US 2022/0185785 A1Published application

Inhibitors of cd40-cd154 binding

AssigneeTonix Pharmaceuticals Holding Corp

InventorsDarryl RIDEOUT, Seth LEDERMAN

Life of this patent

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Abstract

Disclosed herein are compounds including pharmaceutically acceptable salts, esters, prodrugs, hydrates and tautomers thereof which modulate the interactions of CD-40-CD40L. The compounds are useful for treating, ameliorating or preventing an autoimmune disease, inflammatory disease, or other immune-related disease in a patient in need of treatment.

Claims110

Dependent claims

A compound of Formula I:

or a pharmaceutically acceptable salt, ester, prodrug, hydrate and tautomer thereof, wherein:
Ring A is an optionally substituted 6-membered or 5-membered aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycloalkyl ring;
X1, X2, X3, X4 are each separately and independently selected from the group consisting of C, or N;
R4 is selected from the group consisting of CH═CH, CH, S, O, N, N═CH, CH═N, N═N, and CH2CH2, with the proviso that if any of X1, X2, X3, X4 are N, then R4 is restricted to CH;
R1 is selected from the group consisting of SO2NR′2, SO2R′, COR′, COOR′, CON(R′)2, CON(OR′)R′, tetrazole, triazole, optionally linked to the A ring through a bond, C1-C3 alkyl chain, a 6-membered or 5-membered aryl, a 5 or 6-membered cycloalkyl, a 5- or 6-membered heterocycloalkyl, or 6-membered or membered heteroaryl;
wherein each R′ is independently C1-C6 alkyl, C2-C6 heteroalkyl, 2-methoxyethyl, 2′-(2-methoxyethoxy)ethyl wherein each R′ can be optionally substituted with one or more groups selected from fluorine, C1-C4alkyl, C1-C4heteroalkyl, and ═O;
R2 is selected from the group consisting of H, optionally substituted C1-C3 alkylSO2R′, SO2NR′2, COOR′, CON(R′)2, CON(OR)R′, C1-C6 alkenyl, C1-C6 alkynyl, tetrazole, triazole, optionally linked to the A ring through a bond, wherein each R′ is independently H, C1-C6 alkyl, C3-C9cycloalkyl-alkyl, or C2-C13 heteroalkyl (in which 1 to 4 carbons are replaced with oxygen), wherein R′ can be optionally substituted with one or more groups selected from fluorine, CH3;
or
R1 and R2 taken together, form a fused ring with ring A to form benztriazole, substituted on either the 1- or 2-nitrogen with C1-C3 alkyl, 2-methoxyethyl, 2-(2′-methoxyethoxy-ethyl), (CH2)WCOOR′, (CH2)WCON(OR′)R′, wherein R′ is C1-C3 alkyl and w is 0-3;
L1 is a single bond, absent, —NHCO—, CONH—, 1,3,4-thiadiazole-2,5-diyl or else forms part of a ring with R3;
L2 is absent or a single bond or is thia-3,4-thiadiazole-2,5-diyl, —CONH—, —NHCO—, CONHCH2—, —NH—, —NHCH(CF3)—, CON(CH3)SO2—, SO2N(CH3)CO, —CCF3—NH—, —SOCH2—, or —S(O)(NR18)NH—, wherein R18 is selected from C1-C6 alkyl, C4-C10 oxa-alkyl, C4-C10 dioxa-alkyl, or C4-C10 trioxa-alkyl;
Ring B is an optionally substituted 6-membered or 5-membered aryl, or heteroaryl;
X5 and X6 of Ring B are independently and separately selected from the group consisting of C or N;
R6 attached to X6 of Ring B is separately and independently H, F, Cl, Br, I;
or
if R6 is attached to X5, R6 and L1 taken together, along with the two intervening atoms to which they are attached, form an optionally substituted five-membered ring optionally substituted heterocycloalkyl ring having 2-3 heteroatoms independently selected from N, and S;
wherein the rings are optionally substituted with one or more substituents selected from ═O, C1-C6 alkyl, or C2-C13 heteroalkyl, wherein the heteroatoms are 1 to 3 oxygen atoms);
R7 is CH═CH, N═CH, O or S;
Ring C is an optionally substituted 6-membered or 5-membered aryl, or heteroaryl;
X7 and X8 of Ring C are independently and separately selected from the group consisting of C, or N;
L3 is absent, a single bond, or selected from the group consisting of —CONH—, —NHCO—, CONHCH2—, —NH—, —NHCH(CF3)—, CON(CH3)SO2—, SO2N(CH3)CO—, —CH2SO—, SOCH2, —CH(CF3)—NH— and —CONHSO2—;
Ring D is an optionally substituted 6-membered aryl, or heteroaryl ring;
X9 and X10 of Ring D are independently and separately selected from the group consisting of C, or N;
R13 of Ring D is —CH═N—, CH═CH, —N═C—, N═N, or S, all of which can be optionally substituted on carbon atoms except for S and N═N;
R10, R11, R12 are independently and separately selected from H, F, C1-C6alkyl, CH2COOH, CH(CH3)COOH, COOH, SO2NHCOR′, and CONHSO2R′, wherein each R′ is independently C1-C6 alkyl, C2-C6 heteroalkyl, 2-methoxyethyl, 2′-(2-methoxyethoxy)ethyl wherein each R′ can be optionally substituted with one or more of fluorine, C1-C4alkyl, C1-C4 heteroalkyl, and ═O, wherein exactly one of R10, R11, or R12 is CH2COOH or COOH, provided R10 and R11 do not combine to form a 6-membered ring;
or
R10 and R11 taken together, along with the two intervening atoms to which they are attached, form an optionally substituted five or six-membered aromatic, aliphatic heteroaromatic, or heteroaliphatic ring, so that ring D, R10 and R11 taken together form a bicyclic ring system, wherein the bicyclic ring system is substituted with exactly one substituent selected from COOH, SO2NHCOR′, CONHSO2R′, CH2COOH, and CH(CH3)COOH, wherein each R′ is independently C1-C6 alkyl, C2-C6 heteroalkyl, 2-methoxyethyl, or 2′-(2-methoxyethoxy)ethyl and wherein each R′ can be optionally substituted with one or more groups selected from fluorine, C1-C4alkyl, C1-C4 heteroalkyl, and ═O, and R12 is H, F, or C1-C6 alkyl.

