Compounds

• US 8,207,176 B2
• Filed: 03/24/2006
• Issued: 06/26/2012
• Est. Priority Date: 03/25/2005
• Status: Expired due to Fees

• Current Assignee: Glaxo Group Limited (Glaxosmithkline Holdings Ltd.)
• Original Assignee: Glaxo Group Limited (Glaxosmithkline Holdings Ltd.)
• Inventors: Callahan, James F., Boehm, Jeffrey C., Cooper, Anthony William James, Livia, Stefano, Bamborough, Paul, Nevins, Neysa, Wan, Zehong, Norton, Beth A., Lin, Xichen
• Primary Examiner(s): Wilson, James O
• Assistant Examiner(s): Jaisle, Cecilia M
• Application Number:
  US11/908,440
• Publication Number:
  US 20090069318A1
• Time in Patent Office: 2,286 Days
• Field of Search: 544/279, 514/264.1, 546/125
• US Class Current: 514/264.1
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/16 Emollients or protectives, e.g. against radiation
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/06 Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/00 Drugs for disorders of the senses
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/16 Otologicals
• 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 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/04 : specific for metastasis
• 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 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems

Abstract

The present invention is directed to novel substituted 2,4,8-trisubstituted 8H-pyrido[2,3-d]pyrimidin-7-one containing compounds, compositions, and use in therapy as CSBP/RK/p38 kinase inhibitors of Formulas (V) and (Va)

wherein inter alia,

• G₅ and G₆ are nitrogen and CH, provided that only one of G5 or G6 is nitrogen and the other is CH;
• R₁ is C(Z)N(R_10′)(CR₁₀R₂₀)_vR_b, C(Z)O(CR₁₀R₂₀)_vR_b, N(R_10′)C(Z)(CR₁₀R₂₀)_vR_b, N(R_10′)C(Z)N(R_10′)(CR₁₀R₂₀)_vR_b, or N(R_10′)OC(Z)(CR₁₀R₂₀)_vR_b;
• R_1′ is independently selected at each occurrence from halogen, C_1-4 alkyl, halo-substituted-C_1-4 alkyl, cyano, nitro, (CR₁₀R₂₀)_v′NR_dR_d′, (CR₁₀R₂₀)_v′C(O)R₁₂, SR₅, S(O)R₅, S(O)₂R₅, or (CR₁₀R₂₀)_v′OR₁₃;
• R_b is hydrogen, C_1-10 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkyl C_1-10 alkyl, aryl, arylC_1-10alkyl, heteroaryl, heteroarylC_1-10 alkyl, heterocyclic, or heterocyclylC_1-10 alkyl moiety, which moieties, excluding hydrogen, may all be optionally substituted;
• X is R₂, OR_2′, S(O)_mR_2′, (CH₂)_n′N(R_10′)S(O)_mR_2′, (CH₂)_n′N(R_10′)C(O)R_2′, (CH₂)_n′NR₄R₁₄, (CH₂)_n′N(R_2′)(R_2″), or N(R_10′)R_hNH—C(═N—CN)NRqRq′; and
• R₃ is a C_1-10 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkyl C_1-10 alkyl, aryl, arylC_1-10 alkyl, heteroaryl, heteroarylC_1-10 alkyl, heterocyclic or a heterocyclylC_1-10 alkyl moiety, and wherein each of these moieties may be optionally substituted.

Claims

1. A compound of the formula:

2. A pharmaceutical composition comprising an effective amount of a compound, or pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof according to claim 1, in admixture with one or more pharmaceutically acceptable carriers, diluents or excipients.

3. The compound according to claim 1 which is Formula (V), and a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 wherein R₁ is C(Z)N(R_10′

)(CR₁₀R₂₀)_vR_b or N(R_10′

)C(Z)(CR₁₀R₂₀)_vR_b.

5. The compound according to claim 4 wherein R_b is selected from an optionally substituted alkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted aryl C_1-10 alkyl, or an optionally substituted C_3-7 cycloalkyl C_1-10 alkyl.

6. The compound according to claim 5 wherein R_b is propyl, isopropyl, thiazolyl, phenyl, or 4-F phenyl.

7. The compound according to claim 1 wherein R_1′

is independently selected at each occurrence from halogen, C_1-4 alkyl, or halo-substituted-C_1-4 alkyl.

