US 10,738,040 B2Granted

Compounds, compositions, and methods for increasing CFTR activity

AssigneeProteostasis Therapeutics, Inc.

InventorsCecilia M. Bastos, Benito Munoz, Bradley Tait

Life of this patent

Estimating the term…

Abstract

The present disclosure features disclosed compounds which can increase cystic fibrosis transmembrane conductance regulator (CFTR) activity as measured in human bronchial epithelial (hBE) cells. The present disclosure also features methods of treating a condition associated with decreased CFTR activity or a condition associated with a dysfunction of proteostasis comprising administering to a subject an effective amount of a disclosed compound.

Claims23

Dependent claims

A method of treating a patient suffering from cystic fibrosis comprising administering to said patient an effective amount of a compound represented by:

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R22 is selected independently for each occurrence from the group consisting of H and F;
pp is 0, 1, 2 or 3;
R31 is selected from the group consisting of hydrogen, halogen, and C1-4alkyl;
L1 is selected from the group consisting of —C1alkylene-C4cycloalkylene, C4cycloalkylene, and C4cycloalkylene-C1alkylene-, wherein L1 may be optionally substituted by one, two or three substituents selected from the group consisting of halogen, hydroxyl, and C1-3alkyl (optionally substituted by one, two or three substituents each selected independently from Rff);
R44 is selected from the group consisting of C1-3alkyl, 4 to 6 membered heterocycloalkyl, a 5-6 membered monocyclic heteroaryl, and a 9-10 membered bicyclic heteroaryl, wherein the heteroaryl has one, two or three heteroatoms each selected from O, N, and S;
and wherein the heteroaryl or heterocycloalkyl may be optionally substituted by one or two substituents each selected independently from Rgg;
R44 is selected for each occurrence from group consisting of halogen, hydroxyl, C1-4alkyl, C1-4alkyoxy, C2-4alkenyl, oxo, NR′R″, —NR′—S(O)w—C1-3alkyl, S(O)w—NR′R″, and —S(O)w—1-3alkyl, where w is 0, 1, or 2, wherein C1-4alkyl, C1-4alkyoxy, and C2-4alkenyl may be optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, NR′R″, —NR′—S(O)w—C1-3alkyl, S(O)w—NR′R″, and —S(O)w—C1-3alkyl;
Rgg is selected for each occurrence from group consisting of halogen, hydroxyl, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C3-6cycloalkyl, —O—C(O)—C1-6alkyl, —C(O)—O—C1-6alkyl, —C(O)—O— phenyl, —O—C(O)-phenyl, phenyl, 4 to 6 membered heterocycloalkyl, —NR′R″, oxo, —NR′—S(O)w—C1-3alkyl, S(O)w—NR′R″, and —S(O)w—C1-3alkyl, where w is 0, 1, or 2, wherein C1-6alkyl, C1-6alkyoxy, C2-6alkenyl C3-6cycloalkyl, phenyl and heterocycloalkyl may each be optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, C1-6alkyl, C1-6alkoxy, hydroxyl, C(O)OH, —C(O)OC1-6alkyl, —O—C(O)C1-6alkyl, O—C(O)-phenyl, —C(O)O—NR′—C1-6alkyl, —O—C3-6cycloalkyl, —O-heterocycle, phenyl, —O— heteroaryl, —O-phenyl, —NR′R″, —NR′—S(O)w—C1-3alkyl, S(O)w—NR′R″, and —S(O)w—C1-3alkyl, where w is 0, 1, or 2;
and
R′ and R″ are each independently selected for each occurrence from H and C1-4alkyl or taken together with the nitrogen to which they are attached form a heterocyclic ring.

8 more elements

A method of treating a patient suffering from cystic fibrosis comprising administering to said patient an effective amount of a compound having the Formula (IIa) or Formula (IIb):

