Sgc stimulators

Patent metadata

Field	Value
Publication number	US-2016311826-A1
Application number	US-201415103178-A
Country	US
Kind code	A1
Filing date	Dec 10, 2014
Priority date	Dec 11, 2013
Publication date	Oct 27, 2016
Grant date	—

Abstract

The present patent application discloses at least the compounds according to Formula I shown below, or pharmaceutically acceptable salts thereof,

wherein ring J B , n, J D , J, o, X, X 1 , J, R C , and W are as defined herein. These compounds are useful as stimulators of soluble sGC.

First claim

1 . A compound according to Formula I, or a pharmaceutically acceptable salt thereof,

wherein X is selected from N or C;
X 1 is selected from N, CH, C(C 1-4 alkyl), C(C 1-4 fluoroalkyl), C(Cl), and CF;
W is either
i) absent, with J B connected directly to the carbon atom bearing two J groups, each J is independently selected from hydrogen, methyl or fluorine, n is 1 and J B is a C 1-6 alkyl chain optionally substituted by up to 6 instances of fluorine; or
ii) a ring B selected from phenyl or a 5 or 6-membered heteroaryl ring, containing 1 or 2 ring heteroatoms selected from N, O or S; wherein when W is ring B:
each J is hydrogen;
n is 0 or an integer selected from 1 to 3;
and each J B is independently selected from halogen, —CN, a C 1-6 aliphatic, —OR B or a C 3-8 cycloaliphatic group; wherein each said C 1-6 aliphatic and each said C 3-8 cycloaliphatic group is optionally and independently substituted with up to 3 instances of R 3 ;
each R B is independently selected from hydrogen, a C 1-6 aliphatic or a C 3-8 cycloaliphatic;

wherein each said R B that is a C 1-6 aliphatic and each said R B that is a C 3-8 cycloaliphatic ring is optionally and independently substituted with up to 3 instances of R 3a ;
each R 3 is independently selected from halogen, —CN, C 1-4 alkyl, C 1-4 haloalkyl, —O(C 1-4 alkyl) or —O(C 1-4 haloalkyl);
each R 3a is independently selected from halogen, —CN, C 1-4 alkyl, C 1-4 haloalkyl, —O(C 1-4 alkyl) or —O(C 1-4 haloalkyl);

