WO2019193062A1 - Pyrrolidines substituées et leur utilisation - Google Patents

Pyrrolidines substituées et leur utilisation Download PDF

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Publication number
WO2019193062A1
WO2019193062A1 PCT/EP2019/058417 EP2019058417W WO2019193062A1 WO 2019193062 A1 WO2019193062 A1 WO 2019193062A1 EP 2019058417 W EP2019058417 W EP 2019058417W WO 2019193062 A1 WO2019193062 A1 WO 2019193062A1
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group
alkyl
independently selected
membered
optionally substituted
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PCT/EP2019/058417
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English (en)
Inventor
Nicolas Desroy
Elsa DE LEMOS
Sylvain COUTY
Olivier Laurent Picolet
Xueqing Wang
Xenia B SEARLE
Bo Liu
Ming C. Yeung
Robert J Altenbach
Gregory A. Gfesser
Phillip R. Kym
Original Assignee
Abbvie S.Á.R.L
Galapagos Nv
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Publication of WO2019193062A1 publication Critical patent/WO2019193062A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • This invention relates to compounds that are modulators of the Cystic Fibrosis
  • Transmembrane Conductance Regulator (CFTR) protein useful in treating diseases and conditions mediated and modulated by CFTR.
  • This invention also relates to compositions containing compounds of the invention, processes for their preparation, and methods of treatment using them.
  • Cystic fibrosis is the most common fatal genetic disease in humans, and affects -0.04% of white individuals. For example, in the United States, about one in every 2,500 infants is affected, and up to 10 million people carry a single copy of the defective CF gene without apparent ill effects. However, individuals with two copies of the defective CF gene suffer from the debilitating and fatal effects of CF, including chronic lung infections.
  • F508delCFTR the most common CF mutation (present in at least 1 allele in -90% of CF patients) and occurring in approximately 70% of the cases of cystic fibrosis, contains a single amino acid deletion of phenylalanine 508. This deletion prevents the nascent protein from folding correctly, which protein in turn cannot exit the endoplasmic reticulum (ER) and traffic to the plasma membrane, and then is rapidly degraded. As a result, the number of channels present in the membrane is far less than in cells expressing wild-type CFTR. In addition to impaired trafficking, the mutation results in defective channel gating.
  • F508delCFTR is allowed to reach the cell plasma membrane by low-temperature (27 °C) rescue where it can function as a cAMP- activated chloride channel, its activity is decreased significantly compared with WT-CFTR.
  • Other mutations with lower incidence have also been identified that alter the channel regulation or the channel conductance.
  • CFTR activity modulation may be beneficial for other diseases not directly caused by mutations in CFTR, such as, for example, chronic obstructive pulmonary disease (COPD), dry eye disease, and Sjogren's syndrome.
  • COPD chronic obstructive pulmonary disease
  • COPD dry eye disease
  • Sjogren's syndrome a chronic obstructive pulmonary disease
  • the present invention discloses compounds that may act as CFTR modulators for the treatment of cystic fibrosis.
  • the present invention also provides methods for the preparation of these compounds, pharmaceutical compositions comprising these compounds and methods for the treatment of cystic fibrosis by administering the compounds of the invention.
  • R 1 is selected from the group consisting of SO2R 6 , C(0)R 6 , C(0)OR 6 , and C(0)NR 7 R 8 ;
  • R 2 is selected from the group consisting of C(0)OH or a bioisostere thereof;
  • R 3 is selected from the group consisting of Ci-C 6 alkyl, C3-C6 cycloalkyl, 4-12 membered
  • R 3 Ci-C 6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C 6 alkoxy, OH, oxo, CN, NO2, F, Cl, Br, and I; wherein the R 3 C3-C6 cycloalkyl, 4-12 membered heterocyclyl, and phenyl are optionally substituted with one or more substituents independently selected from the group consisting of Ci-C 6 alkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, OH, oxo, CN, Br, and I;
  • R 3A is selected from the group consisting of hydrogen, Ci-C 6 alkyl, and Ci-C 6 haloalkyl;
  • R 3 and R 3A together with the carbon to which they are attached, may form a
  • C 3 -C 6 cycloalkyl wherein the C 3 -C 6 cycloalkyl formed from R 3 and R 3A and the carbon to which they are attached is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C 6 alkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, OH, oxo, CN, NO 2 , F, Cl, Br, and I;
  • R 4 is selected from the group consisting of R 9 , C(0)R 9 , C(0)OR 9 , and C(O)NR 10 R n ;
  • R 5 is selected from the group consisting of 4-12 membered heterocyclyl, Ce-Cm membered aryl, 5-11 membered heteroaryl, C 3 -C 11 cycloalkyl, and C 4 -C 11 cycloalkenyl; wherein the R 5 4-12 membered heterocyclyl, C 6 -Cio membered aryl, 5-11 membered heteroaryl, C 3 -C 11 cycloalkyl, and C 4 -C 11 cycloalkenyl are optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, OXO, CN, N0 2 , F, Cl, Br, and I;
  • R 6 is selected from the group consisting of Ci-C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R 6 Ci-C 6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl are optionally substituted with one or more substituents independently selected from the group consisting of R 15 , OR 15 , 0C(0)R 15 , SR 15 , NR 16 R 17 , NR 16 S0 2 R 15 , OH, CN, NO2, F, Cl, Br, and I; wherein the R 6 6-l0 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, and 4-12 membered hetero
  • R 7 and R 8 are each independently selected from the group consisting of hydrogen, Ci-C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R 7 or R 8 Ci-C 6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R 45 , C(0)NH 2 ,
  • Ci-C 6 alkyl independently selected from the group consisting of Ci-C 6 alkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, 6-10 membered aryl, oxo, OH, CN, NO2, F, Cl, Br, and I;
  • R 9 is each independently selected from the group consisting of Ci-C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R 9 Ci-C 6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R 21 , OR 21 , SR 21 , C(0)R 21 , 0C(0)R 21 , C(0)0R 21 , C(0)NR 22 R 23 , SO2R 21 , NR 22 R 23 , NR 22 C(0)0R 21 , OH, OXO, CN, N0 2 , F, Cl, Br, and I; wherein each R 9 6-10 membered aryl, 5-11 membered hetero
  • R 10 and R 11 are each independently selected from the group consisting of hydrogen, OH, Ci-C 6 alkyl, Ci-C 6 alkoxy, C3-C11 cycloalkyl, phenyl, and 5-6 membered heteroaryl; wherein each R 10 or R 11 Ci-C 6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R 27 , OR 27 , C(0)R 27 , 0C(0)R 27 , C(0)0R 27 , C(0)NR 28 R 29 , SO 2 R 27 , NR 28 R 29 , OH, oxo, CN, NO2, F, Cl, Br, and I; wherein each R 10 or R 11 C3-C11 cycloalkyl, phenyl or 5-6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 30 , OR 30 , C(0)R 30 , OC(0)R 30 , C(0)0R 3 °, SO2
  • R 12 is each independently selected from the group consisting of Ci-C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R 12 6-10 membered aryl, 5-11 membered heteroaryl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkenyl, or 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C 6 alkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, OH, oxo, CN, NO2, F, Cl, Br, and I;
  • R 13 and R 14 are each independently selected from the group consisting of hydrogen and Ci-C 6 alkyl; wherein each R 13 or R 14 C 1 -C 6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C 6 alkoxy, OH, oxo, CN, NO2, F, Cl, Br, and I;
  • R 15 is each independently selected from the group consisting of Ci-C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R 15 Ci-C 6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of OH, oxo, CN, NO2, F, Cl, Br, and I; wherein each R 15 6-10 membered aryl, 5-11 membered heteroaryl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkenyl, or 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting
  • R 18 is each independently selected from the group consisting of Ci-C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 6 -Cio membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R 18 Ci-C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 6 -Cio membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, or 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C 6 alkyl, Ci-C 6 alkoxy, C 6 -Cio membered aryl, C3-C7 cycloalky
  • R 19 and R 20 are each independently selected from the group consisting of hydrogen, Ci-C 6 alkyl, and C 6 -Cio membered aryl; wherein each R 19 or R 20 Ci-C 6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of C 6 -Cio membered aryl, OH, CN, NO2, F, Cl, Br, and I;
  • R 21 is each independently selected from the group consisting of Ci-C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R 21 Ci-C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R 35 ; wherein each R 21 6-10 membered aryl, 5-11 membered heteroaryl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkenyl, or 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 36 , OR 36 , NR 37 NR 38 , OXO, OH,
  • R 25 and R 26 are each independently selected from the group consisting of hydrogen and Ci-C 6 alkyl
  • R 27 is each independently selected from the group consisting of Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -Cio membered aryl, 5-11 membered heteroaryl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R 27 Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -Cio membered aryl, 5-11 membered heteroaryl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkenyl, or 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C 6 alkyl, Ci-C 6 alkoxy, 5-6 membered heteroaryl, OH,
  • R 28 and R 29 are each independently selected from the group consisting of hydrogen and Ci-C 6 alkyl;
  • R 30 is each independently selected from the group consisting of Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -Cio membered aryl, 5-11 membered heteroaryl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R 30 Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -Cio membered aryl, 5-11 membered heteroaryl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkenyl, or 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C 6 alkyl, Ci-C 6 alkoxy, 5-6 membered heteroaryl, OH,
  • R 31 and R 32 are each independently selected from the group consisting of hydrogen and Ci-C 6 alkyl;
  • R 33 and R 34 are each independently selected from the group consisting of hydrogen and Ci-C 6 alkyl;
  • R 35 is each independently selected from the group consisting of 6-10
  • each R 35 6-10 membered aryl, 5-11 membered heteroaryl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkenyl, and 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C 6 haloalkyl and Ci-C 6 alkoxy;
  • R 36 is each independently selected from the group consisting of Ci-C 6 alkyl, 6-10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R 36 Ci-C 6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of OH, oxo, CN, NO2, F, Cl, Br, and I; wherein each R 36 6-10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, or 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C 6 haloalkyl and Ci-C 6 alkoxy;
  • R 37 and R 38 are each independently selected from the group consisting of hydrogen and Ci-C 6 alkyl;
  • R 44 at each occurrence, are each independently selected from the group consisting of 6-10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R 44 6-10 membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C 6 haloalkyl and Ci-C 6 alkoxy;
  • R 45 are each independently selected from the group consisting of 6-10 membered aryl, 5-11 membered heteroaryl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R 45 6-10 membered aryl, 5-11 membered heteroaryl, or 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 alkoxy, C 3 -C 11 cycloalkyl, 6-10 membered aryl, 5-6 membered heteroaryl, 4-12 membered heterocyclyl, OH, oxo, CN, NO2, F, Cl, Br, and I;
  • R 9 is 4-12 membered heterocyclyl, the 4-12 membered heterocyclyl is attached via a suitable carbon atom;
  • Another aspect of the invention relates to pharmaceutical compositions comprising a compound of the invention, and a pharmaceutical carrier.
  • the compounds of the invention, useful in the pharmaceutical compositions and treatment methods disclosed herein are pharmaceutically acceptable as prepared and used.
  • R 1 , R 2 , R 3 , R 3A , R 4 , and R 5 are defined above in the Summary and below in the Detailed Description. Further, compositions comprising such compounds and methods for treating conditions and disorders using such compounds and compositions are also described.
  • variable(s) may contain one or more variable(s) that occur more than one time in any substituent or in the formulae herein. Definition of a variable on each occurrence is independent of its definition at another occurrence. Further, combinations of substituents are permissible only if such combinations result in stable compounds. Stable compounds are compounds, which can be isolated from a reaction mixture.
  • alkenyl as used herein, means a straight or branched hydrocarbon chain containing from 2 to 10 carbons and containing at least one carbon-carbon double bond.
  • C2-C6 alkenyl means an alkenyl group containing 2-6 carbon atoms.
  • Non-limiting examples of C2-C6 alkenyl include buta-l,3-dienyl, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4- pentenyl, and 5-hexenyl.
  • alkoxy means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • Ci-C 6 alkoxy means a Ci-C 6 alkyl group appended to the parent molecular moiety through an oxygen atom.
  • alkoxy include methoxy, ethoxy, propoxy, 2-propoxy, butoxy, /e/7-butoxy, pentyloxy, and hexyloxy.
  • Ci-C 6 alkoxy-Ci-C 6 alkyl as used herein, means a Ci-C 6 alkoxy group, as defined herein, appended to the parent molecular moiety through a Ci-C 6 alkyl group, as defined herein.
  • Non-limiting examples of Ci-C 6 alkoxy-Ci-C 6 alkyl include, but are not limited to, tert- butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, and methoxymethyl.
  • Ci-C 6 alkoxy-OH means a Ci-C 6 alkoxy group, as defined herein, substituted on the Ci-C 6 alkyl group with an -OH group.
  • alkyl as used herein, means a saturated, straight or branched hydrocarbon chain radical. In some instances, the number of carbon atoms in an alkyl moiety is indicated by the prefix“C x -C y ,” wherein x is the minimum and y is the maximum number of carbon atoms in the substituent. Thus, for example,“Ci-C 6 alkyl” means an alkyl substituent containing from 1 to 6 carbon atoms and“C 1 -C 3 alkyl” means an alkyl substituent containing from 1 to 3 carbon atoms.
  • alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, /e/7-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, l-methylbutyl, 2- methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, l,l-dimethylpropyl, l,2-dimethylpropyl, 2,2- dimethylpropyl, l-methylpropyl, 2-methylpropyl, l-ethylpropyl, and l,2,2-trimethylpropyl.
  • the terms“alkyl,”“Ci-C 6 alkyl,”“C 1 -C 4 alkyl,” and“C 1 -C 3 alkyl” used herein are unsubstituted, unless otherwise indicated.
  • Ci-C 6 alkyl-6- 10 membered aryl means a Ci-C 6 alkoxy group, as defined herein, appended to the parent molecular moiety through a Ci-C 6 alkyl group, as defined herein.
  • Ci-C 6 alkoxy-Ci-C 6 alkyl include, but are not limited to, /e/7-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, and methoxymethyl.
  • alkylene or“alkylenyl” means a divalent radical derived from a straight or branched, saturated hydrocarbon chain, for example, of 1 to 10 carbon atoms or of 1 to 6 carbon atoms (Ci-C 6 alkylenyl) or of 1 to 4 carbon atoms or of 1 to 3 carbon atoms (C 1 -C 3 alkylenyl) or of 2 to 6 carbon atoms (C 2 -C 6 alkylenyl).
  • Ci-C 6 alkylenyl examples include, but are not limited to, -CH2-, -CH2CH2-, -C(CH3)2-CH 2 CH 2 CH2-, -C(CH 3 )2CH 2 CH 2 , CH2CH2CH2CH2-, and - CH 2 CH(CH 3 )CH 2 -.
  • alkynyl as used herein, means a straight or branched chain hydrocarbon group containing at least one carbon-carbon triple bond.
  • C2-C6 alkynyl as used herein, means a straight or branched chain hydrocarbon radical containing from 2 to 6 carbon atoms and containing at least one carbon-carbon triple bond.
  • Non-limiting examples of C2-C6 alkynyl include, but are not limited, to acetylenyl, l-propynyl, 2-prop ynyl, 3-butynyl, 2-pentynyl, and l-butynyl.
  • aryl as used herein, means a hydrocarbon ring radical containing carbon atoms, zero heteroatoms, and one or more aromatic rings.
  • the aryl group may be a single-ring (monocyclic) or have two rings (bicyclic).
  • the bicyclic aryl is naphthyl, or a phenyl fused to a monocyclic cycloalkyl, or a phenyl fused to a monocyclic cycloalkenyl.
  • the bicyclic aryl is attached to the parent molecular moiety through any carbon atom contained within the bicyclic ring system.
  • 6-10 membered aryl means a hydrocarbon ring radical containing 6-10 carbon atoms, zero heteroatoms, and one or more aromatic rings.
  • the 6-10 membered aryl group may be a single-ring (monocyclic) or have two rings (bicyclic).
  • Nonlimiting examples of the aryl groups include, include, but are not limited to, phenyl, indenyl,
  • bioisostere means a moiety with substantially similar physical or chemical properties that impart similar biological properties to the compound having Formula (I).
  • -C(0)OH bioisosteres include -P(0)(OH) 2 , -P(0)(OH)(H),
  • R G3a is independently selected from the group consisting of C1-G5 alkyl, Ci-Ce alkyl-0-Ci-C 6 alkyl, Ci-C 6 haloalkyl, and G A ;
  • R G3b is selected from the group consisting of hydrogen, C1-G5 alkyl, C1-G5 haloalkyl and G A ;
  • R J at each occurrence, is independently selected from the group consisting of hydrogen, Ci-C 6 alkyl, and Ci-C 6 haloalkyl;
  • R k at each occurrence, is independently selected from the group consisting of Ci-C 6 alkyl and Ci-C 6 haloalkyl.
  • cycloalkenyl or“cycloalkene” as used herein, means a non-aromatic hydrocarbon ring radical containing carbon atoms, zero heteroatoms, and one or more double bonds.
  • C 4 -C 11 cycloalkenyl as used herein, means a non-aromatic hydrocarbon ring radical containing 4-11 carbon atoms, zero heteroatoms, and one or more double bonds.
  • the cycloalkenyl group may be a single-ring (monocyclic) or have two or more rings (polycyclic or bicyclic).
  • Nonlimiting examples of monocyclic cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cyclooctenyl, and cyclooctadienyl.
  • the bicyclic cycloalkenyl is a monocyclic cycloalkenyl fused to a monocyclic cycloalkyl group, or a monocyclic cycloalkenyl fused to a monocyclic cycloalkenyl group, or a bridged monocyclic ring system in which two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge containing one, two, three, or four carbon atoms.
  • Nonlimiting examples of the bicyclic cycloalkenyl groups include 4,5,6,7-tetrahydro-3a -indene,
  • the monocyclic and bicyclic cycloalkenyl may be attached to the parent molecular moiety through any substitutable atom contained within the ring systems, and can be unsubstituted or substituted.