or a pharmaceutically acceptable salt thereof, wherein:
R1-b is selected from the group consisting of C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C12 cycloalkyl, C3-C12 cycloalkenyl, phenyl, halo, ORe, NRdRd, C(O)ORc, NO2, CN, C(O)Rc, C(O)C(O)Rc, C(O)NRdRd, NRdC(O)Rc, NRdS(O)nRc, NRd(COORc), NRdC(O)C(O)Rc, NRdC(O)NRdRd, NRdS(O)nNRdRd, NRdS(O)nRc, S(O)nRc, S(O)nNRdRd, OC(O)ORc, (C═NRd)Rc, heterocycle and heteroaryl, wherein C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C12 cycloalkyl, C3-C12 cycloalkenyl, heterocyclic, phenyl and heteroaryl may each be optionally substituted by one, two or three substituents each independently selected from Rtt;
each R2 is independently selected from the group consisting of hydrogen, halo, CN, and C1-C10 alkyl;
R3 is hydrogen or fluoro;
each R4 is independently selected from the group consisting of hydrogen, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C12 cycloalkyl, C3-C12 cycloalkenyl, phenyl, halo, ORc, NRdRd, C(O)ORc, NO2, CN, C(O)Rc, C(O)C(O)Rc, C(O)NRdRd, NRdC(O)Rc, NRdS(O)nRc, NRd(COORc), NRdC(O)C(O)Rc, NRdC(O)NRdRd, NRdS(O)nNRdRd, NRdS(O)nRc, S(O)nRc, S(O)nNRdRd, OC(O)ORc, (C═NRd)Rc, heterocycle and heteroaryl;
alternatively, two geminal R4 groups are taken together with the carbon atom to which they are attached to form a Spiro C3-C12 cycloalkyl, a Spiro C3-C12 cycloalkenyl, a spiro heterocyclic, a spiro aryl or spiro heteroaryl;
or yet alternatively, two vicinal R4 groups are taken together with the carbon atoms to which they are attached to form a fused, cyclic group selected from the group consisting of C4-C8 cycloalkyl, C4-C8 cycloalkenyl, 4- to 8-membered heterocyclic, phenyl and heteroaryl, or further alternatively, two R4 groups attached to non-adjacent carbon atoms are taken together with the carbon atoms to which they are attached to form a bridged cyclic group selected from the group consisting of C4-C8 cycloalkyl, C4-C8 cycloalkenyl, and 4- to 8-membered heterocyclic;
each Rb is independently selected from the group consisting of hydrogen, halo, C1-C10 alkyl (optionally substituted by one, two, or three substituents selected from halogen and hydroxyl) and C3-C6 cycloalkyl (optionally substituted by one, two, or three substituents selected from halogen and hydroxyl), or two geminal Rb groups are independently taken together with the carbon atom to which they are attached to form a heterocyclic or a heteroaryl;