24 more elements

A compound selected from one or more of the following:

8-({4′-[3-(5-cyclopropylpent-1-yn-1-yl)-4-[2-(3-cyclopropylpropyl)-2H-
1,2,3,4-tetrazol-5-yl]benzamido]-[1,1′-biphenyl]-4-yl}carbamoyl)naphthalene-
1-carboxylic acid;
5-({4′-[3-(1-butyl-1H-1,2,3-triazol-4-yl)-4-(2-butyl-2H-1,2,3,4-tetrazol-5-
yl)benzamido]-[1,1′-biphenyl]-4-yl}carbamoyl)naphthalene-1-carboxylic acid;
8-[(4′-{[3-(2-hexyl-2H-1,2,3,4-tetrazol-5-yl)-
4(methoxycarbonyl)phenyl]carbamoyl}-[1,1′-biphenyl]-
4yl)carbamoyl]naphthalene-1-carboxylic acid;
5-[(6′-{4-[(2-cyclohexylethyl)(methoxy)carbamoyl]benzamido}-[3,3′-
bipyridazine]-6-yl)carbamoyl]naphthalene-1-carboxylic acid;
4-[3′,5′-difluoro-4′-(5-{4-[methoxy(methyl)carbamoyl]benzamido}-1,3,4-
thiadiazol-2-yl)-[1,1′-biphenyl]-4-amido]naphthalene-1-carboxylic acid;
5-[(6′-{4-[4-(2-ethoxy-2-oxoethyl)-1H-1,2,3-triazol-1-yl]benzamido}-[3,3′-
bipyridine]-6-yl)carbamoyl]naphthalene-1-carboxylic acid;
2-{2-[4′-({5-[4-(methoxycarbonyl)phenyl]-1,3,4-thiadiazol-2-yl}carbamoyl)-
[1,1′-biphenyl]-4-amido]-6-(propan-2-yl)phenyl}acetic acid;
8-({6′-[4-(methoxycarbonyl)benzamido]-[3,3′-bipyridazine]-6-
yl}carbamoyl)naphthalene-1-carboxylic acid;
8-(5-{4-[2-(4-methoxy-4-oxobutyl)-1,1,3-trioxo-2,3-dihydro-1lambda6,2-
benzothiazole-6-amido]phenyl}pyridine-2-amido)naphthalene-1-carboxylic
acid;
8-[5-(4-{N-[2-(2-methoxyethoxy)ethyl]4′-(methoxycarbonyl)-[1,1′-biphenyl]-4-
sulfonoimidamido}phenyl)pyridine-2-amido]naphthalene-1-carboxylic acid;
8-(5-{4-[4′-(methoxycarbonyl)-2-[3-(2-methoxyethoxy)prop-1-yn-1-yl]-[1,1′-
biphenyl]-4-amido]phenyl}pyridine-2-amido)naphthalene-1-carboxylic acid;
8-(5-{4-[4′-(methoxycarbonyl)-2′-[3-(2-methoxyethoxy)prop-1-yn-1-yl]-[1,1′-
biphenyl]-4-amido]phenyl}pyridine-2-amido)naphthalene-1-carboxylic acid;
8-[5-(4-{[1′-(methoxycarbonyl)-[4,4′-bipiperidine]-1-
carbonyl]amino}phenyl)pyridine-2-amido]naphthalene-1-carboxylic acid;
8-(5-(4-((2,2,2-trifluoro-1-(4′-(methoxycarbonyl)-[1,1′-biphenyl]-4-
yl)ethyl)amino)phenyl)picolinamido)-1-naphthoic acid;
4-(4′-{4-[1-(methoxycarbonyl)piperidin-4-yl]benzamido}-[1,1′-biphenyl]-4-
amido)naphthalene-1-carboxylic acid;
4-(4′-{4′-[methoxy(methyl)carbamoyl]-[1,1′-biphenyl]-4-amido}-[1,1′-
biphenyl]-4-amido)naphthalene-1-carboxylic acid;
4-{4′-[4′-(dimethylcarbamoyl)-[1,1′-biphenyl]-4-amido]-[1,1′-biphenyl]-4-
amido}naphthalene-1-carboxylic acid;
