m,1H),1.40(s,9H),1.38-1.25(m,3H)。

Example 412: synthesis of Compound 612

Step 1: to a solution of methyl (R) -2- ((tert-butoxycarbonyl) amino) -3-hydroxypropionate (7.77g, 35.4 mmol) in toluene (80 mL) were added 2, 2-dimethoxypropane (7.38g, 70.9 mmol) and TsOH (610mg, 3.54mmol), and the mixture was stirred at 110 ℃ for 0.5h. The volatiles were distilled at 1atm and the residue was redissolved with EtOAc (100 mL) which was saturated NaHCO ₃ And brine (100 mL each). The organic layer is coated with Na ₂ SO ₄ Drying, concentration, and the residue was purified by chromatography on silica gel eluting with 10% etoac in petroleum ether to give (R) -3-tert-butyl 4-methyl 2, 2-dimethyloxazolidine-3, 4-dicarboxylate as a yellow oil (7.60g, 83% yield).

And 2, step: at 0 ℃ and N ₂ Next, to a suspension of lithium aluminum hydride (3.34g, 87.9mmol) in tetrahydrofuran (80 mL) was added dropwise a solution of (R) -3-tert-butyl 4-methyl 2, 2-dimethyloxazolidine-3, 4-dicarboxylate (7.60g, 29.3mmol) in tetrahydrofuran (5 mL). The reaction was then gradually warmed to 25 ℃ while stirring and stirred at the same temperature for 2h. The reaction was quenched with 10% NaOH solution (3.5 mL). After filtration, the filtrate was concentrated and the residue was partitioned between EtOAc and water (300 mL each). The organic layer was washed with brine (300 mL) and Na ₂ SO ₄ Drying and concentration gave (S) -tert-butyl 4- (hydroxymethyl) -2, 2-dimethyloxazolidine-3-carboxylate as a colorless oil (5.51g, 81% yield).

And step 3: to a solution of (S) -4- (hydroxymethyl) -2, 2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (4.90g, 21.2mmol) and TsCl (6.06g, 31.8mmol) in dichloromethane (50 mL) was added Et ₃ N (5.91mL, 42.4 mmol) and DMAP (259mg, 2.12mmol), and the reaction was stirred at 25 ℃ for 16h. To the reaction mixture was added water and DCM (100 mL each). The organic layer was washed with brine (100mL x 2), concentrated, and the residue was purified by silica gel column, eluting with 20-50% etoac in petroleum ether to give tert-butyl (R) -2, 2-dimethyl-4- ((tosyloxy) methyl) oxazolidine-3-carboxylate as a white solid (4.73g, 58% yield).

Compound 612 (FA salt) was prepared as a white solid from 101E and (R) -tert-butyl 2, 2-dimethyl-4- ((tosyloxy) methyl) oxazolidine-3-carboxylate using an analogous method to that described in example 404. LCMS (methods 5-95AB, ESI): t _R ＝0.611min,[M+H] ⁺ ＝891.4； ¹ H NMR(400MHz,MeOH-d4)δ8.60(br s,1H),8.28-8.12(m,2H),7.54-7.48(m,2H),7.29-7.02(m,3H),6.88-6.81(m,2H),6.65(br s,1H),6.54(s,1H),5.37-5.30(m,1H),4.84-4.80(m,2H),4.73-4.20(m,4H),4.25(s,2H),4.28-4.23(m,3H),3.92-3.77(m,2H),3.64-3.60(m,1H),3.15-3.11(m,2H),3.03(s,3H),2.48(s,6H),2.33-2.29(m,1H),2.21-2.14(m,1H),1.41(s,9H),1.37(d,J＝6.4Hz,3H)。

Example 413: synthesis of Compound 613

Compound 613 (TFA salt) was prepared as a white solid from methyl (S) -2- ((tert-butoxycarbonyl) amino) -3-hydroxypropionate by using an analogous method to that described in example 412. LCMS (method 5-95AB, ESI): t _R ＝0.609min,[M+H] ⁺ ＝891.4； ¹ H NMR(400MHz,MeOH-d4)δ8.36(d,J＝8.4Hz,2H),7.56(d,J＝8.4Hz,2H),7.33-7.30(m,1H),7.20-7.15(m,1H),7.12-7.05(m,1H),6.72-6.93(m,2H),6.91-6.85(m,1H),6.78(br s,1H),6.46(s,1H),5.26-5.22(m,2H),4.43-4.29(m,3H),4.22(s,2H),4.07-4.02(m,2H),3.85-3.73(m,2H),3.03(s,3H),2.52(s,6H),2.30-2.00(m,2H),1.42(s,9H),1.37(d,J＝6.8Hz,3H)。

Example 414: synthesis of Compound 614

Step 1: to a solution of compound 614-1 (from example V (compound 106-A2)) 200mg, 0.31mmol) and DIEA (507. Mu.L, 3.1 mmol) in DMF (5 mL) was added SEM-Cl (543. Mu.L, 3.1 mmol) and the reaction was stirred at 50 ℃ for 16h. The mixture was washed with EtOAc and H ₂ Partition between O (100 mL each). The organic layer was washed with brine, over Na ₂ SO ₄ Drying, concentration, and purification of the residue through a silica gel column, eluting with 10% meoh in DCM, gave compound 614-2 as a yellow oil (200mg, 83% yield). LCMS (method 5-95AB, ESI): t _R ＝1.038min,[M+Na] ⁺ ＝804.0

And 2, step: adding 10% Pd/C (272mg, 0.26mmol) and one drop of ammonia to a solution of compound 614-2 (200mg, 0.26mmol) in EtOH (20 mL) and bringing the mixture to H ₂ (15 psi), stirred at 30 ℃ for 3h. After filtration, the volatiles were concentrated to give compound 614-3 as a white solid (96mg, 67% yield). LCMS (method 5-95AB, ESI): t _R ＝0.758min,[M+Na] ⁺ ＝580.0

Compound 614-4 was prepared from compound 614-3 as a white solid by using a similar method to that described in example 54. LCMS (method 5-95AB, ESI): t _R ＝1.125min,[M+Na] ⁺ ＝1046.3

Compound 614-5 was prepared from compound 614-4 by using a method similar to that described in example 367 as a white solid. LCMS (method 5-95AB, ESI): t _R ＝1.117min,[M+Na] ⁺ ＝1219.2

Compound 614 (FA salt) was prepared from compound 614-5 as a white solid by using a method similar to that described in example 54. LCMS (methods 5-95AB, ESI): t _R ＝0.728min,[M+H] ⁺ ＝891.4； ¹ H NMR(400MHz,MeOH-d4)δ8.55(br s,1H),8.27(d,J＝8.0Hz,2H),7.54(d,J＝8.0Hz,2H),7.14-6.99(m,4H),6.85(br s,1H),6.69(br s,1H),6.58(s,1H),5.35-5.25(m,1H),5.35-5.25(m,2H),4.71-4.40(m,2H),4.31-4.06(m,3H),3.21-3.17(m,1H),3.15-3.07(m,5H),3.03(s,3H),2.51(s,6H),2.33-2.24(m,1H),2.20-2.11(m,1H),1.41(s,9H),1.37(d,J＝6.4Hz,3H)。

Example 415: synthesis of Compound 615

Compound 615 (TFA salt) was prepared as a white solid by using a method analogous to that described in example 374 from compound 615-1 (from example V (compound 106-B2)) and 2- (4- (cyclohexyloxy) phenyl) -4, 6-dimethylpyrimidine-5-carboxylic acid (described in example 137). LCMS (methods 5-95AB, ESI): t _R ＝0.702min,[M+H] ⁺ ＝982.4； ¹ H NMR(400MHz,MeOH-d4)δ8.24-8.08(m,2H),7.27-7.14(m,2H),6.97-6.69(m,6H),6.45(s,1H),5.33-5.24(m,1H),4.81-4.74(m,2H),4.57-4.37(m,4H),4.28-4.20(m,1H),3.42-3.35(m,2H),3.29-3.19(m,2H),3.05(s,3H),2.99-2.74(m,2H),2.44(s,6H),2.24-2.14(m,1H),2.09-1.97(m,3H),1.89-1.79(m,2H),1.66-1.41(m,6H),1.35(d,J＝6.8Hz,3H)。

Example 416: synthesis of Compound 616

Compound 616 (TFA salt) was prepared as a white solid by using a method analogous to that described in example 374 from compound 616-1 (from example V (compound 106-B1)) and 2- (4- (cyclohexyloxy) phenyl) -4, 6-dimethylpyrimidine-5-carboxylic acid (described in example 137). LCMS (method 5-95AB, ESI): t _R ＝0.831min,[M+H] ⁺ ＝968.4； ¹ H NMR(400MHz,MeOH-d4)δ8.10-7.93(m,2H),7.17-6.97(m,4H),6.97-6.81(m,3H),6.72(br s,1H),6.26(br s,1H),5.54-5.50(m,1H),4.83-4.72(m,2H),4.51-4.34(m,3H),4.29(s,2H),4.02-3.74(m,1H),3.58-3.37(m,4H),3.12(s,3H),2.85-2.75(m,1H),2.33(s,6H),2.09-2.02(m,2H),1.89-1.85(m,2H),1.67-1.38(m,9H)。

Example 417: synthesis of Compound 617

Compound 617-2 was prepared as a white solid from compound 617-1 (from example V (compound 106-A2)) by using a similar method to that described in example 367. LCMS (method 5-95AB, ESI): t _R ＝0.817min,[M+Na] ⁺ ＝847.2

