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NZ753471B2 - Magl inhibitors - Google Patents

Magl inhibitors Download PDF

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Publication number
NZ753471B2
NZ753471B2 NZ753471A NZ75347117A NZ753471B2 NZ 753471 B2 NZ753471 B2 NZ 753471B2 NZ 753471 A NZ753471 A NZ 753471A NZ 75347117 A NZ75347117 A NZ 75347117A NZ 753471 B2 NZ753471 B2 NZ 753471B2
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New Zealand
Prior art keywords
compound
acceptable salt
formula
solvate
pharmaceutically acceptable
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Application number
NZ753471A
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NZ753471A (en
Inventor
Daniel J Buzard
Cheryl A Grice
Michael B Shaghafi
Original Assignee
H Lundbeck A/S
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Application filed by H Lundbeck A/S filed Critical H Lundbeck A/S
Priority claimed from PCT/US2017/061870 external-priority patent/WO2018093949A1/en
Publication of NZ753471A publication Critical patent/NZ753471A/en
Publication of NZ753471B2 publication Critical patent/NZ753471B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Abstract

Provided herein are spirocyclic and fused bicyclic carbamates of Formula (I) and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful as modulators of MAGL. Furthermore, the subject compounds and compositions are useful for the treatment of pain.

Description

MAGL TORS CROSS-REFERENCE This application claims benefit of US. Provisional Application No. 62/423,102, filed on November 16, 2016, which is herein incorporated by reference in its entirety.
BACKGROUND Monoacylglycerol lipase (MAGL) is an enzyme responsible for hydrolyzing nnabinoids such as 2-AG (2-arachidonoylglycerol), an arachidonate based lipid, in the nervous system.
BRIEF Y OF THE INVENTION This disclosure provides, for example, compounds and compositions which are modulators of MAGL, and their use as medicinal , processes for their ation, and pharmaceutical compositions that include disclosed compounds as at least one active ingredient. The disclosure also provides for the use of disclosed compounds as medicaments and/or in the cture of medicaments for the inhibition ofMAGL activity in warm-blooded animals such as humans.
In one aspect is a compound of Formula (I): // MOP, Rl—X Formula (I), wherein: w‘r’ N?2i N31; <9, ”00 mo ,r-MQCE X is —o—, —s—, —soz-, -N(R3)-, or -CH2-; Y is -O- or -N(R7)-; R1 is -(CR4R5)m-R6, -(CR4R5)p-Y-(CR4R5)q-R6, or -(CR4R5)t-C3_6cycloalkyl-R6; each R2 is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -C1. 6alkyl(heterocycloalkyl), -OR17, and -C(O)NR18R19; R3 is H or C1-6alkyl, each R4 and R5 is each independently selected from H, F, and C1-6alkyl; or R4 and R5, er with the carbon to which they are attached, form a C3-6cycloalkyl ring, R6 is -C02R9, -C(O)R10, or -C(O)O-(CR12R13)-OC(O)R11; R7 is H, kyl, or —s02R8, R8 is C1_6alkyl; R9 is H or C1_6alkyl; R10 is C1.6alkyl or -NHSOZR21; R11 is kyl or C1.6alkoxy; R12 and R13 is each independently H or C1_6alkyl; each R17 is ndently selected from H, C1.6alkyl, C1.6haloalkyl, aminoalkyl, cycloalkyl, -C1-6alkyl(heterocycloalkyl), —C1-6alkyl-C(O)(heterocycloalkyl), optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; each R18 and R19 is independently selected from H, C1-6alkyl, C1_6haloalkyl, cycloalkyl, aryl, and heteroaryl; or R18 and R19, together with the nitrogen to which they are attached, form a heterocycloalkyl ring optionally substituted with one, two, or three R20; each R20 is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, oxo, -CN, and C3-6cycloalkyl; R21 is C1_6alkyl, mis l, 2, 3 or4; n is 0,1, 2, 3, or4; p is 2, 3, or 4; q is l, 2, or 3; and t is O, l, or 2; or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments is a compound of Formula (I), or a pharmaceutically able salt or solvate thereof, wherein R1 is -(CR4R5)m-R6. In some embodiments is a compound of a (I), or a pharmaceutically acceptable salt or solvate thereof, wherein m is l, 2, or 3. In some embodiments is a compound of a (I), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 2. In some ments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 3. In some embodiments is a compound of Formula (I), or a ceutically acceptable salt or e thereof, n R1 is -(CR4R5)p-Y-(CR4R5)q-R6.
