JPWO2020150115A5

JPWO2020150115A5 -

Info

Publication number: JPWO2020150115A5
Application number: JP2021540533A
Authority: JP
Publication date: 2022-09-05
Anticipated expiration: 2040-01-13

Claims

Formula (I):

[In the formula,
W is independently selected from ^R6 , ^-YR6 , ^-QR6 , and ^-QYR6 ;
Q is independently selected from ^NR5 , ^CHR5 , O, and S;
Y is independently selected from C _1-10 alkylene, C _2-10 alkenylene, and C _2-10 alkynylene, each of which is substituted with 0-4 R ^a and/or each optionally
(i) O; or
(ii) one of N(R ^b ) may be included in the middle;
X ₁ is independently N or CR ¹ ;
X2 is independently _N or ^CR2 ;
_X3 is independently N or ^CR3 ;
_X4 is independently N or ^CR4 ;
provided that less than two of X ₁ , X ₃ and X ₄ are N;
R ¹ and R ³ are each independently selected from H, halogen, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, and C _1-4 haloalkoxy;
R ² and R ⁴ are each independently H, halogen, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, N(C _1-4 alkyl ) ₂ , and 5 ring atoms, wherein 1 to 4 ring atoms are each independently selected from N, NH, N(C _1-4 alkyl), O, and S, and a heteroaryl moiety is selected from -(C _0-3 alkylene)-heteroaryl substituted with 0-3 R ^d ;
R ⁵ is independently H or C _1-4 alkyl;
R ⁶ is independently a bicyclic or tricyclic cycloalkyl or cycloalkenyl containing 5 to 12 ring atoms, where the cycloalkyl or cycloalkenyl can be a spirocycle, or -CR ⁸ R ⁹ -, -(CR ⁸ R ⁹ ) ₂ -, and -C(=O)- containing 1 or 2 bridging linkers selected from 0 to 4 cycloalkyl or cycloalkenyl moieties is replaced by ^Re ;
Alternatively, R ⁶ independently comprises 5-12 ring atoms, wherein 1-4 ring atoms are each independently selected from N, N(R ^b ), O, and S bicyclic or tricyclic heterocycloalkyl, said heterocycloalkyl may be a ^spirocycle , or ^-CR8R9- , ^-O- , - ⁽ ^CR8R9 ) _2- , ^-OCR8R9 -, and ^-CR8R9O- , and -C(=O)-, wherein the heterocycloalkyl is substituted with ^0-4 R ^e ;
R ⁷ independently comprises 5 ring atoms, wherein 1-4 ring atoms are each independently selected from N, NH, N(C _1-4 alkyl), O, and S , heteroaryl substituted with 0-3 R ^d ;
R8 and R9 are each independently selected from H, _OH , _{halogen, C1-4alkyl} ^and ^C1-4alkoxy ;
R ^a is independently F, OH, cyano, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, and C _1-4 alkyl substituted with 0-1 R ^c selected from;
R ^b is independently H, C _1-4 alkyl substituted with 0-1 OH, —C(O)(C _1-4 alkyl), and —C(O)O(C _{1- 4} alkyl);
_Rc is independently selected from OH, ^CONH2 and _C1-4alkoxy ;
R ^d is independently halogen, OH, cyano, C _1-4 alkoxy, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, -C(O)O(C _1-4 alkyl), _NH2 , N( _C1-4alkyl ) ₂ , -C(O) _NH2 , -C(O)N( _C1-4alkyl ) ₂ , _C2-6alkenyl , _C2-6alkynyl , and C _1-6 alkyl substituted with 0-2 R ^a ; and
R ^e is independently oxo or R ^d ]
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

