IP Library › Patent Application 12140120

Patent Application

App. No. 12/140,120

ISOQUINOLINE DERIVATIVES AND METHODS OF USE THEREOF

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Patent No.: US None
App. No.: 12/140,120

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Abstract

The invention provides novel classes of Isoquinoline Derivatives. Pharmaceutical compositions and methods of making and using the compounds, are also described.

Claims (184)

1 . A compound of the formula

or a pharmaceutically acceptable hydrate or salt thereof,

wherein:

R 5 is NH or S;

R 6 is —H or C 1 -C 4 alkyl;

X is —C(O)—, —CH 2 —, —CH(halo)-, —CH(OH)—(CH 2 ) n —, —CH(OH)-arylene-, —O—, —NH—, —S—, —CH(NR 11 R 12 )— or —N(SO 2 Y)—, wherein Y is —OH, —NH 2 or -alkylheterocycle and n is an integer ranging from 0-5;

R 11 and R 12 are independently -hydrogen or —C 1 -C 9 alkyl, or N, R 11 and R 12 are taken together to form a heterocyclic amine;

R 1 is -hydrogen, -halo, —C 1 -C 10 alkyl, -alkylhalo, —C 2 -C 10 alkenyl, —C 3 -C 8 carbocycle, -aryl, —NH 2 , -alkylamino, —C(O)OH, —C(O)O(C 1 -C 5 alkyl), NO 2 or -A′-B′;

A′ is —SO 2 —, —SO 2 NH—, —NHCO—, —NHCONH—, —CO—, —C(O)O—, —CONH—, —CON(C 1 -C 4 alkyl)-, —NH—, —CH 2 —, —S— or —C(S)—;

B′ is —C 1 -C 10 alkyl, —C 2 -C 10 alkenyl, -heterocycle, —C 3 -C 8 carbocycle, -aryl, —NZ 1 Z 2 , —(C 1 -C 5 alkylene)-NZ 1 Z 2 , -alkylamino, -aminodialkyl, -alkylheterocycle, -arylamido, —C(O)OH, —C(O)O—(C 1 -C 5 alkyl), —C(O)O-phenyl or —C(NH)NH 2 any of which are unsubstituted or substituted with one or more of —O—(C 1 -C 5 alkyl), -halo, -alkylhalo, -alkanol, -alkylamino, -hydroxy, —NO 2 , —NH 2 , —CN, -aminoalkyl, -aminodialkyl, -heterocyclic amine, —C 1 -C 10 alkyl, —C 2 -C 10 alkenyl, —C 2 -C 10 alkynyl, -aryl, -benzyl, -alkylamido, -alkylcarboxy, —C(O)OH, —C 1 -C 5 alkylene-C(O)O—(C 1 -C 5 alkyl) or —C 1 -C 5 alkylene-OC(O)—(C 1 -C 5 alkyl);

R 2 , R 3 , R 4 , R 7 , R 8 , R 9 and R 10 are independently -hydrogen, -halo, -hydroxy, —O—(C 1 -C 5 alkyl), —C 1 -C 10 alkyl, -alkylhalo, —C 2 -C 10 alkenyl, —C 3 -C 8 carbocycle, -aryl, —NH 2 , -alkylamino, —C(O)OH, —C(O)O(C 1 -C 5 alkyl), —OC(O)(C 1 -C 5 alkyl), NO 2 or -A-B; and at least one of R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 or R 10 is other than hydrogen;

A is —SO 2 —, —SO 2 N—H—, —NHCO—, —NHCONH—, —O—, —CO—, —OC(O)—, —C(O)O—, —CONH—, —CON(C 1 -C 4 alkyl)-, —NH—, —CH 2 —, —S— or —C(S)—;

