IP Library › Granted Patent US 8,586,582

Granted Patent B2

US 8,586,582 · App. 13/128,687 · Granted Nov 19, 2013

PI3K/mTOR kinase inhibitors

Inventors: Congxin Liang (Palm Beach Gardens, FL); Zhigang Li (Shanghai, CN)

Assignee: Xcovery Holding Company, LLC

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Quick Facts

Patent No.: US 8,586,582
App. No.: 13/128,687
Granted: Nov 19, 2013
Kind: B2

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Abstract

6-morpholin-4-yl-pyrazolo[3,4-d]pyrimidine and 2-morpholin-4-yl-7H-pyrrolo[2,3-d]pyrimidine derivatives have unexpected drug properties as inhibitors of PI3 and/or mTOR kinases and are useful in treating disorders related to abnormal PI3K/mT0R activities such as cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine disorders and neurological disorders.

Claims (311)

1. A compound of Formula II:

or a salt thereof; or a prodrug, or a salt of a prodrug thereof; or a hydrate, solvate, or polymorph thereof; wherein X is N or CR′; Cy is cycloalkyl, cycloalkenyl, aryl, or heteroaryl, each optionally substituted with Z 1 , Z 2 and Z 3 ; R 1 , R 2 , and R′ are independently hydrogen, alkyl, cycloalkyl, or heterocyclo, each optionally substituted with Z 1 , Z 2 and Z 3 ;

Z 2 and Z 3 are each independently:

(1) hydrogen or Z 6 , where Z 6 is (i) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl; (ii) a group (i) which is substituted by one or more groups selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl; or (iii) a group (i) or (ii) which is substituted by one or more of the following groups (2) to (12);

(2) —OH or —OZ 16 ;

(3) —SH or —SZ 16 ;

(4) —C(O) 2 H, C(O) q Z 16 , —C(O)NZ 17 Z 18 , —C(O)C(O)NZ 17 Z 18 , or —O—C(O) q Z 16 , where q is 1 or 2;

(5) —SO 3 H, —S(O) q Z 16 , or —S(O) q NZ 17 Z 18 ;

(6) halo;

(7) cyano;

(8) nitro;

(9) —Z 4 —NZ 17 Z 18 ;

(10) —Z 4 —N(Z 18 )—Z 5 —NZ 19 Z 20 ;

(11) oxo;

(12) —O—C(O)—Z 16 ;

(13) any two of Z 1 , Z 2 , and Z 3 may together be alkylene, alkenylene, aryl, heteroaryl, or heterocyclo completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached;

Z 4 and Z 5 are each independently

(1) a single bond;

(2) —Z 11 —S(O) q —Z 12 —;

(3) —Z 11 —C(O)—Z 12 —;

(4) —Z 11 —O—Z 12 —;

(5) —Z 11 —S—Z 12 —;

(6) —Z 11 —O—C(O)—Z 12 —; or

(7) —Z 11 —C(O)—O—Z 12 ;

Z 11 and Z 12 are each independently

(1) a single bond;

(2) alkylene;

(3) alkenylene; or

(4) alkynylene;

each Z 16 is independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl, each optionally substituted with one or more of the following groups:

(1) hydrogen;

(2) —OH or —OZ 21 ;

(3) —SH or —SZ 21 ;

(4) —C(O) 2 H, C(O) q Z 21 , —C(O)NZ 17 Z 18 , —C(O)C(O)NZ 17 Z 18 , or —O—C(O) q Z 21 , where q is 1 or 2;

(5) —SO 3 H, —S(O) q Z 21 , or —S(O) q NZ 17 Z 18 ;

(6) halo;

(7) cyano;

(8) nitro;

(9) —Z 4 —NZ 17 Z 18 ;

(10) —Z 4 —N(Z 18 )—Z 5 —NZ 19 Z 20 ;

(11) oxo;

(12) —O—C(O)—Z 21 ;

each Z 17 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl;

each Z 18 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenyl alkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl;

each Z 19 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl;

each Z 20 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl;

each Z 21 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl;

each Z 22 is independently is,

(1) hydrogen;

(2) —OH or —OZ 21 ;

(3) —SH or —SZ 21 ;

(4) —C(O) 2 H, C(O) q Z 21 , —C(O)NZ 21 Z 21 , —C(O)C(O)NZ 21 Z 21 , or —O—C(O) q Z 21 , where q is 1 or 2;