each Rc is independently selected from the group consisting of hydrogen, C1-C10 alkyl(optionally substituted by one, two, or three substituents selected from halogen and hydroxyl), C2-C10 alkenyl(optionally substituted by one, two, or three substituents selected from halogen and hydroxyl), C2-C10 alkynyl(optionally substituted by one, two, or three substituents selected from halogen and hydroxyl), C3-C12 cycloalkyl(optionally substituted by one, two, or three substituents selected from halogen and hydroxyl), C3-C12 cycloalkenyl (optionally substituted by one, two, or three substituents selected from halogen and hydroxyl), phenyl(optionally substituted by one, two, or three substituents selected from halogen and hydroxyl) and heteroaryl(optionally substituted by one, two, or three substituents selected from halogen and hydroxyl);
each Rd is independently selected from the group consisting of hydrogen, C1-C10 alkyl(optionally substituted by one, two, or three halogens), C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, C3-C12 cycloalkyl, C3-C12 cycloalkenyl, heterocyclic, phenyl and heteroaryl;
or two geminal Rd groups are taken together with the nitrogen atom to which they are attached to form an heterocyclic or an heteroaryl;
Re is selected from the group consisting of optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;
m is 0, 1 or 2;
each n is independently 0, 1 or 2;
p is 0, 1 or 2;
Rtt is independently selected for each occurrence from the group consisting of:
C1-C6 alkyl (optionally substituted by one, two or three substituents selected from the group consisting of:
heterocyclic, —F, —Cl, —Br, —I, —OH, —NO2, —N3, —CN, —NH2, NHRd, —NRdRd, NRdC(O)Rd, —NRdSOnRd and —ORc), —C2-C6 alkenyl (optionally substituted by one, two or three substituents selected from the group consisting of:
heterocyclic, —F, —Cl, —Br, —I, —OH, —NO2, —N3, —CN, —NH2, NHRd, —NRdRd, NRdC(O)Rd, —NRdSOnRd and —ORc), —C2-C6 alkynyl (optionally substituted by one, two or three substituents selected from the group consisting of:
heterocyclic, —F, —Cl, —Br, —I, —OH, —NO2, —N3, —CN, —NH2, NHRd, —NRdRd, NRdC(O)Rd, —NRdSOnRd and —ORc), —C3-C6 cycloalkyl (optionally substituted by one, two or three substituents selected from the group consisting of:
heterocyclic, C1-C6 alkyl, —F, —Cl, —Br, —I, —OH, —NO2, —N3, —CN, —NH2, NHRd, —NRdRd, NRdC(O)Rd, —NRdSOnRd and —ORc), -heterocyclic (optionally substituted by one, two or three substituents selected from the group consisting of:
C1-C6 alkyl, heterocyclic, —F, —Cl, —Br, —I, —OH, —NO2, —N3, —CN, —NH2, NHRf, —NRfRf, NRfC(O)Rf, —NRfSOnRf and —ORc), —F, —Cl, —Br, —I, —OH, —NO2, —N3, —CN, —NH2, oxo, thioxo, —NHRd, —NRdRd, —ORc, —C(O)Rc, —C(O)C(O)Rc, —OCO2Rc, —OC(O)Rc, OC(O)C(O)Rc, —NHC(O)Rc, —NHCO2Rc, —NHC(O)C(O)Rc, NHC(S)NH2, —NHC(S)NHRd, —NHC(NH)NH2, —NHC(NH)NHRc, —NHC(NH)Rc, —C(NH)NHRc, (C═NRc)Rc;
—NRcC(O)Rc, —NRcC(S)NH2, —NRcC(S)NHRc, —NHSO2Rc, —CH2NH2, —CH2SO2CH3, -phenyl, and heteroaryl;
and
Rf is selected from the group consisting of hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C1-C10 alkoxy, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl.