In some embodiments is a nd of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -O-. In some embodiments is a compound of Formula (I), WO 93949 or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -N(R7)-. In some ments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is -SOZR8. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or e thereof, wherein q is 1. In some embodiments is a compound of Formula (I), or a pharmaceutically able salt or solvate thereof, wherein p is 2. In some embodiments is a compound of Formula (I), or a pharmaceutically able salt or solvate thereof, n R1 is -(CR4R5)t-C3-6cycloalkyl-R6. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein t is 0. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein t is 1. In some ments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein t is 2. In some embodiments is a compound of Formula (I), or a ceutically acceptable salt or e f, wherein each R4 and R5 is each independently selected from H and C1-6alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 and R5 is H. In some ments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is R9. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is H. In some embodiments is a compound of a (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is C1_6alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is -C(O)R10. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate f, wherein R10 is -NHSOZR21. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, n R6 is -C(O)O-(CR12R13)- OC(O)RH. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R11 is C1-6alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R11 is C1-6alkoxy. In some embodiments is a compound of a (I), or a ceutically acceptable salt or solvate thereof, wherein X is -O-. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —SOz-. In some embodiments is a compound of a (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -N(R3)-. In some embodiments is a compound of Formula (I), or a ceutically acceptable salt or solvate thereof, wherein R3 is H. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is kyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or e thereof, wherein X is -CH2-. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or «pr NE solvate thereof, wherein (A) is i In some embodiments is a compound of Formula (I), or a ceutically acceptable salt or solvate thereof, wherein Q) is ~§~N . . .
. In some embod1ments 1s a compound of Formula (I), or a ceutically able salt or solvate thereof, where1n ®. . E 1s --N<j:\/N-§- . In some embod1ments. is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2 is independently selected from halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of a (I), or a pharmaceutically acceptable salt or solvate f, n each R2 is -Cl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2 is —CF3.
In another aspect is a compound selected from: o CF3 NJKOACFa NH HN Fac\©’\‘ i CF3 N oJ\CI=3 7 7 ”0 O o CF3 HN Q o CF3 J]\oJ\CF3 W0 2018/093949 o 0 OH OH NNCpioxCF3 0 {:le o/KCF3 o o o\)‘OH O}OH BOO/fl )1 5:3 mm o CFa N o CF3 \CF3 N N o N\)\OH flpkokcpa 0 CF3 N <9N “jCOOH HOOC\/\NH Cg i i Q :1 {30¢ o CFa c, {:0 o CF3 COOH \( F3C N 0 CF ,SOzMe HOOC f0 HOOC F30CEGMW CEOJWo CF3 F30 0 7 ; or a pharmaceutically acceptable salt or solvate thereof.
In another aspect is a compound ed from: AVCOOH HOOC o o\)<l Facflfi CF3 CAGE? Clflfiiokcfi 7 7 or a pharmaceutically acceptable salt or solvate thereof.
In another embodiment is a ceutical composition comprising a compound of Formula (I) bed herein, or a ceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.
In another embodiment is a method of treating pain in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) described herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pain is neuropathic pain. In some embodiments, the pain is inflammatory pain.
In another embodiment is a method of treating a disease or er in a patient in need f comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) described herein, or a pharmaceutically acceptable salt or solvate f, wherein the disease or disorder is selected from the group consisting of epilepsy/seizure disorder, le sclerosis, neuromyelitis optica (NMO), Tourette syndrome, Alzheimer’s disease, and nal pain associated with irritable bowel syndrome. In some embodiments, the disease or disorder is epilepsy/seizure disorder. In some embodiments, the disease or disorder is multiple sclerosis. In some embodiments, the disease or disorder is neuromyelitis optica (NMO). In some embodiments, the disease or disorder is Tourette syndrome. In some embodiments, the disease or disorder is Alzheimer’s disease. In some embodiments, the disease or disorder is abdominal pain associated with ble bowel syndrome.
In another embodiment is a method of treating ion t and hyperactivity disorder (ADI-ID) in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) described herein, or a pharmaceutically acceptable salt or solvate thereof.
DETAILED PTION OF THE ION This disclosure is directed, at least in part, to nds capable of inhibiting MAGL.
As used herein and in the appended claims, the singular forms "a, and," and "the" include plural referents unless the context clearly dictates otherwise Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or to a plurality of cells) and equivalents thereof. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within mental variability (or within statistical experimental error), and thus the number or numerical range varies between 1% and 15% of the stated number or cal range. The term "comprising" (and related terms such as ise" or "comprises" or "having" or "including") is not intended to exclude that which in other certain embodiments, for example, an embodiment of any ition of matter, composition, method, or process, or the like, described herein, may "consist of" or "consist essentially of" the described es.
Definitions As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.
