US2022153751A1PendingUtilityA1
Bifunctional compounds
Est. expiryJul 27, 2038(~12 yrs left)· nominal 20-yr term from priority
Inventors:Kyle W.H. ChanAparajita Hoskote ChourasiaPaul E. ErdmanLeah FungDavid Aaron HechtFrank MercurioRobert SullivanJoseph P. Vacca
C07D 495/04A61P 35/00C07D 417/14C07D 403/14C07D 401/14A61K 31/4545A61K 31/53A61K 31/55A61K 31/506A61K 31/454
66
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Claims
Abstract
The present application provides compounds that modulate CDK protein function. Methods of making the compounds, compositions containing the compounds, and uses of the compounds for treating or ameliorating of diseases, disorders, or conditions associated with CDK proteins, are also disclosed.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of Formula (I),
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is
wherein R 1 is optionally substituted with one or more R A ;
n is 1, 2, or 3;
each R 2a and R 2b is independently H, deuterium, halogen, or C 1 -C 6 alkyl;
each R 3 is independently H, deuterium, C 1 -C 6 alkyl,
each R A is independently deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, optionally substituted amino, C 1 -C 6 alkylamino, amino(C 1 -C 6 alkyl), —(C═O)NR 10a R 10b (C 1 -C 6 alkoxy)C 1 -C 6 alkyl, —O—(C 1 -C 6 alkoxy)C 1 -C 6 alkyl, or optionally substituted C 3 -C 7 cycloalkyl;
each of R 4 , R 5 and R 6 is independently H, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, optionally substituted C 3 -C 7 cycloalkyl(C 1 -C 3 alkyl), or optionally substituted C 3 -C 7 cycloalkyl;
each of R 7a and R 7b is independently H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 6 -C 10 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C 7 -C 14 aralkyl, optionally substituted 3 to 10 membered heterocyclyl, or optionally substituted C 3 -C 8 carbocyclyl;
each of R 8a and R 8b is independently H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, or C 3 -C 8 carbocyclyl;
each of R 9a and R 9b is independently H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 7 -C 14 aralkyl, or optionally substituted C 3 -C 8 carbocyclyl;
each R 10a and R 10b is independently H or C 1 -C 6 alkyl, or R 10a and R 10b together with the nitrogen atom to which they are attached form an optionally substituted 5 or 6 membered heterocyclyl optionally substituted with one or more R 11 ;
each R 11 is independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkyl, —O—(C 1 -C 6 alkoxy)C 1 -C 6 alkyl, optionally substituted amino, halogen, or cyano; or two geminal R 11 form oxo;
Q is CH 2 or C═O;
L 1 is a bond,
*—Z 1e -Z 3 —(CH 2 ) m5 —,
wherein the asterisk * indicates the point of connection to X 1 ;
each of Z 1a , Z 1b , Z 1c , Z 1d , Z 1e , and Z 1f is independently a bond or —(CR a R b ) q1 —;
Z 2 is —(CR c R d ) q2 —;
Z 3 is a bond, O or NR 12g ;
each of R a , R b , R c and R d is independently H, halogen, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, or optionally substituted C 3 -C 6 cycloalkyl;
each q1 and q2 is independently 1, 2 or 3;
each X a and X b is independently O or S;
each Ring A is independently phenyl or a five to six membered heteroaryl, each optionally substituted with one or more R 11 ;
each of Y 1 , Y 2 , Y 3 , Y 4 , Y 5 and Y 6 is —NR 12h —, —O—, or —S—;
each R 12a , R 12b , R 12c , R 12d , R 12e , R 12f , R 12g and R 12h is independently H or C 1 -C 6 alkyl;
each of m1, m2, m3, m4, m5, m6, k1, k2, k3, k4, k5, k6, p1, p2, p3, p4, p5, and p6 is independently 0, 1, 2, or 3;
L 2 is a bond, —C(═O)—, or —(CH 2 ) 0-3 —C(═O)NR 3 —;
R 13 is H or C 1 -C 6 alkyl;
X 1 is C 1 -C 15 alkylene or heteroalkylene;
X 2 is —NHC(═O)—, —NH—, —O—, —NHC(═O)NH—, —NHCH 2 — or —S—; and
X 3 is —NH—, —O—, or —S—;
provided that when the compound has the structure
R 1 is
Q is C═O, n is 2, R 3 is H, then R 2a is deuterium, halogen, or C 1 -C 6 alkyl.
2 . The compound of claim 1 , wherein R 1 is
3 . The compound of claim 1 or 2 , wherein R 2a is H.
4 . The compound of any one of claims 1 to 3 , wherein R 2b is C 1 -C 6 alkyl.
5 . The compound of any one of claims 1 to 4 , wherein R 3 is H.