Compound 617 (FA salt) was prepared as a white solid from compound 617-2 and (S) -2- (((benzyloxy) carbonyl) amino) -4- ((tert-butoxycarbonyl) amino) butanoic acid by an analogous method to that described in example 414 and example 382. LCMS (method 5-95AB, ESI): t _R ＝0.617min,[M+H] ⁺ ＝891.3； ¹ H NMR(400MHz,MeOH-d4)δ8.45(br s,1H),8.21(d,J＝7.6Hz,2H),7.48(d,J＝7.6Hz,2H),7.31-7.15(m,2H),6.93-6.86(m,2H),6.85-6.81(m,1H),6.59(br s,1H),6.48(s,1H),5.34-5.26(m,1H),4.85-4.76(m,2H),4.30-4.19(m,3H),4.21(s,2H),3.28-3.08(m,4H),3.00(s,3H),2.97-2.70(m,2H),2.47(s,6H),2.36-2.25(m,1H),2.21-2.11(m,1H),1.39(s,9H),1.34(d,J＝6.8Hz,3H)。

Example 418: synthesis of Compound 618

Compound 618-2 was prepared as a white solid from compound 618-1 (from example V (compound 106-B2)) by using a similar method to that described in example 371. LCMS (methods 5-95AB, ESI): t _R ＝0.944min,[M+H] ⁺ ＝1038.9

Compound 618-3 was prepared as a white solid from compound 618-2 by using an analogous method to that described in example 389. LCMS (methods 5-95AB, ESI): t _R ＝0.795min,[M+H] ⁺ ＝1052.8

Compound 618-3A solution of (70mg, 0.07mmol), trimethylsilyl isocyanate (153mg, 1.3mmol) in DCM (5 mL) was stirred at 25 ℃ for 5h. DCM (30 mL) was added to the reaction, which was washed with 0.1M HCl solution and brine (30 mL each). The organic layer was washed with Na ₂ SO ₄ Drying, concentration, and purification of the residue by preparative TLC eluting with 10% meoh in DCM gave compound 618-4 as a white solid (20mg, 27% yield). LCMS (methods 5-95AB, ESI): t _R ＝0.989min,[M+H] ⁺ ＝1095.6

Compound 618 (TFA salt) was prepared as a white solid by using a similar method as described in example 382. LCMS (methods 5-95AB, ESI): t _R ＝0.715min,[M+H] ⁺ ＝919.8； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.21(d,J＝7.6Hz,2H),7.51(d,J＝7.6Hz,2H),7.29(d,J＝7.2Hz,1H),7.22(d,J＝7.2Hz,1H),7.03(br s,1H),6.95(br s,1H),6.61(br s,1H),6.34(s,1H),5.35-5.27(m,1H),4.63-4.33(m,4H),4.26(s,2H),3.43-3.31(m,3H),3.20-3.08(m,2H),3.03(s,3H),2.99-2.92(m,1H),2.49(s,6H),2.40-2.28(m,1H),2.21-2.10(m,1H),1.40(s,9H),1.37(d,J＝6.8Hz,3H)。

Example 419: synthesis of Compound 619

Step 1: mixing compound 619-1 (134mg, 0.12mmol), K ₂ CO ₃ A solution of (86mg, 0.62mmol) and tert-butyl (2-bromoethyl) carbamate (139mg, 0.62mmol) in DMF (5 mL) was stirred at 50 ℃ for 48h while four parts of K were added every 12h ₂ CO ₃ (86mg, 0.62mmol) and tert-butyl (2-bromoethyl) carbamate (139mg, 0.62mmol). After filtration, the filtrate was partitioned between EtOAc and water (40 mL each). The organic layer was washed with brine (30mL x 2) over Na ₂ SO ₄ Drying, concentration, and purification of the residue by preparative TLC eluting with 5% meoh in DCM gave compound 619-2 as a white solid (131mg, 86% yield). LCMS (methods 5-95AB, ESI): t _R ＝1.214min,[M+H] ⁺ ＝1225.8

Compound 619 (FA salt)) Prepared as a white solid by using a similar method to that described in example 418. LCMS (method 10-80AB, ESI,7 min): t _R ＝1.749min,[M+H] ⁺ ＝962.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.53(br s,1H),8.05(s,2H),7.45(d,J＝8.4Hz,2H),7.34-7.23(m,2H),7.20-7.08(m,1H),6.91(s,1H),6.76(br s,1H),6.09(br s,1H),5.42-5.27(m,1H),4.87-4.72(m,2H),4.59-4.40(m,2H),4.23(s,2H),3.74(t,J＝5.2Hz,2H),3.49-3.45(m,2H),3.32-3.31(m,1H),3.14(t,J＝8.4Hz,2H),3.07-3.03(m,2H),3.02(s,3H),2.92-2.77(m,1H),2.38(s,6H),2.30-2.24(m,1H),2.21-2.07(m,1H),1.38(s,9H),1.35(d,J＝6.8Hz,3H)。

Example 420: synthesis of Compound 620

Compound 620-2 was prepared as a white solid from compound 620-1 (from example V (compound 106-B1)) by using a similar method to that described in example 54. LCMS (method 5-95AB, ESI): t _R ＝1.161min,[M+H] ⁺ ＝1138.1

Compound 620-3 was prepared as a white solid by using a method similar to that described in example 418. LCMS (method 5-95AB, ESI): t _R ＝0.986min,[M+Na] ⁺ ＝1074.7

The mixture of 620-3 (100mg, 0.10mmol) and Ac ₂ A solution of O (30. Mu.L, 0.29 mmol) and pyridine (50. Mu.L, 0.57 mmol) in DCM (2 mL) was stirred at 25 ℃ for 2h. EtOAc (50 mL) is added to the mixture, which is washed with brine (50 mL) and Na ₂ SO ₄ Dried and concentrated. The residue was purified by preparative TLC eluting with 5% meoh in DCM to give compound 620-4 as a white solid (108mg, 97% yield). LCMS (methods 5-95AB, ESI): t _R ＝1.059min,[M+H] ⁺ ＝1094.8

Compound 620 (FA salt) was prepared as a white solid by using a similar method to that described in example 382. LCMS (method 20-80AB, ESI,7 min): t _R ＝2.366min,[M/2+H] ⁺ ＝459.9； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.55(br s,1H),8.21(d,J＝8.0Hz,2H),7.54(s,1H),7.46(d,J＝8.0Hz,2H),7.00-6.90(m,2H),6.66(s,1H),6.48(s,1H),6.31(s,1H),5.34-5.31(m,1H),4.86-4.74(m,2H),4.40-4.28(m,4H),3.42-3.32(m,2H),3.31-3.26(m,1H),3.12(t,J＝7.8Hz,2H),2.98(s,3H),2.95-2.89(m,1H),2.43(s,6H),2.36-2.27(m,1H),2.15(m,1H),2.17-2.11(s,3H),1.39(s,9H),1.36(d,J＝6.8Hz,3H)。

Example 421: synthesis of Compound 621

Compound 621 (FA salt) was prepared from compound 621-1 (synthesis described in example 418) as a white solid by using an analogous method to that described in example 418. LCMS (method 20-80AB, ESI,7 min): t _R ＝2.372min,[M+H] ⁺ ＝919.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.70(br s,1H),8.10(d,J＝7.6Hz,2H),7.55-7.40(m,3H),6.99(d,J＝8.4Hz,1H),6.90(br s,1H),6.62(s,1H),6.44(s,1H),6.33(s,1H),5.43-5.32(m,1H),4.87-4.70(m,2H),4.44-4.27(m,4H),3.45-3.34(m,2H),3.21-3.04(m,2H),2.98(s,3H),2.93-2.79(m,1H),2.62-2.51(m,1H),2.41(s,6H),2.36-2.28(m,1H),2.22-2.09(m,1H),1.41(s,9H),1.30(d,J＝6.4Hz,3H)。

Example 422: synthesis of Compound 622

Compound 622 (FA salt) was prepared from compound 622-1 (synthesis described in example 418) as a white solid using a method analogous to that described in example 419. LCMS (method 20-80AB, ESI,7 min): t _R ＝1.930min,[M+H] ⁺ ＝962.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.49(br s,1H),8.26(d,J＝8.0Hz,2H),7.68(s,1H),7.50(d,J＝8.0Hz,2H),7.20(d,J＝8.4Hz,1H),7.08(d,J＝8.4Hz,1H),6.85(s,1H),6.64(s,1H),6.47(s,1H),5.43-5.32(m,1H),4.87-4.70(m,2H),4.44-4.27(m,2H),4.22(s,2H),4.00-3.80(m,2H),3.45-3.34(m,2H),3.21-3.04(m,2H),2.98(s,3H),2.62-2.40(m,2H),2.51(s,6H),2.36-2.28(m,1H),2.22-2.09(m,1H),1.38(s,9H),1.36(d,J＝6.8Hz,3H)。

Example 423: synthesis of Compound 623

Step 1: a solution of compound 623-1 (synthesized as described in example 418, 110mg, 0.10mmol), 1' -carbonyldiimidazole (339mg, 2.1mmol) in anhydrous THF (6 mL) was stirred at 25 ℃ for 16h. The mixture was partitioned between EtOAc and water (40 mL each) and the organic layer was washed with brine (30mL × 2) over Na ₂ SO ₄ Dried and concentrated. The residue was purified by preparative TLC eluting with 5% meoh in DCM to give compound 623-2 as a white solid (91mg, 81% yield). LCMS (methods 5-95AB, ESI): t _R ＝1.047min,[M+H] ⁺ ＝1078.7

Compound 623 (FA salt) was prepared from compound 623-2 as a white solid by using a similar method to that described in example 54. LCMS (method 10-80AB, ESI,7 min): t _R ＝2.188min,[M+H] ⁺ ＝902.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.52(br s,1H),8.34(d,J＝8.4Hz,2H),7.53(d,J＝8.4Hz,2H),7.29-7.19(m,1H),7.14(d,J＝8.4Hz,1H),6.96(s,1H),6.81(br s,1H),6.75(s,1H),6.55(s,1H),5.22-5.18(m,1H),4.73-4.56(m,2H),4.51-4.40(m,1H),3.39-4.27(m,1H),4.22(s,2H),3.47-3.38(m,2H),3.38-3.34(m,2H),3.15-3.11(m,2H),3.00(s,3H),2.57(s,6H),2.33-2.22(m,2H),1.41(s,9H),1.37(d,J＝6.0Hz,3H)。

Example 424: synthesis of Compound 624

Step 1: 4-bromo-2-methoxy-1-nitrobenzene was prepared as a yellow solid from 5-bromo-2-nitrophenol using the methylation procedure described in example 391.