4-(4′-{4-[5-(methoxycarbonyl)furan-2-yl]benzamido}-[1,1′-biphenyl]-4-
amido)naphthalene-1-carboxylic acid;
4-(4′-{3-[(2H-1,2,3,4-tetrazol-5-yl)methyl]benzamido}-[1,1′-biphenyl]-4-
amido)naphthalene-1-carboxylic acid;
4-{4′-[3-(2H-1,2,3,4-tetrazol-5-yl)benzamido]-[1,1′-biphenyl]-4-
amido}naphthalene-1-carboxylic acid;
4-{4′-[4-(2H-1,2,3,4-tetrazol-5-yl)benzamido]-[1,1′-biphenyl]-4-
amido}naphthalene-1-carboxylic acid;
4-[(2,2,2-trifluoro-1-{4′-[4′-(methoxycarbonyl)-[1,1′-biphenyl]-4-amido]-[1,1′-
biphenyl]-4-yl}ethyl)amino]naphthalene-1-carboxylic acid;
methyl 4′-({4′-[(8-{[4-(2-methoxyethoxy)butanamido]sulfonyl}naphthalen-1-
yl)carbamoyl]-[1,1′-biphenyl]-4-yl}carbamoyl)-[1,1′-biphenyl]-4-carboxylate;
methyl4′-[(4′-{[8-(acetamidosulfonyl)naphthalen-1-yl]carbamoyl}-[1,1′-
biphenyl]-4-yl)carbamoyl]-[1,1′-biphenyl]-4-carboxylate;
2-{2-[({4′-[4′-(methoxycarbonyl)-[1,1′-biphenyl]-4-amido]-[1,1′-biphenyl]-4-
yl}formamido)methyl]phenyl}acetic acid;
2-{2-[({4′-[4′-(methoxycarbonyl)-[1,1′-biphenyl]-4-amido]-[1,1′-biphenyl]-4-
yl}formamido)sulfonyl]phenyl}acetic acid;
4-(4-{6-[4′-(methoxycarbonyl)-[1,1′-biphenyl]-4-amido]pyridin-3-
yl}benzamido)naphthalene-1-carboxylic acid;
4-(4-{5-[4′-(methoxycarbonyl)-[1,1′-biphenyl]-4-amido]thiophen-2-
yl}benzamido)naphthalene-1-carboxylic acid;
4-(5-{4-[4′-(methoxycarbonyl)-[1,1′-biphenyl]-4-amido]phenyl}thiophene-2-
amido)naphthalene-1-carboxylic acid and,
4-{N-[2-(2-methoxyethoxy)ethyl]4′-[4′-(methoxycarbonyl)-[1,1′-biphenyl]-4-
amido]-[1,1′-biphenyl]-4-sulfonoimidamido}naphthalene-1-carboxylic acid.
8-(((4′-((5-((2H-tetrazol-5-yl)methyl)-2H-tetrazol-2-yl)methyl)-[1,1′-biphenyl]-
4-yl)methyl)sulfinyl)-1-naphthoic acid
4-(4′-(4′-(methylsulfinyl)-[1,1′-biphenyl]-4-carboxamido)-[1,1′-biphenyl]-4-
carboxamido)-1-naphthoic acid
4-(((4′-(((4-(1-(methoxycarbonyl)piperidin-4-yl)phenyl)sulfinyl)methyl)-[1,1′-
biphenyl]-4-yl)methyl)sulfinyl)-1-naphthoic acid
4-(((4′-(((4-(1-(methoxycarbonyl)piperidin-4-yl)phenyl)sulfinyl)methyl)-[1,1′-
biphenyl]-4-yl)methyl)sulfinyl)-1-naphthoic acid
4-(((4′-(((3-(2H-tetrazol-5-yl)phenyl)sulfinyl)methyl)-[1,1′-biphenyl]-4-
yl)sulfinyl)methyl)-1-naphthoic acid
4-(((4′-(((4-(2H-tetrazol-5-yl)phenyl)sulfinyl)methyl)-[1,1′-biphenyl]-4-
yl)sulfinyl)methyl)-1-naphthoic acid
8-(((4′-((3-(2-hexyl-2H-tetrazol-5-yl)-4-(methoxycarbonyl)phenyl)carbamoyl)-
[1,1′-biphenyl]-4-yl)methyl)sulfinyl)-1-naphthoic acid