B is —C 1 -C 10 alkyl, —C 2 -C 10 alkenyl, -heterocycle, —C 3 -C 8 carbocycle, -aryl, —NZ 1 Z 2 , —(C 1 -C 5 alkylene)-NZ 1 Z 2 , -alkylamino, -aminodialkyl, -alkylheterocycle, -arylamido, —C(O)OH, —C(O)O—(C 1 -C 5 alkyl), —C(O)O-phenyl or —C(NH)NH 2 any of which are unsubstituted or substituted with one or more of —O—(C 1 -C 5 alkyl), -halo, -alkylhalo, -alkanol, -alkylamino, -hydroxy, —NO 2 , —NH 2 , —CN, -aminoalkyl, -aminodialkyl, -heterocyclic amine, —C 1 -C 10 alkyl, —C 2 -C 10 alkenyl, —C 2 -C 10 alkynyl, -aryl, -benzyl, -alkylamido, -alkylcarboxy, —C(O)OH, —C 1 -C 5 alkylene-C(O)O—(C 1 -C 5 alkyl) or —C 1 -C 5 alkylene-OC(O)—(C 1 -C 5 alkyl); and

Z 1 and Z 2 are independently —H or —C 1 -C 10 alkyl, which is unsubstituted or substituted with one or more of -halo, —OH or —N(Z 3 )(Z 4 ), where Z 3 and Z 4 are independently, —H or —C 1 -C 5 alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or —NH 2 ; or N, Z 3 and Z 4 are taken together to form an unsubstituted or substituted heterocyclic amine; or N, Z 1 and Z 2 are taken together to form a heterocyclic amine.

2 . A compound of the formula

or a pharmaceutically acceptable hydrate or salt thereof,

wherein:

R 5 is O, NH or S;

R 6 is —H or C 1 -C 4 alkyl;

R 11 and R 12 are independently -hydrogen or —C 1 -C 9 alkyl, or N, R 11 and R 12 are taken together to form a heterocyclic amine.

R 1 is -hydrogen, -halo, —C 1 -C 10 alkyl, -alkylhalo, —C 2 -C 10 alkenyl, —C 3 -C 8 carbocycle, -aryl, —NH 2 , -alkylamino, —C(O)OH, —C(O)O(C 1 -C 5 alkyl), NO 2 or -A′-B′;

A′ is —SO 2 —, —SO 2 NH—, —NHCO—, —NHCONH—, —CO—, —C(O)O—, —CONH—, —CON(C 1 -C 4 alkyl)-, —NH—, —CH 2 —, —S— or —C(S)—;

A is —SO 2 —, —SO 2 NH—, —NHCO—, —NHCONH—, —O—, —CO—, —OC(O)—, —C(O)O—, —CONH—, —CON(C 1 -C 4 alkyl)-, —NH—, —CH 2 —, —S— or —C(S)—;

3 . A compound of the formula

or a pharmaceutically acceptable hydrate or salt thereof,

wherein:

R 6 is —H or C 1 -C 4 alkyl;

R 1 is -hydrogen, -halo, —C 1 -C 10 alkyl, -alkylhalo, —C 2 -C 10 alkenyl, —C 3 -C 8 carbocycle, -aryl, —NH 2 , -alkylamino, —C(O)OH, —C(O)O(C 1 -C 5 alkyl), NO 2 or -A′-B′;

A′ is —SO 2 —, —SO 2 NH—, —NBCO—, —NHCONH—, —CO—, —C(O)O—, —CONH—, —CON(C 1 -C 4 alkyl)-, —NH—, —CH 2 —, —S— or —C(S)—;

B′ is —C 1 -C 10 alkyl, —C 2 -C 11 alkenyl, -heterocycle, —C 3 -C 8 carbocycle, -aryl, —NH 2 , -alkylamino, -aminodialkyl, -alkylheterocycle, -arylamido, —C(O)OH, —C(O)O—(C 1 -C 5 alkyl), —C(O)O-phenyl or —NZ 1 Z 2 ;

R 2 , R 3 , R 4 , R 7 , R 8 , R 9 and R 10 are independently -hydrogen, -halo, -hydroxy, —O—(C 1 -C 5 alkyl), —C 1 -C 10 alkyl, -alkylhalo, —C 2 -C 10 alkenyl, —C 3 -C 8 carbocycle, -aryl, —NH 2 , -alkylamino, —C(O)OH, —C(O)O(C 1 -C 5 alkyl), —OC(O)(C 1 -C 5 alkyl), NO 2 or -A-B; wherein at least one of R 1 , R 4 and R 10 is other than hydrogen;