Step 2: methyl 2- ((tert-butoxycarbonyl) amino) -3-iodopropionate (4.26g, 12.9mmol), zinc(1.69g, 25.8mmol) and I ₂ (100 mg) solution in DMF (10 mL) in N ₂ Stirred at 20 ℃ for 30min, then under N ₂ Next, 4-bromo-2-methoxy-1-nitrobenzene (2.0g, 8.6mmol), spes (354mg, 0.86mmol) and Pd were added ₂ (dba) ₃ (395mg, 0.43mmol). The mixture was then warmed to 60 ℃ while stirring and stirred at 60 ℃ for 3h. The mixture was taken up in EtOAc (200 mL), which was washed with brine (150mL x 2) over MgSO ₄ Dried and concentrated. The residue was purified by silica gel column, eluting with 0-20% etoac in petroleum ether, to give methyl (S) -2- ((tert-butoxycarbonyl) amino) -3- (3-methoxy-4-nitrophenyl) propionate as a yellow oil (2.0 g,66% yield).

And 3, step 3: to a solution of methyl (S) -2- ((tert-butoxycarbonyl) amino) -3- (3-methoxy-4-nitrophenyl) propionate (2.0 g,5.6 mmol) in DCM (10 mL) at 0 deg.C was added BBr ₃ (3.2mL, 33.9mmol). The mixture was slowly warmed to 25 ℃ while stirring and stirred at the same temperature for 16h. The reaction was slowly added to MeOH (20 mL), and the resulting mixture was concentrated. The residue was redissolved in saturated HCl/MeOH (50 mL) and the mixture was stirred at 25 ℃ for 5h. The volatiles were removed and the resulting residue was redissolved in THF (15 mL) to which Boc was added ₂ O (1.44mL, 6.3 mmol) and 15mL saturated NaHCO ₃ And (3) solution. The reaction mixture was stirred at 25 ℃ for 16h. Thereafter, the mixture was diluted with EtOAc (100 mL), which was washed with brine (100 mL) and Na ₂ SO ₄ Dried and concentrated. The residue was purified by silica gel column, eluting with 0-30% EtOAc in petroleum ether to give methyl (S) -2- ((tert-butoxycarbonyl) amino) -3- (3-hydroxy-4-nitrophenyl) propionate as a yellow solid (1.44g, 74% yield). NMR (400MHz, CDCl) ₃ ) δ 10.59 (s, 1H), 8.04 (d, J =8.0hz, 1h), 6.94 (s, 1H), 6.78 (d, J =8.0hz, 1h), 5.07 (d, J =7.6hz,1h, nh), 4.62 (br s,1H, phenol-OH), 3.76 (s, 3H), 3.27-3.05 (m, 2H), 1.43 (s, 9H).

And 4, step 4: methyl (S) -2-amino-3- (4-nitro-3- (((trifluoromethyl) sulfonyl) oxy) phenyl) propanoate was prepared as a white solid from methyl (S) -2- ((tert-butoxycarbonyl) amino) -3- (3-hydroxy-4-nitrophenyl) propanoate by using a trifluoromethanesulfonate formation procedure (described in example 10) and a Boc removal procedure (described in example 53).

And 5: to a solution of compound 624-1 (10.0 g,18.4 mmol) in DCM/MeOH (150ml, v/v =1 ₂ SO ₄ (4.0 g, 12.9mmol) and iodine (5.1g, 20.2mmol). The mixture was stirred at 25 ℃ for 3h. The mixture was washed with EtOAc and saturated NaHCO ₃ Partitioning between solutions (300 mL each), washing the organic layer with 5% Na2S2O3 and saline (300 mL each), and adding Na ₂ SO ₄ Dried and concentrated. The residue was purified by silica gel column, eluting with 40-60% EtOAc in petroleum ether, to give compound 624-2 as a yellow solid (12.0 g,97% yield). LCMS (methods 5-95AB, ESI): t _R ＝0.959min,[M+Na] ⁺ ＝692.1

Step 6: a solution of compound 624-2 (12.0g, 18mmol), pd (PPh 3) 2Cl2 (1.26g, 1.8mmol), bis (pinacol) diboron (22.7g, 90mmol), KOAc (12.3g, 126mmol) in DMSO (40 mL) in N ₂ Stirred at 60 ℃ for 3h. The mixture was taken up in EtOAc (500 mL), which was washed with brine (500mL. Times.3) and Na ₂ SO ₄ Drying, concentration, and the residue was purified by silica gel column, eluting with 40-60% etoac in petroleum ether, to give compound 624-3 as a white solid (9.0 g,75% yield).

And 7: compound 624-4 was prepared from compound 624-3 and methyl (S) -2-amino-3- (4-nitro-3- (((trifluoromethyl) sulfonyl) oxy) phenyl) propanoate using an analogous method to that described for 101B. LCMS (methods 5-95AB, ESI): t _R ＝0.927min,[M+Na] ⁺ ＝756.3

And 8: compound 624-4 (100mg, 0.14mmol) and SnCl ₂ ·2H ₂ A solution of O (308mg, 1.4mmol) in EtOAc (10 mL) was stirred at 75 ℃ for 2h. To the mixture was added EtOAc (30 mL) with saturated Na ₂ CO ₃ The solution and brine (40 mL each) were washed over MgSO ₄ Dried and concentrated. The resulting residue was redissolved in DCM (10 mL) and Boc was added thereto ₂ O (152. Mu.L, 0.66 mmol) and Et ₃ N (147. Mu.L, 1.1 mmol). The mixture was stirred at 25 ℃ for 32h. Volatiles were removed and the residue was purified by preparative TLCEluted with 10% MeOH in DCM to give compound 624-5 as a white solid (100mg, 94% yield). LCMS (method 5-95AB, ESI): t _R ＝0.994min,[M+Na] ⁺ ＝826.5

Compound 624 (FA salt) was prepared as a white solid from compound 624-5 by using a similar method to that described in example 54. LCMS (method 5-95AB, ESI): t _R ＝0.730min,[M+H] ⁺ ＝860.4； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.55(br s,3H),8.14(d,J＝8.0Hz,2H),7.44(d,J＝8.0Hz,2H),7.30-7.22(m,2H),6.89-6.71(m,4H),6.33(s,1H),5.30(m,1H),4.60-4.50(m,2H),4.39-4.20(m,2H),4.26(s,2H),3.08-2.54(m,8H),3.01(s,3H),2.42(s,6H),2.24-2.11(m,2H),1.38(s,9H),1.35(d,J＝6.4Hz,3H)。

Example 425: synthesis of Compound 625

Step 1: methyl (S) -3- (2- (benzyloxy) -4-methoxyphenyl) -2- ((tert-butoxycarbonyl) amino) propanoate was prepared as a white solid from 2-bromo-5-methoxyphenol and benzyl bromide using a method similar to that described in example 424. ¹ H NMR(400MHz,CDCl ₃ )δ7.47-7.31(m,5H),7.02(d,J＝8.4Hz,1H),6.51(d,J＝2.0Hz,1H),6.44(dd,J＝8.4,2.0Hz,1H),5.12-5.03(m,2H),4.50-4.45(m,1H),3.77(s,3H),3.61(s,3H),3.12-2.98(m,2H),1.39(s,9H)。

And 2, step: compound 625-1 was prepared as a white solid by using a similar method to that described in example 424. LCMS (methods 5-95AB, ESI): t _R ＝0.991min,[M+Na] ⁺ ＝847.5

And 3, step 3: compound 625-2 was prepared as a white solid from (S) -2- (((benzyloxy) carbonyl) amino) -4- ((tert-butoxycarbonyl) amino) butanoic acid by an analogous method to that described in example 382. LCMS (methods 5-95AB, ESI): t _R ＝0.896min,[M+H] ⁺ ＝1068.3

