US 12,275,745 B2Granted

Therapeutic compounds and methods of use

AssigneeGenentech, Inc.

InventorsJason Robert Zbieg, Paul Powell Beroza, Vishal Anil Verma, Bing-Yan Zhu, Ramsay Beveridge, Liang Zhao, Melissa Leblanc, Lisa Marie Barton, Bryan Ka Ip Chan, Samir Bouayad-Gervais, Anwesha Dey, Marie Anne Evangelista, Russell Tyler Smith

Life of this patent

Estimating the term…

Abstract

This disclosure relates to compounds and methods of using said compounds, as well as pharmaceutical compositions containing such compounds, for treating diseases and conditions mediated by TEAD, such as cancer.

Claims20

Dependent claims

A compound of formula (II-A-1):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:
L is methylene optionally substituted with one or more C1-6alkyl;
X1 is C, and X1 is taken together with R1 and the atoms to which they are attached, to form a 5 to 6 membered heteroarylfused to ring A;
wherein the 5 to 6 membered heteroaryl is optionally substituted with one or more Rt,
wherein Rt is independently, at each occurrence, selected from the group consisting of halo, C1-15 alkyl, haloC1-15 alkyl, C6-20aryl, 5 to 15 membered heteroaryl, C3-20cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C1-15 alkoxy, —NRdCORe, —CONRdRe, —SO2Rd, —SO2NRdRe, —NRdSO2Re, and —NRdRe;
and
wherein Rd and Re are each independently H or C1-6alkyl, and wherein the C1-6alkyl of Rd or Re is optionally substituted with one or more substituents selected from the group consisting of halo, oxo, —OH and —CN;
X2 is CRs, wherein Rs is selected from the group consisting of H, halo, C1-15alkyl, hydroxylC1-6alkynyl, C6-20aryl, 5 to 15 membered heteroaryl, C3-20cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, C1-15alkoxy, —NRdCORe, —CONRdRe, —SO2Rd, —S(O)NHRd, —SO2NRdRe, —NRdSO2Re, and —NRdRe;
wherein the C1-15alkyl and C1-15alkoxy of Rs are each independently optionally substituted with one or more Rt1, wherein Rt1 is independently at each occurrence halo, oxo, —OH, —CN, 5-6 membered heteroaryl, or —NRdRe, wherein Rd and Re are each independently H or C1-6alkyl, and wherein the C1-6alkyl of Rd or Re is optionally substituted with one or more substituents selected from the group consisting of halo, oxo, —OH and —CN;
and
wherein the C6-20aryl, 5 to 15 membered heteroaryl, C3-20cycloalkyl, and 3 to 15 membered heterocyclyl of Rs are each independently optionally substituted with one or more Rt2, wherein Rt2 is independently at each occurrence selected from the group consisting of halo, oxo, —OH, —CN and C1-6alkyl;
and
wherein Rd and Re are each independently H or C1-6alkyl, and wherein the C1-6alkyl of Rd or Re is optionally substituted with one or more substituents selected from the group consisting of halo, oxo, —OH and —CN;
X3 is CH;
R2 is halo;
S(Ry)5, wherein each Ry is halo;
or C1-6alkoxy optionally substituted with one or more halo;
R3 is H or C1-6alkyl;
and
Z is —OH, —NRdRe, C1-6alkoxy, —C(O)Ra, or —S(O)2Rb,
wherein Rd and Re are each independently H or C1-6alkyl, and wherein the C1-6alkyl of Rd or Re is optionally substituted with one or more substituents selected from the group consisting of halo, oxo, —OH and —CN;
Ra and Rb are each independently i) C2-6alkenyl optionally substituted with one or more substituents selected from the group consisting of deuterium, C1-6alkyl, hydroxyl C1-6alkyl, halo and haloC1-6alkyl;
ii) C1-6alkyl, optionally substituted with one or more halo;
or iii) cyclobutenyl or bicyclobutanyl.

