IP Library › Granted Patent US 9,567,339

Granted Patent B2

US 9,567,339 · App. 14/315,504 · Granted Feb 14, 2017

Primary carboxamides as BTK inhibitors

Inventors: Dominique Bonafoux (Winthrop, MA); Heather M. Davis (Oxford, MA); Kristine E. Frank (Grayslake, IL); Michael M. Friedman (Brookline, MA); J. Martin Herold (Cambridge, MA); Michael Z. Hoemann (Shrewsbury, MA); Raymond Huntley (Worcester, MA); Augustine Osuma (Lindenhurst, IL); George Sheppard (Wilmette, IL); Gagandeep K. Somal (Ashland, MA); Jennifer Van Camp (Lake Forest, IL); Stacy A. Van Epps (Ashland, MA); Anil Vasudevan (Union Grove, WI); Grier A. Wallace (Sterling, MA); Lu Wang (Westborough, MA); Lu Wang (Northborough, MA); Zhi Wang (Libertyville, IL); Noel S. Wilson (Kenosha, WI); Xiangdong Xu (Buffalo Grove, IL)

Assignee: AbbVie Inc.

C07D487/04 C07D209/08 C07D231/56 C07D401/12 C07D401/14 C07D403/14 C07D417/12 C07D417/14 C07D471/04

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Quick Facts

Patent No.: US 9,567,339
App. No.: 14/315,504
Granted: Feb 14, 2017
Kind: B2

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Abstract

The invention provides compounds of Formula (I) pharmaceutically acceptable salts, pro-drugs, biologically active metabolites, stereoisomers and isomers thereof wherein the variable are defined herein. The compounds of the invention are useful for treating immunological and oncological conditions.

Claims (225)

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

X is NR 2 ;

Y is CR 1 , and Z is CR 1 ;

A is CR 4 ;

E is CR 5 ;

R 1 is independently H, deuterium, CN, halogen, CF 3 , —NR c R c , —N(R a )C(O)R b , optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 3 -C 6 )cycloalkyl, optionally substituted (C 3 -C 6 )cycloalkenyl, optionally substituted heteroaryl, or optionally substituted saturated or partially saturated heterocyclyl;

R 2 is independently H, deuterium, or optionally substituted (C 1 -C 3 )alkyl;

R 3 is —R 301 -L-R 302 wherein

R 301 is a bond, and

L is optionally substituted phenyl, optionally substituted (C 3 -C 6 )cycloalkyl, optionally substituted heteroaryl or a saturated or partially saturated heterocyclyl containing one or more heteroatoms, at least one of which is nitrogen; or

L is -L 1 -L 2 wherein L 1 is attached to R 301 and

L 1 is optionally substituted phenyl, optionally substituted heteroaryl or optionally substituted saturated or partially saturated carbocycle or a saturated or partially saturated heterocyclyl; and

L 2 is a bond, CH 2 , NR d , CH 2 N(H), S(O) 2 N(H), or —O—;

R 302 is —C(O)CH═CH 2 , —C(O)C≡CH, —C(O)CH═CHCl, —C(O)CH═CHCH 3 , —C(O)C (═CH 2 )CH 3 , —C(O)C(CH 2 CH 3 )═CH 2 , —C(O)CH═CHCH(CH 3 ) 2 , —C(O)CH═CHC(O)OH, —C(O)CH═CHC(O)N(H)CH 2 CH 3 , —C(O)CH═CHCH 2 N(CH 3 ) 2 C(O)CH═CHC(O)OCH 3 , —C(O)CH═CHC(O)OCH 2 CH 3 , —C(O)CH═CHC(O)N(H)CH 3 , —C(O)CH═CHC(O)CH 2 CH 2 OCH 3 , —C(O)CH═CHC(O)N(CH 3 ) 2 , —C(O)CH═CHC(O)N(H)CH 2 CH 3 , —C(O)CH═CHC(O)N(H)CH 2 CH 2 OCH 3 , —C(O)CH═CHCH 2 N(H)CH 2 CH 2 OCH 3 , —C(O)C(CN)═C(OH)(CH 3 ), —C(O)CH═CH-pyrazolyl, —C(O)CH═CHCH 2 N(H)-cyclopropyl, —C(O)CH═CHCH 2 N(H)CH 2 -tetrahydrofuranyl, —C(O)CH═CHC(O)NH 2 , —C(O)CH═CHC(O)N(H)-cyclopropyl, —C(O)C(CH 3 )═CHCH 3 , —C(O)C(CH 3 )═CHCH 2 CH 3 , —C(O)C(═CH 2 )CH 2 N(CH 3 ) 2 , —C(O)C(═CH 2 )CH 2 NH 2 , —C(O)C(═CH 2 )CH 2 N(H)(CH 3 ), —C(O)C(═CH 2 )CH 3 , —C(O)C(═CH 2 )CH 2 -morpholinyl, —C(O)C(═CH 2 )-phenyl, —C(O)CH═CH cyclopropyl, -C(O)CH═CHCH 2 -morpholinyl, —C(O)CH═CHCH 2 -piperidinyl, —C(O)CH═CH -pyrazolyl, —C(O)CH═CH-pyridinyl, or —C(O)CH═CH-thiazolyl;