Compound 625 (the FA salt) was prepared as a white solid by using a similar method to that described in example 382. LCMS (methods 5-95AB, ESI): t _R ＝0.743min,[M+Na] ⁺ ＝913.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.56(br s,2H),8.08(d,J＝7.6Hz,2H),7.43(d,J＝7.6Hz,2H),7.18(br s,2H),6.77(br s,1H),6.73(s,1H),6.52(s,1H),6.17(s,1H),5.37-5.35(m,1H),4.79-4.74(m,2H),4.39-4.25(m,2H),4.31(s,2H),3.83(s,3H),3.27-3.15(m,2H),3.10-2.95(m,2H),3.02(s,3H),2.79-2.71(m,2H),2.38(s,6H),2.28-2.08(m,2H),1.40(s,9H),1.34(d,J＝6.8Hz,2H)。

Example 426: synthesis of Compound 626

Step 1: compound 626-2 was prepared as a white solid from compound 626-1 (the synthesis described in example 425) by using the trifluoromethanesulfonate formation procedure described in example 10. LCMS (method 5-95AB, ESI): t _R ＝1.054min,[M+H] ⁺ ＝1199.6

And 2, step: compound 626-2 (240mg, 0.20mmol), zn (CN) ₂ (48mg, 0.40mmol), dppf (44mg, 0.08mmol) and Pd ₂ (dba) ₃ (17mg, 0.04mmol) in DMF (8 mL) in N ₂ And stirred at 100 ℃ for 16h. To the mixture was added EtOAc (80 mL), which was washed with brine (50mL x 2) over Na ₂ SO ₄ Dried and concentrated. The residue was purified by preparative TLC eluting with 10% meoh in DCM to give compound 626-3 as a white solid (160mg, 74% yield). LCMS (methods 5-95AB, ESI): t _R ＝1.148min,[M+H] ⁺ ＝1077.0。

And step 3: compound 626-4 was prepared as a white solid from compound 626-3 by the method described in example 424, except for the Boc addition procedure, in which Boc was used ₂ O、Et ₃ N (described in example 395). LCMS (methods 5-95AB, ESI): t _R ＝1.174min,[M+Na] ⁺ ＝1184.3

And 4, step 4: to the compound 626-4 (50mg, 0.04mmol), boc at 0 deg.C ₂ O (57mg, 0.26mmol) and NiCl ₂ ·6H ₂ To a solution of O (15mg, 0.06mmol) in MeOH (4 mL) was slowly added NaBH ₄ (11mg, 0.30mmol). The reaction was gradually warmed to 25 ℃ while stirring and stirred at the same temperature overnight. EtOAc (40 mL) is added to the mixture, which is washed with brine (40 mL) and Na ₂ SO ₄ Dried and concentrated. The residue was purified by preparative TLC, eluting with 10% meoh in DCM to give compound 626-5 as a white solid (30mg, 55% yield). LCMS (method 5-95AB, ESI): t _R ＝1.133min,[M+Na] ⁺ ＝1288.3

Compound 626 (FA salt) was prepared as a white solid from compound 626-5 by using a method analogous to that described in example 54. LCMS (methods 5-95AB, ESI): t _R ＝0.760min,[M+H] ⁺ ＝891.0； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.49(br s,2H),8.32(d,J＝8.4Hz,2H),7.53(d,J＝8.4Hz,1H),7.30(d,J＝8.4Hz,1H),7.18(d,J＝8.4Hz,1H),7.01(s,1H),6.92(s,1H),6.81(s,1H),6.45(s,1H),5.24-5.21(m,2H),4.85-4.80(m,1H),4.40-4.32(m,2H),4.22(s,2H),4.10-4.04(m,2H),3.35-3.11(m,6H),2.98(s,3H),2.55(s,6H),2.29-2.13(m,2H),1.38(s,9H),1.35(d,J＝6.8Hz,3H)。

Example 427: synthesis of Compound 627

Compound 627-2 was prepared from compound 627-1 (described in example 425) and tert-butyl (2-bromoethyl) carbamate using an analogous method to that described in example 382. LCMS (method 5-95AB, ESI): t _R ＝1.011min,[M+H] ⁺ ＝1299.6

Compound 631 (FA salt) was prepared as a white solid from compound 627-2 by using Boc removal conditions described in example 53. LCMS (method 5-95AB, ESI): t _R ＝0.785min,[M+H] ⁺ ＝999.6； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.53(br s,3H),8.19(d,J＝7.6Hz,2H),7.47(d,J＝7.6Hz,2H),7.24-7.16(m,3H),6.77(s,1H),6.72(s,1H),6.62(br s,1H),6.52(s,1H),5.42-5.40(m,1H),4.78-4.62(m,2H),4.27-4.22(m,6H),3.88(s,3H),3.58-3.53(m,2H),3.40-3.38(m,1H),3.05(s,3H),2.99-2.96(m,2H),2.90-2.75(m,3H),2.49(s,6H),1.38(s,9H),1.37(d,J＝6.4Hz,3H)。

Example 428: synthesis of Compound 628

To a solution of compound 628-1 (synthesis described in example 427, 50mg, 0.04mmol) in DCM (4 mL) at 0 deg.C was added BBr ₃ (36. Mu.L, 0.38 mmol). The reaction was gradually warmed to 25 ℃ while stirring and stirred at the same temperature for 16h. The reaction was quenched with water and the resulting mixture was immediately lyophilized. The residue was purified by preparative HPLC (acetonitrile 23-33/0.225% aqueous FA solution) to give compound 628 (FA salt) as a white solid (2.3mg, 5.9% yield). LCMS (methods 5-95AB, ESI): t _R ＝0.793min,[M+Na] ⁺ ＝1007.8； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.53(br s,3H),8.22(d,J＝7.6Hz,2H),7.48(d,J＝7.6Hz,2H),7.21(d,J＝8.0Hz,1H),7.16(d,J＝8.0Hz,1H),6.82(s,1H),6.63(br s,1H),6.53(s,1H),6.50(br s,1H),5.39-5.35(m,2H),4.81-4.77(m,1H),4.65-4.15(m,6H),4.21(s,2H),3.58-3.53(m,2H),3.39-3.33(m,4H),3.10(s,3H),3.05-2.98(m,2H),2.50(s,6H),1.36(s,9H),1.35(d,J＝6.4Hz,3H)。

Example 429: synthesis of compound 629

Step 1: compound 629-2 was prepared from compound 629-1 (the synthesis described in example 371) by using the iodination conditions described in example 382. LCMS (method 5-95AB, ESI): t _R ＝0.925min,[M+Na] ⁺ ＝853.1

And 2, step: compound 629-2 (200mg, 0.24mmol), pd ₂ dba ₃ (111mg, 0.01mmol), SPhos (10mg, 0.02mmol), potassium N- (difluoroboranylmethyl) carbamic acid tert-butyl ester fluoride (63mg, 0.26mmol), and K ₃ PO ₄ (153mg, 0.72mmol) in toluene (2 mL) and H ₂ Solution in O (0.10 mL) in N ₂ 、85℃And (5) the next 16h. The volatiles were removed and EtOAc (30 mL) was added to the residue. After filtration, the filtrate was washed with brine (35mL x 3) and Na ₂ SO ₄ Drying, concentration, and purification of the residue by preparative TLC eluting with 10% meoh in DCM yielded compound 629-3 as a yellow solid (110mg, 55% yield). LCMS (methods 5-95AB, ESI): t _R ＝0.926min,[M+Na] ⁺ ＝856.1

Compound 629 (FA salt) was prepared as a white solid by using a similar method as described in example 382. LCMS (methods 5-95AB, ESI): t _R ＝0.785min,[M+H] ⁺ ＝955.5； ¹ H NMR(400MHz,MeOH-d ₄ )δ8.44(brs,1H),8.32(d,J＝8.0Hz,1H),7.53(d,J＝8.4Hz,2H),7.23(d,J＝8.0Hz,1H),7.15(s,1H),7.07(d,J＝8.0Hz,1H),6.93(brs,1H),6.86(s,1H),6.79(s,1H),6.48(s,1H),5.30-5.27(m,1H),4.90-4.81(m,2H),4.35(s,2H),4.21(s,2H),4.10-4.00(m,2H),3.60-3.55(m,2H),3.25-3.10(m,4H),3.06(s,3H),2.59(s,6H),1.38(s,9H),1.36(d,J＝6.0Hz,3H)。

Examples 430 to 437: synthesis of Compounds 630-637

The compounds in table 4 below were prepared by using a similar method to that previously described.

TABLE 4

Examples 438 to 449: synthesis of Compounds 638-649

The compounds in table 5 below were prepared by using a similar method to that previously described.

TABLE 5

Biological assay

Example B1: determination of minimum inhibitory concentration

The in vitro Antimicrobial activity of various compounds was determined by measuring the Minimum Inhibitor Concentration (MIC) using liquid medium microdilution techniques Approved by the Clinical and Laboratory Standard Institute (CLSI) (Methods for Dilution of Antimicrobial Succinitility Tests for Bacteria that Grow Aerobically; approved Standard-weight edition. CLSI focus M07-A8.Wayne, PA: clinical and laboratory Standards; 2009). Antibacterial activity was determined against two bacterial strains: methicillin-resistant staphylococcus aureus USA 200 strain (staphylococcus aureus) and escherichia coli ATCC 25922 (escherichia coli), clinically relevant gram-negative strains. The cells were seeded onto trypticase Soy Agar (trypticase Soy Agar) or Luria Agar (Luria Agar), respectively, and grown at 35 ℃ for 20 hours. By scraping cells into 1mL test medium (cation-regulated Mueller Hinton broth supplemented with 0.002% v/v Tween 80) and diluting to a final OD of 0.01 _600nm To prepare an inoculum suspension.

