Primary carboxamides as BTK inhibitors

Patent metadata

Field	Value
Publication number	US-9567339-B2
Application number	US-201414315504-A
Country	US
Kind code	B2
Filing date	Jun 26, 2014
Priority date	Jun 26, 2013
Publication date	Feb 14, 2017
Grant date	Feb 14, 2017

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.

First claim

What is claimed:

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 substitut

Assignees

• Abbvie Inc

Inventors

• 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
• Wang Lu
• Wang Zhi
• Wilson Noel S
• Xu Xiangdong

Classifications

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/405

  Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin · CPC title

• C07D401/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D403/14

  containing three or more hetero rings · CPC title

• C07D417/12

  linked by a chain containing hetero atoms as chain links · CPC title