(5) —SO 3 H, —S(O) q Z 21 , or —S(O) q NZ 21 Z 21 ;

(6) halo;

(7) cyano;

(8) nitro;

(9) —Z 4 —NZ 21 Z 21 ;

(10) —Z 4 —N(Z 21 )—Z 5 —NZ 21 Z 21 ;

(11) oxo;

(12) —O—C(O)—Z 21 ;

where Z 17 , Z 18 , Z 19 or Z 20 may be substituted with 1, 2, or 3 independent Z 22 ;

where Z 17 and Z 18 , or Z 19 and Z 20 , together with the nitrogen atom to which they are attached may be a heterocycle which is unsubstituted or substituted with 1, 2, or 3 independent Z 22 ; and

where any two of Z 18 , Z 19 or Z 20 together with the nitrogen atoms to which they are attached may be a 3- to 12-membered saturated or unsaturated mono-, bi-, or tri-heterocyclic ring which is unsubstituted or substituted with 1, 2, or 3 independent Z 22 .

2. The compound of claim 1 , wherein the compound is of formula IIa:

Wherein Cy is cycloalkyl, cycloalkenyl, aryl, or heteroaryl, each optionally substituted with Z 1 , Z 2 and Z 3 ; R 1 and R 2 are independently hydrogen, alkyl, cycloalkyl, or heterocyclo, each optionally substituted with Z 1 , Z 2 and Z 3 .

3. A compound of formula IIb:

or a salt thereof; or a prodrug, or a salt of a prodrug thereof; or a hydrate, solvate, or polymorph thereof; wherein Cy is cycloalkycloalkenyl, aryl, heteroaryl, or heterocyclo, each optionally substituted with Z 1 , Z 2 and Z 3 ; R 1 , R 2 , and R′ are independently hydrogen, alkyl, cycloalkyl, or heterocyclo, each optionally substituted with Z 1 , Z 2 and Z 3 ;

Z 1 , Z 2 and Z 3 are each independently:

(2) —OH or —OZ 16 ;

(3) —SH or —SZ 16 ;

(4) —C(O) 2 H, C(O) q Z 16 , —C(O)NZ 17 Z 18 , —C(O)C(O)NZ 17 Z 18 , or —O—C(O) q Z 16 , where q is 1 or 2;

(5) —SO 3 H, —S(O) q Z 16 , or —S(O) q NZ 17 Z 18 ;

(6) halo;

(7) cyano;

(8) nitro;

(9) —Z 4 —NZ 17 Z 18 ;

(10) —Z 4 —N(Z 18 )—Z 5 —NZ 19 Z 20 ;

(11) oxo;

(12) —O—C(O)—Z 16 ;

Z 4 and Z 5 are each independently

(1) a single bond;

(2) —Z 11 —S(O) q —Z 12 —;

(3) —Z 11 —C(O)—Z 12 —;

(4) —Z 11 —O—Z 12 —;

(5) —Z 11 —S—Z 12 —;

(6) —Z 11 —O—C(O)—Z 12 —; or

(7) —Z 11 —C(O)—O—Z 12 ;

Z 11 and Z 12 are each independently

(1) a single bond;

(2) alkylene;

(3) alkenylene; or

(4) alkynylene;

(1) hydrogen;

(2) —OH or —OZ 21 ;

(3) —SH or —SZ 21 ;

(4) —C(O) 2 H, C(O) q Z 21 , —C(O)NZ 17 Z 18 , —C(O)C(O)NZ 17 Z 18 , or —O—C(O) q Z 21 , where q is 1 or 2;

(5) —SO 3 H, —S(O) q Z 21 , or —S(O) q NZ 17 Z 18 ;

(6) halo;

(7) cyano;

(8) nitro;

(9) —Z 4 —NZ 17 Z 18 ;

(10) —Z 4 —N(Z 18 )—Z 5 —NZ 19 Z 20 ;

(11) oxo;

(12) —O—C(O)—Z 21 ;

each Z 18 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl;

each Z 2 is independently is,

(1) hydrogen;

(2) —OH or —OZ 21 ;

(3) —SH or —SZ 21 ;

(4) —C(O) 2 H, C(O) a Z 21 , —C(O)NZ 21 Z 21 , —C(O)C(O)NZ 21 Z 21 , or —O—C(O) q Z 21 , where q is 1 or 2;

(5) —SO 3 H, —S(O) q Z 21 , or —S(O) q Z 21 Z 21 ;

(6) halo;

(7) cyano;

(8) nitro;

