WO2023194895A1 - Dérivés pyrroliques utilisés en tant qu'inhibiteurs de l'apolipoprotéine l-1 - Google Patents

Dérivés pyrroliques utilisés en tant qu'inhibiteurs de l'apolipoprotéine l-1 Download PDF

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WO2023194895A1
WO2023194895A1 PCT/IB2023/053398 IB2023053398W WO2023194895A1 WO 2023194895 A1 WO2023194895 A1 WO 2023194895A1 IB 2023053398 W IB2023053398 W IB 2023053398W WO 2023194895 A1 WO2023194895 A1 WO 2023194895A1
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alkyl
halo
hydroxy
group
independently selected
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PCT/IB2023/053398
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Joseph E. Pero
Jing Fang
Mark Andrew Youngman
Jianxing Kang
Peng Li
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Glaxosmithkline Intellectual Property Development Limited
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    • 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
    • C07D403/12—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 chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • C07D207/30—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 two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—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 two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—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 two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/337—Radicals substituted by 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • C07D403/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • This invention relates to compounds which inhibit apolipoprotein L-1 (APOL1), pharmaceutical compositions comprising the compounds, and the use of the compounds for the treatment of diseases mediated by APOL1, including kidney diseases and sepsis.
  • APOL1 apolipoprotein L-1
  • Apolipoprotein L-1 (APOL1) is predominantly synthesized in the liver and circulates in the blood in complex with HDL particles.
  • the circulating APOL1 is known to function as an innate immune system by conferring protection from Trypanosoma brucei brucei (T. b. brucei), a parasite that causes African sleeping sickness.
  • T. b. brucei Trypanosoma brucei brucei
  • Studies have suggested the association of two common variants (G1 and G2) of APOL1 among African ancestry patients with increased risk for developing kidney diseases (Genovese, G. et al. , Science 2010, 329(5993), 841-845).
  • Gl substitution of two amino acids
  • N388 and Y389 deletion of two consecutive amino acids
  • G2 deletion of two consecutive amino acids
  • CKD Chronic kidney disease
  • race e.g., approximately 7.5% for individuals of African ancestry and 2.1% for individuals of European ancestry
  • CKD end-stage kidney disease
  • NKD nondiabetic kidney disease
  • FSGS focal segmental glomerulosclerosis
  • HlV human immunodeficiency virus-associated nephropathy
  • diabetic nephropathy hypertensive nephrosclerosis
  • lupus nephritis arterionephrosclerosis
  • microalbuminuria microalbuminuria
  • FSGS is a clinical syndrome involving podocyte injury and glomerular scarring, and includes genetic forms, reactive forms associated with other illnesses (including HIV-1 disease), and a primary form that accounts for the majority of cases including ESKD (Fogo, Nat. Rev. Nephrol. 2015, 11, 76-87).
  • One defining feature of FSGS includes proteinuria, typically accompanied by hypoalbuminemia, hypercholesterolemia, and peripheral edema.
  • FSGS has been shown to be the leading glomerular cause of ESKD (Rosenberg A. Z. et al., Clin. J. Am. Soc. Nephrol. 2017, 12(3), 502-517).
  • G1 and G2 risk variants of APOL1 are prevalent in individuals of African ancestry and are linked not only to adult-onset FSGS but also to progression of other related kidney diseases including CKD, NDKD, and ESKD, regardless of diabetes status (Parsa, A. et al., N. Engl. J. Med. 2013, 369, 2183-2196; Dummer P. D. et al., Semin. Nephrol. 2015, 35(3), 222-36).
  • An APOL1 inhibitor, VX-147 has been studied in clinical trials for treating APOL1 -Mediated Kidney Disease. (See WO 2020/131807; clinicaltrials.gov, NCT04340362 and NCT05312879).
  • the invention relates to APOL1 inhibitors and uses thereof in the treatment of kidney diseases associated with APOL1 and sepsis.
  • the invention relates to a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein:
  • X 1 is selected from the group consisting of -(Cl-C6)alkyl, halo(Cl-C6)alkyl-, -(C3- C6)cycloalkyl, 5- or 6-membered heterocycloalkyl, 5- or 6-membered heteroaryl, -(C5- C10)bicycloalkyl, 5- to 10-membered heterobicycloalkyl, and phenyl, wherein each -(C3- C6)cycloalkyl, 5- or 6-membered heterocycloalkyl, 5- or 6-membered heteroaryl, -(C5- C10)bicycloalkyl, 5- to 10-membered heterobicycloalkyl, and phenyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, -(Cl-Ce)alkyl, -(Ci-Ce)alkoxy, halo(Ci-C6)alkyl-, halo(
  • X 2 is -(Ci-C 6 )alkyl-Y, -(C 2 -C6)alkenyl-Y, -(C 3 -C6)cycloalkyl-Y, -(C 6 - Cio)bicycloalkyl-Y, -(C3-C6)cycloalkyl-(Ci-Ce)alkyl-Y, -(Ci-C6)alkyl-(C3-C6)cycloalkyl- Y, -piperidinyl-Y, or -(Cs-C ⁇ azabicycloalkyl-Y;
  • Y is -CONH 2 , -CONHR 6 , -NHCOR 6 , -NHR 6 , -OC(O)NHR 6 , or -NHC(O)OR 6 ;
  • R 6 is -(Ci-Ce)alkyl, -(Ci-Ce)alkyl substituted by -CONH 2 , hydroxy(Ci-C6)alkyl-, halo(Ci-C6)alkyl- substituted by hydroxy, amino(Ci-C6)alkyl-, -pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, -(C 3 - Ce)cycloalkyl substituted by one, two, or three substituents independently selected from the group consisting of oxo, hydroxy, amino, hydroxy(Ci-Ce)alkyl-, and amino(Ci-C6)alkyl-, tetrahydrofuranyl substituted by one, two, or three substituent
  • R 7 is hydrogen, halo, cyano, -(Ci-Ce)alkyl, or halo(Ci-C6)alkyl-; and each of R 8 , R 9 , R 10 , R 11 , and R 12 is independently selected from the group consisting of hydrogen, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and hydroxy(Ci-C6)alkyl-.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof as defined herein, and a pharmaceutically acceptable excipient.
  • the invention relates to a method of treatment of a kidney disease or sepsis comprising administering to a human in need thereof a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof as defined herein, or a pharmaceutical composition as defined herein.
  • the invention relates to a compound, or a pharmaceutically acceptable salt thereof as defined herein, or a pharmaceutical composition as defined herein for use in the treatment of a kidney disease or sepsis. In one aspect, the invention relates to use of a compound, or a pharmaceutically acceptable salt thereof as defined herein, or a pharmaceutical composition as defined herein in the manufacture of a medicament for the treatment of a kidney disease or sepsis.
  • alkyl refers to a saturated hydrocarbon radical, straight or branched, having the specified number of carbon atoms.
  • (Ci-C6)alkyl refers to an alkyl group having 1 to 6 carbon atoms.
  • Exemplary alkyls include, but are not limited to, methyl, ethyl, //-propyl, isopropyl, //-butyl, isobutyl, .v-butyl, t-butyl, pentyl, and hexyl.
  • Me refers to a methyl group.
  • alkyl When the term “alkyl” is used in combination with other substituent groups, such as “halo(Ci-C6)alkyl” and “hydroxy(Ci-C6)alkyl”, the term “alkyl” is intended to encompass a divalent straight or branched chain hydrocarbon radical, wherein the point of attachment is through the alkyl moiety.
  • halo(Ci-C6)alkyl refers to a radical having one or more halogen atoms, which may be the same or different, at one or more carbon atoms of an alkyl moiety having 1 to 6 carbon atoms, which is a straight or branched chain carbon radical.
  • halo(Ci-C6)alkyl groups include, but are not limited to, -CH2F (fluoromethyl), -CHF2 (difluoromethyl), -CF3 (trifluoromethyl), -CCh (trichloromethyl), 1,1 -difluoroethyl, 2- fluoro-2-methylpropyl, 2,2-difluoropropyl, 2,2,2-trifluoroethyl, and hexafluoroisopropyl.
  • hydroxy(Ci-C6)alkyl refers to a radical having one or more hydroxy groups at one or more carbon atoms of an alkyl moiety having 1 to 6 carbon atoms, which is a straight or branched chain carbon radical.
  • exemplary groups include, but are not limited to, hydroxymethyl (-CH2OH), hydroxyethyl (-CH2CH2OH), and hydroxyisopropyl.
  • amino(Ci-C6)alkyl refers to a radical having one or more amino groups at one or more carbon atoms of an alkyl moiety having 1 to 6 carbon atoms, which is a straight or branched chain carbon radical.
  • exemplary groups include, but are not limited to, aminomethyl (-CH2NH2), aminoethyl (-CH2CH2NH2), and aminoisopropyl.
  • alkenyl refers to a straight or branched hydrocarbon radical containing the specified number of carbon atoms and at least 1 double bond.
  • (C2- Ce)alkenyl has 2 to 6 carbon atoms.
  • Exemplary groups include, but are not limited to, ethenyl and propenyl.
  • alkoxy refers to an -O-alkyl group, i.e., an alkyl group which is attached through an oxygen linking atom, wherein “alkyl” is defined above.
  • (Ci-C6)alkoxy refers to a straight or branched chain carbon radical having 1 to 6 carbon atoms attached through an oxygen linking atom.
  • Exemplary “(Ci-Ce)alkoxy” groups include, but are not limited to, methoxy, ethoxy, //-propoxy, isopropoxy, //-butoxy, .v-butoxy, isobutoxy, and t-butoxy.
  • halo(Ci-C6)alkoxy refers to a straight or branched chain hydrocarbon radical, having at least 1 and up to 6 carbon atoms with one or more halogen atoms, which may be the same or different, attached to one or more carbon atoms, which radical is attached through an oxygen linking atom.
  • exemplary groups include, but are not limited to, -OCHF2 (difluoromethoxy), -OCF3 (trifluoromethoxy), and OCH(CF3)2 (hexafluoroisopropoxy) .
  • cycloalkyl refers to a non-aromatic, saturated, monocyclic, hydrocarbon ring containing the specified number of carbon atoms.
  • (C3-C6)cycloalkyl refers to a non-aromatic saturated, monocyclic, hydrocarbon ring having 3 to 6 carbon atoms.
  • Exemplary “(C3-C6)cycloalkyl” groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • Examples of “(C3-C6)cycloalkyl(Ci-C4)alkyl-” groups useful in the present invention include, but are not limited to, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclobutylethyl, cyclopentylethyl, and cyclohexylethyl.
  • the term “bicycloalkyl” refers to a saturated bicyclic hydrocarbon ring system containing the specified number of carbon atoms. Bicycloalkyl groups may be bridged, fused, or spiro.
  • bicycloalkyl may contain 5 to 10 carbon atoms, i.e., (C5- Cio)bicycloalkyl, or “bicycloalkyl” may contain 6 to 10 carbon atoms, i.e., (Ce- Cio)bicycloalkyl.
  • Exemplary groups include, but are not limited to bicyclofl.
  • heterocycloalkyl refers to a saturated or unsaturated 3 to 10 membered monocyclic or bicyclic ring, which must contain at least one heteroatom, which is selected from nitrogen, oxygen, and sulfur. Heterocycloalkyl groups may contain one or more C(O), S(O) or SO2 groups. However, heterocycloalkyl groups are not aromatic. Heterocycloalkyl groups containing more than one heteroatom may contain different heteroatoms.
  • the term “5- or 6- membered heterocycloalkyl” refers to a saturated or unsaturated 5- or 6- membered monocyclic ring, which must contain 1 or 2 non-carbon atoms, which are selected from nitrogen, oxygen, and sulfur.
  • Exemplary groups include, but are not limited to, pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, imidazolinyl, oxazolinyl, thiazolinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, dihydrofuranyl, 1,3-dioxolanyl, tetrahydro-2H-pyranyl, dihydropyranyl, morpholinyl, morpholinyl-3-one, 1,3-dioxanyl, 1 ,4-dioxanyl, 1,3-oxathiolanyl, 1,3-oxathianyl, 1,3-dithianyl, 1 ,4-oxathiolanyl, 1,4- oxathianyl, 1,4-dithianyl, piperidyl-2-one, pyrimidinyl-2,4(lH,3H
  • 5- or 6-membered heteroaryl refers to a group or moiety comprising an aromatic monovalent monocyclic radical, containing 5 or 6 ring atoms, including at least one carbon atom and at least one heteroatom independently selected from nitrogen, oxygen, and sulfur.
  • Selected 5-membered heteroaryl groups contain one nitrogen, oxygen, or sulfur ring heteroatom, and optionally contain 1, 2, or 3 additional nitrogen ring atoms.
  • Selected 6-membered heteroaryl groups contain 1, 2, or 3 nitrogen ring heteroatoms.
  • Exemplary groups include, but are not limited to furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, and triazinyl.
  • heterocycloalkyl refers to a saturated or unsaturated bicyclic ring containing at least one heteroatom, which is selected from nitrogen, oxygen, and sulfur.
  • Heterobicycloalkyl groups may be bridged, fused or spiro bicyclic groups. However, heterobicycloalkyl groups are not aromatic.
  • the term “5 to 10-membered heterobicycloalkyl” refers to a saturated or unsaturated 5 to 10- membered bicyclic ring containing 1 or 2 non-carbon atoms, which are selected from nitrogen, oxygen and sulfur.
  • Exemplary 5 to 10-membered heterobicycloalkyl groups include, but are not limited to, azabicycloalkyl, 7-oxabicyclo[2.2.1]heptanyl, 2-oxabicyclo[2.2.1]heptanyl, and 7- oxabicyclo[4.1.0]heptanyl.
  • azabicycloalkyl refers to a saturated bicyclic ring containing one nitrogen ring atom in addition to the specified number of carbon ring atoms.
  • Azabicycloalkyl groups can be bridged or fused.
  • “azabicycloalkyl” may contain 5 to 9 carbon atoms, i.e., (Cs-Cgjazabicycloalkyl.
  • Exemplary groups include, but are not limited to azabicyclo[3.1.0]hexyl, azabicyclo[2.2.1]heptyl, azabicyclo[3.1.1]heptyl, and azabicyclo[2.2.2]octyl.
  • bicyclic ring systems may be attached at any suitable position on either ring.
  • halogen and "halo” represent chloro (-C1), fluoro (-F), bromo (-Br), or iodo (-1) substituents.
  • hydroxy or “hydroxyl” is intended to mean the radical -OH.
  • cyano refers to the group -CN.
  • amino refers to the group -NH2.
  • member atoms refers to the atom or atoms that form a chain or ring. Where more than one member atom is present in a chain and within a ring, each member atom is covalently bound to an adjacent member atom in the chain or ring. Atoms that make up a substituent group attached to a chain or ring are not member atoms in the chain or ring.
  • a group may be unsubstituted or substituted with one or more of the defined substituents.
  • substituted in reference to a group indicates that a hydrogen atom attached to a member atom within a group is replaced by one of the defined substituents.
  • groups may be selected from a number of alternative groups, the selected groups may be the same or different.
