US2020062803A1PendingUtilityA1
Azaindoline compounds as granzyme b inhibitors
Est. expiryAug 1, 2034(~8 yrs left)· nominal 20-yr term from priority
Inventors:Dale R. Cameron
A61P 17/00C07K 5/0812A61K 38/05C07K 5/101A61K 8/64C07K 5/0808A61K 38/00C07K 5/06104A61K 38/06A61Q 7/00C07K 5/0202
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Claims
Abstract
Azaindoline compounds as granzyme B inhibitors, compositions that include the compounds, and methods for using the compounds. Methods for treating cutaneous scleroderma, epidermolysis bullosa, radiation dermatitis, alopecia areata, and discoid lupus erythematosus are provided.
Claims
exact text as granted — not AI-modifiedThe embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:
1 . A compound having Formula (I):
its stereoisomers, tautomers, and pharmaceutically acceptable salts thereof, wherein:
R 1 is a heteroaryl group selected from
(a) 1,2,3-triazolyl, and
(b) 1,2,3,4-tetrazolyl;
n is 1 or 2;
R 2 a and R 2 b are independently selected from hydrogen and C1-C6 alkyl;
R 2 c at each occurrence is independently selected from
(a) hydrogen,
(b) halogen,
(c) C 1 -C 6 alkyl,
(d) —XR 11 , wherein X is selected from O, C(═O), S, S═O, or S(═O) 2 ,
(e) —C(═O)N(R 12 )(R 13 ),
(f) —N(R 11 )(R 12 )(R 13 ),
(g) —N—C(═O)—R 11 , and
(h) —N—C(═O)O—R 11 ,
wherein R 11 , R 12 , and R 13 are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 6 -C 10 aryl, aralkyl, and C 3 -C 10 heteroaryl;
m is 1, 2, or 3;
R 3 is selected from
(a) hydrogen,
(b) C 1 -C 4 alkyl optionally substituted with a carboxylic acid, carboxylate, or carboxylate C 1 -C 8 ester group (—CO 2 H, —CO 2 − , —C(═O)OC 1 -C 8 ), an amide optionally substituted with an alkylheteroaryl group, or a heteroaryl group;
Z is an acyl group selected from the group
(a)
and
(b)
wherein
Y is hydrogen, heterocycle, —NH 2 , or C 1 -C 4 alkyl;
R 4 is selected from
(i) C 1 -C 12 alkyl,
(ii) C 1 -C 6 heteroalkyl optionally substituted with C 1 -C 6 alkyl,
(iii) C 3 -C 6 cycloalkyl,
(iv) C 6 -C 10 aryl,
(v) heterocyclyl,
(vi) C 3 -C 10 heteroaryl,
(vii) aralkyl, and
(viii) heteroalkylaryl;
R 5 is heteroaryl or —C(═O)—R 10 ,
wherein R 10 is selected from
(i) C 1 -C 12 alkyl optionally substituted with C 6 -C 10 aryl, C 1 -C 10 heteroaryl, amino, or carboxylic acid,
(ii) C 1 -C 10 heteroalkyl optionally substituted with C 1 -C 6 alkyl or carboxylic acid,
(iii) C 3 -C 6 cycloalkyl optionally substituted with C 1 -C 6 alkyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 3 -C 10 heteroaryl, amino, or carboxylic acid,
(iv) C 6 -C 10 aryl optionally substituted with C 1 -C 6 alkyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 3 -C 10 heteroaryl, amino, or carboxylic acid,
(v) heterocyclyl,
(vi) C 3 -C 10 heteroaryl,
(vii) aralkyl, and
(viii) heteroalkylaryl.