A is —SO 2 —, —SO 2 NH—, —NHCO—, —NHCONH—, —O—, —CO—, —OC(O)—, —C(O)O—, —CONH—, —CON(C 1 -C 4 alkyl)-, —NH—, —CH 2 —, —S— or —C(S)—;

B is —C 1 -C 10 alkyl, —C 2 -C 10 alkenyl, -heterocycle, —C 3 -C 8 carbocycle, -aryl, —NH 2 , -alkylamino, -aminodialkyl, -alkylheterocycle, -arylamido, —C(O)OH, —C(O)O—(C 1 -C 5 alkyl), —C(O)O-phenyl or —NZ 1 Z 2 ; and

4 . The compound of claim 1 wherein R 5 is O, and R 6 is hydrogen.

5 . The compound of claim 2 wherein R 5 is O, and R 6 is hydrogen.

6 . The compound of claim 3 wherein R 5 is O, and R 6 is hydrogen.

7 . The compound of claim 1 , wherein either R 8 or R 9 but not both, is -A-B.

8 . The compound of claim 7 wherein R 1 , R 2 , R 3 , R 4 , R 7 , and R 10 are hydrogen.

9 . The compound of claim 1 , wherein R 9 is -A-B.

10 . The compound of claim 1 , wherein R 9 is -A-B and R 8 is hydrogen.

11 . The compound of claim 1 , wherein A is —SO 2 —, —SO 2 NH— or —NHCO—.

12 . The compound of claim 1 , wherein R 9 is -A-B and B is —C 1 -C 8 alkyl, -heterocycle, —C 3 -C 8 carbocycle, -aryl, -alkylamino, -alkanol or -alkylheterocycle.

13 . The compound of claim 1 , wherein A is —SO 2 — and B is —NZ 1 Z 2 , and Z 1 and Z 2 are independently hydrogen, or —C 1 -C 5 alkyl, unsubstituted or substituted with -halo, -hydroxy or —NZ 3 Z 4 : wherein Z 3 and Z 4 are independently -hydrogen, —C 1 -C 5 alkyl, unsubstituted or substituted with one or more of -halo; -hydroxy or —NH 2 , or wherein N, Z 1 and Z 2 , taken together, form a heterocyclic amine.

14 . The compound of claim 13 , wherein Z 1 and Z 2 are —(CH 2 ) n D; wherein n is an integer ranging from 1-5, and D is hydrogen, hydroxy, heterocyclic amine or —NZ 3 Z 4 ; wherein Z 3 and Z 4 are independently hydrogen, methyl or ethyl.

15 . The compound of claim 13 , wherein B is a heterocycle, unsubstituted or substituted with methyl, ethyl or -alkanol.

16 . The compound of claim 13 , wherein Z 1 is hydrogen and Z 2 is —(CH 2 ) n NZ 3 Z 4 , wherein n is 2 or 3, and Z 3 and Z 4 are independently methyl or ethyl, or, taken together, NZ 3 Z 4 form a heterocyclic amine.

17 . The compound of claim 1 wherein X is —C(O)—, —CH(OH)—, —CH(Br)-, —CH 2 — or —CH(NR 11 R 12 )— wherein R 11 and R 12 are hydrogen, —C 1 -C 9 alkyl, or NR 11 R 12 , taken together, form a heterocycle.

18 . A compound of the formula

or a pharmaceutically acceptable hydrate or salt thereof,

wherein:

X is —CH 2 — or —O—;

R 2 and R 3 are independently -hydrogen, -halo, -alkylhalo, -hydroxy, —O—(C 1 -C 5 alkyl), —C 1 -C 3 alkyl, —NO 2 , —NH 2 , —CONH 2 , —C(O)OH, —OC(O)—C 1 -C 5 alkyl or —C(O)O—C 1 -C 5 alkyl;

R 8 and R 9 are independently -hydrogen or -A-B;

A is —SO 2 —, —SO 2 NH— or —NHCO—; and

B is —C 1 -C 3 alkyl, —NZ 1 Z 2 , -heterocycle or -alkylamino, each unsubstituted or substituted with one or more of -alkanol, -alkylamino, -aminoalkyl, -aminodialkyl or -heterocycle, each unsubstituted or substituted with —C 1 -C 10 alkyl or -alkanol; and

Z 1 and Z 2 are independently -hydrogen or —C 1 -C 8 alkyl, which is unsubstituted or substituted with one or more of -hydroxy or —NZ 3 Z 4 , where Z 3 and Z 4 are independently —H or —C 1 -C 3 alkyl, which is unsubstituted or substituted with one or more of -hydroxy or —NH 2 , or N, Z 3 and Z 4 are taken together to a heterocyclic amine, or N, Z 1 and Z 2 are taken together to form a heterocyclic amine.