R 4 is H, deuterium, CN, optionally substituted (C 1 -C 3 )alkyl, optionally substituted (C 3 -C 6 ) cycloalkyl or optionally substituted saturated or partially saturated heterocyclyl , or optionally substituted heteroaryl;

wherein the optionally substituted saturated or partially saturated heterocyclyl;

and optionally substituted heteroaryl contain at least one nitrogen atom;

R 5 is H, deuterium, halogen, or optionally substituted (C 1 -C 3 )alkyl;

R a is independently selected from H, —C(O)-optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 1 -C 6 )alkyl, —(CH 2 ) n -optionally substituted (C 3 -C 6 )cycloalkyl, —(CH 2 ) n -optionally substituted heterocyclyl, or —(CH 2 ) n -optionally substituted heteroaryl;

R b is H, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 2 -C 6 )alkynyl, —CH 2 —O-optionally substituted aryl, or —CH 2 —O-optionally substituted heteroaryl;

R c is independently H, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 6 )cycloalkyl, optionally substituted saturated or partially saturated heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;

R d is H, optionally substituted heterocyclyl, —(CH 2 )-optionally substituted (C 3 -C 6 )cycloalkyl, —(CH 2 )-optionally substituted heteroaryl or optionally substituted (C 1 -C 3 )alkyl; and

