US2022315586A1PendingUtilityA1
Shp2 phosphatase inhibitors and methods of use thereof
Est. expiryMar 21, 2038(~11.7 yrs left)· nominal 20-yr term from priority
Inventors:Alexander M. TaylorAndre LescarbeauElizabeth H. KelleyKelley C. ShortsleevesW. Patrick WaltersMark A. MurckoThomas H. McleanHakan GunaydinFabrizio GiordanettoEric Therrien
C07D 401/12C07D 401/14C07D 495/04C07D 401/04C07D 405/14C07D 491/20C07D 221/20A61P 3/10C07D 213/70C07D 513/04C07D 471/04C07D 241/18C07D 417/06A61K 31/519A61K 45/06C07D 519/00A61P 35/00C07D 417/04C07D 487/04A61K 31/4985A61K 31/506A61K 31/433C07D 491/107C07D 498/20C07D 491/10C07D 487/20C07D 401/06C07D 417/14A61K 31/5377A61K 31/454C07D 211/32A61K 31/497C07D 498/22C07D 471/22C07D 491/147A61P 35/02A61P 7/00
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Claims
Abstract
The present disclosure relates to novel compounds including formula (X) and pharmaceutical compositions thereof, and methods for inhibiting the activity of SHP2 phosphatase with the compounds and compositions of the disclosure. The present disclosure further relates to, but is not limited to, methods for treating disorders associated with SHP2 deregulation with the compounds and compositions of the disclosure.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of Formula X:
or a pharmaceutically acceptable salt thereof, wherein;
X is —CH 2 —, —CH(R X )—, —C(R X ) 2 —, —C(O)—, —NH—, —N(R X )—, or —O—;
Y is C, CH, C(R Y ), or N;
is a single bond when Y is CH, C(R Y ), or N; or is a double bond when Y is C;
R 1 is L 1 -Cy B -L 2 -R 2 ;
Cy B is phenyl, a monocyclic 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a bicyclic 8-10 membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Cy B is substituted by m instances of R 3 ;
Cy C is benzo; 5-6 membered heteroarylo having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3-7 membered saturated or partially unsaturated cycloaliphatic-fused; or 3-7 membered saturated or partially unsaturated heterocyclo having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein when Cy C is heterocyclo or heteroarylo, said heteroatoms may occur at any position within Cy C ; and wherein in each case Cy C is substituted by n instances of R 4 ;
L 1 is a covalent bond or —C(O)—;
L 2 is a covalent bond, or a C 1-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —CH(R L )—, —C(R L ) 2 —, C 3-5 cycloalkylene, —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R)S(O) 2 —, —S(O) 2 N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)—, or —S(O) 2 —;
R 2 is hydrogen, R A , or R B , and when R 2 is R B , R 2 is substituted by q instances of R C ;
each instance of R 3 , R 4 , R X , R Y , and R L is independently R A or R B , and is substituted by r instances of R C ;
each instance of R 5 is independently R A or R B , and is substituted by r instances of R C ; or two instances of R 5 are taken together with their intervening atoms to form a 3-6 membered carbocyclic fused ring or a 3-6 membered heterocyclic fused ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each instance of R A is independently oxo, halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —S(O)NR 2 , —C(O)R, —C(O)OR, —C(O)NR 2 , —C(O)N(R)OR, —OC(O)R, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , —N(R)C(NR)NR 2 , —N(R)S(O) 2 NR 2 , or —N(R)S(O) 2 R;
each instance of R B is independently C 1-6 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each instance of R C is independently oxo, halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —S(O)NR 2 , —OS(O) 2 F, —C(O)R, —C(O)OR, —C(O)NR 2 , —C(O)N(R)OR, —OC(O)R, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , —N(R)C(NR)NR 2 , —N(R)S(O) 2 NR 2 , —N(R)S(O) 2 R, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each R is independently hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur;
each of b and c is independently 0 or 1; and
each of a, m, n, q, and r is independently 0, 1, 2, 3, or 4;
wherein the compound is not
2 . The compound of claim 1 wherein the compound is of the one of formulas:
or a pharmaceutically acceptable salt thereof.