(9) —Z 4 —NZ 21 Z 21 ;

(10) —Z 4 N(Z 21 )—Z 5 —NZ 21 Z 21 ;

(11) oxo;

(12) —O—C(O)—Z 21 ;

where Z 17 , Z 18 , Z 19 or Z 20 may be substituted with 1, 2, or 3 independent Z 22 ;

where Z 17 and Z 18 , or Z 19 and Z 20 , together with the nitrogen atom to which they are attached may be a heterocycle which is unsubstituted or substituted with 1, 2, or 3 independent Z 22 ; and

4. A compound of formula IV:

or a salt thereof; or a prodrug, or a salt of a prodrug thereof; or a hydrate, solvate, or polymorph thereof; wherein Cy is cycloalkyl, cycloalkenyl, aryl, or heteroaryl, each optionally substituted with Z 1 , Z 2 and Z 3 ;

R 1 and R 2 are independently hydrogen, alkyl, cycloalkyl, or heterocyclo, each optionally substituted with Z 1 , Z 2 and Z 3 ;

Z 1 , Z 2 and Z 3 are each independently:

(2) —OH or —OZ 16 ;

(3) —SH or —SZ 16 ;

(4) —C(O) 2 H, C(O) q R 16 , —C(O)NZ 17 Z 18 , —C(O)C(O)NZ 17 Z 18 , or —O—C(O) q Z 16 , where q is 1 or 2;

(5) —SO 3 H, —S(O) q Z 16 , or —S(O) q NZ 17 Z 18 ;

(6) halo;

(7) cyano;

(8) nitro;

(9) —Z 4 —NZ 17 Z 18 ;

(10) —Z 4 —N(Z 18 )—Z 5 —NZ 19 Z 20 ;

(11) oxo;

(12) —O—C(O)—Z 16 ;

Z 4 and Z 5 are each independently

(1) a single bond;

(2) —Z 11 —S(O) q —Z 12 —;

(3) —Z 11 —C(O)—Z 12 —;

(4) —Z 11 —O—Z 12 —;

(5) —Z 11 —S—Z 12 —;

(6) —Z 11 —O—C(O)—Z 12 —; or

(7) —Z 11 —C(O)—O—Z 12 ;

Z 11 and Z 12 are each independently

(1) a single bond;

(2) alkylene;

(3) alkenylene; or

(4) alkynylene;

(1) hydrogen;

(2) —OH or —OZ 21 ;

(3) —SH or —SZ 21 ;

(4) —C(O) 2 H, C(O) q Z 21 , —C(O)NZ 17 Z 18 , —C(O)C(O)NZ 17 Z 18 , or —O—C(O) q Z 21 , where q is 1 or 2;

(5) —SO 3 H, —S(O) Q Z 21 , or —S(O) q NZ 17 Z 18 ;

(6) halo;

(7) cyano;

(8) nitro;

(9) —Z 4 —NZ 17 Z 18 ;

(10) —Z 4 —N(Z 18 )—Z 5 —NZ 19 Z 20 ;

(11) oxo;

(12) —O—C(O)—Z 21 ;

each Z 18 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl;

each Z 22 is independently is,

(1) hydrogen;

(2) —OH or —OZ 21 ;

(3) —SH or —SZ 21 ;

(4) —C(O) 2 H, C(O) q Z 21 , —C(O)NZ 21 Z 21 , —C(O)C(O)NZ 21 Z 21 , or —O—C(O) q Z 21 , where q is 1 or 2;

(5) —SO 3 H, —S(O) q Z 21 , or —S(O) q NZ 21 Z 21 ;

(6) halo;

(7) cyano;

(8) nitro;

(9) —Z 4 —NZ 21 Z 21 ;

(10) —Z 4 N(Z 21 )—Z 5 —NZ 21 Z 21 ;

(11) oxo;

(12) —O—C(O)—Z 21 ;

where Z 17 , Z 18 , Z 19 or Z 20 may be substituted with 1, 2, or 3 independent Z 22 ;

where Z 17 and Z 18 , or Z 19 and Z 20 , together with the nitrogen atom to which they are attached may be a heterocycle which is unsubstituted or substituted with 1, 2, or 3 independent Z 22 ; and

and R 3 , R 4 are independently hydrogen, alkyl, cycloalkyl, or heterocyclo, each optionally substituted with Z 1 , Z 2 and Z 3 .