As used herein, C1-CX includes C1-C2, C1-C3 . . . C1-CX. C1-CX refers to the number of carbon atoms that make up the moiety to which it ates ding optional substituents).
"Amino" refers to the -NH2 l.
"Cyano" refers to the -CN radical.
"Nitro" refers to the -N02 radical.
"Oxa" refers to the -O- radical.
"Oxo" refers to the =0 radical.
"Thioxo" refers to the :8 l.
"Imino" refers to the =N-H radical.
"Oximo" refers to the =N—OH radical.
"Alkyl" or "alkylene" refers to a straight or branched hydrocarbon chain l consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C1-C5 alkyl). In certain embodiments, an alkyl comprises one to en carbon atoms (e.g., C1-C13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., C1-C8 alkyl). In other embodiments, an alkyl comprises one to six carbon atoms (e.g., C1-C6 alkyl). In other embodiments, an alkyl ses one to five carbon atoms (e.g., C1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C1-C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g, C1-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., C1 alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C5 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C5-C8 alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C2-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, yl (n-propyl), l—methylethyl (iso—propyl), l-butyl yl), l- methylpropyl utyl), 2-methylpropyl (iso-butyl), l,l-dimethylethyl (lert—butyl), and yl (n-pentyl). The alkyl is attached to the rest of the molecule by a single bond.
Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)Ra, -N(Ra 2, -C(O)Ra, -C(O)ORa, - C(O)N(Ra)2, -N(Ra)C(O)ORf, -OC(O)-NRaRf, -N(Ra)C(O)Rf, -N(Ra)S(O)tRf (where r is 1 or 2), —S(O)tORa (where t is l or 2), -S(O)tRf (where t is l or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl, fluoroalkyl, lkyl, aryl, l, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each Rf is independently alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl.
"Alkoxy" refers to a radical bonded through an oxygen atom of the formula -0— alkyl, where alkyl is an alkyl chain as defined above.
"Alkenyl" refers to a straight or branched arbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an l comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-l-enyl (i.e., allyl), but-l-enyl, pent-l-enyl, penta-1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, - SRa, -OC(O)—Rf, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORf, -OC(O)- NRa Rf, C(O)Rf, -N(Ra)S(O)tRf (where r is 1 or 2), -S(O)tORa (where r is 1 or 2), -S(O)tRf (where t is l or 2) and -S(O)tN(Ra)2 (where t is l or 2) where each Ra is independently hydrogen, alkyl, fluoroalkyl, lkyl, aryl, aralkyl, cycloalkyl, aryl or heteroarylalkyl, and each Rf is independently alkyl, fluoroalkyl, lkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl.
"Alkynyl" refers to a straight or branched hydrocarbon chain l group ting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl has two to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, l, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, —OC(O)Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, —C(O)N(Ra)2, - N(Ra)C(O)ORf, -OC(O)—NRaRf, -N(Ra)C(O)Rf, -N(Ra)S(O)tRf (where t is 1 or 2), —S(0),0Ra (where t is l or 2), Rf (where t is l or 2) and -S(O)tN(Ra)2 (where t is l or 2) where each Ra is independently hydrogen, alkyl, fluoroalkyl, lkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each Rf is independently alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl or heteroarylalkyl.
"Aryl" refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic arbon ring system ns only hydrogen and carbon from six to en carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) TE—electron system in accordance with the Huckel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Unless stated otherwise specifically in the specification, the term "aryl” or the prefix "ar-" (such as in "aralkyl") is meant to include aryl radicals optionally substituted by one or more tuents independently selected from alkyl, alkenyl, l, halo, fluoroalkyl, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, lkyl, heterocycloalkyl, aryl, heteroarylalkyl, -Rb-0Ra, -Rb-OC(O)-Ra, -Rb-OC(O)-0Ra, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, — Rb-C(O)Ra, -Rb-C(O)0Ra, -Rb-C(O)N(Ra)2, -Rb-O-R°-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb- N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa (where t is 1 or 2), -Rb-S(O)10Ra (where t is 1 or 2), -Rb-S(O)tRa (where t is l or 2) and -Rb-S(O)tN(Ra)2 (where t is l or 2), where each R21 is independently hydrogen, alkyl, fluoroalkyl, lkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and RC is a straight or branched alkylene or alkenylene chain.
"Aryloxy" refers to a radical bonded through an oxygen atom of the formula —0- aryl, where aryl is as defined above.
"Aralkyl" refers to a radical of the formula -RC-aryl where Rc is an ne chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally tuted as described above for an aryl group.
"Aralkyloxy" refers to a l bonded through an oxygen atom of the formula — O-aralkyl, where aralkyl is as defined above.