21 more elements

A compound selected from the group consisting of:

Compound
Number
Structure
Compound Name
16
N-[[5-cyano-8-[4- (trifluoromethoxy)phenyl]-6- quinolyl]methyl]prop-2-enamide
27
N-[[4-cyano-3-methyl-7-[4- (trifluoromethoxy)phenyl]benzimidazol-5- yl]methyl]prop-2-enamide
28
N-[5-[(1R)-1,2-dihydroxyethyl]-8-[4- (trifluoromethoxy)phenyl]quinoxalin-6- yl]methyl]prop-2-enamide
29
N-[[4-(hydroxymethyl)-3-methyl-7-[4- (trifluoromethoxy)phenyl]benzimidazol-5- yl]methyl]prop-2-enamide
30
N-[[3-methyl-4-[(1S)-1,2-dihydroxyethyl]- 7-[4- (trifluoromethoxy)phenyl]benzimidazol-5- yl]methyl]prop-2-enamide
31
N-[[3-methyl-4-[(1R)-1,2-dihydroxyethyl]- 7-[4- (trifluoromethoxy)phenyl]benzimidazol-5- yl]methyl]prop-2-enamide
32
N-[[3-methyl-4-[(1R)-1-hydroxyethyl]-7- [4-(trifluoromethoxy)phenyl]benzimidazol- 5-yl]methyl]prop-2-enamide
33
N-[[3-methyl-4-[(1S)-1-hydroxyethyl]-7-[4- (trifluoromethoxy)phenyl]benzimidazol-5- yl]methyl]prop-2-enamide
34
N-[[3-methyl-4-(1H-pyrazol-4-ylmethyl)-7- [4-(trifluoromethoxy)phenyl]benzimidazol- 5-yl]methyl]prop-2-enamide
39
N-[3-(difluoromethyl)-4-(hydroxymethyl)- 7-[4- (trifluoromethoxy)phenyl]benzimidazol-5- yl]methyl]prop-2-enamide
40
(R)-N-((1-(difluoromethyl)-7-(1,2- dihydroxyethyl)-4-(4- (trifluoromethoxy)phenyl)-1H- benzo[d]imidazol-6-yl)methyl)acrylamide
41
(S)-N-((1-(difluoromethyl)-7-(1,2- dihydroxyethyl)-4-(4- (trifluoromethoxy)phenyl)-1H- benzo[d]imidazol-6-yl)methyl)acrylamide
43
N-[8-methyl-5-[4- (trifluoromethoxy)phenyl]-7- quinolyl]methyl]prop-2-enamide
44
N-[8-(hydroxymethyl)-5-[4- (trifluoromethoxy)phenyl]-7- quinolyl]methyl]prop-2-enamide
45
(S)-N-((8-(1,2-dihydroxyethyl)-5-(4- (trifluoromethoxy)phenyl)quinolin-7- yl)methyl)acrylamide
46
(R)-N-((8-(1,2-dihydroxyethyl)-5-(4- (trifluoromethoxy)phenyl)quinolin-7- yl)methyl)acrylamide
47
(S)-N-((5-(1,2-dihydroxyethyl)-8-(4- (trifluoromethoxy)phenyl)quinolin-6- yl)methyl) acrylamide
48
(R)-N-((5-(1,2-dihydroxyethyl)-8-(4- (trifluoromethoxy)phenyl)quinolin-6- yl)methyl) acrylamide
49
N-[[5-(hydroxymethyl)-8-[4- (trifluoromethoxy)phenyl]-6- quinolyl]methyl]-N-methyl-prop-2-enamide
50