  • cycloalkyl or“cycloalkane” as used herein, means a carbocyclic ring radical containing zero heteroatoms, and zero double bonds.
  • C 3 -C 11 cycloalkyl as used herein, means a hydrocarbon ring radical containing 3-11 carbon atoms, zero heteroatoms, and zero double bonds.
  • the cycloalkyl group may be a single-ring (monocyclic) or have two or more rings
  • Monocyclic cycloalkyl groups typically contain from 3 to 8 carbon ring atoms (C 3 -C 8 monocyclic cycloalkyl), and even more typically 3-6 carbon ring atoms (C 3 -C 6 monocyclic cycloalkyl).
  • Nonlimiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyl groups contain two or more rings, and bicyclic cycloalkyls contain two rings.
  • the polycyclic cycloalkyl groups contain 2 or 3 rings.
  • the rings within the polycyclic and the bicyclic cycloalkyl groups may be in a bridged, fused, or spiro orientation, or combinations thereof.
  • a spirocyclic cycloalkyl one atom is common to two different rings.
  • Spirocyclic cycloalkyl is exemplified by a monocyclic or a bicyclic cycloalkyl, wherein two of the substituents on the same carbon atom of the ring, together with said carbon atom, form a monocyclic cycloalkyl.
  • Nonlimiting examples of a spirocyclic cycloalkyl include spiro[2.5]octanyl and spiro[4.5]decanyl.
  • the spirocyclic cycloalkyl groups of the invention can be appended to the parent molecular moiety through any substitutable carbon atom of the groups.
  • the rings In a bridged cycloalkyl, the rings share at least two non-adjacent atoms.
  • Nonlimiting examples of bridged cycloalkyls include
  • fused ring cycloalkyl the rings share one common bond.
  • fused-ring cycloalkyl include decalin (decahydronaphthyl), bicyclo[3.l.0]hexanyl, and bicyclo[2.2.0]octyl.
  • halo or“halogen” as used herein, means Cl, Br, I, and F.
  • haloalkoxy as used herein, means an alkoxy group, as defined herein, in which one, two, three, four, five or six hydrogen atoms are replaced by halogen.
  • Ci-C 6 haloalkoxy means a Ci-C 6 alkoxy group, as defined herein, in which one, two, three, four, five, or six hydrogen atoms are replaced by halogen.
  • haloalkyl as used herein, means an alkyl group, as defined herein, in which one, two, three, four, five or six hydrogen atoms are replaced by halogen.
  • Ci-C 6 haloalkyl means a Ci-C 6 alkyl group, as defined herein, in which one, two, three, four, five, or six hydrogen atoms are replaced by halogen.
  • C 1 -C 3 haloalkyl means a C 1 -C 3 alkyl group, as defined herein, in which one, two, three, four, or five hydrogen atoms are replaced by halogen.
  • haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, 2,2-difluoroethyl, fluoromethyl, 2,2,2-trifluoroethyl, trifluoromethyl, difluoromethyl,
  • heteroaryl as used herein, means a monocyclic heteroaryl or a bicyclic heteroaryl.
  • the monocyclic heteroaryl is a five- or six-membered hydrocarbon ring wherein at least one carbon ring atom is replaced by heteroatom independently selected from the group consisting of O, N, and S.
  • the five-membered ring contains two double bonds.
  • the five-membered ring may contain one heteroatom selected from O, N, or S; or one, two, three, or four nitrogen atoms and optionally one oxygen or sulfur atom.
  • the six-membered ring contains three double bonds and one, two, three or four nitrogen atoms.
  • Nonlimiting examples of monocyclic heteroaryl include furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, l,3-oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, l,3-thiazolyl, thienyl, triazolyl, and triazinyl.
  • the bicyclic heteroaryl consists of a monocyclic heteroaryl fused to a phenyl, or a monocyclic heteroaryl fused to a monocyclic cycloalkyl, or a monocyclic heteroaryl fused to a monocyclic cycloalkenyl, or a monocyclic heteroaryl fused to a monocyclic heteroaryl, or a monocyclic heteroaryl fused to a monocyclic heterocycle.
  • bicyclic heteroaryl groups include 4H-furo[3,2-b]pyrrolyl, benzofuranyl, benzothienyl, benzoisoxazolyl, benzoxazolyl, benzimidazolyl, benzoxadiazolyl, phthalazinyl, 2,6-dihydropyrrolo[3,4-c]pyrazol-5(4 /)-yl, 6,7- dihydro-pyrazolo[ 1 ,5-a]pyrazin-5(4//)-yl, 6,7-dihydro- 1 ,3-benzothiazolyl, imidazo[ 1 ,2- ⁇ r/]pyridinyl, indazolyl, indolyl, isoindolyl, isoquinolinyl, naphthyridinyl, pyridoimidazolyl, quinolinyl, 4, 5,6,7- tetrahydropyrazolo[l,5-a]pyr
  • the nitrogen atom in the heteroaryl rings may optionally be oxidized and may optionally be alkylated.
  • the monocyclic and bicyclic heteroaryl groups of the invention can be substituted or unsubstituted and are connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the ring systems.
  • heterocycle or“heterocyclic” or“heterocyclyl” as used herein, means a hydrocarbon ring radical wherein at least one carbon atom is replaced by a heteroatom(s) independently selected from the group consisting of O, N, and S.
  • the heterocycle ring may be a single ring (monocyclic) or have two or more rings (bicyclic or polycyclic).
  • the monocyclic heterocycle is a four-, five-, six-, seven-, or eight-membered hydrocarbon ring wherein at least one carbon ring atom is replaced by a heteroatom(s) independently selected from the group consisting of O, N, and S.
  • the monocyclic heterocycle is a 4-7 membered hydrocarbon ring wherein at least one carbon ring atom is replaced by a heteroatom(s).
  • a four-membered monocyclic heterocycle contains zero or one double bond, and one heteroatom selected from the group consisting of O, N, and S.
  • a five-membered monocyclic heterocycle contains zero or one double bond and one, two, or three heteroatoms selected from the group consisting of O, N, and S.
  • Nonlimiting examples of five-membered monocyclic heterocycles include those containing in the ring: 1 O; 1 S; 1 N; 2 N; 3 N; 1 S and 1 N; 1 S, and 2 N; 1 O and 1 N; or 1 O and 2 N.
  • Nonlimiting examples of 5-membered monocyclic heterocyclic groups include l,3-dioxolanyl,
  • a six-membered monocyclic heterocycle contains zero, one, or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S.
  • Examples of six-membered monocyclic heterocycles include those containing in the ring: 1 O; 2 O; 1 S; 2 S; 1 N; 2 N; 3 N; 1 S, 1 O, and 1 N; 1 S and 1 N; 1 S and 2 N; 1 S and 1 O; 1 S and 2 O; 1 O and 1 N; and 1 O and 2 N.
  • Nonlimiting examples of six-membered monocyclic heterocycles include dihydropyranyl, l,4-dioxanyl, l,3-dioxanyl, l,4-dithianyl,
  • Seven- and eight-membered monocyclic heterocycles contains zero, one, two, or three double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S.
  • Nonlimiting examples of monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, l,4-diazepanyl, dihydropyranyl, l,3-dioxanyl, l,3-dioxolanyl, l,3-dithiolanyl, l,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxazepanyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxetanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl
  • Polycyclic heterocycle groups contain two or more rings, and bicyclic heterocycles contain two rings.
  • the polycyclic heterocycle groups contain 2 or 3 rings.
  • the rings within the polycyclic and the bicyclic heterocycle groups may be in a bridged, fused, or spiro orientation, or combinations thereof. In a spirocyclic heterocycle, one atom is common to two different rings.
  • Non limiting examples of the spirocyclic heterocycle include 6-oxaspiro[2.5]octanyl, 2- azaspiro[3.3]heptyl, 5-azaspiro[2.4]heptyl, 5-azaspiro[2.5]octyl, 2-azaspiro[3.5]nonyl, 2- azaspiro[3.4]octyl, 3-azaspiro[5.5]undecyl, 5-azaspiro[3.4]octyl, 2-oxaspiro[3.3]heptyl, 2-oxa-6- azaspiro[3.3]heptyl, 6-oxa-2-azaspiro[3.4]octyl, 6-azaspiro[3.4]octyl, 7-azaspiro[3.5]nonyl, 8- azaspiro[4.5]decyl, l-oxa-7-azaspiro[4.4]nonyl, l-oxa-7-azas
  • fused bicyclic heterocycles are a monocyclic heterocycle fused to a phenyl group, or a monocyclic heterocycle fused to a monocyclic cycloalkyl, or a monocyclic heterocycle fused to a monocyclic cycloalkenyl, or a monocyclic heterocycle fused to a monocyclic heterocycle.
  • fused bicyclic heterocycles include, but are not limited to, 1,2- dihydrophthalazinyl, 3,4-dihydro-2H-benzo[/ ][ 1 ,4]dioxepinyl, chromanyl, chromenyl,
  • octahydroimidazo[ 1 ,5-a]pyrazinyl octahydropyrrolo[ 1 ,2-a]pyrazinyl, octahydro- l//-pyrrolo[3,2- c]pyridinyl, and octahydropyrrolo[3,4-c]pyrrolyl.
  • the rings share at least two non-adjacent atoms.
  • bridged heterocycles include, but are not limited to, 8- oxabicyclo[3.2.l]octanyl, 7-oxabicyclo[2.2.l]heptanyl, azabicyclo[2.2.l]heptyl (including 2- azabicyclo[2.2.l]hept-2-yl), 8-azabicyclo[3.2.l]oct-8-yl, octahydro-2,5-epoxypentalene, 8-oxa-3- azabicyclo[3.2.l]octyl, hexahydro- 1 H- 1 ,4-methanocyclopenta[r]furan, aza-admantane
  • the nitrogen and sulfur heteroatoms in the heterocycle rings may optionally be oxidized (e.g. 1,1- dioxidotetrahydro thienyl, l,l-dioxido-l,2-thiazolidinyl, l,l-dioxidothiomorpholinyl)) and the nitrogen atoms may optionally be quaternized.
  • Non limiting examples of the polycyclic heterocycle include 6,7-dihydro-[l,3]dioxolo[4,5-/]benzofuranyl.
  • the monocyclic, bicyclic, polycyclic, and spirocyclic heterocycles are connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the rings, and can be unsubstituted or substituted.
  • heteroatom as used herein, means a nitrogen, oxygen, and sulfur.
  • hydroxyl or“hydroxyl” as used herein, means an -OH group.
  • hydroxyalkyl as used herein, means an alkyl group, as defined herein, which is substituted by an -OH group substituent.
  • alkoxy include hydroxymethyl, l-hydroxyethyl, 2-hydroxyethyl, l-hydroxypropyl, 2-hydroxypropyl, and 3 -hydroxypropyl .
  • the number of carbon atoms in a hydrocarbyl substituent is indicated by the prefix“C x -C y ” or“C x-y ,” wherein x is the minimum and y is the maximum number of carbon atoms in the substituent.
  • Ci-C 6 alkyl refers to an alkyl substituent containing from 1 to 6 carbon atoms.
  • C3-C6 cycloalkyl means a saturated hydrocarbyl ring containing from 3 to 6 carbon ring atoms.
  • a group is a divalent group
  • the group may be attached in any order to the two groups to which it is attached.
  • W and V are attached by the divalent group -CH2O- this will be understood to include W-CH2O-V and V-CH2O-W.
  • the term“radiolabel” refers to a compound of the invention in which at least one of the atoms is a radioactive atom or radioactive isotope, wherein the radioactive atom or isotope spontaneously emits gamma rays or energetic particles, for example alpha particles or beta particles, or positrons.
  • radioactive atoms include, but are not limited to, 3 H (tritium), 14 C, n C, 15 0, 18 F, 35 S, 123 I, and 125 I.
  • a non-hydrogen radical is in the place of hydrogen radical of any substitutable atom of the moiety.
  • a substituted heterocycle moiety is a heterocycle moiety in which at least one non-hydrogen radical is in the place of a hydrogen radical on the heterocycle. It should be recognized that if there are more than one substitution on a moiety, each non-hydrogen radical may be identical or different (unless otherwise stated).
  • a moiety is described as being“optionally substituted,” the moiety may be either (1) not substituted or (2) substituted. If a moiety is described as being optionally substituted with up to a particular number of non-hydrogen radicals, that moiety may be either (1) not substituted; or (2) substituted by up to that particular number of non-hydrogen radicals or by up to the maximum number of substitutable positions on the moiety, whichever is less. Thus, for example, if a moiety is described as a heteroaryl optionally substituted with up to 3 non-hydrogen radicals, then any heteroaryl with less than 3 substitutable positions would be optionally substituted by up to only as many non-hydrogen radicals as the heteroaryl has substitutable positions.
  • tetrazolyl (which has only one substitutable position) would be optionally substituted with up to one non hydrogen radical.
  • an amino nitrogen is described as being optionally substituted with up to 2 non-hydrogen radicals, then a primary amino nitrogen will be optionally substituted with up to 2 non-hydrogen radicals, whereas a secondary amino nitrogen will be optionally substituted with up to only 1 non-hydrogen radical.
  • “treat,”“treating,” and“treatment” refer to a method of alleviating or abrogating a disease and/or its attendant symptoms. In one embodiment,“treat,”“treating,” and “treatment” refer to slowing the progression of disease or disorder.
  • the phrase“therapeutically effective amount” means an amount of a compound, or a pharmaceutically acceptable salt thereof, sufficient to prevent the development of or to alleviate to some extent one or more of the symptoms of the condition or disorder being treated when administered alone or in conjunction with another therapeutic agent or treatment in a particular subject or subject population.
  • Class I mutation(s) refers to mutations which interfere with protein synthesis. They result in the introduction of a premature signal of termination of translation (stop codon) in the mRNA. The truncated CFTR proteins are unstable and rapidly degraded, so, the net effect is that there is no protein at the apical membrane.
  • Class I mutation(s) refers to p.Gly542X (G542X), W1282X, c.489+lG>T (62l+lG>T), or c.579+lG>T (7ll+lG>T) mutation. More particularly, Class I mutation(s) refers to G542X; or W 1282X mutations.
  • Class II mutation(s) refers to mutations which affect protein maturation. These lead to the production of a CFTR protein that cannot be correctly folded and/or trafficked to its site of function on the apical membrane.
  • Class II mutation(s) refers to p.Phe508del (F508del), p.Ile507del, or p.Asnl303Lys (N1303K) mutations. More particularly, Class II mutation(s) refers to F508del or N1303K mutations.
  • Class III mutation(s) refers to mutations which alter the regulation of the CFTR channel.
  • the mutated CFTR protein is properly trafficked and localized to the plasma membrane but cannot be activated, or it cannot function as a chloride channel.
  • Class III mutation(s) refers to p.Gly55lAsp (G551D), G551S, R553G, G1349D, S1251N, G178R, S549N mutations. More particularly, Class III mutation(s) refers to G551D, R553G, G1349D, S1251N, G178R, or S549N mutations.
  • Class IV mutation(s) refers to mutations which affect chloride conductance.
  • the CFTR protein is correctly trafficked to the cell membrane but generates reduced chloride flow or a“gating defect” (most are missense mutations located within the membrane- spanning domain).
  • Class IV mutation(s) refers to p.Argll7His (R117H), R347P, or specialized.Arg334Trp (R334W) mutations.
  • Class V mutation(s) refers to mutations which reduce the level of normally functioning CFTR at the apical membrane or result in a“conductance defect” (for example partially aberrant splicing mutations or inefficient trafficking missense mutations).
  • Class V mutation(s) refers to c.l2lO-l2T[5] (5T allele), c.S3l40-26A>G (3272-26A>G), till.3850-2477C>T (3849+l0kbC>T) mutations.
  • Class VI mutation(s) refers to mutations which decrease the stability of the CFTR which is present or which affect the regulation of other channels, resulting in inherent instability of the CFTR protein. In effect, although functional, the CFTR protein is unstable at the cell surface and it is rapidly removed and degraded by cell machinery.
  • Class VI mutation(s) refers to Rescued F508del, l20del23, N287Y, 4326dellTC, or 4279insA mutations. More particularly, Class VI mutation(s) refers to Rescued F508del mutations.