19 . The compound of claim 18 , wherein A is —SO 2 — and B is —NZ 1 Z 2 .

20 . The compound of claim 19 , wherein Z 1 and Z 2 are independently hydrogen, or —C 1 -C 5 alkyl, unsubstituted or substituted with hydroxy or —NZ 3 Z 4 , or, taken together, —NZ 1 Z 2 form a heterocyclic amine.

21 . The compound of claim 20 , wherein Z 3 and Z 4 are independently hydrogen, or —C 1 -C 3 alkyl, unsubstituted or substituted with hydroxy or —NH 2 , or, taken together, NZ 3 Z 4 form a heterocyclic amine.

22 . The compound of claim 21 , wherein the heterocyclic amine is selected from the group consisting of an unsubstituted piperidine, piperazine or morpholine group, or a piperazine, pyrrolidine or imidazole group which can be unsubstituted or substituted with —N—(C 1 -C 5 alkyl) or —N—C(O)(C 1 -C 5 alkyl).

23 . The compound of claim 20 , wherein either NZ 1 Z 2 or NZ 3 Z 4 is a heterocycle, unsubstituted or substituted with —C 1 -C 5 alkyl, -alkanol or -alkylamino.

24 . A method for inhibiting poly(ADP)-ribose synthase activity in a cell, the method comprising contacting said cell with the compound or pharmaceutically acceptable hydrate or salt of a compound of claim 1 in an amount sufficient to inhibit poly (ADP)-ribose-synthase in said cell.

25 . A method for inhibiting poly(ADP)-ribose synthase activity in a cell, the method comprising contacting said cell with the compound or pharmaceutically acceptable hydrate or salt of a compound of claim 2 in an amount sufficient to inhibit poly (ADP)-ribose-synthase in said cell.

26 . A method for inhibiting poly(ADP)-ribose synthase activity in a cell, the method comprising contacting said cell with the compound or pharmaceutically acceptable hydrate or salt of a compound of claim 3 in an amount sufficient to inhibit poly (ADP)-ribose-synthase in said cell.

27 . A method for inhibiting poly(ADP)-ribose synthase activity in a cell, the method comprising contacting said cell with the compound or pharmaceutically acceptable hydrate or salt of a compound of claim 18 in an amount sufficient to inhibit poly (ADP)-ribose-synthase in said cell.

28 . The method of claim 24 wherein the cell is an in vivo cell.

29 . The method of claim 25 wherein the cell is an in vivo cell.

30 . The method of claim 26 wherein the cell is an in vivo cell.

31 . The method of claim 27 wherein the cell is an in vivo cell.

32 . A method for treating or preventing an inflammatory disease in a subject, the method comprising administering to a subject in need thereof the compound or a pharmaceutically acceptable hydrate or salt of a compound of claim 1 in an amount sufficient to treat or prevent the inflammatory disease.

33 . A method for treating or preventing an inflammatory disease in a subject, the method comprising administering to a subject in need thereof the compound or a pharmaceutically acceptable hydrate or salt of a compound of claim 2 in an amount sufficient to treat or prevent the inflammatory disease.

34 . A method for treating or preventing an inflammatory disease in a subject, the method comprising administering to a subject in need thereof the compound or a pharmaceutically acceptable hydrate or salt of a compound of claim 3 in an amount sufficient to treat or prevent the inflammatory disease.

35 . A method for treating or preventing an inflammatory disease in a subject, the method comprising administering to a subject in need thereof the compound or a pharmaceutically acceptable hydrate or salt of a compound of claim 18 in an amount sufficient to treat or prevent the inflammatory disease.