6 . The compound of any one of claims 1 to 5 , wherein n is 2.
7 . The compound of any one of claims 1 to 6 , wherein R 4 is H.
8 . The compound of any one of claims 1 to 7 , wherein one of R 5 and R 6 is H and the other of R 5 and R 6 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl(C 1 -C 3 alkyl), trifluoromethyl substituted cyclopropyl, or trifluoromethyl substituted cyclopropyl(C 1 -C 3 alkyl).
9 . The compound of any one of claims 1 to 8 , wherein L 1 is
10 . The compound of claim 9 , wherein each of R 12a and R 12b is H; X a is O; Z 1a is a bond or —(CH 2 ) 1-3 —; and m1 is 0 or 1.
11 . The compound of any one of claims 1 to 8 , wherein L 1 is
12 . The compound of claim 11 , wherein each of R 12c and R 12d is H; X a is O; Z 2 is —CH 2 —; Z 1b is a bond or —(CH 2 ) 1-3 —; and m2 is 0 or 1.
13 . The compound of any one of claims 1 to 8 , wherein L 1 is *—Z 1e -Z 3 —(CH 2 ) m5 — and Z 3 is —NR 12g —.
14 . The compound of claim 13 , wherein R 12g is H; Z 1e is a bond or —(CH 2 ) 1-3 —; and m5 is 0 or 1.
15 . The compound of any one of claims 1 to 8 , wherein L 1 is
16 . The compound of claim 15 , wherein R 12f is H; Z 1d is a bond or —(CH 2 ) 1-3 —; X a is O; Ring A is phenyl; Y 4 is —O— or —NH—; each of k4, p4 and m4 is independently 0 or 1.
17 . The compound of any one of claims 1 to 8 , wherein L 1 is
and Z 3 is —NR 12g —.
18 . The compound of claim 17 , wherein R 12g is H; Z 1e is a bond or —(CH 2 ) 1-3 —; Ring A is phenyl; Y 5 is —O— or —NH—; each of k5, p5 and m5 is independently 0 or 1.
19 . The compound of any one of claims 1 to 8 , wherein L 1 is
20 . The compound of claim 19 , wherein Z 1f is a bond or —(CH 2 ) 1-3 —; m6 is 0 or 1.
21 . The compound of any one of claims 1 to 20 , wherein L 2 is a bond or —(CH 2 )C(O)NH—.
22 . The compound of any one of claims 1 to 21 , wherein X 1 is C 1 -C 5 alkylene.
23 . The compound of any one of claims 1 to 21 , wherein X 1 is [—(CH 2 ) 2 O-] 1-5 , —[(CH 2 ) 2 O] 1-5 (CH 2 ) 2 — or —(CH 2 ) 1-3 —NR 14 —(CH 2 ) 1-3 —, and wherein R 14 is H or C 1 -C 6 alkyl.
24 . The compound of any one of claims 1 to 23 , wherein X 2 is —NHC(═O)—.
25 . The compound of any one of claims 1 to 24 , wherein X 3 is —S—.
26 . The compound of claim 1 , selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
27 . A compound of Formula (II),
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is
wherein R 1 is optionally substituted with one or more R A ;
n is 1, 2 or 3;
each R 2a and R 2b is independently H, deuterium, halogen or C 1 -C 6 alkyl;
each R 3 is independently H, deuterium, C 1 -C 6 alkyl,
each R A is independently deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, optionally substituted amino, C 1 -C 6 alkylamino, amino(C 1 -C 6 alkyl), —(C═O)NR 10a R 10b , (C 1 -C 6 alkoxy)C 1 -C 6 alkyl, —O—(C 1 -C 6 alkoxy)C 1 -C 6 alkyl, or optionally substituted C 3 -C 7 cycloalkyl;
each of R 4 and R 6 is independently H, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, optionally substituted C 3 -C 7 cycloalkyl(C 1 -C 3 alkyl), or optionally substituted C 3 -C 7 cycloalkyl;
each of R 5a , R 5b and R 5c is independently H or C 1 -C 6 alkyl;
each of R 7a and R 7b is independently H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 6 -C 10 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C 7 -C 14 aralkyl, optionally substituted 3 to 10 membered heterocyclyl, or optionally substituted C 3 -C 8 carbocyclyl;
each of R 8a and R 8b is independently H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, or C 3 -C 8 carbocyclyl;
each of R 9a and R 9b is independently H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 7 -C 14 aralkyl, or optionally substituted C 3 -C 8 carbocyclyl;