2 . The compound of claim 1 , its stereoisomers, tautomers, and pharmaceutically acceptable salts thereof, wherein:
R 1 is a heteroaryl group selected from
(a) 1,2,3-triazolyl, and
(b) 1,2,3,4-tetrazolyl;
n is 1; R 2 a, R 2 b, and R 2 c are hydrogen; R 3 is selected from
(a) hydrogen,
(b) C 1 -C 4 alkyl optionally substituted with a carboxylic acid, carboxylate, or carboxylate C 1 -C 8 ester group (—CO 2 H, —CO 2 − , —C(═O)OC 1 -C 8 ), an amide optionally substituted with an alkylheteroaryl group, or a heteroaryl group;
Z is an acyl group selected from the group
(a)
and
(b)
3 . The compound of claim 1 , its stereoisomers, tautomers, and pharmaceutically acceptable salts thereof, wherein:
R 1 is tetrazole or triazole; n is 1; R 3 is hydrogen, C 1 -C 4 alkyl substituted with a carboxylic acid or carboxylate group, C 1 -C 4 alkyl substituted with an amide optionally substituted with an alkylheteroaryl group, or a heteroaryl group; and Z is
4 . The compound of claim 1 , its stereoisomers, tautomers, and pharmaceutically acceptable salts thereof, wherein:
R 1 is tetrazole or triazole; n is 1; R 3 is hydrogen, or C 1 -C 4 alkyl substituted with a carboxylic acid or carboxylate group, an amide optionally substituted with an alkylheteroaryl group, or a heteroaryl group; and Z is
wherein
R 4 is selected from
(i) C 1 -C 12 alkyl,
(ii) C 3 -C 6 cycloalkyl,
(iii) C 6 -C 10 aryl, and
(iv) C 3 -C 10 heteroaryl;
R 5 is —C(═O)—R 10 , wherein R 10 is selected from
(i) C 1 -C 12 alkyl optionally substituted with C 6 -C 10 aryl, C 1 -C 10 heteroaryl, amino, or carboxylic acid,
(ii) C 1 -C 10 heteroalkyl optionally substituted with C 1 -C 6 alkyl or carboxylic acid,
(iii) C 3 -C 6 cycloalkyl optionally substituted with C 1 -C 6 alkyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 3 -C 10 heteroaryl, amino, or carboxylic acid,
(iv) C 6 -C 10 aryl optionally substituted with C 1 -C 6 alkyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 3 -C 10 heteroaryl, amino, or carboxylic acid,
(v) C 3 -C 10 heteroaryl; and
Y is hydrogen, C 1 -C 4 alkyl, or —NH 2 .
5 . A compound having Formula (II):
its stereoisomers, tautomers, and pharmaceutically acceptable salts thereof, wherein:
R 1 is a heteroaryl group selected from
(a) 1,2,3-triazolyl, and
(b) 1,2,3,4-tetrazolyl;
R 3 is selected from
(a) hydrogen,
(b) C 1 -C 4 alkyl optionally substituted with a carboxylic acid, carboxylate, or carboxylate C 1 -C 8 ester group (—CO 2 H, —CO 2 —, —C(═O)OC 1 -C 8 ), an amide optionally substituted with an alkylheteroaryl group, or a heteroaryl group;
R 4 is selected from
(i) C 1 -C 12 alkyl,
(ii) C 1 -C 6 heteroalkyl optionally substituted with C 1 -C 6 alkyl,
(iii) C 3 -C 6 cycloalkyl,
(iv) C 6 -C 10 aryl,
(v) heterocyclyl,
(vi) C 3 -C 10 heteroaryl,
(vii) aralkyl, and
(viii) heteroalkylaryl; and
R 10 is selected from
(i) C 1 -C 12 alkyl optionally substituted with C 6 -C 10 aryl, C 1 -C 10 heteroaryl, amino, or carboxylic acid,
(ii) C 1 -C 10 heteroalkyl optionally substituted with C 1 -C 6 alkyl or carboxylic acid,
(iii) C 3 -C 6 cycloalkyl optionally substituted with C 1 -C 6 alkyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 3 -C 10 heteroaryl, amino, or carboxylic acid,
(iv) C 6 -C 10 aryl optionally substituted with C 1 -C 6 alkyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 3 -C 10 heteroaryl, amino, or carboxylic acid,
(v) heterocyclyl,
(vi) C 3 -C 10 heteroaryl,
(vii) aralkyl, and
(viii) heteroalkylaryl.
6 . The compound of claim 5 , its stereoisomers, tautomers, and pharmaceutically acceptable salts thereof, wherein:
R 10 , when defined as C 1 -C 12 alkyl substituted with a carboxylic acid or carboxylate group, is: —(CH 2 ) n —CO 2 H, where n is 2, 3, 4, 5, or 6; optionally wherein one or more single methylene carbons are substituted with a fluoro, hydroxy, amino, C 1 -C 3 alkyl, or C 6 -C 10 aryl group; optionally wherein one or more single methylene carbons are substituted with two fluoro or C 1 -C 3 alkyl groups; optionally wherein one or more single methylene carbons are substituted with two alkyl groups that taken together with the carbon to which they are attached form a 3, 4, 5, or 6-membered carbocyclic ring; and optionally wherein adjacent carbon atoms from an unsaturated carbon-carbon bond or taken form a benzene ring; or
7 . The compound of claim 5 , its stereoisomers, tautomers, and pharmaceutically acceptable salts thereof, wherein:
wherein R 10 , when defined as C 3 -C 6 cycloalkyl substituted with a carboxylic acid or carboxylate group, is:
wherein n is 1, 2, 3, or 4; and optionally, for n=3 or 4, wherein adjacent carbon atoms from an unsaturated carbon-carbon bond.
8 . The compound of claim 5 , its stereoisomers, tautomers, and pharmaceutically acceptable salts thereof, wherein:
R 1 is tetrazole or triazole; R 3 is hydrogen; C 1 -C 4 alkyl optionally substituted with a carboxylic acid, carboxylate, or a carboxylate ester group; or C 1 -C 4 alkyl optionally substituted with an amide, which may be optionally substituted with an alkylheteroaryl group; R 4 is C 1 -C 12 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, C 3 -C 10 heteroaryl, or heterocyclyl; and R 10 is C 1 -C 12 alkyl optionally substituted with C 6 -C 10 aryl, C 1 -C 10 heteroaryl, amino, or carboxylic acid.
