Compounds and compositions for modulating EGFR Activity

Patent metadata

Field	Value
Publication number	US-9440957-B2
Application number	US-201314405773-A
Country	US
Kind code	B2
Filing date	Jun 5, 2013
Priority date	Jun 6, 2012
Publication date	Sep 13, 2016
Grant date	Sep 13, 2016

Abstract

The invention provides compounds and pharmaceutical compositions thereof, which are useful for modulating EGFR activity, as well as methods for using such compounds to treat, ameliorate or prevent a condition associated with abnormal or deregulated EGFR activity.

First claim

The invention claimed is:

1. A compound having Formula (3A) or (3B) or a tautomer thereof:

wherein Ring A is a 5-10 membered heteroaryl comprising 1-4 heteroatoms selected from N, O and S;
Ring B is phenyl;
R 1 and R 1′ are independently hydrogen; halo; cyano; C 1-6 alkyl; C 1-6 haloalkyl; —X 1 —NR 4 R 5 ; —X 1 —OR 3 ; —X 1 —S(O) 0-2 R 6 ; —X 1 —P(O)R 6a R 6b ; phenyl unsubstituted or substituted by C 1-6 alkyl; or a 5-6 membered heteroaryl comprising 1-4 heteroatoms selected from N, O and S;
R 2 is selected from hydrogen, halo; cyano; C 1-6 alkyl; C 1-6 haloalkyl; —X 1 —C(O)OR 3 ; —X 1 —C(O)R 3 ; —X 1 —C(O)NR 4 R 5 ; —X 1 —C(O)NR 4 —X 3 —C(O)OR 3 ; —X 1 —C(O)NR 4 —X 3 —S(O) 0-2 R 6 ; —X 1 —NR 4 R 5 ; —X 1 —NR 4 —X 2 —C(O)R 3 ; —X 1 —NR 4 —X 3 —S(O) 0-2 R 6 ; —X 1 —OR 3 ; —X 1 —O—X 1 —OR 3 ; —X 1 —S(O) 0-2 R 6 ; —X 1 —O—X 4 —NR 4 R 5 ; or a 5-6 membered heteroaryl comprising 1-4 heteroatoms selected from N, O and S and is unsubstituted or substituted by C 1-6 alkyl;
X 1 and X 2 are independently a bond or C 1-6 alkyl;
X 3 is C 1-6 alkyl;
X 4 is C 2-6 alkyl;
R 3 , R 4 and R 5 are independently hydrogen, C 1-6 alkyl or C 1-6 haloalkyl; or wherein R 4 and R 5 together with N in NR 4 R 5 may form a 4-7 membered ring containing 1-2 heteroatoms selected from N, O, and S, and optionally substituted with 1-4 R 7 groups;
R 6 , R 6a and R 6b are C 1-6 alkyl;
R 8 is

R 12 , R 13 , R 16 and R 17 are independently hydrogen or C 1-6 alkyl;
R 14 and R 15 are independently hydrogen; C 1-6 alkyl; —C(O)O—(C 1-6 alkyl); C 3-7 cycloalkyl unsubstituted or substituted with C 1-6 alkyl; or R 14 and R 15 together with N in NR 14 R 15 may form may form a 4-7 membered ring containing 1-2 heteroatoms selected from N, O and S, and optionally substituted with 1-4 R 18 groups;
R 7 and R 18 are independently oxo, halo, hydroxy, C 1-6 alkyl or C 1-6 alkoxy;
n is independently 1-3; and
m and q are independently 1-2;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein: Ring A is pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, oxazolyl, furanyl, thiazolyl, imidazole[2,1-b][1,3]thiazolyl, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, each of which is unsubstituted or substituted by (R 1 ) n and R 1′ ; and
R 1 , R 1′ and n are as defined in claim 1 .

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein said compound is of Formula (5):

wherein one of W 1 and W 2 is CR 1 and the other is N; and
R 1 , R 1′ , R 2 , R 8 and m are as defined in claim 1 .

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 1′ are independently hydrogen; halo; cyano; C 1-6 alkyl; C 1-6 haloalkyl; —X 1 —NR 4 R 5 ; —X 1 —OR 3 ; —X 1 —S(O) 0-2 R 6 ; phenyl unsubstituted or substituted by C 1-6 alkyl; tetrazolyl or pyrrolyl;
each X 1 is a bond or CH 2 ;
R 3 , R 4 and R 5 are independently hydrogen, C 1-6 alkyl or C 1-6 haloalkyl; or wherein R 4 and R 5 together with N in NR 4 R 5 form piperidinyl; and
R 6 is as defined in claim 1 .

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 haloalkyl, tetrazolyl, pyrrolyl, —X 1 —NR 4 R 5 , —X 1 —OR 3 , —X 1 —S(O) 0-2 R 6 or phenyl unsubstituted or substituted by C 1-6 alkyl;
R 1′ is hydrogen, halo or C 1-6 alkyl;
R 3 , R 4 and R 5 are independently hydrogen, C 1-6 alkyl or C 1-6 haloalkyl; or wherein R 4 and R 5 together with N in NR 4 R 5 form piperidinyl;
X 1 is a bond or CH 2 ; and
R 6 is as defined in claim 1 .