5. The compound of claim 1 , wherein the compound is one of

6. The compound of claim 1 , wherein the compound is one of

7. The compound of claim 4 , wherein the compound is one of

8. The compound of claim 4 , wherein the compound is one of

9. The compound of claim 1 , wherein the compound is one of

5-(1-(2H-3,4,5,6-tetrahydropyran-4-yl)-6-morpholin-4-ylpyrazolo[4,5-e]pyrimidin-4-yl)pyrimidine-2-ylamine;

5-(1-(2H-3,4,5,6-tetrahydropyran-4-yl)-6-morpholin-4-yl)pyrazolo[4,5-e]pyrimidin-4-yl)-4-methylpyrimidine-2-ylamine;

4-{1-(2H-3,4,5,6-tetrahydropyran-4-yl)-4[2-(difluoromethyl)benzimidazolyl]pyrazolo[5,4-d]pyrimidin-6-yl}morpholine;

4-[4-(2-aminopyrimidin-5-yl)-6-morpholin-4-ylpyrazolo[5,4-d]pyrimidinyl]piperidyl 4-methylpiperazinyl ketone;

1-[4-(2-aminopyrimidin-5-yl)-6-morpholin-4-ylpyrazolo[5,4-d]pyrimidinyl]-2-methylpropan-2-ol;

2-{4-[2-(difluoromethyl)benzimidazolyl]-6-morpholin-4-ylpyrazolo[5,4-d]pyrimidinyl}ethan-1-ol.

10. The compound of claim 4 , wherein the compound is one of

5-(6-morpholino-1-sec-butyl-pyrazolo[3,4-d]pyrimidin-4-yl)pyrimidin-2-amine;

2-[4-(2-aminopyrimidin-5-yl)-6-morpholino-pyrazolo[3,4-d]pyrimidin-1-yl]propan-1-ol;

N-{4-[1-(2-hydroxy-2-methylpropyl)-6-morpholin-4-ylpyrazolo[4,5-e]pyrimidin-4-yl]phenyl}methoxycarboxamide;

Tert-butyl 4-[4-(2-aminopyrimidin-5-yl)-6-morpholin-4-ylpyrazolo[5,4-d]pyrimidinyl]piperidinecarboxylate;

4-[4-(2-Aminopyrimidin-5-yl)-6-morpholin-4-ylpyrazolo[5,4-d]pyrimidinyl]piperidyl 3-pyridyl ketone HCl salt;

4-[4-(2-Aminopyrimidin-5-yl)-6-morpholin-4-ylpyrazolo[5,4-d]pyrimidinyl]piperidyl 4-pyridyl ketone HCl salt;

4-[4-(2-Aminopyrimidin-5-yl)-6-morpholin-4-ylpyrazolo[5,4-d]pyrimidinyl]piperidyl 4-fluorophenyl ketone HCl salt;

Methoxy-N-[4-(1-{1-[(4-methylpiperazinyl)carbonyl](4-piperidyl)}-6-morpholin-4-ylpyrazolo[4,5-e]pyrimidin-4-yl)phenyl]carboxamide;

N-(4-{1-[1-((2S)-2-aminopropanoyl)(4-piperidyl)]-6-morpholin-4-ylpyrazolo[4,5-e]pyrimidin-4-yl}phenyl)methoxycarboxamide HCl salt;

N-[4-(1-(2H-3,4,5,6-tetrahydropyran-4-yl)-6-morpholin-4-ylpyrazolo[4,5-e]pyrimidin-4-yl)phenyl]methoxycarboxamide;

5-(6-Morpholin-4-yl-1-oxolan-3-ylpyrazolo[4,5-e]pyrimidin-4-yl)pyrimidine-2-ylamine HCl salt;

(Ethylamino)-N-{4-[1-(2-hydroxy-2-methylpropyl)-6-morpholin-4-ylpyrazolo[4,5-e]pyrimidin-4-yl]phenyl}carboxamide;

1-{4-[4-(2-Aminopyrimidin-5-yl)-6-morpholin-4-ylpyrazolo[5,4-d]pyrimidinyl]piperidyl}-2-(dimethylamino)ethan-1-one;

(2R)-2-Amino-1-{4-[4-(2-aminopyrimidin-5-yl)-6-morpholin-4-ylpyrazolo[5,4-d]pyrimidinyl]piperidyl}propan-1-one;

2-Amino-1-{4-[4-(2-aminopyrimidin-5-yl)-6-morpholin-4-yl pyrazolo[5,4-d]pyrimidinyl]piperidyl}-2-methylpropan-1-one; or

Aminocyclopropyl 4-[4-(2-aminopyrimidin-5-yl)-6-morpholin-4-ylpyrazolo[5,4-d]pyrimidinyl]piperidyl ketone.