Test compounds were prepared in DMSO at a concentration of 10 mg/ml. Compounds were tested at several different dilutions and the data are shown in tables 6, 7 and 8. In scheme 1, stock solutions of these compounds were diluted in the assay medium at a concentration of 64 μ g/mL in 96-well U-bottom microtiter dishes and serial 2-fold dilutions were made in the same medium for a total of 10 compound concentrations. In scheme 2, compound stock solutions were diluted at a concentration of 4 μ g/mL in the test medium in 96-well U-bottom microtiter dishes and serial 2-fold dilutions were made in the same medium for a total of 10 compound concentrations. In scheme 3, stock solutions of these compounds were diluted at a concentration of 0.5. Mu.g/mLReleased into the test medium, serial 2-fold dilutions were performed as described above. In scheme 4, stock solutions of these compounds were diluted in the assay medium at a concentration of 0.13 μ g/mL, with serial 2-fold dilutions performed as described above. The inoculum suspension was added to 2-fold serial dilutions of the test compound to OD _600nm At a final density of 0.0005 and incubated at 35 ℃ for 22 hours. The plates were visually inspected after incubation and the lowest concentration of test compound that completely prevented bacterial growth was recorded as the MIC. The results are listed in tables 6, 7 and 8.

TABLE 6

TABLE 7

TABLE 8

NT = not tested

Example B2: whole cell SpsB biochemical screening assay

Evaluation of inhibition of SpsB (Staphylococcus aureus signal peptidase) activity using a kinetic luciferase Activity assay and determination of IC ₅₀ . This assay used a suspension of staphylococcus aureus cells instead of recombinant SpsB protein as the source of SpsB.

Cell preparation: luria Broth (LB) was inoculated with Staphylococcus aureus (USA 300 background, overexpressing SpsB) and shaken at 37 ℃ until OD was reached _600nm From 1.5 to 2.0 (about 4 hours). The culture was then diluted to OD with LB _600nm At 1.0, aliquote and centrifuge at 10,000x g for 2 minutes. The supernatant was removed and the pellet resuspended in phosphate buffer (1xPBS, 12.5mg/L MgCl ₂ ，25mg/L CaCl ₂ 0.1% Tween-80) to OD _600nm 0.5, and then centrifuged at 10,000x g for an additional 2 minutes. The supernatant was removed and the pellet was frozen at-20 ℃.

Test compounds were prepared in DMSO at a concentration of 10 mg/ml. Stock solutions of these compounds were diluted in DMSO to a concentration of 25 μ g/mL and serial 3-fold dilutions were made in DMSO for a total of 11 compound concentrations. 20nL of each compound solution was pre-spotted onto a white 384-well plate (50. Mu.L/well polypropylene, nunc) using acoustic fluid transfer (Echo).

Frozen S.aureus pellets were resuspended in assay buffer (1X PBS,12.5mg/L MgCl ₂ ，25mg/L CaCl ₂ 0.1% tween-80) to an OD600nm of 0.05, then mixed with 20 μ M substrate ((Dabcyl) β Ala-KPAKAAE (Edans)) at 1 (v/v) in assay buffer and this solution was added (20 μ L/well) to 384-well plates pre-spotted with compound. Fluorescence intensity was then immediately read kinetically for 30 minutes at 2 minute read intervals to monitor cleavage of the internally quenched peptide substrate (excitation wavelength =340nm, emission wavelength =490nm, molecular Devices spectra mmax M5). Reaction rate (slope) was plotted against inhibition concentration to derive IC ₅₀ 。

Example B3: activity in a neutropenic thigh infection model

The ability of a compound to inhibit infection by a bacterial pathogen can be measured using a murine neutropenic thigh infection model. The reduction in bacterial load is a measure of the antibacterial activity in vivo.

Neutropenia induced in jugular-vein-intubated CD-1 mice by injection of 150mg/kg and 100mg/kg cyclophosphamide on days-5 and-2, respectively: (<100 cells/mm ³ ) On day-1, saline was infused at 20 μ L/hr for 12 hours using a Harvard Apparatus PHD 2000 infusion pump. On day 0, mice were infected with 1X10 in thigh muscle ⁵ CFU/50. Mu.L of E.coli strain ATCC 25922. There were four test groups and one vehicle group starting at 1 hour post infection:

group 1-vehicle control (3% HP-beta-Cyclodextrin in PBS)

Group 2-Compound group disclosed herein, administered at a concentration of 0.62mg/mL solution, infused at 80 μ L/hr for 23 hours with a target steady state concentration (Css) of 13 μ g/mL.

Group 3-Compound group disclosed herein, was administered at a concentration of 0.21mg/mL solution, infused at 80 μ L/hr for 23 hours to reach a steady state concentration (Css) of 3.4 μ g/mL.

Group 4-group of compounds disclosed herein, administered as a 0.07mg/mL solution (Css 1.2. Mu.g/mL) and infused at 80. Mu.L/hr for 23 hours.

Group 5-Compound group disclosed herein, was administered as a 0.02mg/mL solution (Css 0.31. Mu.g/mL) and infused at 80. Mu.L/hr for 23 hours.

24 hours after infection, the bacterial load in the thigh muscle was determined by inoculating serial dilutions of the tissue homogenate onto blood agar plates.

Example B4: clinical trials of the safety and efficacy of compounds of formulae (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V) or (Va) - (Vc) in patients with Clostridium difficile-associated diarrhea

The purpose is as follows: the objective of this study was to determine the safety and efficacy of the compounds proposed herein in treating the symptoms of clostridium difficile-associated diarrhea and reducing the risk of recurrent episodes of diarrhea. The compounds were evaluated compared to the current standard antibiotic treatment, and therefore all patients will receive active drug treatment. All care related to the study is provided, including physician visits, physical examinations, laboratory examinations, and study medication. The total length of time involved was approximately 10 weeks.

The patients: eligible subjects were males and females 18 years of age and older.

The standard is as follows:

and (3) inclusion standard:

at least 18 years old;

has active mild to moderate Clostridium Difficile Associated Diarrhea (CDAD);

can tolerate oral drug treatment;

absence of pregnancy or lactation; and

signed and dated on an informed consent.

Research design: this is a randomized, double-blind, active controlled study of the effectiveness, safety and tolerability of compounds of formula (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V) or (Va) - (Vc) in c.

Example B5: clinical trials of compounds of formulae (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V) or (Va) - (Vc) for the treatment of MRSA osteomyelitis compared to vancomycin

The purpose is as follows: the objective of this study was to determine the efficacy of the compounds provided herein in treating methicillin-resistant staphylococcus aureus (MRSA) osteomyelitis as compared to vancomycin.

The patients: eligible subjects will be males and females 18 years of age and older.

And (3) standard:

and (3) inclusion standard:

culture-confirmed MRSA obtained in an operating room or from sterile biopsy procedures of a bone site. The infection and sampling site is either deep within the bone or soft tissue adjacent to the bone, or is a radiographic abnormal binding positive MRSA blood culture consistent with osteomyelitis;

Surgical debridement of the infected site, if necessary;

the subject is able to provide written informed consent; and

the subject can receive 12 weeks of outpatient parenteral treatment.

Exclusion criteria：

(II) is hypersensitive to compounds of formulae (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V) or (Va) - (Vc) or vancomycin;

staphylococcus aureus resistant to a compound of formulae (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V) or (Va) - (Vc) or vancomycin;

osteomyelitis, which develops directly from chronic, open wounds;

multi-microorganism culture (the only exception being the presence of coagulase-negative staphylococci in the culture and clinical evaluation that this is a contaminant);

subjects were positive for pregnancy test when added to the study;

baseline renal or hepatic insufficiency that would prevent study drug administration;

actively using the injected drug for 3 months under safe conditions without administration of intravenous antibiotics; and

antibiotics are expected to be used for more than 14 days for infections other than osteomyelitis.

Research design: this is a randomized, open label, active controlled efficacy test comparing vancomycin to compounds of formula (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V), or (Va) - (Vc) for treatment of MRSA osteomyelitis.

Example B5: clinical trials evaluating compounds of formulae (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V) or (Va) - (Vc) for selected severe infections caused by vancomycin-resistant enterococci (VRE)

The purpose is as follows: the purpose of this study was to determine the safety and efficacy of compounds of formula (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V) or (Va) - (Vc) in the treatment of selected severe infections caused by VRE.

The standard is as follows:

and (3) inclusion standard:

isolating one of the following multi-antibiotic resistant bacteria: vancomycin-resistant enterococcus faecium, vancomycin-resistant enterococcus faecalis, alone or as part of a polymicrobial infection; and

confirmed as a severe infection requiring Intravenous (IV) antibiotic therapy (e.g., bacteremia [ unless due to excluded infection ], complicated intraperitoneal infection, complicated skin and skin structure infection, or pneumonia)

Exclusion criteria:

the subject has any concomitant condition or takes any concomitant medication that the investigator believes may interfere with the assessment of the response, or result in the impossibility of completing the expected course of therapy or follow-up assessment, or will substantially increase the risk associated with the subject's participation in the study.

The expected length of antibiotic treatment is less than 7 days.

Research and design: this is a randomized, double-blind study of the safety and efficacy of compounds of formula (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V) or (Va) - (Vc) in the treatment of selected severe infections caused by VRE.

Pharmaceutical composition

Example C1: parenteral compositions

To prepare a parenteral pharmaceutical composition suitable for administration by injection, 100mg of a compound of formula (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V) or (Va) - (Vc) is dissolved in DMSO and then mixed with 10mL of 0.9% sterile saline. The mixture is incorporated into a dosage unit form suitable for administration by injection.