o is 0 or an integer selected from 1 to 3;
each J D is either absent or independently selected from hydrogen, halogen, —CN, —NO 2 , —OR D , —SR D , —C(O)R D , —C(O)OR D , —OC(O)R D , —C(O)N(R D ) 2 , —N(R D ) 2 , —N(R d )C(O)R D , —N(R d )C(O)OR D , —N(R d )C(O)N(R D ) 2 , OC(O)N(R D ) 2 , —SO 2 R D , —SO 2 N(R D ) 2 , —N(R d )SO 2 R D , a C 1-6 aliphatic, —(C 1-6 aliphatic)-R D , a C 3-8 cycloaliphatic ring, a 6 to 10-membered aryl ring, a 4 to 8-membered heterocyclic ring or a 5 to 10-membered heteroaryl ring; wherein each said 4 to 8-membered heterocyclic ring and each said 5 to 10-membered heteroaryl ring contains between 1 and 3 heteroatoms independently selected from O, N or S; and wherein each of said C 1-6 aliphatic chains, each said C 3-8 cycloaliphatic ring, each said 6 to 10-membered aryl ring, each said 4 to 8-membered heterocyclic ring and each said 5 to 10-membered heteroaryl ring is optionally and independently substituted with up to 5 instances of R 5 ;
each R D is independently selected from hydrogen, a C 1-6 aliphatic, —(C 1-6 aliphatic)-R f , a C 3-8 cycloaliphatic ring, a 4 to 8-membered heterocyclic ring, phenyl or a 5 to 6-membered heteroaryl ring; wherein each said 4 to 8-membered heterocyclic ring and each said 5 to 6-membered heteroaryl ring contains between 1 and 3 heteroatoms independently selected from O, N or S; and wherein each of said C 1-6 aliphatic chains, each said C 3-8 cycloaliphatic ring, each said 4 to 8-membered heterocyclic ring, each said phenyl and each said 5 to 6-membered heteroaryl ring is optionally and independently substituted with up to 5 instances of R 5a ; wherein when any R D is one of a C 1-6 aliphatic or a —(C 1-6 aliphatic)-R f group, one or two —CH 2 — units that form said C 1-6 aliphatic chains may, optionally, be replaced by a group independently selected from —C(O)—, —N(R d )— or —O—; provided that when X 1 is one of CH, C(C 1-4 alkyl), C(C 1-4 fluoroalkyl), C(Cl) or CF; X is C; and at least one J D is —N(R D ) 2 and is attached to one of the pyrimidine ring D carbons ortho to the two nitrogen atoms of said ring D, one instance of R D is not a pyridine or a pyrimidine;
each R d is independently selected from hydrogen, a C 1-6 aliphatic, —(C 1-6 aliphatic)-R f , a C 3-8 cycloaliphatic ring, a 4 to 8-membered heterocyclic ring, phenyl or a 5 to 6-membered heteroaryl ring; wherein each said 4 to 8-membered heterocyclic ring and each said 5 or 6-membered heteroaryl ring contains between 1 and 3 heteroatoms independently selected from O, N or S; and wherein each of said C 1-6 aliphatic chains, each said C 3-8 cycloaliphatic ring, each said 4 to 8-membered heterocyclic ring, each said phenyl and each said 5 to 6-membered heteroaryl ring is optionally and independently substituted by up to 5 instances of R 5 b;
each R f is independently selected from a C 1-3 alkyl, a C 3-8 cycloaliphatic ring, a 4 to 8-membered heterocyclic ring, phenyl or a 5 to 6-membered heteroaryl ring; wherein each said 4 to 8-membered heterocyclic ring and each said 5 to 6-membered heteroaryl ring contains between 1 and 4 heteroatoms independently selected from O, N or S; and wherein each said C 3-8 cycloaliphatic ring, each said 4 to 8-membered heterocyclic ring, each said phenyl and each said 5 to 6-membered heteroaryl ring is optionally and independently substituted by up to 5 instances of R 5 c;
when J D is —C(O)N(R D ) 2 , —N(R D ) 2 , —N(R d )C(O)N(R D ) 2 , —OC(O)N(R D ) 2 or —SO 2 N(R D ) 2 , the two R D groups together with the nitrogen atom attached to the two R D groups may form a 4 to 8-membered heterocyclic ring or a 5-membered heteroaryl ring; wherein each said 4 to 8-membered heterocyclic ring and each said 5-membered heteroaryl ring optionally contains up to 3 additional heteroatoms independently selected from N, O or S, in addition to the nitrogen atom to which the two R D groups are attached; and wherein each said 4 to 8-membered heterocyclic ring and each said 5-membered heteroaryl ring is optionally and independently substituted by up to 5 instances of R 5d ;
when J D is —N(R d )C(O)R D , the R D group together with the carbon atom attached to the R D group, with the nitrogen atom attached to the R d group, and with the R d group may form a 4 to 8-membered heterocyclic ring or a 5-membered heteroaryl ring; wherein each said 4 to 8-membered heterocyclic ring and each said 5-membered heteroaryl ring optionally contains up to 2 additional heteroatoms independently selected from N, O or S, in addition to the nitrogen atom to which the R d group is attached; and wherein each said 4 to 8-membered heterocyclic ring and each said 5-membered heteroaryl ring is optionally and independently substituted by up to 5 instances of R 5d ;
when J D is —N(R d )C(O)OR D , the R D group together with the oxygen atom attached to the R D group, with the carbon atom of the —C(O)— portion of the —N(R d )C(O)OR D group, with the nitrogen atom attached to the R d group, and with said R d group, may form a 4 to 8-membered heterocyclic ring; wherein said 4 to 8-membered heterocyclic ring optionally contains up to 2 additional heteroatoms independently selected from N, O or S, and is optionally and independently substituted by up to 5 instances of R 5d ;
when J D is —N(R d )C(O)N(R D ) 2 , one of the R D groups attached to the nitrogen atom, together with said nitrogen atom, and with the N atom attached to the R d group and said R d group may form a 4 to 8-membered heterocyclic ring; wherein said 4 to 8-membered heterocyclic ring optionally contains up to 2 additional heteroatoms independently selected from N, O or S, and is optionally and independently substituted by up to 5 instances of R 5d ;
when J D is —N(R d )SO 2 R D , the R D group together with the sulfur atom attached to the R D group, with the nitrogen atom attached to the R d group, and with said R d group may combine to form a 4 to 8-membered heterocyclic ring; wherein said 4 to 8-membered heterocyclic ring optionally contains up to 2 additional heteroatoms independently selected from N, O or S, and is optionally and independently substituted by up to 5 instances of R 5d ;
each R 5

Assignees

• Ironwood Pharmaceuticals Inc

Inventors

• Renhowe Paul Allan
• Sheppeck James Edward
• Nakai Takashi
• Iyer Karthik
• Perl Nicholas Robert
• Rennie Glen Robert
• Currie Mark G
• Long Kimberly Kafadar
• Milne George Todd
• Iyengar Rajesh R

Classifications

• A61P9/12

  Antihypertensives · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P9/02

  Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title