n is independently 0 or 1,

wherein the optional substituent is one or more groups independently selected from (C 1 -C 8 )alkyl groups, (C 2 -C 8 )alkenyl groups, (C 2 -C 8 )alkynyl groups, (C 3 -C 10 )cycloalkyl groups, halogen, halogenated (C 1 -C 8 )alkyl groups, —CF 3 , —O—(C 1 —C 8 )alkyl groups, ═O, ═CH 2 , —OH, —CH 2 OH, —CH 2 NH 2 , (C 1 -C 4 )alkyl-OH, —CH 2 CH(OH)CH 2 OH, —CH 2 CH 2 OCH 2 CH 3 , —S—(C 1 -C 8 )alkyl groups, —SH, —NH(C 1 -C 8 )alkyl groups, —N((C 1 -C 8 )alkyl) 2 groups, —NH 2 , —C(O)NH 2 , —CH 2 NHC(O)(C 1 -C 4 )alkyl, —CH 2 NHC(O)CH 2 Cl, —CH 2 NHC(O)CH 2 CN, —CH 2 NHC(O)CH 2 CH 2 N(CH 3 ) 2 , —CH 2 NHC(O)C(═CH 2 )CH 3 , —CH 2 NHC(O)CH═CH 2 , —CH 2 NHC(O)CH═CHCH 3 , —CH 2 NHC(O)(C 2 -C 4 )alkynyl, —CH 2 NHC(O)CH 2 CH 2 -piperidinyl, —(C 1 -C 4 )alkyl-morpholinyl, (C 1 -C 4 )alkoxy, —C(O)(C 1 -C 4 )alkyl, —C(O)(C 1 -C 4 )alkoxy, —C(O)N(H) 2 , —C(O)N(CH 3 ) 2 , —C(O)(C 1 -C 6 )heteroaryl, —C(O)-morpholinyl, —C(O)-pyrrolidinyl, —N(CH 3 ) 2 , —NHC(O)(C 1 -C 4 )alkyl, —NHC(O)(C 2 -C 4 )alkenyl, —NHC(O)CH 2 CN, —S(O) 2 (C 1 -C 4 )alkyl, —S(O) 2 (C 1 -C 6 )heteroaryl, —S(O) 2 (C 1 -C 6 )heterocyclyl, 4-methylpiperazinecarbonyl, -(C 1 -—C 4 )alkylCN, —(C 1 - C 4 )alkylC(O)NH 2 , —C(O)NH(C 1 -C 8 )alkyl groups, —C(O)N((C 1 -C 8 )alkyl) 2 , —C(O)N(H)(C 3 -C 8 )cycloalkyl groups, —C(O)(C 1 -C 4 )alkoxy, —NHC(O)H, —NHC(O)(C 1 -C 8 )alkyl groups, —NHC(O)(C 3 -C 8 )cycloalkyl groups, —N((C 1 -C 8 )alkyl)C(O)H, —N((C 1 -C 8 )alkyl)C(O)(C 1 -C 8 )alkyl groups, —NHC(O)NH 2 , —NHC(O)NH(C 1 -C 8 )alkyl groups, —N((C 1 -C 8 )alkyl)C(O)NH 2 groups, —NHC(O)N((C 1 -C 8 )alkyl) 2 groups, —N((C 1 -C 8 )alkyl)C(O)N((C 1 -C 8 )alkyl) 2 groups, —N((C 1 -C 8 )alkyl)C(O)NH((C 1 -C 8 )alkyl), —NHCH 2 -heteroaryl, benzyl, —OCH 2 -heteroaryl, benzyloxy, —C(O)H, —C(O)(C 1 -C 8 )alkyl groups, —CN, —NO 2 , —S(O)(C 1 -C 8 )alkyl groups, —S(O) 2 (C 1 —C 8 )alkyl groups, —S(O) 2 N((C 1 -C 8 )alkyl) 2 groups, —S(O) 2 NH(C 1 -C 8 )alkyl groups, —S(O) 2 NH(C 3 -C 8 )cycloalkyl groups, —S(O) 2 NH 2 groups, —NHS(O) 2 (C 1 -C 8 )alkyl groups, —N((C 1 -C 8 )alkyl)S(O) 2 (C 1 -C 8 )alkyl groups, —(C 1 -C 8 )alkyl-O—(C 1 -C 8 )alkyl groups, —O—(C 1 -C 8 )alkyl-O—(C 1 -C 8 )alkyl groups, —C(O)OH, —C(O)O(C 1 -C 8 )alkyl groups, NHOH, NHO(C 1 -C 8 )alkyl groups, —O-halogenated (C 1 -C 8 )alkyl groups, —OCF 3 , —S(O) 2 -halogenated (C 1 -C 8 )alkyl groups, —S(O) 2 CF 3 , —S-halogenated C 1 -C 8 )alkyl groups, —SCF 3 , (C 1 -C 6 )heterocyclyl, pyrrolidine, tetrahydrofuran, pyran, morpholine, —(C 1 -C 6 )heteroaryl, tetrazole, imidazole, furan, pyrazine, pyrazole, -phenyl, benzyl, —NHC(O)O—(C 1 -C 6 )alkyl groups, —N((C 1 -C 6 )alkyl)C(O)O—(C 1 -C 6 )alkyl groups, —C(═NH)—(C 1 -C 6 )alkyl groups, —C(═NOH)—(C 1 -C 6 )alkyl groups, —C(═N—O—(C 1 -C 6 )alkyl)-(C l -C 6 )alkyl groups, C(O)-heterocyclyl, or —CH 2 NHC(O)CH 2 O-phenyl wherein the phenyl is optionally substituted with halogen.

2. The compound according to claim 1 wherein

L is optionally substituted azetidinyl, optionally substituted cyclopentyl, optionally substituted 3,6-diazabicyclo[3.2.0]heptanyl, optioinally substituted 1,4-dioxanyl, optionally substituted morpholinyl, optionally substituted[1.4]oxepanyl, optionally substituted phenyl, optionally substituted piperidinyl, or optionally substituted pyrrolidinyl; or

L is L 1 -L 2 wherein

L 1 is optionally substituted cyclohexyl, optionally substituted cyclopentyl, optionally substituted phenyl, optionally substituted piperidinyl, optionally substituted pyridinyl;

L 2 is N(H), N(CH 3 ), N(CH 2 CH 2 OH), N(CH 2 CH(CH 3 ) 2 ), N(oxetanyl), N(CH 2 -cyclopentyl), N(CH 2 -thiazolyl), O, S(O) 2 N(H), or CH 2 N(H).

3. The compound according to claim 2 , wherein L or L 1 is optionally substituted with one or more substituents independently selected from halogen, CN, OH, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkyl, —CH 2 OH, —N(H)CH 2 -heteroaryl, benzyloxy, and —OCH 2 -heteroaryl.

