INHIBITING TRABID
The present disclosure is directed to compounds of formulas (I)-(VII), which are useful as modulators of TRABID. The compounds are further useful in the inhibition of TRABID and the treatment of diseases or disorders associated with the inhibition of TRABID. For instance, the disclosure is concerned with compounds and compositions for inhibition of TRABID, methods of treating diseases associated with the inhibition of TRABID (e.g., autoimmune inflammatory diseases including, but not limited to, psoriasis), and methods of synthesis of these compounds.
1 . A compound of formula (I):
and pharmaceutically acceptable salts thereof, wherein z is zero or one, and
(A) when z is one:
R 1 and R 1 ′ are each independently hydrogen, (C 1 -C 4 ) alkyl, or together with one of R 2 , R 3 , or R 4 , form a heterocycloalkyl;
R 2 and R 2 ′ are each independently hydrogen, (C 1 -C 4 ) alkyl, or together with one of R 1 , R 3 , or R 4 , form a cycloalkyl or heterocycloalkyl;
R 3 and R 3 ′ are each independently hydrogen, (C 1 -C 4 ) alkyl, or together with one of R 1 , R 2 , or R 4 , form a cycloalkyl or heterocycloalkyl;
x and y are each independently zero or one;
L is —C(O)NR 4 — or —NR 4 C(O)—;
R 4 is hydrogen, (C 1 -C 6 ) alkyl, or together with any one of R 1 , R 2 , or R 3 , form a heterocycloalkyl;
Ar 1 is unsubstituted heteroaryl with up to two heteroatoms independently selected from the group consisting of N, O, and S;
Ar 2 is independently an aryl or heteroaryl optionally substituted with one or more R 10 , R 12 , or —OR 12 , or together with Ar 1 , form a fused bicyclic (C 8 -C 10 ) aryl or heteroaryl optionally substituted with one or more R 11 ;
each R 10 is independently halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) cycloalkyl, (C 1 -C 6 ) alkoxy, aryloxy, or aryl or heteroaryl optionally substituted with one or more R 11 ;
each R 11 is independently hydroxyl or halogen; and
R 12 is aryl or heteroaryl, optionally substituted with one or more R 10 ;
(1) wherein, when L is —C(O)NR 4 —, x is one;
R 1 , R 1 ′, R 2 ′, and R 4 are each hydrogen;
R 2 is hydrogen or (C 1 -C 4 ) alkyl;
R 3 , if present, is hydrogen or (C 1 -C 4 ) alkyl;
R 3 ′, if present, is hydrogen; and
no combination of R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, and R 4 forms a cycloalkyl or heterocycloalkyl;
(2) wherein, when L is —NR 4 C(O)—,
(a) when an R 10 or R 12 is heteroaryl substituted with alkyl, and at least two of R 1 , R 1 ′, R 2 , R 2 ′, R 3 , R 3 ′, and R 4 combine to define a spirocyclyl comprising (i) a pyrrolidinyl and a cyclobutyl having a carbon atom as a spiro atom, or (ii) an azetidinyl and a cyclobutyl having a carbon atom as a spiro atom, the spiro atom is not adjacent a nitrogen of the pyrrolidinyl or the azetidinyl;
(b) when Ar 2 is substituted with more than one halogen, and R 4 forms a 5- or 6-membered heterocyclyl with another substituent, R 1 and R 1 ′ are each hydrogen;
(c) when Ar 2 is unsubstituted phenyl, and one of R 2 , R 3 , and R 4 forms a cyclobutyl or a spirocyclyl which includes a cyclobutyl, R 1 and R 1 ′ are each hydrogen;
(B) when z is zero:
R 1 and R 1 ′ are each independently hydrogen, (C 1 -C 4 ) alkyl, or together with one of R 2 , R 3 , or R 4 , form a cycloalkyl or heterocycloalkyl;
R 2 and R 2 ′ are each independently hydrogen, (C 1 -C 4 ) alkyl, or together with one of R 1 , R 3 , or R 4 , form a cycloalkyl or heterocycloalkyl;
R 3 and R 3 ′ are each independently hydrogen, (C 1 -C 4 ) alkyl, or together with one of R 1 , R 2 , or R 4 , form a cycloalkyl or heterocycloalkyl;
x and y are each independently zero or one;
L is —C(O)NR 4 — or —NR 4 C(O)—;
R 4 is hydrogen, (C 1 -C 6 ) alkyl, or together with any one of R 1 , R 2 , or R 3 , form a heterocycloalkyl; and
Ar 1 is independently an aryl or heteroaryl substituted with one aryloxy.
2 . The compound of claim 1 , wherein z is one.
3 . The compound of claim 1 , wherein Ar 1 is selected from the group consisting of: pyrazolyl, thiazolyl, and isoxazolyl.
4 . The compound of claim 1 , wherein Ar 1 is unsubstituted pyrazolyl, unsubstituted thiazolyl, or unsubstituted isoxazolyl.
5 . The compound of claims 1 - 4 , wherein the compound is further given by formula (II):
and pharmaceutically acceptable salts thereof, wherein L is —NR 4 C(O)—; R 13 is selected from halogen, (C 1 -C 4 ) alkoxy, and aryloxy; and m is 1 or 2.
6 . The compound of claim 1 , wherein R 13 is selected from the group consisting of: —Cl, —OCH 3 , and —OC 6 H 5 .
7 . (canceled)
8 . The compound of claim 1 , wherein the compound is further given by formula (III):
and pharmaceutically acceptable salts thereof, wherein R 14 is (C 1 -C 4 ) alkoxy or aryloxy; and n is 0 or 1.
9 . The compound of claim 1 , wherein R 14 is —OCH 3 or —OC 6 H 5 .
10 . (canceled)
11 . The compound of claim 1 , wherein the compound is further given by formula (IV):
and pharmaceutically acceptable salts thereof, wherein L is —NR 4 C(O).
12 . (canceled)
13 . The compound of claim 1 , wherein the compound is further given by formula (V):
and pharmaceutically acceptable salts thereof, wherein L is —NR 4 C(O); and R 15 is (C 1 -C 4 ) alkyl or (C 1 -C 4 ) alkoxy.
14 . The compound of claim 1 , wherein R 15 is methyl or —OCH 3 .
15 . (canceled)
16 . The compound of claim 1 , wherein the compound is further given by formula (VI):
and pharmaceutically acceptable salts thereof, wherein Q is N or CH; R 16 is (C 1 -C 4 ) alkoxy or heteroaryl substituted with (C 1 -C 4 ) alkyl; and o is 0 or 1.
17 . The compound of claim 1 , wherein R 16 is —OCH 3 or pyrazolyl substituted with one methyl.
18 . (canceled)
19 . The compound of claim 1 , wherein z is zero.
20 . The compound of claim 1 , wherein the compound is further given by formula (VII):
and pharmaceutically acceptable salts thereof.
21 . A pharmaceutical composition comprising the compound of claim 1 and one or more of a pharmaceutically acceptable carrier, adjuvant, or vehicle.
22 . A method of inhibiting TRABID in a patient comprising administering to the patient in need thereof, an effective amount of the compound of claim 1 .
23 . A method of inhibiting TRABID in a patient comprising administering to the patient in need thereof, an effective amount of the pharmaceutical composition of claim 21 .
24 . A method of treating, preventing, inhibiting, or eliminating a disease or disorder associated with the activity of TRABID in a patient comprising:
administering to the patient in need thereof, a therapeutically effective amount of the compound of claim 1 .
25 . (canceled)
26 . The method of claim 24 , wherein the disease or disorder is an autoimmune inflammatory disease.
27 . (canceled)