22 more elements

A method of treating a patient suffering from cystic fibrosis comprising administering to said patient an effective amount of a compound selected from the group consisting of:

N-trans-3-(5-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-trans-3-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-cis-3-(5-(hydroxymethyl)-1H-1,2,3-triazol-1-yl) cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-cis-3-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl) cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-cis-3-(4-((S)-1-hydroxyethyl)-1H-1,2,3-triazol-1-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-cis-3-(5-((S)-1-hydroxyethyl)-1H-1,2,3-triazol-1-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-((trans-3-(5-(hydroxymethyl)-1,3,4-thiadiazol-2-yl)cyclobutyl)methyl)-5-phenylisoxazole-3-carboxamide;
N-((cis-3-(5-(hydroxymethyl)-1,3,4-thiadiazol-2-yl)cyclobutyl)methyl)-5-phenylisoxazole-3-carboxamide;
N-((trans-3-((5-(hydroxymethyl)-1,3,4-thiadiazol-2-yl)methyl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-((cis-3-((5-(hydroxymethyl)-1,3,4-thiadiazol-2-yl)methyl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-(trans-3-(5-((S)-1-hydroxyethyl)-1H-1,2,3-triazol-1-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-(trans-3-(4-((S)-1-hydroxyethyl)-1H-1,2,3-triazol-1-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-(trans-3-(5-((R)-1-hydroxyethyl)-1H-1,2,3-triazol-1-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-(trans-3-(4-((R)-1-hydroxyethyl)-1H-1,2,3-triazol-1-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-(cis-3-(5-((R)-1-hydroxyethyl)-1H-1,2,3-triazol-1-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-(cis-3-(4-((R)-1-hydroxyethyl)-1H-1,2,3-triazol-1-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-(trans-3-(5-((R)-1-hydroxyethyl)-1,3,4-oxadiazol-2-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-(trans-3-(5-((S)-1-hydroxyethyl)-1,3,4-oxadiazol-2-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-(trans-3-(5-(hydroxymethyl)-1,3,4-oxadiazol-2-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-trans-3-(5-((R)-1-hydroxyethyl)-1,3,4-thiadiazol-2-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-trans-3-(5-((S)-1-hydroxyethyl)-1,3,4-thiadiazol-2-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-trans-3-(5-(hydroxymethyl)-1,3,4-thiadiazol-2-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-cis-3-(5-(hydroxymethyl)-1,3,4-thiadiazol-2-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-cis-3-(5-((S)-1-hydroxyethyl)-1,3,4-thiadiazol-2-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-cis-3-(5-((R)-1-hydroxyethyl)-1,3,4-thiadiazol-2-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-cis-3-(5-(hydroxymethyl)-1,3,4-oxadiazol-2-yl)cyclobutyl)-5-phenylioxazole-3-carboxamide;
N-cis-3-(5-((R)-1-hydroxyethyl)-1,3,4-oxadiazol-2-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-cis-3-(5-((S)-1-hydroxyethyl)-1,3,4-oxadiazol-2-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-cis-3-(5-((R)-1,2-dihydroxyethyl)-1,3,4-thiadiazol-2-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
(1-cis-3-(5-phenylisoxazole-3-carboxamido)cyclobutyl)-1H-1,2,3-triazol-4-yl)methyl butylcarbamate;
N-trans-3-(4-(R)-1-hydroxyethyl)-1H-pyrazol-1-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-trans-3-(4-(S)-1-hydroxyethyl)-1H-pyrazol-1-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-trans-3-(5-((R)-1-hydroxyethyl)-1H-pyrazol-1-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-trans-3-(5-((S)-1-hydroxyethyl)-1H-pyrazol-1-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-(cis-3-(4-(hydroxymethyl)-1H-pyrazol-1-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-(trans-3-(4-(hydroxymethyl)-1H-pyrazol-1-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-cis-3-(3-(hydroxymethyl)-1H-pyrazol-1-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-trans-3-(3-(hydroxymethyl)-1H-pyrazol-1-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-trans-3-(3-(hydroxymethyl)-1,2,4-oxadiazol-5-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-cis-3-(3-(hydroxymethyl)-1,2,4-oxadiazol-5-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-(cis-3-(5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-(trans-3-(5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-(trans-3-((5-((S)-1-hydroxyethyl)-1,3,4-thiadiazol-2-yl)methyl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-(cis-3-((5-((S)-1-hydroxyethyl)-1,3,4-thiadiazol-2-yl)methyl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