36 . The method of claim 32 , wherein said inflammatory disease is an inflammatory disease of a joint, a chronic inflammatory disease of the gum, an inflammatory bowel disease, an inflammatory lung disease, an inflammatory disease of the central nervous system, an inflammatory disease of the eye, gram-positive shock, gram negative shock, hemorrhagic shock, anaphylactic shock, traumatic shock or chemotherapeutic shock.

37 . The method of claim 33 , wherein said inflammatory disease is an inflammatory disease of a joint, a chronic inflammatory disease of the gum, an inflammatory bowel disease, an inflammatory lung disease, an inflammatory disease of the central nervous system, an inflammatory disease of the eye, gram-positive shock, gram negative shock, hemorrhagic shock, anaphylactic shock, traumatic shock or chemotherapeutic shock.

38 . The method of claim 34 , wherein said inflammatory disease is an inflammatory disease of a joint, a chronic inflammatory disease of the gum, an inflammatory bowel disease, an inflammatory lung disease, an inflammatory disease of the central nervous system, an inflammatory disease of the eye, gram-positive shock, gram negative shock, hemorrhagic shock, anaphylactic shock, traumatic shock or chemotherapeutic shock.

39 . The method of claim 35 , wherein said inflammatory disease is an inflammatory disease of a joint, a chronic inflammatory disease of the gum, an inflammatory bowel disease, an inflammatory lung disease, an inflammatory disease of the central nervous system, an inflammatory disease of the eye, gram-positive shock, gram negative shock, hemorrhagic shock, anaphylactic shock, traumatic shock or chemotherapeutic shock.

40 . A method for treating or preventing a reperfusion disease in a subject, the method comprising administering to a subject in need thereof the compound or pharmaceutically acceptable hydrate or salt of a compound of claim 1 in an amount sufficient to treat or prevent the reperfusion disease.

41 . A method for treating or preventing a reperfusion disease in a subject, the method comprising administering to a subject in need thereof the compound or pharmaceutically acceptable hydrate or salt of a compound of claim 2 in an amount sufficient to treat or prevent the reperfusion disease.

42 . A method for treating or preventing a reperfusion disease in a subject, the method comprising administering to a subject in need thereof the compound or pharmaceutically acceptable hydrate or salt of a compound of claim 3 in an amount sufficient to treat or prevent the reperfusion disease.

43 . A method for treating or preventing a reperfusion disease in a subject, the method comprising administering to a subject in need thereof the compound or pharmaceutically acceptable hydrate or salt of a compound of claim 18 in an amount sufficient to treat or prevent the reperfusion disease.

44 . The method of claim 40 , wherein the reperfusion disease is stroke or myocardial infarction.

45 . The method of claim 41 , wherein the reperfusion disease is stroke or myocardial infarction.

46 . The method of claim 42 , wherein the reperfusion disease is stroke or myocardial infarction.

47 . The method of claim 43 , wherein the reperfusion disease is stroke or myocardial infarction.

48 . A method for treating or preventing diabetes or a diabetic complication in a subject, the method comprising administering to a subject in need thereof the compound or pharmaceutically acceptable hydrate or salt of a compound of claim 1 in an amount sufficient to treat or prevent diabetes or the diabetic complication.

49 . A method for treating or preventing diabetes or a diabetic complication in a subject, the method comprising administering to a subject in need thereof the compound or pharmaceutically acceptable hydrate or salt of a compound of claim 2 in an amount sufficient to treat or prevent diabetes or the diabetic complication.

50 . A method for treating or preventing diabetes or a diabetic complication in a subject, the method comprising administering to a subject in need thereof the compound or pharmaceutically acceptable hydrate or salt of a compound of claim 3 in an amount sufficient to treat or prevent diabetes or the diabetic complication.

51 . A method for treating or preventing diabetes or a diabetic complication in a subject, the method comprising administering to a subject in need thereof the compound or pharmaceutically acceptable hydrate or salt of a compound of claim 18 in an amount sufficient to treat or prevent diabetes or the diabetic complication.

52 . A method for treating or preventing reoxygenation injury resulting from organ transplantation, the method comprising administering to a subject in need thereof the compound or pharmaceutically acceptable hydrate or salt of a compound of claim 1 in an amount sufficient to treat or prevent the reoxygenation injury.