74 more elements

A compound of Formula II

or a pharmaceutically acceptable salt, ester, prodrug, hydrate and tautomer thereof, wherein:
Rings A and D are optionally substituted 5- or 6-membered aromatic or heteroaromatic rings with 2-4 nitrogens;
Rings B and C are optionally substituted 5- or 6-membered aromatic or heteroaromatic rings with 0-4 nitrogens;
X1, X2, X3, X4 are each separately and independently selected from the group consisting of C, or N;
L1 is a bond, (CH2) where (n=1-3), NH—, 1,2,3-triazole linked at 1 and 4, or 5-alkyl-tetrazole linked at the 2 position and the alkyl terminus (alkyl is 0-3 carbons);
L2 is a bond, (CH2)n where n is 1 to 5, CH(OH), C(CH3)2, —CH(OH)—, —CH2NH—, benzene-1,2-diyl, benzene-1,3-diyl, benzene-1,4-diyl, pyridine-3,5-diyl;
R1 is H, F, COOR14, CONR14, OR15, SO2R14, SO2NR14, COR15, tetrazole linked through its carbon, or CH2-tetrazole linked through its carbon;
R2 is H, F, COOR14, CONR14(OR15), SO2R14, SO2NR14COR15, tetrazole linked through its carbon, CH2-tetrazole linked through its carbon;
with the proviso that R1 and R2 cannot both be H or F;
R3 is H, For absent;
R4 is selected from the group of CH, CH═CR16, CH═CH, S, O, N, N═CH, CH═N, N═N, and CH2CH2, wherein R16 is OH, OCHF2, NHCOR14, H, F, CH═N, or N═CH;
R6 is H, F, methyl or absent;
R7 is CH, N, CR6═CH, or N═CH, optionally substituted with methyl on carbon atoms;
R8 is CH, N, CH═CH, CH═N, or N═CH, optionally substituted with methyl on carbon atoms;
R9 is H, F, Cl, methyl, NH2 or absent;
R10 is H, CH3, CH2COOH, CH2SO2NHCOR17, SO2NHCOR17, or tetrazole linked from its carbon (5 position);
R11 is H, COOH, CH2COOH, CH2SO2NHCOR17, SO2NHCOR17, or tetrazole linked from its carbon (5 position);
or
R10 and R11 optionally form an aromatic ring fused to ring D, including without limitation a fused benzene, or pyridine ring.
R12 is H or SO2NHCOR17;
R13 is CH═CH, CH═C(COOH), CH═C(CH2COOH), CH═C(SO2NHCOR16), CH═C(CH2SO2NHCOR17);
R14 and R15 are, independently, C1-C10 alkyl, C3-C8 cycloalkyl, or C3-C6 cycloalkyl linked through bonds or 1-8 carbon alkyl chains {(CH2)n with n=1 to 8} which can be optionally substituted with 1-3 fluorine atoms;
and R17 is H, CH3, N(CH3)2, (CH2CH2O)nCH3, NCH3((CH2CH2O)nCH3, where n=1 to 6.

