Inhibitors of tyrosine kinases and uses thereof

1. A method for treating an autoimmune disease, a heteroimmune condition or disease, or an inflammatory disease in a subject comprising administering to a subject in need thereof a therapeutically effective amount of the compound of Formula (III):

wherein:

R a and R b are each independently selected from among H, halogen, CN, NO 2 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and C 1 -C 4 alkoxy;

T is 1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-2,7-ylene, or 1,7-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-2,6-ylene;

L is —X 250a —Y 250 — or —Y 250 —X 250a —, wherein,

X 250a is a substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 5 -C 8 cycloalkenyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 haloalkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, or substituted or unsubstituted C 2 -C 6 haloalkynyl;

Y 250 is a bond, —O—, —S(═O)—, —S(═O) 2 —, —C(═O)—, —NR 45 —, —NH—, —NHC(═O)—, —NR 45 C(═O)—, —NR 45 C(═O)NR 45 —, —C(═O)NH—, —C(═O)NR 45 —, —OC(═O)—, —C(═O)O—, —NHSO 2 —, —NR 45 SO 2 —, —SO 2 NH—, —SO 2 NR 45 —, —C(R 45 )═NO—, —CH═NO—, —ON═CH—, aryl, —NHC(═O)O—, —OC(═O)NH—, —NR 45 C(═O)O—, or —OC(═O)NR 45 —;

where each R 45 is independently selected from among hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl;

M is N or CH;

W is

E is oxygen or sulfur;

R 100 is halogen, —OH, or an optionally substituted group selected from among C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, phenyl, C 1 -C 4 alkyl(phenyl), C 3 -C 8 cycloalkyl, C 1 -C 4 alkyl(C 3 -C 8 cycloalkyl), C 2 -C 8 heterocycloalkyl, C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl), C 1 -C 6 alkoxy, C 1 -C 6 alkenyloxy, C 1 -C 6 alkynyloxy, or —NR 102a R 102b ;

R 102a and R 102b are independently hydrogen, or an option ally substituted group selected from among C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, aralkyl, C 3 -C 8 cycloalkyl, C 1 -C 4 alkyl(C 3 -C 8 cycloalkyl), C 2 -C 8 heterocycloalkyl, and C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl);

R 200 is an optionally substituted group selected from among C 2 -C 10 acyl, aryl, C 1 -C 6 alkylsulfonyl, C 2 -C 6 alkenylsulfonyl, arylsulfonyl, C 1 -C 10 alkoxycarbonyl, aminosulfonyl, C 1 -C 6 alkylaminosulfonyl, and di(C 1 -C 6 alkyl)aminosulfonyl;

R 350a is hydrogen, a substituted or unsubstituted C 1 -C 6 alkyl, a substituted or unsubstituted C 2 -C 6 alkenyl, a substituted or unsubstituted C 2 -C 6 alkynyl, a substituted or unsubstituted C 1 -C 6 haloalkyl, a substituted or unsubstituted C 2 -C 6 haloalkenyl, or a substituted or unsubstituted C 2 -C 6 haloalkynyl;

n is 1;

or a pharmaceutically acceptable salt, or a pharmaceutically acceptable prodrug thereof.

2. The method of claim 1 , wherein:

T is 1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5]isoquinolin-2,7-ylene substituted at the 2 position with

and substituted at the 7 position with

3. The method of claim 2 , wherein

Y 250 is a bond, —O—, —S(═O)—, —S(═O) 2 —, —C(═O)—, —NH—, —NHC(═O)—, —NHC(═O)NH—, —C(═O)NH—, —OC(═O)—, —C(═O)O—, —NHSO 2 —, —SO 2 NH—, —NHC(═O)O—, or —OC(═O)NH—;

E is O;

R 350a is hydrogen, a substituted or unsubstituted C 1 -C 6 alkyl, or a substituted or unsubstituted C 1 -C 6 haloalkyl;

X 250a is a substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 haloalkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, or substituted or unsubstituted C 2 -C 6 haloalkynyl; and

n is 1.

4. The method of claim 3 , wherein compound has a structure selected from among:

5. The method of claim 4 , wherein:

R 100 is halogen, or an optionally substituted group selected from among C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, phenyl, C 1 -C 4 alkyl(phenyl), C 3 -C 8 cycloalkyl, C 1 -C 4 alkyl(C 3 -C 8 cycloalkyl), C 2 -C 8 heterocycloalkyl, and C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl);

R 200 is an optionally substituted group selected from among C 2 -C 10 acyl, aryl, C 1 -C 6 alkylsulfonyl, C 2 -C 6 alkenylsulfonyl, arylsulfonyl, C 1 -C 10 alkoxycarbonyl, aminosulfonyl, C 1 -C 6 alkylaminosulfonyl, and di(C 1 -C 6 alkyl)aminosulfonyl.

6. The method of claim 5 , wherein:

R 350a is hydrogen;

Y 250 is a bond, —C(═O)—, —NHC(═O)—, —C(═O)NH—.

7. The method of claim 6 , wherein L is selected from among: C 1 -C 4 alkyl,

8. The method of claim 7 , wherein the compound has a structure of Formula (IIIc).

9. The method of claim 8 , wherein:

L is C 1 -C 4 alkyl or

and

R 200 is an optionally substituted group selected from among C 2 -C 10 acyl, aryl, C 1 -C 6 alkylsulfonyl, C 2 -C 6 alkenylsulfonyl, arylsulfonyl, C 1 -C 10 alkoxycarbonyl, aminosulfonyl, C 1 -C 6 alkylaminosulfonyl, and di(C 1 -C 6 alkyl)aminosulfonyl.