4. The compound according to claim 3 , wherein X is NR 2 and R 2 is H.

5. The compound according to claim 4 , wherein Y is CR 1 and R 1 of Y is optionally substituted with one or more substituents independently selected from halogen, CN, ═O, (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, —CH 2 NH 2 , —CH 2 CH 2 OH, —CH 2 CH(OH)CH 2 CH 3 , —CH 2 CH(OH)CH 2 OH, —CH 2 CH 2 OCH 2 CH 3 , —CH 2 C(OH)(CH 3 ) 2 , —CH 2 NHC(O)(C 1 -C 4 )alkyl, —CH 2 NHC(O)CH 2 Cl, —CH 2 NHC(O)CH 2 CN, —CH 2 NHC(O)CH 2 CH 2 N(CH 3 ) 2 , —CH 2 NHC(O)C(═CH 2 )CH 3 , —CH 2 NHC(O)(C 2 -C 4 )alkynyl, —CH 2 NHC(O)CH 2 CH 2 -piperidinyl, —(C 1 -C 4 )alkyl-morpholinyl, —CH 2 NHC(O)CH 2 O-phenyl wherein the phenyl is optionally substituted with halogen, (C 1 -C 4 )alkoxy, —C(O)(C 1 -C 4 )alkyl, —C(O)(C 1 -C 4 )alkoxy, —C(O)N(H) 2 , —C(O)N(CH 3 ) 2 , —C(O)-morpholinyl, —C(O)-pyrrolidinyl, —N(CH 3 ) 2 , —NHC(O)(C 1 -C 4 )alkyl, —NHC(O)(C 2 -C 4 )alkenyl, —NHC(O)CH 2 CN, —S(O) 2 (C 1 -C 4 )alkyl, —S(O) 2 -pyrrolidinyl, morpholinyl, tetrahydropyranyl, or 4-methylpiperazinecarbonyl.

6. The compound according to claim 5 , wherein Z is CR 1 and R 1 of Z is H, (C 1 -C 4 )alkyl, —NHC(O)CH 2 Cl, —NHC(O)CH 2 CN, —NHC(O)(C 2 -C 4 )alkenyl, —NHC(O)(C 2 -C 4 )alkynyl, —NHC(O)C(═CH 2 )CH 3 , —NHC(O)CH 2 -phenyl, or pyrazolyl substituted with CH 3 .

7. The compound according to claim 1 , wherein

X is NR 2 wherein R 2 is H;

Y is CR 1 wherein R 1 is H, CH 3 , substituted pyrazolyl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl or tetrahydrofuranyl;

Z is CR 1 wherein R 1 is H;

E is CR 5 wherein R 5 is H;

R 3 is —R 301 -L—R 302 wherein

R 301 is a bond;

L is azetidinyl, 3,6-diazabicyclo[3.2.0]heptanyl, morpholinyl, [1,4]oxepanyl, piperidinyl, or pyrrolidinyl;

wherein the azetidinyl is optionally substituted with CH 3 , and

wherein the piperidinyl is optionally substituted with —CH 2 OH; and

R 302 is —C(O)CH═CH 2 or —C(O)C≡CH.

8. A compound selected from

4-((1-acryloylazetidin-3-yl)(methyl)amino)-1H-indole-7-carboxamide;

4-(3-acrylamido-2-methylphenyl)-2(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;

(R)-4-(3-acrylamidopiperidin-1-yl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;

4-(2-methyl-3-(N-(thiazol-2-ylmethyl)acrylamido)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;

4-(3-methacrylamido-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamidel;

(Z)-4-(3-(3-chloroacrylamido)-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;

4-(3-acrylamido-2-methylphenyl)-2-(4,4-difluorocyclohex-1-enyl)-1H-indole-7-carboxamide;

4-(2-(acrylamidomethyl)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;

4-(2-acrylamidophenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;

4-(3-(acrylamidomethyl)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;

4-(3-acrylamidophenyl)-1H-indole-7-carboxamide;

4-(3-acrylamido-2-methylphenyl)-1H-indole-7-carboxamide;

4-(3-acrylamido-2-methylphenyl)-2-(2-methoxypyridin-3-yl)-1H-indole-7-carboxamide;

methyl 3-(4-(3-acrylamido-2-methylphenyl)-7-carbamoyl-1H-indol-2-yl)benzoate;

4-(3-acrylamido-2-methylphenyl)-2-(3-methoxyphenyl)-1H-indole-7-carboxamide;

4-(3-acrylamido-2-methylphenyl)-2-(4-methoxyphenyl)-1H-indole-7-carboxamide;

4-(3-acrylamido-2-methylphenyl)-2-6-methylpyridin-3-yl)-1H-indole7-carboxamide;

4-(3-acrylamido-2-methylphenyl)-2-(3-carbamoylphenyl)-1H-indole-7-carboxamide;