  • R 1 is selected from the group consisting of S0 2 R 6 , C(0)R 6 , C(0)OR 6 , and C(0)NR 7 R 8 ;
  • R 2 is selected from the group consisting of C(0)OH or a bioisostere thereof;
  • R 3 is selected from the group consisting of Ci-C 6 alkyl, C3-C6 cycloalkyl, 4-12 membered heterocyclyl, and phenyl; wherein the R 3 C 1 -G 5 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C 6 alkoxy, OH, oxo, CN, N0 2 , F, Cl, Br, and I; wherein the R 3 C3-C6 cycloalkyl, 4-12 membered heterocyclyl, and phenyl are optionally substituted with one or more substituents independently selected from the group consisting of Ci-C 6 alkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, OH, oxo, CN, Br, and I;
  • R 3A is selected from the group consisting of hydrogen, Ci-C 6 alkyl, and Ci-C 6 haloalkyl; wherein R 3 and R 3A , together with the carbon to which they are attached, may form a C3-C6 cycloalkyl; wherein the C3-C6 cycloalkyl formed from R 3 and R 3A and the carbon to which they are attached is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C 6 alkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, OH, oxo, CN, N0 2 , F, Cl, Br, and I;
  • R 4 is selected from the group consisting of R 9 , C(0)R 9 , C(0)0R 9 , and C(O)NR 10 R n ;
  • R 5 is selected from the group consisting of 4-12 membered heterocyclyl, C 6 -Cio membered aryl, 5-11 membered heteroaryl, C 3 -C 11 cycloalkyl, and C 4 -C 11 cycloalkenyl; wherein the R 5 4-12 membered heterocyclyl, C 6 -Cio membered aryl, 5-11 membered heteroaryl, C 3 -C 11 cycloalkyl, and C 4 -C 11 cycloalkenyl are optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, OXO, CN, N0 2 , F, Cl, Br, and I;
  • R 6 is selected from the group consisting of Ci-C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R 6 Ci-C 6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl are optionally substituted with one or more substituents independently selected from the group consisting of R 15 , OR 15 , 0C(0)R 15 , SR 15 , NR 16 R 17 ,
  • NR l 6 S0 2 15 OH, CN, NO2, F, Cl, Br, and I; wherein the R 6 6-l0 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, and 4-12 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of R 18 , OR 18 , C(0)R 18 , 0C(0)R 18 , C(0)0R 18 , SO2R 18 , C(0)NR 19 R 20 , NR 19 R 20 , S0 2 NR 19 R 20 , OH, OXO, CN, N0 2 , F, Cl, Br, and I;
  • R 7 and R 8 are each independently selected from the group consisting of hydrogen, Ci-C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R 7 or R 8 Ci-C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R 45 , C(0)NH 2 , C(0)NHCH 3 , OH, OXO, CN, N0 2 , F, Cl, Br, and I; wherein each R 7 or R 8 6-10 membered aryl, 5-11 membered heteroaryl, C 3 -C 11 cycloalkyl, C 4 -C 11
  • cycloalkenyl, or 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C , haloalkyl, 6-10 membered aryl, oxo, OH, CN, N0 2 , F, Cl, Br, and i;
  • R 9 is each independently selected from the group consisting of Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R 9 Ci-C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R 21 , OR 21 , SR 21 , C(0)R 21 , OC(0)R 21 , C(0)OR 21 , C(0)NR 22 R 23 , S0 2 R 21 , NR 22 R 23 , NR 22 C(0)0R 21 , OH, OXO, CN, N0 2 , F, Cl, Br, and I; wherein each R 9 6-10 membered aryl
  • R 10 and R 11 are each independently selected from the group consisting of hydrogen, OH, Ci-Ce alkyl, Ci-C 6 alkoxy, C3-C11 cycloalkyl, phenyl, and 5-6 membered heteroaryl; wherein each R 10 or R 11 Ci-C 6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R 27 , OR 27 , C(0)R 27 , 0C(0)R 27 , C(0)0R 27 , C(0)NR 28 R 29 , S0 2 R 27 , NR 28 R 29 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; wherein each R 10 or R 11 C3-C11 cycloalkyl, phenyl or 5-6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 30 , OR 30 , C(0)R 3 °, 0C(0)R 3 °, C(0)0
  • R 12 is each independently selected from the group consisting of Ci-C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 haloalkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R 12 6-10 membered aryl, 5-11 membered heteroaryl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkenyl, or 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C 6 alkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, OH, oxo, CN, N0 2 , F, Cl,
  • R 13 and R 14 are each independently selected from the group consisting of hydrogen and Ci-C 6 alkyl; wherein each R 13 or R 14 C i -C 6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C 6 alkoxy, OH, oxo, CN, N0 2 , F, Cl, Br, and I;
  • R 15 is each independently selected from the group consisting of Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R 15 Ci-C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of OH, oxo,
  • each R 15 6-10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, or 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C 6 alkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, Ci-C 6 haloalkoxy, oxo, OH, CN, N0 2 , F, Cl, Br, and I;
  • R 16 and R 17 are each independently selected from the group consisting of hydrogen, Ci-C 6 alkyl, and 5-11 membered heteroaryl; wherein each R 16 or R 17 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C 6 alkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkyl, Ci-C 6 haloalkoxy, oxo, C(0)NR 33 R 34 , OH, CN, N0 2 , F, Cl, Br, and I;
  • R 18 is each independently selected from the group consisting of Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -Cio membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R 18 Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -Cio membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, or 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C 6 alkyl, Ci-C 6 alkoxy, C 6 -Cio membered aryl, C3
  • R 19 and R 20 are each independently selected from the group consisting of hydrogen, Ci-C 6 alkyl, and C6-C10 membered aryl; wherein each R 19 or R 20 Ci-C 6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of C 6 -Cio membered aryl, OH, CN, N0 2 , F, Cl, Br, and I;
  • R 21 is each independently selected from the group consisting of Ci-C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R 21 Ci-C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R 35 ; wherein each R 21 6-10 membered aryl, 5-11 membered heteroaryl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkenyl, or 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 36 , OR 36 , NR 37 NR 38 , oxo, OH,
  • R 22 and R 23 are each independently selected from the group consisting of hydrogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, 6-10 membered aryl, and 5-11 membered heteroaryl; wherein each R 22 or R 23 Ci-C 6 alkyl is optionally substituted with one or more R 44 ; wherein each R 22 or R 23 6-10 membered aryl, or 5-11 membered heteroaryl, is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 alkoxy, Ci-C 6 haloalkoxy, Ci-C 6 alkoxy-OH, 5-6 membered heteroaryl, OH, oxo, CN, NO2, F, Cl, Br, and I;
  • R 24 is each independently selected from the group consisting of Ci-C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R 24 Ci-C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkenyl, or 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 alkoxy, C 3 - C 11 cycloalkyl, 6-10 membered
  • R 25 and R 26 are each independently selected from the group consisting of hydrogen and
  • R 27 is each independently selected from the group consisting of Ci-C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 6 -Cio membered aryl, 5-11 membered heteroaryl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R 27 Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 membered aryl, 5-11 membered heteroaryl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkenyl, or 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C 6 alkyl, Ci-C 6 alkoxy, 5-6 membered heteroaryl, OH, oxo,
  • R 28 and R 29 are each independently selected from the group consisting of hydrogen and Ci-C 6 alkyl;
  • R 30 is each independently selected from the group consisting of Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -Cio membered aryl, 5-11 membered heteroaryl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R 30 Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -Cio membered aryl, 5-11 membered heteroaryl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkenyl, or 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C 6 alkyl, Ci-C 6 alkoxy, 5-6 membered heteroaryl, OH,
  • R 31 and R 32 are each independently selected from the group consisting of hydrogen and Ci-C 6 alkyl;
  • R 33 and R 34 are each independently selected from the group consisting of hydrogen and Ci-C 6 alkyl;
  • R 35 is each independently selected from the group consisting of 6-10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R 35 6-10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, or 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C 6 haloalkyl and Ci-C 6 alkoxy;
  • R 36 is each independently selected from the group consisting of Ci-C 6 alkyl, 6-10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R 36 Ci-C 6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of OH, oxo, CN, NO2, F, Cl, Br, and I; wherein each R 36 6-10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, or 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C 6 haloalkyl and Ci-C 6 alkoxy;
  • R 37 and R 38 are each independently selected from the group consisting of hydrogen and Ci-C 6 alkyl;
  • R 44 at each occurrence, are each independently selected from the group consisting of 6-10 membered aryl, 5-11 membered heteroaryl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R 44 6-10 membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C 6 haloalkyl and Ci-C 6 alkoxy;
  • R 45 at each occurrence, are each independently selected from the group consisting of 6-10 membered aryl, 5-11 membered heteroaryl, C3-C11 cycloalkyl, C4-C11 cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R 45 of 6-10 membered aryl, 5-11 membered heteroaryl, or 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 alkoxy, C3-C11 cycloalkyl, 6-10 membered aryl, 5-6 membered heteroaryl, 4-12 membered heterocyclyl, OH, oxo, CN, NO2, F, Cl, Br, and i;
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where
  • R 1 is selected from the group consisting of S0 2 R 6 , C(0)R 6A , C(0)0R 6 , and C(0)NR 7 R 8 ;
  • R 6A is selected from the group consisting of C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R 6 C2-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl are optionally substituted with one or more substituents independently selected from the group consisting of R 15 , OR 15 , OC(0)R 15 , SR 15 , NR 16 R 17 , NR l 6 S0 2 15 , OH, CN, NO2, F, Cl, Br, and I; wherein the R 6 6-l0 membered aryl, 5-11 membered heteroaryl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkenyl, and 4
  • R 4 is selected from the group consisting of R 9 , C(0)R 9A , C(0)OR 9 , and C(O)NR 10 R n ;
  • R 9A is selected from the group consisting of Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R 9A Ci-C 6 alkyl, C 2 -C 6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R 21 , OR 21 , SR 21 , C(0)R 21 , OC(0)R 21 , C(0)OR 21 , C(0)NR 22 R 23 , SO 2 R 21 , NR 22 R 23 , NR 22 C(0)0R 21 , OH, OXO, CN, N0 2 , F, Cl, Br, and I; wherein each R 9A 5-11 membered heteroaryl
  • R 9B is selected from the group consisting of hydrogen, R 24 , OR 24 , C(0)R 24 , 0C(0)R 24 ,
  • R 9C is selected from the group consisting of hydrogen, R 24 , OR 24 , C(0)R 24 , 0C(0)R 24 ,
  • R 5 is selected from the group consisting of 4-12 membered heterocyclyl, C 6 -Cio membered aryl, C 3 -C 11 cycloalkyl, and C 4 -C 11 cycloalkenyl; wherein the R 5 C 6 -Cio membered aryl, is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, NO2,
  • R 5 4-12 membered heterocyclyl, C 3 -C 11 cycloalkyl, and C 4 -C 11 cycloalkenyl are optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 ,
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 2 is C(0)0H; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 2 is C(0)0H; R 3 is Ci-C 6 alkyl which is optionally substituted with Ci-C 6 alkoxy; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 2 is C(0)0H; R 3 is Ci-C 6 alkyl which is optionally substituted with Ci-C 6 alkoxy; R 3A is selected from the group consisting of hydrogen and C 1 -C 6 alkyl; wherein R 3 and R 3A , together with the carbon to which they are attached, may form a C3-C6 cycloalkyl; R 5 is phenyl; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 2 is C(0)0H; R 3 is /e/7-butyl; R 3A is hydrogen; R 5 is phenyl; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 2 is C(0)OH; R 3 is /e/7-butyl; R 3A is hydrogen; R 4 is C(0)R 9 ; R 5 is phenyl; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 2 is C(0)OH; R 3 is /e/7-butyl; R 3A is hydrogen; R 4 is C(0)R 9 ; R 5 is phenyl; R 9 is 6-10 membered aryl which may be optionally substituted with one or more substituents independently selected from the group consisting of R 24 , OR 24 , C(0)R 24 , 0C(0)R 24 , C(0)0R 24 , SO2R 24 , NR 25 R 26 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 2 is C(0)OH; R 3 is /e/ -butyl; R 3A is hydrogen; R 4 is C(0)R 9 ; R 5 is phenyl; R 9 is 6-10 membered aryl which may be optionally substituted with one or more substituents independently selected from the group consisting of R 24 , OR 24 , OH, CN, F, Cl, and Br; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 2 is C(0)OH; R 3 is /e/ -butyl; R 3A is hydrogen; R 4 is C(0)R 9 ; R 5 is phenyl; R 9 is 6-10 membered aryl which may be optionally substituted with one or more substituents independently selected from the group consisting of R 24 , OR 24 , OH, CN, F, Cl, and Br; R 24 , at each occurrence, is each independently selected from the group consisting of Ci-C 6 alkyl, 6-10 membered aryl, and C3-C11 cycloalkyl; wherein each R 24 Ci-C 6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C 6 alkoxy, C3-C11 cycloalkyl, 6-10 membered aryl, 4-12 membered heterocyclyl, OH, and F; and the remaining variables
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 2 is C(0)OH; R 3 is /e /7 -butyl; R 3A is hydrogen; R 4 is R 9 ; R 5 is phenyl; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 2 is C(0)OH; R 3 is /e /7 -butyl; R 3A is hydrogen; R 4 is R 9 ; R 5 is phenyl; R 9 , at each occurrence, is each independently selected from the group consisting of Ci-C 6 alkyl, C2-C6 alkenyl, and 5-11 membered heteroaryl; wherein each R 9 Ci-C 6 alkyl, or C2-C6 alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R 21 , OR 21 , SR 21 , C(0)R 21 , 0C(0)R 21 , C(0)0R 21 ,
  • each R 9 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 24 , OR 24 , C(0)R 24 , 0C(0)R 24 , C(0)0R 24 , SO2R 24 , NR 25 R 26 , OH, oxo, CN, NO2, F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 2 is C(0)0H; R 3 is /e/7-butyl; R 3A is hydrogen; R 4 is R 9 ; R 5 is phenyl; R 9 , at each occurrence, is each independently selected from the group consisting of Ci-C 6 alkyl, C2-C6 alkenyl, and 5-11 membered heteroaryl; wherein each R 9 Ci-C 6 alkyl, or C2-C6 alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R 21 , OR 21 , SR 21 , SO2R 21 , NR 22 R 23 , NR 22 C(0)0R 21 , and OH; and wherein each R 9 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 24 and Cl; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 2 is C(0)OH; R 3 is /e/7-butyl; R 3A is hydrogen; R 4 is R 9 ; R 5 is phenyl; R 9 , at each occurrence, is each independently selected from the group consisting of Ci-C 6 alkyl and C2-C6 alkenyl; wherein each R 9 Ci-C 6 alkyl, or C2-C6 alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of R 21 , OR 21 , SR 21 , SO2R 21 , NR 22 R 23 , NR 22 C(0)0R 21 , and OH; R 21 , at each occurrence, is each independently selected from the group consisting of Ci-C 6 alkyl, 6-10 membered aryl, 5-11 membered heteroaryl, and 4-12 membered heterocyclyl; wherein each R 21 Ci-C 6 alkyl is
  • R 36 independently selected from the group consisting of R 36 , OR 36 , NR 37 NR 38 , oxo, CN, F, and Cl;
  • R 35 at each occurrence, is 6-10 membered aryl; wherein each R 35 6-10 membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-C 6 haloalkyl and Ci-C 6 alkoxy;
  • R 36 at each occurrence, is each independently selected from the group consisting of Ci-C 6 alkyl, 6-10 membered aryl, C3-C11 cycloalkyl, and 4-12 membered heterocyclyl; wherein each R 36 C I -C 6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of F and OH; wherein each R 36 6-10 membered aryl is optionally substituted with one or more substituents Ci-C 6 haloalkyl; and the remaining variables are as defined for formula (
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 2 is C(0)OH; R 3 is /e/7-butyl; R 3A is hydrogen; R 4 is R 9 ; R 5 is phenyl; R 9 is 5-11 membered heteroaryl; and wherein each R 9 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 24 and Cl; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 2 is C(0)OH; R 3 is /e/7-butyl; R 3A is hydrogen; R 4 is R 9 ; R 5 is phenyl; R 9 is 5-11 membered heteroaryl; and wherein each R 9 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 24 and Cl; R 24 , at each occurrence, is each independently selected from the group consisting of Ci-C 6 alkyl, 6-10 membered aryl, and C3-C11 cycloalkyl; wherein each R 24 6-10 membered aryl, is optionally substituted with one or more substituents independently selected from the group consisting of C1-G5 alkyl, C1-G5 haloalkyl, C1-G5 alkoxy, F, Cl, and Br; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 2 is C(0)OH; R 3 is /e/7-butyl; R 3A is hydrogen; R 4 is C(0)OR 9; R 5 is phenyl; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 2 is C(0)OH; R 3 is /e/7-butyl; R 3A is hydrogen; R 4 is C(0)OR 9; R 5 is phenyl; R 9 is C1-G5 alkyl; wherein each R 9 C1-G5 alkyl is optionally substituted with one or more substituents R 21 ; R 21 is 6-10 membered aryl; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 2 is a bioisostere of C(0)OH; wherein the bioisostere is -C(0)NHS0 2 R G3a ;
  • R G3a is independently selected from the group consisting of C1-G5 alkyl, Ci-Ce alkyl-O-Ci-Ce alkyl, Ci-C 6 haloalkyl, and G A ;
  • G a is independently selected from the group consisting of cycloalkyl, cycloalkenyl, aryl, and heteroaryl; wherein each G A cycloalkyl, cycloalkenyl, aryl, or heteroaryl is independently unsubstituted or substituted with 1, 2, or 3 independently selected R u groups;
  • R u at each occurrence, is independently selected from the group consisting of Ci-C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, Ci-C 6 haloalkyl, -CN, oxo, -NO2, -OR j , -0C(0)R k ,
  • R J at each occurrence, is independently selected from the group consisting of hydrogen, Ci-C 6 alkyl, and Ci-C 6 haloalkyl;
  • R k at each occurrence, is independently selected from the group consisting of Ci-C 6 alkyl and Ci-C 6 haloalkyl.
  • compounds of the present disclosure are selected from the group consisting of rac-(2R,3S,4R,5S)-3-tert-buty ⁇ -l- (cyclopentylacetyl)-4-(2,5-dichlorobenzoyl)-5-phenylpyrrolidine-2-carboxylic acid; rac- (2R,33',4R,53 , )-3-/er/-butyl-l-(cyclohexanecarbonyl)-4-(2,5-dichlorobenzoyl)-5-phenylpyrrolidine- 2-carboxylic acid; rac-(2R,3SAR,5S)- 1 -benzoyl-3-/e/ -butyl-4-(2,5-dichlorobenzoyl)-/V- (methanesulfonyl)-5-phenylpyrrolidine-2-carboxamide; rac-(2R,3S,
  • compounds of the present disclosure are selected from the group consisting of Examples 4 through 57, 1-1 through 1-52, 1-54, 1-56 through 1-62, II- 1 through 11-794, 11-796 through 11-800, 11-802 through II- 815, 11-818 through 11-863.