3 . The compound of claim 1 wherein Cy B is selected from the group consisting of:
wherein Cy B is substituted by m instances of R 3 .
4 . The compound of claim 1 wherein the compound is of one of formulas:
or a pharmaceutically acceptable salt thereof.
5 . The compound of claim 1 wherein the compound is of one of formulas:
or a pharmaceutically acceptable salt thereof.
6 . The compound of claim 1 wherein the compound is of one of formulas:
or a pharmaceutically acceptable salt thereof.
7 . The compound of claim 1 wherein the compound is of one of formulas:
or a pharmaceutically acceptable salt thereof.
8 . The compound of claim 1 wherein the compound is of one of formulas:
or a pharmaceutically acceptable salt thereof.
9 . The compound of claim 1 wherein the compound is of one of formulas:
or a pharmaceutically acceptable salt thereof.
10 . The compound of claim 1 wherein variable a is 2, or a pharmaceutically acceptable salt thereof.
11 . The compound of claim 1 wherein two instances of R 5 are taken together with their intervening atoms to form a 3-6 membered carbocyclic fused ring or a 3-6 membered heterocyclic fused ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a pharmaceutically acceptable salt thereof.
12 . The compound of claim 11 of one of formulas:
or a pharmaceutically acceptable salt thereof.
13 . The compound of claim 1 of the formula:
or a pharmaceutically acceptable salt thereof.
14 . The compound of claim 1 of the formula:
or a pharmaceutically acceptable salt thereof.
15 . The compound of claim 1 of the formula:
or a pharmaceutically acceptable salt thereof.
16 . The compound of claim 1 of the formula:
or a pharmaceutically acceptable salt thereof.
17 . The compound of claim 1 of the formula:
or a pharmaceutically acceptable salt thereof.
18 . The compound of claim 1 of the formula:
or a pharmaceutically acceptable salt thereof.
19 . The compound of claim 1 of the formula:
or a pharmaceutically acceptable salt thereof.
20 . The compound of claim 1 of the formula:
or a pharmaceutically acceptable salt thereof.
21 . The compound of claim 1 of the formula:
or a pharmaceutically acceptable salt thereof.
22 . The compound according to any one of the preceding claims wherein at least one instance of R 3 is —CH 3 , —CHF 2 , —CH 2 OH, —CH(CH 3 )OH, or cyclopropyl.
23 . The compound according to any one of the preceding claims wherein X is —CH 2 —, or a pharmaceutically acceptable salt thereof.
24 . The compound according to any one of the preceding claims wherein X is —O—, or a pharmaceutically acceptable salt thereof.
25 . The compound according to any one of the preceding claims wherein Cy C is benzo, or a pharmaceutically acceptable salt thereof.
26 . The compound according to any one of the preceding claims wherein Cy C is 5-6 membered heteroarylo having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a pharmaceutically acceptable salt thereof.
27 . The compound according to any one of the preceding claims wherein Y is —N—, or a pharmaceutically acceptable salt thereof.
28 . The compound according to any one of the preceding claims wherein Y is —CH 2 —, or a pharmaceutically acceptable salt thereof.
29 . The compound according to any one of the preceding claims wherein L 1 is a covalent bond, or a pharmaceutically acceptable salt thereof.
30 . The compound according to any one of the preceding claims wherein L 1 is —C(O)—, or a pharmaceutically acceptable salt thereof.
31 . The compound according to any one of the preceding claims wherein L 2 is a covalent bond, or a pharmaceutically acceptable salt thereof.
32 . The compound according to any one of the preceding claims wherein L 2 is —S—, or a pharmaceutically acceptable salt thereof.
33 . The compound according to any one of the preceding claims wherein L 2 is —O—, or a pharmaceutically acceptable salt thereof.
34 . The compound according to any one of the preceding claims wherein L 2 is —C(O)—, or a pharmaceutically acceptable salt thereof.