9 . The compound of claim 5 , its stereoisomers, tautomers, and pharmaceutically acceptable salts thereof, wherein:
R 1 is tetrazole or triazole; R 3 is C 1 -C 4 alkyl optionally substituted with a carboxylic acid, carboxylate, or a carboxylate ester group; R 4 is C 1 -C 8 alkyl or C 3 -C 6 cycloalkyl; and R 10 is selected from:
(a) C 1 -C 3 alkyl substituted with C 6 -C 10 aryl (e.g., phenyl) or C 1 -C 10 heteroaryl (e.g., triazolyl or tetrazolyl);
(b) —(CH 2 ) n —CO 2 H, where n is 2, 3, 4, 5, or 6;
(c)
wherein n is 1, 2, 3, or 4.
10 . A compound having Formula (III):
its stereoisomers, tautomers, and pharmaceutically acceptable salts thereof, wherein
R 1 is a heteroaryl group selected from
(a) 1,2,3-triazolyl, and
(b) 1,2,3,4-tetrazolyl;
R 3 is selected from
(a) hydrogen,
(b) C 1 -C 4 alkyl optionally substituted with a carboxylic acid, carboxylate, or carboxylate C 1 -C 8 ester group (—CO 2 H, —CO 2 —, —C(═O)OC 1 -C 8 ), an amide optionally substituted with an alkylheteroaryl group, or a heteroaryl group;
Y is hydrogen, heterocycle, —NH 2 , or C 1 -C 4 alkyl; and
R 4 is selected from
(i) C 1 -C 12 alkyl,
(ii) C 1 -C 6 heteroalkyl optionally substituted with C 1 -C 6 alkyl,
(iii) C 3 -C 6 cycloalkyl,
(iv) C 6 -C 10 aryl,
(v) heterocyclyl,
(vi) C 3 -C 10 heteroaryl,
(vii) aralkyl, and
(viii) heteroalkylaryl.
11 . The compound of claim 10 , its stereoisomers, tautomers, and pharmaceutically acceptable salts thereof, wherein:
R 1 is tetrazole or triazole; R 3 is hydrogen; C 1 -C 4 alkyl optionally substituted with a carboxylic acid, carboxylate, or a carboxylate ester group; or C 1 -C 4 alkyl optionally substituted with an amide, which may be optionally substituted with an alkylheteroaryl group; R 4 is C 1 -C 12 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, C 3 -C 10 heteroaryl, or heterocyclyl; and Y is hydrogen, C 1 -C 4 alkyl, or —NH 2 .
12 . The compound of claim 10 , its stereoisomers, tautomers, and pharmaceutically acceptable salts thereof, wherein:
R 1 is tetrazole or triazole; R 3 is C 1 -C 4 alkyl optionally substituted with a carboxylic acid, carboxylate, or a carboxylate ester group; R 4 is selected from
(i) C 1 -C 8 alkyl,
(ii) C 3 -C 6 cycloalkyl,
(iii) C 6 -C 10 aryl,
(iv) C 3 -C 10 heteroaryl, and
(v) heterocyclyl; and
Y is hydrogen.
13 . A compound as shown in Table 1.
14 . A pharmaceutical composition, comprising a compound of any one of claims 1 - 13 and a pharmaceutically acceptable carrier.
15 . A method for inhibiting Granzyme B in a subject, comprising administering an effective amount of a compound of any one of claims 1 - 13 or a pharmaceutical composition of claim 14 to a subject in need thereof.
16 . A method for treating a disease, disorder, or condition treatable by inhibiting Granzyme B, comprising administering a therapeutically effective amount of a compound of any one of claims 1 - 13 or a pharmaceutical composition of claim 14 to a subject in need thereof.
17 . The method of claim 16 , wherein the disease, disorder, or condition treatable by inhibiting Granzyme B is selected from treating dissection, aneurysm, and atherosclerosis.
18 . The method of claim 16 , wherein the condition treatable by inhibiting Granzyme B is a wound and administering the compound or composition promotes wound healing.
19 . The method of any one of claims 15 - 18 , wherein administering the compound or composition comprises topical administration, oral administration, and administration by injection.
20 . A method for treating cutaneous scleroderma, epidermolysis bullosa, radiation dermatitis, alopecia areata, or discoid lupus erythematosus, comprising administering a therapeutically effective amount of a compound of any one of claims 1 - 13 or a pharmaceutical composition of claim 14 to a subject in need thereof.
21 . The method of claim 20 , wherein administering the compound or compositin comprises topical administration.Join the waitlist — get patent alerts
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