  • the invention relates to a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein:
  • X 1 is selected from the group consisting of -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, -(C3- Ce)cycloalkyl, 5- or 6-membered heterocycloalkyl, 5- or 6-membered heteroaryl, -(C5- Cio)bicycloalkyl, 5- to 10-membered heterobicycloalkyl, and phenyl, wherein each -(C3- Ce)cycloalkyl, 5- or 6-membered heterocycloalkyl, 5- or 6-membered heteroaryl, -(C5- Cio)bicycloalkyl, 5- to 10-membered heterobicycloalkyl, and phenyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, -(Ci-Ce)alkyl, -(Ci-Ce)alkoxy, halo(Ci-C6)alkyl-,
  • X 2 is -(Ci-Ce)alkyl-Y, -(C 2 -C6)alkenyl-Y, -(C 3 -C6)cycloalkyl-Y, -(C 6 - Cio)bicycloalkyl-Y, -(C3-C6)cycloalkyl-(Ci-Ce)alkyl-Y, -(Ci-C6)alkyl-(C3-C6)cycloalkyl- Y, -piperidinyl-Y, or -(Cs-C ⁇ azabicycloalkyl-Y;
  • Y is -CONH 2 , -CONHR 6 , - NHCOR 6 , -NHR 6 , -OC(O)NHR 6 , or -NHC(O)OR 6 ;
  • R 6 is -(Ci-Ce)alkyl, -(Ci-Ce)alkyl substituted by -CONH2, hydroxy(Ci-C6)alkyl-, halo(Ci-C6)alkyl- substituted by hydroxy, amino(Ci-C6)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, -(C3- Ce)cycloalkyl substituted by one, two, or three substituents independently selected from the group consisting of oxo
  • R 7 is hydrogen, halo, cyano, -(Ci-Ce)alkyl, or halo(Ci-Ce)alkyl-; and each of R 8 , R 9 , R 10 , R 11 , and R 12 is independently selected from the group consisting of hydrogen, -(Ci-Ce)alkyl, halo(Ci-Ce)alkyl-, and hydroxy(Ci-Ce)alkyl-.
  • X 1 is selected from the group consisting of -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, - (C3-Ce)cycloalkyl, 5- or 6-membered heterocycloalkyl, 5- or 6-membered heteroaryl, -(C5- Cio)bicycloalkyl, 5- to 10-membered heterobicycloalkyl, and phenyl, wherein each -(C3- Ce)cycloalkyl, 5- or 6-membered heterocycloalkyl, 5- or 6-membered heteroaryl, -(C5- Cio)bicycloalkyl, 5- to 10-membered heterobicycloalkyl, and phenyl is optionally substituted with one or two substituents independently selected from the group consisting of halo, -(Ci-Ce)alkyl, -(Ci-Ce)al
  • X 1 is selected from the group consisting of -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, - (C3-Ce)cycloalkyl, -(Cs-Cio)bicycloalkyl, and phenyl, wherein each -(C3-Ce)cycloalkyl, - (Cs-Cio)bicycloalkyl, and phenyl is optionally substituted with one or two substituents independently selected from the group consisting of halo, -(Ci-Ce)alkyl, -(Ci-Ce)alkoxy, halo(Ci-Ce)alkyl-, -halo(Ci-Ce)alkoxy, cyano, hydroxy, -COOR 8 , -CONR 9 R 10 , - SO 2 NR U R 12 , -SO 2
  • X 1 is selected from the group consisting of -(Ci-Ce)alkyl, -(C3-Ce)cycloalkyl, 5- or 6-membered heterocycloalkyl, 5- or 6-membered heteroaryl, -(Cs-Cio)bicycloalkyl, 5- to 10-membered heterobicycloalkyl, and phenyl, wherein each -(C3-Ce)cycloalkyl, 5- or 6- membered heterocycloalkyl, 5- or 6-membered heteroaryl, -(C5-Cio)bicycloalkyl, 5- to 10- membered heterobicycloalkyl, and phenyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, -(Ci-Ce)alkyl, -(Ci- Ce)alkoxy, halo(Ci)
  • X 1 is selected from the group consisting of -(Ci-Ce)alkyl, -(C3-Ce)cycloalkyl, 5- or 6-membered heterocycloalkyl, 5- or 6-membered heteroaryl, -(Cs-Cio)bicycloalkyl, 5- to 10-membered heterobicycloalkyl, and phenyl, wherein each -(C3-Ce)cycloalkyl, 5- or 6- membered heterocycloalkyl, 5- or 6-membered heteroaryl, -(C5-Cio)bicycloalkyl, 5- to 10- membered heterobicycloalkyl, and phenyl is optionally substituted with one or two substituents independently selected from the group consisting of halo, -(Ci-Ce)alkyl, -(Ci- Ce)alkoxy, halo(Ci-C6)
  • X 1 is selected from the group consisting of -(Ci-Ce)alkyl, -(C3-Ce)cycloalkyl, - (Cs-Cio)bicycloalkyl, and phenyl, wherein each -(C3-Ce)cycloalkyl, -(Cs-Cio)bicycloalkyl, and phenyl is optionally substituted with one or two substituents independently selected from the group consisting of halo, -(Ci-Ce)alkyl, -(Ci-Ce)alkoxy, halo(Ci-C6)alkyl-, - halo(Ci-C 6 )alkoxy, cyano, hydroxy, -COOR 8 , -CONR 9 R 10 , -SO 2 NR U R 12 , -SO 2 (Ci- Ce)alkyl, and -
  • X 1 is selected from the group consisting of -(C3-C6)cycloalkyl, -(Cs- Cio)bicycloalkyl, phenyl and 5- or 6-membered heteroaryl, wherein each -(C3- Ce)cycloalkyl, -(Cs-Cio)bicycloalkyl, phenyl and 5- or 6- membered heteroaryl is optionally substituted with one or two substituents independently selected from the group consisting of halo, -(Ci-Ce)alkyl, -(Ci-Ce)alkoxy, halo(Ci-C6)alkyl-, halo(Ci-Ce)alkoxy-, cyano, hydroxy, -COOR 8 , -CONR 9 R 10 , -SO 2 NR U R 12 , -SO 2 (Ci-C 6 )alkyl, and
  • X 1 is selected from the group consisting of -(C3- Ce)cycloalkyl, -(Cs-Cio)bicycloalkyl, phenyl and 5- or 6-membered heteroaryl, wherein each -(C3-C6)cycloalkyl, -(C5-Cio)bicycloalkyl, phenyl and 5- or 6- membered heteroaryl is optionally substituted with one or two substituents independently selected from the group consisting of halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano.
  • X 1 is selected from the group consisting of -(C3-Ce)cycloalkyl, -(Cs-Cio)bicycloalkyl, phenyl and 5- or 6-membered heteroaryl, wherein each -(C3-Ce)cycloalkyl, -(C5- Cio)bicycloalkyl, phenyl and 5- or 6- membered heteroaryl is optionally substituted with one or two substituents independently selected from the group consisting of -F, -Cl, -Br, methyl, -CHF2, -CF3, and cyano.
  • X 1 is phenyl or 5- or 6-membered heteroaryl, wherein each phenyl and 5- or 6- membered heteroaryl is optionally substituted with one or two substituents independently selected from the group consisting of halo, -(Ci-Ce)alkyl, -(Ci-Ce)alkoxy, halo(Ci- C 6 )alkyl-, halo(Ci-C 6 )alkoxy-, cyano, hydroxy, -COOR 8 , -CONR 9 R 10 , -SO 2 NR U R 12 , - SO2(Ci-Ce)alkyl, and -SO(Ci-Ce)alkyl.
  • X 1 is phenyl or 5- or 6- membered heteroaryl, wherein each phenyl and 5- or 6- membered heteroaryl is optionally substituted with one or two substituents independently selected from the group consisting of halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano.
  • X 1 is phenyl or 5- or 6-membered heteroaryl, wherein each phenyl and 5- or 6- membered heteroaryl is optionally substituted with one or two substituents independently selected from the group consisting of -F, -Cl, -Br, methyl, -CHF2, -CF3, and cyano.
  • X 1 is a 5- or 6-membered heteroaryl optionally substituted with one or two substituents independently selected from the group consisting of halo, -(Ci-Ce)alkyl, and halo(Ci-C6)alkyl-.
  • X 1 is a 5- or 6-membered heteroaryl having one ring heteroatom selected from nitrogen, sulfur and oxygen, and optionally one additional ring nitrogen atom, wherein the 5- or 6 -membered heteroaryl is optionally substituted with one or two substituents independently selected from the group consisting of halo, -(Ci-Ce)alkyl, and halo(Ci-C6)alkyl-.
  • X 1 is a 5- or 6- membered heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, thienyl, thiazolyl, oxazolyl, and imidazolyl, wherein the 5- or 6-membered heteroaryl is optionally substituted with halo, -(Ci-Ce)alkyl, or halo(Ci-C6)alkyl-.
  • X 1 is a 5- or 6-membered heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, thienyl, thiazolyl, oxazolyl, and imidazolyl, wherein the 5- or 6-membered heteroaryl is optionally substituted with methyl, -F, or -CF3.
  • X 1 is -(Ci-Ce)alkyl or halo(Ci-C6)alkyl-. In another embodiment, X 1 is -(Ci- Ce)alkyl. In another embodiment, X 1 is methyl, -CF3, or -C(CH3)3. In another embodiment, X 1 is methyl or -C(CH3)3-
  • X 1 is a -(C5-Cio)bicycloalkyl optionally substituted with one or two substituents independently selected from the group consisting of halo and halo(Ci- Ce)alkyl-.
  • X 1 is -(Cs-Cejbicycloalkyl optionally substituted with one or two substituents independently selected from the group consisting of halo and halo(Ci-C6)alkyl-.
  • X 1 is bicyclofl.1.1. Jpentanyl optionally substituted with halo or halo(Ci-C6)alkyl-.
  • X 1 is bicyclofl.1.1. Jpentanyl optionally substituted with -F or -CF3.
  • X 1 is 5- or 6-membered heterocycloalkyl optionally substituted with one or two substituents independently selected from the group consisting of halo, -(Ci-Ce)alkyl, (Ci-Ce)alkoxy-, halo(Ci-C6)alkyl-, halo(Ci-Ce)alkoxy-, cyano, hydroxy, -COOR 8 , - CONR 9 R 10 , -SO 2 NR U R 12 , -SO 2 (Ci-C 6 )alkyl, and -SO(Ci-C 6 )alkyl.
  • X 1 is 5- or 6-membered heterocycloalkyl optionally substituted with one or two substituents independently selected from the group consisting of halo, -(Ci-Ce)alkyl, and halo(Ci-C6)alkyl-.
  • X 1 is a 5- or 6-membered heterocycloalkyl selected from the group consisting of piperidinyl and tetrahydro-2H-pyranyl, wherein the 5- or 6-membered heterocycloalkyl is optionally substituted with -(Ci-Ce)alkyl.
  • X 1 is a 5- or 6-membered heterocycloalkyl selected from the group consisting of piperidinyl and tetrahydro-2H-pyranyl, wherein the 5- or 6-membered heterocycloalkyl is optionally substituted with methyl.
  • X 1 is a -(C Cr cycloalkyl optionally substituted with one or two substituents independently selected from the group consisting of halo, -(Ci-Ce)alkyl, halofCi-CeJalkyl-, and cyano.
  • X 1 is a -(C i-Crjcycloalkyl optionally substituted with halolCi-Ce Jalkyl-.
  • X 1 is cyclopropyl optionally substituted with - CF 3 .
  • each of R la , R 2a , R 3a , R 4a , and R 5a is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, -(Ci-Ce)alkoxy, halofCi-CeJalkyl-, halo(Ci- C 6 )alkoxy-, cyano, hydroxy, -COOR 8 , -CONR 9 R 10 , -SO 2 NR U R 12 , -SO 2 (Ci-C 6 )alkyl, and - SO(Ci-Ce)alkyl, provided at least three of R la , R 2a , R 3a , R 4a , and R 5a are hydrogen.
  • each of R la , R 2a , R 3a , R 4a , and R 5a is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano, provided at least two of R la , R 2a , R 3a , R 4a , and R 5a are hydrogen.
  • each of R la , R 2a , R 3a , R 4a , and R 5a is independently selected from the group consisting of hydrogen, -F, -Br, -Cl, methyl, -CHF2, -CF3, and cyano, provided at least two of R la , R 2a , R 3a , R 4a , and R 5a are hydrogen.
  • each of R la , R 2a , R 3a , R 4a , and R 5a is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-Ce)alkyl-, and cyano, provided at least three of R la , R 2a , R 3a , R 4a , and R 5a are hydrogen.
  • each of R la , R 2a , R 3a , R 4a , and R 5a is independently selected from the group consisting of hydrogen, -F, -Br, -Cl, methyl, -CHF2, -CF3, and cyano, provided at least three of R la , R 2a , R 3a , R 4a , and R 5a are hydrogen.
  • X 1 is selected from the group consisting of -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, - (C3-Ce)cycloalkyl, 5- or 6-membered heterocycloalkyl, 5- or 6-membered heteroaryl, -(C5- Cio)bicycloalkyl, 5- to 10-membered heterobicycloalkyl, and phenyl, wherein each -(C3- Ce)cycloalkyl, 5- or 6-membered heterocycloalkyl, 5- or 6-membered heteroaryl, -(C5- Cio)bicycloalkyl, 5- to 10-membered heterobicycloalkyl, and phenyl is optionally substituted with one or two substituents independently selected from the group consisting of halo, -(Ci-Ce)alkyl, -(Ci-Ce)al
  • X 1 is selected from the group consisting of -(C3-C6)cycloalkyl, -(C5- Cio)bicycloalkyl, phenyl and 5- or 6-membered heteroaryl, wherein each -(C3- Ce)cycloalkyl, -(Cs-Cio)bicycloalkyl, phenyl and 5- or 6- membered heteroaryl is optionally substituted with one or two substituents independently selected from the group consisting of halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano; and each of R la , R 2a , R 3a , R 4a , and R 5a is independently selected from the group consisting of hydrogen, halo, -(Ci- Ce)alkyl, halo(Ci-C6)alkyl-, and cyano, provided at
  • X 1 is phenyl or 5- or 6-membered heteroaryl, wherein each phenyl and 5- or 6- membered heteroaryl is optionally substituted with one or two substituents independently selected from the group consisting of halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano; and each of R la , R 2a , R 3a , R 4a , and R 5a is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-Ce)alkyl-, and cyano, provided at least three of R la , R 2a , R 3a , R 4a , and R 5a are hydrogen.
  • X 1 is a -(C3-C6)cycloalkyl optionally substituted with one or two substituents independently selected from the group consisting of halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano; and each of R la , R 2a , R 3a , R 4a , and R 5a is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano, provided at least three of R la , R 2a , R 3a , R 4a , and R 5a are hydrogen.
  • X 2 is -(Ci-C6)alkyl-Y, -(C3-C6)cycloalkyl-Y, -(C3-C6)cycloalkyl-(Ci-C6)alkyl- Y, or -(Ci-C6)alkyl-(C3-C6)cycloalkyl-Y.
  • X 2 is -(Ci-Ce)alkyl-Y or -(C3-Ce)cycloalkyl-Y.
  • X 2 is -(C3-C6)cycloalkyl-Y.
  • X 2 is -(Ci-Ce)alkyl-Y.
  • X 2 is -(CH2)2-Y or -(CH2)3- Y.
  • Y is -CONHR 6 , -NHCOR 6 , -NHR 6 , -OC(O)NHR 6 , or -NHC(O)OR 6 .
  • Y is -CONHR 6 , -NHCOR 6 , or -NHR 6 .
  • Y is - CONHR 6 or -NHR 6 .
  • Y is -CONHR 6 or -NHCOR 6 .
  • Y is -CONHR 6 .
  • R 6 is -(Ci-Ce)alkyl substituted by -CONH2, hydroxy(Ci-Ce)alkyl-, halo(Ci- Ce)alkyl- substituted by hydroxy, amino(Ci-C6)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, -(C3-Ce)cycloalkyl substituted by one, two, or three substituents independently selected from the group consisting of oxo, hydroxy, amino, hydroxy(Ci-Ce)alkyl-, and amino(Ci-C6)alkyl-, tetrahydrofuranyl substituted by one, two,
  • R 6 is -(Ci-Ce)alkyl substituted by -CONH2, hydroxy(Ci-Ce)alkyl-, halo(Ci- Ce)alkyl- substituted by hydroxy, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, or -(C3-Ce)cycloalkyl substituted by one, two, or three substituents independently selected from the group consisting of oxo, hydroxy, amino, hydroxy(Ci-Ce)alkyl-, and amino(Ci-C6)alkyl-.