4-(3-acrylamido-2-methylphenyl)-2-(3,5-dimethylisoxazol-4-yl)-1H-indole-7-carboxamide;

4-(3-acrylamido-2-methylphenyl)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-1H-indole-7-carboxamide;

4-(3-acrylamido-2-methylphenyl)-2-(3,5-dimethyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;

4-(3-acrylamido-2-methylphenyl)-2-(1-isopropyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;

4-(3-acrylamido-2-methylphenyl)-2-(1,3-dimethyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;

4-(3-acrylamido-2-methylphenyl)-2-(1-ethyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;

4-(3-acrylamido-2-methylphenyl)-2-(1-isobutyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;

N-(3-(7-carbamoyl-3-methacrylamido-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;

4-(3-acrylamido-2-methylphenyl)-2-(2-fluoropyridin-3-yl)-1H-indole-7-carboxamide;

4-(3-acrylamido-2-methylphenyl)-2-(1-ethyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;

2-(3-acetamidophenyl)-4-(3-acrylamido-2-methylphenyl)-1H-indole7-carboxamide;

4-(3-acrylamido-2-methylphenyl)-2-(2-methoxypyridin-4-yl)-1H-indole-7-carboxamide;

4-(3-acrylamido-2-methylphenyl)-2-(3-cyanophenyl)-1H-indole-7-carboxamide;

methyl 4-(4-(3-acrylamido-2-methylphenyl)-7-carbamoyl-1H-indol-2-yl)benzoate;

4-(3-acrylamido-2-methylphenyl)-2-(2,3-dihydrobenzofuran-5-yl)-1H-indole-7-carboxamide;

4-(3-acrylamido-2-methylphenyl)-2-(3-fluorophenyl)-1H-indole-7-carboxamide;

4-(3-acrylamido-2-methylphenyl)-2-(3-(dimethylamino)phenyl)-1H-indole-7-carboxamide;

4-(3-acrylamido-2-methylphenyl)-2-(2-methyl-5-(pyrrolidin-1-ylsulfonyl)phenyl)-1H-indole-7-carboxamide;

4-(3-acrylamido-2-methylphenyl)-2-(2-fluorophenyl)-1H-indole-7-carboxamide;

N-(3-(3-acrylamido-7-carbamoyl-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;

4-(3-acrylamido-2-methylphenyl)-2-(1-methyl-1H-pyrazol-5-yl)-1H-indole-7-carboxamide;

4-(3-acrylamido-2-methylphenyl)-2-(pyridin-4-yl)-1H-indole-7-carboxamide;

4-(3-acrylamido-2-methylphenyl)-2-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;

4-(3-acrylamido-2-methylphenyl)-2-(6-morpholinopyridin-3-yl)-1H-indole-7-carboxamide;

4-(3-acrylamido-2-methylphenyl)-2-(3-(4-methylpiperazine-1-carbonyl)phenyl)-1H-indole-7-carboxamide;

N-(3-(2-(2-(acrylamidomethyl)phenyl)-7-carbamoyl-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;

N-(3-(7-carbamoyl-2-(2-(methacrylamidomethyl)phenyl)-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;

4-(3-acrylamido-2-methylphenyl)-2-(4-fluorophenyl)-1H-indole-7-carboxamide;

4-(3-acrylamido-2-methylphenyl)-2-phenyl-1H-indole-7-carboxamide;

4-(3-acrylamido-2-methylphenyl)-2-(2-(methylsulfonyl)phenyl)-1H-indole-7-carboxamide;

4-(3-acrylamido-2-methylphenyl)-2-(4-(dimethylcarbamoyl)phenyl)-1H-indole-7-carboxamide;

4-(3-acrylamido-2-methylphenyl)-2-(pyrimidin-5-yl)-1H-indole-7-carboxamide;

4-(3-acrylamido-2-methylphenyl)-2-(pyridin-3-yl)-1H-indole-7-carboxamide;

4-(3-acrylamido-2-methylphenyl)-2-(4-(morpholine-4-carbonyl)phenyl)-1H-indole-7-carboxamide;

4-(3-acrylamido-2-methylphenyl)-2-(4-(pyrrolidine-1-carbonyl)phenyl)-1H-indole-7-carboxamide;

4-(3-acrylamido-2-methylphenyl)-2-(4-(4-methylpiperazine-1-carbonyl)phenyl)-1H-indole-7-carboxamide;

4-(3-acrylamido-2-methylphenyl)-2-(4-(methylsulfonyl)phenyl)-1H-indole-7-carboxamide;

4-(3-acrylamido-2-methylphenyl)-2-6-methoxypyridin-3-yl)-1H-indole-7-carboxamide;

