US2018244629A1PendingUtilityA1
Compounds And Compositions For The Treatment Of Cancer
Est. expiryMar 11, 2033(~6.7 yrs left)· nominal 20-yr term from priority
Inventors:Timothy A. LewisBenito MunozLucian De WaalHeidi GreulichMatthew MeyersonLara Nicole Gechijian
A61P 35/00C07D 403/10C07D 237/04C07D 413/10C07D 401/10
45
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Claims
Abstract
Disclosed are compounds, such as pyridazinones, that can be, inter alia, used for treating cancer.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound, or a pharmaceutically acceptable salt, ester or prodrug thereof having Formula II-i
wherein
Ri is optionally substituted alkyl, optionally substituted alkenyl, alkynyl haloallcyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocycle, optionally substituted heterocycle, halo, H, optionally substituted alkoxy, optionally substituted amine, cyano, or optionally substituted arylalkyl;
R.2 is selected from an optionally substituted C 1 -C 8 alkyl, haloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocycle, optionally substituted heterocycle, halo, H, —OH, optionally substituted alkoxy, optionally substituted amino, cyano, or optionally substituted arylalkyl;
R 4 is halo, OR 5 , NR 5 R 6 , NR 5 C(═O)R 6 , or
R 5 and R 6 ; are independently null, H, —OH, ═O, halo, haloalkyl, alkyl, alkynyl, alkenyl, aryl, arylalkyl, heteroaryl, carbocycle, heterocycle, cyano, alkoxy, amino or, wherein R 5 and R 6 can be further substituted; and
R 10 is C, N, O, or S.
2 . The compound of claim 1 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R 1 is H, halo or NR 5 R 6 and R 4 is H, halo or NR 5 R 6 .
3 . The compound of claim 1 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R 1 is halo and R 4 is H or NR 5 R 6 .
4 . The compound of claim 1 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R 1 is halo and R 4 is NH 2 .
5 . The compound of claim 1 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R 4 is halo and R 1 is H.
6 . The compound of claim 5 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R 4 is chloro, flouro, or iodo.
7 . The compound of claim 4 , The compound of claim 21 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R 1 is chloro or flouro.
8 . The compound of claim 1 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein Rt and R 4 are halo.
9 . The compound of claim 28 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R 1 and R 4 are iodo, flouro or chloro.
10 . The compound of any of claims 1 - 9 , wherein R 2 is optionally substituted C 1 -C 8 alkyl.
11 . The compound of claim 10 , wherein R 2 is methyl.
12 . The compound of claim 1 , or a pharmaceutically acceptable salt, ester or prodrug thereof, having Formula II-j
Wherein R 2 is C 1 -C 6 alkyl and R 1 is halo.
13 . The compound of claim 12 , or a pharmaceutically acceptable salt, ester or prodrug thereof, having a formula of:
wherein R 2 is methyl and R 1 is chloro or fluoro.
14 . The compound of claim 1 , or a pharmaceutically acceptable salt, ester or prodrug thereof, having Formula II-1
wherein
R 1 is H or halo;
R 2 is C 1 -C 6 alkyl;
R 5 is H or C 1 -C 6 alkyl; and
R 10 is C or N.
15 . The compound of claim 14 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R 10 is N.
16 . The compound of claim 15 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R 5 is C 1 -C 6 alkyl.
17 . The compound of claim 15 or 16 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R 1 is H.
18 . The compound of claim 14 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R 10 is C.
19 . The compound of claim 18 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R 5 is H.
20 . The compound of claim 18 or 19 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R 2 is methyl.
21 . The compound of claim 1 , or a pharmaceutically acceptable salt, ester or prodrug thereof, having Formula II-m,
wherein R 4 is cycloalkyl, cycloalkenyl, heteroaryl, C 1 -C 6 alkyl, or C 3 -C 6 alkenyl.
22 . The compound of claim 21 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R 4 is C 5 -C 7 cycloalkyl.
23 . The compound of claim 21 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R 4 is cyclohexanyl.
24 . The compound of claim 21 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R 4 is C 1 -C 6 alkyl.
25 . The compound of claim 21 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R 4 is C 3 -C 6 alkenyl.
26 . The compound of claim 21 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R 4 is cyclohexenyl.
27 . The compound of claim 21 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R 4 is C 5 -C 7 cycloalkenyl.
28 . The compound of claim 21 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R 4 is pyrimidyl.
29 . The compound of claim 21 - 28 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R 2 is optionally substituted C 1 -C 6 alkyl.
30 . The compound of claim 29 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R 2 is methyl.
31 . The compound of claim 1 , wherein the compound is
or a prodrug, or pharmaceutically salt thereof.
