Compositions and methods for the production of pyrimidine and pyridine compounds with BTK inhibitory activity

Patent metadata

Field	Value
Publication number	US-10016448-B2
Application number	US-201715417953-A
Country	US
Kind code	B2
Filing date	Jan 27, 2017
Priority date	Jun 10, 2011
Publication date	Jul 10, 2018
Grant date	Jul 10, 2018

Abstract

The present invention provides novel pyrimidine and pyridine compounds according to Formula (I), Formula (II), Formula (III), Formula (IV) and Formula (V) their manufacture and use for the treatment of hyperproliferative diseases including, but not limited to, cancer, lupus, allergic disorders, Sjogren's disease and rheumatoid arthritis. In preferred embodiments, the present invention describes irreversible kinase inhibitors including, but not limited to, inhibitors of Bruton's tyrosine kinase.

First claim

What is claimed is:

1. A method of treating rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, Sjögren's Syndrome, atherosclerosis, psoriatic arthritis, psoriasis, eczema, sclerodema, asthma, diabetes, diabetic retinopathy, retinopathy of prematurity, or age-related macular degeneration, comprising administering to a subject a compound of formula I

wherein
X denotes CH or N,
R 1 denotes NH 2 , CONH 2 or H,
R 2 denotes Hal, Ar 1 or Het 1 ,
R 3 denotes NR 5 [C(R 5 ) 2 ] n Het 2 , NR 5 [C(R 5 ) 2 ] n Cyc, Het 2 , O[C(R 5 ) 2 ] n Ar 2 , NR 5 [C(R 5 ) 2 ] n Ar 2 , O[C(R 5 ) 2 ] n Het 2 , NR 5 (CH 2 ) p NR 5 R 6 , O(CH 2 ) p NR 5 R 6 or NR 5 (CH 2 ) p CR 7 R 8 NR 5 R 6 ,
R 4 denotes H, CH 3 or NH 2 ,
R 5 each independently denotes H or alkyl having 1, 2, 3 or 4 C atoms,
R 6 each independently denotes N(R 5 ) 2 CH 2 CH═CHCONH, Het 3 CH 2 CH═CHCONH, CH 2 ═CHCONH(CH 2 ) n , Het 4 (CH 2 ) n COHet 3 -diyl-CH 2 CH═CHCONH, HC≡CCO, CH 3 C≡CCO, CH 2 ═CH—CO, CH 2 ═C(CH 3 )CONH, CH 3 CH═CHCONH(CH 2 ) n , N≡CCR 7 R 8 CONH(CH 2 ) n , Het 4 NH(CH 2 ) p COHet 3 -diyl-CH 2 CH═CHCONH, Het 4 (CH 2 ) p CONH(CH 2 CH 2 O) p (CH 2 ) p COHet 3 -diyl-CH 2 CH═CHCONH, CH 2 ═CHSO 2 , ACH═CHCO, CH 3 CH═CHCO, Het 4 (CH 2 ) p CONH(CH 2 ) p Het 3 -diyl-CH 2 CH═CHCONH, Ar 3 CH═CHSO 2 , CH 2 ═CHSO 2 NH or N(R 5 )CH 2 CH═CHCO,
R 7 , R 8 denote together alkylene having 2, 3, 4, or 5 C atoms,
Ar 1 denotes phenyl or naphthyl, each of which is unsubstituted or mono-, di- or trisubstituted by R 6 , Hal, (CH 2 ) n NH 2 , CONHAr 3 , (CH 2 ) n NHCOA, O(CH 2 ) n Ar 3 , OCyc, A, COHet 3 , OA and/or OHet 3 (CH 2 ),
Ar 2 denotes phenyl, naphthyl or pyridyl each of which is unsubstituted or mono-, di- or trisubstituted by R 6 , Hal, OAr 3 , (CH 2 ) n NH 2 , (CH 2 ) n NHCOA and/or Het 3 ,
Ar 3 denotes phenyl, which is unsubstituted or mono-, di- or trisubstituted by OH, OA, Hal, CN and/or A,
Het 1 denotes a mono- or bicyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-, di- or trisubstituted by R 6 , O(CH 2 ) n Ar 3 and/or (CH 2 ) n Ar 3 ,
Het 2 each independently denotes a mono- or bicyclic saturated heterocycle having 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-, di- or trisubstituted by R 6 , Het 3 , CycSO 2 , OH, Hal, COOH, OA, COA, COHet 3 , CycCO, SO 2 and/or ═O,
Het 3 each independently denotes a monocyclic unsaturated, saturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-, di- or trisubstituted by Hal, A and/or ═O,
Het 4 each independently denotes a bi- or tricyclic unsaturated, saturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-, di-, tri- or tetrasubstituted by A, NO 2 , Hal and/or ═O,
Cyc each independently denotes cyclic alkyl having 3, 4, 5 or 6 C atoms, which is unsubstituted, monosubstituted or disubstituted by R 6 and/or OH and which may comprise a double bond,
A each independently denotes unbranched or branched alkyl having 1-10 C atoms, in which 1-7 H atoms may be replaced by F and/or Cl and/or in which one or two non-adjacent CH 2 and/or CH-groups may be replaced by O, NH and/or by N,
Hal each independently denotes F, Cl, Br or I,
n each independently denotes 0, 1, 2, 3 or 4,
p each independently denotes 1, 2, 3, 4, 5 or 6,
and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