  • R 6 is -(Ci-Ce)alkyl substituted by -CONH 2 , hydroxy(Ci-Ce)alkyl-, halo(Ci- Ce)alkyl- substituted by hydroxy, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy.
  • R 6 is hydroxy(Ci- Ce)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy.
  • R 6 is pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo, and hydroxy.
  • X 2 is -(Ci-C6)alkyl-Y, -(C3-C6)cycloalkyl-Y, -(C3-C6)cycloalkyl-(Ci-C6)alkyl- Y, or -(Ci-C6)alkyl-(C3-C 6 )cycloalkyl-Y;
  • Y is -CONHR 6 , -NHCOR 6 , -NHR 6 , - OC(O)NHR 6 , or -NHC(O)OR 6 ;
  • R 6 is hydroxy(Ci-Ce) alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy.
  • X 2 is - (Ci-Ce)alkyl-Y or -(C3-C 6 )cycloalkyl-Y;
  • Y is -CONHR 6 , -NHCOR 6 , or -NHR 6 ; and R 6 is hydroxy(Ci-Ce)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy.
  • X 2 is -(Ci-C6)alkyl-Y or -(C3- C6)cycloalkyl-Y; Y is -CONHR 6 , -NHCOR 6 , or -NHR 6 ; and R 6 is pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy.
  • X 2 is -(Ci-Ce)alkyl-Y or -(C3-Ce)cycloalkyl-Y; Y is -CONHR 6 or -NHR 6 ; and R 6 is pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy.
  • R 7 is hydrogen, halo, cyano, -(Ci-Ce)alkyl, or halo(Ci-Ce)alkyl-.
  • R 7 is hydrogen, halo, cyano, methyl, or -CF3.
  • R 7 is hydrogen, halo, or -(Ci-Ce)alkyl.
  • R 7 is hydrogen, -F, -I, -CN, methyl, or -CF3.
  • R 7 is hydrogen, -F, or methyl.
  • R 7 is hydrogen.
  • R 7 is hydrogen, halo, cyano, or halo(Ci-Ce)alkyl-. In another embodiment, R 7 is hydrogen, halo, cyano, or -CF3. In another embodiment, R 7 is hydrogen, -F, -I, -CN, or - CF 3 .
  • each of R 8 , R 9 , R 10 , R 11 , and R 12 is independently selected from the group consisting of hydrogen and -(Ci-Ce)alkyl.
  • X 1 is selected from the group consisting of -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, -(C3- Ce)cycloalkyl, -(Cs-Cio)bicycloalkyl, and phenyl, wherein each -(C3-C6)cycloalkyl, -(C5- Cio)bicycloalkyl, and phenyl is optionally substituted with one or two substituents independently selected from the group consisting of halo, -(Ci-Ce)alkyl, -(Ci-Ce)alkoxy, halo(Ci-Ce)alkyl-, halo(Ci-Ce)alkoxy-, cyano, hydroxy, -COOR 8 , -CONR 9 R 10 , - SO 2 NR U R 12 , -SO 2 (Ci-C 6 )alkyl, and -SO(Ci-C 6
  • X 2 is -(Ci-Ce)alkyl-Y, -(C3-C 6 )cycloalkyl-Y, -(C3-C6)cycloalkyl-(Ci-C 6 )alkyl-Y, or -(Ci-C6)alkyl-(C 3 -C6)cycloalkyl-Y;
  • Y is -CONHR 6 , -NHCOR 6 , -NHR 6 , -OC(O)NHR 6 , or -NHC(O)OR 6 ;
  • R 6 is -(Ci-C6)alkyl substituted by -CONH 2 , hydroxy(Ci-Ce)alkyl-, halo(Ci- Ce)alkyl- substituted by hydroxy, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy;
  • R 7 is hydrogen, halo, cyano, methyl, or halo(Ci-C6)alkyl-; and each of R 8 , R 9 , R 10 , R 11 , and R 12 is independently selected from the group consisting of hydrogen and -(Ci-Ce)alkyl.
  • X 1 is selected from the group consisting of -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, -(C3- Ce)cycloalkyl, -(Cs-Cio)bicycloalkyl, and phenyl, wherein each -(C3-C6)cycloalkyl, -(C5- Cio)bicycloalkyl, and phenyl is optionally substituted with one or two substituents independently selected from the group consisting of halo, -(Ci-Ce)alkyl, -(Ci-Ce)alkoxy, halo(Ci-C 6 )alkyl-, halo(Ci-C 6 )alkoxy-, cyano, hydroxy, -COOR 8 , -CONR 9 R 10 , - SO 2 NR U R 12 , -SO 2 (Ci-C6)alkyl, and -SO(Ci-C 6
  • X 2 is -(Ci-C 6 )alkyl-Y, -(C 3 -C6)cycloalkyl-Y, -(C3-C6)cycloalkyl-(Ci-C 6 )alkyl-Y, or -(Ci-C6)alkyl-(C 3 -C6)cycloalkyl-Y;
  • Y is -CONHR 6 , -NHCOR 6 , -NHR 6 , -OC(O)NHR 6 , or -NHC(O)OR 6 ;
  • R 6 is -(Ci-C6)alkyl substituted by -CONH 2 , hydroxy(Ci-Ce)alkyl-, halo(Ci- Ce)alkyl- substituted by hydroxy, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy;
  • R 7 is hydrogen, halo, cyano, or halo(Ci-C6)alkyl-; and each of R 8 , R 9 , R 10 , R 11 , and R 12 is independently selected from the group consisting of hydrogen and -(Ci-Ce)alkyl.
  • X 1 is selected from the group consisting of -(C3-Ce)cycloalkyl, -(C5- Cio)bicycloalkyl, phenyl and 5- or 6-membered heteroaryl, wherein each -(C3- Ce)cycloalkyl, -(Cs-Cio)bicycloalkyl, phenyl and 5- or 6- membered heteroaryl is optionally substituted with one or two substituents independently selected from the group consisting of halo, -(Ci-Ce)alkyl, halo(Ci-Ce)alkyl-, and cyano; each of R la , R 2a , R 3a , R 4a , and R 5a is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-Ce)alkyl-, and cyano, provided at least three of R la , R 2a , R 3a ,
  • X 2 is -(Ci-C6)alkyl-Y or -(C3-C6)cycloalkyl-Y;
  • Y is -CONHR 6 , -NHCOR 6 , or -NHR 6 ;
  • R 6 is hydroxy(Ci-C6)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo, and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo, and hydroxy; and
  • R 7 is hydrogen, halo, cyano, methyl, or halo(Ci-C6)alkyl-.
  • X 1 is selected from the group consisting of -(C3-Ce)cycloalkyl, -(C5- Cio)bicycloalkyl, phenyl and 5- or 6-membered heteroaryl, wherein each -(C3- Ce)cycloalkyl, -(Cs-Cio)bicycloalkyl, phenyl and 5- or 6- membered heteroaryl is optionally substituted with one or two substituents independently selected from the group consisting of halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano; each of R la , R 2a , R 3a , R 4a , and R 5a is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano, provided at least three of R la , R 2a , R 3a , R 4
  • X 2 is -(Ci-Ce)alkyl-Y or -(C3-Ce)cycloalkyl-Y;
  • Y is -CONHR 6 , -NHCOR 6 , or -NHR 6 ;
  • R 6 is hydroxy(Ci-C6)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo, and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo, and hydroxy; and
  • R 7 is hydrogen, halo, cyano, or halo(Ci-C6)alkyl-.
  • X 1 is phenyl or 5- or 6-membered heteroaryl, wherein each phenyl and 5- or 6- membered heteroaryl is optionally substituted with one or two substituents independently selected from the group consisting of halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano; each of R la , R 2a , R 3a , R 4a , and R 5a is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-Ce)alkyl-, and cyano, provided at least three of R la , R 2a , R 3a , R 4a , and R 5a are hydrogen;
  • X 2 is -(Ci-C6)alkyl-Y or -(C3-C6)cycloalkyl-Y;
  • Y is -CONHR 6 , -NHCOR 6 , or -NHR 6 ;
  • R 6 is hydroxy(Ci-Ce)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy; and
  • R 7 is hydrogen, halo, cyano, methyl, or halo(Ci-C6)alkyl-.
  • X 1 is phenyl or 5- or 6-membered heteroaryl, wherein each phenyl and 5- or 6- membered heteroaryl is optionally substituted with one or two substituents independently selected from the group consisting of halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano; each of R la , R 2a , R 3a , R 4a , and R 5a is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano, provided at least three of R la , R 2a , R 3a , R 4a , and R 5a are hydrogen;
  • X 2 is -(Ci-Ce)alkyl-Y or -(C3-Ce)cycloalkyl-Y;
  • Y is -CONHR 6 , -NHCOR 6 , or -NHR 6 ;
  • R 6 is hydroxy(Ci-C6)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy; and
  • R 7 is hydrogen, halo, cyano, or halo(Ci-C6)alkyl-.
  • the invention also relates to a compound of Formula (II): or a pharmaceutically acceptable salt thereof, wherein: X 2 is -(Ci-Ce)alkyl-Y, -(C 2 -C6)alkenyl-Y, -(C 3 -C6)cycloalkyl-Y, -(C 6 - Cio)bicycloalkyl-Y, -(C3-C6)cycloalkyl-(Ci-Ce)alkyl-Y, -(Ci-C6)alkyl-(C3-C6)cycloalkyl- Y, -piperidinyl-Y, or -(Cs-C ⁇ azabicycloalkyl-Y;
  • Y is -CONH2, -CONHR 6 , -NHCOR 6 , -NHR 6 , -OC(O)NHR 6 , or -NHC(O)OR 6 ; each of R la , R lb , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , and R 5b is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, -(Ci-Ce)alkoxy, halo(Ci- C 6 )alkyl-, halo(Ci-C 6 )alkoxy-, cyano, hydroxy, -COOR 8 , -CONR 9 R 10 , -SO 2 NR U R 12 , - SO 2 (Ci-C 6 )alkyl, and -SO(Ci-C 6 )alkyl, provided at least two of R la , R 2
  • R 6 is -(Ci-Ce)alkyl, -(Ci-Ce)alkyl substituted by -CONH 2 , hydroxy(Ci-Ce)alkyl-, halo(Ci-Ce)alkyl- substituted by hydroxy, amino(Ci-C6)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, -(C3- Ce)cycloalkyl substituted by one, two, or three substituents independently selected from the group consisting of oxo, hydroxy, amino, hydroxy(Ci-Ce)alkyl-, and amino(Ci-C6)alkyl-, tetrahydrofuranyl substituted by one, two, or three substituent
  • R 7 is hydrogen, halo, cyano, -(Ci-Ce)alkyl, or halo(Ci-Ce)alkyl-; and each of R 8 , R 9 , R 10 , R 11 , and R 12 is independently selected from the group consisting of hydrogen, -(Ci-Ce)alkyl, halo(Ci-Ce)alkyl, and hydroxy(Ci-Ce)alkyl-.
  • each of R la , R 2a , R 3a , R 4a , R 5a , R lb , R 2b , R 3b , R 4b , and R 5b is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, -(Ci-Ce)alkoxy, halo(Ci-Ce)alkyl-, halo(Ci-Ce)alkoxy-, cyano, hydroxy, -COOR 8 , -CONR 9 R 10 , - SO 2 NR U R 12 , -SO 2 (Ci-C 6 )alkyl, and -SO(Ci-C 6 )alkyl, provided at least three of R la , R 2a , R 3a , R 4a , and R 5a are hydrogen and at least three of R lb , R 2b
  • each of R la , R 2a , R 3a , R 4a , R 5a , R lb , R 2b , R 3b , R 4b , and R 5b is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-Ce)alkyl-, and cyano, provided at least two of R la , R 2a , R 3a , R 4a , and R 5a are hydrogen and at least two of R lb , R 2b , R 3b , R 4b , and R 5b are hydrogen.
  • each of R la , R 2a , R 3a , R 4a , R 5a , R lb , R 2b , R 3b , R 4b , and R 5b is independently selected from the group consisting of hydrogen, -F, -Br, -Cl, methyl, -CHF 2 , -CF3, and cyano, provided at least two of R la , R 2a , R 3a , R 4a , and R 5a are hydrogen and at least two of R lb , R 2b , R 3b , R 4b , and R 5b are hydrogen.
  • each of R la , R 2a , R 3a , R 4a , R 5a , R lb , R 2b , R 3b , R 4b , and R 5b is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano, provided at least three of R la , R 2a , R 3a , R 4a , and R 5a are hydrogen and at least three of R lb , R 2b , R 3b , R 4b , and R 5b are hydrogen.
  • each of R la , R 2a , R 3a , R 4a , R 5a , R lb , R 2b , R 3b , R 4b , and R 5b is independently selected from the group consisting of F, -Br, -Cl, methyl, -CHF2, -CF3, and cyano, provided at least three of R la , R 2a , R 3a , R 4a , and R 5a are hydrogen and at least three of R lb , R 2b , R 3b , R 4b , and R 5b are hydrogen.
  • X 2 is -(Ci-C6)alkyl-Y, -(C3-C6)cycloalkyl-Y, -(C3-C6)cycloalkyl-(Ci-C6)alkyl- Y, or -(Ci-C6)alkyl-(C3-C6)cycloalkyl-Y.
  • X 2 is -(Ci-Ce)alkyl-Y or -(C3-Ce)cycloalkyl-Y.
  • X 2 is -(C3-C6)cycloalkyl-Y.
  • X 2 is -(Ci-Ce)alkyl-Y. In another embodiment, X 2 is -(CH2)2-Y or -(CH2)3- Y. In another embodiment, X 2 is -(CH2)2-Y.
  • Y is -CONHR 6 , -NHCOR 6 , -NHR 6 , -OC(O)NHR 6 , or -NHC(O)OR 6 .
  • Y is -CONHR 6 , -NHCOR 6 , or -NHR 6 .
  • Y is - CONHR 6 or -NHCOR 6 .
  • Y is -CONHR 6 or -NHR 6 .
  • Y is -CONHR 6 .
  • R 6 is -(Ci-Ce)alkyl substituted by -CONH2, hydroxy(Ci-Ce)alkyl-, halo(Ci- Ce)alkyl- substituted by hydroxy, amino(Ci-C6)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, -(C3-Ce)cycloalkyl substituted by one, two, or three substituents independently selected from the group consisting of oxo, hydroxy, amino, hydroxy(Ci-Ce)alkyl-, and amino(Ci-C6)alkyl-, tetrahydrofuranyl substituted by one,
  • R 6 is -(Ci-Ce)alkyl substituted by -CONH2, hydroxy(Ci-Ce)alkyl-, halo(Ci- Ce)alkyl- substituted by hydroxy, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, or -(C3-Ce)cycloalkyl substituted by one, two, or three substituents independently selected from the group consisting of oxo, hydroxy, amino, hydroxy(Ci-Ce)alkyl-, and amino(Ci-C6)alkyl-.
  • R 6 is -(Ci- Ce)alkyl substituted by -CONH2, hydroxy(Ci-Ce)alkyl-, halo(Ci-Ce) alkyl- substituted by hydroxy, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy.
  • R 6 is hydroxy(Ci-Ce)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy.
  • R 6 is pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy.
  • R 6 is
  • X 2 is -(Ci-C6)alkyl-Y, -(C3-C6)cycloalkyl-Y, -(C3-C6)cycloalkyl-(Ci-C6)alkyl- Y, or -(Ci-C6)alkyl-(C 3 -C6)cycloalkyl-Y;
  • Y is -CONHR 6 , -NHCOR 6 , -NHR 6 , - OC(O)NHR 6 , or -NHC(O)OR 6 ;
  • R 6 is hydroxy(Ci-Ce) alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy.