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)R 6 ; R 2 is C(0)OH; R 3 is Ci-Ce alkyl; R 3A is hydrogen; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)OR 6 ; R 2 is C(0)OH; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)NR 7 R 8 ; R 2 is C(0)OH; R 3 is Ci-Ce alkyl; R 3A is hydrogen; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, R 4 is C(0)R 9 , and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(0)R 9 ; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(0)R 9 ; R 5 is C 6 -Cio membered aryl, wherein the R 5 C 6 -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, OXO, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 2 is C(0)0H; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(0)R 9 ; R 5 is C 6 -Cio membered aryl, wherein the R 5 C 6 -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)R 6 ; R 2 is C(0)OH; R 3 is Ci-Ce alkyl; R 3A is hydrogen; R 4 is C(0)R 9 ; R 5 is C 6 -Cio membered aryl, wherein the R 5 C 6 -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is CO(0)R 6 ; R 2 is C(0)OH; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(0)R 9 ; R 5 is C 6 -Cio membered aryl, wherein the R 5 C 6 -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)NR 7 R 8 ; R 2 is C(0)OH; R 3 is Ci-Ce alkyl; R 3A is hydrogen; R 4 is C(0)R 9 ; R 5 is C 6 -Cio membered aryl, wherein the R 5 C 6 -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(0)R 9 ; R 5 is 5-11 membered heteroaryl; wherein the R 5 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, OXO, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 2 is C(0)0H; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(0)R 9 ; R 5 is 5-11 membered heteroaryl; wherein the R 5 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 C(0)R 6 ; R 2 is C(0)OH; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(0)R 9 ; R 5 is 5-11 membered heteroaryl; wherein the R 5 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)OR 6 ; R 2 is C(0)OH; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(0)R 9 ; R 5 is 5-11 membered heteroaryl; wherein the R 5 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)NR 7 R 8 ; R 2 is C(0)OH; R 3 is Ci-Ce alkyl; R 3A is hydrogen; R 4 is C(0)R 9 ; R 5 is 5-11 membered heteroaryl; wherein the R 5 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(0)R 9 ; R 5 is 4-12 membered heterocyclyl; wherein the R 5 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 2 is C(0)0H; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(0)R 9 ; R 5 is 4-12 membered heterocyclyl; wherein the R 5 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)R 6 ; R 2 is C(0)OH; R 3 is Ci-Ce alkyl; R 3A is hydrogen; R 4 is C(0)R 9 ; R 5 is 4-12 membered heterocyclyl; wherein the R 5 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, NO2, F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)OR 6 ; R 2 is C(0)OH; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(0)R 9 ; R 5 is 4-12 membered heterocyclyl; wherein the R 5 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, NO2, F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)NR 7 R 8 ; R 2 is C(0)OH; R 3 is Ci-Ce alkyl; R 3A is hydrogen; R 4 is C(0)R 9 ; R 5 is 4-12 membered heterocyclyl; wherein the R 5 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, NO2, F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 2 is C(0)NHS0 2 R 39 ; R 3 is Ci-Ce alkyl; R 3A is hydrogen; R 4 is C(0)R 9 ; R 5 is C 6 -Cio membered aryl, wherein the R 5 C 6 -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, NO2, F, Cl, Br, and I; R 39 is selected from the group consisting of NR 40 R 41 , Ci-C 6 alkyl, C3-C6 cycloalkyl, C 6 -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R 39 Ci-C 6 alkyl and C3-
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)R 6 ; R 2 is C(0)NHS0 2 R 39 ; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(0)R 9 ; R 5 is C 6 -Cio membered aryl, wherein the R 5 C 6 -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; R 39 is selected from the group consisting of NR 40 R 41 , Ci-C 6 alkyl, C3-C6 cycloalkyl, C 6 -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R 1 is C(0)R 6
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is CO(0)R 6 ; R 2 is C(0)NHS0 2 R 39 ; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(0)R 9 ; R 5 is C 6 -Cio membered aryl, wherein the R 5 C 6 -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; R 39 is selected from the group consisting of NR 40 R 41 , Ci-C 6 alkyl, C3-C6 cycloalkyl, C 6 -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R 1 is CO(0)R 6
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)NR 7 R 8 ; R 2 is C(0)NHS0 2 R 39 ; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(0)R 9 ; R 5 is C 6 -Cio membered aryl, wherein the R 5 C 6 -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; R 39 is selected from the group consisting of NR 40 R 41 , Ci-C 6 alkyl, C3-C6 cycloalkyl, C 6 -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 2 is C(0)NHS0 2 R 39 ; R 3 is Ci-Ce alkyl; R 3A is hydrogen; R 4 is C(0)R 9 ; R 5 is 5-11 membered heteroaryl; wherein the R 5 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; R 39 is selected from the group consisting of NR 40 R 41 , Ci-C 6 alkyl, C3-C6 cycloalkyl, C 6 -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R 39 Ci-C 6 alkyl and C3-C6 cycloalky
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 C(0)R 6 ; R 2 is C(0)NHS0 2 R 39 ; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(0)R 9 ; R 5 is 5-11 membered heteroaryl; wherein the R 5 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; R 39 is selected from the group consisting of NR 40 R 41 , Ci-C 6 alkyl, C3-C6 cycloalkyl, C 6 -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R 39 Ci-C 6 alkyl and C3
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)OR 6 ; R 2 is C(0)NHS0 2 R 39 ; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(0)R 9 ; R 5 is 5-11 membered heteroaryl; wherein the R 5 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; R 39 is selected from the group consisting of NR 40 R 41 , Ci-C 6 alkyl, C3-C6 cycloalkyl, C 6 -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R 39 Ci-C 6 alkyl and C
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)NR 7 R 8 ; R 2 is C(0)NHS0 2 R 39 ; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(0)R 9 ; R 5 is 5-11 membered heteroaryl; wherein the R 5 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; R 39 is selected from the group consisting of NR 40 R 41 , Ci-C 6 alkyl, C3-C6 cycloalkyl, C 6 -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R 39 Ci-C 6 alkyl
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 2 is C(0)NHS0 2 R 39 ; R 3 is Ci-Ce alkyl; R 3A is hydrogen; R 4 is C(0)R 9 ; R 5 is 4-12 membered heterocyclyl; wherein the R 5 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; R 39 is selected from the group consisting of NR 40 R 41 , Ci-C 6 alkyl, C3-C6 cycloalkyl, C 6 -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R 39 Ci-C 6 alkyl and C3-C6 cyclo
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)R 6 ; R 2 is C(0)NHS0 2 R 39 ; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(0)R 9 ; R 5 is 4-12 membered heterocyclyl; wherein the R 5 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; R 39 is selected from the group consisting of NR 40 R 41 , Ci-C 6 alkyl, C3-C6 cycloalkyl, C 6 -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R 39 Ci-C 6 alkyl
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)OR 6 ; R 2 is C(0)NHS0 2 R 39 ; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(0)R 9 ; R 5 is 4-12 membered heterocyclyl; wherein the R 5 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; R 39 is selected from the group consisting of NR 40 R 41 , Ci-C 6 alkyl, C3-C6 cycloalkyl, C 6 -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R 39 Ci-C 6 alkyl
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)NR 7 R 8 ; R 2 is C(0)NHS0 2 R 39 ; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(0)R 9 ; R 5 is 4-12 membered heterocyclyl; wherein the R 5 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; R 39 is selected from the group consisting of NR 40 R 41 , Ci-C 6 alkyl, C3-C6 cycloalkyl, C 6 -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R 39 Ci-C 6 alkyl, C3-C
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, R 4 is C(0)0R 9 , and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(0)OR 9 ; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(0)OR 9 ; R 5 is C 6 -Cio membered aryl, wherein the R 5 C 6 -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, OXO, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 2 is C(0)OH; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(0)OR 9 ; R 5 is C 6 -Cio membered aryl, wherein the R 5 C 6 -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)R 6 ; R 2 is C(0)0H; R 3 is Ci-Ce alkyl; R 3A is hydrogen; R 4 is C(0)0R 9 ; R 5 is C 6 -Cio membered aryl, wherein the R 5 C 6 -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is CO(0)R 6 ; R 2 is C(0)OH; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(0)OR 9 ; R 5 is C 6 -Cio membered aryl, wherein the R 5 C 6 -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)NR 7 R 8 ; R 2 is C(0)OH; R 3 is Ci-Ce alkyl; R 3A is hydrogen; R 4 is C(0)OR 9 ; R 5 is C 6 -Cio membered aryl, wherein the R 5 C 6 -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(0)OR 9 ; R 5 is 5-11 membered heteroaryl; wherein the R 5 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, OXO, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 2 is C(0)OH; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(0)OR 9 ; R 5 is 5-11 membered heteroaryl; wherein the R 5 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 C(0)R 6 ; R 2 is C(0)OH; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(0)0R 9 ; R 5 is 5-11 membered heteroaryl; wherein the R 5 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)0R 6 ; R 2 is C(0)0H; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(0)0R 9 ; R 5 is 5-11 membered heteroaryl; wherein the R 5 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)NR 7 R 8 ; R 2 is C(0)0H; R 3 is Ci-Ce alkyl; R 3A is hydrogen; R 4 is C(0)0R 9 ; R 5 is 5-11 membered heteroaryl; wherein the R 5 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(0)OR 9 ; R 5 is 4-12 membered heterocyclyl; wherein the R 5 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 2 is C(0)OH; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(0)OR 9 ; R 5 is 4-12 membered heterocyclyl; wherein the R 5 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)R 6 ; R 2 is C(0)OH; R 3 is Ci-Ce alkyl; R 3A is hydrogen; R 4 is C(0)OR 9 ; R 5 is 4-12 membered heterocyclyl; wherein the R 5 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)0R 6 ; R 2 is C(0)0H; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(0)0R 9 ; R 5 is 4-12 membered heterocyclyl; wherein the R 5 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)NR 7 R 8 ; R 2 is C(0)OH; R 3 is Ci-Ce alkyl; R 3A is hydrogen; R 4 is C(0)OR 9 ; R 5 is 4-12 membered heterocyclyl; wherein the R 5 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, NO2, F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 2 is C(0)NHS0 2 R 39 ; R 3 is Ci-Ce alkyl; R 3A is hydrogen; R 4 is C(0)OR 9 ; R 5 is C 6 -Cio membered aryl, wherein the R 5 C 6 -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, NO2, F, Cl, Br, and I; R 39 is selected from the group consisting of NR 40 R 41 , Ci-C 6 alkyl, C3-C6 cycloalkyl, C 6 -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R 39 Ci-C 6 alkyl and C3-
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)R 6 ; R 2 is C(0)NHS0 2 R 39 ; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(0)OR 9 ; R 5 is C 6 -Cio membered aryl, wherein the R 5 C 6 -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; R 39 is selected from the group consisting of NR 40 R 41 , Ci-C 6 alkyl, C 3 -C6 cycloalkyl, C 6 -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C0(0)R 6 ; R 2 is C(0)NHS0 2 R 39 ; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(0)0R 9 ; R 5 is C 6 -Cio membered aryl, wherein the R 5 C 6 -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; R 39 is selected from the group consisting of NR 40 R 41 , Ci-C 6 alkyl, C3-C6 cycloalkyl, C 6 -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)NR 7 R 8 ; R 2 is C(0)NHS0 2 R 39 ; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(0)0R 9 ; R 5 is C 6 -Cio membered aryl, wherein the R 5 C 6 -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; R 39 is selected from the group consisting of NR 40 R 41 , Ci-C 6 alkyl, C3-C6 cycloalkyl, C 6 -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, where
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 2 is C(0)NHS0 2 R 39 ; R 3 is Ci-Ce alkyl; R 3A is hydrogen; R 4 is C(0)0R 9 ; R 5 is 5-11 membered heteroaryl; wherein the R 5 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; R 39 is selected from the group consisting of NR 40 R 41 , Ci-C 6 alkyl, C3-C6 cycloalkyl, C 6 -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R 39 Ci-C 6 alkyl and C3-C6 cycloal
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 C(0)R 6 ; R 2 is C(0)NHS0 2 R 39 ; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(0)0R 9 ; R 5 is 5-11 membered heteroaryl; wherein the R 5 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; R 39 is selected from the group consisting of NR 40 R 41 , Ci-C 6 alkyl, C3-C6 cycloalkyl, C 6 -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R 39 Ci-C 6 alkyl and C
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)0R 6 ; R 2 is C(0)NHS0 2 R 39 ; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(0)0R 9 ; R 5 is 5-11 membered heteroaryl; wherein the R 5 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; R 39 is selected from the group consisting of NR 40 R 41 , Ci-C 6 alkyl, C3-C6 cycloalkyl, C 6 -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R 39 Ci-C 6 alkyl
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)NR 7 R 8 ; R 2 is C(0)NHS0 2 R 39 ; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(0)0R 9 ; R 5 is 5-11 membered heteroaryl; wherein the R 5 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; R 39 is selected from the group consisting of NR 40 R 41 , Ci-C 6 alkyl, C3-C6 cycloalkyl, C 6 -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R 39 Ci-C 6 alky
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 2 is C(0)NHS0 2 R 39 ; R 3 is Ci-Ce alkyl; R 3A is hydrogen; R 4 is C(0)OR 9 ; R 5 is 4-12 membered heterocyclyl; wherein the R 5 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; R 39 is selected from the group consisting of NR 40 R 41 , Ci-C 6 alkyl, C3-C6 cycloalkyl, C 6 -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R 39 Ci-C 6 alkyl and C3-C6 cyclo
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)R 6 ; R 2 is C(0)NHS0 2 R 39 ; R 3 is Ci-Ce alkyl; R 3A is hydrogen; R 4 is C(0)OR 9 ; R 5 is 4-12 membered heterocyclyl; wherein the R 5 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; R 39 is selected from the group consisting of NR 40 R 41 , Ci-C 6 alkyl, C3-C6 cycloalkyl, C 6 -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R 39 Ci-C 6 alkyl
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)0R 6 ; R 2 is C(0)NHS0 2 R 39 ; R 3 is Ci-Ce alkyl; R 3A is hydrogen; R 4 is C(0)0R 9 ; R 5 is 4-12 membered heterocyclyl; wherein the R 5 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; R 39 is selected from the group consisting of NR 40 R 41 , Ci-C 6 alkyl, C3-C6 cycloalkyl, C 6 -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R 39 Ci-C 6 alkyl, C3-C
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)NR 7 R 8 ; R 2 is C(0)NHS0 2 R 39 ; R 3 is Ci-Ce alkyl; R 3A is hydrogen; R 4 is C(0)0R 9 ; R 5 is 4-12 membered heterocyclyl; wherein the R 5 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; R 39 is selected from the group consisting of NR 40 R 41 , Ci-C 6 alkyl, C3-C6 cycloalkyl, C 6 -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R 39 Ci-C 6
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, R 4 is C(O)NR 10 R n , and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(O)NR 10 R n ; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(O)NR 10 R n ; R 5 is C 6 -Cio membered aryl, wherein the R 5 C 6 -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, OXO, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 2 is C(0)0H; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(O)NR 10 R n ; R 5 is C 6 -Cio membered aryl, wherein the R 5 C 6 -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)R 6 ; R 2 is C(0)OH; R 3 is Ci-Ce alkyl; R 3A is hydrogen; R 4 is C(O)NR 10 R n ; R 5 is C 6 -Cio membered aryl, wherein the R 5 C 6 -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is CO(0)R 6 ; R 2 is C(0)OH; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(O)NR 10 R n ; R 5 is C 6 -Cio membered aryl, wherein the R 5 C 6 -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)NR 7 R 8 ; R 2 is C(0)0H; R 3 is Ci-Ce alkyl; R 3A is hydrogen; R 4 is C(O)NR 10 R n ; R 5 is C 6 -Cio membered aryl, wherein the R 5 C 6 -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(O)NR 10 R n ; R 5 is 5-11 membered heteroaryl; wherein the R 5 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 2 is C(0)OH; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(O)NR 10 R n ; R 5 is 5-11 membered heteroaryl; wherein the R 5 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 C(0)R 6 ; R 2 is C(0)OH; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(O)NR 10 R n ; R 5 is 5-11 membered heteroaryl; wherein the R 5 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)OR 6 ; R 2 is C(0)OH; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(O)NR 10 R n ; R 5 is 5-11 membered heteroaryl; wherein the R 5 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)NR 7 R 8 ; R 2 is C(0)OH; R 3 is Ci-Ce alkyl; R 3A is hydrogen; R 4 is C(O)NR 10 R n ; R 5 is 5-11 membered heteroaryl; wherein the R 5 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(O)NR 10 R n ; R 5 is 4-12 membered heterocyclyl; wherein the R 5 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 2 is C(0)0H; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(O)NR 10 R n ; R 5 is 4-12 membered heterocyclyl; wherein the R 5 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)R 6 ; R 2 is C(0)OH; R 3 is Ci-Ce alkyl; R 3A is hydrogen; R 4 is C(O)NR 10 R n ; R 5 is 4-12 membered heterocyclyl; wherein the R 5 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)OR 6 ; R 2 is C(0)OH; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(O)NR 10 R n ; R 5 is 4-12 membered heterocyclyl; wherein the R 5 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)NR 7 R 8 ; R 2 is C(0)OH; R 3 is Ci-Ce alkyl; R 3A is hydrogen; R 4 is C(O)NR 10 R n ; R 5 is 4-12 membered heterocyclyl; wherein the R 5 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 2 is C(0)NHS0 2 R 39 ; R 3 is Ci-Ce alkyl; R 3A is hydrogen; R 4 is C(O)NR 10 R n ; R 5 is C 6 -Cio membered aryl, wherein the R 5 C 6 -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; R 39 is selected from the group consisting of NR 40 R 41 , Ci-C 6 alkyl, C3-C6 cycloalkyl, C 6 -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R 39 Ci-C