53 . A method for treating or preventing reoxygenation injury resulting from organ transplantation, the method comprising administering to a subject in need thereof the compound or pharmaceutically acceptable hydrate or salt of a compound of claim 2 in an amount sufficient to treat or prevent the reoxygenation injury.

54 . A method for treating or preventing reoxygenation injury resulting from organ transplantation, the method comprising administering to a subject in need thereof the compound or pharmaceutically acceptable hydrate or salt of a compound of claim 3 in an amount sufficient to treat or prevent the reoxygenation injury.

55 . A method for treating or preventing reoxygenation injury resulting from organ transplantation, the method comprising administering to a subject in need thereof the compound or pharmaceutically acceptable hydrate or salt of a compound of claim 18 in an amount sufficient to treat or prevent the reoxygenation injury.

56 . A composition comprising a compound or pharmaceutically acceptable salt or hydrate of the compound of claim 1 and a pharmaceutically acceptable carrer.

57 . A composition comprising a compound or pharmaceutically acceptable salt or hydrate of the compound of claim 2 and a pharmaceutically acceptable carrier.

58 . A composition comprising a compound or pharmaceutically acceptable salt or hydrate of the compound of claim 3 and a pharmaceutically acceptable carrier.

59 . A composition comprising a compound or pharmaceutically acceptable salt or hydrate of the compound of claim 18 and a pharmaceutically acceptable carrier.

60 . The compound or pharmaceutically acceptable salt or hydrate of claim 18 , wherein either R 8 is hydrogen and R 9 is -A-B, or R 8 is -A-B and R 9 is hydrogen.

61 . A method for making a compound of formula 13

wherein

R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 and R 10 are independently -hydrogen, -halo, -hydroxy, —O—(C 1 -C 5 alkyl), —C 1 -C 10 alkyl, -alkylhalo, —C 2 -C 10 alkenyl, —C 3 -C 8 carbocycle, -aryl, —NH 2 , -alkylamino, —C(O)OH, —C(O)O(C 1 -C 5 alkyl), —OC(O)(C 1 -C 5 alkyl), NO 2 or -A-B;

A is —SO 2 —, —SO 2 NH—, —NHCO—, —NHCONH—, —O—, —CO—, —OC(O)—, —C(O)O—, —CONH—, —CON(C 1 -C 4 alkyl)-, —NH—, —CH 2 —, —S— or —C(S)—;

B is —C 1 -C 10 alkyl, —C 2 -C 10 alkenyl, -heterocycle, —C 3 -C 8 carbocycle, -aryl, —NZ 1 Z 2 , —(C 1 -C 5 alkylene)-NZ 1 Z 2 , -alkylamino, -aminodialkyl, -alkylheterocycle, -arylamido, —C(O)OH, —C(O)O—(C 1 -C 5 alkyl), —C(O)O-phenyl or —C(NH)NH 2 any of which are unsubstituted or substituted with one or more of —O—(C 1 -C 5 alkyl), -halo, -alkylhalo, -alkanol, -alkylamino, -hydroxy, —NO 2 , —NH 2 , —CN, -aminoalkyl, -aminodialkyl, -heterocyclic amine, C 1 -C 10 alkyl, —C 2 -C 10 alkenyl, —C 2 -C 10 alkynyl, -aryl, -benzyl, -alkylamido, -alkylcarboxy, —C(O)OH, —C 1 -C 5 alkylene-C(O)O—(C 1 -C 5 alkyl) or —C 1 -C 5 alkylene-OC(O)—(C 1 -C 5 alkyl); and

comprising contacting a compound of formula 11a

with a compound of formula 12

wherein

R b is —Cl, —Br, —I, —OMs, —OTs or —OTf,

in the presence of a base, for a time and at a temperature sufficient to make the compound of formula 13.

62 . A method for making a compound of formula 22

wherein

A is —SO 2 —, —SO 2 NH—, —NHCO—, —NHCONH—, —O—, —CO—, —OC(O)—, —C(O)O—, —CONH—, —CON(C 1 -C 4 alkyl)-, —NH—, —CH 2 —, —S— or —C(S)—;

comprising contacting a compound of formula 21

wherein

R c is C 1 -C 3 alkyl,

with a compound of formula 20

wherein

each occurrence of R a is independently C 1 -C 3 alkyl; and

R b is —Cl, —Br, —I, —OMs, —OTs or —OTf,

in the presence of a base, for a time and at a temperature sufficient to make the compound of formula 22.

