sGC STIMULATORS

Patent metadata

Field	Value
Publication number	US-2016031903-A1
Application number	US-201414775954-A
Country	US
Kind code	A1
Filing date	Mar 14, 2014
Priority date	Mar 15, 2013
Publication date	Feb 4, 2016
Grant date	—

Abstract

Compounds of Formulae I′ and I are described, which are useful as stimulators of sGC, particularly NO-independent, heme-dependent stimulators. These compounds are also useful for treating, preventing or managing various disorders that are herein disclosed.

First claim

1 - 67 . (canceled)

68 . The compound represented by Formula I, or a pharmaceutically acceptable salt thereof

wherein:
X 1 is selected from N, CH, C(C 1-4 alkyl), C(C 1-4 haloalkyl), CCl and CF;
ring B is a phenyl or a 6-membered heteroaryl ring containing 1 or 2 ring nitrogen atoms, or ring B is a thiophene;
n is 0 or an integer selected from 1 to 3;
each J B is independently selected from halogen, —CN, a C 1-6 aliphatic, —OR B or a C 3-8 cycloaliphatic ring; wherein each of said C 1-6 aliphatic and each of said C 3-8 cycloaliphatic group is optionally substituted with up to 3 instances of halogen;
each R B is independently selected from hydrogen, a C 1-6 aliphatic or a C 3-8 cycloaliphatic ring;
wherein each of said R B that is a C 1-6 aliphatic and each of said R B that is a C 3-8 cycloaliphatic ring is optionally substituted with up to 3 instances of halogen;

J A is selected from hydrogen, halogen, methyl, methoxy, trifluoromethyl, trifluoromethoxy or —NR a R b , wherein R a and R b are each independently selected from hydrogen, C 1-6 alkyl or a 3-6 cycloalkyl ring;
J D is absent or selected from halogen, —CN, —CF 3 , methoxy, trifluoromethoxy, nitro, amino or methyl;
R 1 and R 2 , together with the nitrogen atom to which they are attached, form a 4 to 8-membered heterocyclic ring or 5 membered heteroaryl ring; wherein said 4 to 8-membered heterocyclic ring or 5 membered heteroaryl ring optionally contains in addition to the nitrogen atom up to 3 ring heteroatoms independently selected from N, O or S, and is optionally substituted by up to 5 instances of R 5 ; or
alternatively, R 1 and R 2 are each independently selected from hydrogen, C 1-6 alkyl, a C 3-8 cycloalkyl ring, a 4 to 8-membered heterocyclic ring, a 5 or 6-membered heteroaryl or a C 1-6 alkyl-R Y ; wherein each of said 4 to 8-membered heterocyclic ring and each of said 5 or 6-membered heteroaryl ring contains up to 3 ring heteroatoms independently selected from N, O and S; and wherein each of said C 1-6 alkyl, C 3-8 cycloalkyl ring, 4 to 8-membered heterocyclic ring group, 5 or 6-membered heteroaryl and the C 1-6 alkyl portion of said C 1-6 alkyl-R Y is optionally and independently substituted with up to 5 instances of R 5a ; provided that R 1 and R 2 are never simultaneously hydrogen; wherein when X 1 is one of CH, C(C 1-4 alkyl), C(C 1-4 haloalkyl), CCl or CF, one instance of R 1 or R 2 is not a pyridine or a pyrimidine;
alternatively, J D and one of R 1 or R 2 can form a 5-6 membered heterocyclic ring containing up to two heteroatoms selected from O, N and S and optionally substituted with up to 3 instances of oxo or —(Y)—R 9 ;
wherein Y is either absent or is a linkage in the form of a C 1-6 alkyl chain, optionally substituted by up to 6 instances of fluoro;
each R 9 is independently selected from hydrogen, fluoro, —CN, —OR 10 , —COR 10 , —OC(O)R 10 , —C(O)OR 10 , —C(O)N(R 10 ) 2 , —C(O)N(R 10 )SO 2 R 10 , —N(R 10 )C(O)R 10 , —N(R 10 )C(O)OR 10 , —N(R 10 )C(O)N(R 10 ) 2 , —N(R 10 ) 2 , —SO 2 R 10 , —SO 2 N(R 10 ) 2 , —SO 2 N(R 10 )COOR 10 , —SO 2 N(R 10 )C(O)R 10 , —N(R 10 )SO 2 R 10 , —(C═O)NHOR 10 , a C 3-6 cycloalkyl ring, a 4-8-membered heterocyclic ring or a 5-6 membered heteroaroaryl ring;
wherein each said 4 to 8-membered heterocyclic ring or 5 to 6-membered heteroaromatic ring contains up to 4 ring heteroatoms independently selected from N, O or S; and
wherein each of said C 3-6 cycloalkyl rings, each of said 4 to 8-membered heterocyclic rings and each of said 5 to 6-membered heteroaromatic rings is optionally substituted with up to 3 instances of R 11 ;