each R 10a and R 10b is independently H or C 1 -C 6 alkyl, or R 10a and R 10b together with the nitrogen atom to which they are attached form an optionally substituted 5 or 6 membered heterocyclyl optionally substituted with one or more R 11 ;
each R 11 is independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkyl, —O—(C 1 -C 6 alkoxy)C 1 -C 6 alkyl, optionally substituted amino, halogen, or cyano; or two geminal R 11 form oxo;
Q is CH 2 or C═O;
L 1 is a bond
*—Z 1e -Z 3 —(CH 2 ) m5 —,
wherein the asterisk * indicates the point of connection to X 1 ;
each of Z 1a , Z 1b , Z 1c , Z 1d , Z 1e , and Z 1f is independently a bond or —(CR a R b ) q1 —;
Z 2 is —(CR c R d ) q2 —;
Z 3 is a bond, O or NR 12g ;
each of R a , R b , R c and R d is independently H, halogen, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, or optionally substituted C 3 -C 6 cycloalkyl;
each q1 and q2 is independently 1, 2 or 3;
each X a and X b is independently O or S;
each Ring A is independently phenyl or a five to six membered heteroaryl, each optionally substituted with one or more R 11 ;
each of Y 1 , Y 2 , Y 3 , Y 4 , Y 5 and Y 6 is —NR 12h —, —O—, or —S—
each R 12a , R 12b , R 12c , R 12d , R 12e , R 12f , R 12g and R 12h is independently H or C 1 -C 6 alkyl;
each of m1, m2, m3, m4, m5, m6, k1, k2, k3, k4, k5, k6, p1, p2, p3, p4, p5, and p6 is independently 0, 1, 2, or 3;
L 2 is a bond, —(CH 2 ) 1-6 NH—, —(CH 2 ) 0-6 —C(═O)—, or —(CH 2 ) 0-3 —C(═O)NR 3 —;
R 13 is H or C 1 -C 6 alkyl;
X 1 is C 1 -C 15 alkylene or heteroalkylene; and
Ring B is phenyl or a 6 membered heteroaryl, optionally substituted with one or more R 11 .
28 . The compound of claim 27 , wherein the compound of Formula (II) is also represented by Formula (II′):
or a pharmaceutically acceptable salt thereof.
29 . The compound of claim 27 or 28 , wherein R 1 is
30 . The compound of any one of claims 27 to 29 , wherein R 2a is H.
31 . The compound of any one of claims 27 to 30 , wherein R 2b is C 1 -C 6 alkyl.
32 . The compound of any one of claims 27 to 31 , wherein R 3 is H.
33 . The compound of any one of claims 27 to 32 , wherein n is 2.
34 . The compound of any one of claims 27 to 33 , wherein R 1 is substituted with one R A and wherein R A is halogen or optionally substituted C 1 -C 6 alkyl.
35 . The compound of any one of claims 27 to 34 , wherein each of R 5b and R 5c is H.
36 . The compound of any one of claims 27 to 35 , wherein L 1 is
37 . The compound of claim 36 , wherein each of R 12a and R 12b is H; X a is O; Z 1a is a bond or —(CH 2 ) 1-3 —; and m1 is 0 or 1.
38 . The compound of any one of claims 27 to 35 , wherein L 1 is
39 . The compound of claim 38 , wherein each of R 12c and R 12d is H; X a is O; Z 2 is —CH 2 —; Z 1b is a bond or —(CH 2 ) 1-3 —; and m2 is 0 or 1.
40 . The compound of any one of claims 27 to 35 , wherein L 1 is *—Z 1e -Z 3 —(CH 2 ) m5 — and Z 3 is —NR 12g .
41 . The compound of claim 40 , wherein R 12g is H; Z 1e is a bond or —(CH 2 ) 1-3 —; and m5 is 0 or 1.
42 . The compound of any one of claims 27 to 35 , wherein L 1 is
43 . The compound of claim 42 , wherein R 12f is H; Z 1d is a bond or —(CH 2 ) 1-3 —; X a is O; Ring A is phenyl; Y 4 is —O— or —NH—; each of k4, p4 and m4 is independently 0 or 1.
44 . The compound of any one of claims 27 to 35 , wherein L 1 is
and Z 3 is —NR 12g —.
45 . The compound of claim 44 , wherein R 12g is H; Z 1e is a bond or —(CH 2 ) 1-3 —; Ring A is phenyl; Y 5 is —O— or —NH—; each of k5, p5 and m5 is independently 0 or 1.
46 . The compound of any one of claims 27 to 35 , wherein L 1 is
47 . The compound of claim 46 , wherein each of R 12c and R 12d is H; X a is O; Z 1b is a bond or —(CH 2 ) 1-3 —; Z 2 is —(CH 2 ) 1-3 —; Ring A is phenyl; and each of k2, p2 and m2 is independently 0 or 1.
48 . The compound of any one of claims 27 to 35 , wherein L 1 is
49 . The compound of claim 46 , wherein Z 1f is a bond or —(CH 2 ) 1-3 —; m6 is 0 or 1.