  • X 2 is - (Ci-Ce)alkyl-Y or -(C3-C 6 )cycloalkyl-Y;
  • Y is -CONHR 6 , -NHCOR 6 , or -NHR 6 ; and R 6 is hydroxy(Ci-Ce)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy.
  • X 2 is -(Ci-C6)alkyl-Y or -(C3- Ce)cycloalkyl-Y; Y is -CONHR 6 , -NHCOR 6 , or -NHR 6 ; and R 6 is pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy.
  • X 2 is -(Ci-C6)alkyl-Y or -(C3-C6)cycloalkyl-Y; Y is -CONHR 6 or -NHR 6 ; and R 6 is pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy.
  • R 7 is hydrogen, halo, cyano, -(Ci-Ce)alkyl, or halo(Ci-C6)alkyl-. In another embodiment, R 7 is hydrogen, halo, cyano, methyl, or -CF3. In another embodiment, R 7 is hydrogen, -F, -I, -CN, methyl, or -CF3.
  • R 7 is hydrogen, halo, cyano, or halo(Ci-C6)alkyl-. In another embodiment, R 7 is hydrogen, halo, cyano, or -CF3. In another embodiment, R 7 is hydrogen, -F, -I, -CN, or - CF 3 .
  • each of R 8 , R 9 , R 10 , R 11 , and R 12 is independently selected from the group consisting of hydrogen and -(Ci-Ce)alkyl.
  • each of R la , R 2a , R 3a , R 4a , R 5a , R lb , R 2b , R 3b , R 4b , and R 5b is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano, provided at least three of R la , R 2a , R 3a , R 4a , and R 5a are hydrogen and at least three of R lb , )cycloalkyl-Y; NHR 6 ;
  • R 6 is hydroxy(Ci-C6)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy; and
  • R 7 is hydrogen, halo, cyano, -(Ci-Ce)alkyl, or halo(Ci-C6)alkyl-.
  • each of R la , R 2a , R 3a , R 4a , R 5a , R lb , R 2b , R 3b , R 4b , and R 5b is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano, provided at least three of R la , R 2a , R 3a , R 4a , and R 5a are hydrogen and at least three of R lb , R 2b , R 3b , R 4b , and R 5b are hydrogen;
  • X 2 is -(Ci-Ce)alkyl-Y or -(C3-Ce)cycloalkyl-Y; Y is -CONHR 6 , -NHCOR 6 , or -NHR 6 ;
  • R 6 is hydroxy(Ci-Ce)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy; and
  • R 7 is hydrogen, halo, cyano, or halo(Ci-Ce)alkyl-.
  • the invention also relates to a compound of formula (III): or a pharmaceutically acceptable salt thereof, wherein: each of R la , R lb , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , and R 5b is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, -(Ci-Ce)alkoxy, halo(Ci- C 6 )alkyl-, halo(Ci-C 6 )alkoxy-, cyano, hydroxy, -COOR 8 , -CONR 9 R 10 , -SO 2 NR U R 12 , - SO2(Ci-Ce)alkyl, and -SO(Ci-Ce)alkyl, provided at least two of R la , R 2a , R 3a , R 4a , and R 5a are hydrogen and at least two of R lb
  • R 6 is -(Ci-C6)alkyl substituted by -CONH2, hydroxy(Ci-Ce) alkyl-, halo(Ci-Ce) alkyl- substituted by hydroxy, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy;
  • R 7 is hydrogen, halo, cyano, -(Ci-Ce)alkyl, or halo(Ci-Ce)alkyl-; and each of R 8 , R 9 , R 10 , R 11 , and R 12 is independently selected from the group consisting of hydrogen, -(Ci-Ce)alkyl, halo(Ci-Ce)alkyl-, and hydroxy(Ci-Ce)alkyl-.
  • each of R la , R 2a , R 3a , R 4a , R 5a , R lb , R 2b , R 3b , R 4b , and R 5b is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, -(Ci-Ce)alkoxy, halo(Ci-Ce)alkyl-, halo(Ci-Ce)alkoxy-, cyano, hydroxy, -COOR 8 , -CONR 9 R 10 , - SO 2 NR U R 12 , -SO 2 (Ci-C6)alkyl, and -SO(Ci-C 6 )alkyl, provided at least three of R la , R 2a , R 3a , R 4a , and R 5a are hydrogen and at least three of R lb , R 2b , R 3
  • each of R la , R 2a , R 3a , R 4a , R 5a , R lb , R 2b , R 3b , R 4b , and R 5b is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-Ce)alkyl-, and cyano, provided at least two of R la , R 2a , R 3a , R 4a , and R 5a are hydrogen and at least two of R lb , R 2b , R 3b , R 4b , and R 5b are hydrogen.
  • each of R la , R 2a , R 3a , R 4a , R 5a , R lb , R 2b , R 3b , R 4b , and R 5b is independently selected from the group consisting of hydrogen, -F, -Br, -Cl, methyl, -CHF2, -CF3, and cyano, provided at least two of R la , R 2a , R 3a , R 4a , and R 5a are hydrogen and at least two of R lb , R 2b , R 3b , R 4b , and R 5b are hydrogen.
  • each of R la , R 2a , R 3a , R 4a , R 5a , R lb , R 2b , R 3b , R 4b , and R 5b is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano, provided at least three of R la , R 2a , R 3a , R 4a , and R 5a are hydrogen and at least three of R lb , R 2b , R 3b , R 4b , and R 5b are hydrogen.
  • each of R la , R 2a , R 3a , R 4a , R 5a , R lb , R 2b , R 3b , R 4b , and R 5b is independently selected from the group consisting of F, -Br, -Cl, methyl, -CHF2, -CF3, and cyano, provided at least three of R la , R 2a , R 3a , R 4a , and R 5a are hydrogen and at least three of R lb , R 2b , R 3b , R 4b , and R 5b are hydrogen.
  • R 6 is hydroxy(Ci-Ce)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy.
  • R 6 is pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo, and hydroxy.
  • R 6 is ,
  • R 7 is hydrogen, halo, cyano, -(Ci-Ce)alkyl, or halo(Ci-C6)alkyl-. In another embodiment, R 7 is hydrogen, halo, cyano, methyl, or -CF3. In another embodiment, R 7 is hydrogen, -F, -I, -CN, methyl, or -CF3. In an embodiment of a compound of formula (III), or a pharmaceutically acceptable salt thereof, R 7 is hydrogen, halo, cyano, or halo(Ci-Ce)alkyl-. In another embodiment, R 7 is hydrogen, halo, cyano, or -CF3. In another embodiment, R 7 is hydrogen, -F, -I, -CN, or - CF 3 .
  • each of R 8 , R 9 , R 10 , R 11 , and R 12 is independently selected from the group consisting of hydrogen and -(Ci-Ce)alkyl.
  • each of R la , R 2a , R 3a , R 4a , R 5a , R lb , R 2b , R 3b , R 4b , and R 5b is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano, provided at least three of R la , R 2a , R 3a , R 4a , and R 5a are hydrogen and at least three of R lb , R 2b , R 3b , R 4b , and R 5b are hydrogen;
  • R 6 is hydroxy(Ci-C6)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy; and
  • R 7 is hydrogen, halo, cyano, -(Ci-Ce)alkyl, or halo(Ci-C6)alkyl-.
  • each of R la , R 2a , R 3a , R 4a , R 5a , R lb , R 2b , R 3b , R 4b , and R 5b is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano, provided at least three of R la , R 2a , R 3a , R 4a , and R 5a are hydrogen and at least three of R lb , R 2b , R 3b , R 4b , and R 5b are hydrogen;
  • R 6 is hydroxy(Ci-C6)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy; and
  • R 7 is hydrogen, halo, cyano, or halo(Ci-C6)alkyl-.
  • the invention also relates to a compound of formula (IV): or a pharmaceutically acceptable salt thereof, wherein: each of R 3a and R 3b is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano;
  • R 6 is hydroxy(Ci-C6)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy; and
  • R 7 is hydrogen, halo, cyano, -(Ci-Ce)alkyl, or halo(Ci-C6)alkyl-.
  • each of R 3a and R 3b is independently selected from the group consisting of hydrogen, -F, -Cl, and -CF3.
  • R 6 is pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy.
  • R 6 is pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo, and hydroxy.
  • R 6 is pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo, and hydroxy.
  • R 7 is hydrogen, halo, cyano, -(Ci-Ce)alkyl, or halo(Ci-C6)alkyl-. In another embodiment, R 7 is hydrogen, halo, cyano, methyl, or -CF3. In another embodiment, R 7 is hydrogen, -F, -I, -CN, methyl, or -CF3.
  • R 7 is hydrogen, halo, cyano, or halo(Ci-C6)alkyl-. In another embodiment, R 7 is hydrogen, halo, cyano, or -CF3. In another embodiment, R 7 is hydrogen, -F, -I, -CN, or - CF 3 .
  • the invention also relates to a compound of Formula (V): or a pharmaceutically acceptable salt thereof, wherein:
  • X la is halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, or cyano.
  • X 2 is -(Ci-Ce)alkyl-Y, -(C 2 -C6)alkenyl-Y, -(C 3 -C6)cycloalkyl-Y, -(C 6 - Cio)bicycloalkyl-Y, -(C3-C6)cycloalkyl-(Ci-Ce)alkyl-Y, -(Ci-C6)alkyl-(C3-C6)cycloalkyl- Y, -piperidinyl-Y, or -(Cs-C9)azabicycloalkyl-Y;
  • Y is -CONH2, -CONHR 6 , -NHCOR 6 , -NHR 6 , -OC(O)NHR 6 , or -NHC(O)OR 6 ; each of R la , R 2a , R 3a , R 4a , and R 5a is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, -(Ci-Ce)alkoxy, halo(Ci-C6)alkyl-, halo(Ci- C 6 )alkoxy-, cyano, hydroxy, -COOR 8 , -CONR 9 R 10 , -SO 2 NR U R 12 , -SO 2 (Ci-C 6 )alkyl, and - SO(Ci-Ce)alkyl, provided at least two of R la , R 2a , R 3a , R 4a , and R 5a are hydrogen;
  • R 6 is -(Ci-C6)alkyl, -(Ci-Ce)alkyl substituted by -CONH 2 , hydroxy(Ci-C6)alkyl-, halo(Ci-C6)alkyl- substituted by hydroxy, amino(Ci-C6)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, -(C3- Ce)cycloalkyl substituted by one, two, or three substituents independently selected from the group consisting of oxo, hydroxy, amino, hydroxy(Ci-Ce)alkyl-, and amino(Ci-C6)alkyl-, tetrahydrofuranyl substituted by one, two, or three substituents independently selected
  • R 7 is hydrogen, halo, cyano, -(Ci-Ce)alkyl, or halo(Ci-C6)alkyl-; each of R 8 , R 9 , R 10 , R 11 , and R 12 is independently selected from the group consisting of hydrogen, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl, and hydroxy(Ci-Ce)alkyl-; and n is 1, 2, 3, or 4.
  • X la is halo(Ci-Ce)alkyl-.
  • X la is -CF3.
  • each of R la , R 2a , R 3a , R 4a , and R 5a is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, -(Ci-Ce)alkoxy, halo(Ci-C6)alkyl-, halo(Ci- C 6 )alkoxy-, cyano, hydroxy, -COOR 8 , -CONR 9 R 10 , -SO 2 NR U R 12 , -SO 2 (Ci-C 6 )alkyl, and - SO(Ci-Ce)alkyl, provided at least three of R la , R 2a , R 3a , R 4a , and R 5a are hydrogen.
  • each of R la , R 2a , R 3a , R 4a , and R 5a is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano, provided at least two of R la , R 2a , R 3a , R 4a , and R 5a are hydrogen.
  • each of R la , R 2a , R 3a , R 4a , and R 5a is independently selected from the group consisting of hydrogen, -F, -Br, -Cl, methyl, -CHF 2 , -CF3, and cyano, provided at least two of R la , R 2a , R 3a , R 4a , and R 5a are hydrogen.
  • each of R la , R 2a , R 3a , R 4a , and R 5a is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano, provided at least three of R la , R 2a , R 3a , R 4a , and R 5a are hydrogen.
  • each of R la , R 2a , R 3a , R 4a , and R 5a is independently selected from the group consisting of F, -Br, -Cl, methyl, -CHF 2 , -CF3, and cyano, provided at least three of R la , R 2a , R 3a , R 4a , and R 5a are hydrogen.
  • X 2 is -(Ci-C6)alkyl-Y, -(C3-C6)cycloalkyl-Y, -(C3-C6)cycloalkyl-(Ci-C6)alkyl- Y, or -(Ci-C6)alkyl-(C3-C6)cycloalkyl-Y.
  • X 2 is -(Ci-Ce)alkyl-Y or -(C3-Ce)cycloalkyl-Y.
  • X 2 is -(C3-C6)cycloalkyl-Y.
  • X 2 is -(Ci-Ce)alkyl-Y. In another embodiment, X 2 is -(CH 2 ) 2 -Y or -(CH 2 )3- Y. In another embodiment, X 2 is -(CH 2 ) 2 -Y.
  • Y is -CONHR 6 , -NHCOR 6 , -NHR 6 , -OC(O)NHR 6 , or -NHC(O)OR 6 .
  • Y is -CONHR 6 , -NHCOR 6 , or -NHR 6 .
  • Y is - CONHR 6 or -NHCOR 6 .
  • Y is -CONHR 6 or -NHR 6 .
  • Y is -CONHR 6 .
  • R 6 is -(Ci-Ce)alkyl substituted by -CONH 2 , hydroxy(Ci-Ce)alkyl-, halo(Ci- Ce)alkyl- substituted by hydroxy, amino(Ci-C6)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, -(C Cr cycloalkyl substituted by one, two, or three substituents independently selected from the group consisting of oxo, hydroxy, amino, hydroxy(Ci-Ce)alkyl-, and amino(Ci-C6)alkyl-, tetrahydrofuranyl substituted by one, two,
  • R 6 is -(Ci-Ce)alkyl substituted by -CONH2, hydroxy(Ci-Ce)alkyl-, halo(Ci- Ce)alkyl- substituted by hydroxy, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, or -(C3-C6)cycloalkyl substituted by one, two, or three substituents independently selected from the group consisting of oxo, hydroxy, amino, hydroxy(Ci-Ce)alkyl-, and amino(Ci-C6)alkyl-.
  • R 6 is -(Ci- Ce)alkyl substituted by -CONH2, hydroxy(Ci-Ce)alkyl-, halo(Ci-Ce) alkyl- substituted by hydroxy, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy.
  • R 6 is hydroxy(Ci-Ce)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy.
  • R 6 is pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy.
  • R 6 is ,
  • X 2 is -(Ci-C6)alkyl-Y, -(C3-C6)cycloalkyl-Y, -(C3-C6)cycloalkyl-(Ci-C6)alkyl- Y, or -(Ci-C6)alkyl-(C 3 -C6)cycloalkyl-Y;
  • Y is -CONHR 6 , -NHCOR 6 , -NHR 6 , - OC(O)NHR 6 , or -NHC(O)OR 6 ;
  • R 6 is hydroxy(Ci-Ce) alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy.
  • X 2 is - (Ci-C 6 )alkyl-Y or -(C3-C 6 )cycloalkyl-Y; Y is -CONHR 6 , -NHCOR 6 , or -NHR 6 ; and R 6 is hydroxy(Ci-Ce)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy.
  • X 2 is -(Ci-C6)alkyl-Y or -(C3- Ce)cycloalkyl-Y; Y is -CONHR 6 , -NHCOR 6 , or -NHR 6 ; and R 6 is pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy.
  • X 2 is -(Ci-Ce)alkyl-Y or -(C3-Ce)cycloalkyl-Y; Y is -CONHR 6 or -NHR 6 ; and R 6 is pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy.