N-[[5-(hydroxymethyl)-8-[4- (trifluoromethoxy)phenyl]-6- quinolyl]methyl]prop-2-enamide
51
N-[5-[(1S)-1,2-dihydroxyethyl]-8-[4- (trifluoromethoxy)phenyl]-6- quinolyl]methyl]-N-methyl-prop-2-enamide
52
N-[5-[(1R)-1,2-dihydroxyethyl]-8-[4- (trifluoromethoxy)phenyl]-6- quinolyl]methyl]-N-methyl-prop-2-enamide
57
N-[[3-methyl-4-methylsulfonyl-7-[4- (trifluoromethoxy)phenyl]benzimidazol-5- yl]methyl]prop-2-enamide
58
N-[4-(3-hydroxyprop-1-ynyl)-3-methyl-7- [4-(trifluoromethoxy)phenyl]benzimidazol- 5-yl]methyl]prop-2-enamide
60
(S)-N-((1-methyl-7-(S- methylsulfonimidoyl)-4-(4- (trifluoromethoxy)phenyl)-1H- benzo[d]imidazol-6-yl)methyl)acrylamide
61
(R)-N-((1-methyl-7-(S- methylsulfonimidoyl)-4-(4- (trifluoromethoxy)phenyl)-1H- benzo[d]imidazol-6-yl)methyl)acrylamide
63
2-fluoro-N-[[4-(hydroxymethyl)-3-methyl- 7-[4- (trifluoromethoxy)phenyl]benzimidazol-5- yl]methyl]prop-2-enamide
64
(E)-4-hydroxy-N-[[4-(hydroxymethyl)-3- methyl-7-[4- (trifluoromethoxy)phenyl]benzimidazol-5- yl]methyl]-N-methyl-but-2-enamide
65
(R)-N-((7-(1,2-dihydroxyethyl)-1-methyl-4- (4-(trifluoromethoxy)phenyl)-1H- benzo[d]imidazol-6-yl)methyl)-2-fluoro-N- methylacrylamide
66
(S)-N-((7-(1,2-dihydroxyethyl)-1-methyl-4- (4-(trifluoromethoxy)phenyl)-1H- benzo[d]imidazol-6-yl)methyl)-2-fluoro-N- methylacrylamide
68
N-[[1-methyl-7-[4- (trifluoromethoxy)phenyl]benzimidazol-5- yl]methyl]prop-2-enamide
72
N-[[3-methyl-4-(1H-pyrazol-4-yl)-7-[4- (trifluoromethoxy)phenyl]benzimidazol-5- yl]methyl]prop-2-enamide
74
(S)-N-((7-(3,4-dihydroxybut-1-yn-1-yl)-1- methyl-4-(4-(trifluoromethoxy)phenyl)-1H- benzo[d]imidazol-6-yl)methyl)acrylamide
75
(R)-N-((7-(3,4-dihydroxybut-1-yn-1-yl)-1- methyl-4-(4-(trifluoromethoxy)phenyl)-1H- benzo[d]imidazol-6-yl)methyl)acrylamide
76
3-methyl-5-[(prop-2-enoylamino)methyl]- 7-[4- (trifluoromethoxy)phenyl]benzimidazole-4- carboxamide
77
N-[[4-(difluoromethyl)-3-methyl-7-[4- (trifluoromethoxy)phenyl]benzimidazol-5- yl]methyl]prop-2-enamide
78
N-((7-(1H-imidazol-1-yl)-1-methyl-4-(4- (trifluoromethoxy)phenyl)-1H- benzo[d]imidazol-6-yl)methyl)acrylamide
79
(S)-N-((5-(1,2-Dihydroxyethyl)-8-(4- (trifluoromethoxy)phenyl)quinoxalin-6- yl)methyl)acrylamide
