Nicotinamide compounds useful as kinase modulators

• US 8,586,751 B2
• Filed: 06/10/2010
• Issued: 11/19/2013
• Est. Priority Date: 06/12/2009
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: De Lucca, George V., Shi, Qing, Liu, Chunjian, Duan, Jingwu, Tebben, Andrew J.
• Primary Examiner(s): Chu, Yong
• Assistant Examiner(s): WRIGHT, SONYA N
• Application Number:
  US13/377,157
• Publication Number:
  US 20120082702A1
• Time in Patent Office: 1,258 Days
• Field of Search: 548/400, 546/268.4, 514/333
• US Class Current: 546/268.4
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: C07D 213/82 in position 3
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 498/10 Spiro-condensed systems

Abstract

Disclosed are nicotinamide compounds of Formula (I): or stereoisomers or pharmaceutically acceptable salts thereof. Also disclosed are methods of using such compounds in the treatment of at least one Btk associated condition, such as, for example, inflammatory disease, and pharmaceutical compositions comprising such compounds.

Claims

1. A compound having Formula (I):

2. The compound according to claim 1 or stereoisomers or pharmaceutically acceptable salts thereof, wherein:

G is;

i) 1- to 2-ring heteroaryl or 1- to 2-ring heterocyclyl substituted with zero to 3 substituents independently selected from alkyl, phenyl, —

NR_dR_d, —

NR_dC(O)O(alkyl), —

C(O)(alkyl), —

C(O)(phenyl), and/or —

C(O)(benzyl);

ii)

3. The compound according to claim 2 or stereoisomers or pharmaceutically acceptable salts thereof, wherein:

R_a is H, C_1-6alkyl, C_1-6hydroxyalkyl, or —

(CH₂)_nphenyl, wherein said phenyl in turn is substituted with zero to 4 R_h;

one of R₄ and R₅ is H, halo, —

CH₃, —

CF₃, —

CN, —

NH₂, —

OH, C_1-3alkoxy, —

OCF₃, —

C(O)NR_b(C_1-2alkyl), —

NR_b(C_1-2alkyl), —

NR_bS(O)₂(C_1-2alkyl), —

NR_bS(O)₂(phenyl), —

NR_bC(O)(phenyl), pyrrolidine-2,5-dione, —

NR_bC(O)NR_b(phenyl), —

NR_bS(O)₂(pyrrolidinyl), —

S(O)₂(C_1-4alkyl), —

NR_bS(O)₂(C_1-4alkyl), —

NR_bS(O)₂(fluorophenyl), —

NR_bS(O)₂(biphenyl), —

NR_bS(O)₂(naphthalenyl), —

NR_bS(O)₂(imidazolyl), —

NR_bS(O)₂(chlorothiophenyl), —

NR_bS(O)₂(benzyl), —

NR_bS(O)₂(pyridinyl), —

NR_b(S(O)₂(C_1-4haloalkyl), —

N(S(O)₂(C_1-4haloalkyl))₂, or —

NR_bC(O)O(C_1-4alkyl);

and the other of R₄ and R₅ is;

a) H, halo, —

CN, or C_1-6alkoxy;

b) -L-A;

or

c) -L-C(O)-A;

wherein L is a bond or —

(CR_cR_c)_t—

; and

A is selected from A₁, A₂, and A₃, wherein;

A₁ is C_1-6alkyl or C_5-7cycloalkyl, each independently substituted with 0 to 3 substituents independently selected from —

OH, —

NH₂, C_1-3alkoxy, —

C(O)NH₂, —

C(O)(C_1-6alkyl), —

C(O)OR_b, —

NH(C_1-6alkyl), —

N(C_1-6alkyl)₂, —

C(O)NR_b(C_1-6alkyl), —

C(O)NR_b(C_1-6hydroxyalkyl), —

C(O)NR_b(heterocyclyl), —

NR_bC(O)(C_1-6alkyl), —

C(O)NR_b(CR_bR_b)_qNH(C_1-6alkyl), and/or —

C(O)NR_b(CR_bR_b)_qN(C_1-6alkyl)₂;

A₂ is 4- to 6-membered heterocyclyl or 5- to 6-membered heteroaryl having 1- to 3-heteroatoms independently selected from N, O, and/or S, and substituted with zero to 4 substituents independently selected from —