5-phenyl-N-[(trans-3-([54(1R)-1-hydroxyethyl]-1,3,4-thiadiazol-2-yl]methyl)cyclobutyl]isoxazole-3-carboxamide;
5-phenyl-N-[(cis-3-([5-[(1R)-1-hydroxyethyl]-1,3,4-thiadiazol-2-yl]methyl)cyclobutyl]isoxazole-3-carboxamide;
N-trans-3-(2-hydroxyethyl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-cis-3-(2-hydroxyethyl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-(cis-3-(methylsulfonamidomethyl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-(trans-3-(3-((S)-1-hydroxyethyl)-1,2,4-oxadiazol-5-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-(trans-3-(3-((R)-1-hydroxyethyl)-1,2,4-oxadiazol-5-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-(cis-3-((5-((R)-1-hydroxyethyl)-1,3,4-oxadiazol-2-yl)methyl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-(trans-3-((5-((R)-1-hydroxyethyl)-1,3,4-oxadiazol-2-yl)methyl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-((trans-3-((5-((S)-1-hydroxyethyl)-1,3,4-oxadiazol-2-yl)methyl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-((cis-3-((5-((S)-1-hydroxyethyl)-1,3,4-oxadiazol-2-yl)methyl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-(trans-3-(5-((R)-1-hydroxyethyl)-1,2,4-oxadiazol-3-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-(trans-3-(5-((S)-1-hydroxyethyl)-1,2,4-oxadiazol-3-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
5-phenyl-N-[trans-3-(1-methylazetidin-3-yl)-1,3,4-oxadiazol-2-yl]cyclobutyl]isoxazole-3-carboxamide;
5-(4-fluorophenyl)-N-[trans-3-[5-[(1R)-1-hydroxyethyl]-1,3,4-oxadiazol-2-yl]cyclobutyl]isoxazole-3-carboxamide;
5-phenyl-N-[trans-3-[(1R)-1-methoxyethyl]-1,3,4-oxadiazol-2-yl]cyclobutyl]isoxazole-3-carboxamide;
(1R)-145-[trans-3-(5-phenylisoxazole-3-amido)cyclobutyl]-1,3,4-oxadiazol-2-yl]ethyl acetate;
(R)-1-(5-(trans-3-(5-phenylisoxazole-3-carboxamido)cyclobutyl)-1,3,4-oxadiazol-2-yl)ethyl benzoate;
N-(trans-3-(5-((R)-1-isopropoxyethyl)-1,3,4-oxadiazol-2-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-(trans-3-(5-((R)-1-isobutoxyethyl)-1,3,4-oxadiazol-2-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
tert-butyl 3-(5-(trans-3-(5-phenylisoxazole-3-carboxamido)cyclobutyl)-1,3,4-oxadiazol-2-yl)azetidine-1-carboxylate;
5-phenyl-N-[trans-3-[5-(azetidin-3-yl)-1,3,4-oxadiazol-2-yl]cyclobutyl]isoxazole-3-carboxamide;
N-(trans-3-(5-(oxetan-3-yl)-1,3,4-oxadiazol-2-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-(trans-3-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
5-(2,4-difluorophenyl)-N-(trans-3-(5-((R)-1-hydroxyethyl)-1,3,4-oxadiazol-2-yl)cyclobutyl)isoxazole-3-carboxamide;
5-(3-fluorophenyl)-N-(trans-3-(5-((R)-1-hydroxyethyl)-1,3,4-oxadiazol-2-yl)cyclobutyl)isoxazole-3-carboxamide;
5-(2-fluorophenyl)-N-(trans-3-(5-((R)-1-hydroxyethyl)-1,3,4-oxadiazol-2-yl)cyclobutyl)isoxazole-3-carboxamide;
5-(4-hydroxyphenyl)-N-(trans-3-(5-((R)-1-hydroxyethyl)-1,3,4-oxadiazol-2-yl)cyclobutyl)isoxazole-3-carboxamide;
5-(3-hydroxyphenyl)-N-(trans-3-(5-((R)-1-hydroxyethyl)-1,3,4-oxadiazol-2-yl)cyclobutyl)isoxazole-3-carboxamide;
5-(3,4-difluorophenyl)-N-(trans-3-(5-((R)-1-hydroxyethyl)-1,3,4-oxadiazol-2-yl)cyclobutyl)isoxazole-3-carboxamide;
N-(trans-3-(5-((R)-1-(methyl sulfonyl)ethyl)-1,3,4-oxadiazol-2-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-(trans-3-(5-cyclobutyl-1,3,4-oxadiazol-2-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-(trans-3-(1H-imidazol-1-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-(3-(5-((R)-1-hydroxyethyl)-1,3,4-oxadiazol-2-yl)cyclohexyl)-5-phenylisoxazole-3-carboxamide;
N-(3-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)cyclohexyl)-5-phenylisoxazole-3-carboxamide;
N-(3-(5-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)cyclohexyl)-5-phenylisoxazole-3-carboxamide;
N-[3-(hydroxymethyl)-1,3,4-oxadiazol-2-yl]cyclopentyl]-5-phenylisoxazole-3-carboxamide;
N-(cis/trans-4-(5-(hydroxymethyl)-1,3,4-oxadiazol-2-yl)cyclohexyl)-5-phenylisoxazole-3-carboxamide;
5-(3,4-dihydroxyphenyl)-N-(trans-3-(5-((R)-1-hydroxyethyl)-1,3,4-oxadiazol-2-yl)cyclobutyl)isoxazole-3-carboxamide;
N-(trans-3-(1H-benzo[d]imidazol-1-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-(trans-3-(5-(1, 1-dioxidothietan-3-yl)-1,3,4-oxadiazol-2-yl)cyclobutyl)-5-phenylisoxazole-3-carboxamide;
N-(3-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)cyclopentyl)-5-phenylisoxazole-3-carboxamide;
and N-(3-(5-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)cyclopentyl)-5-phenylisoxazole-3-carboxamide, and pharmaceutically acceptable salts thereof.