4-(3-acrylamido-2-methylphenyl)-2-(4-cyanophenyl)-1H-indole-7-carboxamide;

4-(3acrylamido-2-methylphenyl)-2-(2-methoxyphenyl)-1H-indole-7-carboxamide;

4-(2-acrylamidophenyl)-1H-indole-7-carboxamide;

4-(3-acrylamido-2-methylphenyl)-2-(4-(morpholinomethyl)phenyl)-1H-indole-7-carboxamide;

4-(3-acrylamido-2-methylphenyl)-2-(4-carbamoylphenyl)-1H-indole-7-carboxamide;

4-(3-acrylamido-5-(thiazol-2-ylmethylamino)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;

4-(2methyl-3-(N-methylacrylamido)phenyl)-1H-indole-7-carboxamide;

4-(3-(N-methylacrylamido)phenyl)-1H-indole-7-carboxamide;

4-(3-methacrylamido-2-methylphenyl)-1H-indole-7-carboxamide;

(E)-4-(3-(3-cyclopropylacrylamido)-2-methylphenyl)-1H-indole-7-carboxamide;

(E)-4-(2-methyl-3-(3-(pyridin-2-yl)acrylamido)phenyl)-1H-indole-7-carboxamide;

(E)-4-(2-methyl-3-(3-(1-methyl-1H-pyrazol-4-yl)acrylamido)phenyl)-1H-indole-7-carboxamide;

(E)-4-(2-methyl-3-(3-(pyridin-3-yl)acrylamido)phenyl)-1H-indole-7-carboxamide;

(E)-4-(2-methyl-3-(3-(thiazol-2-yl)acrylamido)phenyl)-1H-indole-7-carboxamide;

4-(2-methyl-3-(2-phenylacrylamido)phenyl)-1H-indole-7-carboxamide;

4-(3-acrylamido-4-(benzyloxy)phenyl)-1H-indole-7-carboxamide;

4-(3-acrylamido-5-(benzyloxy)phenyl)-1H-indole-7-carboxamide;

4-(3-acrylamido-4-(thiazol-2-ylmethoxy)phenyl)-1H-indole-7-carboxamide;

4-(3-acrylamido-5-(thiazol-2-ylmethoxy)phenyl)-1H-indole-7-carboxamide;

4-(2-acrylamido-4-(thiazol-2-ylmethoxy)phenyl)-1H-indole-7-carboxamide;

4-(2-acrylamido-4-(benzyloxy)phenyl)-1H-indole-7-carboxamide;

4-(5-acrylamidopyridin-3-yl)-1H-indole-7-carboxamide;

4-(2-acrylamidopyridin-4-yl)-1H-indole-7-carboxamide;

4-(3-(N-isobutylacrylamido)phenyl)-1H-indole-7-carboxamide;

1-Acryloyl-1,2,3,6-tetrahydro-pyrrolo[2,3-e]indole-5-carboxylic acid amide;

4-acrylamido-1H-indole-7-carboxamide;

4-(3-acrylamido-2-methoxyphenyl)-1H-indole-7-carboxamide;

4-(3-acrylamido-2-fluorophenyl)-1H-indole-7-carboxamide;

4-(5-acrylamido-2-fluorophenyl)-1H-indole-7-carboxamide;

4-(3-acrylamido-4-fluorophenyl)-1H-indole-7-carboxamide;

4-(5-acrylamido-2-chlorophenyl)-1H-indole-7-carboxamide;

4-(5-acrylamido-2,4-difluorophenyl)-1H-indole-7-carboxamide;

4-(3-acrylamido-4-cyanophenyl)-1H-indole-7-carboxamide;

4-(3-acrylamido-2,6-difluorophenyl)-1H-indole-7-carboxamide;

4-(3-acrylamido-5-methylphenyl)-1H-indole-7-carboxamide;

4-(3-acrylamido-4-methylphenyl)-1H-indole-7-carboxamide;

4-(3-acrylamido-4-methoxyphenyl)-1H-indole-7-carboxamide;

4-(3-acrylamido-5-methoxyphenyl)-1H-indole-7-carboxamide;

4-(3-acrylamido-4-chlorophenyl)-1H-indole-7-carboxamide;

4-(5-acrylamido-2,3-difluorophenyl)-1H-indole-7-carboxamide;

4-(3-acrylamido-5-cyanophenyl)-1H-indole-7-carboxamide;

4-(3-acrylamido-2-cyanophenyl)-1H-indole-7-carboxamide;

4-(3-acrylamidophenyl)-2-vinyl-1H-indole-7-carboxamide;