11. The compound of claim 4 , wherein the compound is one of

Methyl N-[4-[6-morpholino-1-(2,2,2-trifluoroethyl)pyrazolo[3,4-d]pyrimidin-4-yl]phenyl]carbamate;

Methyl N-[4-[1-(methylsulfonylmethyl)-6-morpholino-pyrazolo[3,4-d]pyrimidin-4-yl]phenyl]carbamate;

Methyl N-[4-[6-[(3R)-3-methylmorpholin-4-yl]-1-tetrahydropyran-4-yl-pyrazolo[3,4-d]pyrimidin-4-yl]phenyl]carbamate;

(2S)-2-amino-1-[4-[4-(2-aminothiazol-4-yl)-6-morpholino-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidyl]propan-1-one;

4-(6-morpholino-1-tetrahydropyran-4-yl-pyrazolo[3,4-d]pyrimidin-4-yl)thiazol-2-amine;

1-methyl-3-[4-(6-morpholino-1-tetrahydropyran-4-yl-pyrazolo[3,4-d]pyrimidin-4-yl)thiazol-2-yl]urea;

5-(6-morpholino-1-tetrahydropyran-4-yl-pyrazolo[3,4-d]pyrimidin-4-yl)thiazol-2-amine;

1-methyl-3-[5-(6-morpholino-1-tetrahydropyran-4-yl-pyrazolo[3,4-d]pyrimidin-4-yl)thiazol-2-yl]urea;

Methyl N-[5-(6-morpholino-1-tetrahydropyran-4-yl-pyrazolo[3,4-d]pyrimidin-4-yl)pyrimidin-2-yl]carbamate;

1-methyl-3-[5-(6-morpholino-1-tetrahydropyran-4-yl-pyrazolo yl)pyrimidin-2-yl]urea;

6-(6-morpholino-1-tetrahydropyran-4-yl-pyrazolo[3,4-d]pyrimidin-4-yl)-1,3-benzothiazol-2-amine;

1-methyl-3-[6-(6-morpholino-1-tetrahydropyran-4-yl-pyrazolo[3,4-d]pyrimidin-4-yl)-1,3-benzothiazol-2-yl]urea;

5-(6-morpholino-1-tetrahydropyran-4-yl-pyrazolo[3,4-d]pyrimidin-4-yl)-1,3-benzothiazol-2-amine;

1-methyl-3-[5-(6-morpholino-1-tetrahydropyran-4-yl-pyrazolo[3,4-d]pyrimidin-4-yl)-1,3-benzothiazol-2-yl]urea;

6-(6-morpholino-1-tetrahydropyran-4-yl-pyrazolo[3,4-d]pyrimidin-4-yl)quinazolin-2-amine;

7-(6-morpholino-1-tetrahydropyran-4-yl-pyrazolo[3,4-d]pyrimidin-4-yl)quinazolin-2-amine;

1-methyl-3-[7-(6-morpholino-1-tetrahydropyran-4-yl-pyrazolo[3,4-d]pyrimidin-4-yl)quinazolin-2-yl]urea; or

1-methyl-3-[6-(6-morpholino-1-tetrahydropyran-4-yl-pyrazolo[3,4-d]pyrimidin-4-yl)quinazolin-2-yl]urea.

12. A method of treating a PI-3 kinase mediated disease or mTOR kinase mediated disease in a subject having said disease comprising administering to the subject a compound of any one of claims 1 - 3 , 4 - 6 and 7 - 11 .

13. A method of treating a PI-3 kinase mediated disease or mTOR kinase mediated disease in a subject having said disease comprising administering to the subject a composition comprising a compound of any one of claims 1 - 3 , 4 - 6 and 7 - 11 .

14. The method of claim 13 , wherein the disease is selected from cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine disorders and neurological disorders.