63 . A method for making a compound of formula 37

wherein

A is —SO 2 —, —SO 2 NH—, —NHCO—, —NHCONH—, —O—, —CO—, —OC(O)—, —C(O)O—, —CONH—, —CON(C 1 -C 4 alkyl)-, —NH—, —CH 2 —, —S— or —C(S)—;

B is —C 1 -C 11 alkyl, —C 2 -C 11 alkenyl, -heterocycle, —C 3 -C 8 carbocycle, -aryl, —NZ 1 Z 2 , —(C 1 -C 5 alkylene)-NZ 1 Z 2 , -alkylamino, -aminodialkyl, -alkylheterocycle, -arylamido, —C(O)OH, —C(O)O—(C 1 -C 5 alkyl), —C(O)O-phenyl or —C(NH)NH 2 any of which are unsubstituted or substituted with one or more of —O—(C 1 -C 5 alkyl), -halo, -alkylhalo, -alkanol, -alkylamino, -hydroxy, —NO 2 , —NH 2 , —CN, -aminoalkyl, -aminodialkyl, -heterocyclic amine, —C 1 -C 10 alkyl, —C 2 -C 11 alkenyl, —C 2 -C 10 alkynyl, -aryl, -benzyl, -alkylamido, -alkylcarboxy, —C(O)OH, —C 1 -C 5 alkylene-C(O)O—(C 1 -C 5 alkyl) or —C 1 -C 5 alkylene-OC(O)—(C 1 -C 5 alkyl); and

comprising contacting a compound of formula 36

wherein

R c is C 1 -C 3 alkyl,

with a compound of formula 11a or a compound of formula 20

wherein

each occurrence of R a is independently C 1 -C 3 alkyl; and

R b is —Cl, —Br, —I, —OMs, —OTs or —OTf,

in the presence of a base, for a time and at a temperature sufficient to make the compound of formula 37.

64 . A method for making a compound of formula 40

wherein

A is —SO 2 —, —SO 2 NH—, —NHCO—, —NHCONH—, —O—, —CO—, —OC(O)—, —C(O)O—, —CONH—, —CON(C 1 -C 4 alkyl)-, —NH—, —CH 2 —, —S— or —C(S)—;

B is —C 1 -C 10 alkyl, —C 2 -C 10 alkenyl, -heterocycle, —C 3 -C 8 carbocycle, -aryl, —NZ 1 Z 2 , —(C 1 -C 5 alkylene)-NZ 1 Z 2 , -alkylamino, -aminodialkyl, -alkylheterocycle, -arylamido, —C(O)OH, —C(O)O—(C 1 -C 5 alkyl), —C(O)O-phenyl or —C(NH)NH 2 any of which are unsubstituted or substituted with one or more of —O—(C 1 -C 5 alkyl), -halo, -alkylhalo, -alkanol, -alkylamino, -hydroxy, —NO 2 , —NH 2 , —CN, -aminoalkyl, -aminodialkyl, -heterocyclic amine, —C 1 -C 10 alkyl, —C 2 -C 10 alkenyl, —C 2 -C 10 alkynyl, -aryl, -benzyl, -alkylamido , -alkylcarboxy, —C(O)OH, —C 1 -C 5 alkylene-C(O)O—(C 1 -C 5 alkyl) or —C 1 -C 5 alkylene-OC(O)—(C 1 -C 5 alkyl); and

comprising contacting a compound of formula 39

with a compound of formula 11 or formula 20

wherein

each occurrence of R a is independently C 1 -C 3 alkyl;

R b is —Cl, —Br, —I, —OMs, —OTs or —OTf; and

R d is —H or —Br,

in the presence of a base, for a time and at a temperature sufficient to make the compound of formula 40.

