Compositions and methods for inhibition of the JAK pathway

Patent metadata

Field	Value
Publication number	US-RE47396-E
Application number	US-201514918353-A
Country	US
Kind code	E1
Filing date	Oct 20, 2015
Priority date	Jul 28, 2010
Publication date	May 21, 2019
Grant date	May 21, 2019

Abstract

Disclosed are compounds of formula I, compositions containing them, and methods of use for the compounds and compositions in the treatment of conditions in which modulation of the JAK pathway or inhibition of JAK kinases, particularly JAK 2 and JAK3, are therapeutically useful. Also disclosed are methods of making the compounds.

First claim

We claim:

1. A compound of formula IA:

or salt thereof, wherein:
R 1 is H, optionally substituted C 1-6 alkyl, C(O)—C 1-6 alkyl, CO 2 —C 1-6 alkyl or R 50 ;
each R 50 is —C(R 9 ) 2 -A-R 10 , where A is O or S; each R 9 is independently for each occurrence H, optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl or optionally substituted C 7-16 arylalkyl; or alternatively, two R 9 , together with the carbon to which they are attached, form an optionally substituted C 3-8 cycloalkyl group or an optionally substituted 3-8 membered heteroalicyclyl; R 10 is R a , —P(O)(OR 11 ) 2 , —P(O)(OR 11 )N(R 12 ) 2 or —P(O)(N(R 12 ) 2 ) 2 ; each R 11 is independently for each occurrence R a or a monovalent cationic group; or two R 11 , together with the atoms to which they are attached, form a 4-8 membered cyclic phosphate group; each R 12 is independently for each occurrence R c or —C 1-3 alkyl-N(R c ) 2 ; or two R 12 , each on separate nitrogens of —P(O)(N(R 12 ) 2 ) 2 , together with the atoms to which they are attached, form a 4-8 membered cyclic phosphonic acid bisamide group; or one R 12 along with R 11 , of the group —P(O)(OR 11 )N(R 12 ) 2 , together with the atoms to which they are attached, form a 4-8 membered cyclic phosphonamidate group;
R 2a , R 2b and R 2c are each independently CH 3 , —OCH 3 , or F;
R 2d is H or F;
R 2e is H, R e , R b , R e substituted with one or more of the same or different R a and/or R b , —OR e substituted with one or more of the same or different R a and/or R b , —SR e substituted with one or more of the same or different R a and/or R b , —C(O)R e substituted with one or more of the same or different R a and/or R b , —N(R a )R e where R e is substituted with one or more of the same or different R a and/or R b , —S(O) 2 R e substituted with one or more of the same or different R a and/or R b , —N(R a )—S(O) 2 R e where R e is substituted with one or more of the same or different R a and/or R b , —B(OR a ) 2 , —B(N(R c ) 2 ) 2 , —(C(R a ) 2 ) m —R b , —O—(C(R a ) 2 ) m —R b , —S—(C(R a ) 2 ) m —R b , —O—(C(R b ) 2 ) m —R a , —N(R a )—(C(R a ) 2 ) m —R b , —O—(CH 2 ) m —CH((CH 2 ) m R b )R b , —C(O)N(R a )—(C(R a ) 2 ) m —R b , —O—(C(R a ) 2 ) m —C(O)N(R a )—(C(R a ) 2 ) m —R b , —N((C(R a ) 2 ) m R b ) 2 , —S—(C(R a ) 2 ) m —C(O)N(R a )—(C(R a ) 2 ) m —R b , —N(R a )—C(O)—N(R a )—(C(R a ) 2 ) m —R b , —N(R a )—C(O)—(C(R a ) 2 ) m —C(R a )(R b ) 2 or —N(R a )—(C(R a ) 2 ) m —C(O)—N(R a )—(C(R a ) 2 ) m —R b halogen or methyl;