"Aralkenyl" refers to a radical of the formula —Rd-aryl where Rd is an alkenylene chain as defined above. The aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group. The alkenylene chain part of the nyl radical is optionally substituted as defined above for an alkenylene group.
"Aralkynyl" refers to a radical of the formula -Re-aryl, where R6 is an alkynylene chain as defined above. The aryl part of the aralkynyl radical is optionally substituted as bed above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.
"Cycloalkyl " refers to a stable non-aromatic clic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a cycloalkyl compnses three to ten carbon atoms. In other embodiments, a cycloalkyl comprises five to seven carbon atoms. The cycloalkyl is attached to the rest of the molecule by a single bond. Cycloalkyls are ted, (L6, containing single C-C bonds only) or partially unsaturated (i.e., containing one or more double bonds or triple bonds.) Examples of monocyclic lkyls include, e.g, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In certain embodiments, a cycloalkyl comprises three to eight carbon atoms (e.g, C3-C8 lkyl). In other embodiments, a lkyl comprises three to seven carbon atoms (e.g., C3-C7 cycloalkyl). In other embodiments, a cycloalkyl ses three to six carbon atoms (e.g., C3-C6 cycloalkyl). In other embodiments, a cycloalkyl ses three to five carbon atoms (e.g., C3-C5 cycloalkyl). In other embodiments, a cycloalkyl comprises three to four carbon atoms (e.g., C3-C4 cycloalkyl). A partially unsaturated cycloalkyl is also referred to as "cycloalkenyl." Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and ctenyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbomyl (i.e., bicyclo[2.2.l]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2. l]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term "cycloalkyl" is meant to include cycloalkyl radicals ally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -Rb-0Ra, -Rb-OC(O)-Ra, -Rb-OC(O)-0Ra, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, — Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-RC-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb- (O)Ra, -Rb-N(Ra)S(O)[Ra (where t is l or 2), -Rb-S(O)1ORa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), where each R21 is independently hydrogen, alkyl, lkyl, lkyl, cycloalkylalkyl, aryl (optionally tuted with one or more halo groups), l, heterocycloalkyl, heteroaryl or heteroarylalkyl, each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and RC is a straight or branched alkylene or alkenylene chain.
"Halo" or "halogen" refers to bromo, chloro, fluoro or iodo substituents.
"Haloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above.
"Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, l-fluoromethylfluoroethyl, and the like. The alkyl part of the fluoroalkyl radical are optionally substituted as defined above for an alkyl group.
"Haloalkoxy" refers to an alkoxy radical, as defined above, that is substituted by one or more halo radicals, as defined above.
"Heterocycloalkyl" refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which include fused, spiro, or bridged ring systems. The heteroatoms in the heterocycloalkyl radical are optionally ed. One or more nitrogen atoms, if t, are optionally nized. The heterocycloalkyl radical is lly or fully saturated. In some embodiments, the heterocycloalkyl is attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocycloalkyl ls include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, ydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term ocycloalkyl" is meant to include cycloalkyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, , cyano, nitro, aryl, aralkyl, aralkenyl, nyl, cycloalkyl, heterocycloalkyl, heteroaryl, arylalkyl, a, -Rb-OC(O)-Ra, -Rb-OC(O)-0Ra, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, — )Ra, -Rb-C(O)0Ra, -Rb-C(O)N(Ra)2, RC-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb- N(Ra)C(O)Ra, -Rb-N(Ra)S(O)[Ra (where t is l or 2), -Rb-S(O)IORa (where t is 1 or 2), -Rb-S(O)tRa (where t is l or 2) and -Rb-S(O)tN(Ra 2 (where t is l or 2), where each Ra is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and RC is a straight or branched alkylene or alkenylene chain.
"Heteroaryl" refers to a radical derived from a 5- to 18-membered aromatic ring l that comprises one to een carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring , wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) rt—electron system in accordance with the HUCkel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more en atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Unless stated otherwise specifically in the specification, the term oaryl” is meant to include heteroaryl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, oxo, thioxo, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -Rb-0Ra, -Rb-OC(O)—Ra, -Rb- OC(O)—ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, — Rb-O-RC-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa (where t is l or 2), -Rb-S(O)tORa (where t is l or 2), -Rb-S(O)tRa (where t is l or 2) and —Rb- S(O)[N(Ra)2 (where t is l or 2), where each Ra is ndently hydrogen, alkyl, lkyl, cycloalkyl, lkylalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each Rb is independently a direct bond or a straight or ed alkylene or alkenylene chain, and RC is a straight or branched alkylene or alkenylene chain.