During the ceremony,
each Q is independently selected from NH, N(C _1-4 alkyl), CH ₂ , and O;
each Y is independently selected from C _1-10 alkylene, C _2-6 alkenylene, and C _2-6 alkynylene, each of which is substituted with 0-4 R ^a ;
^R2 is independently selected from H, halogen, cyano, _C1-4 alkyl, _C1-4 haloalkyl, _C1-4 alkoxy, and _C1-4 haloalkoxy;
R ⁴ is independently H, halogen, cyano, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, N(C _1-4 alkyl) ₂ , and selected from N, NH, O, and 5-membered heteroaryl containing 1-2 ring atoms each independently selected from S;
R ⁶ is independently a bi- or tricyclic cycloalkyl or cycloalkenyl containing 5-10 ring atoms, where the cycloalkyl or cycloalkenyl can be a spiro ring, or -CH ₂ may contain 1 or ₂ bridging linkers selected from - and _-CH2CH2- , wherein the cycloalkyl or cycloalkenyl moiety is substituted with 0-4 R ^e ;
Alternatively, R ⁶ independently comprises 5-10 ring atoms, wherein 1-2 ring atoms are each independently selected from N, N(R ^b ), O, and S bicyclic heterocycloalkyl, wherein the bicyclic ring can be a spiro ring, or _-CH2- , _-O- , _-CH2CH2- , _-OCH2- , and _-CH2 may contain a bridging linker selected from O-, wherein the heterocycloalkyl is substituted with 0-4 R ^e ;
R ⁷ is a 5-membered heteroaryl containing 1-2 ring atoms each independently selected from N, NH, O, and S; and
^3. The compound of Claim ¹ , or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R8 and R9 are each independently H or _C1-4 alkyl.

The compound is of formula (II):

[In the formula,
W is independently R6 ^- NH ^- R6, or -NH- _CH2 ^- R6;
X2 is independently _N or ^CR2 ;
R ¹ , R ² , R ³ and R ⁴ are each independently selected from H, halogen and C _1-4 alkyl;
R ⁶ is independently a bicyclic or tricyclic cycloalkyl containing 5-10 ring atoms, where the cycloalkyl can be a spirocycle or -CH ₂ - and -CH ₂ CH ₂ may contain 1 or 2 bridging linkers selected from -, wherein said cycloalkyl is substituted with 0-2 R ^e ;
Alternatively, R ⁶ independently comprises 5-10 ring atoms, wherein 1-2 ring atoms are each independently selected from N, N(R ^b ), and O. heterocycloalkyl, wherein the bicyclic ring can be a spiro ring or from _-CH2- , _-O- , _-CH2CH2- , _-OCH2- , and _-CH2O- may contain selected bridging linkers, wherein the heterocycloalkyl is substituted with 0-2 R ^e ;
R ^b is independently selected from H, C _1-4 alkyl, and —C(O)O(C _1-4 alkyl); and
R ^e is independently oxo, halogen, cyano, OH, _CH2OH , _{C1-4alkoxy, C1-4haloalkyl, N(C1-4alkyl} ₎ ₂ _, -C(O) _NH2 , -C(O)O(C _1-4 alkyl), C _2-6 alkenyl, and C _1-4 alkyl substituted with 0-2 C _1-4 alkoxy]
3. The compound of claim 1 or claim 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which is.

During the ceremony,
W is each independently -NH ^- R6, -NH- _CH2 ^- R6,

is selected from; and
R ⁶ independently

4. The compound of Claim 3, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, selected from:

During the ceremony,
W are each independently -NH ^- R6,

is selected from; and
R ⁶ independently,

5. A compound of claim 3 or claim 4, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, selected from:

The compound is of formula (III):

[In the formula,
X2 is independently _N or ^CR2 ;
R ¹ , R ² , R ³ and R ⁴ are each independently selected from H, halogen and C _1-4 alkyl;
R ⁶ is independently a bicyclic or tricyclic cycloalkyl containing 5-10 ring atoms, where the cycloalkyl can be a spirocycle or -CH ₂ - and -CH ₂ CH ₂ may contain 1 or 2 bridging linkers selected from -, wherein said cycloalkyl is substituted with 0-2 R ^e ;
Alternatively, R ⁶ is independently a bicyclic heterocycloalkyl containing 5-10 ring atoms, wherein 1-2 ring atoms are each independently selected from N and O; _A bicyclic ring may be a spiro ring or may contain a bridging linker selected from _-CH2- , -O-, and _-CH2CH2- , wherein said heterocycloalkyl is 0-2 are substituted with R ^e ; and
R ^e is independently selected from oxo, OH, CH ₂ OH, C _1-4 alkoxy, and C _1-4 alkyl substituted with 0-2 C _1-4 alkoxy]
5. The compound of any one of claims 1-4, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which is