  • R 7 is hydrogen, halo, cyano, -(Ci-Ce)alkyl, or halo(Ci-Ce)alkyl-. In another embodiment, R 7 is hydrogen, halo, cyano, methyl, or -CF3. In another embodiment, R 7 is hydrogen, -F, -I, -CN, methyl, or -CF3. In another embodiment of a compound of formula (V), or a pharmaceutically acceptable salt thereof, R 7 is hydrogen, -F, or methyl. In another embodiment of a compound of formula (V), or a pharmaceutically acceptable salt thereof, R 7 is hydrogen.
  • R 7 is hydrogen, halo, cyano, or halo(Ci-Ce)alkyl-. In another embodiment, R 7 is hydrogen, halo, cyano, or -CF3. In another embodiment, R 7 is hydrogen, -F, -I, -CN, or - CF 3 .
  • each of R 8 , R 9 , R 10 , R 11 , and R 12 is independently selected from the group consisting of hydrogen and -(Ci-Ce)alkyl.
  • n is 1, 2, or 3. In another embodiment of a compound of formula (V), or a pharmaceutically acceptable salt thereof, n is 1 or 2. In another embodiment of a compound of formula (V), or a pharmaceutically acceptable salt thereof, n is 1. In another embodiment of a compound of formula (V), or a pharmaceutically acceptable salt thereof, n is 2. In an embodiment of a compound of formula (V), or a pharmaceutically acceptable salt thereof:
  • X la is halo(Ci-C 6 )alkyl-; each of R la , R 2a , R 3a , R 4a , and R 5a is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-Ce)alkyl-, and cyano, provided at least three of R la , R 2a , R 3a , R 4a , and R 5a are hydrogen;
  • X 2 is -(Ci-C6)alkyl-Y or -(C3-C6)cycloalkyl-Y;
  • Y is -CONHR 6 , -NHCOR 6 , or -NHR 6 ;
  • R 6 is hydroxy(Ci-C6)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy;
  • R 7 is hydrogen, halo, cyano, -(Ci-Ce)alkyl, or halo(Ci-C6)alkyl-; and n is 1, 2, or 3.
  • X la is -CF 3 ; each of R la , R 2a , R 3a , R 4a , and R 5a is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano, provided at least drogen; )cycloalkyl-Y; NHR 6 ;
  • R 6 is hydroxy(Ci-C6)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy; and
  • R 7 is hydrogen, halo, cyano, or halo(Ci-C6)alkyl-; and n is 1.
  • each of R la , R 2a , R 3a , R 4a , and R 5a is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, -(Ci-Ce)alkoxy, halo(Ci-C6)alkyl-, halo(Ci- C 6 )alkoxy-, cyano, hydroxy, -COOR 8 , -CONR 9 R 10 , -SO 2 NR U R 12 , -SO 2 (Ci-C 6 )alkyl, and - SO(Ci-Ce)alkyl, provided at least two of R la , R 2a , R 3a , R 4a , and R 5a are hydrogen;
  • R 6 is -(Ci-C6)alkyl substituted by -CONH 2 , hydroxy(Ci-Ce) alkyl-, halo(Ci-Ce) alkyl- substituted by hydroxy, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of halo, oxo, and hydroxy;
  • R 7 is hydrogen, halo, cyano, -(Ci-Ce)alkyl, or halo(Ci-C6)alkyl-; and each of R 8 , R 9 , R 10 , R 11 , and R 12 is independently selected from the group consisting of hydrogen, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and hydroxy(Ci-C6)alkyl-.
  • each of R la , R 2a , R 3a , R 4a , and R 5a is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, -(Ci-Ce)alkoxy, halo(Ci-C6)alkyl-, halo(Ci- C 6 )alkoxy-, cyano, hydroxy, -COOR 8 , -CONR 9 R 10 , -SO 2 NR U R 12 , -SO 2 (Ci-C 6 )alkyl, and - SO(Ci-Ce)alkyl, provided at least three of R la , R 2a , R 3a , R 4a , and R 5a are hydrogen.
  • each of R la , R 2a , R 3a , R 4a , and R 5a is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano, provided at least two of R la , R 2a , R 3a , R 4a , and R 5a are hydrogen.
  • each of R la , R 2a , R 3a , R 4a , and R 5a is independently selected from the group consisting of hydrogen, -F, -Br, -Cl, methyl, -CHF 2 , -CF3, and cyano, provided at least two of R la , R 2a , R 3a , R 4a , and R 5a are hydrogen.
  • each of R la , R 2a , R 3a , R 4a , and R 5a is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano, provided at least three of R la , R 2a , R 3a , R 4a , and R 5a are hydrogen.
  • each of R la , R 2a , R 3a , R 4a , and R 5a is independently selected from the group consisting of -F, -Br, -Cl, methyl, -CHF 2 , -CF3, and cyano, provided at least three of R la , R 2a , R 3a , R 4a , and R 5a are hydrogen.
  • each of R la , R 2a , R 4a , and R 5a is hydrogen and R 3a is hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci- Ce)alkyl-, or cyano.
  • each of R la , R 2a , R 4a , and R 5a is hydrogen and R 3a is halo or halo(Ci-C6)alkyl-.
  • each of R la , R 2a , R 4a , and R 5a is hydrogen and R 3a is -F, -Cl, or -CF3.
  • R 6 is hydroxy(Ci-Ce)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy.
  • R 6 is pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo, and hydroxy.
  • R 6 is ,
  • R 7 is hydrogen, halo, cyano, -(Ci-Ce)alkyl, or halo(Ci-C6)alkyl-. In another embodiment, R 7 is hydrogen, halo, cyano, methyl, or -CF3. In another embodiment, R 7 is hydrogen, -F, -I, -CN, methyl, or -CF3. In another embodiment of a compound of formula (VI), or a pharmaceutically acceptable salt thereof, R 7 is hydrogen, -F, or methyl. In another embodiment of a compound of formula (VI), or a pharmaceutically acceptable salt thereof, R 7 is hydrogen.
  • R 7 is hydrogen, halo, cyano, or halo(Ci-C6)alkyl-. In another embodiment, R 7 is hydrogen, halo, cyano, or -CF3. In another embodiment, R 7 is hydrogen, -F, -I, -CN, or - CF 3 .
  • each of R 8 , R 9 , R 10 , R 11 , and R 12 is independently selected from the group consisting of hydrogen and -(Ci-Ce)alkyl.
  • each of R la , R 2a , R 3a , R 4a , and R 5a is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-C6)alkyl-, and cyano, provided at least three of R la , R 2a , R 3a , R 4a , and R 5a are hydrogen;
  • R 6 is hydroxy(Ci-Ce)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy;
  • R 7 is hydrogen, halo, cyano, -(Ci-Ce)alkyl, or halo(Ci-Ce)alkyl-.
  • each of R la , R 2a , R 3a , R 4a , and R 5a is independently selected from the group consisting of hydrogen, halo, -(Ci-Ce)alkyl, halo(Ci-Ce)alkyl-, and cyano, provided at least three of R la , R 2a , R 3a , R 4a , and R 5a are hydrogen;
  • R 6 is hydroxy(Ci-Ce)alkyl-, pyrrolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy, or imidazolidinyl substituted by one, two, or three substituents independently selected from the group consisting of oxo and hydroxy; and R 7 is hydrogen, -F, or methyl.
  • the invention relates to a compound selected from the group consisting of:
  • the invention relates to a compound selected from the group consisting of:
  • the invention relates to a compound selected from the group consisting of: pharmaceutically acceptable salt thereof. In another embodiment, the invention relates to a compound selected from the or a pharmaceutically acceptable salt thereof.
  • references herein to a compound of formula (I), (II), (III), (IV), (V), or (VI) or a salt thereof includes a compound of formula (I), (II), (III), (IV), (V), or (VI) as a free base or acid, or as a salt thereof, for example as a pharmaceutically acceptable salt thereof.
  • the invention is directed to a compound of formula (I), (II), (III), (IV), (V), or (VI).
  • the invention is directed to a salt of a compound of formula (I), (II), (III), (IV), (V), or (VI).
  • the invention is directed to a pharmaceutically acceptable salt of a compound of formula (I), (II), (III), (IV), (V), or (VI).
  • the invention is directed to a compound of formula (I), (II), (III), (IV), (V), or (VI), or a salt thereof.
  • the invention is directed to a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof.
  • a salt of a compound of formula (I), (II), (III), (IV), (V), or (VI) is preferably pharmaceutically acceptable.
  • pharmaceutically acceptable refers to those compounds (including salts), materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively. Furthermore, pharmaceutically acceptable salts of the compound of formulas (I)-(VI) may be prepared during further processing of the free acid or base form, for example in situ during manufacture into a pharmaceutical formulation.
  • Pharmaceutically acceptable salts include, amongst others, those described in Berge, J. Pharm. Sci., 1977, 66, 1-19, or those listed in P H Stahl and C G Wermuth, editors, Handbook of Pharmaceutical Salts; Properties, Selection and Use, Second Edition Stahl/Wermuth: Wiley- VCH/VHCA, 2011.
  • Non-pharmaceutically acceptable salts may be used, for example as intermediates in the preparation of a compound of formula (I), (II), (III), (IV), (V), or (VI) or a pharmaceutically acceptable salt thereof.
  • Suitable pharmaceutically acceptable salts can include acid or base addition salts.
  • Such base addition salts can be formed by reaction of a compound of formula (I), (II), (III), (IV), (V), or (VI) (which, for example, contains a carboxylic acid or other acidic functional group) with the appropriate base, optionally in a suitable solvent such as an organic solvent, to give the salt which can be isolated by a variety of methods, including crystallisation and filtration.
  • Such acid addition salts can be formed by reaction of a compound of formula (I), (II), (III), (IV), (V), or (VI) (which, for example contains a basic amine or other basic functional group) with the appropriate acid, optionally in a suitable solvent such as an organic solvent, to give the salt which can be isolated by a variety of methods, including crystallization and filtration.
  • Salts may be prepared in situ during the final isolation and purification of a compound of formula (I), (II), (III), (IV), (V), or (VI). If a basic compound of formula (I),
  • salt formation may include 1, 2 or more equivalents of acid.
  • Such salts would contain 1, 2 or more acid counterions, for example, a dihydrochloride salt.
  • Representative pharmaceutically acceptable acid addition salts include, but are not limited to, 4-acetamidobenzoate, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate (besylate), benzoate, bisulfate, bitartrate, butyrate, calcium edetate, camphorate, camphorsulfonate (camsylate), caprate (decanoate), caproate (hexanoate), caprylate (octanoate), cinnamate, citrate, cyclamate, digluconate, 2,5-dihydroxybenzoate, disuccinate, dodecylsulfate (estolate), edetate (ethylenediaminetetraacetate), estolate (lauryl sulfate), ethane- 1 ,2-disulfonate (edisylate), ethanesulfonate (esylate), formate, fumarate, galacta
  • Representative pharmaceutically acceptable base addition salts include, but are not limited to, aluminium, 2-amino-2-(hydroxymethyl)-l,3-propanediol (TRIS, tromethamine), arginine, benethamine (N-benzylphenethylamine), benzathine (N,N’- dibenzylethylenediamine), bis-(2-hydroxyethyl)amine, bismuth, calcium, chloroprocaine, choline, clemizole (1-p chlorobenzyl-2-pyrrolildine-r-ylmethylbenzimidazole), cyclohexylamine, dibenzylethylenediamine, diethylamine, diethyltriamine, dimethylamine, dimethylethanolamine, dopamine, ethanolamine, ethylenediamine, L-histidine, iron, isoquinoline, lepidine, lithium, lysine, magnesium, meglumine (N-methylglucamine), piperazine, piperidine, potassium,
  • solvates complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as “solvates.” For example, a complex with water is known as a “hydrate.” Solvents with high boiling points and/or solvents with a high propensity to form hydrogen bonds such as water, ethanol, zTo-propyl alcohol, and /V-mcthyl pyrrolidinone may be used to form solvates. Methods for the identification of solvates include, but are not limited to, NMR and microanalysis. Compounds of formula (I), (II), (III), (IV), (V), or (VI), or salts thereof, may exist in solvated and unsolvated form.
  • the compounds of the invention may be in crystalline or amorphous form.
  • the most thermodynamically stable crystalline form of a compound of the invention is of particular interest.
  • Crystalline forms of compounds of the invention may be characterized and differentiated using a number of conventional analytical techniques, including, but not limited to, X-ray powder diffraction (XRPD), infrared spectroscopy (IR), Raman spectroscopy, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and solid-state nuclear magnetic resonance (ssNMR).
  • XRPD X-ray powder diffraction
  • IR infrared spectroscopy
  • Raman spectroscopy Raman spectroscopy
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • ssNMR solid-state nuclear magnetic resonance
  • the compounds of formula (I), (II), (III), (IV), (V), or (VI), and pharmaceutically acceptable salts thereof may contain one or more asymmetric center (also referred to as a chiral center) and may, therefore, exist as individual enantiomers, diastereomers, or other stereoisomeric forms, or as mixtures thereof.
  • Chiral centers, such as chiral carbon atoms may also be present in a substituent such as an alkyl group.
  • the stereochemistry of a chiral center present in a compound of formula (I), (II), (III), (IV), (V), or (VI) or in any chemical structure illustrated herein is not specified the structure is intended to encompass all individual stereoisomers and all mixtures thereof.
  • compounds of formula (I), (II), (III), (IV), (V), or (VI) and pharmaceutically acceptable salts thereof containing one or more chiral centers may be used as racemic mixtures, enantiomerically enriched mixtures, or as enantiomerically pure individual stereoisomers.
  • stereoisomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.
  • the invention also includes all suitable isotopic variations of a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof.
  • An isotopic variation of a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 0, 18 O, 18 F and 36 C1, respectively.
  • isotopic variations of a compound of formula (I), (II), (III), (IV), (V), or (VI) or a salt or solvate thereof, for example, those in which a radioactive isotope such as 3 H or 14 C is incorporated, are useful in drug and/or substrate tissue distribution studies. Tritiated, i.e., 3 H, and carbon- 14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with 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.
  • Isotopic variations of a compound of formula (I), (II), (III), (IV), (V), or (VI) or a pharmaceutically salt thereof can generally be prepared by conventional procedures such as by the illustrative methods or by the preparations described in the Examples hereafter using appropriate isotopic variations of suitable reagents.
  • the invention in another aspect, relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), (II), (III), (IV), (V), or (VI) or a pharmaceutically acceptable salt thereof, according to any one of the embodiments disclosed herein, and a pharmaceutically acceptable excipient (also referred to as carriers and/or diluents in the pharmaceutical arts).
  • the excipients are acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof (i.e., the patient).
  • Suitable pharmaceutically acceptable excipients will vary depending upon the particular dosage form chosen.
  • suitable pharmaceutically acceptable excipients may be chosen for a particular function that they may serve in the composition.
  • certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms.
  • Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms.
  • Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the carrying or transporting of the compound or compounds of the invention once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body.
  • Certain pharmaceutically acceptable excipients may be chosen for their ability to enhance patient compliance.
  • Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, hemectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents.
  • excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation.
  • Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically acceptable excipients in appropriate amounts for use in the invention.
  • resources that are available to the skilled artisan which describe pharmaceutically acceptable excipients and may be useful in selecting suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).
  • compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).
  • compositions may be in unit dose form containing a predetermined amount of active ingredient per unit dose.
  • a unit may contain a therapeutically effective dose of the compound of formula (I), (II), (III), (IV), (V), or (VI), or salt thereof or a fraction of a therapeutically effective dose such that multiple unit dosage forms might be administered at a given time to achieve the desired therapeutically effective dose.
  • Preferred unit dosage formulations are those containing a daily dose or sub-dose, as described herein, or an appropriate fraction thereof, of an active ingredient.
  • such pharmaceutical compositions may be prepared by any of the methods well-known in the pharmacy art.
  • compositions may be adapted for administration by any appropriate route, for example, by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual, or transdermal), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal) routes.