each R a is independently for each occurrence H, deuterium, C 1-6 alkyl, C 3-8 cycloalkyl, C 4-11 cycloalkylalkyl, C 6-10 aryl, C 7-16 arylalkyl, 2-6 membered heteroalkyl, 3-10 membered heteroalicyclyl, 4-11 membered heteroalicyclylalkyl, 5-15 membered heteroaryl or 6-16 membered heteroarylalkyl;
each R b is independently for each occurrence ═O, —OR a , —O—(C(R a ) 2 ) m —OR a , haloC 1-3 alkyloxy, ═S, —SR a , ═NR a , ═NOR a , —N(R c ) 2 , halo, —CF 3 , —CN, —NC, —OCN, —SCN, —NO, —NO 2 , ═N 2 , —N 3 , —S(O)R a , —S(O) 2 R a , —SO 3 R a , —S(O)N(R c ) 2 , —S(O) 2 N(R c ) 2 , —OS(O)R a , —OS(O) 2 R a , —OSO 3 R a , —OS(O) 2 N(R c ) 2 , —C(O)R a , —CO 2 R a , —C(O)N(R c ) 2 , —C(NR a )—N(R c ) 2 , —C(NOH)—R a , —C(NOH)—N(R c ) 2 , —OC(O)R a , —OC(O)OR a , —OC(O)N(R c ) 2 , —OC(NH)—N(R c ) 2 , —OC(NR a )—N(R c ) 2 , —N(R a )—S(O) 2 H, —[N(R a )C(O)] n R a , —[N(R a )C(O)] n OR a , —[N(R a )C(O)] n N(R c ) 2 or —[N(R a )C(NR a )] n —N(R c ) 2 ;
each R c is independently for each occurrence R a , or, alternatively, two R c are taken together with the nitrogen atom to which they are bonded to form a 3 to 10-membered heteroalicyclyl or a 5-10 membered heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which is optionally substituted with one or more of the same or different R a and/or R d groups;
each R d is ═O, —OR a , haloC 1-3 alkyloxy, C 1-6 alkyl, ═S, —SR a , ═NR a , ═NOR a , —N(R a ) 2 , halo, —CF 3 , —CN, —NC, —OCN, —SCN, —NO, —NO 2 , ═N 2 , —N 3 , —S(O)R a , —S(O 2 )R a , —SO 3 R a , —S(O)N(R a ) 2 , —S(O) 2 N(R a ) 2 , —OS(O)R a , —OS(O) 2 R a , —OSO 3 R a , —OS(O) 2 N(R a ) 2 , —C(O)R a , —CO 2 R a , —C(O)N(R a ) 2 , —C(NR a )N(R a ) 2 , —C(NOH)R a , —C(NOH)N(R a ) 2 , —OCO 2 R a , —OC(O)N(R a ) 2 , —OC(NR a )N(R a ) 2 , —[N(R a )C(O)] n R a , —(C(R a ) 2 ) n —OR a , —N(R a )—S(O) 2 R a , —C(O)—C 1-6 haloalkyl, —S(O) 2 C 1-6 haloalkyl, —OC(O)R a , —O(C(R a ) 2 ) m —OR a , —S(C(R a ) 2 ) m —OR a , —N(R a )C 1-6 haloalkyl, —P(O)(OR a ) 2 , —N(R a )—(C(R a ) 2 ) m —OR a , —[N(R a )C(O)] n OR a , —[N(R a )C(O)] n N(R a ) 2 , —[N(R a )C(NR a )] n N(R a ) 2 or —N(R a )C(O)C 1-6 haloalkyl; or two R d , taken together with the atom or atoms to which they are attached, combine to form a 3-10 membered partially or fully saturated mono or bicyclic ring, optionally containing one or more heteroatoms and optionally substituted with one or more R a ;
each R e is independently for each occurrence C 1-6 alkyl, C 3-8 cycloalkyl, C 4-11 cycloalkylalkyl, C 6-10 aryl, C 7-16 arylalkyl, 2-6 membered heteroalkyl, 3-10 membered heteroalicyclyl, 4-11 membered heteroalicyclylalkyl, 5-15 membered heteroaryl or 6-16 membered heteroarylalkyl;
each m is 1, 2 or 3;
each n is 0, 1, 2 or 3;
R 4 is H or optionally substituted C 1-6 alkyl; and
R 5 is H, halo, —CN, optionally substituted C 1-6 alkyl, nitro, —N(R a ) 2 , —C(O)N(R a ) 2 , —CO 2 R a or —C(O)R a .