In another embodiment, the following ingredients are mixed to form an injectable formulation:

all the above ingredients except water are combined and stirred if necessary and heated slightly if necessary. Sufficient water is then added.

Example C2: oral composition

To prepare a pharmaceutical composition for oral delivery, 100mg of a compound of formula (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V) or (Va) - (Vc) is mixed with 750mg of starch. The mixture is added to an oral dosage unit suitable for oral administration, such as a hard gelatin capsule.

In another embodiment, the following ingredients are intimately mixed and compressed into a single scored tablet.

In yet another embodiment, the following ingredients are intimately mixed and enclosed in a hard shell gelatin capsule.

In yet another embodiment, the following ingredients are mixed to form a solution/suspension for oral administration:

example C3: topical gel compositions

To prepare a topical gel pharmaceutical composition, 100mg of a compound of formula (I), (Ia) - (If), (II), (IIa) - (IIe), (III), (IIIa) - (IIIc), (IV), (IVa) - (IVc), (V), or (Va) - (Vc) is mixed with 1.75g of hydroxypropyl cellulose, 10mL of propylene glycol, 10mL of isopropyl myristate and 100mL of purified alcohol USP. The resulting gel mixture is then added to a container, such as a tube, suitable for topical administration.

While preferred embodiments of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will occur to those skilled in the art without departing from the invention herein. It should be understood that various alternatives to the embodiments described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

1. A compound of formula (V), or a pharmaceutically acceptable salt thereof:

wherein:

R ¹ and R ² Are each independently H, - (C) ₁ -C ₆ ) Alkyl, -CH ₂ CH(OH)CH ₂ NH ₂ Or is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² Provided that R is ¹ And R ² Not H at the same time;

R ⁶ 、R ⁷ and R ⁸ Each independently is H;

R ⁹ is H or- (C) ₁ -C ₆ ) An alkyl group;

R ¹⁰ is H;

R ¹² is H;

R ¹¹ is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² Or- (C) ₁ -C ₆ ) alkyl-N (H) S (O) ₂ NR ²⁵ R ²⁶ ；

R ¹⁵ 、R ¹⁶ 、R ¹⁷ And R ¹⁸ Each independently is H or- (C) ₁ -C ₆ ) An alkyl group;

x is optionally substituted heteroaryl;

y is a bond, optionally substituted- (C) ₁ -C ₆ ) Alkyl-or optionally substituted aryl;

z is H, - (C) ₁ -C ₁₂ ) Alkyl, -O- (C) ₁ -C ₁₂ ) Alkyl, -O- [ optionally substituted (C) ₃ -C ₇ ) Cycloalkyl radicals]Optionally substituted- (C) ₃ -C ₇ ) Cycloalkyl or optionally substituted aryl;

each R ²¹ And R ²² Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

each R ²⁵ And R ²⁶ Is H;

each R ²⁷ Is optionally substituted- (C) ₁ -C ₆ ) A heteroalkylamino group;

or R ¹ And R ²⁷ And the atoms to which they are attached form an optionally substituted 5-or 6-membered heterocycloalkyl ring; and

each R ²⁸ Is absent;

p is 0 or 1 and q is 0;

wherein the optional substituents on each of the heteroalkylamino, alkyl, heterocycloalkyl, aryl, cycloalkyl, and heteroaryl groups are independently selected from the group consisting of halogen, OH, -NR ^25’ R ^26’ Oxo, - (C) ₃ -C ₇ ) Cycloalkyl and optionally substituted by halogen, NH ₂ Or OH substituted- (C) ₁ -C ₆ ) Alkyl, wherein R ^25’ And R ^26’ Each independently is H or- (C) ₁ -C ₆ ) An alkyl group.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (Va):

3. the compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R ¹⁵ And R ¹⁶ Is H.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R ¹⁷ is-CH ₃ 。

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R ¹⁸ Is H.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R ⁹ Is- (C) ₁ -C ₆ ) An alkyl group.

7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein R ⁹ is-CH ₃ 。

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² 。

9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-NH ₂ 。

10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein p is 1.

11. The method of claim 1A compound, or a pharmaceutically acceptable salt thereof, wherein X is pyridinyl or pyrimidinyl mono-or disubstituted with substituents independently selected from-NR ^25’ R ^26’ Or optionally halogen, NH ₂ Or OH substituted- (C) ₁ -C ₆ ) Alkyl radical, wherein R ^25’ And R ^26’ Each independently is H or- (C) ₁ -C ₆ ) An alkyl group.

12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Y is phenyl.

13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Z is- (C) ₁ -C ₁₂ ) Alkyl, -O- (C) ₁ -C ₁₂ ) Alkyl or optionally substituted- (C) ₃ -C ₇ ) Cycloalkyl, wherein the optional substituents are independently selected from the group consisting of halogen, OH, -NR ^25’ R ^26’ Oxo, - (C) ₃ -C ₇ ) Cycloalkyl and optionally substituted by halogen, NH ₂ Or OH-substituted- (C) ₁ -C ₆ ) Alkyl, wherein R ^25’ And R ^26’ Each independently is H or- (C) ₁ -C ₆ ) An alkyl group.

14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein Z is optionally- (C) substituted with ₁ -C ₆ ) Alkyl substituted- (C) ₃ -C ₇ ) A cycloalkyl group.

15. A compound of formula (I), or a pharmaceutically acceptable salt thereof:

wherein:

R ¹ and R ² Are each independently H, - (C) ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-OR ²³ 、-CH ₂ CH(OH)CH ₂ NH ₂ 、-(C ₁ -C ₆ ) alkyl-NR ²¹ R ²² 、-(C ₁ -C ₆ ) alkyl-N (R) ²³ )C(O)(C ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-NR ²³ C(＝NH)NR ²¹ R ²² 、-(C ₁ -C ₆ ) alkyl-NR ²³ C(＝NH)R ²³ 、-(C ₁ -C ₆ ) Alkyl- [ (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² ] ₂ 、-(C ₁ -C ₆ ) Heteroalkyl or optionally substituted heterocycloalkyl;

R ³ is H;

R ⁴ Is H;

R ⁵ is H;

R ⁶ 、R ⁷ and R ⁸ Each independently is H;

R ⁹ is H, - (C) ₁ -C ₆ ) Alkyl or- (C) ₃ -C ₆ ) A cycloalkyl group;

R ¹⁰ is H;

R ¹² is H;

R ¹¹ is- (C) ₁ -C ₆ ) alkyl-OR ²³ 、-(C ₁ -C ₆ ) alkyl-SR ²³ 、-(C ₁ -C ₆ ) alkyl-NR ²¹ R ²² 、-(C ₁ -C ₆ ) alkyl-NR ²³ OR ²³ 、-(C ₁ -C ₆ ) alkyl-NHC (O) NR ²³ OR ²³ 、-(C ₁ -C ₆ ) alkyl-O- (C) ₁ -C ₆ ) alkyl-NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) alkyl-CN, - (C) ₁ -C ₆ ) alkyl-NR ²³ C(O)R ²³ 、-(C ₁ -C ₆ ) alkyl-C (O) NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) alkyl-C (NH) ₂ )＝NH、-(C ₁ -C ₆ ) alkyl-N (H) C (= NH) NH ₂ 、-(C ₁ -C ₆ ) alkyl-N (H) S (O) ₂ NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) alkyl-N (H) S (O) ₂ (C ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-N (H) -C (O) NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) Alkyl N (H) C (O) (C) ₁ -C ₆ ) alkyl-OR ²³ 、-(C ₁ -C ₆ ) Alkyl C (O) NR ²⁵ R ²⁶ 、-(C ₁ -C ₆ ) alkyl-N (H) -C (O) - (C) ₁ -C ₆ ) alkyl-NR ²⁵ R ²⁶ Or- (C) ₁ -C ₆ ) alkyl-N (H) - (C) ₁ -C ₆ ) Alkyl C (O) NR ²⁵ R ²⁶ ；

Or R ¹¹ And R ¹⁸ Combine to form an optionally substituted heterocycloalkyl ring;

x is optionally substituted- (C) ₁ -C ₆ ) Alkyl-, optionally substituted- (C) ₃ -C ₇ ) Cycloalkyl-, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

y is a bond, -O-, optionally substituted- (C) ₁ -C ₆ ) Alkyl-, - (C) ₂ -C ₆ ) Alkenyl-, - (C) ₂ -C ₆ ) Alkynyl, optionally substituted- (C) ₃ -C ₇ ) Cycloalkyl-, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;

z is H, halogen, -CN, -CF ₃ 、-(C ₁ -C ₁₂ ) Alkyl, - (C) ₂ -C ₁₂ ) Alkenyl, -CH = ((C) ₃ -C ₇ ) Cycloalkyl), -O- (C) ₁ -C ₁₂ ) Alkyl, -S- (C) ₁ -C ₁₂ ) Alkyl, -O- [ optionally substituted (C) ₃ -C ₇ ) Cycloalkyl radicals ]Optionally substituted- (C) ₃ -C ₇ ) Cycloalkyl, - (C) ₁ -C ₆ ) Alkyl radical- (C) ₃ -C ₇ ) Cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

each R ²¹ And R ²² Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

each R ²³ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

each R ²⁷ Independently is-NR ²³ R ²⁴ 、-NHC(O)R ²³ 、-NHC(O)NR ²³ R ²⁴ Optionally substituted- (C) ₁ -C ₆ ) Heteroalkyl, optionally substituted- (C) ₁ -C ₆ ) Heteroalkyloxy or optionally substituted- (C) ₁ -C ₆ ) A heteroalkylamino group;

each R ²⁴ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

each R ²⁸ Independently halogen, -NHC (O) R ²³ 、-NHC(O)NR ²³ R ²⁴ Hydroxy, optionally substituted- (C) ₁ -C ₆ ) Heteroalkyloxy or optionally substituted- (C) ₁ -C ₆ ) A heteroalkylamino group;

p is 0, 1 or 2, and

q is 0, 1 or 2;

the optional substituents on each of the heteroalkyloxy, heteroalkyl, heteroalkylamino, alkyl, heterocycloalkyl, aryl, cycloalkyl, and heteroaryl groups are independently selected from the group consisting of halogen, optionally substituted with halogen- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ 、-NO ₂ Oxo, CN and- (C) ₃ -C ₇ ) Cycloalkyl groups.