  • oral including buccal or sublingual
  • rectal nasal
  • topical including buccal, sublingual, or transdermal
  • vaginal or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal) routes.
  • parenteral including subcutaneous, intramuscular, intravenous, or intradermal
  • compositions When adapted for oral administration, pharmaceutical compositions may be in discrete units such as tablets or capsules; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; oil-in-water liquid emulsions or water-in-oil liquid emulsions.
  • the compound or salt thereof of the invention or the pharmaceutical composition of the invention may also be incorporated into a candy, a wafer, and/or tongue tape formulation for administration as a “quick-dissolve” medicine.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • Powders or granules are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing, and coloring agents can also be present.
  • Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin or non-gelatinous sheaths.
  • Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, solid polyethylene glycol can be added to the powder mixture before the filling operation.
  • a disintegrating or solubilizing agent such as agar-agar, calcium carbonate, or sodium carbonate can also be added to improve the availability of the medicine when the capsule is ingested.
  • suitable binders include starch, gelatin, natural sugars, such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrators include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum, and the like.
  • Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and pressing into tablets.
  • a powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, and aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt, and/or an absorption agent such as bentonite, kaolin, or dicalcium phosphate.
  • a binder such as carboxymethylcellulose, and aliginate, gelatin, or polyvinyl pyrrolidone
  • a solution retardant such as paraffin
  • a resorption accelerator such as a quaternary salt
  • an absorption agent such as bentonite, kaolin, or dicalcium phosphate.
  • the powder mixture can be granulated by wetting a binder such as syrup, starch paste, acadia mucilage, or solutions of cellulosic or polymeric materials and forcing through a screen.
  • a binder such as syrup, starch paste, acadia mucilage, or solutions of cellulosic or polymeric materials
  • the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules.
  • the granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc, or mineral oil. The lubricated mixture is then compressed into tablets.
  • the compound or salt of the present invention can also be combined with a free-flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps.
  • a clear opaque protective coating consisting of a sealing coat of shellac, a coating of sugar, or polymeric material, and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different dosages.
  • Oral fluids such as solutions, syrups, and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of active ingredient.
  • Syrups can be prepared by dissolving the compound or salt thereof of the invention in a suitably flavoured aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle.
  • Suspensions can be formulated by dispersing the compound or salt of the invention in a non-toxic vehicle.
  • Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavor additives such as peppermint oil, natural sweeteners, saccharin, or other artificial sweeteners, and the like, can also be added.
  • dosage unit formulations for oral administration can be microencapsulated.
  • the formulation can also be prepared to prolong or sustain the release as, for example, by coating or embedding particulate material in polymers, wax, or the like.
  • a pharmaceutical composition is a tablet or capsule for oral delivery.
  • compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the pharmaceutical compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • compositions may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • Pharmaceutical compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Such a unit may contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, more preferably 5 mg to 100 mg of a compound of formula (I), (II), (III), (IV), (V), or (VI) depending on the condition being treated, the route of administration and the age, weight and condition of the patient, or pharmaceutical compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose.
  • Preferred unit dosage compositions are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
  • such pharmaceutical compositions may be prepared by any of the methods well known in the pharmacy art.
  • a therapeutically effective amount of a compound as defined herein will depend upon a number of factors including, for example, the age and weight of the intended recipient, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration, and will ultimately be at the discretion of the attendant prescribing the medication.
  • an effective amount of a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof of the invention for the treatment of kidney diseases will generally be in the range of 0.001 to 100 mg/kg body weight of recipient per day, suitably in the range of 0.01 to 10 mg/kg body weight per day.
  • the actual amount per day would suitably be from 7 to 700 mg and this amount may be given in a single dose per day or in a number (such as two, three, four, five or six) of sub-doses per day such that the total daily dose is the same.
  • Inhaled daily dosages range from 10 pg - 10 mg/day, with preferred 10 pg - 2 mg/day, and more preferred 50 pg - 500 pg/day.
  • An effective amount of a salt or solvate, etc. may be determined as a proportion of the effective amount of the compound of formula (I), (II), (III), (IV), (V), or (VI) per se. It is envisaged that similar dosages would be appropriate for treatment of the other conditions referred to above.
  • a process for the preparation of a pharmaceutical composition comprising mixing (or admixing) a compound of formula (I), (II), (III), (IV), (V), or (VI) or salt thereof (e.g., pharmaceutically acceptable salt thereof) with at least one excipient.
  • the invention also provides a method of treatment in a subject, especially a human.
  • Disease states which can be treated by the methods and compositions provided herein include, but are not limited to, kidney diseases associated with AP0L1, for example, chronic kidney disease (CKD), end-stage kidney disease (ESKD), non-diabetic kidney disease (NDKD), focal segmental glomerulosclerosis (FSGS), Human Immunodeficiency Virus (HlV)-associated nephropathy (a distinct form of FSGS, also termed collapsing glomerulopathy), diabetic nephropathy, hypertensive nephrosclerosis, lupus nephritis, arterionephrosclerosis, microalbuminuria, diabetic nephropathy, IgA nephropathy, transplant nephropathy, autoimmune nephropathy, drug-induced nephropathy, and hypertension-related nephropathy.
  • kidney diseases associated with AP0L1 for example,
  • kidney disease(s) associated with AP0F1 refers to a disease or condition that impairs kidney function and can be attributed to AP0F1.
  • a kidney disease associated with AP0F1 can be found in patients having two AP0F1 risk alleles (i.e., homozygous or heterozygous for the G1 or G2 alleles).
  • the kidney disease associated with AP0F1 includes, but is not limited to, CKD, ESKD, NDKD, FSGS, HIV-associated nephropathy, arterionephrosclerosis, lupus nephritis, and microalbuminuria.
  • treatment refers to alleviating the specified condition, eliminating or reducing one or more symptoms of the condition, slowing or eliminating the progression of the condition, and delaying the reoccurrence of the condition in a previously afflicted patient or subject.
  • terapéuticaally effective amount refers to the quantity of a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, which will elicit the desired biological response in the human body. It may vary depending on the compound, the disease and its severity, and the age and weight of the subject to be treated.
  • subject refers to a human body.
  • the invention provides a method of treatment of a kidney disease or sepsis comprising administering to a human in need thereof a therapeutically effective amount of a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, according to any one of the embodiments disclosed herein, or a pharmaceutical composition disclosed herein.
  • the invention provides a method of treatment of a kidney disease.
  • the invention provides a method of treatment of sepsis.
  • the invention provides a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, according to any one of the embodiments disclosed herein, or a pharmaceutical composition disclosed herein for use in the treatment of a kidney disease or sepsis.
  • a compound or pharmaceutical composition according to any one of the embodiments disclosed herein for use in the treatment of sepsis is provided.
  • the invention provides use of a compound of formula (I), (II), (III), (IV), (V), or (VI) or a pharmaceutically acceptable salt thereof, according to any one of the embodiments disclosed herein, or a pharmaceutical composition disclosed herein, in the manufacture of a medicament for the treatment of a kidney disease or sepsis.
  • a compound or pharmaceutical composition according to any one of the embodiments disclosed herein in the manufacture of a medicament for the treatment of a kidney disease in one embodiment, provided is use of a compound or pharmaceutical composition according to any one of the embodiments disclosed herein in the manufacture of a medicament for the treatment of sepsis.
  • the kidney disease includes, but is not limited to, chronic kidney disease (CKD), end-stage kidney disease (ESKD), non-diabetic kidney disease (NDKD), focal segmental glomerulosclerosis (FSGS), human immunodeficiency virus- associated nephropathy (HIV AN), diabetic kidney disease (also called diabetic nephropathy), hypertensive nephrosclerosis, arterionephrosclerosis, lupus nephritis, proteinuria, microalbuminuria and sickle cell nephropathy.
  • CKD chronic kidney disease
  • EKD end-stage kidney disease
  • NKD non-diabetic kidney disease
  • FGS focal segmental glomerulosclerosis
  • HAV AN human immunodeficiency virus- associated nephropathy
  • diabetic kidney disease also called diabetic nephropathy
  • hypertensive nephrosclerosis arterionephrosclerosis
  • lupus nephritis proteinuri
  • the kidney disease includes, but is not limited to, chronic kidney disease (CKD), end-stage kidney disease (ESKD), non-diabetic kidney disease (NDKD), focal segmental glomerulosclerosis (FSGS), and human immunodeficiency virus-associated nephropathy (HIV AN).
  • the kidney disease includes, but is not limited to, chronic kidney disease, diabetic kidney disease (diabetic nephropathy), hypertensive nephrosclerosis, arterionephrosclerosis, lupus nephritis, proteinuria, and microalbuminuria.
  • the kidney disease includes diabetic kidney disease (diabetic nephropathy).
  • the kidney disease includes FSGS.
  • the kidney disease includes FSGS, wherein the FSGS is primary FSGS, virus-associated FSGS, or drug-associated FSGS.
  • Combination therapies according to the invention comprise the administration of at least one compound of the invention and the use of at least one other treatment method, including administration of one or more other therapeutic agents.
  • co-administration refers to either simultaneous administration or any manner of separate sequential administration of an AP0L1 inhibiting compound of the invention, as described herein, and a further active ingredient or ingredients.
  • further active ingredient or ingredients includes any compound or therapeutic agent known to or that demonstrates advantageous properties when administered to a patient in need of treatment.
  • the compounds are administered in a close time proximity to each other.
  • the compounds may be administered in the same or separate dosage form, e.g., one compound may be administered orally and another compound may be administered intravenously.
  • therapeutic agents which may be used in combination with a compound of the invention include, but are not limited to, antigen immunotherapy, anti-histamines, corticosteroids (e.g., fluticasone propionate, fluticasone furoate, beclomethasone dipropionate, budesonide, ciclesonide, mometasone furoate, triamcinolone, flunisolide), mineralocorticoid receptor antagonists e.g., spironolactone, epleronone, canrenone), sodium-glucose transport protein 2 (SGLT2) inhibitors (e.g., canagliflozin, dapagliflozin, empagliflozin, ertugliflozin), angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, NSAIDs, leukotriene modulators (e.g., montelukast, zafirlukast, pr
  • Preparative HPLC was performed using a Gilson Preparative System with variable wavelength UV detection or an Agilent Mass Directed AutoPrep (MDAP) system with both mass and variable wavelength UV detection or Waters Preparative System with UV / PDA detection or a Shimadzu PREP LC 20AP.
  • MDAP Agilent Mass Directed AutoPrep
  • a variety of reverse phase columns, e.g., Luna 5m Cl 8(2) 100A, SunFire Cl 8, XBridge Cl 8, Atlantics T3 were used in the purification with the choice of column support dependent upon the conditions used in the purification.
  • the compounds are eluted using a gradient of CH3CN and water.
  • Neutral conditions used an CH3CN and water gradient with no additional modifier
  • acidic conditions used an acid modifier, 0.1% TFA (added to both the CH3CN and water) or 0.1 % formic acid
  • basic conditions used a basic modifier, 0.1% NH4OH (added to the water) or 10 mM ammonium bicarbonate.
  • LC-MS was determined using either a PE Sciex Single Quadrupole 150EX LC-MS, or Waters ZQ Single Quadrupole LC-MS or Agilent 1200 series SL (detectors: Agilent 6140 single quadrupole and Agilent 1200 MWD SL) instruments.
  • the compound is analyzed using a reverse phase column, e.g., Thermo Hypersil Gold C18, eluted using a gradient of CH3CN and water with a low percentage of an acid modifier such as 0.02% TFA or 0.1 % formic acid or a base modifier such as 5mM ammonium bicarbonate (adjusted to pH 10 with aqueous ammonia).
  • an acid modifier such as 0.02% TFA or 0.1 % formic acid or a base modifier such as 5mM ammonium bicarbonate (adjusted to pH 10 with aqueous ammonia).
  • base modifier such as 5mM ammonium bicarbonate
  • Preparative Chiral SFC was performed using a Thar/W aters Preparative SFC System with single wavelength UV detection system or PDA detector.
  • a variety of chiral SFC columns e.g. Chiralpak IA, IC, AY, AD. OD, OJ, C2 were used in the purification.
  • the compounds are eluted using supercritical fluid CO2 and co-solvents, such as MeOH, EtOH, IP A, and combination of these solvent in different ratio based on the compound selectivity. Modifiers (0.1 % of TFA, NH4OH, DEA) would be used as needed.
  • Analytical Chiral SFC was run using a Thar/W aters SFC system with variable wavelength UV detection or PDA detector.
  • a variety of chiral SFC columns e.g. Chiralpak IA, IB, IC, ID, AY, AD, AS, CCL4 were used in the purification.
  • the compounds are eluted using supercritical fluid CO2 and co-solvents, such as MeOH, EtOH, IPA, and combination of these solvent in different ratio based on the compound selectivity. Modifiers (0.1 % of TFA, NH4OH, DEA) would be used as needed.
  • Celite® is a filter aid composed of acid-washed diatomaceous silica, and is a registered trademark of Manville Corp., Denver, Colorado.
  • Isolute® is a functionalized silica gel based sorbent, and is a registered trademark of Biotage AB Corp., Sweden.
  • Nuclear magnetic resonance spectra were recorded at 400 MHz using a Bruker AVANCE 400 or Brucker DPX400 or Varian MR400 400 MHz spectrometer.
  • CDCh is deuteriochloroform
  • DMSO-De is hexadeuteriodimethylsulfoxide
  • MeOD is tetradeuteriomethanol
  • CD2CI2 is deuteriodichloromethane. Chemical shifts are reported in parts per million (5) downfield from the internal standard tetramethylsilane (TMS) or calibrated to the residual proton signal in the NMR solvent (e.g., CHCh in
  • Heating of reaction mixtures with microwave irradiations was carried out on a Biotage Initiator® or CEM microwave reactor, typically employing the high absorbance setting.
  • Cartridges or columns containing polymer based functional groups can be used as part of compound workup.
  • the "amine” columns or cartridges are used to neutralize or basify acidic reaction mixtures or products. These include NH2 Aminopropyl SPE-ed SPE Cartridges available from Applied Separations and diethylamino SPE cartridges available from United Chemical Technologies, Inc.
  • Nebulizer Pressure 60 psig
  • Nebulizer Pressure 60 psig
  • Step 2 Methyl (S)-2-(((benzyloxy)carbonyl)amino)but-3-enoate
  • Step 5 Benzyl ((3S,4 ⁇ )-4-hydroxy-2-oxopyrrolidin-3-yl)carbamate
  • Step 6 (3.S,4/?)-3-Ainiiio-4-liydroxypyrrolidin-2-one
  • Step 4 benzyl (E)-3-(2,5-bis(4-fluorophenyl)-lH-pyrrol-3-yl)acrylate
  • Step 6 3-(2,5-bis(4-fluorophenyl)-lH-pyrrol-3-yl)-N-((3S,4R)-4-hydroxy-2- oxopyrrolidin-3-yl)propanamide
  • Step 1 l,4-bis(4-(trifluoromethyl)phenyl)butane-l, 4-dione
  • Step 3 5-((2,5-bis(4-(trifluoromethyl)phenyl)-lH-pyrrol-3-yl)methyl)-2,2-dimethyl- l,3-dioxane-4, 6-dione
  • Step 4 3-(2,5-bis(4-(trifluoromethyl)phenyl)-lH-pyrrol-3-yl)-N-((3S,4R)-4-hydroxy-2- oxopyrroIidin-3-yI)propanamide and 3-(2,5-bis(4-(trifluoromethyl)phenyl)-lH-pyrrol- 3-yl)propanoic acid
  • Step 1 3-iodo-2,5-diphenyl-lH-pyrrole To a solution of 2,5-diphenyl-lH-pyrrole (923 mg, 4.17 mmol) in N,N-
  • Step 3 ethyl 3-(2,5-diphenyl-lH-pyrrol-3-yl)propanoate
  • Step 4 ethyl 3-(4-iodo-2,5-diphenyl-lH-pyrrol-3-yl)propanoate
  • Step 6 N-((3S,4R)-4-hydroxy-2-oxopyrrolidin-3-yl)-3-(4-iodo-2,5-diphenyl-lH- pyrrol-3-yl)propanamide
  • 3-(4-iodo-2,5-diphenyl-lH-pyrrol-3-yl)propanoic acid 192 mg, 0.446 mmol
  • triethylamine 0.249 mL, 1.785 mmol
  • DMF N,N-Dimethylformamide
  • DMTMMT 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholin-4-ium tetrafluoroborate
  • the combined organic extract was washed with 5% LiCl, brine twice, dried over Na2SC>4, filtered and concentrated under vacuum on added, and the mixture was filtered through a pad of Celite. The filtrate was transferred to a separatory funnel. The organic layer was separated, and the aqueous layer was further extracted with EtOAc (20 mL). The combined organic extract was washed with 5% LiCl, brine twice, dried over Na2SC>4, filtered and concentrated under vacuum on rotavap to give a brown viscous oil, which was purified by silica gel chromatography (0% to 10% MeOH:DCM) to give the title compound as a brown solid (21.2 mg, 30 % yield).