50 . The compound of any one of claims 27 to 49 , wherein X 1 is C 1 -C 8 alkylene.
51 . The compound of any one of claims 27 to 49 , wherein X 1 is [—(CH 2 ) 2 O-] 1-5 -, —[(CH 2 ) 2 O] 1-5 (CH 2 ) 2 — or —(CH 2 ) 1-3 —NR 14 —(CH 2 ) 1-3 — and wherein R 14 is H or C 1 -C 6 alkyl.
52 . The compound of any one of claims 27 to 51 , wherein L 2 is a bond, —C(O)—, or —(CH 2 )C(O)NH—.
53 . The compound of any one of claims 27 to 52 , wherein Ring B is phenyl optionally substituted with one or more R 11 .
54 . The compound of any one of claims 27 to 52 , wherein Ring B is a 6 membered heteroaryl containing one, two or three nitrogen atoms, optionally substituted with one or more R 11 .
55 . The compound of claim 54 , wherein Ring B is
each optionally substituted with one R 11 .
56 . The compound of claim 55 , wherein Ring B is
57 . The compound of any one of claims 53 to 56 , wherein R 11 is halogen.
58 . The compound of any one of claims 27 to 57 , wherein R 5a is methyl.
59 . The compound of any one of claims 27 to 58 , one of R 4 and R 6 is H and the other of R 4 and R 6 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl(C 1 -C 3 alkyl), trifluoromethyl substituted cyclopropyl, or trifluoromethyl substituted cyclopropyl (C 1 -C 3 alkyl).
60 . The compound of any one of claims 27 to 59 , wherein R 4 is H and R 6 is cyclopropyl(C 1 -C 3 alkyl).
61 . The compound of claim 27 , selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
62 . A pharmaceutical composition comprising a compound of any one of claims 1 to 61 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.
63 . A method of decreasing cellular levels of CDK, comprising contacting one or more cells with an effective amount of a compound of any one of claims 1 to 61 , or a pharmaceutically acceptable salt thereof.
64 . A method of inhibiting the activity of CDK in a biological sample, comprising contacting the biological sample with an effective amount of a compound of any one of claims 1 to 61 , or a pharmaceutically acceptable salt thereof.
65 . The method of claim 63 or 64 , wherein the cell is a cancer cell selected from the group consisting of small cell lung cancer cell, non-small cell lung cancer cell, breast cancer cell, prostate cancer cell, head and neck cancer cell, pancreatic cancer cell, colon cancer cell, rectal cancer cell, teratoma cell, gastric cancer cell, ovarian cancer cell, endometrial cancer cell, brain cancer cell, retinoblastoma cell, leukemia cell, skin cancer cell, melanoma cell, squamous cell carcinoma cell, liposarcoma cell, lymphoma cell, multiple myeloma cell, testicular cancer cell, liver cancer cell, esophageal cancer cell, kidney carcinoma cell, astrogliosis cell, relapsed/refractory multiple myeloma cell, and neuroblastoma cell.
66 . A method of treating or ameliorating a disease, disorder, or condition associated with CDK, comprising administering an effective amount of a compound of any one of claims 1 to 61 , or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 62 , to a subject in need thereof; wherein the disease, disorder, or condition is small cell lung cancer, non-small cell lung cancer, breast cancer, prostate cancer, head and neck cancer, pancreatic cancer, colon cancer, rectal cancer, teratoma, gastric cancer, ovarian cancer, endometrial cancer, brain cancer, retinoblastoma, leukemia, skin cancer, melanoma, squamous cell carcinoma, liposarcoma, lymphoma, multiple myeloma, testicular cancer, liver cancer, esophageal cancer, kidney carcinoma, astrogliosis, relapsed/refractory multiple myeloma, or neuroblastoma.
67 . The method of any one of claims 63 to 66 , wherein the CDK is a wild-type, a mutant form of CDK, or is overexpressed.
68 . A method of treating or ameliorating cancer, comprising administering an effective amount of a compound of any one of claims 1 to 61 , or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 62 to a subject in need thereof; wherein the cancer is small cell lung cancer, non-small cell lung cancer, breast cancer, prostate cancer, head and neck cancer, pancreatic cancer, colon cancer, rectal cancer, teratoma, gastric cancer, ovarian cancer, endometrial cancer, brain cancer, retinoblastoma, leukemia, skin cancer, melanoma, squamous cell carcinoma, liposarcoma, lymphoma, multiple myeloma, testicular cancer, liver cancer, esophageal cancer, kidney carcinoma, astrogliosis, relapsed/refractory multiple myeloma, or neuroblastoma.
69 . The method of claim 68 , wherein the cancer is associated with CDK.Cited by (0)
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