each R 11 is independently selected from halogen, C 1-6 alkyl, —CN, —OR 12 , —COR 12 , —C(O)OR 12 , —C(O)N(R 12 ) 2 , —N(R 12 )C(O)R 12 , —N(R 12 )C(O)OR 12 , —N(R 12 )C(O)N(R 12 ) 2 , —N(R 12 ) 2 , —SO 2 R 12 , —SO 2 N(R 12 ) 2 , and —N(R 12 )SO 2 R 12 ; wherein each of said C 1-6 alkyl is optionally and independently substituted by up to 3 instances of fluoro, or phenyl;
wherein each R 10 is independently selected from hydrogen, a C 1-6 alkyl, phenyl, benzyl, a C 3-8 cycloalkyl ring, a 4 to 7-membered heterocyclic ring or a 5 or 6-membered heteroaryl ring, wherein each 5 or 6-membered heteroaryl ring or 4 to 7-membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S; and wherein each of said C 1-6 alkyl, each said phenyl, each said benzyl, each said C 3-8 cycloalkyl group, each said 4 to 7-membered heterocyclic ring and each 5 or 6-membered heteroaryl ring is optionally and independently substituted with up to 3 instances of halogen, C 1-4 alkyl, C 1-4 (fluoroalkyl), —OH, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —CN, —COOH, —COO(C 1-4 alkyl), —O(C 1-4 alkyl), —O(C 1-4 fluoroalkyl) or oxo; and
wherein each R 12 is independently selected from hydrogen, a C 1-6 alkyl, phenyl, benzyl, a C 3-8 cycloalkyl ring, a 4 to 7-membered heterocyclic ring or a 5 or 6-membered heteroaryl ring, wherein each 5 or 6-membered heteroaryl ring or 4 to 7-membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S; and wherein each of said C 1-6 alkyl, each said phenyl, each said benzyl, each said C 3-8 cycloalkyl group, each said 4 to 7-membered heterocyclic ring and each 5 or 6-membered heteroaryl ring is optionally and independently substituted with up to 3 instances of halogen, C 1-4 alkyl, C 1-4 (fluoroalkyl), —OH, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —CN, —COOH, —COO(C 1-4 alkyl), —O(C 1-4 alkyl), —O(C 1-4 fluoroalkyl) or oxo;
R Y is selected from a C 3-8 cycloalkyl ring, a 4 to 8-membered heterocyclic ring, phenyl, or a 5 to 6-membered heteroaromatic ring; wherein each of said 4 to 8-membered heterocyclic ring or 5 to 6-membered heteroaromatic ring contains up to 4 ring heteroatoms independently selected from N, O or S; and wherein each of said C 3-8 cycloalkyl ring, each of said 4 to 8-membered heterocyclic ring, each of said phenyl, and each of said 5 to 6-membered heteroaromatic ring is optionally substituted with up to 5 instances of R 5c ;
each R 5c is independently selected from halogen, —CN, C 1-6 alkyl, —OR 6b , —SR 6b , —COR 6b , —OC(O)R 6b , —C(O)OR 6b , —C(O)N(R 6b ) 2 , —C(O)N(R 6b )SO 2 R 6b , —N(R 6b )C(O)R 6b , —N(R 6b )C(O)OR 6b , —N(R 6b )C(O)N(R 6b ) 2 , —N(R 6b ) 2 , —SO 2 R 6b , —SO 2 N(R 6b ) 2 , —SO 2 N(R 6b )COOR 6b , —SO 2 N(R 6b )C(O)R 6b , —N(R 6b )SO 2 R 6b , —(C═O)NHOR 6b , a C 3-8 cycloalkyl ring, a 4 to 7-membered heterocyclic ring, a 5 or 6-membered heteroaryl ring, phenyl, benzyl, an oxo group, or a bicyclic group; wherein each of said 5 or 6-membered heteroaryl ring and each of said 4 to 7-membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S; and wherein each of said C 1-6 alkyl, each of said C 3-8 cycloalkyl ring, each of said 4 to 7-membered heterocyclic ring, each of said 5 or 6-membered heteroaryl ring, each of said benzyl and each of said phenyl group is optionally and independently substituted with up to 3 instances of halogen, C 1-4 alkyl, —OH, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —CN, —COOH, —COO(C 1-4 alkyl), —O(C 1-4 alkyl), —O(C 1-4 haloalkyl) or oxo; wherein said bicyclic group contains a first ring and a second ring in a fused or bridged relationship, said first ring is a 4 to 7-membered heterocyclic ring, a 5 or 6-membered heteroaryl ring, phenyl or benzyl, and said second ring is a phenyl ring or a 5 or 6-membered heteroaryl ring containing up to 3 ring heteroatoms selected from N, O or S; and wherein said bicyclic group is optionally and independently

Assignees

• Ironwood Pharmaceuticals Inc

Inventors

• Nakai Takashi
• Moore Joel
• Perl Nicholas Robert
• Iyengar Rajesh R
• Mermerian Ara
• Im G-Yoon Jamie
• Lee Thomas Wai-Ho
• Hudson Colleen
• Rennie Glen Robert
• Jia James
• Renhowe Paul Allan
• Barden Timothy Claude
• Yu Xiang Y
• Sheppeck James Edward
• Iyer Karthik
• Jung Joon
• Milne George Todd
• Long Kimberly Kafadar

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P15/00

  Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives · CPC title

• C07D487/10

  Spiro-condensed systems · CPC title

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61K31/55

  having seven-membered rings, e.g. azelastine, pentylenetetrazole · CPC title