OH, ═

O, C_1-6alkyl, C_1-4-hydroxyalkyl, C_3-6cycloalkyl, —

C(O)(C_1-6alkyl), —

NH(C_1-6alkyl), —

N(C_1-6alkyl)₂, —

C(O)NR_b(C_1-6alkyl), —

C(O)NR_b(C_1-6hydroxyalkyl), —

C(O)NR_b(C_3-6cycloalkyl), —

C(O)NR_b(CR_bR_b)_qNH(C_1-6alkyl), —

C(O)NR_b(phenyl), —

C(O)NR_b(CR_bR_b)_qN(C_1-6alkyl)₂, —

C(O)NR_bR_b, —

NR_bC(O)(C_1-6alkyl), —

C(O)O(C_1-4alkyl), and/or —

C(O)O(benzyl);

A₃ is —

OH, —

NH₂, C_1-6alkoxy, —

NH(C_1-6alkyl), —

N(C_1-6alkyl)₂, di-(C_1-2alkyl) N-oxide, —

NR_b(C_1-6hydroxyalkyl), —

NR_b(C_3-7cycloalkyl), —

NR_b(CR_bR_b)_qNH(C_1-6alkyl), —

NR_b(CR_bR_b)_qN(C_1-6alkyl)₂, —

NR_b(phenyl), —

NR_bC(O)(C_1-6alkyl), —

S(C_1-6alkyl), —

S(O)₂(C_1-6alkyl), —

S(O)₂(C_1-4fluoroalkyl), —

S(O)₂NR_dR_d, —

S(O)₂(CR_bR_b)_qN(C_1-2alkyl)₂, —

O(CR_bR_b)_qCR_b(C_1-2alkoxy)₂, —

O(CR_bR_b)_qNR_b(C_3-6cycloalkyl), —

O(CR_bR_b)_qN(C_1-2alkyl)₂, —

NR_bC(O)NR_bA₂, —

NR_bC(O)A₂, —

NR_bA₂, —

NR_bC(O)(CR_bR_d)_qA₂, or —

O(CR_cR_c)_qA₂;

G is;

i) 1- to 2-ring heteroaryl or 1- to 2-ring heterocyclyl substituted with zero to 3 substituents independently selected from —

OH, ═

O, C_1-6alkyl, —

CR_bR_bC(O)OH, —

CR_bR_bC(O)O(C_1-4alkyl), —

CR_bR_bC(O)NH(phenyl), —

CR_bR_bS(O)₂(phenyl), phenyl, —

NR_b(C_1-6alkyl), —

N(C_1-6alkyl)C(O)O(C_1-6alkyl), —

C(O)(C_1-4alkyl), —

C(O)(phenyl), and/or —

C(O)(benzyl);

ii)

4. The compound according to claim 3, or stereoisomers or pharmaceutically acceptable salts thereof,

R₆ is H or C_1-2alkoxy;

one of R₄ and R₅ is H, halo, C_1-2alkoxy, —

C(O)NR_b(C_1-2alkyl), —

NR_b(C_1-2alkyl), —

NR_bS(O)₂(C_1-2alkyl), —

NR_bS(O)₂(phenyl), —

C(O)NH(C_1-2alkyl), —

N(CH₃)C(O)(phenyl), pyrrolidine-2,5-dione, —

NR_bC(O)NR_b(phenyl), —

CH₂S(O)₂(pyrrolidinyl), —

S(O)₂(C_1-2alkyl), —

NR_bS(O)₂(C_1-2alkyl), —

NR_bS(O)₂(fluorophenyl), —

NR_bS(O)₂(biphenyl), —

NR_bS(O)₂(naphthalenyl), —

NR_bS(O)₂(imidazolyl), —

NR_bS(O)₂(chlorothiophenyl), —

NR_bS(O)₂(benzyl), —

NR_bS(O)₂(pyridinyl), —

NR_b(S(O)₂(C_1-4chloroalkyl), —

N(S(O)₂(C_1-4chloroalkyl))₂, or —

NR_bC(O)O(C_1-4alkyl);

and the other of R₄ and R₅ is;

a) H, halo, —

CN, or C_1-2alkoxy;

b) -L-A;

or

c) -L-C(O)-A;

wherein L is a bond or —

(CR_cR_c)_t—

; and

A is selected from A₁, A₂, and A₃, wherein;