16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, having the structure of formula (Ia):

17. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein R ¹⁵ And R ¹⁶ Is H.

18. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein R ¹⁷ is-CH ₃ 。

19. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein R ¹⁸ Is H.

20. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein R ⁹ Is- (C) ₁ -C ₆ ) An alkyl group.

21. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein R ⁹ is-CH ₃ 。

22. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-OR ²³ 。

23. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein R ¹¹ is-CH ₂ CH ₂ OH。

24. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² 。

25. The compound of claim 24, or a pharmaceutically acceptable salt thereof, wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-NH ₂ 。

26. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein R ¹¹ is-CH ₂ NH ₂ 。

27. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein R ¹¹ is-CH ₂ CH ₂ NH ₂ 。

28. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein R ¹¹ is-CH ₂ CH ₂ CH ₂ NH ₂ 。

29. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein R ¹¹ is-CH ₂ CH ₂ CH ₂ CH ₂ NH ₂ 。

30. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein R ¹ And R ² Each independently is H or- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² 。

31. The compound of claim 30, or a pharmaceutically acceptable salt thereof, wherein R ¹ And R ² Each independently is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² 。

32. The compound of claim 31, or a pharmaceutically acceptable salt thereof, wherein R ¹ And R ² Each is-CH ₂ CH ₂ NH ₂ 。

33. The compound of claim 30, or a pharmaceutically acceptable salt thereof, wherein R ¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² And R is ² Is H.

34. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein R ¹ is-CH ₂ CH ₂ NH ₂ And R is ² Is H.

35. The compound of claim 30, or a pharmaceutically acceptable salt thereof, wherein R ¹ Is H and R ² Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² 。

36. The compound of claim 35, or a pharmaceutically acceptable salt thereof, wherein R ¹ Is H and R ² is-CH ₂ CH ₂ NH ₂ 。

37. The compound of claim 30, or a pharmaceutically acceptable salt thereof, wherein R ¹ Is H and R ² Is H.

38. A compound of formula (II), or a pharmaceutically acceptable salt thereof:

wherein:

R ¹ and R ² Are each independently H, - (C) ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-OR ²³ 、-CH ₂ CH(OH)CH ₂ NH ₂ 、-(C ₁ -C ₆ ) alkyl-NR ²¹ R ²² 、-(C ₁ -C ₆ ) alkyl-N (R) ²³ )C(O)(C ₁ -C ₆ ) Alkyl, - (C) ₁ -C ₆ ) alkyl-NR ²³ C(＝NH)NR ²¹ R ²² 、-(C ₁ -C ₆ ) alkyl-NR ²³ C(＝NH)R ²³ 、-(C ₁ -C ₆ ) Alkyl- [ (C) ₁ -C ₆ ) Alkane (I) and its preparation methodradical-NR ²¹ R ²² ] ₂ 、-(C ₁ -C ₆ ) Heteroalkyl or optionally substituted heterocycloalkyl;

R ³ is H;

R ⁴ is H;

R ⁵ is H;

R ⁶ 、R ⁷ and R ⁸ Each independently is H;

R ⁹ is H, - (C) ₁ -C ₆ ) Alkyl or- (C) ₃ -C ₆ ) A cycloalkyl group;

R ¹⁰ is H;

R ¹² is H;

R ¹³ And R ¹⁴ Are each independently H, - (C) ₁ -C ₆ ) Alkyl or- (C) ₁ -C ₆ ) alkyl-OR ²³ ；

R ¹⁵ 、R ¹⁶ 、R ¹⁷ 、R ¹⁸ And R ¹⁹ Each independently is H or- (C) ₁ -C ₆ ) An alkyl group;

z is H, halogen, -CN, -CF ₃ 、-(C ₁ -C ₁₂ ) Alkyl, - (C) ₂ -C ₁₂ ) Alkenyl, -CH = ((C) ₃ -C ₇ ) Cycloalkyl), -O- (C) ₁ -C ₁₂ ) Alkyl, -S- (C) ₁ -C ₁₂ ) Alkyl, -O- [ optionally substituted (C) ₃ -C ₇ ) Cycloalkyl radicals]、-O-(C ₁ -C ₆ ) alkyl-OR ²³ Optionally substituted- (C) ₃ -C ₇ ) Cycloalkyl, - (C) ₁ -C ₆ ) Alkyl radical- (C) ₃ -C ₇ ) Cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

each R ²¹ And R ²² Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

each R ²³ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

each R ²⁵ And R ²⁶ Independently is H or optionally substituted-(C ₁ -C ₆ ) An alkyl group;

each R ²⁴ Independently is H or- (C) ₁ -C ₆ ) An alkyl group;

n is 1;

p is 0,1 or 2; and is

q is 0,1 or 2;

wherein the optional substituents on each of the heteroalkyloxy, heteroalkyl, heteroalkylamino, alkyl, heterocycloalkyl, aryl, cycloalkyl, and heteroaryl groups are independently selected from the group consisting of halogen, optionally halogen substituted- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ 、-NO ₂ Oxo, CN and- (C) ₃ -C ₇ ) Cycloalkyl groups.

39. The compound of claim 38, or a pharmaceutically acceptable salt thereof, wherein R ¹⁵ And R ¹⁶ Is H.

40. The compound of claim 38, or a pharmaceutically acceptable salt thereof, wherein R ¹⁸ Is H.

41. The compound of claim 38, or a pharmaceutically acceptable salt thereof, wherein R ¹⁹ Is H.

42. The compound of claim 38, or a pharmaceutically acceptable salt thereof, wherein R ¹⁷ is-CH ₃ 。

43. The compound of claim 38, or a pharmaceutically acceptable salt thereof, wherein R ⁹ Is- (C) ₁ -C ₆ ) An alkyl group.

44. The compound of claim 43, or a pharmaceutically acceptable salt thereof, wherein R ⁹ is-CH ₃ 。

45. The compound of claim 38, or a pharmaceutically acceptable salt thereof, wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-OR ²³ 。

46. The compound of claim 45, or a pharmaceutically acceptable salt thereof, wherein R ¹¹ is-CH ₂ CH ₂ OH。

47. The compound of claim 38, or a pharmaceutically acceptable salt thereof, wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² 。

48. The compound of claim 47, or a pharmaceutically acceptable salt thereof, wherein R ¹¹ Is- (C) ₁ -C ₆ ) alkyl-NH ₂ 。

49. The compound of claim 48, or a pharmaceutically acceptable salt thereof, wherein R ¹¹ is-CH ₂ NH ₂ 。

50. The compound of claim 48, or a pharmaceutically acceptable salt thereof, wherein R ¹¹ is-CH ₂ CH ₂ NH ₂ 。

51. The compound of claim 48, or a pharmaceutically acceptable salt thereof, wherein R ¹¹ is-CH ₂ CH ₂ CH ₂ NH ₂ 。

52. The compound of claim 48, or a pharmaceutically acceptable salt thereof, wherein R ¹¹ is-CH ₂ CH ₂ CH ₂ CH ₂ NH ₂ 。

53. The compound of claim 38, or a pharmaceutically acceptable salt thereof, wherein R ¹³ Is- (C) ₁ -C ₆ ) alkyl-OR ²³ 。

54. The compound of claim 53, or a pharmaceutically acceptable salt thereof, wherein R ¹³ is-CH ₂ OH。

55. The compound of claim 53, or a pharmaceutically acceptable salt thereof, wherein R ¹³ is-CH ₂ CH ₂ OH。

56. The compound of claim 38, or a pharmaceutically acceptable salt thereof, wherein R ¹ And R ² Each independently is H or- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² 。

57. The compound of claim 56, or a pharmaceutically acceptable salt thereof, wherein R ¹ And R ² Each independently is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² 。

58. The compound of claim 57, or a pharmaceutically acceptable salt thereof, wherein R ¹ And R ² Each is-CH ₂ CH ₂ NH ₂ 。

59. The compound of claim 58, or a pharmaceutically acceptable salt thereof, wherein R ¹ Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² And R is ² Is H.

60. The compound of claim 59, or a pharmaceutically acceptable salt thereof, wherein R ¹ is-CH ₂ CH ₂ NH ₂ And R is ² Is H.

61. The compound of claim 56, or a pharmaceutically acceptable salt thereof, wherein R ¹ Is H and R ² Is- (C) ₁ -C ₆ ) alkyl-NR ²¹ R ²² 。

62. The compound of claim 61, or a pharmaceutically acceptable salt thereof, wherein R ¹ Is H and R ² is-CH ₂ CH ₂ NH ₂ 。

63. The compound of claim 15 or 38, or a pharmaceutically acceptable salt thereof, wherein X is optionally substituted aryl, wherein each optional substituent is independently selected from the group consisting of halogen, optionally halogen substituted- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ 、-NO ₂ CN and- (C) ₃ -C ₇ ) Cycloalkyl groups.