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)R 6 ; R 2 is C(0)NHS0 2 R 39 ; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(O)NR 10 R n ; R 5 is C 6 -Cio membered aryl, wherein the R 5 C 6 -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, NO2, F, Cl, Br, and I; R 39 is selected from the group consisting of NR 40 R 41 , Ci-C 6 alkyl, C3-C6 cycloalkyl, C 6 -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C0(0)R 6 ; R 2 is C(0)NHS0 2 R 39 ; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(O)NR 10 R n ; R 5 is C 6 -Cio membered aryl, wherein the R 5 C 6 -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; R 39 is selected from the group consisting of NR 40 R 41 , Ci-C 6 alkyl, C3-C6 cycloalkyl, C6-C10 membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl,
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)NR 7 R 8 ; R 2 is C(0)NHS0 2 R 39 ; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(O)NR 10 R n ; R 5 is C 6 -Cio membered aryl, wherein the R 5 C 6 -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; R 39 is selected from the group consisting of NR 40 R 41 , Ci-C 6 alkyl, C3-C6 cycloalkyl, C 6 -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered hetero
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 2 is C(0)NHS0 2 R 39 ; R 3 is Ci-Ce alkyl; R 3A is hydrogen; R 4 is C(O)NR 10 R n ; R 5 is 5-11 membered heteroaryl; wherein the R 5 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; R 39 is selected from the group consisting of NR 40 R 41 , Ci-C 6 alkyl, C3-C6 cycloalkyl, C 6 -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R 39 Ci-C 6 alkyl and C3-C6
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 C(0)R 6 ; R 2 is C(0)NHS0 2 R 39 ; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(O)NR 10 R n ; R 5 is 5-11 membered heteroaryl; wherein the R 5 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; R 39 is selected from the group consisting of NR 40 R 41 , Ci-C 6 alkyl, C3-C6 cycloalkyl, C 6 -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R 39 Ci-C 6 alkyl, C3-C
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)0R 6 ; R 2 is C(0)NHS0 2 R 39 ; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(O)NR 10 R n ; R 5 is 5-11 membered heteroaryl; wherein the R 5
  • 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I;
  • R 39 is selected from the group consisting of NR 40 R 41 , Ci-C 6 alkyl, C3-C6 cycloalkyl, C6-C10 membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R 39 Ci-C 6 alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR 42 R 43 , Ci-C 6 alkyl, Ci-C 6 alkoxy and phenyl; and wherein the R 39 4-12 membered heterocyclyl, C 6 -Cio membered aryl, and 5-6 member
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)NR 7 R 8 ; R 2 is C(0)NHS0 2 R 39 ; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is C(O)NR 10 R n ; R 5 is 5-11 membered heteroaryl; wherein the R 5 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; R 39 is selected from the group consisting of NR 40 R 41 , Ci-C 6 alkyl, C3-C6 cycloalkyl, C 6 -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R 39 Ci-
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 2 is C(0)NHS0 2 R 39 ; R 3 is Ci-Ce alkyl; R 3A is hydrogen; R 4 is C(O)NR 10 R n ; R 5 is 4-12 membered heterocyclyl; wherein the R 5 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; R 39 is selected from the group consisting of NR 40 R 41 , Ci-C 6 alkyl, C3-C6 cycloalkyl, C 6 -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R 39 Ci-C 6 alkyl and C3-
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)R 6 ; R 2 is C(0)NHS0 2 R 39 ; R 3 is Ci-Ce alkyl; R 3A is hydrogen; R 4 is C(O)NR 10 R n ; R 5 is 4-12 membered heterocyclyl; wherein the R 5 4-12 membered heterocyclyl is optionally substituted with one or more substituents
  • R 39 is selected from the group consisting of NR 40 R 41 , Ci-C 6 alkyl, C3-C6 cycloalkyl, C 6 -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R 39 Ci-C 6 alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR 42 R 43 , Ci-C 6 alkyl, Ci-C 6 alkoxy and phenyl; and wherein the R 39 4-12 membered heterocyclyl, C 6 -Cio membered aryl, and
  • 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Cl, CN, NH 2 , Ci-C 6 alkyl, Ci-C 6 alkoxy, and Ci-C 6 hydroxyalkyl; wherein R 40 and R 41 , at each occurrence, are each independently selected from the group consisting of hydrogen and Ci-C 6 alkyl; and wherein R 42 and R 43 , at each occurrence, are each independently Ci-C 6 alkyl; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)OR 6 ; R 2 is C(0)NHS0 2 R 39 ; R 3 is Ci-Ce alkyl; R 3A is hydrogen; R 4 is C(O)NR 10 R n ; R 5 is 4-12 membered heterocyclyl; wherein the R 5 4-12 membered heterocyclyl is optionally substituted with one or more substituents
  • R 39 is selected from the group consisting of NR 40 R 41 , Ci-C 6 alkyl, C3-C6 cycloalkyl, C 6 -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R 39 Ci-C 6 alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR 42 R 43 , Ci-C 6 alkyl, Ci-C 6 alkoxy and phenyl; and wherein the R 39 4-12 membered heterocyclyl, C 6 -Cio membered aryl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)NR 7 R 8 ; R 2 is C(0)NHS0 2 R 39 ; R 3 is Ci-Ce alkyl; R 3A is hydrogen; R 4 is C(O)NR 10 R n ; R 5 is 4-12 membered heterocyclyl; wherein the R 5 4-12 membered heterocyclyl is optionally substituted with one or more substituents
  • R 39 is selected from the group consisting of NR 40 R 41 , Ci-C 6 alkyl, C3-C6 cycloalkyl, C 6 -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R 39 Ci-C 6 alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of NR 42 R 43 , Ci-C 6 alkyl, Ci-C 6 alkoxy and phenyl; and wherein the R 39 4-12 membered heterocyclyl, C 6 -Cio membered aryl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, R 4 is R 9 , and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is R 9 ; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is R 9 ; R 5 is C 6 -Cio membered aryl, wherein the R 5 C 6 -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 2 is C(0)0H; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is R 9 ; R 5 is C 6 -Cio membered aryl, wherein the R 5 C 6 -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, OXO, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)R 6 ; R 2 is C(0)0H; R 3 is Ci-Ce alkyl; R 3A is hydrogen; R 4 is R 9 ; R 5 is C 6 -Cio membered aryl, wherein the R 5 C 6 -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C0(0)R 6 ; R 2 is C(0)0H; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is R 9 ; R 5 is C 6 -Cio membered aryl, wherein the R 5 C 6 -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)NR 7 R 8 ; R 2 is C(0)0H; R 3 is Ci-Ce alkyl; R 3A is hydrogen; R 4 is R 9 ; R 5 is C 6 -Cio membered aryl, wherein the R 5 C 6 -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is R 9 ; R 5 is 5-11 membered heteroaryl; wherein the R 5 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, OXO, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 2 is C(0)0H; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is R 9 ; R 5 is 5-11 membered heteroaryl; wherein the R 5 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 C(0)R 6 ; R 2 is C(0)0H; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is R 9 ; R 5 is 5-11 membered heteroaryl; wherein the R 5 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)OR 6 ; R 2 is C(0)OH; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is R 9 ; R 5 is 5-11 membered heteroaryl; wherein the R 5 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)NR 7 R 8 ; R 2 is C(0)OH; R 3 is Ci-Ce alkyl; R 3A is hydrogen; R 4 is R 9 ; R 5 is 5-11 membered heteroaryl; wherein the R 5 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is R 9 ; R 5 is 4-12 membered heterocyclyl; wherein the R 5 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, OXO, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 2 is C(0)OH; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is R 9 ; R 5 is 4-12 membered heterocyclyl; wherein the R 5 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)R 6 ; R 2 is C(0)0H; R 3 is Ci-Ce alkyl; R 3A is hydrogen; R 4 is R 9 ; R 5 is 4-12 membered heterocyclyl; wherein the R 5 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)0R 6 ; R 2 is C(0)0H; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is R 9 ; R 5 is 4-12 membered heterocyclyl; wherein the R 5 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)NR 7 R 8 ; R 2 is C(0)OH; R 3 is Ci-Ce alkyl; R 3A is hydrogen; R 4 is R 9 ; R 5 is 4-12 membered heterocyclyl; wherein the R 5 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; and the remaining variables are as defined for formula (I).
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 2 is C(0)NHS0 2 R 39 ; R 3 is Ci-Ce alkyl; R 3A is hydrogen; R 4 is R 9 ; R 5 is C 6 -Cio membered aryl, wherein the R 5 C 6 -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, OXO, CN, N0 2 , F, Cl, Br, and I; R 39 is selected from the group consisting of NR 40 R 41 , Ci-C 6 alkyl, C3-C6 cycloalkyl, C 6 -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R 39 Ci-C 6 alkyl and C3-
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)R 6 ; R 2 is C(0)NHS0 2 R 39 ; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is R 9 ; R 5 is C 6 -Cio membered aryl, wherein the R 5 C 6 -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; R 39 is selected from the group consisting of NR 40 R 41 , Ci-C 6 alkyl, C3-C6 cycloalkyl, C 6 -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R 39 Ci
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C0(0)R 6 ; R 2 is C(0)NHS0 2 R 39 ; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is R 9 ; R 5 is C 6 -Cio membered aryl, wherein the R 5 C 6 -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; R 39 is selected from the group consisting of NR 40 R 41 , Ci-C 6 alkyl, C3-C6 cycloalkyl, C 6 -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R 39
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)NR 7 R 8 ; R 2 is C(0)NHS0 2 R 39 ; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is R 9 ; R 5 is C 6 -Cio membered aryl, wherein the R 5 C 6 -Cio membered aryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; R 39 is selected from the group consisting of NR 40 R 41 , Ci-C 6 alkyl, C3-C6 cycloalkyl, C 6 -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R 1 is C(0)NR 7 R
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 2 is C(0)NHS0 2 R 39 ; R 3 is Ci-Ce alkyl; R 3A is hydrogen; R 4 is R 9 ; R 5 is 5-11 membered heteroaryl; wherein the R 5 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; R 39 is selected from the group consisting of NR 40 R 41 , Ci-C 6 alkyl, C3-C6 cycloalkyl, C 6 -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R 39 Ci-C 6 alkyl and C3-C6 cycloalkyl are
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 C(0)R 6 ; R 2 is C(0)NHS0 2 R 39 ; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is R 9 ; R 5 is 5-11 membered heteroaryl; wherein the R 5 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; R 39 is selected from the group consisting of NR 40 R 41 , Ci-C 6 alkyl, C3-C6 cycloalkyl, C 6 -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R 39 Ci-C 6 alkyl and C3-C
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)0R 6 ; R 2 is C(0)NHS0 2 R 39 ; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is R 9 ; R 5 is 5-11 membered heteroaryl; wherein the R 5 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; R 39 is selected from the group consisting of NR 40 R 41 , Ci-C 6 alkyl, C3-C6 cycloalkyl, C 6 -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R 39 Ci-C 6 alkyl and C3
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)NR 7 R 8 ; R 2 is C(0)NHS0 2 R 39 ; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is R 9 ; R 5 is 5-11 membered heteroaryl; wherein the R 5 5-11 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; R 39 is selected from the group consisting of NR 40 R 41 , Ci-C 6 alkyl, C3-C6 cycloalkyl, C 6 -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R 39 Ci-C 6 alkyl and C
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 2 is C(0)NHS0 2 R 39 ; R 3 is Ci-Ce alkyl; R 3A is hydrogen; R 4 is R 9 ; R 5 is 4-12 membered heterocyclyl; wherein the R 5 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; R 39 is selected from the group consisting of NR 40 R 41 , Ci-C 6 alkyl, C3-C6 cycloalkyl, C 6 -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R 39 Ci-C 6 alkyl and C3-C6 cycloalky
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)R 6 ; R 2 is C(0)NHS0 2 R 39 ; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is R 9 ; R 5 is 4-12 membered heterocyclyl; wherein the R 5 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; R 39 is selected from the group consisting of NR 40 R 41 , Ci-C 6 alkyl, C3-C6 cycloalkyl, C6-C10 membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R 39 Ci-C 6 alkyl and C3-
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)0R 6 ; R 2 is C(0)NHS0 2 R 39 ; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is R 9 ; R 5 is 4-12 membered heterocyclyl; wherein the R 5 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; R 39 is selected from the group consisting of NR 40 R 41 , Ci-C 6 alkyl, C3-C6 cycloalkyl, C 6 -Cio membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R 39 Ci-C 6 alkyl and
  • compounds of the present disclosure are represented by formula (I), and pharmaceutically acceptable salt thereof, where R 1 is C(0)NR 7 R 8 ; R 2 is C(0)NHS0 2 R 39 ; R 3 is Ci-C 6 alkyl; R 3A is hydrogen; R 4 is R 9 ; R 5 is 4-12 membered heterocyclyl; wherein the R 5 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , NR 13 C(0)R 12 , OH, oxo, CN, N0 2 , F, Cl, Br, and I; R 39 is selected from the group consisting of NR 40 R 41 , Ci-C 6 alkyl, C3-C6 cycloalkyl, C6-C10 membered aryl, 4-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the R 39 Ci-C 6 alkyl and C
  • stereoisomers of the present disclosure may exist as stereoisomers wherein asymmetric or chiral centers are present. These stereoisomers are“R” or“5” depending on the configuration of substituents around the chiral carbon atom.
  • the terms“R” and“5” used herein are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, in Pure Appl. Chem., 1976, 45: 13-30.
  • the present disclosure contemplates various stereoisomers and mixtures thereof and these are specifically included within the scope of this disclosure.
  • Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or
  • stereoisomers of compounds of the present disclosure may be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by methods of resolution well-known to those of ordinary skill in the art.
  • Compounds of the present disclosure may exist as cis or trans isomers, wherein substituents on a ring may attached in such a manner that they are on the same side of the ring (cis) relative to each other, or on opposite sides of the ring relative to each other (trans).
  • cyclobutane may be present in the cis or trans configuration, and may be present as a single isomer or a mixture of the cis and trans isomers.
  • Individual cis or trans isomers of compounds of the present disclosure may be prepared synthetically from commercially available starting materials using selective organic transformations, or prepared in single isomeric form by purification of mixtures of the cis and Irons isomers.
  • the present disclosure includes pharmaceutically acceptable isotopically-labelled compounds of formula (I) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.
  • isotopes suitable for inclusion in the compounds of the disclosure include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as n C, 13 C and 14 C, chlorine, such as 36 Cl, fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 0, 17 0 and 18 0, phosphorus, such as 32 P, and sulfur, such as 35 S.
  • isotopically-labelled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e. 3 H, and carbon-l4, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Substitution with heavier isotopes such as deuterium, i.e. 2 H may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.
  • compositions comprising a
  • the pharmaceutical composition comprises a compound of this disclosure, or a pharmaceutically acceptable salt thereof, one potentiator, and one or more additional correctors.
  • the pharmaceutical composition comprises a compound of this disclosure, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents.
  • the additional therapeutic agents may be selected from the group consisting of CFTR modulators and CFTR amplifiers.
  • the additional therapeutic agents are CFTR modulators.
  • the other therapeutic agent is a cystic fibrosis treatment agent.
  • the additional therapeutic agent(s) are one potentiator, and one or more additional correctors.
  • the additional therapeutic agent(s) is selected from the group consisting of CFTR modulators and CFTR amplifiers.
  • the other therapeutic agent(s) is a CFTR modulator.
  • the cystic fibrosis is caused by a Class I, II, III, IV, V, and/or VI mutation.
  • CFTR potentiators include, but are not limited to, Ivacaftor (VX-770), CTP-656, NVS-QBW251, FD1860293, GLPG2451, GLPG3067, GLPG1837, PTI-808, V-(3- carbamo T5,5,7,7-tetrameth T5,7-dihydro-4/7-thieno[2,3-r]pyran-2-yl)- 1 /7-pyrazole-5- carboxamide, and 3-amino-/V-[(25 , )-2-hydroxypropyl]-5- ⁇ [4-
  • the potentiator can be selected from the group consisting of Ivacaftor (VX-770, V-(2,4-di-/er/-butyl-5-hydroxyphenyl)-4-oxo-l,4-dihydroquinoline-3- carboxamide); GLPG1837; GLP-2451; PTI-808; CTP-656; NVS-QBW251; FD1860293;
  • Non-limiting examples of correctors include Lumacaftor (VX-809), l-(2,2-difluoro-l,3- benzodioxol-5-yl)-/V- ⁇ l-[(2i?)-2,3-dihydroxypropyl]-6-fluoro-2-(l-hydroxy-2-methylpropan-2-yl)- l//-indol-5-yl]cyclopropanecarboxamide (VX-661), VX-983, GLPG2851, GLPG2222, GLPG2665, GLPG2737, GLPG3221, PTI-801, VX-152, VX-440, VX-445, VX-659, FDL169, FDL304, FD2052160, and FD2035659.
  • the corrector(s) can be selected from the group consisting of Lumacaftor (VX-809); 1 -(2,2-difluoro- 1 ,3-benzodioxol-5-yl)-/V- ⁇ l-[(2Z?)-2,3-dihydroxypropyl]-6- fhioro-2-(l-hydroxy-2-methylpropan-2-yl)-l//-indol-5-yl ⁇ cyclopropanecarboxamide (VX-661); PTI-801; VX-983; GLPG2665; GLPG2851; GLPG2222; GLPG2737; GLPG3221; VX-152; VX- 440; VX-659; VX-445; FDL169; FDL304; FD2052160; FD2035659; 3-[(2Z?,4Z?)-4-( ⁇ [l-(2,2- difhioro-l,3-benz
  • the additional therapeutic agent is a CFTR amplifier.
  • CFTR amplifiers enhance the effect of known CFTR modulators, such as potentiators and correctors.
  • Examples of CFTR amplifiers are PTI130 and PTI-428. Examples of amplifiers are also disclosed in WO2015138909 and WO2015138934.
  • the additional therapeutic agent is a CFTR stabilizer.
  • CFTR stabilizers enhance the stability of corrected CFTR that has been treated with a corrector, corrector/ potentiator or other CFTR modulator combination(s).
  • An example of a CFTR stabilizer is cavosonstat (N91115). Examples of stabilizers are also disclosed in W02012048181.
  • the additional therapeutic agent is an agent that reduces the activity of the epithelial sodium channel blocker (ENaC) either directly by blocking the channel or indirectly by modulation of proteases that lead to an increase in ENaC activity (e.g., serine proteases, channel-activating proteases).
  • ENaC activity e.g., serine proteases, channel-activating proteases.
  • agents include camostat (a trypsin-like protease inhibitor), QAU145, 552-02, GS-9411, INO-4995, Aerolytic, amiloride, and VX-371.
  • Additional agents that reduce the activity of the epithelial sodium channel blocker (ENaC) can be found, for example, in W02009074575 and W02013043720; and US Patent No. US8,999,976.