32 . A compound of Formula I or a pharmaceutically acceptable salt, ester or prodrug thereof:
wherein:
X 1 is -A 1 -A 2 -A 3 -A 4 -
X 2 is C or N,
X 3 is C or N
R 1 is H, halo, optionally substituted alkyl, optionally substituted alkenyl, alkynyl, haloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted alkoxy, optionally substituted amine, cyano, or optionally substituted arylalkyl,
R 2 is optionally substituted C 1 -C 8 alkyl, haloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocycle, optionally substituted heterocycle, halo, H, —OH, optionally substituted alkoxy, optionally substituted amine, cyano, or optionally substituted arylalkyl,
R 3 is an optionally substituted, saturated or unsaturated alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocycle, or optionally substituted heterocycle, H, halo, alkoxy, haloalkyl, optionally substituted alkoxy, cyano, optionally substituted arylalkyl,
R 4 is C 1 -C 6 alkyl, C 1 -C 6 , alkenyl, cycloalkyl, cycloalkenyl, heteroaryl, OR 5 , NR 5 R 6 , NR 5 C(═O)R 6 , or
or R 4 and R 1 together with the atoms to which they are connected form an aryl, heteroaryl, heterocycle or carbocycle ring of 5-8 atoms,
wherein A 1 , A 2 , A 3 , and A 4 are independently carbon or null, wherein when two or more of A 1 , A 2 , A 3 , and A 4 are carbons, the bonds between the carbons are optionally double bonds, wherein each R 2 connected to each of A 1 , A 2 , A 3 , and A 4 is independent of one another, wherein R 5 and R 6 are independently null, H, —OH, ═O, halo, haloalkyl, alkyl, alkynyl, alkenyl, aryl, arylalkyl, heteroaryl, carbocycle, heterocycle, cyano, alkoxy, amine, wherein R 5 and R 6 can be further substituted,
wherein R 10 is C, N, O, or S.
33 . The compound of claim 32 or a pharmaceutically acceptable salt, ester or prodrug thereof having Formula I-a or Formula I-b
34 . The compound of claim 32 or a pharmaceutically acceptable salt, ester or prodrug thereof having Formula II
wherein
---- is an optional double bond,
X 2 is C or N,
X 3 is C or N
R 1 is optionally substituted alkyl, optionally substituted alkenyl, alkynyl haloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocycle, optionally substituted heterocycle, halo, H, optionally substituted alkoxy, optionally substituted amine, cyano, or optionally substituted arylalkyl, each R 2 is independently selected from an optionally substituted C 1 -C 8 alkyl, haloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocycle, optionally substituted heterocycle, halo, H, —OH, optionally substituted alkoxy, optionally substituted amino, cyano, or optionally substituted arylalkyl, R 3 is an optionally substituted, saturated or unsaturated alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocycle, or optionally substituted heterocycle, H, halo, alkoxy, haloalkyl, optionally substituted alkoxy, cyano, optionally substituted arylalkyl,
R 4 is halo, OR 5 , NR 5 R 6 , NR 5 C(═O)R 6 , or
R 4 and R 1 form a aryl, heteroaryl, heterocycle or carbocycle ring of 5-8 atoms fused to the atoms to which R 4 and Ri are attached,
wherein
R 5 and R 6 are independently null, H, —OH, ═O, halo, haloalkyl, alkyl, alkynyl, alkenyl, aryl, arylalkyl, heteroaryl, carbocycle, heterocycle, cyano, alkoxy, amino or, wherein R 5 and R 6 can be further substituted;
R 7 and R 8 are independently null, H, —OH, ═O, halo, haloalkyl, alkyl, alkynyl, alkenyl, aryl, arylalkyl, heteroaryl, carbocycle, heterocycle, cyano, alkoxy, amino or R 7 and R 8 form a ring with the N, such that the ring formed by R 7 , R 8 , and N is fused with the ring that the N is attached to, wherein R 7 and R 8 can be further substituted; and
R 10 is C, N, O, or S.
35 . The compound of any one of claims 32 - 34 , wherein X 2 is C and X 3 is C.
36 . The compound of any one of claims 32 - 35 , wherein R 1 is H, NH 2 , halo, NO 2 , or SO 2 .
37 . The compound of any one of claims 32 - 36 , wherein R 4 is —NH 2 , —N((CH 2 ) q CH 3 ) 2 , —NH(CH 2 ) q CH 3 , —NHC(═O)(CH 2 ) q CH 3 ),
or wherein q is 0-6.
