BENZOTHIOPHENE INHIBITORS OF RHO KINASE

• US 20080021026A1
• Filed: 07/20/2007
• Published: 01/24/2008
• Est. Priority Date: 07/20/2006
• Status: Abandoned Application

• Current Assignee: Kalypsys Inc
• Original Assignee: Allen Borchardt, Elizabeth Gardiner, James Malecha, Mehmet Kahraman, Robert B. Davis, Stewart Noble, Thomas Prins, Travis Cook
• Inventors: Borchardt, Allen, Gardiner, Elisabeth, Kahraman, Mehmet, Noble, Stewart, Davis, Robert, Cook, Travis, Malecha, James, Prins, Thomas
• Application Number:
  US11/780,834
• Publication Number:
  US 20080021026A1
• Time in Patent Office: Days
• US Class Current: 514/233.5
• CPC Class Codes: A61K 31/395 having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 Antimigraine agents
• 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 27/06 Antiglaucoma agents or miotics
• 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 3/10 : for hyperglycaemia, e.g. antidiabetics
• 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 37/06 : 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: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/06 : Antianaemics
• 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 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 409/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems

Abstract

The present invention relates to compounds and methods which may be useful as inhibitors of Rho kinase for the treatment or prevention of disease.

Claims

1. A method of inhibition of Rho kinase comprising contacting Rho kinase with a compound of structural Formula I

or a salt, ester, or prodrug thereof, wherein:

A is optionally substituted heteroaryl;

G¹ is optionally substituted fused bicyclic heteroaryl;

G² is selected from the group consisting of (CR^aR^b)_mZ(CR^cR^d)_p and null;

m and p are independently 0, 1, 2, 3, or 4;

Z is selected from the group consisting of O, N(R¹), S(O)_n, N(R^e)CO, CON(R^e), N(R^e)SO₂, SO₂N(R^e), C(O), optionally substituted cycloalkyl, and null;

R^e is selected from the group consisting of hydrogen and optionally substituted C₁-C₄ alkyl;

n is 0, 1 or 2;

R^a, R^b, R^c, and R^d are independently selected from the group consisting of hydrogen, alkyl, amino, aminoalkyl, amidoalkyl, aminoalkylcarboxyl, carboxylalkyl, halo, heterocycloalkyl, heterocycloalkylalkyl, hydroxyalkyl, heteroarylalkyl and heterocycloalkylalkylcarboxyl;

G³ is selected from the group consisting of lower alkyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl, heteroaryl, lower alkoxy, lower alkylthio, acyl, carboxyl, sulfonamide, hydroxy and null, any of which may be optionally substituted;

G⁴ is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, amino, aminoalkyl, amido, amidoalkyl, alkylamido, aminoalkylcarboxyl, carboxyl, alkylcarboxyl, cycloalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, heterocycloalkylalkyl, heterocycloalkylalkoxy, heterocycloalkylalkylcarboxy, heterocycloalkylalkylamido, aryl, arylalkoxy, arylamido, arylalkyl, arylacyl, arylcarboxy, heteroarylalkyl, and urea, any of which may be optionally substituted; and

R¹ is selected from the group consisting of alkyl, alkylcarbonyl, alkylene, alkynyl, amino, alkylamino, carbonyl, cycloalkyl, ester, heterocycloalkyl, heterocycloalkylalkyl, heteroalkyl, and hydrogen, any of which may be optionally substituted.

2. A method of inhibition of Rho kinase comprising contacting Rho kinase with a compound selected from the group consisting of Examples 1 to 571.