  • the ENaC inhibitor is VX-371.
  • the ENaC inhibitor is SPX-101 (S18).
  • Compounds of the invention are useful as modulators of CFTR.
  • the compounds and compositions are particularly useful for treating or lessening the severity or progression of a disease, disorder, or a condition where hyperactivity or inactivity of CFTR is involved.
  • the invention provides a method for treating cystic fibrosis in a subject, wherein the method comprises the step of administering to said subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a preferred embodiment thereof as set forth above, with or without a pharmaceutically acceptable carrier.
  • the cystic fibrosis is caused by a Class I, II, III, IV, V, and/or VI mutation.
  • One embodiment is directed to the use of a compound according to Formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for use in the treatment of cystic fibrosis.
  • the cystic fibrosis is caused by a Class I, II, III, IV, V, and/or VI mutation.
  • This invention also is directed to the use of a compound according to Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cystic fibrosis.
  • the cystic fibrosis is caused by a Class I, II, III,
  • present compounds or pharmaceutically acceptable salts thereof may be administered as the sole active agent or it may be co-administered with other therapeutic agents.
  • co-administered means the administration of two or more different therapeutic agents to a subject in a single pharmaceutical composition or in separate pharmaceutical compositions.
  • co-administration involves administration at the same time of a single pharmaceutical composition comprising two or more therapeutic agents or administration of two or more different compositions to the same subject at the same or different times.
  • the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with one or two CFTR modulators and one CFTR amplifier.
  • the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with one potentiator, one or more correctors, and one CFTR amplifier. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with one or more CFTR modulators. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with one potentiator and one or more correctors. In one embodiment, the compounds of the invention or
  • compositions thereof may be co-administered with one potentiator.
  • Optimum reaction conditions and reaction times for each individual step can vary depending on the particular reactants employed and substituents present in the reactants used. Unless otherwise specified, solvents, temperatures and other reaction conditions can be readily selected by one of ordinary skill in the art. Specific procedures are provided in the Examples section. Unless otherwise described, the starting materials and reagents are either commercially available or can be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature.
  • Many of the compounds of the present disclosure have at least one basic nitrogen whereby the compound can be treated with an acid to form a desired salt.
  • a compound may be reacted with an acid at or above room temperature to provide the desired salt, which is deposited, and collected by filtration after cooling.
  • the compounds of the present disclosure can be better understood in connection with the following synthetic schemes and methods which illustrate a means by which the compounds can be prepared.
  • the compounds of this disclosure can be prepared by a variety of synthetic procedures. Representative procedures are shown in, but are not limited to, Schemes 1-10.
  • core compounds of formula (1-3) can be prepared from compounds of formula (1-2).
  • Compounds of formula (1-2), wherein R 2A is typically Ci-C 6 alkyl and R 5 is as described herein, can be treated first with lithium bromide, followed by compounds of formula (1-1) in the presence of a base such as, but not limited to, l,8-diazabicyclo[5.4.0]undec-7- ene (DBU), triethylamine, or potassium carbonate in a solvent such as but not limited to toluene or tetrahydrofuran to provide a racemic mixture of compounds of formula (1-3).
  • DBU l,8-diazabicyclo[5.4.0]undec-7- ene
  • triethylamine triethylamine
  • potassium carbonate in a solvent such as but not limited to toluene or tetrahydrofuran to provide a racemic mixture of compounds of formula (1-3).
  • the reaction is typically performed at a reduced
  • a mixture of compounds of formula (1-3) and ((£)-l-(2-methoxy-5- (trifluoromethyl)phenyl)-4,4-dimethylpent-2-en-l-one, wherein R 2 is typically Ci-C 6 alkyl and R 5 is as described herein, can be treated with acetyl(oxo) silver in the presence of molecular sieves and a base such as, but not limited to, l,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine, or potassium carbonate in a solvent such as but not limited to toluene or tetrahydrofuran to provide a racemic mixture of core compounds of formula (1-3).
  • the reaction is typically performed in an ice bath before warming to room temperature and quenching with aqueous saturated aqueous ammonium chloride.
  • Compounds (1-3) may be obtained as a mixture or may be separated by precipitation or chromato graphy.
  • Enones of formula (2-3) can be prepared via aldol condensation of compounds of formula (2-1) where R 9 is as defined for fomula (I) with compounds of formula (2-2) to provide compounds of formula (2-3).
  • aldol condensation conditions include treating compounds of formula (2-1) with a base such as potassium hydroxide in a suitable solvent such as methanol, followed by addition of an aldehyde of formula (2-2).
  • the aldol condensation reaction is typically performed at a suitable temperature, typically ranging from 0-50 °C.
  • enones of formula (2-3) can be prepared by coupling acid chlorides of formula (2-4) where R 9 is as defined for fomula (I) with suitable compounds such as and including organotin compounds of formula (2- 5).
  • Organotin compounds of formula (2-5) can be treated with acid chlorides of formula (2-4) in the presence of a catalyst such as tetrakis(triphenylphosphine)palladium(0).
  • a catalyst such as tetrakis(triphenylphosphine)palladium(0).
  • Co-catalysts such as tri(2- furyl)phosphine may be employed.
  • the coupling reaction is performed in a suitable solvent including, but not limited to tetrahydrofuran at a suitable temperature, which may be an elevated temperature such as 60 °C.
  • Examples of conditions known to generate compounds of formula (3-2) from a mixture of a carboxylic acid and an amine include, but are not limited to, adding a coupling reagent such as, but not limited to, l-chloro-/V,/V,2-trimethylprop-l-en-l -amine (Ghosez reagent), N-( 3- dimethylaminopropyl)-/V-ethylcarbodiimide or 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC, ED AC or EDCI) or the corresponding hydrochloride salt, l,3-dicyclohexylcarbodiimide (DCC), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPC1), /V-[(dimethylamino)- 1 H- 1 ,2,3- triazolo-[4,5-/ ]pyridin- 1 -ylmethylene
  • the coupling reagents may be added as a solid, a solution, or as the reagent bound to a solid support resin.
  • auxiliary-coupling reagents may facilitate the coupling reaction.
  • Auxiliary coupling reagents that are often used in the coupling reactions include but are not limited to 4- (dimethylamino)pyridine (DMAP), l-hydroxy-7-azabenzotriazole (HO AT) and 1- hydroxybenzotriazole (HOBT).
  • DMAP dimethylamino)pyridine
  • HO AT l-hydroxy-7-azabenzotriazole
  • HOBT 1- hydroxybenzotriazole
  • the reaction may be carried out optionally in the presence of a base such as, but not limited to, triethylamine, /V,/V-diisopropylethylamine or pyridine.
  • the coupling reaction may be carried out in solvents such as, but not limited to, tetrahydrofuran, N,N- dimethylformamide, /V,/V-di methyl acetamide, dimethyl sulfoxide, dichloromethane, and ethyl acetate.
  • solvents such as, but not limited to, tetrahydrofuran, N,N- dimethylformamide, /V,/V-di methyl acetamide, dimethyl sulfoxide, dichloromethane, and ethyl acetate.
  • the reactions may be carried out at ambient temperature or heated. The heating can be accomplished either conventionally or with microwave irradiation.
  • carboxylic acids of formula (3-1B) can be converted to the corresponding acid chlorides of formula (3-1 A) where R 1A is R 6 , OR 6 , or NR 7 R 8 as defined in formula (I), by reaction with thionyl chloride, PCE, PCI5, cyanuric chloride, oxalyl chloride, or 1 -chloro-/V,/V,2- trimethylprop-l-en-l -amine.
  • the reactions with thionyl chloride and oxalyl chloride can be catalyzed with /V,/V-di methyl form amide at ambient temperature in a solvent such as
  • the resultant acid chlorides of formula (3-1 A) (or commercially available acid chlorides of formula (3-1 A)) can then be treated with core amines of formula (1-3) optionally in the presence of a base such as a tertiary amine base such as but not limited to triethylamine or /V,/V- diisopropylethylamine or an aromatic base such as pyridine, at room temperature or heated in a solvent such as dichloro methane to provide compounds of formula (3-2).
  • a base such as a tertiary amine base such as but not limited to triethylamine or /V,/V- diisopropylethylamine or an aromatic base such as pyridine
  • Esters of formula (3-2) can be hydrolyzed in an aqueous hydroxide solution to provide acids of formula (3-3) which are representative of Formula (I).
  • the reaction may be performed in a solvent such as but not limited to methanol, tetrahydrofuran, or mixtures thereof, and may be performed at ambient temperature or an elevated temperature.
  • hydrolysis can be accomplished by treating the former with an acid such as, but not limited to, trifluoroacetic acid.
  • the reaction is typically performed at ambient temperature in a solvent such as, but not limited to, dichloromethane.
  • Compounds (3-3) may be obtained as a mixture or may be separated by precipitation or
  • compounds of formula (4-1) can be prepared from compounds of formula (3-3).
  • Carboxylic acids of formula (3-3) can be coupled with methanesulfonamide to provide compounds of formula (4-1).
  • Examples of conditions known to generate compounds of formula (4-1) from a mixture of a carboxylic acid and methanesulfonamide include but are not limited to, adding a coupling reagent such as di( 1 //-imidazol- 1 -yljmethanone.
  • the reaction may be carried out in the presence of a base such as, but not limited to l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and in solvents such as, but not limited to dichloromethane, and l,2-dichloroethane.
  • a base such as, but not limited to l,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
  • solvents such as, but not limited to dichloromethane, and l,2-dichloroethane.
  • the reaction is typically performed at elevated temperature, such as 42 °C.
  • Scheme 5 depicts examples of ways to diversify the substituents on the pyrrolidine ring, specifically the R 4 substituent.
  • Compounds of formula (5-3) which are representative of Formula (I) can be prepared from compounds of formula (1-2).
  • a base such as, but not limited to, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), triethylamine, or potassium carbonate in a solvent such as but not limited to tol
  • Scheme 6 depicts further examples of ways to diversify R 4 substituents on the pyrrolidine ring.
  • Compounds of formula (6-2) can be prepared from compounds of formula (5-2).
  • Compounds of formula (5-2) can be treated with sodium borohydride to afford compounds of formula (6-1).
  • esters of formula (6-1) can be hydrolyzed to compounds of formula (6-2) which are representative of compounds for Formula (I), using methods as described for Scheme 3.
  • hydroxymethyl R 4 substituents on the pyrrolidine ring can be synthesized as shown in Scheme 7.
  • Compounds of formula (7-6) can be prepared from compounds of formula (7-1).
  • Compounds of formula (7-1) where R 4b is typically substituted or unsubstituted alkyl or cycloalkyl are commercially available or can be synthesized by methods known to one skilled in the art.
  • Compounds of formula (7-1) can be coupled with compounds of formula (1-2) to afford compounds of formula (7-2) by methods discussed above for Scheme 1 for the coupling of compounds of formula (1-1) with those of formula (1-2).
  • Compounds of formula (7-2) can be hydrolyzed to the corresponding carboxylic acid of formula (7-4) by methods known to one skilled in the art.
  • R 4b is benzyl
  • the benzyl group can selectively be removed using hydrogenation conditions.
  • Typical catalysts for hydrogenation include, but are not limited to 10% Pd/C catalyst in a solvent including for example, tetrahydrofuran, or ethyl acetate.
  • the hydrogenation reaction is performed under pressure, such as 15-50 psi H 2 pressure in a pressure bottle.
  • Compounds of formula (7-4) can be treated with isobutyl chloroformate or ethyl chloroformate in the presence of a base including, for example, /V-methyl morpholine or triethylamine.
  • a base including, for example, /V-methyl morpholine or triethylamine.
  • the reaction is performed in a suitable solvent such as for example, tetrahydrofuran, typically at a temperature ⁇ 0 °C.
  • Sodium borohydride is added to afford primary alcohols of formula (7-5).
  • Esters of formula (7-5) can be hydrolyzed to compounds of formula (7-6) which are representative of compounds for Formula (I), using methods as described for Scheme 3.
  • Primary alcohols of formula (7-5) can be further diversified to ethers, esters, sulfonate, and the like by methods known to one skilled in the art. For example, as illustrated in Scheme 8, compounds of formula (8-2) can be prepared from compounds of formula (7-5).
  • compounds of formula (7-5) can be treated with a nucleophile in the presence of a phosphine such as, and including tributyl phosphine and a coupling agent such as, and including (TG ⁇ -L ⁇ ,L ⁇ ,L ⁇ ,/n 2 - tetramethyldiazene-l, 2-dicarboxamide (TMAD) or diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD) under Mitsunobu conditions.
  • a phosphine such as, and including tributyl phosphine and a coupling agent such as, and including (TG ⁇ -L ⁇ ,L ⁇ ,L ⁇ ,/n 2 - tetramethyldiazene-l, 2-dicarboxamide (TMAD) or diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD) under Mitsunobu conditions.
  • esters of formula (8-1) can be hydrolyzed to compounds of formula (8-2) which are representative of compounds for Formula (I), using methods as described for Scheme 3.
  • aminomethyl compounds of formula (9-3) can be prepared from hydroxymethyl compounds of formula (7-5).
  • Compounds of formula (7-5) can be treated with methanesulfonyl chloride in the presence of a suitable base including, but not limited to
  • Additional compounds of varying R 4 substituent can be prepared by functionalizing the amino group of compounds of formula (9-3) by methods known to one skilled in the art.
  • compounds of formula (10-2) can be prepared by coupling compounds of formula (10-1), where X is I, Br, Cl or triflate, and R 22 is as defined in formula (I), with amines compounds of formula (9-3) under Buchwald-Hartwig amination conditions known to those skilled in the art and widely available in the literature.
  • the reaction typically requires the use of a base, catalyst, and optionally, a ligand.
  • bases include, but are not limited to, potassium carbonate, potassium /-butoxide, sodium /-butoxide, sodium carbonate, cesium carbonate, and cesium fluoride.
  • catalysts include, but are not limited to, dichloro[4,5-dichloro-l,3-bis(2,6-di-3- pentylphenyl)imidazol-2-ylidene] (3-chloropyridyl)palladium(II) (PEPPSTIPentCl), chloro-(2- dicyclohexylphosphino-2',6'-diisopropoxy- 1 , 1 '-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) - methyl- /-butyl ether adduct (RuPhos palladacycle), tetrakis(triphenylphosphine)nickel(0), tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) dichloride, [1,1’- bis(diphenylphosphino)ferroc
  • optional ligands include, but are not limited to, XPhos (2-(dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl), BINAP (2,2'-bis(diphenylphosphino)-l,r-binaphthyl), DPPF (I,G- bis(diphenylphosphino)ferrocene), and Xantphos (4,5-bis(diphenylphosphino)-9,9- dimethylxanthene).
  • the reaction may be conducted in a solvent such as, but not limited to, water, dioxane, l-methyl-2-pyrrolidinone, N,N-dimethylacetamide, dimethoxyethane, N,N- dimethylformamide, toluene, ethanol, tetrahydrofuran, and the like or mixtures thereof.
  • a solvent such as, but not limited to, water, dioxane, l-methyl-2-pyrrolidinone, N,N-dimethylacetamide, dimethoxyethane, N,N- dimethylformamide, toluene, ethanol, tetrahydrofuran, and the like or mixtures thereof.
  • the reaction may be conducted at ambient or elevated temperatures, and optionally in a microwave oven.
  • Esters of formula (10-2) can be hydrolyzed to compounds of formula (10-3) which are representative of compounds for Formula (I), using methods as described for Scheme 3.
  • Electrospray MS spectra were obtained on a Waters platform LC/MS spectrometer or with Waters Acquity H-Class UPLC coupled to a Waters Mass detector 3100 spectrometer. Columns used: Waters Acquity UPLC BEH C18 1.7 pm, 2.1 mm ID x 50 mm L, Waters Acquity UPLC BEH C18 1.7 pm, 2.1 mm ID x 30 mm L, or Waters Xterra® MS 5 pm C18, 100 x 4.6 mm.
  • the methods were using either acetonitnle/H 2 0 gradients (H 2 0 contains either 0.1% TFA or 0.1% NH 3 ) or CH3OH/H2O gradients (H 2 0 contains 0.05% TFA). Microwave heating was performed with a Biotage® Initiator.
  • Racemic mixtures were separated on an Agilent HP 1100 system with UV detection. Column used: Chiralpak® IA (10 x 250 mm, 5 pm). Solvents used: Ao-propyl alchohol and tert- butyl methyl ether. Enantiomeric purity was determined on an Agilent HP 1100 system with UV detection. Column used: Chiralpak® IA (4.6 x 250 mm, 5pm). Solvents used were A - propyl alchohol and /e/7-butyl methyl ether.
  • Samples were purified by reverse phase preparative HPLC on a Phenomenex ® Luna ® C8(2) 5 pm 100A AXIATM column (50 mm x 21.2 mm).
  • a gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 40 mL/minute (0-0.5 minute 35% A, 0.5- 8.0 minute linear gradient 35-100% A, 8.0-9.0 minute 100% A, 7.0-8.9 minute 100% A, 9.0-9.1 minute linear gradient 100-35% A, 9.1- 10 minute 35% A).
  • a custom purification system was used, consisting of the following modules: Gilson 305 and 306 pumps; Gilson 806 Manometric module; Gilson UV/Vis 155 detector; Gilson 506C interface box; Gilson FC204 fraction collector; Agilent G1968D Active Splitter; Thermo MSQ Plus mass spectrometer.
  • the system was controlled through a combination of Thermo Xcalibur 2.0.7 software and a custom application written in-house using Microsoft Visual Basic 6.0.
  • a custom purification system was used, consisting of the following modules: Gilson 305 and 306 pumps; Gilson 806 Manometric module; Gilson UV/Vis 155 detector; Gilson 506C interface box; Gilson FC204 fraction collector; Agilent G1968D Active Splitter; Thermo MSQ Plus mass spectrometer.
  • the system was controlled through a combination of Thermo Xcalibur 2.0.7 software and a custom application written in-house using Microsoft Visual Basic 6.0.