38 . The compound of claim 37 , wherein, R 4 is
39 . The compound of claim 32 or a pharmaceutically acceptable salt, ester or prodrug thereof having Formula II-a
40 . The compound of claim 39 , wherein R 1 is H, NH 2 , halo, NO 2 , or SO 2 .
41 . The compound of claim 39 or 40 , wherein R 4 is —NH 2 , —N((CH 2 ) q CH 3 ) 2 , —NH(CH 2 ) q CH 3 , —NHC(═O)(CH 2 ) q CH 3 ), or
wherein q is 0-6.
42 . The compound of any one of claims 39 - 41 , wherein:
R 4 is
R 10 is S or O.
43 . The compound of any one of claims 39 - 42 , wherein R 5 is null.
44 . The compound of claim 39 , or a pharmaceutically acceptable salt, ester or prodrug thereof having Formula II-b
45 . The compound of claim 44 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R 1 is H and each R 2 is independently H or C 1 -C 6 alkyl.
46 . The compound of claim 39 , or a pharmaceutically acceptable salt, ester or prodrug thereof having Formula II-c
47 . The compound of claim 46 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R 1 is H, NO 2 , NH 2 , or halo and R 2 is C 1 -C 6 alkyl.
48 . The compound of claim 39 , or a pharmaceutically acceptable salt, ester or pro drug thereof having Formula II-d
49 . The compound of claim 48 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R 1 is H, NO 2 , NH 2 , or halo and R 2 is C 1 -C 6 alkyl.
50 . The compound of claim 39 , or a pharmaceutically acceptable salt, ester or prodrug thereof having Formula II-e or II-f
51 . The compound of claim 50 , or a pharmaceutically acceptable salt, ester or prodrug thereof having Formula II-g or II-h
52 . The compound of claim 51 , or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R 1 is H, alkylamino, NO 2 , NH 2 , or halo and R 2 is C 1 -C 6 alkyl.
53 . The compound of any one of claims 1 - 52 , wherein the compound is substantially optically pure.
54 . A compound selected from the group consisting of:
55 . A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt, ester or prodrug thereof, of any of claims 1 - 54 .
56 . The pharmaceutical composition of claim 55 , wherein the compound or a pharmaceutically acceptable salt, ester or prodrug thereof, is at least 90% optically pure.
57 . The pharmaceutical composition of claim 55 , wherein the compound or a pharmaceutically acceptable salt, ester or prodrug thereof, is at least 90-99% optically pure.
58 . The pharmaceutical composition of claim 55 , wherein the compound or a pharmaceutically acceptable salt, ester or prodrug thereof, is at least 99-100% optically pure.
59 . The pharmaceutical composition of claim 55 , wherein the compound or a pharmaceutically acceptable salt, ester or prodrug thereof, is optically pure.
60 . A method of treating cancer comprising administering to a subject with cancer a compound or a pharmaceutically acceptable salt, ester or prodrug thereof, of any of claims 1 - 54 or a pharmaceutical composition of claim 55 .
61 . The method of claim 60 , wherein the cancer is melanoma, endometrium, lung, hematopoietic/lymphoid, ovarian, cervical, soft-tissue sarcoma, urinary tract, pancreas, thyroid, kidney, glioblastoma, breast cancer.
62 . The method of claim 60 or 61 , wherein the subject is a subject in need thereof.
63 . The method of claim 60 , further comprising administering an additional cancer therapeutic.
64 . The method of claim 63 , wherein the additional cancer therapeutic is zardaverine, anagrelide, imazodan, or quazinone, or any combination thereof.
65 . The method of claim 63 , wherein the additional cancer therapeutic is a PDE inhibitor.
66 . A method of treating cancer comprising administering to a subject in need thereof with cancer a compound or a pharmaceutically acceptable salt, ester or prodrug thereof, of a PDE inhibitor.
67 . The method of 66 , wherein the PDE inhibitor is a PDE3 inhibitor.
68 . The method of claim 66 , wherein the PDE inhibitor is zardaverine, anagrelide, imazodan, or quazinone, or any combination thereof.
69 . The method of claim 66 , wherein the cancer is melanoma, endometrium, lung, hematopoietic/lymphoid, ovarian, cervical, soft-tissue sarcoma, urinary tract, pancreas, thyroid, kidney, glioblastoma, breast cancer.
70 . The method of claim 66 , wherein the cancer is not a B-cell proliferative type cancer.
71 . The method of claim 66 , wherein the cancer is not multiple myeloma.
72 . A method of making,
wherein Z 1 is C 1 -C 6 alkyl and X is chloro or iodo, the method comprising reacting
under conditions to sufficient to make
73 . A method of making
wherein Z 1 is C 1 -C 6 alkyl, the method comprising reacting
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