3. A method of treatment of a Rho kinase-mediated disease, in a patient in need of such treatment, comprising the administration of a therapeutically effective amount of a compound of structural Formula I

or a salt, ester, or prodrug thereof, wherein:

A is optionally substituted heteroaryl;

G¹ is optionally substituted fused bicyclic heteroaryl;

G² is selected from the group consisting of (CR^aR^b)_mZ(CR^cR^d)_p and null;

m and p are independently 0, 1, 2, 3, or 4;

Z is selected from the group consisting of O, N(R¹), S(O)_n, N(R^e)CO, CON(R^e), N(R^e)SO₂, SO₂N(R^e), C(O), optionally substituted cycloalkyl, and null;

R^e is selected from the group consisting of hydrogen and optionally substituted C₁-C₄ alkyl;

n is 0, 1 or 2;

R^a, R^b, R^c, and R^d are independently selected from the group consisting of hydrogen, alkyl, amino, aminoalkyl, amidoalkyl, aminoalkylcarboxyl, carboxylalkyl, halo, heterocycloalkyl, heterocycloalkylalkyl, hydroxyalkyl, heteroarylalkyl and heterocycloalkylalkylcarboxyl;

G³ is selected from the group consisting of lower alkyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl, heteroaryl, lower alkoxy, lower alkylthio, acyl, carboxyl, sulfonamide, hydroxy and null, any of which may be optionally substituted;

G⁴ is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, amino, aminoalkyl, amido, amidoalkyl, alkylamido, aminoalkylcarboxyl, carboxyl, alkylcarboxyl, cycloalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, heterocycloalkylalkyl, heterocycloalkylalkoxy, heterocycloalkylalkylcarboxy, heterocycloalkylalkylamido, aryl, arylalkoxy, arylamido, arylalkyl, arylacyl, arylcarboxy, heteroarylalkyl, and urea, any of which may be optionally substituted; and

R¹ is selected from the group consisting of alkyl, alkylcarbonyl, alkylene, alkynyl, amino, alkylamino, carbonyl, cycloalkyl, ester, heterocycloalkyl, heterocycloalkylalkyl, heteroalkyl, and hydrogen, any of which may be optionally substituted.

4. The method as recited in claim 3 wherein said Rho kinase-mediated disease is selected from the group consisting of angina, coronary artery vasospasm, myocardial infarction, coronary ischemia, congestive heart failure, cardiac allograft vasculopathy, vein graft disease and vascular restenosis, ischemic reperfusion injury, transplant reperfusion injury, cerebral artery vasospasm, stroke, cerebral ischemia, essential hypertension, pulmonary hypertension, renal hypertension, a secondary hypertensive disorder, atherosclerosis, bronchial asthma, an acute or chronic obstructive pulmonary disease, an acute or chronic pulmonary inflammatory disease, erectile dysfunction, a neurodegenerative disorder, Alzheimer'"'"'s disease, multiple sclerosis, brain or spinal cord injury, a disease or trauma-related neuropathy, neuropathic pain, an autoimmune disease, a chronic musculoskeletal inflammatory disease, rheumatoid arthritis, osteoarthritis, a chronic inflammatory bowel disease, Crohn'"'"'s disease, ulcerative colitis, acute or chronic inflammatory pain, osteoporosis, a bone disorder, cancer, a disease of pathological angiogenesis, and an ophthalmic disease.

5. The method as recited in claim 4, wherein said Rho kinase-mediated disease is an ophthalmic disease.

6. The method as recited in claim 5, wherein said ophthalmic disease is selected from the group consisting of elevated intraocular pressure and glaucoma.

7. A method of treatment of a Rho kinase-mediated disease, in a patient in need of such treatment, comprising the administration of a therapeutically effective amount of a compound selected from the group consisting of Examples 1 to 571.