20 more elements

A compound selected from one or more of the following:

8-[4′-({5-[(2H-1,2,3,4-tetrazol-5-yl)methyl]-2H-1,2,3,4-tetrazol-2-yl}methyl)-[1,1′-
biphenyl]-4-amido]naphthalene-1-carboxylic acid,
5-{4-[hydroxy(1-{2-hydroxy-5-[methoxy(methyl)carbamoyl]phenyl}-1H-1,2,3-
triazol-4-yl)methyl]-1H-1,2,3-triazol-1-yl}naphthalene-1-carboxylic acid,
5-[4-(5-{1-[2-hydroxy-5-(methoxycarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}pyridin-
3-yl)-1H-1,2,3-triazol-1-yl]naphthalene-1-carboxylic acid,
3-{[5-({2-[(2-butanamido-5-nitrophenyl)methyl]-2H-1,2,3,4-tetrazol-5-yl}methyl)-
2H-1,2,3,4-tetrazol-2-yl]methyl}naphthalene-1-carboxylic acid,
5-{4-[2-(1-{2-hydroxy-5-[methoxy(methyl)carbamoyl]phenyl}-1H-1,2,3-triazol-4-
yl)phenyl]-1H-1,2,3-triazol-1-yl}naphthalene-1-carboxylic acid,
5-{4-[2-(1-{2-acetamido-5-[methoxy(methyl)carbamoyl]phenyl}-1H-1,2,3-triazol-
4-yl)propan-2-yl]-1H-1,2,3-triazol-1-yl}naphthalene-1-carboxylic acid,
5-[4-(4-{1-[2-acetamido-5-(methoxycarbonyl)phenyl]-1H-1,2,3-triazol-4-
yl}phenyl)-1H-1,2,3-triazol-1-yl]naphthalene-1-carboxylic acid,
8-[4′-({5-[(2H-1,2,3,4-tetrazol-5-yl)methyl]-2H-1,2,3,4-tetrazol-2-yl}methyl)-[1,1′-
biphenyl]-4-amido]naphthalene-1-carboxylic acid,
5-[4-(3-{1-[2-acetamido-5-(methoxycarbonyl)phenyl]-1H-1,2,3-triazol-4-
yl}phenyl)-1H-1,2,3-triazol-1-yl]naphthalene-1-carboxylic acid,
5-[(4-{4-[1-({3-[methoxy(methyl)carbamoyl]phenyl}methyl)-1H-1,2,3-triazol-4-
yl]phenyl}-1H-1,2,3-triazol-1-yl)methyl]naphthalene-1-carboxylic acid,
5-[4-(4′-{1-[2-hydroxy-5-(methoxycarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-[1,1′-
biphenyl]-4-yl)-1H-1,2,3-triazol-1-yl]naphthalene-1-carboxylic acid,
5-[4-(6′-{1-[2-hydroxy-5-(methoxycarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-[3,3′-
bipyridine]-6-yl)-1H-1,2,3-triazol-1-yl]naphthalene-1-carboxylic acid,
N-{4-[4-(3-{1-[4-(acetamidosulfonyl)phenyl]-1H-1,2,3-triazol-4-yl}phenyl)-1H-
1,2,3-triazol-1-yl]benzenesulfonyl}-N-pentylacetamide,
5-(4-(3-(1-(2-acetamido-5-(methylsulfinyl)phenyl)-1H-1,2,3-triazol-4-yl)phenyl)-
1H-1,2,3-triazol-1-yl)-1-naphthoic acid,
3-[(5-{[2-({3-[methoxy(methyl)carbamoyl]phenyl}methyl)-2H-1,2,3,4-tetrazol-5-
yl]methyl}-2H-1,2,3,4-tetrazol-2-yl)methyl]benzoic acid,
5-[(6-chloro-3-{[(5-methanesulfonyl-1H-1,3-benzodiazol-2-yl)methyl]amino}-
1,2,4-triazin-5-yl)carbamoyl]naphthalene-1-carboxylic acid, and
2-[5-amino-3-(4-{4-[methoxy(methyl)carbamoyl]benzamido}-4-methylpiperidin-1-
yl)-1,2,4-triazin-6-yl]pyridine-4-carboxylic acid.