10. The method of claim 1 , wherein:

T is 1,7-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-2,6-ylene substituted at the 2 position with

and substituted at the 6 position with

11. The method of claim 10 , wherein

Y 250 is a bond, —O—, —S(═O)—, —S(═O) 2 —, —C(═O)—, —NH—, —NHC(═O)—, —NHC(═O)NH—, —C(═O)NH—, —OC(═O)—, —C(═O)O—, —NHSO 2 —, —SO 2 NH—, —NHC(═O)O—, or —OC(═O)NH—;

E is O;

R 350a is hydrogen, or a substituted or unsubstituted C 1 -C 6 alkyl;

X 250a is a substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 haloalkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, or substituted or unsubstituted C 2 -C 6 haloalkynyl; and

n is 1.

12. The method of claim 11 , wherein compound has a structure selected from among:

13. The method of claim 12 , wherein:

R 100 is halogen, or an optionally substituted group selected from among C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, phenyl, C 1 -C 4 alkyl(phenyl), C 3 -C 8 cycloalkyl, C 1 -C 4 alkyl(C 3 -C 8 cycloalkyl), C 2 -C 8 heterocycloalkyl, and C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl);

R 200 is an optionally substituted group selected from among C 2 -C 10 acyl, aryl, C 1 -C 6 alkylsulfonyl, C 2 -C 6 alkenylsulfonyl, arylsulfonyl, C 1 -C 10 alkoxycarbonyl, aminosulfonyl, C 1 -C 6 alkylaminosulfonyl, and di(C 1 -C 6 alkyl)aminosulfonyl.

14. The method of claim 13 , wherein:

R 350a is hydrogen;

Y 250 is —C(═O)—; and

X 250a is a substituted or unsubstituted C 1 -C 6 alkyl.

15. The method of claim 14 , wherein L is

16. The method of claim 15 , wherein the compound has a structure of Formula (IIIb).

17. The method of claim 1 , wherein the compound is selected from:

2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(4-methyl-4-oxo-4λ 5 [1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 1);

2-(2,6-dichloro-phenylamino)-1,6-dimethyl-7-[3-(4-methyl-4-oxo-4λ 5 [1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 2);

2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-phenyl-4λ 5 -[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 3);

2-(3-fluoro-6-methylphenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-phenyl-4λ 5 -[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 4);

2-(2,6-dichlorophenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-phenyl-4λ 5 -[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 5);

2-(2,4-dichloro-6-methylphenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-phenyl-4λ 5 -[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 6);

2-(3-fluoro-6-methylphenylamino)-1,6-dimethyl-7-{2-[(4-oxo-4-phenyl-4λ 5 -[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 7);

2-(2,4-dichloro-6-methylphenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-phenyl-4λ 5 -[1,4]azaphosphinan-1-yl)-propyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 8);

2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-phenyl-4λ 5 -[1,4]azaphosphinan-1-yl)-propyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 9);

2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-(4-fluorophenyl)-4λ 5 -[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h] isoquinolin-9-one (Compound 10);

2-(3-fluoro-6-methylphenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-(4-methoxyphenyl)-4λ 5 -[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h] isoquinolin-9-one (Compound 11);

2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-{3-[4-(4-fluorophenylmethyl)-4-oxo-4λ 5 -[1,4]azaphosphinan-1-yl]-propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 12);

2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-{3-[4-(cyclopropylmethyl)-4-oxo-4λ 5 -[1,4]azaphosphinan-1-yl]-propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 13);

2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-{3-[4-(cyclopropyl)-4-oxo-4λ 5 -[1,4]azaphosphinan-1-yl]-propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 14);

2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-{3-[(1-oxo-1-methyl-1λ 5 -phosphinan-4-yl)-carbonylamino]propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 15);

2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-{3-[(1-oxo-1-trans-phenyl-1λ 5 -phosphinan-4-yl)-carbonylamino]propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 16);

2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-7-{3-[(1-oxo-1-cis-phenyl-1λ 5 -phosphinan-4-yl)-carbonylamino]propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 17);

2-(2,6-dichlorophenylamino)-1,6-dimethyl-7-[3-(N-phenylpiperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 18);

2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-phenylpiperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 19);

2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-(4-chlorophenyl)-piperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 20);

2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-methylcarbonylpiperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 21);

2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-phenylcarbonylpiperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 22);

2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-methylsulfonylpiperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 24);

2-(3-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-methylsulfonylpiperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 25);

2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-(2,6-dichlorophenylmethyl)-piperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 28);

2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-phenylsulfonylpiperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 29);

2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-(4-fluorophenyl)-piperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 30);

2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-tert-butyloxycarbonylpiperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 31);

2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N—(N,N-dimethylaminosulfonyl)-piperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 32);

2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-ethylcarbonylpiperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 33);

2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-(isopropylsulfonyl)-piperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 34);

2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-(ethylsulfonyl)-piperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 35); and

2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-isopropylcarbonylpiperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 36).

18. The method of claim 1 , wherein the autoimmune disease is selected from inflammatory bowel disease, arthritis, lupus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease Sjögren's syndrome, multiple sclerosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitisis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, coeliac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behçet's disease, chronic fatigue, dysautonomia, endometriosis, interstitial cystitis, neuromyotonia, scleroderma, or vulvodynia.

19. The method of claim 1 , wherein the heteroimmune condition or disease is selected from graft versus host disease, transplantation, transfusion, anaphylaxis, allergy, type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, or atopic dermatitis.

20. The method of claim 1 , wherein the inflammatory disease is selected from asthma, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, or vulvitis.