8. The compound according to claim 7 wherein R_1′

is independently selected at each occurrence from fluorine, methyl, or CF₃.

9. The compound according to claim 1 wherein X is S(O)_mR₂.

10. The compound according to claim 1 wherein X is (CH₂)_n′

NR₄R₁₄, or (CH₂)_nN(R_2′

)(R_2″

).

11. The compound according to claim 10 wherein the R₄ and R₁₄ moieties, are optionally substituted, 1 to 4 times, independently at each occurrence, by halogen;

hydroxy;

hydroxy substituted C_1-10alkyl;

C_1-10 alkoxy;

halosubstituted C_1-10 alkoxy;

C_1-10 alkyl;

halosubstituted C_1-4 alkyl;

SR₅;

S(O)R₅;

S(O)₂R₅;

C(O)R_j;

C(O)ORj;

C(O)NR_4′

R_14′

;

NR_4′

C(O)C_1-10alkyl;

NR_4′

C(O)aryl;

NR_4′

R_14′

;

cyano, nitro, C_1-10 alkyl, C_3-7cycloalkyl, or C_3-7cycloalkyl C_1-10 alkyl;

halosubstituted C_1-10 alkyl;

an unsubstituted or substituted aryl, or arylC_1-4 alkyl;

an unsubstituted or substituted heteroaryl or hetero C_1-4 alkyl;

an unsubstituted or substituted heterocyclic or heterocyclic C_1-4 alkyl, and wherein these aryl, heteroaryl or heterocyclic containing moieties are substituted one to two times independently at each occurrence by halogen;

C_1-4 alkyl, hydroxy;

hydroxy substituted C_1-4 alkyl;

C_1-4 alkoxy;

S(O)_malkyl;

amino, mono &

di-substituted C_1-4 alkyl amino, or CF₃; and

wherein

R_j is independently selected at each occurrence from hydrogen, C_1-4alkyl, aryl, aryl C_1-4alkyl, heteroaryl, heteroaryl C_1-4alkyl, heterocyclic, or a heterocyclic C_1-4alkyl moiety, and wherein these moieties, excluding hydrogen, may be optionally substituted.

12. The compound according to claim 11 wherein R₄ and R₁₄ are independently selected from hydrogen, optionally substituted C_1-10 alkyl, optionally substituted aryl, optionally substituted aryl-C_1-4 alkyl, optionally substituted heterocyclic, optionally substituted heterocyclic C_1-4 alkyl, optionally substituted heteroaryl or optionally substituted heteroaryl C_1-4 alkyl.

13. The compound according to claim 12 wherein the C_1-10 alkyl is substituted one or more times, independently at each occurrence with NR_4′

R_14′

;

halogen, hydroxy, alkoxy, C(O)NR_4′

R_14′

;

or NR₄C(O)C_1-10alkyl.

14. The compound according to claim 11 wherein X is (CH₂)_n′

NR₄R₁₄;

one of R₄ and R₁₄ is an optionally substituted heteroaryl C_1-4 alkyl, and the heteroaryl moiety is selected from thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzimidazolyl, and benzothiazolyl;

or one of R₄ and R₁₄ is an optionally substituted heterocyclic or heterocyclic C_1-4 alkyl moiety selected from tetrahydropyrrole, tetrahydropyran, tetrahydrofuran, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, indolinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, piperazinyl, and morpholino, tetrahydropyrrole C_1-4 alkyl, tetrahydropyran C_1-4 alkyl, tetrahydrofuran C_1-4 alkyl, pyrrolinyl C_1-4 alkyl, pyrrolidinyl C_1-4 alkyl, imidazolinyl C_1-4 alkyl, imidazolidinyl C_1-4 alkyl, indolinyl C_1-4 alkyl, pyrazolinyl C_1-4 alkyl, pyrazolidinyl C_1-4 alkyl, piperidinyl C_1-4 alkyl, piperazinyl C_1-4 alkyl, and morpholino C_1-4 alkyl.