8. A method of treatment of a Rho kinase-mediated disease comprising the administration of

a. a therapeutically effective amount of a compound of structural Formula I

or a salt, ester, or prodrug thereof, wherein:

A is optionally substituted heteroaryl;

G¹ is optionally substituted fused bicyclic heteroaryl;

G² is selected from the group consisting of (CR^aR^b)_mZ(CR^cR^d)_p and null;

m and p are independently 0, 1, 2, 3, or 4;

Z is selected from the group consisting of O, N(R¹), S(O)_n, N(R^e)CO, CON(R^e), N(R^e)SO₂, SO₂N(R^e), C(O), optionally substituted cycloalkyl, and null;

R^e is selected from the group consisting of hydrogen and optionally substituted C₁-C₄ alkyl;

n is 0, 1 or 2;

R^a, R^b, R^c, and R^d are independently selected from the group consisting of hydrogen, alkyl, amino, aminoalkyl, amidoalkyl, aminoalkylcarboxyl, carboxylalkyl, halo, heterocycloalkyl, heterocycloalkylalkyl, hydroxyalkyl, heteroarylalkyl and heterocycloalkylalkylcarboxyl;

G³ is selected from the group consisting of lower alkyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl, heteroaryl, lower alkoxy, lower alkylthio, acyl, carboxyl, sulfonamide, hydroxy, and null, any of which may be optionally substituted;

G⁴ is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, amino, aminoalkyl, amido, amidoalkyl, alkylamido, aminoalkylcarboxyl, carboxyl, alkylcarboxyl, cycloalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, heterocycloalkylalkyl, heterocycloalkylalkoxy, heterocycloalkylalkylcarboxy, heterocycloalkylalkylamido, aryl, arylalkoxy, arylamido, arylalkyl, arylacyl, arylcarboxy, heteroarylalkyl, and urea, any of which may be optionally substituted; and

R¹ is selected from the group consisting of alkyl, alkylcarbonyl, alkylene, alkynyl, amino, alkylamino, carbonyl, cycloalkyl, ester, heterocycloalkyl, heterocycloalkylalkyl, heteroalkyl, and hydrogen, any of which may be optionally substituted; and

b. another therapeutic agent.

9. A method for:

a. reducing apoptosis of human embryonic stem cells;

b. increasing survival of human embryonic stem cells;

c. increasing cloning efficiency of human embryonic stem cells after gene transfer; and

d. enhancing differentiation of cultured human embryonic stem cells any one of said methods comprising the contacting of at least one human embryonic stem cell with an effective amount of a compound of structural Formula I

or a salt, ester, or prodrug thereof, wherein;

A is optionally substituted heteroaryl;

G¹ is optionally substituted fused bicyclic heteroaryl;

G² is selected from the group consisting of (CR^aR^b)_mZ(CR^cR^d)_p and null;

m and p are independently 0, 1, 2, 3, or 4;

Z is selected from the group consisting of O, N(R¹), S(O)_n, N(R^e)CO, CON(R^e), N(R^e)SO₂, SO₂N(R^e), C(O), optionally substituted cycloalkyl, and null;

R^e is selected from the group consisting of hydrogen and optionally substituted C₁-C₄ alkyl;

n is 0, 1 or 2;

R^a, R^b, R^c, and R^d are independently selected from the group consisting of hydrogen, alkyl, amino, aminoalkyl, amidoalkyl, aminoalkylcarboxyl, carboxylalkyl, halo, heterocycloalkyl, heterocycloalkylalkyl, hydroxyalkyl, heteroarylalkyl and heterocycloalkylalkylcarboxyl;

G³ is selected from the group consisting of lower alkyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl, heteroaryl, lower alkoxy, lower alkylthio, acyl, carboxyl, sulfonamide, hydroxy, and null, any of which may be optionally substituted;

G⁴ is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, amino, aminoalkyl, amido, amidoalkyl, alkylamido, aminoalkylcarboxyl, carboxyl, alkylcarboxyl, cycloalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, heterocycloalkylalkyl, heterocycloalkylalkoxy, heterocycloalkylalkylcarboxy, heterocycloalkylalkylamido, aryl, arylalkoxy, arylamido, arylalkyl, arylacyl, arylcarboxy, heteroarylalkyl, and urea, any of which may be optionally substituted; and

R¹ is selected from the group consisting of alkyl, alkylcarbonyl, alkylene, alkynyl, amino, alkylamino, carbonyl, cycloalkyl, ester, heterocycloalkyl, heterocycloalkylalkyl, heteroalkyl, and hydrogen, any of which may be optionally substituted.

