Compounds useful for inhibiting RAF dimers

Patent metadata

Field	Value
Publication number	US-12440494-B2
Application number	US-202017432589-A
Country	US
Kind code	B2
Filing date	Feb 25, 2020
Priority date	Feb 25, 2019
Publication date	Oct 14, 2025
Grant date	Oct 14, 2025

Abstract

The disclosure provides compounds of Formula I (Formula I) (c) And the pharmaceutically acceptable salts thereof. The A, B, C, and D rings and the variables, R A , R B , R C , R D , L 0 , L 1 , L 2 , and L 2 , are defined herein. Compounds and salts of Formula I are useful as inhibitors of RAF kinase dimerization, including dimerization of wild type and mutant BRAF kinases. The disclosure includes pharmaceutical compositions comprising a compound or salt of Formula I. The disclosure also includes methods of treating a cancer susceptible to treatment with an inhibitor of BRAF dimers or BRAF dimerization, comprising administering a therapeutically effective amount of a compound or salt of Formula I to a patient in need of such treatment. These cancers susceptible to treatment with an inhibitor of BRAF dimers or BRAF dimerization include melanoma, thyroid cancer, hairy cell leukemia, ovarian cancer, lung cancer, and colorectal cancer.

First claim

What is claimed is:

1. A compound having the structure

or a pharmaceutically acceptable salt or any of the foregoing, where
Ring C is a 5-6-membered heterocycloalkyl, partially unsaturated, or heteroaryl group containing at least one Nitrogen ring atom and containing 0-3 additional ring heteroatoms independently chosen from N, O, and S, that is optionally substituted by one or more substituents independently chosen from R C ;

L 2 is a C 1 -C 4 alkylene linker in which one single bond is optionally replaced by a triple bond;
L 3 is a bond or a C 1 -C 4 alkylene linker, which is optionally substituted with an oxo group;
R A , R B , and R D are independently chosen at each occurrence from halogen, hydroxyl, cyano, nitro, amino, oxo, and Y;
R C is independently chosen at each occurrence from halogen, hydroxyl, cyano, nitro, amino, oxo, —SO 2 F, —SO 2 NH 2 , Y, and Z;
Y is a C 1 -C 8 alkyl group, optionally chosen at each occurrence, in which any single bond is optionally replaced by a double or triple bond and one or more CH 2 groups in the C 1 -C 8 alkyl is optionally replaced by —O—, —S—, —S(═O)—, —S(═O) 2 —, —P(═O)—, or N(R 2 )—, and which is optionally substituted by one or more substituents independently chosen from halogen, hydroxyl, amino, cyano, oxo (═O), thiol (—SH), thione (═S), ═NR 1 , and C 3 -C 6 cycloalkyl;
Z is C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl(C 0 -C 2 alkyl)-, aryl(C 0 -C 2 alkyl)-, (5- to 7-membered heterocycloalkyl)(C 0 -C 2 alkyl)-, (5- to 6-membered partially unsaturated heterocycloalkyl)(C 0 -C 2 alkyl), or (5- to 6 membered heteroaryl)(C 0 -C 2 alkyl)-, which Z is optionally substituted by one or more substituents independently chosen from halogen, hydroxyl, cyano, nitro, oxo, amino, —SO 2 F, —SO 2 CH 3 , and C 1 -C 6 alkyl, in which any single bond is optionally replaced by a double or triple bond, and each —CH 2 group is optionally replaced by a S, N, or O heteroatom and which is optionally substituted by one or more independently chosen halogen, hydroxyl, amino, cyano, oxo, and amino substituents; and
R 2 is independently chosen and each occurrence from hydrogen, C 1 -C 6 alkyl, and (C 3 -C 6 cycloalkyl)C 0 -C 4 alkyl.

2. A compound or salt of claim 1 , wherein R A is 4-methyl and R B is 3-trifluoromethyl.

3. A compound of claim 1 , of the formula

or a pharmaceutically acceptable salt thereof, wherein L 2 is —CH 2 —, —≡—, or —≡—CH 2 and L 3 is a bond, —CH 2 —, or —CH 2 CH 2 —.

4. A compound of claim 1 , of the formula

or a pharmaceutically acceptable salt thereof,
wherein L 2 is —CH 2 —, —C≡C—, or —C≡C—CH 2 and L 3 is a bond, —CH 2 —, or —CH 2 CH 2 —.

5. A compound or salt of claim 1 wherein
L 3 is —CH 2 CH 2 ; and
Ring C is a morpholine, thiomorpholine, or piperazine group that is unsubstituted or substituted with 1 or 2 substituents independently chosen from halogen, oxo, C 1 -C 2 alkyl, and C 1 -C 2 alkoxy.

6. A compound or salt of claim 1 , wherein
Ring C

is a morpholine, piperidine, piperazine, oxadiazine, pyridine, pyrimidine, tetrahydropyrimidine, or dihydropyrimidine ring and the Ring C substituent; and
Y is a C 1 -C 6 alkyl group, in which any single bond is optionally replaced by a double or triple bond and one or more CH 2 groups in the C 1 -C 6 alkyl is optionally replaced by —O—, —S—, or N(R 2 )—, and which is optionally substituted by one or more substituents independently chosen from halogen, hydroxyl, amino, and oxo (═O).