4-(3-acrylamidophenyl)-2-ethyl-1H-indole-7-carboxamide;

4-(3-(2-(morpholinomethyl)acrylamido)phenyl)-1H-indole-7-carboxamide;

4-(3-(2-((dimethylamino)methyl)acrylamido)phenyl)-1H-indole-7-carboxamide;

4-(1R,3S)-3-acrylamidocyclohexyl)-1H-indole-7-carboxamide;

4-(cis-3-acrylamidocyclohexyl)-1H-indole-7-carboxamide;

4-((1S,3S)-3-acrylamidocyclohexyl)-1H-indole-7-carboxamide;

4-(trans-3-acrylamidocyclohexyl)-1H-indole-7-carboxamide;

4-(cis-3-acrylamidocyclohexyl)-1H-indole-7-carboxamide;

4-(3-(2-(aminomethyl)acrylamido)phenyl)-1H-indole-7-carboxamide;

4-(1R,3S)-3-acrylamidocyclopentyl)-1H-indole-7-carboxamide;

4-(3-(2-((methylamino)methyl)acrylamido)phenyl)-1H-indole-7-carboxamide;

4-(3-acrylamidophenyl)-2-methyl-1H-indole-7-carboxamide;

4-((1S,3S)-3-acrylamidocyclopentyl)-1H-indole-7-carboxamide;

4-(3-acrylamidophenyl)-2-(2-ethoxyethyl)-1H-indole-7-carboxamide;

4-(3-acrylamidophenyl)-2-(2-hydroxyethyl)-1H-indole-7-carboxamide;

4-(1-acryloylpiperidin 3-yl)-2-(1 -methyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;

4-(3-acrylamido-2-methylphenyl)-2-(1-isopropyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;

4-(3-(N-(cyclopentylmethyl)acrylamido)phenyl)-1H-indole-7-carboxamide;

4-(cis-3-acrylamidocyclopentyl)-1H-indole-7-carboxamide;

4-(trans-3-acrylamidocyclopentyl)-1H-indole-7-carboxamide;

(S)-4-(1-(1-acryloylazetidin-3-yl)ethyl)-1H-indole-7-carboxamide;

(R)-4-(1-(1-acryloylazetidin-3-yl)ethyl)-1H-indole-7-carboxamide;

(R)-4-(1-acryloylpiperidin-3-yl)-1H-indole-7-carboxamide;

(S)-4-(1-acryloylpiperidin-3-yl)-1H-indole-7-carboxamide;

(S)-4-(1-acryloylpiperidin-3-yl)-2-methyl-1H-indole-7-carboxamide;

(R)-4-(1-acryloylpiperidin-3-yl)-2-methyl-1H-indole-7-carboxamide;

(R)-4-(4-acryloylmorpholin-2-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;

(S)-4-(4-acryloylmorpholin-2-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;

(R)-4-(1 -acryloylpyrrolidin-3-yl)-2-(6,7-dihydro-4H-pyrazolo-[5,1-c][1,4]oxazin-2-yl)-1H-indole-7-carboxamide;

2-methyl-4-(methyl(1-propioloylazetidin-3-yl)amino)-1H-indole-7-carboxamide;

(S)-4-(1-acryloylpyrrolidin-3-yl)-2-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4-]oxazin-2-yl)-1H-indole-7-carboxamide;

(S)-4-(4-acryloyl-1,4-oxazepan-6-yl)-1H-indole-7-carboxamide;

4-((3S,5R)-1-acryloyl-5-(hydroxymethyl)piperidin-3-yl)-1H-indole-7-carboxamide;

4-((3S,5S)-1-acryloyl-5-(hydroxymethyl)piperidin-3-yl)-1H-indole-7-carboxamide;

4-((3R,5S)-1-acryloyl-5-(hydroxymethyl)piperidin-3-yl)-1H-indole-7-carboxamide;

4-((3R,5R)-1-acryloyl-5-(hydroxymethyl)piperidin-3-yl)-1H-indole-7-carboxamide;

(R)-4-(1-acryloylpyrrolidin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;

(S)-4-(1-acryloylpyrrolidin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;

4-((1R,3R)-3-acrylamidocyclopentyl)-1H-indole-7-carboxamide;

4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(isochroman-7-yl)-1H-indole-7-carboxamide;

4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)- 1H -indole-7-carboxamide;

4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(4,4-difluorocyclohex-1-en-1-yl)-1H-indole-7-carboxamide;

4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(4-(methylsulfonyl)cyclohex-1-en-1-yl)-1H-indole-7-carboxamide;