15. The compound according to claim 11 wherein X is (CH₂)_n′

NR₄R₁₄ and R₄ and R₁₄ together with the nitrogen cyclize to form an optionally substituted ring selected from pyrrolidine, piperidine, piperazine, and morpholine.

16. The compound according to claim 11 wherein X is 1,4′

-bipiperin-1′

yl or 4-methyl-1,4′

-bipiperin-1′

yl.

17. The compound according to claim 1 wherein the R_2′

moieties, excluding hydrogen, are optionally substituted 1 to 4 times, independently, by C_1-10 alkyl, halo-substituted C_1-10 alkyl, C_2-10 alkenyl, C_2-10 alkynyl, C_3-7 cycloalkyl, C_3-7cycloalkylC_1-10alkyl, C_5-7cycloalkenyl, C_5-7 cycloalkenyl C_1-10 alkyl, halogen, —

C(O), cyano, nitro, (CR₁₀R₂₀)_nOR₆, (CR₁₀R₂₀)_nSH, (CR₁₀R₂₀)_nS(O)_mR₇, (CR₁₀R₂₀)_nN(R_10′

)S(O)₂R₇, (CR₁₀R₂₀)_nNR_eR_e′

, (CR₁₀R₂₀)_nNR_eR_e′

C_1-4-alkylNR_eR_e′

, (CR₁₀R₂₀)_nCN, (CR₁₀R₂₀)_nS(O)₂NR_eR_e′

, (CR₁₀R₂₀)_nC(Z)R₆, (CR₁₀R₂₀)_nOC(Z)R₆, (CR₁₀R₂₀)_nC(Z)OR₆, (CR₁₀R₂₀)_nC(Z)NR_eR_e′

, (CR₁₀R₂₀)_nN(R_10′

)C(Z)R₆, (CR₁₀R₂₀)_nN(R_10′

)C(═

N(R_10′

))NR_eR_e′

, (CR₁₀R₂₀)_nC(═

NOR₆)NR_eR_e′

, (CR₁₀R₂₀)_nOC(Z)NR_eR_e′

, (CR₁₀R₂₀)_nN(R_10′

)C(Z)NR_eR_e′

, or (CR₁₀R₂₀)_nN(R_10′

)C(Z)OR₇; and

wherein R_e are R_e′

are each independently selected at each occurrence from hydrogen, C_1-4 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkylC_1-4alkyl, aryl, aryl-C_1-4 alkyl, heteroaryl or a heteroaryl C_1-4 alkyl moiety, which moieties, excluding hydrogen may be optionally substituted;

or R_e and R_e′

together with the nitrogen which they are attached form an optionally substituted heterocyclic ring of 4 to 7 members, which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR₉;

R₆ is independently selected at each occurrence from hydrogen, C_1-10 alkyl, C_3-7 cycloalkyl, heterocyclyl, heterocyclyl C_1-10alkyl, aryl, arylC_1-10 alkyl, heteroaryl or heteroarylC_1-10 alkyl, wherein each of these moieties, excluding hydrogen are optionally substituted;

R₇ is independently selected at each occurrence from C_1-6alkyl, aryl, arylC_1-6alkyl, heterocyclic, heterocyclylC_1-6 alkyl, heteroaryl, or heteroarylC_1-6alkyl moiety, and wherein each of these moieties may be optionally substituted; and

n is independently selected at each occurrence from 0 or an integer having a value of 1 to 10.

18. The compound according to claim 17 wherein X is (CH₂)_n′

N(R_2′

)(R_2″

);

R₂ is an optionally substituted C_1-10 alkyl moiety, and the alkyl is substituted by (CR₁₀R₂₀)_nNR_eR_e′

or (CR₁₀R₂₀)_nNR_eR_e′

C_1-4-alkyl NR_eR_e′

.

19. The compound according to claim 18 wherein R_e are R_e′

are independently selected at each occurrence from hydrogen, or C_1-4 alkyl.

20. The compound according to claim 10 wherein X moiety is 3-(diethylamino)propylamino, 3-(dimethylamino)propyl(methyl)amino, 3-(dimethylamino)propyl(methyl)amino, 2-(dimethylamino)ethylamino, 1-methylethyl)amino-propylamino, (1,1-dimethylethyl)aminopropylamino, (1-methylethyl)aminoethylamino, 2-(methylamino)ethylamino, 2-aminoethyl(methyl)amino, or a 2-(dimethylamino)ethyl(methyl)amino.

