US 2021/0198249 A1Published application

Indanes as nrf2 activators

AssigneeBriwa S.R.L.

InventorJeffrey K. KERNS

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Abstract

The present invention relates to indane compounds, methods of making them, pharmaceutical compositions containing them and their use as NRF2 activators. In particular, the invention relates to compounds of Formula (I) or Formula (II), and pharmaceutically acceptable salts thereof:

Claims18

Dependent claims

A compound of Formula (I):

wherein:
B is benzotriazolyl, phenyl, triazolopyridinyl, —O—(CH2)-triazolyl, or —(CH2)2-triazolyl wherein each of benzotriazolyl, phenyl, triazolopyridinyl, —O—(CH2)-triazolyl, or —(CH2)2-triazolyl is unsubstituted or substituted by 1, 2, or 3 substituents independently selected from —C1-3alkyl, —O—C1-3alkyl,
—CN, —(CH2)2—O—(CH2)2—OR3 and halo;
D is —C(O)OH, —C(O)NR3R4, —C(O)NHSO2CH3, —SO2NHC(O)CH3, -5-(trifluoromethyl)-4H-1,2,4-triazol-2-yl, —NR3—C(O)—R4, —NR3—C(O)—NR3R4;
—NR3—C(O)—O—R4 or tetrazolyl;
R1 is independently hydrogen, —C1-3alkyl, F, —C3-6spirocycloalkyl, oxetane, or the two R1 groups together with the carbon to which they are attached form a cyclopropyl group;
R2 is hydrogen, methyl, —CF3, or halo;
R3 is hydrogen or —C1-3alkyl;
R4 is hydrogen, —C1-5alkyl, —C3-7cycloalkyl, —C4-8heterocycloalkyl, —C1-5alkoxy, —C1-3alkyl-O—C1-3alkyl, —C1-3alkyl-NH—C1-3alkyl, —C1-3alkyl-SO2C1-3alkyl, —C1-3alkyl-C4-8heterocycloalkyl, —C1-3alkyl-C(O)NR4R5, aryl or heteroaryl, wherein each of —C1-5 alkyl, —C3-7 cycloalkyl, —C4-7 heterocycloalkyl, —C1-5alkoxy, —C1-3alkyl-O—C1-3alkyl, —C1-3alkyl-NH—C1-3alkyl, —C1-3alkyl-C(O)NR4R5, aryl or heteroaryl is unsubstituted or substituted by one or two substituents selected from —OH, —CO2H, —C(O)NR4R5, —C(O)OR3, —N—C(O)—C1-3alkyl, F, —CN, —CH—F2, —CF3, —(CH2)n—O—(CH2)m—CH3, —C3-7cycloalkyl and a 5-6-membered heteroaryl ring containing 1, 2 or 3 heteroatoms selected from O, N and S;
or R3 and R4 together with the nitrogen atom to which they are attached form a 5-8-membered heterocyclic ring, an 8-11-membered bicyclic heterocyclic ring or a 9-10-membered bridged bicyclic heterocyclic ring, wherein each 5-8-membered ring, 8-11-membered bicyclic ring, or 9-10-membered bridged bicyclic ring optionally includes one —C(O) or one —S(O)2, and wherein each 5-8-membered ring, 8-11-membered bicyclic ring, or 9-10-membered bridged bicyclic ring optionally contains one, two or three oxygen ring atoms, one, two or three sulfur ring atoms or one, two or three nitrogen ring atoms, and wherein each 5-8-membered ring, 8-11-membered bicyclic ring, or 9-10-membered bridged bicyclic ring is unsubstituted or substituted by one, two or three substituents independently selected from —C1-5alkyl, —C3-7cycloalkyl, —C4-7heterocycloalkyl, —(CH2)phenyl, halogen, —NR3R5, —CHF2, —CF3, and —(CH2)n—O—(CH2)m—CH3;