35 . The compound according to any one of the preceding claims wherein L 2 is C 1-3 aliphatic, or a pharmaceutically acceptable salt thereof.
36 . The compound according to any one of the preceding claims wherein n is 1, 2, 3, or 4, or a pharmaceutically acceptable salt thereof.
37 . The compound according to any one of the preceding claims wherein n is 0, or a pharmaceutically acceptable salt thereof.
38 . The compound according to any one of the preceding claims, wherein at least one instance of R 4 is fluoro, or a pharmaceutically acceptable salt thereof.
39 . The compound according to any one of the preceding claims wherein R 2 is C 1-6 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein R 2 is substituted by q instances of R C , or a pharmaceutically acceptable salt thereof.
40 . The compound according to any one of the preceding claims wherein R 2 is C 1-6 aliphatic substituted with q instances of R C , or a pharmaceutically acceptable salt thereof.
41 . The compound according to any one of the preceding claims wherein R 2 is phenyl substituted with q instances of R C , or a pharmaceutically acceptable salt thereof.
42 . The compound according to any one of the preceding claims wherein R 2 is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with q instances of R C , or a pharmaceutically acceptable salt thereof; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
43 . The compound according to any one of the preceding claims wherein R 2 is a 3-7 membered saturated or partially unsaturated carbocyclic ring substituted with q instances of R C , or a pharmaceutically acceptable salt thereof.
44 . The compound according to any one of the preceding claims wherein R 2 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with q instances of R C , or a pharmaceutically acceptable salt thereof.
45 . The compound according to any one of the preceding claims wherein R 2 is 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with q instances of R C , or a pharmaceutically acceptable salt thereof.
46 . The compound according to any one of the preceding claims wherein R 2 is:
isopropyl, ethyl, or methyl, each of which is substituted with q instances of R C , or a pharmaceutically acceptable salt thereof.
47 . The compound according to any one of the preceding claims wherein R 2 is:
or a pharmaceutically acceptable salt thereof.
48 . A compound selected from the group consisting of the compounds depicted in Table 1, and a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof.
49 . A pharmaceutical composition comprising a compound of any of claims 1 - 48 and a pharmaceutically acceptable carrier.
50 . A method of inhibiting SHP2 phosphatase activity in a subject comprising administration of a therapeutically effective amount of the compound of any of claims 1 - 48 , or the composition of claim 49 , to a subject in need thereof.
51 . The method of claim 50 , further comprising administration of a therapeutically effective amount of an antibody, an antibody-drug conjugate, an immunomodulator, or a histone deacetylase inhibitor.
52 . The method of claim 50 or 51 , wherein the subject is a human.
53 . A method of treating a disorder in a subject comprising administration of a therapeutically effective amount of the compound of any of claims 1 - 48 , or the composition of claim 49 , to a subject in need thereof.
54 . The method of claim 53 , further comprising administration of a therapeutically effective amount of an antibody, an antibody-drug conjugate, an immunomodulator, or a histone deacetylase inhibitor.
55 . The method of claim 53 or 54 , wherein the disorder is Noonan syndrome.
56 . The method of claim 53 or 54 , wherein the disorder is neutropenia.
57 . The method of claim 53 or 54 , wherein the disorder is diabetes.
58 . The method of claim 53 or 54 , wherein the disorder is neuroblastoma.
59 . The method of claim 53 or 54 , wherein the disorder is melanoma.
60 . The method of claim 53 or 54 , wherein the disorder is acute myeloid leukemia.
61 . The method of claim 53 or 54 , wherein the disorder is juvenile leukemia.
62 . The method of claim 53 or 54 , wherein the disorder is juvenile myelomonocytic leukemia.
63 . The method of claim 53 or 54 , wherein the disorder is breast cancer.
64 . The method of claim 53 or 54 , wherein the disorder is lung cancer.
65 . The method of claim 53 or 54 , wherein the disorder is colorectal cancer.Join the waitlist — get patent alerts
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