10. A compound of structural Formula I:

or a salt, ester, or prodrug thereof, wherein;

A is optionally substituted heteroaryl;

G¹ is optionally substituted fused bicyclic heteroaryl;

G² is selected from the group consisting of (CR^aR^b)_mZ(CR^cR^d)_p and null;

m and p are independently 0, 1, 2, 3, or 4;

Z is selected from the group consisting of O, N(R¹), S(O)_n, N(R^e)CO, CON(R^e), N(R^e)SO₂, SO₂N(R^e), C(O), optionally substituted cycloalkyl, and null;

R^e is selected from the group consisting of hydrogen and optionally substituted C₁-C₄ alkyl;

n is 0, 1 or 2;

R^a, R^b, R^c, and R^d are independently selected from the group consisting of hydrogen, alkyl, amino, aminoalkyl, amidoalkyl, aminoalkylcarboxyl, carboxylalkyl, halo, heterocycloalkyl, heterocycloalkylalkyl, hydroxyalkyl, heteroarylalkyl and heterocycloalkylalkylcarboxyl;

G³ is selected from the group consisting of lower alkyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl, heteroaryl, lower alkoxy, lower alkylthio, acyl, carboxyl, sulfonamide, hydroxy, and null, any of which may be optionally substituted;

G⁴ is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, amino, aminoalkyl, amido, amidoalkyl, alkylamido, aminoalkylcarboxyl, carboxyl, alkylcarboxyl, cycloalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, heterocycloalkylalkyl, heterocycloalkylalkoxy, heterocycloalkylalkylcarboxy, heterocycloalkylalkylamido, aryl, arylalkoxy, arylamido, arylalkyl, arylacyl, arylcarboxy, heteroarylalkyl, and urea, any of which may be optionally substituted; and

R¹ is selected from the group consisting of alkyl, alkylcarbonyl, alkylene, alkynyl, amino, alkylamino, carbonyl, cycloalkyl, ester, heterocycloalkyl, heterocycloalkylalkyl, heteroalkyl, and hydrogen, any of which may be optionally substituted.

11. The compound as recited in claim 10, or a salt, ester, or prodrug thereof, wherein:

A is selected from the group consisting of optionally substituted monocyclic 5 to 6 membered heteroaryl containing at least one ring nitrogen, or an optionally substituted bicyclic heteroaryl which comprises a five-membered ring fused to a six-membered ring and which contains at least one ring nitrogen.

12. The compound as recited in claim 11, or a salt, ester, or prodrug thereof, wherein G¹ is selected from the group consisting of:

X¹ is N or C(R⁶);

X² is N or C(R⁷);

X³ is N or C(R⁸);

X⁴ is N or C(R⁹);

X⁵ is N or C(R¹⁰);

X⁶ is N or C(R¹¹);

X⁷ is N or C(R¹²);

X⁸ is N or C(R¹³);

X⁹ is N or C(R¹⁴);

X¹⁰ is N or C(R¹⁵);

Y is O or S; and

R⁴-R¹⁵ are independently selected from the group consisting of hydrogen, halogen, lower alkyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, lower alkoxy, lower alkylthio, lower haloalkyl, acyl, amino, carboxyl, cyano, and nitro, any of which may be optionally substituted.

13. The compound as recited in claim 12, or a salt, ester, or prodrug thereof, wherein A is selected from the group consisting of

any of which may be optionally substituted.

14. The compound as recited in claim 13, or a salt, ester, or prodrug thereof, wherein

G² is (CR^aR^b)_mZ(CR^cR^d)_p;

m and p are independently 0, 1, or 2;

Z is selected from the group consisting of O, N(R¹), S(O)_n, N(R^e)CO, CON(R^e), C(O), and null;

R^e is selected from the group consisting of hydrogen and optionally substituted C₁-C₄ alkyl; and

n is 0 or 2.