A is tetrahydrobenzoxazepinyl, tetrahydro-pyrido-oxazepinyl, piperidinyl, tetrahydrobenzazepinyl, phenyl, tetrahydropyrrolopyrazinyl, imidazopyridinyl, tetrahydrobenzodiazepinyl, piperidopyrimidinyl, dioxidotetrahydrothiophenyl, tetrahydroimidazodiazepinyl, oxazepane or morpholinyl;
wherein each of tetrahydrobenzoxazepinyl, tetrahydro-pyrido-oxazepinyl, piperidinyl, tetrahydrobenzazepinyl, tetrahydropyrrolopyrazinyl, imidazopyridinyl, tetrahydrobenzodiazepinyl, piperidopyrimidinyl, dioxidotetrahydrothiophenyl, tetrahydroimidazodiazepinyl, oxazepane or morpholinyl is unsubstituted or substituted by 1, 2, or 3 substituents independently selected from —C1-3alkyl, —C3-6spirocycloalkyl, halo, —CN, —O—C1-3alkyl, —CH2—O—CH3, and —OH;
and wherein the oxazepane is further unsubstituted or substituted by 1 or 2 substituents independently selected from —C1-3alkyl and —C3-7cycloalkyl;
and wherein the morpholinyl is further unsubstituted or substituted by phenyl which phenyl is unsubstituted or substituted by a substituent independently selected from —C1-3 alkyl and —O—C1-3 alkyl;
or A is
Y is independently selected from N or CH;
Z is O, CH2, NR5, S, S(O) or S(O)2;
R5 is independently selected from hydrogen or —C1-4alkyl;
R6 is hydrogen, —C1-5alkyl or —(CH2)m—C3-5cycloalkyl;
R7 is hydrogen or —C1-4alkyl;
or R6 and R7, together with the carbon to which they are attached form a C3-C5-membered cycloalkyl ring;
and, wherein when A is
it is unsubstituted or substituted with one, two or three substituents independently selected from halo, —CF3, —C1-4alkyl, —CN, —OMe, —C(O)NH2, —OCF3 and —C1-4alkyNR7R8;
R8 is —C1-3alkyl, aryl, heteroaryl, —C(O)C1-3alkyl, —SO2C1-3alkyl, —C(O)aryl, —C(O)heteroaryl, —SO2aryl, —SO2heteroaryl, —C3-7cycloalkyl, —C1-3alkyC3-7cycloalkyl, —C1-3alkylC3-7heterocycloalkyl,
C1-3alkyl-heteroaryl or —C1-3alkyl-aryl, wherein each of —C1-3alkyl, aryl, heteroaryl, —C(O)C1-3alkyl, —SO2C1-3alkyl, —C(O)aryl, —C(O)heteroaryl, —SO2aryl, —SO2heteroaryl, —C3-7cycloalkyl, —C1-3alkylC3-7cycloalkyl, —C1-3alkylC3-7heterocycloalkyl, —C1-3alkyl-heteroaryl or —C1-3alkyl-aryl is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from halo, —CN, —CF3, —OCF3,
—OCH3, —C1-3alkyl, —OC1-3alkyl, —OC3-7cycloalkyl, —OC3-7heterocycloalkyl, —O-aryl and —O-heteroaryl;
R9 is hydrogen, —C1-5alkyl or —(CH2)m—C3-5cycloalkyl;
R10 is H, SO2R6, C(O)R6;
m is 0, 1 or 2;
and
n is 1 or 2;
or a pharmaceutically acceptable salt thereof.