4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(6-morpholinopyridin-3-yl)-1H-indole-7-carboxamide;

4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(7,8-dihydro-5H-pyrano[4,3]pyridin-3-yl)-1H-indole-7-carboxamide;

4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(chroman-7-yl)-1H-indole-7-carboxamide;

4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(5-(morpholinomethyl)pyridin-2-yl)-1H-indole-7-carboxamide;

4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;

4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1H-indole-7-carboxamide;

4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(1-methyl-1H-pyrazol-5-yl)-1H-indole-7-carboxamide;

4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(2-ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-indole-7-carboxamide;

4-((1-acryloylazetidin-3-yl)(methyl)amino)-2(1,3-dimethyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;

4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxamide;

4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(1-propylpiperidin-4-yl)-1H-indole-7-carboxamide;

4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(tetrahydrofuran-3-yl)-1H-indole-7-carboxamide;

4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(3-hydroxyoxetan-3-yl)-1H-indole-7-carboxamide;

4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-methyl-1H-indole-7-carboxamide;

(R)-4-(4-acryloyl-1,4-oxazepan-6-yl)-1H-indole-7-carboxamide;

(S)-4-(1-acryloylpyrrolidin-3-yl)-2-methyl-1H-indole-7-carboxamide;

(R)-4-(1-acryloylpyrrolidin-3-yl)-2-methyl-1H-indole-7-carboxamide;

4-((1R,5S)-6-acryloyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)-1H-indole-7-carboxamide;

4-(1S,5R)-6-acryloyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)-1H-indole-7-carboxamide;

4-((1-acryloyl-3-methylazetidin-3-yl)(methyl)amino)-1H-indole-7-carboxamide;

(S)-4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(tetrahydrofuran-3-yl)-1H-indole-7-carboxamide;

(R)-4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(tetrahydrofuran-3-yl)-1H-indole-7-carboxamide;

(S)-4-(1-acryloylpiperidin-3-yl)-2-(1-methyl- 1H-pyrazol-4-yl)-1H-indole-7-carboxamide;

(R)-4-(1-acryloylpiperidin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide, or a pharmaceutically acceptable salt thereof.

9. A method of treating a disease comprising administering a therapeutically effective amount of a compound of claim 1 to a patient in need thereof, wherein the disease is mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, or multiple myeloma.

10. A kit comprising a packaged product comprising components with which to administer a compound of claim 1 for treatment of a disease, wherein the disease is mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, or multiple myeloma.

11. A pharmaceutical composition comprising a compound according to claim 1 and one or more pharmaceutically acceptable excipients.

12. A pharmaceutical composition comprising a compound according to claim 8 and one or more pharmaceutically acceptable excipients.

13. A method of treating a disease comprising administering a therapeutically effective amount of a compound of claim 8 to a patient in need thereof, wherein the disease is mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, or multiple myeloma.

14. A kit comprising a packaged product comprising components with which to administer a compound of claim 8 for treatment of a disease, wherein the disease is mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, or multiple myeloma.

15. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is (S)-4-(1-acryloylpiperidin-3-yl)-1H-indole-7-carboxamide.

16. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is (R)-4-(1-acryloylpiperidin-3-yl)-1H-indole-7-carboxamide.

17. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is 4-(1-acryloylpiperidin 3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide.

18. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is 4-((1-acryloylazetidin-3-yl)(methyl)amino)-1H-indole-7-carboxamide.

19. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is 4-(3-acrylamidophenyl)-2-(2-hydroxyethyl)-1H-indole-7-carboxamide.

20. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is 4-(3-acrylamidophenyl)-2-ethyl-1H-indole-7-carboxamide.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 27, 2014

From: BONAFOUX, DOMINIQUE; DAVIS, HEATHER M.; FRANK, KRISTINE E.; FRIEDMAN, MICHAEL M.; HEROLD, J. MARTIN; HOEMANN, MICHAEL Z.; HUNTLEY, RAYMOND; OSUMA, AUGUSTINE; SHEPPARD, GEORGE; SOMAL, GAGANDEEP K.; VAN CAMP, JENNIFER; VAN EPPS, STACY A.; VASUDEVAN, ANIL; WALLACE, GRIER A.; WANG, LU, MS.; WANG, LU; WANG, ZHI; WILSON, NOEL S.; XU, XIANGDONG

To: ABBVIE INC.

Reel/Frame 033193/0088 →

Continuity (3)

Provisional Application 61897577 · Oct 30, 2013

Provisional Application 61839729 · Jun 26, 2013

Related Publication 20150005279A1 · Jan 1, 2015