"N—heteroaryl" refers to a heteroaryl radical as defined above containing at least one en and where the point of attachment of the heteroaryl l to the rest of the le is through a nitrogen atom in the heteroaryl radical. An N—heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
"C—heteroaryl" refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. A C—heteroaryl radical is optionally tuted as described above for heteroaryl radicals. oaryloxy" refers to radical bonded through an oxygen atom of the formula - O-heteroaryl, where heteroaryl is as defined above.
"Heteroarylalkyl" refers to a radical of the formula —RC-heteroaryl, where RC is an alkylene chain as defined above. If the heteroaryl is a en-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl l is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is ally substituted as defined above for a heteroaryl group.
"Heteroarylalkoxy" refers to a radical bonded through an oxygen atom of the formula heteroaryl, where RC is an alkylene chain as defined above. If the heteroaryl is a nitrogen—containing heteroaryl, the heteroaryl is ally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkoxy radical is optionally tuted as defined above for a heteroaryl group.
In some embodiments, the compounds disclosed herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are , in terms of absolute stereochemistry, as (R)— or (S)-.
Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds bed herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z ric isomers (e.g., cis or trans.) Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms " geometric isomer" refers to E are also intended to be included. The term or Z ric isomers (e.g., cis or trans) of an alkene double bond. The term ional isomer" refers to structural isomers around a central ring, such as 0rth0-, meta-, and para- isomers around a benzene ring.
A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. In certain embodiments, the compounds presented herein exist as tautomers. In circumstances where tautomerization is possible, a chemical brium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include: 9%“: JV \ifi = \iflfi H H o OH = NH2 NH \ANHZ \ NH \kN/xi‘ \ ”A EYNO ‘5 H “H "4‘ [\L /N /N 'N = | ,:N = = :NH H N\N HN~N NxN\ "Optional” or "optionally" means that a subsequently described event or circumstance may or may not occur and that the description includes instances when the event or circumstance occurs and ces in which it does not. For e, nally substituted aryl" means that the aryl radical are or are not substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.
"Pharmaceutically acceptable salt" includes both acid and base addition salts. A ceutically able salt of any one of the pyrazole compounds bed herein is intended to encompass any and all pharmaceutically le salt forms. Preferred pharmaceutically acceptable salts of the nds described herein are ceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
"Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as tic mono— and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, ic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate tes, sebacates, tes, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, esulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge SM. et al., "Pharmaceutical " Journal ofPharmaceutical Science, 66: 1-19 (1997). Acid addition salts of basic compounds are prepared by contacting the free base forms with a sufficient amount ofthe desired acid to produce the salt. aceutically acceptable base on salt" refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases e, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, ese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, ohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N—dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, nedianiline, N—methylglucamine, glucosamine, methylglucamine, omine, purines, zine, piperidine, N—ethylpiperidine, polyamine resins and the like. See Berge et al., supra.
As used herein, "treatment" or "treating " or "palliating" or "ameliorating" are used hangeably herein. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic beneflt and/or a prophylactic benefit. By "therapeutic benefit" is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is ed in the patient, hstanding that the patient is still afflicted with the underlying disorder. For prophylactic benefit, the itions are stered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.
Compounds The nds of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc) described herein which are modulators of MAGL. These compounds, and compositions comprising these compounds, are useful for the treatment of pain. In some embodiments, the compounds of Formula (I), (la), (Iaa), (Ib), (Ibb), (Ic), or (Icc) bed herein are useful for treating epilepsy/seizure er, le sclerosis, neuromyelitis optica (NMO), Tourette syndrome, Alzheimer’s disease, or abdominal pain associated with ble bowel syndrome.
In some embodiments is a compound of a (I): (R2)n E\\ O R,_X// MOP, Formula (I), wherein: @300 «00 Momas}: N377: N115: X is —o—, —s—, —s02—, -N(R3)-, or -CH2-; Y is -O- or -N(R7)-; R1 is -(CR4R5)m-R6, -(CR4R5)p-Y-(CR4R5)q-R6, or -(CR4R5)t-C3-6cycloalkyl-R6; each R2 is independently selected from halogen, -CN, C1-6alkyl, C1_6haloalkyl, -C1- (heterocycloalkyl), -OR17, and -C(O)NR18R19; R3 is H or C1-6alkyl, each R4 and R5 is each independently selected from H, F, and C1.6alkyl; or R4 and R5, together with the carbon to which they are attached, form a C3-6cycloalkyl ring; R6 is -C02R9, -C(O)R10, or -C(O)O-(CR12R13)-OC(O)R11; R7 is H, C1_6alkyl, or —s02R8; R8 is C1-6alkyl; R9 is H or C1.6alkyl; R10 is C1_6alkyl or —NHs02R21; R11 is C1.6alkyl or C1.6alkoxy; R12 and R13 is each independently H or C1.6alkyl; each R17 is independently selected from H, C1-6alkyl, loalkyl, aminoalkyl, cycloalkyl, -C1-6alkyl(heterocycloalkyl), lkyl—C(O)(heterocycloalkyl), optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; each R18 and R19 is ndently ed from H, C1-6alkyl, C1-6haloalkyl, cycloalkyl, aryl, and heteroaryl; or R18 and R19, together with the nitrogen to which they are attached, form a heterocycloalkyl ring optionally substituted with one, two, or three R20, each R20 is independently selected from halogen, C1.6alkyl, C1.5haloalkyl, oxo, -CN, and C3-6cycloalkyl, R21 is kyl; mis l, 2, 3 or4, n is 0,1, 2, 3, or4; p is 2, 3, or 4, q is 1, 2, or 3; and tis O, 1, or 2, or a pharrnaceutically acceptable salt or solvate thereof.