29 more elements

A compound of Formula (II):

wherein:
B is benzotriazolyl, phenyl, triazolopyridinyl, —O—(CH2)-triazolyl, or —(CH2)2-triazolyl wherein each of benzotriazolyl, phenyl, triazolopyridinyl, —O—(CH2)-triazolyl, or —(CH2)2-triazolyl is unsubstituted or substituted by 1, 2, or 3 substituents independently selected from —C1-3alkyl, —O—C1-3alkyl,
—CN, —(CH2)2—O—(CH2)2—OR3 and halo;
D is —C(O)OH, —C(O)NR3R4, —C(O)NHSO2CH3, —SO2NHC(O)CH3, -5-(trifluoromethyl)-4H-1,2,4-triazol-2-yl, —NR3—C(O)—R4, —NR3—C(O)—NR3R4;
—NR3—C(O)—O—R4 or tetrazolyl;
R1 is independently hydrogen, —C1-3alkyl, F, —C3-6spirocycloalkyl, oxetane, or the two R1 groups together with the carbon to which they are attached form a cyclopropyl group;
R2 is hydrogen, methyl, —CF3, or halo;
R3 is hydrogen or —C1-3alkyl;
R4 is hydrogen, —C1-5alkyl, —C3-7cycloalkyl, —C4-8heterocycloalkyl, —C1-5alkoxy, —C1-3alkyl-O—C1-3alkyl, —C1-3alkyl-NH—C1-3alkyl, —C1-3alkyl-SO2C1-3alkyl, —C1-3alkyl-C4-8heterocycloalkyl, —C1-3alkyl-C(O)NR4R5, aryl or heteroaryl, wherein each of —C1-5 alkyl, —C3-7 cycloalkyl, —C4-7 heterocycloalkyl, —C1-5alkoxy, —C1-3alkyl-O—C1-3alkyl, —C1-3alkyl-NH—C1-3alkyl, —C1-3alkyl-C(O)NR4R5, aryl or heteroaryl is unsubstituted or substituted by one or two substituents selected from —OH, —CO2H, —C(O)NR4R5, —C(O)OR3, —N—C(O)—C1-3alkyl, F, —CN, —CH—F2, —CF3, —(CH2)n—O—(CH2)m—CH3, —C3-7cycloalkyl and a 5-6-membered heteroaryl ring containing 1, 2 or 3 heteroatoms selected from O, N and S;
or R3 and R4 together with the nitrogen atom to which they are attached form a 5-8-membered heterocyclic ring, an 8-11-membered bicyclic heterocyclic ring or a 9-10-membered bridged bicyclic heterocyclic ring, wherein each 5-8-membered ring, 8-11-membered bicyclic ring, or 9-10-membered bridged bicyclic ring optionally includes one —C(O) or one —S(O)2, and wherein each 5-8-membered ring, 8-11-membered bicyclic ring, or 9-10-membered bridged bicyclic ring optionally contains one, two or three oxygen ring atoms, one, two or three sulfur ring atoms or one, two or three nitrogen ring atoms, and wherein each 5-8-membered ring, 8-11-membered bicyclic ring, or 9-10-membered bridged bicyclic ring is unsubstituted or substituted by one, two or three substituents independently selected from —C1-5alkyl, —C3-7cycloalkyl, —C4-7heterocycloalkyl, —(CH2)phenyl, halogen, —NR3R5, —CHF2, —CF3, and —(CH2)n—O—(CH2)m—CH3;
A is tetrahydrobenzoxazepinyl, tetrahydro-pyrido-oxazepinyl, piperidinyl, tetrahydrobenzazepinyl, phenyl, tetrahydropyrrolopyrazinyl, imidazopyridinyl, tetrahydrobenzodiazepinyl, piperidopyrimidinyl, dioxidotetrahydrothiophenyl, tetrahydroimidazodiazepinyl, oxazepane or morpholinyl;
wherein each of tetrahydrobenzoxazepinyl, tetrahydro-pyrido-oxazepinyl, piperidinyl, tetrahydrobenzazepinyl, tetrahydropyrrolopyrazinyl, imidazopyridinyl, tetrahydrobenzodiazepinyl, piperidopyrimidinyl, dioxidotetrahydrothiophenyl, tetrahydroimidazodiazepinyl, oxazepane or morpholinyl is unsubstituted or substituted by 1, 2, or 3 substituents independently selected from —C1-3alkyl, —C3-6spirocycloalkyl, halo, —CN, —O—C1-3alkyl, —CH2—O—CH3, and —OH;
and wherein the oxazepane is further unsubstituted or substituted by 1 or 2 substituents independently selected from —C1-3alkyl and —C3-7cycloalkyl;
and wherein the morpholinyl is further unsubstituted or substituted by phenyl which phenyl is unsubstituted or substituted by a substituent independently selected from —C1-3 alkyl and —O—C1-3 alkyl;
or A is
Y is independently selected from N or CH;
E is independently S, O, N;
G is independently C, N;
Z is O, CH2, NR5, S, S(O) or S(O)2;
R5 is independently selected from hydrogen or —C1-4alkyl;
R6 is hydrogen, —C1-5alkyl or —(CH2)m—C3-5cycloalkyl;
R7 is hydrogen or —C1-4alkyl;
or R6 and R7, together with the carbon to which they are attached form a C3-C5-membered cycloalkyl ring;
and, wherein when A is
it is unsubstituted or substituted with one, two or three substituents independently selected from halo, —CF3, —C1-4alkyl, —CN, —OMe, —C(O)NH2, —OCF3 and —C1-4alkylNR7R8;
R8 is —C1-3alkyl, aryl, heteroaryl, —C(O)C1-3alkyl, —SO2C1-3alkyl, —C(O)aryl, —C(O)heteroaryl, —SO2aryl, —SO2heteroaryl, —C3-7cycloalkyl, —C1-3alkyC3-7cycloalkyl, —C1-3alkylC3-7heterocycloalkyl,
C1-3alkyl-heteroaryl or —C1-3alkyl-aryl, wherein each of —C1-3alkyl, aryl, heteroaryl, —C(O)C1-3alkyl, —SO2C1-3alkyl, —C(O)aryl, —C(O)heteroaryl, —SO2aryl, —SO2heteroaryl, —C3-7cycloalkyl, —C1-3alkylC3-7cycloalkyl, —C1-3alkylC3-7heterocycloalkyl, —C1-3alkyl-heteroaryl or —C1-3alkyl-aryl is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from halo, —CN, —CF3, —OCF3,
—OCH3, —C1-3alkyl, —OC1-3alkyl, —OC3-7cycloalkyl, —OC3-7heterocycloalkyl, —O-aryl and —O-heteroaryl;
R9 is hydrogen, —C1-5alkyl or —(CH2)m—C3-5cycloalkyl;
R10 is H, SO2R6, C(O)R6;
m is 0, 1 or 2;
and
n is 1 or 2;
or a pharmaceutically acceptable salt thereof.