31 more elements

Dependencies are inferred from the claim text.

Facts

Application: 17/603,260Filed 13 Apr 2020
Priority: 12 Apr 2019
Published: 16 Jun 2022
Term ends: Not estimatedThe source records don’t support an estimate.

Classification30 codes

C07D 257/04
Not condensed with other rings: five-membered rings
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…
A61P 25/00
Drugs for disorders of the nervous system
A61P 29/00
Non-central analgesic, antipyretic or antiinflammatory agents

Family

Application62/833,473Us provisional application · filed 12 Apr 2019
US 2022/0185785 A1This patent

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

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Abstract

A compound of Formula I:

or a pharmaceutically acceptable salt, ester, prodrug, hydrate and tautomer thereof, wherein:
Ring A is an optionally substituted 6-membered or 5-membered aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycloalkyl ring;
X1, X2, X3, X4 are each separately and independently selected from the group consisting of C, or N;
R4 is selected from the group consisting of CH═CH, CH, S, O, N, N═CH, CH═N, N═N, and CH2CH2, with the proviso that if any of X1, X2, X3, X4 are N, then R4 is restricted to CH;
R1 is selected from the group consisting of SO2NR′2, SO2R′, COR′, COOR′, CON(R′)2, CON(OR′)R′, tetrazole, triazole, optionally linked to the A ring through a bond, C1-C3 alkyl chain, a 6-membered or 5-membered aryl, a 5 or 6-membered cycloalkyl, a 5- or 6-membered heterocycloalkyl, or 6-membered or membered heteroaryl;
wherein each R′ is independently C1-C6 alkyl, C2-C6 heteroalkyl, 2-methoxyethyl, 2′-(2-methoxyethoxy)ethyl wherein each R′ can be optionally substituted with one or more groups selected from fluorine, C1-C4alkyl, C1-C4heteroalkyl, and ═O;
R2 is selected from the group consisting of H, optionally substituted C1-C3 alkylSO2R′, SO2NR′2, COOR′, CON(R′)2, CON(OR)R′, C1-C6 alkenyl, C1-C6 alkynyl, tetrazole, triazole, optionally linked to the A ring through a bond, wherein each R′ is independently H, C1-C6 alkyl, C3-C9cycloalkyl-alkyl, or C2-C13 heteroalkyl (in which 1 to 4 carbons are replaced with oxygen), wherein R′ can be optionally substituted with one or more groups selected from fluorine, CH3;
or
R1 and R2 taken together, form a fused ring with ring A to form benztriazole, substituted on either the 1- or 2-nitrogen with C1-C3 alkyl, 2-methoxyethyl, 2-(2′-methoxyethoxy-ethyl), (CH2)WCOOR′, (CH2)WCON(OR′)R′, wherein R′ is C1-C3 alkyl and w is 0-3;
L1 is a single bond, absent, —NHCO—, CONH—, 1,3,4-thiadiazole-2,5-diyl or else forms part of a ring with R3;
L2 is absent or a single bond or is thia-3,4-thiadiazole-2,5-diyl, —CONH—, —NHCO—, CONHCH2—, —NH—, —NHCH(CF3)—, CON(CH3)SO2—, SO2N(CH3)CO, —CCF3—NH—, —SOCH2—, or —S(O)(NR18)NH—, wherein R18 is selected from C1-C6 alkyl, C4-C10 oxa-alkyl, C4-C10 dioxa-alkyl, or C4-C10 trioxa-alkyl;
Ring B is an optionally substituted 6-membered or 5-membered aryl, or heteroaryl;