80
(R)-N-((5-(1,2-Dihydroxyethyl)-8-(4- (trifluoromethoxy)phenyl)quinoxalin-6- yl)methyl)-2-fluoroacrylamide
81
(R)-N-((5-(1,2-Dihydroxyethyl)-8-(4- (trifluoromethoxy)phenyl)quinoxalin-6- yl)methyl)cyclobut-1-ene-1-carboxamide
82
(R)-N-((5-(1-Hydroxyethyl)-8-(4- (trifluoromethoxy)phenyl)quinoxalin-6- yl)methyl)acrylamide
83
(S)-N-((5-(1-hydroxyethyl)-8-(4- (trifluoromethoxy)phenyl)quinoxalin-6- yl)methyl)acrylamide
84
N-((5-(Hydroxymethyl)-8-(4- (trifluoromethoxy)phenyl)quinoxalin-6- yl)methyl)acrylamide
85
N-((5-Cyano-8-(4- (trifluoromethoxy)phenyl)quinoxalin-6- yl)methyl)acrylamide
104
N-((7-(5-Oxo-4,5-dihydro-1,2,4-oxadiazol- 3-yl)-4-(4- (trifluoromethoxy)phenyl)benzo[d]thiazol- 6-yl)methyl)acrylamide
105
(S)-N-((7-(1,2-Dihydroxyethyl)-4-(4- (trifluoromethoxy)phenyl)benzo[d]oxazol- 6-yl)methyl)acrylamide
106
(R)-N-((7-(1,2-dihydroxyethyl)-4-(4- (trifluoromethoxy)phenyl)benzo[d]oxazol- 6-yl)methyl)acrylamide
107
(S)-N-((7-(1,2-Dihydroxyethyl)-4-(4- (trifluoromethoxy)phenyl)benzo[d]oxazol- 6-yl)methyl)-N-methylacrylamide
108
(R)-N-((7-(1,2-dihydroxyethyl)-4-(4- (trifluoromethoxy)phenyl)benzo[d]oxazol- 6-yl)methyl)-N-methylacrylamide
109
(S)-N-((7-(1,2-Dihydroxyethyl)-4-(4- (trifluoromethyl)phenyl)benzo[d]oxazol-6- yl)methyl)acrylamide
110
(R)-N-((7-(1,2-dihydroxyethyl)-4-(4- (trifluoromethyl)phenyl)benzo[d]oxazol-6- yl)methyl)acrylamide
111
(S)-N-((7-(2-Oxooxazolidin-5-yl)-4-(4- (trifluoromethoxy)phenyl)benzo[d]oxazol- 6-yl)methyl)acrylamide
112
(R)-N-((7-(2-oxooxazolidin-5-yl)-4-(4- (trifluoromethoxy)phenyl)benzo[d]oxazol- 6-yl)methyl)acrylamide
113
N-((7-(Hydroxymethyl)-4-(4- (trifluoromethoxy)phenyl)benzo[d]oxazol- 6-yl)methyl)acrylamide
138
(R)-N-((7-(1-Hydroxyethyl)-1-methyl-4-(4- (trifluoromethoxy)phenyl)-1H- benzo[d]imidazol-6-yl)methyl)acrylamide
139
(S)-N-((7-(1-hydroxyethyl)-1-methyl-4-(4- (trifluoromethoxy)phenyl)-1H- benzo[d]imidazol-6-yl)methyl)acrylamide
140
N-((7-((2-Hydroxyethyl)amino)-1-methyl- 4-(4-(trifluoromethoxy)phenyl)-1H- benzo[d]imidazol-6-yl)methyl)acrylamide, and
143
N-((7-Cyano-4-(2-fluoro-4- (trifluoromethoxy)phenyl)-1-methyl-1H- benzo[d]imidazol-6-yl)methyl)acrylamide