15. The compound as recited in claim 14, or a salt, ester, or prodrug thereof, wherein G¹ is:

16. The compound as recited in claim 15, or a salt, ester, or prodrug thereof, wherein A is selected from the group consisting of

17. The compound as recited in claim 16, or a salt, ester, or prodrug thereof, having structural Formula II

or a salt, ester, or prodrug thereof, wherein:

Y is O or S;

G² is (CR^aR^b)_mZ(CR^cR^d)_p;

m and p are independently 0, 1, or 2;

Z is selected from the group consisting of O, N(R¹), S(O)_n, N(R^e)CO, CON(R^e), C(O), and null;

R^e is selected from the group consisting of hydrogen and optionally substituted C₁-C₄ alkyl; and

n is 0 or 2;

G³ is selected from the group consisting of lower alkyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl, heteroaryl, lower alkoxy, lower alkylthio, acyl, carboxyl, sulfonamide, hydroxy, and null, any of which may be optionally substituted;

G⁴ is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, amino, aminoalkyl, amido, amidoalkyl, alkylamido, aminoalkylcarboxyl, carboxyl, alkylcarboxyl, cycloalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, heterocycloalkylalkyl, heterocycloalkylalkoxy, heterocycloalkylalkylcarboxy, heterocycloalkylalkylamido, aryl, arylalkoxy, arylamido, arylalkyl, arylacyl, arylcarboxy, heteroarylalkyl, and urea, any of which may be optionally substituted;

R¹⁶ is selected from the group consisting of lower alkenyl, alkynyl, lower alkyl, alkylthio, haloalkyl, heteroalkyl, hydroxyalkyl, halogen, and hydrogen; and

R¹⁷-R¹⁹ are independently selected from the group consisting of acyl, lower alkenyl, alkynyl, lower alkoxy, lower alkoxyalkyl, lower alkyl, alkylthio, amido, amino, aminoalkyl, aminocarbonyl, carboxyl, haloalkyl, hydroxyalkyl and hydrogen, any of which may be optionally substituted.

18. The compound as recited in claim 17, or a salt, ester, or prodrug thereof, wherein:

Y is S;

R¹⁶ is selected from the group consisting of lower alkyl and hydrogen; and

R¹⁷-R¹⁹ are all hydrogen.

19. The compound as recited in claim 18, or a salt, ester, or prodrug thereof, wherein G³ is selected from the group consisting of aryl, heterocycloalkyl, heteroaryl, any of which may be optionally substituted.

20. The compound as recited in claim 19, or a salt, ester, or prodrug thereof, wherein either

m and p are both 0;

and

Z is selected from the group consisting of O, NH, S, and C(O);

or

m is 1;

Z is null; and

p is 0.

21. The compound as recited in claim 20, or a salt, ester, or prodrug thereof, wherein R¹⁶ is selected from the group consisting of methyl, ethyl, heteroalkyl, and halogen.

22. The compound as recited in claim 21, or a salt, ester, or prodrug thereof, wherein G⁴ is selected from the group consisting of hydrogen, halogen, alkoxy, amino, alkylamido, carboxyl, alkylcarboxyl, heterocycloalkylalkyl, heterocycloalkylalkoxy, heterocycloalkylalkylcarboxy, and heterocycloalkylalkylamido, any of which may be optionally substituted.

24. A compound as recited in claim 10 for use as a medicament.

25. A compound as recited in claim 10 for use in the manufacture of a medicament for the prevention or treatment of a disease or condition ameliorated by the inhibition of Rho kinase.

26. A pharmaceutical composition comprising a compound as recited in claim 10 together with a pharmaceutically acceptable carrier.

23. A compound selected from the group consisting of Examples 3-93 and 95-571.