During the ceremony,
X ₂ is independently N or CH;
R ¹ , R ³ and R ⁴ are H; and
R ⁶ independently,

7. The compound of Claim 6, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, selected from:

The following compounds:

2. The compound of claim 1, which is a compound selected from or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising a compound according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 9, for use as a medicament.

A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 9, for use in treating cancer.

Cancer is acute myeloid leukemia, adrenocortical carcinoma, Kaposi's sarcoma, lymphoma, anal cancer, appendiceal cancer, teratoma/rhabdoid tumor, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bone cancer, brain Cancer, breast cancer, bronchial tumor, carcinoid tumor, cardiac tumor, cervical cancer, chordoma, chronic lymphocytic leukemia, chronic myeloproliferative tumor, colon cancer, colorectal cancer, craniopharyngioma, endometrial cancer , ependymoma, esophageal cancer, nasal neuroblastoma, Ewing sarcoma, eye tumor, fallopian tube cancer, gallbladder cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, germ cell tumor, hairy cell leukemia, head and neck cervical cancer, heart tumor, liver cancer, hypopharyngeal cancer, pancreatic cancer, kidney cancer, laryngeal cancer, chronic myelogenous leukemia, lip and oral cavity cancer, lung cancer, melanoma, Merkel cell carcinoma, medium dermatoma, lip cancer, lip cancer, osteosarcoma, ovarian cancer, penile cancer, pharyngeal cancer, prostate cancer, rectal cancer, salivary gland cancer, skin cancer, small intestine cancer, soft tissue sarcoma 12. The compound of claim 11, or a pharmaceutically acceptable salt, or pharmaceutical composition.

12. The compound of Claim 11, or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from breast cancer, colon cancer, rectal cancer, colorectal cancer, pancreatic cancer, and prostate cancer, or pharmaceutical composition.

12. The compound or a pharmaceutically acceptable salt thereof according to claim 11, wherein the cancer is selected from hormone receptor positive breast cancer, microsatellite stable colon or rectal cancer, pancreatic cancer and prostate cancer. , or a pharmaceutical composition.

15. A compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 10-14, wherein the compound is administered in combination with one or more other cancer therapies.

16. The compound of Claim 15 or a pharmaceutically acceptable compound thereof, wherein the one or more additional cancer treatments include surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or combinations thereof. acceptable salts, or pharmaceutical compositions.

Other cancer treatments include nivolumab, pembrolizumab, PDR001, MEDI-0680, semipilimab, JS001, BGB-A317, INCSHR1210, TSR-042, GLS-010, AM-0001, STI-1110, AGEN2034, MGD013, IBI308, BMS -936559, Atezolizumab, Durvalumab, Avelumab, STI-1014, CX-072, LY3300054, CK-301, Urelumab, PF-05082566, MEDI6469, TRX518, Vallilumab, CP-870893, BMS-986016, MGA271, Lililumab, Emactuzumab, IPH2201 , INCB024360, garnisertib, urocuplumab, BKT140, bavituximab, CC-90002, bevacizumab, MNRP1685A, ipilimumab, MK-1308, AGEN-1884, and tremelimumab. A compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition.

16. A compound or a pharmaceutically acceptable salt thereof, or a medicament according to claim 15, wherein another cancer treatment comprises one or more agents selected from nivolumab, ipilimumab, pembrolizumab, atezolizumab, durvalumab and avelumab Composition.