  • Step 4 3-(2,5-diphenyl-4-(trifluoromethyl)-lH-pyrrol-3-yl)propanoic acid
  • Step 6 3-(2,5-diphenyl-4-(trifluoromethyl)-lH-pyrrol-3-yl)-N-((3S,4R)-4-hydroxy-2- oxopyrrolidin-3-yl)propanamide
  • ETHYLACETATE SOLVATE
  • DMMF N,N-Dimethylformamide
  • DMTMMT 4-(4,6- dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholin-4-ium tetrafluoroborate
  • Step 3 5-((2-(4-fluorophenyl)-5-(4-(trifluoromethyl)phenyl)-lH-pyrrol-3-yl)methyl)- 2,2
  • Step 4 3-(5-(4-fluorophenyl)-2-(4-(trifluoromethyl)phenyl)-lH-pyrrol-3-yl)-N- ((3S,4R)-4-hydroxy-2-oxopyrroIidin-3-yI)propanamide and 3-(2-(4-fluorophenyl)-5- (4-(trifluoromethyl)phenyl)-lH-pyrrol-3-yl)-N-((3S,4R)-4-hydroxy-2-oxopyrrolidin-3-
  • Step 1 2,5-bis(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrrole
  • IH-pyrrole (0.25 g, 3.73 mmol)
  • fhpim 0.46 g, 3.73 mmol
  • [Ir (cod) OMe]2 0.037 g, 0.056 mmol
  • 4, 4'-di-tert-butyl-2, 2'-dipyridyl 0.035 g, 0.130 mmol
  • THF tetrahydrofuran
  • Step 4 3-(2,5-bis(4-(difluoromethyl)phenyl)-lH-pyrrol-3-yl)-N-((3S,4R)-4-hydroxy-2- oxopyrrolidin-3-yl)propanamide
  • NMP N- methyl-2-pyrrolidone
  • Step 2 tert -Butyl 2-(4-fluorophenyl)-4-(3-methoxy-3-oxopropyl)-lH-pyrrole-l- carboxylate
  • Step 4 tert -Butyl 2-(4-fluorophenyl)-4-(3-(((3S,4R)-4-hydroxy-2-oxopyrrolidin-3- yl)amino)-3-oxopropyl)-lH-pyrrole-l-carboxylate
  • 3-(l-(tert-butoxycarbonyl)-5-(4-fluorophenyl)-lH-pyrrol-3-yl)propanoic acid (5.55 g, 13.32 mmol)
  • (3S,4R)-3-amino-4-hydroxypyrrolidin-2-one hydrochloride (3.05 g, 19.98 mmol)
  • 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholin-4-ium tetrafluoroborate (DMTMMT) (6.55 g, 19.98 mmol) and TEA (8.35 ml, 59.9 mmol) in N
  • Step 6 tert- Butyl 5-(4-fluorophenyl)-3-(3-(((3S,4R)-4-hydroxy-2-oxopyrrolidin-3- yl)amino)-3-oxopropyl)-2-(p-tolyl)-lH-pyrrole-l-carboxylate
  • Step 1 ethyl 3-(2,5-bis(4-fluorophenyl)-17Z-pyrrol-3-yl)propanoate
  • a solution of (3-(2,5-bis(4-fluorophenyl)-177-pyrrol-3-yl)propanoic acid) (3 g, 9.17 mmol) and H2SO4 (0.049 mL, 0.917 mmol) in ethanol (61 mL) was heated at 70 °C for 3 h. The reaction was concentrated in vacuo. The residue was diluted with EtOAc (125 mL), and the mixture was washed with saturated NaHCCL (50 mL), then saturated NaCl (10 mL).
  • Step 1 2,5-bis(4-fluorophenyl)-1H-pyrrole
  • 4-(4-fluoro 2.258 mmol), (4- fluorophenyl)boronic acid (632 mg, 4.52 mmol), and zinc chloride (615 mg, 4.52 mmol) in THF (15 mL) was bubbled by nitrogen for 5 min before the addition of Ni(dppe)Cl 2 (120 mg, 0.226 mmol).
  • the reaction mixture was stirred at 100 °C overnight.
  • the mixture was diluted with EtOAc and washed with NaHCO 3 and brine.
  • the organic layer was dried (MgSO4), filtered, and concentrated in vacuo.
  • Step 2 3-(2,5-bis(4-fluorophenyl )-l/7-pyrrol-3-yl)cyclobutane-l-carboxylic acid
  • Step 3 3-(2,5-bis(4-fluorophenyl)-l/7-pyrrol-3-yl)-iV-((3/f,4S)-4-hydroxy-2- oxopyrrolidin-3-yl)cyclobutane-l-carboxamide
  • 3-(2,5-bis(4-fluorophenyl)-177-pyrrol-3-yl)cyclobutane-l -carboxylic acid 200 mg, 0.566 mmol
  • 2-chloro-4,6-dimethoxy-l,3,5-triazine 119 mg, 0.679 mmol
  • DMF 5 mL
  • /V-mcthylmorpholinc (0.187 mL, 1.698 mmol
  • (32?,4S)-3- amino-4-hydroxypyrrolidin-2-one hydrochloride (104 mg, 0.679 mmol).
  • the reaction mixture was stirred at rt for 1 h.
  • the crude product mixture was purified by MDAP system, using XS ELECT CSH Cl 8 column (150 mm X 30 mm i.d. 5 pm packing diameter at ambient temperature), eluting with 30-85% McCN/lLO/O.1 % formic acid, to provide the title compound (160 mg, 63%).
  • LCMS (ES) m/z 452 [M+H] + .
  • Step 4 ( ls,3.S)-3-(2,5-bis(4-fluoroplieiiyl)-l//-pyrrol-3-yl)-A-((3/?,4.S)-4-hydro ⁇ y-2- oxopyrrolidin-3-yl)cyclobutane-l-carboxamide
  • Step 2 3-(2,5-bis(4-fluorophenyl)-lH-pyrrol-3-yl)-N-((3R,4S)-4-hydroxy-2- oxopyrrolidin-3-yl)propanamide
  • the crude material was purified on MDAP HPLC (Phenomenex Gemini C 18, 50 x 30 mm, 5um column, 25-65% gradient acetonitrile/water with 0.1% formic Acid, 40 mL/min flow rate, 22 min run time).
  • Example 39 was purified on a Teledyne ISCO ACCQPrep HP150 HPLC (CSH XSelect column, 30 x 75 mm, 5 um) 40-70% gradient acetonitrile/water with 0.1% formic Acid, 45 mL/min flow rate, 10 min run time).
  • Title compound resulted as a white solid (31.7 mg, 0.078 mmol, 33.4 % yield).
  • Example 49 was purified on a Teledyne ISCO ACCQPrep HP150 HPLC, XBridge (30 x 75 mm, 5 um column), 30-60% gradient, acetonitrile/ lOmM
  • the reaction was heated to 60 °C and stirred overnight. Upon completion, the reaction mixture was cooled to 20 °C, and the solvent was swapped to DCM (250 mL, 5 V). Then water (250 mL, 5 vol) was added. The mixture was stirred for 10 min. Stirring was stopped, and the layers were allowed to separate. The DCM layer was collected, and the remaining aqueous layer was extracted with additional DCM (250 mL, 5 V). The combined DCM layers were dried over anhydrous MgSCL. concentrated, reconstituted in 500 mL DCM, then and charged back into the cleaned OptiMax reactor. The temperature was adjusted to 10 °C.
  • a NaHCCh solution 250 mL, 5 V, 10wt% aqueous was charged to the reactor, and the mixture was stirred for 30 minutes at 25 °C. The aqueous layer was removed, and the organic layer was dried over anhydrous MgSCL, filtered, and concentrated to dryness. The resulting off-white solid was redissolved in hot EtOH (500 mL, 10 V) at 80 °C. Upon clarifying, the solution was held at 80 °C for 30 minutes and then cooled to 20 °C over 3 hours. The mixture was aged overnight.
  • the resulting white solids were collected via filtration and washed with EtOH (2 X 100 mL, 2 V). The solids were dried in a vacuum oven overnight.
  • the title compound was oxopentanoate (50 g, 208.9 mmol, 1 equiv) and acetonitrile (400 mL, 8 V). Then sodium iodide (47.184 g, 314.8 mmol, 1.5 equiv) was charged to the reactor, and the mixture was stirred for approximately 15 minutes until all of the sodium iodide dissolved.
  • Triethylamine (31.854 g, 43.876 mL, 314.8 mmol, 1.5 equiv) was added next followed by chlorotrimethylsilane (34.198 g, 39.951 mL, 314.8 mmol, 1.5 equiv). The reaction was stirred at 25 °C overnight.
  • the reaction mixture was cooled to room temperature, and the solvent was swapped to EtOAc (100 mL, 10 V). Then a K2CO3 solution (100 mL, 10 V, 20 wt% aqueous) was charged, and the mixture was stirred at 300 RPM for 15 min. Stirring was stopped, and the layers were allowed to separate for 15 min. The top organic layer was a clear orange solution, and the bottom aqueous layer was dark red slurry. The organic layer solvent was swapped from EtOAc to THF (37.5mL, 5 V) and used directly in the hydrolysis.
  • the mixture was stirred for 15 min at 250 RPM and then held for 10 minutes for layer separation.
  • the aqueous layer was removed.
  • Additional TBME 56 mL, 7.5V was added, and the organic layer was washed sequentially with NH4CI (75 mL, 10 V, 20wt% aqueous), NH4CI (2 X 75 mL, 10 V, 5wt% aqueous), and NaHSCL (75 mL, 10 V, 1 M aqueous).
  • the organic layer was azeotroped dry twice with TBME.
  • the resulting oil was diluted with TBME (75 mL, 10V).
  • Step 4 3-(2,5-Bis(4-fluorophenvI)-4-methvI-lH-pyrroI-3-vI)-N-((3S,4R)-4-hydroxy-2- oxopyrrolidin-3-yl)propanamide
  • reaction mixture was stirred at 200RPM, and then /V-Ethyldiisopropylamiiic (1.607 g, 2.172 mL, 0.74 g/mL, 12.436 mmol, 1.3 equiv) was charged.
  • the reaction was heated to 60 °C and stirred at 250RPM for 16 hours.
  • Step 1 l-(4-Fluorophenyl)-4-(2,4,6-trifluorophenyl)butane-l,4-dione
  • Step 2 2-(4-Fhioroplieiiyl)-5-(2,4,6-trifhioroi)henyl )-!//- pyrrole l-(4-Fluorophenyl)-4-(2, 4, 6-trifluorophenyl)butane- 1,4-dione (5 g, 16.1 mmol, 1 equiv), ammonium acetate (2.46 g, 32.2 mmol, 2 eq.) and IPA (25 mL, 5 vol.) were charged to a 100 mL EasyMax reactor. The reaction mixture was heated to 95 °C for 18 h.
  • Step 5 3-(2-(4-Fluorophenyl)-5-(2,4,6-trifluorophenyl)-1H-pyrrol-3-yl)-N-((3S,4R)-4- hydroxy-2-oxopyrrolidin-3-yl)propanamide
  • 3-(2-(4-fluo 1H-pyrrol-3-yl)propanoic acid (33.3 g, 1 equiv, 91.6 mmol)
  • (3S,4R)-3-amino-4-hydroxypyrrolidin-2-one Hydrochloride (15.5 g, 1.1 equiv, 101.3 mmol) and DIPEA (29.7 g, 40.0 mL, 2.5 equiv, 230 mmol) in DCM (600 mL) under nitrogen was treated with DMTMMT (33.1 g, 1.1 equiv, 101.0 mmol).
  • Step 1 3-[Methoxy(methyl)amino]-l-[l-(trifluoromethyl)cyclopropyl]propan-l-one
  • N-methoxy-N-methyl-1- (trifluoromethyl)cyclopropane-l -carboxamide 10 g, 50.721 mmol, 1.0 equiv
  • THF 100 mL, 10 V
  • the solution was cooled to -20 °C.
  • a vinylmagnesium bromide solution in THF 76.1 mL, 76.1 mmol, 1 M, 1.5 equiv
  • the reaction was warmed to 25 °C over 1 hour and stirred for 30 minutes at this temperature.
  • reaction mixture was cooled to 10 °C and slowly quenched with water (50 mL, 5 V). Brine (50 mL, 5 V) was added. The mixture was stirred for 10 minutes and then allowed to separate. The aqueous layer was removed and back extracted with THF (50 mL, 5 V). The combined organic extracts were dried over MgSCL, filtered, and concentrated. The product was purified by column chromatography (120 g column, 0-100% EtOAc in hexane).
  • the title compound was lodomethane (7.8 mL, 125 mmol) was charged to a vial containing 3- [methoxy(methyl)amino]-l-[l-(trifluoromethyl)cyclopropyl]propan-l-one (6.1 g, 27.1 mmol).
  • the vial was wrapped in aluminium foil to shield from light.
  • the resulting solution was stirred at ambient temperature for 4 days.
  • Tetrahydrofuran (22 mL) was added to the solidified mass and the mixture stirred for 0.25 h giving a slurry.
  • the solid was filtered off and washed with tetrahydrofuran (3 x 6 mL), then dried to give an off- white solid (6.13 g, 62% yield).
  • Step 3 l-(4-Fluorophenyl)-4-(l-(trifluoromethyl)cyclopropyl)butane-l, 4-dione
  • Methoxydimethyl ⁇ 3-oxo-3-[l-(trifluoromethyl)cyclopropyl]propyl ⁇ azanium iodide (1.0 g, 2.72 mmol) and 3-benzyl-5-(2-hydroxyethyl)-4-methyl-l,3-thiazol-3-ium chloride (0.234 g, 0.872 mmol, 0.3 equiv) were charged to a 20 mL vial with stirrer and placed under an inert atmosphere in a glove box.
  • the vial was removed from the glove box.
  • the mixture was diluted with ethyl acetate (25 mL) and washed with IM aqueous hydrochloric acid (14 mL, pH was 1-2 afterwards), water (10 mL) and brine, dried (MgSCL) and evaporated under reduced pressure to give a pale orange oil.
  • Step 4 2-(4-Fluorophenyl)-5-(l-(trifluoromethyl)cyclopropyl)-17/-pyrrole l-(4-Fluorophenyl)-4-[l-(trifluoromethyl)cyclopropyl]butane-l, 4-dione (0.835 g, 2.90 mmol) was charged to a 20 mL vial. 2-Propanol (4.2 mL, 5 vol) was added, followed by ammonium acetate (0.497 g, 6.45 mmol). The mixture was stirred in a heating block at 90 °C for 3.5 h.
  • Step 5 3-(2-(4-Fluorophenyl)-5-(l-(trifluoromethyl)cyclopropyl)-177-pyrrol-3- yl)propanoic acid
  • the reaction was capped and stirred at ambient temperature for 15 hours at which time it was combined with other similar crude reaction mixtures from other runs.