64. The compound of claim 63, or a pharmaceutically acceptable salt thereof, wherein X is optionally substituted phenyl, wherein the optional substituents are each independently selected from the group consisting of halogen, optionally halogen-substituted- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ 、-NO ₂ CN and- (C) ₃ -C ₇ ) Cycloalkyl groups.

65. A compound according to claim 15 or 38, or a pharmaceutically acceptable salt thereof(iii) a salt of (iv) wherein X is optionally substituted heteroaryl, wherein the optional substituents are each independently selected from the group consisting of- (C) substituted with halogen, optionally substituted with halogen ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ 、-NO ₂ CN and- (C) ₃ -C ₇ ) Cycloalkyl groups.

66. The compound of claim 65, or a pharmaceutically acceptable salt thereof, wherein X is disubstituted heteroaryl.

67. The compound of claim 66, or a pharmaceutically acceptable salt thereof, wherein X is heteroaryl disubstituted with substituents each independently selected from the group consisting of halogen, -CN, and- (C) optionally substituted with halogen ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ and-NO ₂ Group (d) of (a).

68. The compound of claim 67, or a pharmaceutically acceptable salt thereof, wherein X is- (C) optionally substituted with halogen, each independently ₁ -C ₆ ) Alkyl substituents disubstituted heteroaryl.

69. The compound of claim 68, or a pharmaceutically acceptable salt thereof, wherein X is heteroaryl disubstituted with methyl.

70. The compound according to claim 65, or a pharmaceutically acceptable salt thereof, wherein X is pyridinyl disubstituted with substituents each independently selected from the group consisting of halogen, -CN, optionally halogen substituted- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ Group (iii) of (iv).

71. The compound of claim 70, or a pharmaceutically acceptable salt thereof, wherein X is- (C) optionally substituted with halogen, each independently ₁ -C ₆ ) Alkyl substituent disubstituted pyridyl.

72. The compound of claim 71, or a pharmaceutically acceptable salt thereof, wherein X is pyridyl disubstituted with methyl.

73. The compound according to claim 65, or a pharmaceutically acceptable salt thereof, wherein X is pyrimidinyl disubstituted with substituents each independently selected from the group consisting of halogen, -CN, - (C) optionally substituted with halogen ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ or-NO ₂ Group (d) of (a).

74. The compound of claim 73, or a pharmaceutically acceptable salt thereof, wherein X is- (C) optionally substituted with halogen, each independently ₁ -C ₆ ) Alkyl substituent disubstituted pyrimidinyl.

75. The compound of claim 74, or a pharmaceutically acceptable salt thereof, wherein X is pyrimidinyl disubstituted with methyl.

76. The compound of claim 15 or 38, or a pharmaceutically acceptable salt thereof, wherein X is optionally substituted- (C) ₁ -C ₆ ) Alkyl-, wherein the optional substituents are each independently selected from- (C) substituted by halogen, optionally by halogen ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ 、-NO ₂ CN and- (C) ₃ -C ₇ ) Cycloalkyl groups.

77. The compound of claim 15 or 38, or a pharmaceutically acceptable salt thereof, wherein Y is optionally substituted aryl, wherein each optional substituent is independently selected from- (C) substituted with halogen, optionally substituted with halogen ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ 、-NO ₂ CN and- (C) ₃ -C ₇ ) Cycloalkyl groups.

78. The compound of claim 77, or a pharmaceutically acceptable salt thereof, wherein Y is optionally substituted phenyl, wherein the optional substituents are each independently selected from- (C) substituted with halogen, optionally substituted with halogen ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ 、-NO ₂ CN and- (C) ₃ -C ₇ ) Cycloalkyl groups.

79. The compound of claim 15 or 38, or a pharmaceutically acceptable salt thereof, wherein Y is optionally substituted heteroaryl, wherein each optional substituent is independently selected from- (C) substituted with halogen, optionally substituted with halogen ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ 、-NO ₂ CN and- (C) ₃ -C ₇ ) Cycloalkyl groups.

80. The compound of claim 15 or 38, or a pharmaceutically acceptable salt thereof, wherein Y is optionally substituted- (C) ₁ -C ₆ ) Alkyl-, wherein the optional substituents are each independently selected from- (C) substituted by halogen, optionally by halogen ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ 、-NO ₂ CN and- (C) ₃ -C ₇ ) Cycloalkyl groups.

81. The compound of claim 15 or 38, or a pharmaceutically acceptable salt thereof, wherein Y is optionally substituted (C) ₃ -C ₇ ) Cycloalkyl-wherein each optional substituent is independently selected from the group consisting of halogen, optionally halogen substituted- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ 、-NO ₂ CN and- (C) ₃ -C ₇ ) Cycloalkyl groups.

82. According to claim 15 or 38, or a pharmaceutically acceptable salt thereof, wherein Y is optionally substituted heterocycloalkyl, wherein the optional substituents are each independently selected from the group consisting of halogen, optionally halogen-substituted- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ 、-NO ₂ CN and- (C) ₃ -C ₇ ) Cycloalkyl groups.

83. The compound of claim 15 or 38, or a pharmaceutically acceptable salt thereof, wherein Y is-O-.

84. The compound of claim 15 or 38, or a pharmaceutically acceptable salt thereof, wherein Y is- (C) ₂ -C ₆ ) Alkynyl.

85. The compound of claim 15 or 38, or a pharmaceutically acceptable salt thereof, wherein Y is a bond.

86. The compound of claim 15 or 38, or a pharmaceutically acceptable salt thereof, wherein Z is- (C) ₁ -C ₁₂ ) An alkyl group.

87. The compound of claim 86, or a pharmaceutically acceptable salt thereof, wherein Z is n-butyl, isobutyl, or tert-butyl.

88. The compound of claim 15 or 38, or a pharmaceutically acceptable salt thereof, wherein Z is-O- (C) ₁ -C ₁₂ ) An alkyl group.

89. The compound of claim 15 or 38, or a pharmaceutically acceptable salt thereof, wherein Z is-O- (C) ₃ -C ₇ ) A cycloalkyl group.

90. The compound of claim 15 or 38, or a pharmaceutically acceptable salt thereof, wherein Z is- (C) ₂ -C ₁₂ ) An alkenyl group.

91. The compound of claim 15 or 38, or a pharmaceutically acceptable salt thereof, wherein Z is optionally substituted aryl, wherein each optional substituent is independently selected from- (C) substituted with halogen, optionally substituted with halogen ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ 、-NO ₂ CN and- (C) ₃ -C ₇ ) Cycloalkyl groups.

92. The compound of claim 91, or a pharmaceutically acceptable salt thereof, wherein Z is optionally substituted phenyl, wherein each optional substituent is independently selected from the group consisting of halogen, optionally halogen substituted- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ 、-NO ₂ CN and- (C) ₃ -C ₇ ) Cycloalkyl groups.

93. The compound of claim 92, or a pharmaceutically acceptable salt thereof, wherein Z is- (C) independently selected from optionally substituted with halogen ₁ -C ₆ ) Alkyl substituents are monosubstituted or disubstituted phenyl.

94. The compound of claim 93, or a pharmaceutically acceptable salt thereof, wherein Z is phenyl monosubstituted with n-butyl, isobutyl, or tert-butyl.

95. The compound of claim 94, or a pharmaceutically acceptable salt thereof, wherein Z is phenyl monosubstituted with n-butyl.

96. The compound of claim 94, or a pharmaceutically acceptable salt thereof, wherein Z is phenyl monosubstituted with isobutyl.

97. The compound of claim 94, or a pharmaceutically acceptable salt thereof, wherein Z is phenyl monosubstituted with tert-butyl.

98. The compound of claim 15 or 38, or a pharmaceutically acceptable salt thereof, wherein Z is optionally substituted heteroaryl, wherein each optional substituent is independently selected from the group consisting of halogen, optionally halogen substituted- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ 、-NO ₂ CN and- (C) ₃ -C ₇ ) Cycloalkyl groups.

99. The compound of claim 15 or 38, wherein Z is optionally substituted- (C) ₃ -C ₇ ) Cycloalkyl wherein the optional substituents are each independently selected from the group consisting of halogen, optionally halogen substituted- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ 、-NO ₂ CN and- (C) ₃ -C ₇ ) Cycloalkyl groups.

100. The compound of claim 15 or 38, or a pharmaceutically acceptable salt thereof, wherein Z is optionally substituted heterocycloalkyl, wherein optional substituents are each independently selected from the group consisting of halogen, optionally halogen-substituted- (C) ₁ -C ₆ ) Alkyl, OR ²³ 、-NR ²⁵ R ²⁶ 、-NO ₂ CN and- (C) ₃ -C ₇ ) Cycloalkyl groups.

101. The compound of claim 15 or 38, or a pharmaceutically acceptable salt thereof, wherein Z is halogen.

102. The compound of claim 15 or 38, or a pharmaceutically acceptable salt thereof, wherein Z-Y-X-is not

103. A compound selected from the group consisting of:

104. a pharmaceutical composition comprising a compound of any one of claims 1-103, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

105. Use of a compound of any one of claims 1-103, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 104, in the manufacture of a medicament for treating a bacterial infection in a patient.