31 more elements

Dependencies are inferred from the claim text.

Facts

Application: 17/056,495Filed 16 May 2019
Priority: IT 1020180000061057 Jun 2018
Published: 1 Jul 2021
Term ends: Not estimatedThe source records don’t support an estimate.

Classification13 codes

C07D 249/18
Condensed with carbocyclic rings or ring systems: benzotriazoles
C07D 417/10
Containing two hetero rings: linked by a carbon chain containing aromatic rings
A61K 31/4192
Having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole: 1,2,3-Triazoles
A61K 31/554
Having seven-membered rings, e.g. azelastine, pentylenetetrazole: having at least one nitrogen and one sulfur as ring hetero atoms, e.g.…

Family

Application62/675,247Us provisional application · filed 23 May 2018
US 11,643,407 B2Related patent
US 2021/0198249 A1This patent

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

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Abstract

A compound of Formula (I):

wherein:
B is benzotriazolyl, phenyl, triazolopyridinyl, —O—(CH2)-triazolyl, or —(CH2)2-triazolyl wherein each of benzotriazolyl, phenyl, triazolopyridinyl, —O—(CH2)-triazolyl, or —(CH2)2-triazolyl is unsubstituted or substituted by 1, 2, or 3 substituents independently selected from —C1-3alkyl, —O—C1-3alkyl,
—CN, —(CH2)2—O—(CH2)2—OR3 and halo;
D is —C(O)OH, —C(O)NR3R4, —C(O)NHSO2CH3, —SO2NHC(O)CH3, -5-(trifluoromethyl)-4H-1,2,4-triazol-2-yl, —NR3—C(O)—R4, —NR3—C(O)—NR3R4;
—NR3—C(O)—O—R4 or tetrazolyl;
R1 is independently hydrogen, —C1-3alkyl, F, —C3-6spirocycloalkyl, oxetane, or the two R1 groups together with the carbon to which they are attached form a cyclopropyl group;
R2 is hydrogen, methyl, —CF3, or halo;
R3 is hydrogen or —C1-3alkyl;
R4 is hydrogen, —C1-5alkyl, —C3-7cycloalkyl, —C4-8heterocycloalkyl, —C1-5alkoxy, —C1-3alkyl-O—C1-3alkyl, —C1-3alkyl-NH—C1-3alkyl, —C1-3alkyl-SO2C1-3alkyl, —C1-3alkyl-C4-8heterocycloalkyl, —C1-3alkyl-C(O)NR4R5, aryl or heteroaryl, wherein each of —C1-5 alkyl, —C3-7 cycloalkyl, —C4-7 heterocycloalkyl, —C1-5alkoxy, —C1-3alkyl-O—C1-3alkyl, —C1-3alkyl-NH—C1-3alkyl, —C1-3alkyl-C(O)NR4R5, aryl or heteroaryl is unsubstituted or substituted by one or two substituents selected from —OH, —CO2H, —C(O)NR4R5, —C(O)OR3, —N—C(O)—C1-3alkyl, F, —CN, —CH—F2, —CF3, —(CH2)n—O—(CH2)m—CH3, —C3-7cycloalkyl and a 5-6-membered heteroaryl ring containing 1, 2 or 3 heteroatoms selected from O, N and S;
or R3 and R4 together with the nitrogen atom to which they are attached form a 5-8-membered heterocyclic ring, an 8-11-membered bicyclic heterocyclic ring or a 9-10-membered bridged bicyclic heterocyclic ring, wherein each 5-8-membered ring, 8-11-membered bicyclic ring, or 9-10-membered bridged bicyclic ring optionally includes one —C(O) or one —S(O)2, and wherein each 5-8-membered ring, 8-11-membered bicyclic ring, or 9-10-membered bridged bicyclic ring optionally contains one, two or three oxygen ring atoms, one, two or three sulfur ring atoms or one, two or three nitrogen ring atoms, and wherein each 5-8-membered ring, 8-11-membered bicyclic ring, or 9-10-membered bridged bicyclic ring is unsubstituted or substituted by one, two or three substituents independently selected from —C1-5alkyl, —C3-7cycloalkyl, —C4-7heterocycloalkyl, —(CH2)phenyl, halogen, —NR3R5, —CHF2, —CF3, and —(CH2)n—O—(CH2)m—CH3;