  • the combined mixtures were partitioned between 1000 mL 1:1 Et2O/hexanes and 500 mL water. The layers were separated and the organics were washed once with 500 mL water then once with 100 mL 15% Na2SC>4.
  • the organics were dried with MgSCL. filtered and concentrated under reduced pressure to a foam. The foam was scraped and suspended in hexanes.
  • Step 6 Dicyclohexylammonium 3-(2-(4-fluorophenyl)-5-(l-(trifluoromethyl)- cyclopropyl)-l//-pyrrol-3-yl)propanoate
  • Step 7 3-(2-(4-FIuorophenyI)-5-(l-(trifluoromethyI)cydopropyI)-17/-pyrroI-3-yI)-iV-
  • the flask was capped and stirred at ambient temperature. After 20 hours the reaction was quenched with 500 mL water. The mixture was treated with approximately 50 g Na2SC>4 then extracted three times with 100 mL EtOAc. The combined organics were washed twice with 50 mL IN HC1, once with 50 mL saturated NaHCCh and once with 50 mL 15% Na2SC>4. The organics were dried with MgSCL, filtered and concentrated under reduced pressure. The material was chromatographed over silica gel (ISCO, 750 g Gold, 300 ml/min, 0-47.9% (3:1 EtOAc / EtOH) / Hexanes over 95.7 minutes). The fractions containing product were collected and concentrated on the rotovap.
  • the residue was further purified via reverse-phase Cl 8 chromatography in multiple similar runs (ISCO Cl 8 Reverse Phase, 415 g Gold, 150 ml/min, 5-60% acetonitrile / water both with 0.1% NH4OH over 45 minutes).
  • the fractions containing product were concentrated on the rotovap to a slurry, frozen and lyophilized.
  • the residue was transferred to a RBF using DCM, acetonitrile and heptane.
  • Step 1 l-(4-Chlorophenyl)-4-(l-(trifluoromethyl)cyclopropyl)butane-l, 4-dione
  • Anhydrous zinc(II) chloride (867 mg, 6.17 mmol) was stirred in toluene (4 mL), and to this mixture was added diethylamine (638 pL, 6.17 mmol) dropwise followed by addition of 2- methylpropan-2-ol (590 pL, 6.17 mmol). The mixture was stirred at room temperature for 2 h.
  • Step 3 5-((2-(4-Chlorophenyl)-5-(l-(trifluoromethyl)cyclopropyl)-l//-pyrrol-3- yl)methyl)-2,2-dimethyl-l,3-dioxane-4, -dione/ 5-((5-(4-chlorophenyl)-2-(l- (trifluoromethyl)cyclopropyl)-l//-pyrrol-3-yl)methyl)-2,2-dimethyl-l,3-dioxane-4,6- dione
  • reaction mixture was again cooled in an acetone/ice bath at -10 °C, more 2,2-dimethyl-4-oxo-5- (pyridin-l-ium-l-ylmethyl)-4//-l,3-dioxin-6-olate (45.2 mg, 183 pmol) was added, and the reaction mixture was allowed to warm up to room temperature and stirred at room temperature for 66 h.
  • Step 4 3-(2-(4-Chlorophenyl)-5-(l-(trifluoromethyl)cyclopropyl)-l//-pyrrol-3-yl)-/V-
  • the vial was capped and the reaction mixture was stirred at room temperature for 45 minutes, then heated at 120 °C overnight. Cooled to room temperature, 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholin-4- ium tetrafluoroborate (DMTMMT) (39.6 mg, 117 pmol) was added, and the mixture was stirred at room temperature for 30 minutes, (3>S',47?)-3-amino-4-hydroxypyrrolidin-2-one hydrochloride (25.1 mg, 156 pmol) was added. The reaction mixture was stirred at room temperature overnight. Water was added, and the mixture was extracted with EtOAc twice (50 mL, 30 mL).
  • DMTMMT 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholin-4- ium tetrafluoroborate
  • Step 1 (E)-l-(l-(trifluoromethyl)cyclopropyl)propan-l-one O-(4-nitrobenzoyl) oxime
  • the crude ethyl ketone was dissolved in methanol (11.25 mL, 7.5 vol) to which hydroxylamine hydrochloride (0.634 g, 9.13 mmol, 1.2 equiv) and ammonium acetate (0.704, 9.13 mmol, 1.2 equiv) were added and the resulting suspension was heated to 60 °C and stirred overnight. Following completion of reaction, the methanol was removed via simple distillation and the resulting residue was dissolved in dichloromethane (15 mL, 10 vol) and washed with water (7.5 mL, 5 vol). The DCM layer was dried over anhydrous MgSCL which was washed with an additional 15 mL (10 vol) of DCM and the combined DCM extract azeotroped to 10 volumes (15 mL) via simple distillation.
  • a NaHCCh solution (7.5 mL, 5 V, 10wt% aqueous) was charged to the reactor, and the mixture was stirred for 30 minutes at 25 °C. The aqueous layer was removed, and the organic layer was dried over anhydrous MgSCL, filtered, and concentrated to dryness.
  • Triethylamine (31.854 g, 43.876 mL, 314.8 mmol, 1.5 equiv) was added next followed by chlorotrimethylsilane (34.198 g, 39.951 mL, 314.8 mmol, 1.5 equiv). The reaction was stirred at 25 °C overnight.
  • Step 3 Dicyclohexylammonium 3-(2-(4-fluorophenyl)-4-methyl-5-(l- (trifluoromethyl)cyclopropyl)-177-pyrrol-3-yl)propanoate
  • reaction mixture was cooled to room temperature, and the CAN solvent was swapped to EtOAc (6.6 mL, 20 vol). Then a K2CO3 solution (3.3 mL, 10 V, 20 wt% aqueous) was charged, and the mixture was stirred at ambient temperature for 15 min then phase cut.
  • the ethyl ester was dissolved in THF (0.55 mL, 10 vol) and LiOH solution (0.55 mL, 2.5 M aqueous) was charged to the stirred mixture which was heated to 55 °C and aged for 2 hours. After assessing completion by HPLC, the mixture was cooled to 25 °C and TBME (5 mL) was charged followed by IM HC1 (0.25 mL) and the resulting biphase was stirred for 1 h then phase cut. The organic layer was dried over anhydrous MgSCL. which was then washed with additional TBME and the combined filtered organic extracts were reduced in volume to 0.55 mL (10 vol) in vacuo.
  • Step 4 3-(2-(4-Fluorophenyl)-4-methyl-5-(l-(trifluoromethyl)cyclopropyl)-17Z-pyrrol-
  • Step 1 iV-Methoxy-iV-methyl-l-(trifluoromethyl)cyclobutane-l-carboxamide
  • Oxalyl chloride (606 pL, 6.92 mmol) was added dropwise to a stirred cold solution of l-(trifluoromethyl)cyclobutane-l -carboxylic acid (1.00 g, 5.77 mmol) and 2 drops of DMF in DCM (25 mL) at 0 °C. The mixture was allowed to warm up to room temperature and stirred at room temperature for 4 h.
  • Step 2 l-(l-(Trifluoromethyl)cyclobutyl)ethan-l-one
  • Step 4 2-(4-Fluorophenyl)-5-(l-(trifluoromethyl)cyclobutyl)-17/-pyrrole
  • Step 5 5-((2-(4-Fluorophenyl)-5-(l-(trifluoromethyl)cyclobutyl)-l//-pyrrol-3- yl)methyl)-2,2-dimethyl-l,3-dioxane-4, -dione/ 5-((5-(4-fluorophenyl)-2-(l- (trifluoromethyl)cyclobutyl)-l//-pyrrol-3-yl)methyl)-2,2-dimethyl-l,3-dioxane-4,6- dione
  • reaction mixture was again cooled in an acetone/ice bath at -15 °C, more 2,2-dimethyl-4-oxo-5-(pyridin-l-ium- l-ylmethyl)-4//-l,3-dioxin-6-olate (23.8 mg, 95% Wt, 0.2 Eq, 96.2 pmol) was added, and the reaction mixture was allowed to warm up to room temperature and stirred at room temperature for two days.
  • Step 6 3-(2-(4-Fluorophenyl)-5-(l-(trifluoromethyl)cyclobutyl)-l//-pyrrol-3-yl)-/V- ((3S,4 ⁇ )-4-hydroxy-2-oxopyrrolidin-3-yl)propanamide
  • the vial was capped and the reaction mixture was stirred at room temperature for 45 minutes, then heated at 115 °C overnight. Cooled to room temperature, 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholin-4- ium tetrafluoroborate (DMTMMT) (32.2 mg, 95.3 pmol) was added, and the mixture was stirred at room temperature for 30 minutes, after which (3>S',47?)-3-amino-4- hydroxypyrrolidin-2-one hydrochloride (20.4 mg, 127 pmol) was added. The reaction mixture was stirred at room temperature overnight. Water was added, and the mixture was extracted with EtOAc twice (50 mL, 30 mL).
  • DMTMMT 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholin-4- ium tetrafluoroborate
  • reaction mixture was cooled to 20 °C, and the reaction mixture was used in the next step without work-up.
  • the mixture was quenched with water (100 mL) at 0 °C, and l-fluoro-4-iodobenzene (54.3 g, 245 mmol, 1.10 equiv), Pd(Ph3P)4 (12.9 g, 11.13 mmol, 0.05 equiv), K2CO3 (92.0 g, 668 mmol, 3.00 equiv) were added at 0 °C, and then the reaction mixture was warmed up to 100 °C and stirred for 4 h, then cooled to 20 °C, combined with two crude reaction mixtures for work up (15.98g, 63.6 mmol, 63g, 223 mmol), and the combined reaction mixtures were diluted with brine (600 mL) and extracted with ethyl acetate (500 mL x 3).
  • the organic extract was washed with water (300 mL x 2) and dried over anhydrous Na2SC>4, filtered and concentrated in vacuo to obtain crude product.
  • the crude product (320 g) was dissolved in DCM (1.00 L), and 400 g of silica gel (100-200 mesh silica gel) was added. The resulting mixture was concentrated at 40 °C in vacuo to give a dry flowing solid.
  • the fraction was combined and evaporated in vacuo at 40 °C to give product as tan solid (150 g).
  • Step 4 3-(5-(Ethoxycarbonyl)-4-fluoro-2-(4-fluorophenyl)-17Z-pyrrol-3-yl)propanoic acid
  • the resulting mixture was extracted with ethyl acetate (800 mL x 3) and the organic extract was washed with water (2 x 500 mL).
  • the organic extract was dried over Na2SC>4, filtered and concentrated in vacuo at 45 °C to give the crude product (58.0 g) which was dissolved in DCM (400 mL), and 70.0 g of silica gel (100-200 mesh silica gel) was added.
  • the resulting mixture was concentrated at 40 °C in vacuo to give a flowing solid.
  • Step 7 3-(5-Bromo-4-fluoro-2-(4-fluorophenyl)-177-pyrrol-3-yl)-N-((3S,4 ⁇ )-4- hydroxy-2-oxopyrroIidin-3-yI)propanamide
  • Step 8 3-(4-Fluoro-2-(4-fluorophenyl)-5-(3,3,3-trifluoroprop-l-en-2-yl)-LH-pyrrol-3- yl)-iV-((3S,4 ⁇ )-4-hydroxy-2-oxopyrrolidin-3-yl)propanamide
  • the reaction vial was placed into a Photoreactor m2 setup at 450 nm and irradiated for 1 hour. Following this duration, the mixture was diluted with water (30 mL) and ethyl acetate (30 mL). The resulting suspension was filtered through Celite. The filtrate was diluted wit brine (10 mL) and the organic layer was separated and washed with water (2 x 40 mL). It was subsequently dried over anhydrous MgSCL and filtered. The filtrate was concentrated and the crude product was purified by flash column chromatography on silica gel eluting with a gradient of 5 to 55% ethyl acetate/ethanol (3:1) in heptane.
  • Step 1 A-Methoxy-iV-methyl-l-(trifluoromethyl)cyclopropane-l-carboxamide
  • Step 3 tert-Butyl 4-bromo-2-( 1 -(trifl uoromethy Dey clop ropy y role- 1- carboxylate
  • the reaction was stirred and refluxed for 22 hours, then cooled to room temperature. It was diluted with satd. NH4CI and diethyl ether and filtered through a Celite plug to remove solids. The layers of the filtrate were separated, and the organics were dried over sodium sulfate, filtered and concentrated under vacuum on rotovap.
  • the crude product was purified by a short silica gel plug, eluting with 0-40% DCM:heptane. The less pure fractions were combined, concentrated and purified by silica gel chromatography (0-5% EtOAc:heptane).
  • Step 5 tert-Butyl 2-bromo-3-(3-ethoxy-3-oxopropyl)-5-(l-
  • Step 6 tert-Butyl 3-(3-ethoxy-3-oxopropyl)-5-(l-(trifluoromethyl)cyclopropyl)-2-(4- (trifluoromethyl)phenyl)-lH-pyrrole-l-carboxylate tert-Butyl 2-bromo-3-(3-ethoxy-3-oxopropyl)-5-( 1 -(trifluoromethyl)cyclopropyl)-l H- pyrrole-1 -carboxylate (12.2 g, 97% Wt, 1.0 equiv, 26.1 mmol) was dissolved in 1,4- dioxane (150 mL) and water (40 mL), then added (4-(trifluoromethyl)phenyl)boronic acid (5.9 g, 1.2 equiv, 31.3 mmol), tetrakis(triphenylphosphine)palladium(0) (1.51 g, 0.05 equiv,
  • Step 7 3-(5-(l-(Trifluoromethyl)cyclopropyl)-2-(4-(trifluoromethyl)phenyl)-177- pyrrol-3-yl)propanoic acid
  • Step 3 3-(5-(2,2-Difluoro-l-(trifluoromethyl)cyclopropyl)-2-(4-fluorophenyl)-177- pyrrol-3-yl)-A r -((3S,41f)-4-hydroxy-2-oxopyrrolidin-3-yl)propanamide
  • APOL1 gene is a pleiotropic gene with an association with increased likelihood of renal disease. It is expressed in the human kidney and has a soluble circulating form associated with innate immunity, which is part of human immunity to trypanosome infection.
  • the wild-type version (GO) is the most widespread, but two isoforms, G1 and G2 are commonly found in African populations as well as populations with African ancestry.
  • the gain of function associated with G1 and G2 leads to increased likelihood of podocyte death, as well as increased mortality of other kidney cell types, but do provide the advantage of increased resistance to subspecies of trypanosomes which have developed a resistance to the wild-type AP0L1 GO associated immunity.
  • AP0L1 proteins form potassium-permeable cation pores in the plasma membrane.
  • AP0L1 risk variants induce greater potassium flux than GO in cells.
  • Thallium has identical charge and very similar atomic radius when compared to potassium and is known to pass through the ligand-gated potassium channels.
  • a FLIPR thallium assay was performed to measure the flux of thallium (T1+) through ligand-gated potassium channels.
  • Negative control will be vehicle (1% DMSO) in columns 11 and 12 of each compound plate.

Abstract

La présente invention concerne de nouveaux composés qui sont des inhibiteurs de APOL1, des compositions pharmaceutiques contenant les composés, des procédés pour leur préparation, et leurs utilisations en thérapie pour le traitement de maladies rénales et de sepsis.
PCT/IB2023/053398 2022-04-06 2023-04-04 Dérivés pyrroliques utilisés en tant qu'inhibiteurs de l'apolipoprotéine l-1 WO2023194895A1 (fr)

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US11976067B2 (en) 2022-01-18 2024-05-07 Maze Therapeutics, Inc. APOL1 inhibitors and methods of use
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CN117126093B (zh) * 2023-10-24 2023-12-29 潍坊医学院 伏诺拉生中间体的制备方法

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