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 1′ are independently hydrogen; methyl; t-butyl; trifluoromethyl; methoxy; ethoxy; trifluoromethoxy; difluoromethoxy; fluoro; chloro; cyano; dimethylamino; methylsulfonyl; dimethylphosphoryl; tetrazolyl; pyrrolyl; phenyl unsubstituted or substituted by methyl; or piperidin-1-yl.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:
R 2 is hydrogen; chloro; methyl; trifluoromethyl; methoxy; isoproproxy; cyano; hydroxymethyl; methoxymethyl; ethoxymethyl; methylsulfonyl; methylcarbonyl; carboxy; methoxycarbonyl; carbamoyl; dimethylaminomethyl; pyrrolidin-1-ylmethyl unsubstituted or substituted by 1-2 hydroxy, halo or methoxy; morpholin-4-ylmethyl; azetidin-1-ylmethyl unsubstituted or substituted by 1-2 halo or methoxy; piperidin-1-ylmethyl; ((4-methyl-3-oxo-piperazin-1-yl)methyl); (1,1-dioxidothiomorpholine-4-carbonyl); pyrrolidin-1-yl carbonyl unsubstituted or substituted by 1-2 hydroxy; pyrrolidin-1-ylethoxy; (1,1-dioxido-thiomorpholin-4-yl)methyl; or 1,2,4-oxadiazolyl unsubstituted or substituted by C 1-6 alkyl;
alternatively, R 2 is —CH 2 —N(CH 3 )—C(O)—CH 3 ; —CH 2 —O—(CH 2 ) 2 —OCH 3 ;

—CH 2 —N(CH 3 )—(CH 2 ) 2 —SO 2 (CH 3 ); —C(O)NH—(CH 2 ) 1-2 —C(O)—OCH 3 ;
—C(O)NH—(CH 2 ) 1-2 —C(O)OH; or —C(O)NH—(CH 2 ) 2 —SO 2 (CH 3 ).

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 8 is

wherein R 14 and R 15 are independently hydrogen, C 1-6 alkyl or C 3-7 cycloalkyl; or R 14 and R 15 together with N in NR 14 R 15 may form an azetidinyl, piperidyl, pyrrolidinyl or morpholinyl; where said azetidinyl or pyrrolidinyl can be optionally substituted with 1-2 halo, methoxy or hydroxyl; and
R 12 , R 13 , R 16 , R 17 and q are as defined in claim 1 .

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein said compound is selected from:
N-{7-chloro-1-[(3R)-1-[4-(pyrrolidin-1-yl)but-2-enoyl]azepan-3-yl]-1H-1,3-benzodiazol-2-yl}-2-methylpyridine-4-carboxamide;
N-{7-chloro-1-[1-[4-(pyrrolidin-1-yl)but-2-enoyl]azepan-3-yl]-1H-1,3-benzodiazol-2-yl}-2-methylpyridine-4-carboxamide;
N-{7-chloro-1-[(3R)-1-[4-(3-fluoroazetidin-1-yl)but-2-enoyl]azepan-3-yl]-1H-1,3-benzodiazol-2-yl}-2-methylpyridine-4-carboxamide;
N-{7-chloro-1-[1-[4-(3-fluoroazetidin-1-yl)but-2-enoyl]azepan-3-yl]-1H-1,3-benzodiazol-2-yl}-2-methylpyridine-4-carboxamide;
N-{7-chloro-1-[(3R)-1-{4-[(3R)-3-fluoropyrrolidin-1-yl]but-2-enoyl}azepan-3-yl]-1H-1,3-benzodiazol-2-yl}-2-methylpyridine-4-carboxamide;
N-{7-chloro-1-[1-{4-[3-fluoropyrrolidin-1-yl]but-2-enoyl}azepan-3-yl]-1H-1,3-benzodiazol-2-yl}-2-methylpyridine-4-carboxamide;
N-{7-chloro-1-[(3R)-1-{4-[(3S)-3-fluoropyrrolidin-1-yl]but-2-enoyl}azepan-3-yl]-1H-1,3-benzodiazol-2-yl}-2-methylpyridine-4-carboxamide;
N-{7-chloro-1-[(3R)-1-[4-(3,3-difluoropyrrolidin-1-yl)but-2-enoyl]azepan-3-yl]-1H-1,3-benzodiazol-2-yl}-2-methylpyridine-4-carboxamide;
N-{7-chloro-1-[1-[4-(3,3-difluoropyrrolidin-1-yl)but-2-enoyl]azepan-3-yl]-1H-1,3-benzodiazol-2-yl}-2-methylpyridine-4-carboxamide;
N-{7-chloro-1-[(3R)-1-{4-[(3R)-3-methoxypyrrolidin-1-yl]but-2-enoyl}azepan-3-yl]-1H-1,3-benzodiazol-2-yl}-2-methylpyridine-4-carboxamide;
N-{7-chloro-1-[1-{4-[3-methoxypyrrolidin-1-yl]but-2-enoyl}azepan-3-yl]-1H-1,3-benzodiazol-2-yl}-2-methylpyridine-4-carboxamide;
N-{7-chloro-1-[(3R)-1-{4-[(3S)-3-methoxypyrrolidin-1-yl]but-2-enoyl}azepan-3-yl]-1H-1,3-b

Assignees

• Lelais Gerald
• Epple Robert
• Marsilje Iii Thomas H
• Michellys Pierre-Yves
• Mcneill Matthew
• Long Yun
• Lu Wenshuo
• Chen Bei
• Bursulaya Badry
• Jiang Songchun
• Novartis Ag

Inventors

• Lelais Gerald
• Epple Robert
• Marsilje Iii Thomas H
• Michellys Pierre-Yves
• Mcneill Matthew
• Long Yun
• Lu Wenshuo
• Chen Bei
• Bursulaya Badry
• Jiang Songchun

Classifications

• A61P5/00

  Drugs for disorders of the endocrine system · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C07D513/04

  Ortho-condensed systems · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title