  • a custom purification system was used, consisting of the following modules: Gilson 305 and 306 pumps; Gilson 806 Manometric module; Gilson UV/Vis 155 detector; Gilson 506C interface box; Gilson FC204 fraction collector; Agilent G1968D Active Splitter; Thermo MSQ Plus mass spectrometer.
  • the system was controlled through a combination of Thermo Xcalibur 2.0.7 software and a custom application written in-house using Microsoft Visual Basic 6.0.
  • Example 1A 1.312 g, 5.98 mmol
  • tetrahydrofuran 29.9 mL
  • lithium bromide 5.98 mL, 8.97 mmol
  • Example 1B 1.539 g, 5.98 mmol
  • DBU 1.082 mL, 7.18 mmol
  • Example 1C A solution of Example 1C (216 mg, 0.453 mmol) and triethylamine (0.126 mL, 0.907 mmol) in dichloromethane (2.0 mL) at 25 °C was treated dropwise with benzoyl chloride (76 mg, 0.544 mmol). After 1 h, the reaction was quenched with 10 drops of 1N aqueous ammonium hydroxide and the solvent removed under a stream of nitrogen. The crude material was purified using 5-50-% methyl /e/7-butyl ether/heptanes to give the title compound (208 mg, 0.358 mmol,
  • Example 1D (100 mg, 0.172 mmol) was dissolved in trifluoro acetic acid (0.5 mL). After 30 minutes, the solvent was removed under a stream of nitrogen and the crude material triturated with diethyl ether and «-heptane to give the title compound (83 mg, 0.158 mmol, 92 % yield).
  • Example 1 The product of Example 1 (43 mg) was purified by chiral supercritical fluid chromatography [Whelk-01 (5,5) column, gradient of 5-50% methanol (containing 0.1% diethylamine)-C0 2 over 10 minutes, flow rate 3 mL/minute, pressure 150 bar] to obtain the crude title compound as the first eluting peak (5.57 min). The resulting sample was dissolved in ethyl acetate (5 mL), washed with aqueous 1 N HC1 and brine, and concentrated to afford the title compound (19 mg, 99% ee).
  • Example 1 The product of Example 1 (43 mg) was purified by chiral supercritical fluid chromatography [Whelk-Ol (S,S) column, gradient of 5-50% methanol (containing 0.1% diethylamine)-C0 2 over 10 minutes, flow rate 3 mL/minute, pressure 150 bar] to obtain the crude title compound as the second eluting peak (6.67 min). The resulting sample was dissolved in ethyl acetate (5 mL), washed with aqueous 1 N HC1 and brine, and concentrated to afford the title compound (20 mg, 97% ee). The absolute chemistry was confirmed by X-ray analysis.
  • Example 1C A solution of Example 1C (82 mg, 0.172 mmol) and triethylamine (48.0 pL, 0.344 mmol) in dichloromethane (861 pL) at 25 °C was treated with cyclopentylacetyl chloride (25.5 pL, 0.189 mmol) dropwise. After 1 h, the reaction was quenched with 4 drops of ammonium hydroxide and the solvent removed under a stream of nitrogen. The crude material and purified using 5-50-% methyl /e/7-butyl ether/heptanes to give the title compound (99 mg, 0.169 mmol, 98 % yield).
  • Example 4A (20 mg, 0.034 mmol) was dissolved in trifluoroacetic acid (0.5 mL) and warmed to 40 °C. After 30 minutes, the solvent was removed under a stream of nitrogen and the crude material triturated with water to give the title compound (17 mg, 0.032 mmol, 94 % yield).
  • Example 1E A solution of Example 1E (50 mg, 0.095 mmol) and di( 1 /7-imidazol- 1 -yl)methanone (34.3 mg, 0.212 mmol) in l,2-dichloroethane (1 mL) was stirred 2 h at 42 °C. To this mixture was added methanesulfonamide (27.2 mg, 0.286 mmol) and 2,3,4,6,7,8,9,l0-octahydropyrimido[l,2- a]azepine (DBU, 0.043 mL, 0.286 mmol).
  • DBU 2,3,4,6,7,8,9,l0-octahydropyrimido[l,2- a]azepine
  • Example 9A A solution of Example 9A (50 mg, 0.113 mmol) and triethylamine (0.031 mL, 0.225 mmol) in dichloromethane (0.5 mL) at 25 °C was treated with cyclohexanecarbonyl chloride (0.019 mL, 0.141 mmol) dropwise, stirred for 2 h, diluted with methyl /e/7-butyl ether (20 mL), washed with saturated aqueous NaHCCh (5 mL) and with 1 N aqueous NH 4 OH (1 mL) solution, dried over sodium sulfate, filtered, concentrated to give a yellow oil.
  • the crude material was chromatographed on a 12 g column eluting with a gradient of 0-2% methanol/dichloromethane over a period of 20 minutes to provide the title compound (48 mg, 0.087 mmol, 77 % yield).
  • Example 9B To Example 9B (47 mg, 0.085 mmol) in dichloromethane (0.8 mL) was added trifluoroacetic acid (0.082 mL, 1.061 mmol) and the mixture was stirred at 44 °C for 4 h. The solvent was removed in vacuo and the resulting solid was chromatographed using a 12 g silica gel cartridge with a gradient of 1-10% methanol/dichloromethane over a period of 12 minutes to give the title compound (36 mg, 0.072 mmol, 85 % yield).
  • Example 12A A solution of Example 12A (50 mg, 0.110 mmol) and triethylamine (0.031 mL, 0.220 mmol) in dichloromethane (0.5 mL) at 25 °C was treated with cyclohexanecarbonyl chloride (0.018 mL, 0.137 mmol) dropwise, stirred for 2 h, diluted with dichloromethane (1 mL), washed with saturated aqueous NaHCCh (1 mL) and with 10% aqueous NH 4 OH (1 mL) solution to convert any left over acid chloride to the coresponding amide, dried over sodium sulfate, filtered, concentrated to give a yellow oil.
  • Example 12B To Example 12B (57 mg, 0.101 mmol) was added trifluoroacetic acid (0.311 mL, 4.04 mmol) and the mixture was stirred at 24 °C for 2 h. The solvent was removed in vacuo and the resulted solid was chromatographed using a 12 g silica gel cartridge with a gradient of 0-6% methanol/dichloromethane over a period of 20 minutes to give the title compound (50 mg, 0.098 mmol, 97 % yield).
  • Example 1A (1.909 g, 8.70 mmol) tetrahydrofuran (39.6 mL), and lithium bromide (7.91 mL, 11.87 mmol) was cooled to ⁇ -70 °C and a solution of Example 13A' (2.00 g, 7.91 mmol) in tetrahydrofuran (10 mL) was added followed by dropwise addition of
  • Example 13B A solution of Example 13B (50 mg, 0.106 mmol) and triethylamine (0.030 mL, 0.212 mmol) in dichloromethane (0.5 mL) at 25 °C was treated dropwise with cyclohexanecarbonyl chloride (0.018 mL, 0.132 mmol), stirred for 2 h, then diluted with dichloromethane (1 mL). The organic layer was washed with saturated aqueous NaHCCh (1 mL), then with 10% aqueous NH 4 OH (1 mL) solution, dried over sodium sulfate, filtered, and concentrated to give a yellow oil.
  • the crude material was chromatographed on a 12 g silica gel cartridge eluting with a gradient of 0-70% methyl /e/7-butyl ether/heptanes over a period of 20 minutes provided the title compound (61 mg, 0.105 mmol, 99 % yield).
  • Methyltriphenylphosphonium bromide (145 mg, 0.405 mmol) was suspended in 1.5 mL of toluene and potassium 2-methylpropan-2-olate (1 M solution in tetrahydrofuran, 0.385 mL, 0.385 mmol) was added dropwise. The resulting yellow solution was stirred for 30 min at rt, at which point Example 13C (118 mg, 0.203 mmol) was added to the vial as a solution in toluene (1 mL).
  • Example 14A A solution of Example 14A (26 mg, 0.045 mmol) was treated with trifluoroacetic acid, and stirred at ambient temperature for 30 minutes. The reaction was concentrated and
  • Example 1A 1.5 g, 6.84 mmol
  • Example 15A 1.958 g, 6.84 mmol
  • 3A molecular sieves 1 g.
  • Triethylamine 1.907 mL, 13.68 mmol
  • Example 15B To the solution of Example 15B (1.2 g, 2.374 mmol) and triethylamine (0.498 mL, 3.56 mmol) in dichloromethane (40 mL) cooled in an ice bath was slowly added cyclohexanecarbonyl chloride (0.413 mL, 3.09 mmol). The mixture was stirred at 0 °C for 30 minutes and warmed to room temperature and stirred for another 1 h. Dichloromethane (20 mL) was added. The mixture was washed with saturated NaHCCL, then brine, dried over MgS0 4 , and concentrated.
  • Example 15C The mixture of Example 15C (80 mg, 0.130 mmol) in trifluoroacetic acid (1.5 mL) was stirred at room temperature overnight. Purification was performed via chromatography, eluting with ethyl acetate/methanol (9:1) in heptane at 0-60% gradient to yield the title compound (66 mg, 91 % yield).
  • Example 13D A solution of Example 13D (100 mg, 0.190 mmol) and di( 1 /7-imidazol- 1 -yl)methanone (68.4 mg, 0.422 mmol) in l,2-dichloroethane (1.5 mL) was stirred 2 h at 42 °C. To this mixture was added methanesulfonamide (54.2 mg, 0.570 mmol) and 2,3,4,6,7,8,9,l0-octahydropyrimido[l,2- a]azepine (DBU, 0.086 mL, 0.570 mmol). DBU was dried with powdered 4A molecular sieves at 42 °C for 2 h prior to usage.
  • Example 17B (7 g, 18.66 mmol) was dissolved in tetrahydrofuran (141 mL). Tri(2- furyl)phosphine (0.158 g, 0.678 mmol) and Pd 2 (dba) 3 (155 mg, 0.17 mmol) were added, followed by addition of Example 17A (3.48 g, 16.96 mmol) as a solution in tetrahydrofuran (1 mL).
  • Example 17C (1.4 g, 5.50 mmol) was dissolved in /V,/V-dimethylformaiuide (2 mL).
  • the solution was cooled to ⁇ 5 °C in an ice bath before sodium hydride (0.440 g, 10.99 mmol) was added in one portion.
  • the resulting slurry was stirred for 1 min before adding iodomethane (1.718 mL, 27.5 mmol).
  • the thin suspension was stirred for 5 min in the ice bath then warmed to room temperature for 10 min.
  • the vial was recooled to ⁇ 5 °C and slowly quenched with saturated ammonium chloride then extracted with methyl /e/7-butyl ether (3 x 20 mL).
  • Example 1A (1408 mg, 6.42 mmol) was dissolved in tetrahydrofuran (3 mL) and the solution was cooled to -78 °C. A solution of lithium bromide (4.28 mL, 6.42 mmol) was added, followed by addition of Example 17D (1150 mg, 4.28 mmol) in tetrahydrofuran (13 mL).
  • Example 17E (30 mg, 0.061 mmol) was dissolved in tetrahydrofuran (0.615 mL) and triethylamine (0.013 mL, 0.092 mmol) was added, followed by cyclohexanecarbonyl chloride (8.19 pL, 0.068 mmol). The reaction was stirred for 1 h at room temperature, at which point complete conversion to the amide was observed by LC/MS. Trifluoro acetic acid (0.1 mL, 1.298 mmol) was added, and the reaction mixture was stirred at room temperature for 30 min.
  • Example 13B 100 mg, 0.212 mmol
  • triethylamine 89 pL, 0.636 mmol
  • dichloromethane 942 pL
  • 4- methoxycyclohexanecarbonyl chloride 94 mg, 0.530 mmol
  • 2 drops of methanol stirred for 20 minutes, then quenched with 2 drops of methanol, concentrated under a stream of nitrogen and purified using a 12 g silica gel cartridge eluting with a gradient of 5-100% methyl /e/7-butyl ether/heptanes over a period of 20 minutes to give the title compound (91 mg, 0.149 mmol, 70.2 % yield) as the first eluting compound.
  • Example 18A (50 mg, 0.082 mmol) was treated with trifluoro acetic acid (363 m L) and after 20 minutes, concentrated under a stream of nitrogen.
  • the crude material purified using a 12 g silica gel cartridge eluting with a 3: 1:4 ethyl acetate ⁇ ethanol ⁇ heptanes solvent system over a period of 20 minutes to give the title compound (37 mg, 0.067 mmol, 81 % yield).
  • Example 13B 100 mg, 0.212 mmol
  • triethylamine 89 pL, 0.636 mmol
  • dichloromethane 942 pL
  • 3-methoxy-2,2- dimethylpropanoyl chloride 80 mg, 0.530 mmol
  • stirred for 30 minutes then quenched with 2 drops of methanol, concentrated under a stream of nitrogen.
  • Example 19A (50 mg, 0.085 mmol) was treated with trifluoro acetic acid (379 pL) and after 20 minutes, LC/MS showed the desired mass. The reaction was concentrated under a stream of nitrogen and purified using a 12 g silica gel cartridge eluting with a 3: 1:4 ethyl
  • Example 13B 100 mg, 0.212 mmol
  • triethylamine 89 pL, 0.636 mmol
  • dichloromethane 942 pL
  • 4- methoxycyclohexanecarbonyl chloride 94 mg, 0.530 mmol
  • 2 drops of methanol stirred for 20 minutes, then quenched with 2 drops of methanol, concentrated under a stream of nitrogen and purified using a 12 g silica gel cartridge eluting with a gradient of 5-100% methyl /e/7-butyl ether/heptanes over a period of 20 minutes provided the title compound (28 mg, 0.046 mmol, 21.59 % yield) as the second eluting compound.
  • Example 20A (28 mg, 0.046 mmol) was treated with trifluoro acetic acid (203 pL) and after 20 minutes, LC/MS showed desired mass. The reaction was concentrated under a stream of nitrogen and purified using a 12 g silica gel cartridge eluting with a 3:1:4 ethyl
  • This reagent (0.05 g, 0.338 mmol) was added to a mixture Example 13B (0.12 g, 0.254 mmol) and triethylamine (0.089 mL, 0.635 mmol) in 1 mL of dichloromethane. After 2 h, the mixture was quenched with saturated aqueous sodium bicarbonate, the aqueous layer removed, the resulting oil dissolved in dichloromethane and purified using a 12 g silica gel cartridge with 10-100% ethyl acetate/heptanes in 20 min to give the title compound (106 mg, 0.181 mmol, 71.4 % yield). ⁇
  • Example 21A 103 mg, 0.176 mmol was added trifluoroacetic acid (0.621 mL, 8.06 mmol) and the mixture was stirred at 24 °C for 2 h. The solvent was removed in vacuo and the resulting solid was chromatographed using a 12 g silica gel cartridge with a gradient of 0-6% methanol/dichloromethane over a period of 20 minutes to give the title compound (88 mg, 0.167 mmol, 95 % yield).
  • Example 13B 100 mg, 0.212 mmol
  • triethylamine 89 pL, 0.636 mmol
  • dichloromethane 942 pL
  • 3- methoxycyclohexanecarbonyl chloride 94 mg, 0.530 mmol
  • reaction was quenched with 2 drops of methanol, concentrated under a stream of nitrogen, and purified using a 12 g silica gel cartridge eluting with a gradient of 5- 100% methyl /e/7-butyl ether/heptanes over a period of 20 minutes provided the rac-tert- butyl (2i?,35',4i?,55 , )-3-tert-butyl-4-(5-chloro-2-methoxybenzoyl)-l-(3-methoxycyclohexane-l-carbonyl)- 5-phenylpyrrolidine-2-carboxylate as the first eluting compound.
  • MS (EST) m/z 610 (M-H) .
  • Example l5C (l.l8 g, 1.916 mmol) and tetrabutylammonium iodide (2.124 g, 5.75 mmol) in dichloromethane (60 mL) was cooled to -20 °C in a dry ice bath was treated with trichloroborane (0.674 g, 5.75 mmol). The reaction mixture was stirred at -20 °C for 30 minutes, and allowed to warm to rt for 30 minutes. LC/MS indicated the conversion was complete, and de-methyl by-product was also detected. The reaction mixture was poured in cold water (50 mL) slowly and extracted with dichloromethane (3 x 20 mL).
  • Example 24A was isolated as the first eluting peak from the purification of Example 23 (570 mg, 53.1 % yield).
  • l H NMR 400 MHz, CDCE
  • 7.08 - 6.90 m, 4H
  • 4.79 - 4.60 m, 2H
  • 3.96 - 3.80 m, 1H)
  • 2.34 - 2.22 m, 1H)
  • 1.17 1.17
  • 0.96 s, 9H
  • 0.91 - 0.70 0.91 - 0.70 (m, 3H
  • MS ESI+) m/z 560 (M+H) + .
  • Example 24A was separated via chiral supercritical fluid chromatography.
  • the preparative supercritical fluid chromatography was performed on a THAR/Waters SFC 80 system running under SuperChrom software control.
  • the preparative supercritical fluid chromatography system was equipped with an 8-way preparative column switcher, CO2 pump, modifier pump, automated back pressure regulator (ABPR), UV detector, and 6-position fraction collector.
  • the mobile phase comprised of supercritical CO2 supplied by a dewar of bone-dry non-certified CO2 pressurized to 350 psi with a modifier of isopropyl alcohol at a flow rate of 70 g/min.
  • the column was at ambient temperature and the backpressure regulator was set to maintain 100 bar.
  • the sample was loaded into the modifier stream in 2 mL (130 mg) injections.
  • the mobile phase was held isocratically at 25% CosolvenkCCE. Fraction collection was time and/or threshold triggered.
  • the instrument was fitted with a Regis Whelk-0 (S, S) column with dimensions 21 mm i.d. x 250 mm length with 5 pm particles. Peak A eluted at 4.6 minutes and Peak B eluted at 6.2 minutes.
  • the title compound is the first eluting peak (102 mg, 29.1 % yield).