In some embodiments is a compound of Formula (I), or a pharrnaceutically w‘r' N715 G) N acceptable salt or solvate thereof, wherein is . In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein (9. -§~N . . 1s . In some embodiments 1s a compound of Formula (I), or a E g pharmaceutlcally able salt or solvate thereof, wherein ® is .
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -O-, -S—, -SOz—, -N(R3)—, or -CH2-. In some embodiments is a nd of a (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O-. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -S-. In some embodiments is a nd of a (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -SOz-. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -N(R3)—. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -N(H)-. In some embodiments is a nd of a (I), or a pharmaceutically acceptable salt or solvate f, wherein X is -N(CH3)-. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —N(CH2CH3)-. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -CH2-.
In some embodiments is a nd of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6 and R6 is -C02R9. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate f, wherein R1 is -(CR4R5)m-R6 and R6 is -C02H. In some ments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6 and R6 is -C02CH3. In some embodiments is a compound of Formula (I), or a pharmaceutically able salt or e thereof, wherein R1 is 5)m-R6 and R6 is 2CH3. In some ments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6 and R6 is -C(O)R10, In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6 and R6 is -C(O)NHSOZCH3. In some embodiments is a compound of Formula (I), or a pharmaceutically able salt or solvate thereof, wherein R1 is -(CR4R5)m-R6 and R6 is - C(O)O-(CR12R13)-OC(O)R11. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6 and R6 is - C(O)OCH20C(O)R”. In some embodiments is a nd of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6 and R6 is - C(O)OCH20C(O)OCH2CH3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6 and R6 is - C(O)OCH20C(O)OCH(CH3)2. In some embodiments is a compound of a (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6 and R6 is - C(O)OCH20C(O)OC(CH3)3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is 5)m-R6 and R6 is - C(O)OCH20C(O)CH(CH3)2. In some ments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6 and m is 1.
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is 5)m-R6 and m is 2. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6 and m is 3. In some embodiments is a compound of a (I), or a pharmaceutically able salt or solvate thereof, wherein R1 is -(CR4R5)m-R6 and m is 4.
In some ments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6 and each R4 and R5 is each independently selected from H and C1-6alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, n R1 is -(CR4R5)m-R6 and each R4 and R5 is H.
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, n R1 is -(CR4R5)m-R6, R6 is -C02H, m is l, and R4 and R5 is independently selected from H and C1.6alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02H, m is 2, and each R4 and R5 is each independently selected from H and kyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is - COZH, m is 3, and each R4 and R5 is each independently selected from H and C1-6alky1. In some embodiments is a nd of Formula (I), or a pharmaceutically acceptable salt or e thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02H, m is 4, and each R4 and R5 is each independently selected from H and kyl.
In some embodiments is a compound of a (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02H, m is 1, and R4 and R5 are H. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02H, m is 2, and each R4 and R5 is H. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is - COZH, m is 3, and each R4 and R5 is H. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or e thereof, wherein R1 is 5)m-R6, R6 is -C02H, m is 4, and each R4 and R5 is H.
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is 5)m-R6, R6 is -C02R9, R9 is C1.6alkyl, m is l, and R4 and R5 is independently selected from H and C1-6alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate f, wherein R1 is -(CR4R5)m-R6, R6 is -C02R9, R9 is kyl, m is 2, and each R4 and R5 is each independently selected from H and C1-6alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02R9, R9 is C1-6alkyl, m is 3, and each R4 and R5 is each ndently ed from H and C1-6alkyl. In some embodiments is a compound of a (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is - (CR4R5)m-R6, R6 is -C02R9, R9 is kyl, m is 4, and each R4 and R5 is each independently ed from H and C1-6alkyl.