65 . A compound of the formula

or a pharmaceutically acceptable hydrate or salt thereof,

wherein

R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , W and R 10 are independently -hydrogen, -halo, -hydroxy, —O—(C 1 -C 5 alkyl), —C 1 -C 10 alkyl, -alkylhalo, —C 2 -C 10 alkenyl, —C 3 -C 8 carbocycle, -aryl, —NH 2 , -alkylamino, —C(O)OH, —C(O)O(C 1 -C 5 alkyl), —OC(O)(C 1 -C 5 alkyl), NO 2 or -A-B;

A is —SO 2 —, —SO 2 NH—, —NHCO—, —NHCONH—, —O—, —CO—, —OC(O)—, —C(O)O—, —CONH—, —CON(C 1 -C 4 alkyl)-, —NH—, —CH 2 —, —S— or —C(S)—;

Z 1 and Z 2 are independently —H or —C 1 -C 11 alkyl, which is unsubstituted or substituted with one or more of -halo, —OH or —N(Z 3 )(Z 4 ), where Z 3 and Z 4 are independently, —H or —C 1 -C 5 alkyl, which is unsubstituted or substituted with one or more of -halo, -hydroxy or —NH 2 ; or N, Z 3 and Z 4 are taken together to form an unsubstituted or substituted heterocyclic amine; or N, Z 1 and Z 2 are taken together to form a heterocyclic amine.

66 . A compound of the formula

or a pharmaceutically acceptable hydrate or salt thereof,

wherein:

A is —SO 2 —, —SO 2 NH—, —NHCO—, —NHCONH—, —O—, —CO—, —OC(O)—, —C(O)O—, —CONH—, —CON(C 1 -C 4 alkyl)-, —NH—, —CH 2 —, —S— or —C(S)—;

B is —C 1 -C 10 alkyl, —C 2 -C 10 alkenyl, -heterocycle, —C 3 -C 8 carbocycle, -aryl, —NZ 1 Z 2 , —(C 1 -C 5 alkylene)-NZ 1 Z 2 , -alkylamino, -aminodialkyl, -alkylheterocycle, -arylamido, —C(O)OH, —C(O)O—(C 1 -C 5 alkyl), —C(O)O-phenyl or —C(NH)NH 2 any of which are unsubstituted or substituted with one or more of —O—(C 1 -C 5 alkyl), -halo, -alkylhalo, -alkanol, -alkylamino, -hydroxy, —NO 2 , —NH 2 , —CN, -aminoalkyl, -aminodialkyl, -heterocyclic amine, —C 1 -C 10 alkyl, —C 2 -C 10 alkenyl, —C 2 -C 10 alkynyl, -aryl, -benzyl, -alkylamido , -alkylcarboxy, —C(O)OH, —C 1 -C 5 alkylene-C(O)O—(C 1 -C 5 alkyl) or —C 1 -C 5 alkylene-OC(O)—(C 1 -C 5 alkyl); and

67 . A compound of the formula

or a pharmaceutically acceptable hydrate or salt thereof,

wherein

A is —SO 2 —, —SO 2 NH—, —NHCO—, —NHCONH—, —O—, —CO—, —OC(O)—, —C(O)O—, —CONH—, —CON(C 1 -C 4 alkyl)-, —NH—, —CH 2 —, —S— or —C(S)—;

68 . A compound of the formula

or a pharmaceutically acceptable hydrate or salt thereof,

wherein

A is —SO 2 —, —SO 2 NH—, —NHCO—, —NHCONH—, —O—, —CO—, —OC(O)—, —C(O)O—, —CONH—, —CON(C 1 -C 4 alkyl)-, —NH—, —CH 2 —, —S— or —C(S)—;

Assignments (2)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 20, 2008

From: JAGTAP, PRAKASH; BALOGLU, ERKEN; VAN DUZER, JOHN H.; SZABO, CSABA; SALZMAN, ANDREW L.; ROY, ALOKA; WILLIAMS, WILLIAM; NIVOROZHKIN, ALEXANDER

To: INOTEK PHARMACEUTICALS CORPORATION

Reel/Frame 021417/0553 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 19, 2008

From: JAGTAP, PRAKASH; BALOGLU, ERKAN; VAN DUZER, JOHN H.; SZABO, CSABA; SALZMAN, ANDREW L.; ROY, ALOKA; WILLIAMS, WILLIAM; NIVOROZHKIN, ALEXANDER

To: INOTEK PHARMACEUTICALS CORPORATION

Reel/Frame 021413/0409 →