A₁ is C_1-4alkyl or C_5-7cycloalkyl, each independently substituted with 0 to 2 substituents independently selected from —

OH, —

NH₂, C_1-2alkoxy, —

C(O)(C_1-6alkyl), —

C(O)OR_b, —

NH(C_1-4alkyl), —

N(C_1-6alkyl)₂, —

C(O)NR_b(C_1-6alkyl), —

C(O)NR_b(C_1-6hydroxyalkyl), —

C(O)NR_b(heterocyclyl), —

C(O)NR_b(CR_bR_b)_qNH(C_1-6alkyl), —

C(O)NR_b(CR_bR_b)_qN(C_1-6alkyl)₂, and/or —

NR_bC(O)(C_1-6alkyl);

A₂ is 4- to 6-membered heterocyclyl or 5- to 6-membered heteroaryl having 1- to 3-heteroatoms independently selected from N, O, and/or S, and substituted with zero to 4 substituents independently selected from —

OH, ═

O, C_1-4alkyl, C_1-4hydroxyalkyl, C_3-5cycloalkyl, —

C(O)(C_1-4alkyl), —

NH(C_1-4alkyl), —

N(C_1-4alkyl)₂, —

C(O)NR_b(C_1-4alkyl), —

C(O)NR_b(C_1-4-hydroxyalkyl), —

C(O)NR_b(C_3-4cycloalkyl), —

C(O)NR_b(CR_bR_b)_qNH(C_1-4alkyl), —

C(O)NR_b(phenyl), —

C(O)NR_b(CR_bR_b)_qN(C_1-4alkyl)₂, —

C(O)NR_bR_b, —

NR_bC(O)(C_1-4alkyl), —

C(O)O(C_1-4alkyl), and/or —

C(O)O(benzyl);

A₃ is —

OH, —

NH₂, C_1-4alkoxy, —

NH(C_1-6alkyl), —

N(C_1-6alkyl)₂, di-(C_1-2alkyl) N-oxide, —

NR_b(C_1-4-hydroxyalkyl), —

NR_b(C_3-6cycloalkyl), —

NR_b(CR_bR_b)_qNH(C_1-4alkyl), —

NR_b(CR_bR_b)_qN(C_1-4alkyl)₂, —

NR_b(phenyl), —

NR_bC(O)(C_1-4alkyl), —

NR_bC(O)(C_1-4alkyl), —

S(C_1-4alkyl), —

S(O)₂(C_1-4alkyl), —

S(O)₂(C_1-3fluoroalkyl), —

S(O)₂NR_dR_d, —

S(O)₂(CR_b)_qN(C_1-2alkyl)₂, —

O(CR_bR_b)_qCR_b(C_1-2alkoxy)₂, —

O(CR_bR_b)_qNR_b(C_3-6cycloalkyl), —

O(CR_bR_b)_qN(C_1-2alkyl)₂, —

NR_bC(O)NR_bA₂, —

NR_bC(O)A₂, —

NR_bA₂, —

NR_bC(O)(CR_bR_d)_qA₂, or —

O(CR_cR_c)_qA₂;

G is;

i) 1- to 2-ring heteroaryl or heterocyclyl substituted with zero to 3 substituents independently selected from —

OH, ═

O, C_1-6alkyl, —

CR_bR_bC(O)OH, —

CR_bR_bC(O)O(C_1-4alkyl), —

CR_bR_bC(O)NH(phenyl), —

CR_bR_bS(O)₂(phenyl), phenyl, —

NR_b(C_1-6alkyl), —

N(C_1-6alkyl)C(O)O(C_1-6alkyl), —

C(O)(C_1-4alkyl), —

C(O)(phenyl), and/or —

C(O)(benzyl);

ii)

5. The compound according to claim 4, or stereoisomers or pharmaceutically acceptable salts thereof, wherein:

R₁ is H;

R₂ is H, F, or Br;

R₆ is C_1-2alkoxy, R₅ is H, and R₄ is H;

or

R₆ is H, R₅ is halo, and R₄ is 5- to 6-membered heterocyclyl having 1- to 3-heteratoms independently selected from N, O, and/or S, and substituted with zero to 2 substituents independently selected from C_1-4alkyl, C_1-4-hydroxyalkyl, and/or —