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02R9, R9 is C1_6alkyl, m is 1, and R4 and R5 are H. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is - COzRg, R9 is C1-6alkyl, m is 2, and each R4 and R5 is H. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02R9, R9 is C1_6alkyl, m is 3, and each R4 and R5 is H. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or e thereof, wherein R1 is -(CR4R5)m-R6, R6 is , R9 is kyl, m is 4, and each R4 and R5 is H.
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)10-Y-(CR4R5)q-R6. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p-Y-(CR4R5)q—R6 and R6 is -C02R9. In some embodiments is a nd of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p-Y-(CR4R5)q-R6 and R6 is -C02H. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p-Y-(CR4R5)q-R6 and R6 is -C02CH3. In some embodiments is a nd of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is - (CR4R5)p-Y-(CR4R5)q-R6 and R6 is -C02CH2CH3. In some embodiments is a nd of Formula (I), or a phannaceutically acceptable salt or solvate thereof, wherein R1 is - (CR4R5)p-Y-(CR4R5)q-R6 and Y is -O—. In some embodiments is a nd of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p-Y- (CR4R5)q-R6 and Y is -N(R7)—. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is 5)lo-Y-(CR4R5)q-R6 and Y is -N(H)—. In some ments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p—Y-(CR4R5)q-R6 and Y is -N(SOzMe)—. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or e thereof, wherein R1 is -(CR4R5)lo-Y-(CR4R5)q-R6 and p is 2. In some embodiments is a compound of a (I), or a ceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)I,-Y-(CR4R5).;l—R6 and p is 3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is —(CR4R5)p-Y-(CR4R5)q-R6 and p is 4. In some embodiments is a compound of a (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is 5)p-Y-(CR4R5)q-R6 and q is 1. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is - (CR4R5)P-Y-(CR4R5)q—R6 and q is 2. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p-Y- (CR4R5)q-R6 and q is 3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, n R1 is -(CR4R5)10-Y-(CR4R5)q-R6 and each R4 and R5 is each ndently selected from H and kyl. In some embodiments is a nd of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p-Y—(CR4R5)q-R6 and each R4 and R5 is H.
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, n R1 is -(CR4R5)10-Y-(CR4R5)q-Ré, R6 is -C02H, Y is -O-, p is 2, q is l, and R4 and R5 is independently selected from H and C1-(,alkyl. In some embodiments is a compound of Formula (I), or a ceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p-Y-(CR4R5)q—R6, R6 is -C02H, Y is -N(H)-, p is 2, q is l, and each R4 and R5 is each independently selected from H and kyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p-Y—(CR4R5)q-R6, R6 is -C02H, Y is -N(SOzMe)-, p is 2, q is l, and each R4 and R5 is each independently ed from H and C1-6alkyl.
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p-Y-(CR4R5)q—R6, R6 is -C02H, Y is -O-, p is 2, q is l, and R4 and R5 are H. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p-Y— (CR4R5)q-R6, R6 is -C02H, Y is -N(H)-, p is 2, q is l, and each R4 and R5 is H. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, n R1 is -(CR4R5)p-Y-(CR4R5)q-R6, R6 is -C02H, Y is Me)-, p is 2, q is l, and each R4 and R5 is H.
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)1,-Y-(CR4R5)q-R6, R6 is , R9 is C1-6alkyl, Y is -O-, p is 2, q is l, and R4 and R5 is independently selected from H and C1- . In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p-Y-(CR4R5)q—R6, R6 is -C02R9, R9 is C1_6alkyl, Y is -N(H)-, p is 2, q is 1, and each R4 and R5 is each independently selected from H and C1_6alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p-Y-(CR4R5)q-R6, R6 is -C02R9, R9 is C1.6alkyl, Y is Me)-, p is 2, q is l, and each R4 and R5 is each independently selected from H and C1-6alkyl.
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or e thereof, wherein R1 is -(CR4R5)10-Y-(CR4R5)q-R6, R6 is -C02R9, R9 is kyl, Y is -O-, p is 2, q is 1, and R4 and R5 are H. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p-Y-(CR4R5)q-R6, R6 is £02119, R9 is C1.6alkyl, Y is -N(H)-, p is 2, q is 1, and each R4 and R5 is H. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or e thereof, wherein R1 is -(CR4R5)p-Y-(CR4R5)q-R6, R6 is -C02R9, R9 is kyl, Y is -N(SOzMe)-, p is 2, q is l, and each R4 and R5 is H.