84 more elements

Dependencies are inferred from the claim text.

Facts

Application: 16/190,964Filed 14 Nov 2018 · continuation
Priority: 19 Jun 2014
Published: US 2019/0308960 A110 Oct 2019
Granted: 11 Aug 2020
Term ends: Not estimatedThe source records don’t support an estimate.

Classification24 codes

C07D 413/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
A61K 31/16
Medicinal preparations containing organic active ingredients: amides, e.g. hydroxamic acids
A61K 31/42
Having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole: oxazoles
A61K 31/422
Oxazoles: not condensed and containing further heterocyclic rings

Family

Application62/014,400Us provisional application · filed 19 Jun 2014
Application62/014,409Us provisional application · filed 19 Jun 2014
Application62/096,389Us provisional application · filed 23 Dec 2014
Application62/102,230Us provisional application · filed 12 Jan 2015
PCT/US2015/036691Parent of this continuation · filed 19 Jun 2015
US 2019/0308960 A1Pre-grant publication · published 10 Oct 2019
Application15/320,172Parent of this continuation
US 10,174,014 B2Parent of this continuation
US 2017/0233379 A1Published application
US 10,738,040 B2This patent

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

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Abstract

A method of treating a patient suffering from cystic fibrosis comprising administering to said patient an effective amount of a compound represented by:

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R22 is selected independently for each occurrence from the group consisting of H and F;
pp is 0, 1, 2 or 3;
R31 is selected from the group consisting of hydrogen, halogen, and C1-4alkyl;
L1 is selected from the group consisting of —C1alkylene-C4cycloalkylene, C4cycloalkylene, and C4cycloalkylene-C1alkylene-, wherein L1 may be optionally substituted by one, two or three substituents selected from the group consisting of halogen, hydroxyl, and C1-3alkyl (optionally substituted by one, two or three substituents each selected independently from Rff);
R44 is selected from the group consisting of C1-3alkyl, 4 to 6 membered heterocycloalkyl, a 5-6 membered monocyclic heteroaryl, and a 9-10 membered bicyclic heteroaryl, wherein the heteroaryl has one, two or three heteroatoms each selected from O, N, and S;
and wherein the heteroaryl or heterocycloalkyl may be optionally substituted by one or two substituents each selected independently from Rgg;
R44 is selected for each occurrence from group consisting of halogen, hydroxyl, C1-4alkyl, C1-4alkyoxy, C2-4alkenyl, oxo, NR′R″, —NR′—S(O)w—C1-3alkyl, S(O)w—NR′R″, and —S(O)w—1-3alkyl, where w is 0, 1, or 2, wherein C1-4alkyl, C1-4alkyoxy, and C2-4alkenyl may be optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, NR′R″, —NR′—S(O)w—C1-3alkyl, S(O)w—NR′R″, and —S(O)w—C1-3alkyl;
Rgg is selected for each occurrence from group consisting of halogen, hydroxyl, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C3-6cycloalkyl, —O—C(O)—C1-6alkyl, —C(O)—O—C1-6alkyl, —C(O)—O— phenyl, —O—C(O)-phenyl, phenyl, 4 to 6 membered heterocycloalkyl, —NR′R″, oxo, —NR′—S(O)w—C1-3alkyl, S(O)w—NR′R″, and —S(O)w—C1-3alkyl, where w is 0, 1, or 2, wherein C1-6alkyl, C1-6alkyoxy, C2-6alkenyl C3-6cycloalkyl, phenyl and heterocycloalkyl may each be optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, C1-6alkyl, C1-6alkoxy, hydroxyl, C(O)OH, —C(O)OC1-6alkyl, —O—C(O)C1-6alkyl, O—C(O)-phenyl, —C(O)O—NR′—C1-6alkyl, —O—C3-6cycloalkyl, —O-heterocycle, phenyl, —O— heteroaryl, —O-phenyl, —NR′R″, —NR′—S(O)w—C1-3alkyl, S(O)w—NR′R″, and —S(O)w—C1-3alkyl, where w is 0, 1, or 2;
and
R′ and R″ are each independently selected for each occurrence from H and C1-4alkyl or taken together with the nitrogen to which they are attached form a heterocyclic ring.

8 more elements

Facts

Application

16/190,964Filed 14 Nov 2018 · continuation

Priority

19 Jun 2014

Published

US 2019/0308960 A110 Oct 2019

Granted

11 Aug 2020

Term ends

Not estimatedThe source records don’t support an estimate.

Classification24 codes

C07D 413/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
A61K 31/16
Medicinal preparations containing organic active ingredients: amides, e.g. hydroxamic acids
A61K 31/42
Having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole: oxazoles
A61K 31/422
Oxazoles: not condensed and containing further heterocyclic rings

Family

Application62/014,400Us provisional application · filed 19 Jun 2014

Application62/014,409Us provisional application · filed 19 Jun 2014

Application62/096,389Us provisional application · filed 23 Dec 2014

Application62/102,230Us provisional application · filed 12 Jan 2015

PCT/US2015/036691Parent of this continuation · filed 19 Jun 2015

US 2019/0308960 A1Pre-grant publication · published 10 Oct 2019

Application15/320,172Parent of this continuation

US 10,174,014 B2Parent of this continuation

US 2017/0233379 A1Published application

US 10,738,040 B2This patent

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