C(O)(C_1-4alkyl);

or

R₆ is H, R₅ is H, —

OCH₃, —

NH(CH₃), —

C(O)NHCH₃, —

N(CH₃)C(O)(phenyl), pyrrolidine-2,5-dione, —

N(CH₃)C(O)NH(phenyl), —

CH₂S(O)₂(pyrrolidinyl), —

S(O)₂CH₃, —

NR_bS(O)₂CH₃, —

NR_bS(O)₂CH₂CH₃, —

NR_bS(O)₂(phenyl), —

NR_bS(O)₂(fluorophenyl), —

NR_bS(O)₂(biphenyl), —

NR_bS(O)₂(naphthalenyl), —

NR_bS(O)₂(chlorothiophenyl), —

NR_bS(O)₂(imidazolyl), —

NR_bS(O)₂(benzyl), —

NR_bS(O)₂(pyridinyl), —

NR_b(S(O)₂CH₂CH₂CH₂Cl), —

N(S(O)₂CH₂CH₂CH₂Cl)₂, or —

NR_bC(O)O(butyl), and R₄ is;

a) H, halo, or —

CN;

b) -L-A;

or

c) -L-C(O)-A;

wherein L is a bond or —

(CR_cR_c)_t—

; and

A is selected from A₁, A₂, and A₃;

wherein;

A₁ is C_1-4alkyl substituted with 0 to 2 substituents independently selected from —

OH, —

NH₂, —

OCH₃, —

C(O)OH, —

NH(C_1-2alkyl), and/or —

N(C_1-2alkyl)₂;

A₂ is 4- to 6-membered heterocyclyl or 5- to 6-membered heteroaryl having 1- to 3-heteroatoms independently selected from N, O, and/or S, and substituted with zero to 4 substituents independently selected from —

OH, ═

O, C_1-3alkyl, C_1-2hydroxyalkyl, C_3-4cycloalkyl, —

C(O)(C_1-2alkyl), —

C(O)O(C_1-4alkyl), and/or —

C(O)O(benzyl);

A₃ is —

OH, —

NH₂, C_1-4alkoxy, —

OCH₂CH(OCH₂CH₃)₂, —

OCH₂CH₂NH(cyclopropyl), —

OCH₂CH₂(pyrrolidinyl)), —

OCH₂CH₂N(CH₃)₂, N,N-dimethylethamine oxide, —

NH(C_1-4alkyl), —

N(C_1-2alkyl)₂, —

NH(C_1-2hydroxyalkyl), —

NH(C_3-6cycloalkyl), —

NH(CH₂)_qNH(C_1-4alkyl), —

NH(CH₂)_qN(C_1-2alkyl)₂, —

NH(phenyl), —

NHC(O)(C_1-2alkyl), —

S(C_1-4alkyl), —

S(O)₂(C_1-4alkyl), —

S(O)₂(C_1-2fluoroalkyl), —

S(O)₂NR_dR_d, —

S(O)₂(CH₂)_qN(C_1-2alkyl)₂, —

NHC(O)A₂, —

NHA₂, —

NHC(O)(CH₂)_qA₂, or —

O(CH₂)_qA₂;

G is;

i) 1- to 2-ring heteroaryl or heterocyclyl substituted with zero to 3 substituents independently selected from —

OH, ═

O, C_1-4alkyl, —

CH₂C(O)OH, —

CH₂C(O)NH(phenyl), —

CH₂C(O)O(C_1-2alkyl), —

CH₂S(O)₂(phenyl), phenyl, —

NR_b(C_1-4alkyl), —

N(C_1-4alkyl)C(O)O(C_1-4alkyl), —

C(O)(C_1-4alkyl), —

C(O)(phenyl), and/or —

C(O)(benzyl);

ii)

6. The compound according to claim 1, or stereoisomers or pharmaceutically acceptable salts thereof, wherein:

R₃ is H.