A is tetrahydrobenzoxazepinyl, tetrahydro-pyrido-oxazepinyl, piperidinyl, tetrahydrobenzazepinyl, phenyl, tetrahydropyrrolopyrazinyl, imidazopyridinyl, tetrahydrobenzodiazepinyl, piperidopyrimidinyl, dioxidotetrahydrothiophenyl, tetrahydroimidazodiazepinyl, oxazepane or morpholinyl;
wherein each of tetrahydrobenzoxazepinyl, tetrahydro-pyrido-oxazepinyl, piperidinyl, tetrahydrobenzazepinyl, tetrahydropyrrolopyrazinyl, imidazopyridinyl, tetrahydrobenzodiazepinyl, piperidopyrimidinyl, dioxidotetrahydrothiophenyl, tetrahydroimidazodiazepinyl, oxazepane or morpholinyl is unsubstituted or substituted by 1, 2, or 3 substituents independently selected from —C1-3alkyl, —C3-6spirocycloalkyl, halo, —CN, —O—C1-3alkyl, —CH2—O—CH3, and —OH;
and wherein the oxazepane is further unsubstituted or substituted by 1 or 2 substituents independently selected from —C1-3alkyl and —C3-7cycloalkyl;
and wherein the morpholinyl is further unsubstituted or substituted by phenyl which phenyl is unsubstituted or substituted by a substituent independently selected from —C1-3 alkyl and —O—C1-3 alkyl;
or A is
Y is independently selected from N or CH;
Z is O, CH2, NR5, S, S(O) or S(O)2;
R5 is independently selected from hydrogen or —C1-4alkyl;
R6 is hydrogen, —C1-5alkyl or —(CH2)m—C3-5cycloalkyl;
R7 is hydrogen or —C1-4alkyl;
or R6 and R7, together with the carbon to which they are attached form a C3-C5-membered cycloalkyl ring;
and, wherein when A is
it is unsubstituted or substituted with one, two or three substituents independently selected from halo, —CF3, —C1-4alkyl, —CN, —OMe, —C(O)NH2, —OCF3 and —C1-4alkyNR7R8;
R8 is —C1-3alkyl, aryl, heteroaryl, —C(O)C1-3alkyl, —SO2C1-3alkyl, —C(O)aryl, —C(O)heteroaryl, —SO2aryl, —SO2heteroaryl, —C3-7cycloalkyl, —C1-3alkyC3-7cycloalkyl, —C1-3alkylC3-7heterocycloalkyl,
C1-3alkyl-heteroaryl or —C1-3alkyl-aryl, wherein each of —C1-3alkyl, aryl, heteroaryl, —C(O)C1-3alkyl, —SO2C1-3alkyl, —C(O)aryl, —C(O)heteroaryl, —SO2aryl, —SO2heteroaryl, —C3-7cycloalkyl, —C1-3alkylC3-7cycloalkyl, —C1-3alkylC3-7heterocycloalkyl, —C1-3alkyl-heteroaryl or —C1-3alkyl-aryl is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from halo, —CN, —CF3, —OCF3,
—OCH3, —C1-3alkyl, —OC1-3alkyl, —OC3-7cycloalkyl, —OC3-7heterocycloalkyl, —O-aryl and —O-heteroaryl;
R9 is hydrogen, —C1-5alkyl or —(CH2)m—C3-5cycloalkyl;
R10 is H, SO2R6, C(O)R6;
m is 0, 1 or 2;
and
n is 1 or 2;
or a pharmaceutically acceptable salt thereof.

29 more elements

Facts

Application

17/056,495Filed 16 May 2019

Priority

IT 1020180000061057 Jun 2018

Published

1 Jul 2021

Term ends

Not estimatedThe source records don’t support an estimate.

Classification13 codes

C07D 249/18
Condensed with carbocyclic rings or ring systems: benzotriazoles
C07D 417/10
Containing two hetero rings: linked by a carbon chain containing aromatic rings
A61K 31/4192
Having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole: 1,2,3-Triazoles
A61K 31/554
Having seven-membered rings, e.g. azelastine, pentylenetetrazole: having at least one nitrogen and one sulfur as ring hetero atoms, e.g.…