2. The method according to claim 1 wherein
Het 1 denotes piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, benzimidazolyl, benzotriazolyl, indolyl, benzo-1,3-dioxolyl, indazolyl, azabicyclo[3.2.1]octyl, azabicyclo[2.2.2]octyl, imidazolidinyl, azetidinyl, azepanyl, benzo-2,1,3-thiadiazolyl, tetrahydrofuryl, dioxolanyl, tetrahydrothienyl, dihydropyrrolyl, tetrahydroimidazolyl, dihydropyrazolyl, tetrahydropyrazolyl, tetrahydropyridyl, dihydropyridyl or dihydrobenzodioxinyl, each of which is unsubstituted or mono-, di- or trisubstituted by R 6 , O(CH 2 ) n Ar 3 and/or (CH 2 ) n Ar 3 , and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

3. The method according to claim 2 wherein Het 1 denotes pyrazolyl, pyridyl, pyrimidinyl, dihydropyridyl or dihydrobenzodioxinyl, each of which is unsubstituted or mono-, di- or trisubstituted by R 6 , O(CH 2 ) n Ar 3 and/or (CH 2 ) n Ar 3 , and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

4. The method according to claim 1 wherein
Het 2 denotes piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, azabicyclo[3.2.1]octyl, azabicyclo[2.2.2]octyl, 2,7-diazaspiro[3.5]nonyl, 2,8-diazaspiro[4.5]decyl, 2,7-diazaspiro[4.4]nonyl, 3-azabicylo[3.1.0]hexyl, 2-azaspiro[3.3]heptyl, 6-azaspiro[3.4]octyl, 7-azaspiro[3.5]nonyl, 5-azaspiro[3.5]nonyl, imidazolidinyl, azetidinyl, azepanyl, tetrahydrofuryl, dioxolanyl, tetrahydrothienyl, tetrahydroimidazolyl, tetrahydropyrazolyl, tetrahydropyridyl, each of which is unsubstituted or mono-, di- or trisubstituted by R 6 , Het 3 , CycSO 2 , OH, OA, COA, COHet 3 , CycCO, SO 2 and/or ═O, and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

5. The method according to claim 1 wherein
Het 3 denotes piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, imidazolidinyl, azetidinyl, azepanyl, tetrahydrofuryl, dioxolanyl, tetrahydrothienyl, dihydropyrrolyl, tetrahydroimidazolyl, dihydropyrazolyl, tetrahydropyrazolyl, tetrahydropyridyl or dihydropyridyl, each of which may be unsubstituted or mono-, di- or trisubstituted by Hal, A and/or ═O,
and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

6. The method according to claim 5 wherein
Het 3 denotes piperidinyl, pyrrolidinyl, morpholinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, dihydropyrrolyl, dihydropyrazolyl or dihydropyridyl, each of which may be unsubstituted or mono-, di- or trisubstituted by Hal, A and/or ═O,
and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

7. The method according to claim 1 wherein
Het 4 denotes hexahydrothieno[3,4-d]imidazolyl, benzo[c][1,2,5]oxadiazolyl or 5H-dipyrrolo[1,2-c:2′,1′-f][1,3,2]diazaborinin-4-ium-uidyl, each of which may be unsubstituted or mono-, di-, tri- or tetrasubstituted by A, NO 2 , Hal and/or ═O, and pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

8. The method according to claim 1 wherein
X denotes CH or N,
R 1 denotes NH 2 , CONH 2 or H,
R 2 denotes Hal, Ar 1 or Het 1 ,
R 3 denotes NR 5 [C(R 5 ) 2 ] n Het 2 , NR 5 [C(R 5 ) 2 ] n Cyc, Het 2 , O[C(R 5 ) 2 ] n Ar 2 , NR 5 [C(R 5 ) 2 ] n Ar 2 , O[C(R 5 ) 2 ] n Het 2 , NR 5 (CH 2 ) p NR 5 R 6 , O(CH 2 ) p NR 5 R 6 NR 5 (CH 2 ) p CR 7 R 8 NR 5 R 6 ,
R 4 denotes H,
R 5 each independently denotes H or alkyl having 1, 2

Assignees

• Merck Patent Gmbh

Inventors

• Hodous Brian L
• Liu-Bujalski Lesley
• Jones Reinaldo
• Bankston Donald
• Johnson Theresa L
• Mochalkin Igor
• Nguyen Ngan
• Qiu Hui
• Goutopoulos Andreas
• Brugger Nadia

Classifications

• A61P5/00

  Drugs for disorders of the endocrine system · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P43/00

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

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P31/02

  Local antiseptics · CPC title