7. The compound according to claim 1, or stereoisomers or pharmaceutically acceptable salts thereof, wherein:

R₆ is —

OCH₃, R₅ is H, and R₄ is H;

or

R₆ is H, R₅ is F, and R₄ is morpholinyl or N-methyl piperazinyl;

or

R₆ is H, R₅ is —

OCH₃, and R₄ is H, —

OCH₂CH(OCH₂CH₃)₂, —

OCH₂CH₂N(CH₃)₂, —

OCH₂CH₂NH(cyclopropyl), or —

OCH₂CH₂(pyrrolidinyl);

or

R₆ is H, R₅ is —

NH(CH₃), —

C(O)NHCH₃, —

N(CH₃)C(O)(phenyl), pyrrolidine-2,5-dione, —

N(CH₃)C(O)NH(phenyl), —

CH₂S(O)₂(pyrrolidinyl), —

S(O)₂CH₃, —

NR_bS(O)₂CH₃, —

NR_bS(O)₂CH₂CH₃, —

NR_bS(O)₂(phenyl), —

N(CH₃)S(O)₂(fluorophenyl), —

N(CH₃)S(O)₂(biphenyl), —

N(CH₃)S(O)₂(naphthalenyl), —

N(CH₃)S(O)₂(imidazolyl), —

N(CH₃)S(O)₂(chlorothiophenyl), —

N(CH₃)S(O)₂(benzyl), —

N(CH₃)S(O)₂(pyridinyl), —

NH(S(O)₂CH₂CH₂CH₂Cl), —

N(S(O)₂CH₂CH₂CH₂Cl)₂, or —

N(CH₃)C(O)O(butyl), and R₄ is H or —

C(O)(morpholinyl);

or

R₆ is H, R₅ is H, and R₄ is H, F, —

CN, ethyl, butyl, hydroxyethyl, dimethylaminoethyl, N,N-dimethylethamine oxide, —

OCH₃, —

NHC(O)CH₃, —

NH₂, —

N(ethyl)₂, —

C(O)CH₃, —

C(O)OH, —

C(O)O(butyl), —

C(O)NH(cyclopropyl), —

C(O)NH(butyl), —

C(O)NH(phenyl), —

C(O)N(CH₃)₂, —

C(O)N(ethyl)₂, —

C(O)NHCH₂CH₂N(CH₃)₂, —

C(O)NH(hydroxyethyl), —

C(CH₃)₂CH₂OH, —

C(CH₃)₂C(O)OCH₂CH₃, —

CH₂CH₂NH(butyl), —

CH₂CH₂(azetidinyl), —

CH₂CH₂(imidazolyl), —

CH₂CH₂(pyrrolidinyl), —

C(CH₃)₂C(O)NH(oxetanyl), —

CH₂CH(CH₂OH)NHC(O)(pyrrolidinyl), —

CH₂CH(CH₂OH)NHC(O)(piperidinyl), —

C(CH₃)₂C(O)NHCH₂CH₂N(CH₃)₂, —

NHC(O)CH₂(pyrrolidinyl), —

C(CH₃)₂C(O)NH(cyclopropyl), —

C(CH₃)₂C(O)NHCH₂CH₂OH, —

S(O)₂N(CH₃)₂, —

C(CH₃)₂C(O)OH, —

S(O)₂CH₃, —

S(O)₂CF₃, —

S(O)₂CH₂CH₂N(CH₂CH₃)₂, pyrrolidinyl, oxazolyl, tetrahydropyranyl, morpholinyl, 4-hydroxymorpholinyl, morpholinonyl, piperidinyl, N-methyl piperidinyl, N-(butyl-OC(O))piperidinyl, 1-(ethyl-OC(O))-4-methylpiperidinyl, 1,4-dimethyl piperidinyl, N-acetyl piperazinyl, piperazinyl, N-methyl piperazinyl, N-ethyl piperazinyl, N-propyl piperazinyl, N-cyclopropyl-piperazinyl, N-cyclobutyl piperazinyl, N-(benzyl-OC(O))piperazinyl, —

C(O)(azetidinyl), —

C(O)(pyrrolidinyl), —

C(O)(morpholinyl), —

C(O)(piperidinyl), —

C(O)(N-methyl piperazinyl), —

C(O)(N-hydroxyethyl piperazinyl), —

CH₂(morpholinyl), —

CH₂(oxazolidinonyl),

9. A pharmaceutical composition, comprising;

a pharmaceutically acceptable carrier and a compound of claim 1, or stereoisomers or pharmaceutically acceptable salts thereof.

10. A method of using a compound of claim 1, or stereoisomers or pharmaceutically acceptable salts thereof, for treatment of an allergic disorder, and/or inflammatory disease.

8. A compound having Formula (II):