7. A compound or salt of claim 1 , wherein
Ring C

is a morpholine, piperidine, piperazine, oxadiazine, pyridine, pyrimidine, tetrahydropyrimidine, or dihydropyrimidine ring and the Ring C substituent,
R C , is zero, or one or more substituents independently chosen from oxo, —C 1 -C 4 alkyl, —SO 2 F, —SO 2 NH 2 , —SO 2 C 1 -C 4 alkyl, —C(═O)OC 1 -C 4 alkyl, and trifluoromethyl.

8. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is
3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(4-(((2-morpholinoethyl)amino)methyl)-3-(trifluoromethyl)phenyl)benzamide;
N-(4-(((1-(6-ethylpyrimidin-4-yl)piperidin-4-yl)amino)methyl)-3-(trifluoromethyl)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide;
4-[2-[([4-[3-(2-[imidazo[1,2-b]pyridazin-3-yl]ethynyl)-4-methylbenzamido]-2-(trifluoromethyl)phenyl]methyl)amino]ethyl]piperazine-1-carboxylate;
3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-N-(4-(((2-(4-(6-methoxypyrimidin-4-yl)piperazin-1-yl)ethyl)amino)methyl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide;
3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(4-(((2-(4-oxopiperidin-1-yl)ethyl)amino)methyl)-3-(trifluoromethyl)phenyl)benzamide;
3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(4-(((2-(4-(methylsulfonyl)piperazin-1-yl)ethyl)amino)methyl)-3-(trifluoromethyl)phenyl)benzamide;
3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(4-(((2-(pyrimidin-4-yl)ethyl)amino)methyl)-3-(trifluoromethyl)phenyl)benzamide;
Methyl 4-[2-([[4-(3-Ethynyl-4-Methylbenzamido)-2-(Trifluoromethyl)Phenyl]Methyl]Amino)Ethyl]Piperazine-1-Carboxylate;
Tert-Butyl 4-[2-([[4-(3-Ethynyl-4-Methylbenzamido)-2-(Trifluoromethyl)Phenyl]Methyl]Amino)Ethyl]Piperazine-1-Carboxylate;
3-ethynyl-4-methyl-N-(4-(((2-morpholinoethyl)amino)methyl)-3-(trifluoromethyl)phenyl)benzamide;
3-Ethynyl-4-Methyl-N-[4-([[2-(4-Phenylpiperazin-1-yl)Ethyl]Amino]Methyl)-3-(Trifluoromethyl)Phenyl]benzamide;
3-Ethynyl-4-Methyl-N-[4-([[2-(Piperazin-1-yl)Ethyl]Amino]Methyl)-3-(Trifluoromethyl)Phenyl]benzamide;
3-(2-[imidazo[1,2-b]pyridazin-3-yl]ethynyl)-4-methyl-N-[4-([[2-(piperazin-1-yl)ethyl]amino]methyl)-3-(trifluoromethyl)phenyl]benzamide;
3-Ethynyl-4-Methyl-N-(4-(((2-(4-(Pyridin-2-yl)Piperazin-1-yl)Ethyl)Amino)Methyl)-3-(Trifluoromethyl)Phenyl) benzamide;
3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(4-(((2-(5-oxo-2-(trifluoromethyl)-5,6-dihydropyrimidin-4-yl)ethyl)amino)methyl)-3-(trifluoromethyl)phenyl)benzamide;
3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(4-(((2-(2-oxomorpholino)ethyl)amino)methyl)-3-(trifluoromethyl)phenyl)benzamide;
N-(4-(((2-(3,5-dioxopiperazin-1-yl)ethyl)amino)methyl)-3-(trifluoromethyl)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide;
3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(4-(((2-(6-oxo-1,3,4-oxadiazinan-4-yl)ethyl)amino)methyl)-3-(trifluoromethyl)phenyl)benzamide;
3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(4-(((2-(5-oxo-2-(trifluoromethyl)-5,6-dihydropyrimidin-4-yl)ethyl)amino)methyl)-3-(trifluoromethyl)phenyl)benzamide;
N-(4-(((2-(2,5-dioxo-1,2,5,6-tetrahydropyrimidin-4-yl)ethyl)amino)methyl)-3-(trifluoromethyl)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide;
3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(4-(3-((2-morpholinoethyl)amino)prop-1-yn-1-yl)-3-(trifluoromethyl) phenyl)benzamide;
3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(4-(((2-(4-sulfamoylpiperazin-1-yl)ethyl)amino)methyl)-3-(trifluoromethyl)phenyl)benzamide;
N-(4-(((2-(4-(hydroxymethyl)piperazin-1-yl)ethyl)amino)methyl)-3-(trifluoromethyl)phenyl)-3-(imida

Assignees

• Albert Einstein College Medicine

Inventors

• Gavathiotis Evripidis
• Agianian Bogos

Classifications

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07D295/13

  to an acyclic saturated chain · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/5025

  ortho- or peri-condensed with heterocyclic ring systems · CPC title

• A61K31/495

  having six-membered rings with two {or more} nitrogen atoms as the only ring heteroatoms, e.g. piperazine {or tetrazines}(A61K31/48 takes precedence {; with three nitrogen atoms A61K31/53}) · CPC title