2. The compound of claim 1 , wherein two of R 2a , R 2b and R 2c are CH 3 ; the other of R 2a , R 2b and R 2c is F; and R 2d is H or F.

3. The compound of claim 1 , wherein two of R 2a , R 2b and R 2c are CH 3 ; the other of R 2a , R 2b and R 2c is —OCH 3 ; and R 2d is H or F.

4. The compound of claim 1 , wherein two of R 2a , R 2b and R 2c are —OCH 3 ; the other of R 2a , R 2b and R 2c is F; and R 2d is H or F.

5. The compound of claim 1 , wherein two of R 2a , R 2b and R 2c are —OCH 3 ; the other of R 2a , R 2b and R 2c is CH 3 ; and R 2d is H or F.

6. The compound of claim 1 , wherein one of R 2a , R 2b and R 2c is CH 3 ; one of R 2a , R 2b and R 2c is —OCH 3 ; and one of R 2a , R 2b and R 2c is F; and R 2d is H or F.

7. The compound of claim 1 wherein the compound is:
I-6: 5-(5-chloro-2-(3,4,5-trimethylphenylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one trifluoroacetate salt;
I-16: 5-(5-bromo-2-(3,4,5-trimethylphenylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one formate salt;
I-18: 5-[5-Ethynyl-2-(3,4,5-trimethyl-phenylamino)-pyrimidin-4-ylamino]-3H-benzooxazol-2-one trifluoroacetate salt;
I-40: 4-(2-Oxo-2,3-dihydro-benzooxazol-5-ylamino)-2-(3,4,5-trimethyl-phenylamino)-pyrimidine-5-carboxylic acid methyl ester trifluoroacetate salt;
I-42: 5-(5-nitro-2-(3,4,5-trimethylphenylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one trifluoroacetate salt;
I-49: 4-(2-Oxo-2,3-dihydro-benzooxazol-5-ylamino)-2-(3,4,5-trimethyl-phenylamino)-pyrimidine-5-carboxylic acid trifluoroacetate salt;
I-52: 5-(5-chloro-2-(3-methoxy-4,5-dimethylphenylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one;
I-58: 2-(4-Fluoro-3-methoxy-5-methyl-phenylamino)-4-(2-oxo-2,3-dihydro-benzooxazol-5-ylamino)-pyrimidine-5-carboxylic acid methyl ester trifluoroacetate salt;
I-59: 2-(3-Methoxy-4,5-dimethyl-phenylamino)-4-(2-oxo-2,3-dihydro-benzooxazol-5-ylamino)-pyrimidine-5-carboxylic acid methyl ester trifluoroacetate salt;
I-63: 5-[5-Hydroxymethyl-2-(3,4,5-trimethyl-phenylamino)-pyrimidin-4-ylamino]-3H-benzooxazol-2-one;
I-74: methyl 2-(4-fluoro-3,5-dimethylphenylamino)-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)pyrimidine-5-carboxylate trifluoroacetate salt;
I-79: 5-

Assignees

• Rigel Pharmaceuticals Inc

Inventors

• Li Hui
• Heckrodt Thilo J
• Chen Yan
• Mcmurtrie Darren John
• Taylor Vanessa
• Singh Rajinder
• Ding Pingyu
• Yen Rose

Classifications

• A61P43/00

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

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title