  • Example 13B A solution of Example 13B and triethylamine (89 pL, 0.636 mmol) in dichloromethane (942 pL) at 25 °C was treated with dropwise addition of 3-methoxycyclohexanecarbonyl chloride (94 mg, 0.530 mmol) as a solution in dichloromethane (0.2 mL), stirred for 20 minutes, then quenched with 2 drops of methanol, concentrated under a stream of nitrogen and purified using a 12 g silica gel cartridge eluting with a gradient of 5-100% methyl /e/7-butyl ether/heptanes over a period of 20 minutes to provide rac-tert- butyl (2A > ,3.S , ,4A > ,5.S , )-3- / e /7 -butyl-4-(5-chloi O -2- methoxybenzoyl)- 1 -(3-methoxycyclohexane-
  • the reaction was concentrated under a stream of nitrogen and purified using a 12 g silica gel cartridge eluting with a gradient of 5-100% methyl /e/7-butyl ether/heptanes over a period of 20 minutes to provide the title compound (12 mg, 0.019 mmol, 22.43 % yield).
  • Example 24A (87 mg, 0.155 mmol) and di( 1 /7-imidazol- 1 -yl)methanone (55.5 mg,
  • AXIATM column (30 mm x 75 mm).
  • Example 13D (195 mg) was separated by chiral preparative supercritical fluid chromatography using a CHIRALPAK IA, column size 30 x 250 mm, 5 micron, serial Number: IA00SALC002-812121, using a concentration of 50 mg/mL in methanol at a flow rate of 49 g/min C0 2 to provide 75 mg of the title compound. Retention time (chiral supercritical fluid
  • a solution of (5)-benzyl 2-(chlorocarbonyl)pyrrolidine-l-carboxylate was prepared by treating (5 , )-l-((benzyloxy)carbonyl)pyrrolidine-2-carboxylic acid (0.451 g, 1.809 mmol) in dichloromethane (9 mL) with /V,/V-dimethylformamide (0.014 mL, 0.181 mmol) followed by oxalyl chloride (0.475 mL, 5.43 mmol) and stirred at ambient temperature for 30 min. The mixture was concentrated and azeotroped with dichloromethane (2 x 2 mL) to provide the desired product.
  • Example 29 A The title compound was prepared following the procedure of Example 1B and Example 1C, substituting Example 29 A for 2',5'-dichloroacetophenone in Example 1B.
  • Example 29B (25 mg, 0.040 mmol) was treated with trifluoro acetic acid (0.3 mL) at 25 °C and stirred for 20 minutes. The reaction was concentrated under a stream of nitrogen and purified by reverse-phase preparative HPLC on a Phenomenex ® Luna ® C8(2) 5 pm 100A AXIATM column (30 mm x 75 mm).
  • Example 30A 202 mg, 0.287 mmol
  • 5% Pd/C 101 mg, 0.287 mmol
  • tetrahydrofuran (2.02 mL)
  • 4 M HC1 in dioxane (0.206 mL, 0.824 mmol).
  • the reactor was purged with H 2 and stirred at room temperature under 60 psig of hydrogen (g) for 2 h.
  • the reaction was filtered and the solvent was removed in vacuo to give 175 mg (96%) of the title compound.
  • MS (ESI+) m/z 569 (M+H) + .
  • Example 30B To a solution of Example 30B (25 mg, 0.041 mmol) in dichloromethane (0.3 mL) at 25 °C was added triethylamine (30 m L, 0.215 mmol) followed by methyl carbonochloridate (8 pL, 0.104 mmol). The reaction was stirred for 20 minutes, the solvent removed, and the residue purified using a 4 g silica gel cartridge with a gradient of 5-100% ethyl acetate ⁇ heptanes over 20 minutes to give 17 mg (0.027 mmol, 65% yield) of the desired ester. The ester was treated with trifluoroacetic acid (0.3 mL).
  • Example 13B (140 mg, 0.297 mmol) was dissolved in dichloromethane (1 mL).
  • Triethylamine (0.062 mL, 0.445 mmol) was added, followed by cyclohexanecarbonyl chloride (47.8 mg, 0.326 mmol) and the reaction was stirred at room temperature for 1 h.
  • the reaction mixture was loaded directly onto a 12 g silica gel column and was eluted with 0:100 to 100:0 ethyl acetate:heptanes over 20 min to give the title compound. (170 mg, 98% yield).
  • Methyltriphenylphosphonium bromide (145 mg, 0.405 mmol) was suspended in toluene (1.5 m) and potassium 2-methylpropan-2-olate (1 M solution in tetrahydrofuran, 0.385 mL, 0.385 mmol) was added dropwise. The resulting solution was stirred for 30 min at room temperature, then Example 31A (118 mg, 0.203 mmol) was added as a solution in toluene (1 mL). The reaction was stirred at room temperature. After 16 h, the reaction was complete as indicated by TLC.
  • Example 31B (123 mg, 0.212 mmol) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (0.25 mL, 3.24 mmol) was added. The reaction was stirred for 1 h at room temperature, and was complete as indicated by LC/MS.
  • the solvent was removed in vacuo, and the residue was azeotroped with dichloromethane (2 x 10 mL) in vacuo to give the crude product, which was purified via Chiral supercritical fluid chromatography, eluting on a 21 x 250 mm, 5 micron Chiralcel OJ-H column with a sample concentration of 30 mg/mL in 1:1 methanohDMSO and an eluent composition of 15% methanol in C0 2 .
  • the first eluting peak was Example 11-254 (11 mg) and the second-eluting peak was Example 31 (12.8 mg).
  • Example 32B (7 g, 18.66 mmol) was dissolved in tetrahydrofuran (141 mL). Tri(2- furyl)phosphine (0.158 g, 0.678 mmol) and Pd 2 (dba) 3 (155 mg, 0.17 mmol) were added, followed by addition of 5-chloro-2-methoxybenzoyl chloride (3.48 g, 16.96 mmol) as a solution in tetrahydrofuran (1 mL). The reaction was heated to 60 °C for 1 h.
  • reaction was cooled to room temperature, concentrated in vacuo and purified using a 120 g silica gel column (10-60% ethyl acetate/heptanes over 20 min, then 10 min at 60% ethyl acetate/heptanes) to afford the title compound (3.98 g), which was stored in the freezer when not in use.
  • Example 32C (1.4 g, 5.50 mmol) was dissolved in /V,/V-dimethylformaiuide (2 mL).
  • the solution was cooled to ⁇ 5 °C in an ice bath before sodium hydride (0.440 g, 10.99 mmol) was added in one portion.
  • the reaction was stirred for 1 min (yellow-orange suspension) before iodomethane (1.718 mL, 27.5 mmol) added.
  • the reaction was stirred for 5 min in the ice bath, then warmed to room temperature for 10 min.
  • the reaction was recooled to ⁇ 5 °C, and quenched slowly with saturated ammonium chloride, then extracted with methyl /e/7-butyl ether.
  • Example 1A (1408 mg, 6.42 mmol) was dissolved in tetrahydrofuran (3 mL) and the solution was cooled to -78 °C. A solution of lithium bromide (4.28 mL, 6.42 mmol) was added, followed by addition Example 32D (1150 mg, 4.28 mmol) in tetrahydrofuran (13 mL).
  • Example 32E (1.54 g, 3.16 mmol) was dissolved in toluene (5 mL). In a separate flask, methyltriphenylphosphonium bromide (1.691 g, 4.73 mmol) was suspended in toluene and potassium 2-methylpropan-2-olate (4.42 mL, 4.42 mmol) was added dropwise. The resulting yellow suspension was stirred for 16 h. The reaction was filtered through a one inch silica pad using a fritted funnel, eluting with 50% methyl /e/7-butyl ether/heptanes. Concentrated fractions containing product were purified using a 40 g silica gel column (10-30% methyl /e/7-butyl
  • Example 34B To a solution of Example 34B (1.127 g, 3.99 mmol) and /e/7-butylchlorodi methyl si lane (0.721 g, 4.78 mmol) in /V,/V-d i meth y 1 f o rm am i de (15 mL) was added 1 //-imidazole (0.678 g, 9.96 mmol). The reaction was stirred at rt for 5 h, then added to water (100 mL), and the aqueous layer extracted with ethyl acetate (2 x 100 mL).
  • Example 1A A solution of Example 1A (0.758 g, 3.11 mmol) and lithium bromide (0.312 g, 3.59 mmol) in tetrahydrofuran (15 mL) was cooled to -78 °C.
  • Example 34C (0.95 g, 2.393 mmol) in tetrahydrofuran (5 mL) and 2,3,4,6,7,8,9,l0-octahydropyrimido[l,2-a]azepine (0.546 g, 3.59 mmol) was added drop wise at -78 °C.
  • Example 34F A mixture of Example 34F (100 mg, 0.163 mmol) in 4 M HC1 in dioxane (4 mL) was stirred at room temperature overnight. Solvent was removed and the residue purified via HPLC on a Phenomenex ® Luna ® C8(2) 5 pm 100A AXIATM column (30 mm x 75 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/min (0- 1.0 min 5% A, 1.0-8.5 min linear gradient 5-100% A, 8.5-11.5 min 100% A, 11.5-12.0 min linear gradient 95-5% A) to yield title compound (73 mg, 80 % yield).
  • A acetonitrile
  • B trifluoroacetic acid in water
  • Example 13B A solution of Example 13B (50 mg, 0.106 mmol) and triethylamine (0.030 mL, 0.212 mmol) in dichloromethane (0.5 mL) at 25 °C was treated with diisopropylcarbamoyl chloride (21.67 mg, 0.132 mmol), heated to 45 °C and stirred for 16 h. The reaction was directly chromatographed on a 12 g silica gel cartridge, eluting with a gradient of 0-70% methyl /er/-butyl ether/heptanes over a period of 20 minutes to provide the title compound (48 mg, 0.080 mmol, 76 % yield).
  • Example 35A (42 mg, 0.070 mmol) was added trifluoroacetic acid (0.324 mL, 4.21 mmol) and the mixture was stirred at 25 °C for 4 h. The solvent was removed in vacuo and the resulting oil was chromatographed using a 4 g silica gel cartridge eluting with a gradient of 0-80% methyl /e/7-butyl ether/heptanes over a period of 20 minutes.
  • Example 13B (102.0 mg, 0.216 mmol) was dissolved in dichloromethane (1 mL).
  • Triethylamine (80 pL, 0.574 mmol) was added followed by isopropyl chloroformate solution (1 M in dichloromethane, 280 pL, 0.28 mmol). The reaction was stirred at ambient temperature for 1 h. The reaction was concentrated and purified by reverse phase HPLC purification, ammonium acetate method. Samples were purified by preparative HPLC on a Phenomenex ® Luna ® C8(2) 5 pm 100A AXIATM column (30 mm x 75 mm).
  • Example 36A (84.7 mg, 0.152 mmol) was dissolved in dichloromethane (1 mL).
  • Trifluoroacetic acid (0.5 mL, 6.49 mmol) was added and the reaction was stirred at ambient temperature for 1 h.
  • the reaction was concentrated and purified by reverse phase purification: Samples were purified by preparative HPLC on a Phenomenex ® Luna ® C8(2) 5 pm 100A AXIATM column (30 mm x 75 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/min (0-1.0 min 5% A, 1.0-8.5 min linear gradient 5-100% A, 8.5- 11.5 min 100% A, 11.5-12.0 min linear gradient 95-5% A) to afford the title compound (51.8 mg, 68%).
  • Example 36 (201.1 mg, 0.401 mmol) and 1 , 1 '-carbonyldiimidazole (142.7 mg, 0.880 mmol) were dissolved in dichloromethane (4 mL) and stirred at 40 °C for 2 h. 1,8- diazabicyclo[5.4.0]undec-7-ene (183.6 mg, 1.206 mmol) and methanesulfonamide (119.6 mg, 1.257 mmol) were added and the reaction was stirred for an additional 2 h at 40 °C. The reaction was diluted with dichloromethane (50 mL) and washed with aqueous 1 N HC1 (2 x 35 mL) and brine (50 mL). The organic layer was dried over Na 2 S0 4 , filtered and concentrated to give a solid. The residue was purified by silica gel chromatography (25 g column, 10% ethyl acetate in
  • Example 39A A solution of Example 39A (2.00 g, 4.07 mmol) and NaOH (0.081 g, 2.035 mmol) in methylene chloride (20 mL) was stirred at 25 °C for 1 hour. The mixture was diluted with methylene chloride (50 mL), and washed with water (30 mL). The organic layer was separated and concentrated to give the title compound (1.5 g, 3.25 mmol, 80 % yield).
  • Example 39B To a solution of Example 39B (5 g, 11.57 mmol) and benzoic acid (0.601 g, 4.92 mmol) in toluene (50 mL) at 80 °C was added Example 39C (1.391 g, 11.57 mmol). The mixture was stirred at 80 °C for 5 hours and then concentrated. The residue was purified by column
  • Example 39D (1.8 g, 7.17 mmol) and 1,8- diazabicyclo[5.4.0]undec-7-ene (1.62 mL, 10.76 mmol). After stirred for 30 minutes at -78 °C, the mixture was warmed to 0 °C for 45 minutes and then at 25 °C for 2 hours. LCMS showed complete conversion to the desired product. The reaction was quenched with saturated aq NH 4 Cl (10 mL) and water (10 mL).
  • Example 50B A solution of Example 50B (1.5 g, 3.43 mmol) and triethylamine (0.956 mL, 6.86 mmol) in dichloromethane (8.57 mL) at 25 °C was treated with diisoprop ylcarbamoyl chloride (0.701 g, 4.29 mmol), heated to 48 °C and stirred for 16 h. The reaction was directly loaded and chromatographed on a 40 g silica gel cartridge, eluting with a gradient of 0-60% methyl /e/7-butyl ether/heptanes over a period of 20 minutes to provide the title compound (1.9 g, 3.36 mmol, 98 % yield).
  • Example 40A 50 mg, 0.089 mmol was added trifluoroacetic acid (0.307 mL, 3.98 mmol) and the mixture was stirred at 25 °C for 4 h. The solvent was removed in vacuo and the resulting oil was chromatographed using a 4 g silica gel cartridge eluting with a gradient of 0-70% methyl /er/-butyl ether/heptanes over a period of 20 minutes. The combined product fractions were chromatographed again on 12 g silica gel cartridge with a gradient of 0-6%
  • Example 5 A solution of Example 5 (99 mg, 0.187 mmol) in methanol (933 pL) at -15 °C was treated with sodium borohydride (17.65 mg, 0.467 mmol) and stirred for 15 minutes. The reaction was quenched with 5 drops of saturated aqueous ammonium chloride, the solvent removed under a stream of nitrogen and the crude material filtered and washed with water to give a solid. The solid was chromatographed using a 12 g silica gel cartridge with an ethyl aceate ⁇ ethanol ⁇ heptanes solvent system to give the title compound (60 mg, 0.113 mmol, 60.4 % yield).
  • the aqueous phase was separated and extracted twice with methyl /e/7-butyl ether, and the combined organic phases were washed with brine, dried (Na 2 S0 4 ), and concentrated to a syrup which was loaded and chromatographed on a 80 g silica gel cartridge eluting with a gradient of 0-90% methyl /e/7-butyl ether/heptanes over a period of 20 minutes to provide the crude product, which was dissolved into heptane and placed in the freezer for over 1 h to induce precipitation.
  • the biphasic mixture was swirled for a while, resulting in additional precipitation, a process which was accelerated with brief sonication.
  • Example 42B A solution of Example 42B (5.6 g, 14.16 mmol) and triethylamine (3.95 mL, 28.3 mmol) in dichloromethane (8 mL) at 25 °C was treated with diisopropylcarbamoyl chloride (2.66 g, 16.28 mmol), amd stirred for 20 min at rt, then heated to 50 °C for 16 h.
  • Example 42C (7.29 g, 13.95 mmol) and ethyl acetate (140 mL) were added to 10% Pd/C, dry (1.484 g, 1.395 mmol) in a 250 mL stainless steel pressure bottle and shaken for 16 h at 50 psi and ambient temperature. The reaction was filtered and the solvent was evaporated leaving crude solid which was purified via a 24 g silica gel cartridge with a gradient of 0-10 %
  • Example 42D To a solution of Example 42D (1.00 g, 2.312 mmol) in tetrahydrofuran (7.2 mL) at - 10 °C (ice/acetone) was added /V-methyl morpholine (0.280 mL, 2.54 mmol). To this solution was added slowly isobutyl chloroformate (0.334 mL, 2.54 mmol). After 30 minutes, the mixture was filtered into a solution of sodium borohydride (0.175 g, 4.62 mmol) in water (1.4 mL) at 0 °C and warmed to 10 °C. After 40 minutes, the mixture was quenched via addition of saturated solution of aqueous NH 4 Cl (25 mL).
  • the reaction mixture was diluted with dichloromethane (50 mL) and the organics separated, filtered and the solvent removed.
  • the crude material was purified with a 12 g silica gel cartridge using a gradient of 0-100 % ethyl acetate/heptane over 30 min to give the title compound (814 mg, 1.945 mmol, 84 % yield).
  • Example 42E 50 mg, 0.119 mmol
  • (bromomethyl)benzene 24.52 mg, 0.143 mmol
  • sodium hydride 7.17 mg
  • Example 42E (52 mg, 0.124 mmol) was azeotroped with toluene before combining with tributylphosphine (0.037 mL, 0.149 mmol), and phenol (10.52 mg, 0.112 mmol) in

Abstract

L'invention concerne des composés de formule (I) dans laquelle R1, R2, R3, R3A, R4, et R5 sont tels que définis dans la description. La présente invention concerne des composés et leur utilisation dans le traitement de la mucoviscidose, des procédés pour leur production, des compositions pharmaceutiques les comprenant, et des méthodes de traitement de la mucoviscidose par administration d'un composé selon l'invention.
PCT/EP2019/058417 2018-04-03 2019-04-03 Pyrrolidines substituées et leur utilisation WO2019193062A1 (fr)

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