21. The compound according to claim 1 wherein R₂ is optionally substituted one or more times, independently at each occurrence, with C_1-10 alkyl, halo-substituted C_1-10 alkyl, C_2-10 alkenyl, C_2-10 alkynyl, C_3-7 cycloalkyl, C_3-7cycloalkylC_1-10alkyl, C_5-7cycloalkenyl, C_5-7 cycloalkenyl C_1-10 alkyl, halogen, —

C(O), cyano, nitro, (CR₁₀R₂₀)_nOR₆, (CR₁₀R₂₀)_nSH, (CR₁₀R₂₀)_nS(O)_mR₇, (CR₁₀R₂₀)_nN(R_10′

)S(O)₂R₇, (CR₁₀R₂₀)_nNR_eR_e′

, (CR₁₀R₂₀)_nNR_eR_e′

C_1-4alkyl NR_eR_e′

, (CR₁₀R₂₀)_nCN, (CR₁₀R₂₀)_nS(O)₂NR_eR_e′

, (CR₁₀R₂₀)_nC(Z)R₆, (CR₁₀R₂₀)_nOC(Z)R₆, (CR₁₀R₂₀)_nC(Z)OR₆, (CR₁₀R₂₀)_nC(Z)NR_eR_e′

, (CR₁₀R₂₀)_nN(R_10′

)C(Z)R₆, (CR₁₀R₂₀)_nN(R_10′

)C(═

N(R_10′

))NR_eR_e′

, (CR₁₀R₂₀)_nC(═

NOR₆)NR_eR_e′

, (CR₁₀R₂₀)_nOC(Z)NR_eR_e′

, (CR₁₀R₂₀)_nN(R_10′

)C(Z)NR_eR_e′

, or (CR₁₀R₂₀)_nN(R_10′

)C(Z)OR₇; and

wherein

R_e are R_e′

are each independently selected at each occurrence from hydrogen, C_1-4 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkylC_1-4alkyl, aryl, aryl-C_1-4 alkyl, heteroaryl or a heteroaryl C_1-4 alkyl moiety, which moieties, excluding hydrogen may be optionally substituted;

or R_e and R_e′

together with the nitrogen which they are attached form an optionally substituted heterocyclic ring of 4 to 7 members, which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR₉;

R₆ is independently selected at each occurrence from hydrogen, C_1-10 alkyl, C_3-7 cycloalkyl, heterocyclyl, heterocyclyl C_1-10alkyl, aryl, arylC_1-10 alkyl, heteroaryl or heteroarylC_1-10 alkyl, wherein each of these moieties, excluding hydrogen are optionally substituted;

R₇ is independently selected at each occurrence from C_1-6alkyl, aryl, arylC_-6alkyl, heterocyclic, heterocyclylC_1-6 alkyl, heteroaryl, or heteroarylC_1-6alkyl moiety, and wherein each of these moieties may be optionally substituted; and

n is independently selected at each occurrence from 0 or an integer having a value of 1 to 10.

22. The compound according to claim 21 wherein R₂ is a C_1-10 alkyl optionally substituted by (CR₁₀R₂₀)_nC(Z)OR₆, (CR₁₀R₂₀)_nOR₆, or (CR₁₀R₂₀)_nNR₄R₁₄.

23. The compound according to claim 1 wherein R₂ is the (CR₁₀R₂₀)_q′

X₁(CR₁₀R₂₀)_qC(A₁)(A₂)(A₃), or (CR₁₀R₂₀)_q′

C(A₁)(A₂)(A₃), and X₁ is oxygen or N(R₁₀).

24. The compound according to claim 23 wherein R₂ is (CR₁₀R₂₀)_q′

X₁(CR₁₀R₂₀)_qC(A₁)(A₂)(A₃), at least one of A₁, A₂ or A₃ is substituted by (CR₁₀R₂₀)_nOR₆, q is 0 or 1, and q′

is 0.

25. The compound according to claim 1 wherein R₃ is an optionally substituted C_1-10 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkylalkyl, or aryl.