15. A compound of formula IV:

or a salt thereof; or a prodrug, or a salt of a prodrug thereof; or a hydrate, solvate, or polymorph thereof; wherein Cy is cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclo, each optionally substituted with Z 1 , Z 2 and Z 3 ;

R 1 is independently hydrogen, C 2 -C 12 alkyl, cycloalkyl, or heterocyclo, each optionally substituted with Z 1 , Z 2 and Z 3 ;

R 2 is independently hydrogen, alkyl, cycloalkyl, or heterocyclo, each optionally substituted with Z 1 , Z 2 and Z 3 ;

Z 1 , Z 2 and Z 3 are each independently:

(1) hydrogen or Z 6 , where Z 6 is (i) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl; (ii) a group (1) which is substituted by one or more groups selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl; or (iii) a group (i) or (ii) which is substituted by one or more of the following groups (2) to (12);

(2) —OH or —OZ 16 ;

(3) —SH or —SZ 16 ;

(4) —C(O) 2 H, C(O) q Z 16 , —C(O)NZ 17 Z 18 , —C(O)C(O)NZ 17 Z 18 , or —O—C(O) q Z 16 , where q is 1 or 2;

(5) —SO 3 H, —S(O) q Z 16 , or —S(O) q NZ 17 Z 18 ;

(6) halo;

(7) cyano;

(8) nitro;

(9) —Z 4 —NZ 17 Z 18 ;

(10) —Z 4 —N(Z 18 )—Z 5 —NZ 19 Z 20 ;

(11) oxo;

(12) —O—C(O)—Z 16 ;

Z 4 and Z 5 are each independently

(1) a single bond;

(2) —Z 11 —S(O) q —Z 12 —;

(3) —Z 11 —C(O)—Z 12 —;

(4) —Z 11 —O—Z 12 —;

(5) —Z 11 —S—Z 12 —;

(6) —Z 11 —O—C(O)—Z 12 —; or

(7) —Z 11 —C(O)—O—Z 12 ;

Z 11 and Z 12 are each independently

(1) a single bond;

(2) alkylene;

(3) alkenylene; or

(4) alkynylene;

each Z 16 is independently alkyl, alkenyl, alkynyl, cycloalkyl, cyeloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl, each optionally substituted with one or more of the following groups:

(1) hydrogen;

(2) —OH or —OZ 21 ;

(3) —SH or —SZ 21 ;

(4) —C(O) 2 H, C(O) q Z 21 , —C(O)NZ 17 Z 18 , —C(O)C(O)NZ 17 Z 18 , or —O—C(O) q Z 21 , where q is 1 or 2;

(5) —SO 3 H, —S(O) q Z 21 , or —S(O) q NZ 17 Z 18 ;

(6) halo;

(7) cyano;

(8) nitro;

(9) —Z 4 —NZ 17 Z 18 ;

(10) —Z 4 —N(Z 18 )—Z 5 —NZ 19 Z 20 ;

(11) oxo;

(12) —O—C(O)Z 21 ;

each Z 18 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl;

each Z 22 is independently is,

(1) hydrogen;

(2) —OH or —OZ 21 ;

(3) —SH or —SZ 21 ;

(4) —C(O) 2 H, C(O) q Z 21 , —C(O)NZ 21 Z 21 , —O—C(O)C(O)NZ 21 Z 21 , or —O—C(O) q Z 21 , where q is 1 or 2;

(5) —SO 3 H, —S(O) q Z 21 , or —S(O) q NZ 21 Z 21 ;

(6) halo;

(7) cyano;

(8) nitro;

(9) —Z 4 —NZ 21 Z 21 ;

(10) —Z 4 —N(Z 21 )—Z 5 —NZ 21 Z 21 ;

(11) oxo;

(12) —O—C(O)—Z 21 ;

where Z 17 , Z 18 , Z 19 or Z 20 may be substituted with 1, 2, or 3 independent Z 22 ;

where Z 17 and Z 18 , or Z 19 and Z 20 , together with the nitrogen atom to which they are attached may be a heterocycle which is unsubstituted or substituted with 1, 2, or 3 independent Z 22 ; and

R 3 is hydrogen, alkyl, cycloalkyl, or heterocyclo, each optionally substituted with Z 1 , Z 2 and Z 3 ; and

R 4 is hydrogen, alkyl, cycloalkyl, or heterocyclo, each optionally substituted with Z 1 , Z 2 and Z 3 .

16. The method of claim 12 , wherein the disease is selected from cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine disorders and neurological disorders.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 24, 2011

From: LIANG, CONGXIN; LI, ZHIGANG

To: XCOVERY HOLDING COMPANY, LLC

Reel/Frame 026329/0252 →

Continuity (3)

Provisional Application 61199019 · Nov 11, 2008

Provisional Application 61214828 · Apr 28, 2009

Related Publication 20110281857A1 · Nov 17, 2011