117 more elements

Dependencies are inferred from the claim text.

Facts

Application: 18/057,742Filed 21 Nov 2022 · us provisional application
Priority: 24 Nov 2021
Published: US 2023/0203062 A129 Jun 2023
Granted: 15 Apr 2025
Term ends: Not estimatedThe source records don’t support an estimate.

Classification27 codes

C07D 513/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61P 35/00
Antineoplastic agents
C07D 215/12
Having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring…:…
C07D 215/14
With substituted hydrocarbon radicals attached to ring carbon atoms: radicals substituted by oxygen atoms

Family

Application63/283,119Us provisional application · filed 24 Nov 2021
Application63/344,027Us provisional application · filed 19 May 2022
US 2023/0203062 A1Pre-grant publication · published 29 Jun 2023
US 12,275,745 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Therapeutic compounds and methods of use

AssigneeGenentech, Inc.

Life of this patent

Estimating the term…

Abstract

A compound of formula (II-A-1):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:
L is methylene optionally substituted with one or more C1-6alkyl;
X1 is C, and X1 is taken together with R1 and the atoms to which they are attached, to form a 5 to 6 membered heteroarylfused to ring A;
wherein the 5 to 6 membered heteroaryl is optionally substituted with one or more Rt,
wherein Rt is independently, at each occurrence, selected from the group consisting of halo, C1-15 alkyl, haloC1-15 alkyl, C6-20aryl, 5 to 15 membered heteroaryl, C3-20cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, oxo, C1-15 alkoxy, —NRdCORe, —CONRdRe, —SO2Rd, —SO2NRdRe, —NRdSO2Re, and —NRdRe;
and
wherein Rd and Re are each independently H or C1-6alkyl, and wherein the C1-6alkyl of Rd or Re is optionally substituted with one or more substituents selected from the group consisting of halo, oxo, —OH and —CN;
X2 is CRs, wherein Rs is selected from the group consisting of H, halo, C1-15alkyl, hydroxylC1-6alkynyl, C6-20aryl, 5 to 15 membered heteroaryl, C3-20cycloalkyl, 3 to 15 membered heterocyclyl, —OH, —CN, C1-15alkoxy, —NRdCORe, —CONRdRe, —SO2Rd, —S(O)NHRd, —SO2NRdRe, —NRdSO2Re, and —NRdRe;
wherein the C1-15alkyl and C1-15alkoxy of Rs are each independently optionally substituted with one or more Rt1, wherein Rt1 is independently at each occurrence halo, oxo, —OH, —CN, 5-6 membered heteroaryl, or —NRdRe, wherein Rd and Re are each independently H or C1-6alkyl, and wherein the C1-6alkyl of Rd or Re is optionally substituted with one or more substituents selected from the group consisting of halo, oxo, —OH and —CN;
and
wherein the C6-20aryl, 5 to 15 membered heteroaryl, C3-20cycloalkyl, and 3 to 15 membered heterocyclyl of Rs are each independently optionally substituted with one or more Rt2, wherein Rt2 is independently at each occurrence selected from the group consisting of halo, oxo, —OH, —CN and C1-6alkyl;
and
wherein Rd and Re are each independently H or C1-6alkyl, and wherein the C1-6alkyl of Rd or Re is optionally substituted with one or more substituents selected from the group consisting of halo, oxo, —OH and —CN;
X3 is CH;
R2 is halo;
S(Ry)5, wherein each Ry is halo;
or C1-6alkoxy optionally substituted with one or more halo;
R3 is H or C1-6alkyl;
and
Z is —OH, —NRdRe, C1-6alkoxy, —C(O)Ra, or —S(O)2Rb,
wherein Rd and Re are each independently H or C1-6alkyl, and wherein the C1-6alkyl of Rd or Re is optionally substituted with one or more substituents selected from the group consisting of halo, oxo, —OH and —CN;
Ra and Rb are each independently i) C2-6alkenyl optionally substituted with one or more substituents selected from the group consisting of deuterium, C1-6alkyl, hydroxyl C1-6alkyl, halo and haloC1-6alkyl;
ii) C1-6alkyl, optionally substituted with one or more halo;
or iii) cyclobutenyl or bicyclobutanyl.

21 more elements

Facts

Application

18/057,742Filed 21 Nov 2022 · us provisional application

Priority

24 Nov 2021

Published

US 2023/0203062 A129 Jun 2023

Granted

15 Apr 2025

Term ends

Not estimatedThe source records don’t support an estimate.

Classification27 codes

C07D 513/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61P 35/00
Antineoplastic agents
C07D 215/12
Having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring…:…
C07D 215/14
With substituted hydrocarbon radicals attached to ring carbon atoms: radicals substituted by oxygen atoms