X5 and X6 of Ring B are independently and separately selected from the group consisting of C or N;
R6 attached to X6 of Ring B is separately and independently H, F, Cl, Br, I;
or
if R6 is attached to X5, R6 and L1 taken together, along with the two intervening atoms to which they are attached, form an optionally substituted five-membered ring optionally substituted heterocycloalkyl ring having 2-3 heteroatoms independently selected from N, and S;
wherein the rings are optionally substituted with one or more substituents selected from ═O, C1-C6 alkyl, or C2-C13 heteroalkyl, wherein the heteroatoms are 1 to 3 oxygen atoms);
R7 is CH═CH, N═CH, O or S;
Ring C is an optionally substituted 6-membered or 5-membered aryl, or heteroaryl;
X7 and X8 of Ring C are independently and separately selected from the group consisting of C, or N;
L3 is absent, a single bond, or selected from the group consisting of —CONH—, —NHCO—, CONHCH2—, —NH—, —NHCH(CF3)—, CON(CH3)SO2—, SO2N(CH3)CO—, —CH2SO—, SOCH2, —CH(CF3)—NH— and —CONHSO2—;
Ring D is an optionally substituted 6-membered aryl, or heteroaryl ring;
X9 and X10 of Ring D are independently and separately selected from the group consisting of C, or N;
R13 of Ring D is —CH═N—, CH═CH, —N═C—, N═N, or S, all of which can be optionally substituted on carbon atoms except for S and N═N;
R10, R11, R12 are independently and separately selected from H, F, C1-C6alkyl, CH2COOH, CH(CH3)COOH, COOH, SO2NHCOR′, and CONHSO2R′, wherein each R′ is independently C1-C6 alkyl, C2-C6 heteroalkyl, 2-methoxyethyl, 2′-(2-methoxyethoxy)ethyl wherein each R′ can be optionally substituted with one or more of fluorine, C1-C4alkyl, C1-C4 heteroalkyl, and ═O, wherein exactly one of R10, R11, or R12 is CH2COOH or COOH, provided R10 and R11 do not combine to form a 6-membered ring;
or
R10 and R11 taken together, along with the two intervening atoms to which they are attached, form an optionally substituted five or six-membered aromatic, aliphatic heteroaromatic, or heteroaliphatic ring, so that ring D, R10 and R11 taken together form a bicyclic ring system, wherein the bicyclic ring system is substituted with exactly one substituent selected from COOH, SO2NHCOR′, CONHSO2R′, CH2COOH, and CH(CH3)COOH, wherein each R′ is independently C1-C6 alkyl, C2-C6 heteroalkyl, 2-methoxyethyl, or 2′-(2-methoxyethoxy)ethyl and wherein each R′ can be optionally substituted with one or more groups selected from fluorine, C1-C4alkyl, C1-C4 heteroalkyl, and ═O, and R12 is H, F, or C1-C6 alkyl.

24 more elements

Facts

Application

17/603,260Filed 13 Apr 2020

Priority

12 Apr 2019

Published

16 Jun 2022

Term ends

Not estimatedThe source records don’t support an estimate.

Classification30 codes

C07D 257/04
Not condensed with other rings: five-membered rings
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…
A61P 25/00
Drugs for disorders of the nervous system
A61P 29/00
Non-central analgesic, antipyretic or antiinflammatory agents