26. The compound according to claim 25 wherein R₃ is optionally substituted one or more times, independently at each occurrence, with wherein these moieties are all optionally substituted one or more times, independently at each occurrence, by hydrogen, halogen, nitro, C_1-10 alkyl, halo-substituted C_1-10 alkyl, C_2-10 alkenyl, C_2-10alkynyl, C_3-7cycloalkyl, C_3-7cycloalkylC_1-10 alkyl, C_5-7cycloalkenyl, C_5-7cycloalkenylC_1-10 alkyl, (CR₁₀R₂₀)_nOR₆, (CR₁₀R₂₀)_nSH, (CR₁₀R₂₀)_nS(O)_mR₇, (CR₁₀R₂₀)_nN(R_10′

)S(O)₂R₇, (CR₁₀R₂₀)_nNR₁₆R₂₆, (CR₁₀R₂₀)_nCN, (CR₁₀R₂₀)_nS(O)₂NR₁₆R₂₆, (CR₁₀R₂₀)_nC(Z)R₆, (CR₁₀R₂₀)_nOC(Z)R₆, (CR₁₀R₂₀)_nC(Z)OR₆, (CR₁₀R₂₀)_nC(Z)NR₁₆R₂₆, (CR₁₀R₂₀)_nN(R_10′

)C(Z)R₆, (CR₁₀R₂₀)_nN(R_10′

)C(═

N(R_10′

))NR₁₆R₂₆, (CR₁₀R₂₀)_nOC(Z)NR₁₆R₂₆, (CR₁₀R₂₀)_nN(R_10′

)C(Z)NR₁₆R₂₆, or (CR₁₀R₂₀)_nN(R_10′

)C(Z)OR₇; and

wherein

R₁₆ and R₂₆ are each independently selected at each occurrence from hydrogen, or C_1-4 alkyl;

or the R₁₆ and R₂₆ together with the nitrogen which they are attached form an unsubstituted or substituted heterocyclic ring of 4 to 7 members, which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR_9′

,

R₇ is independently selected at each occurrence from C_1-6alkyl, aryl, arylC_1-6alkyl, heterocyclic, heterocyclylC_1-6 alkyl, heteroaryl, or heteroarylC_1-6alkyl moiety, and wherein each of these moieties may be optionally substituted; and

n is 0 or an integer having a value of 1 to 10.

27. The compound according to claim 26 wherein the R₃ optional substituent is independently selected at each occurrence from halogen, C_1-10 alkyl, (CR₁₀R₂₀)_nOR₆, (CR₁₀R₂₀)_nNR₁₆R₂₆, or halo-substituted C_1-10 alkyl.

28. The compound according to claim 26 wherein R₃ is a phenyl substituted one or more times by independently at each occurrence by fluorine, chlorine, hydroxy, methoxy, amino, methyl, or trifluoromethyl.

29. The compound according to claim 1 wherein R₃ is a 2,6-difluorophenyl.

30. The compound according to claim 1 wherein R₃ is an aryl ring substituted 1 to 4 times, independently at each occurrence by halogen, C_1-10 alkyl, (CR₁₀R₂₀)_nOR₆, (CR₁₀R₂₀)_nNR₁₆R₂₆, or halo-substituted C_1-10 alkyl;

R_1′

is independently selected at each occurrence from halogen, C_1-4 alkyl, or halo-substituted-C_1-4 alkyl;

g is 0, or 1;

R₁ is C(Z)N(R_10′

)(CR₁₀R₂₀)_vR_b;

v is 0;

R_b is thiazolyl;

Z is oxygen, R_10′

is hydrogen;

X is (CH₂)_n′

NR₄R₁₄;

one of R₄ and R₁₄ is an optionally substituted heteroaryl C_1-4 alkyl, and the other of R₄ and R₁₄ is hydrogen.

31. A pharmaceutical composition comprising an effective amount of a compound, or pharmaceutically acceptable salt, solvate or physiologically functional derivative, according to claim 1, in admixture with one or more pharmaceutically acceptable carriers, diluents or excipients, for administration by intravenous, intramuscular, subcutaneous, intranasal, oral inhalation, intrarectal, intravaginal or intraperitoneal means.