In some embodiments is a compound of Formula (I), or a pharmaceutically able salt or solvate thereof, wherein R1 is -(CR4R5)t-C3-6cycloalkyl-R6. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is 5)t-cyclopropyl—R6. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is - (CR4R5)t-cyclobutyl—R6. In some embodiments is a compound of Formula (I), or a ceutically acceptable salt or solvate thereof, n R1 is 5)t-cyclopentyl-R6.
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate f, wherein R1 is -(CR4R5)t-cyclohexyl-R6. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)t-C3.6cycloalkyl-R6 and R6 is -C02R9. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is — (CR4R5)t-C3_6cycloalkyl-R6 and R6 is -C02H. In some embodiments is a compound of Formula (I), or a pharmaceutically able salt or solvate thereof, wherein R1 is - (CR4R5)t-C3.6cycloalkyl-R6 and R6 is -C02CH3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is - (CR4R5)t-C3_6cycloalkyl-R6 and R6 is -C02CH2CH3. In some embodiments is a compound of Formula (I), or a pharmaceutically able salt or solvate f, wherein R1 is — (CR4R5)t-C3.6cycloalkyl-R6 and t is 0. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate f, wherein R1 is -(CR4R5)t-C3. 6cycloalkyl-R6 and t is 1. In some embodiments is a nd of Formula (I), or a pharmaceutically able salt or e thereof, wherein R1 is -(CR4R5)t-C3_6cycloalkyl- R6 and t is 2.
In some embodiments is a nd of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)t-C3.6cycloalkyl-R6, R6 is -C02H, t is 0, and R4 and R5 is independently selected from H and C1-6alkyl. In some embodiments is a compound of Formula (I), or a ceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)t-C3-6cycloalkyl-R6, R6 is -C02H, tis l, and each R4 and R5 is each independently selected from H and C1-6alkyl. In some embodiments is a compound of Formula (I), or a ceutically acceptable salt or solvate thereof, wherein R1 is - (CR4R5)t-C3_6cycloalkyl-R6, R6 is -C02H, t is 2, and each R4 and R5 is each independently selected from H and C1-6alkyl.
In some embodiments is a compound of Formula (I), or a ceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)t-C3.6cycloalkyl-R6, R6 is -C02H, t is 0, and R4 and R5 are H. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)t-C3.6cycloalkyl- R6, R6 is -C02H, t is l, and each R4 and R5 is H. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is - (CR4R5)t-C3_6cycloalkyl-R6, R6 is -C02H, t is 2, and each R4 and R5 is H.
In some embodiments is a compound of Formula (I), or a pharmaceutically able salt or solvate thereof, wherein R1 is -(CR4R5)t-C3.6cycloalkyl-R6, R6 is -C02R9, R9 is kyl, t is 0, and R4 and R5 is ndently selected from H and C1-6alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)t-C3.6cycloalkyl-R6, R6 is -COZR9, R9 is C1-6alkyl, t is l, and each R4 and R5 is each ndently selected from H and C1-6alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)t-C3-6cycloalkyl-R6, R6 is £02119, R9 is C1_6alkyl, tis 2, and each R4 and R5 is each independently selected from H and C1-6alkyl, In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)t-C3_6cycloalkyl-R6, R6 is -C02R9, R9 is C1_6alkyl, tis 0, and R4 and R5 are H. In some ments is a compound of Formula (I), or a ceutically acceptable salt or solvate thereof, wherein R1 is - (CR4R5)t-C3.6cycloalkyl-R6, R6 is -C02R9, R9 is C1-6alkyl, tis l, and each R4 and R5 is H. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is —(CR4R5)t-C3.6cycloalkyl-R6, R6 is -C02R9, R9 is C1-6alkyl, t is 2, and each R4 and R5 is H.
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is -OCH2C(O)OH. In some embodiments is a nd of Formula (I), or a pharmaceutically acceptable salt or e thereof, wherein -X-R1 is -N(H)CH2C(O)OH. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is - OCH(CH3)C(O)OH. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, n -X-R1 is - N(H)CH(CH3)C(O)OH. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is -OCH2CH2C(O)OH.
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is -N(H)CH2CH2C(O)OH. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein - X-R1 is H2CH2C(O)OH. In some ments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is - N(H)CH2CH2CH2C(O)OH. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, n -X-R1 is - OCH2CH2C(CH3)2C(O)OH. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is - N(H)CH2CH2C(CH3)2C(O)OH.
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is -OCH2C(O)OCH3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is H2C(O)OCH3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or e thereof, wherein —X-R1 is — OCH(CH3)C(O)OCH3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is - N(H)CH(CH3)C(O)OCH3. In some embodiments is a compound of Formula (I), or a ceutically acceptable salt or e thereof, n -X—R1 is —OCH2CH2C(O)OCH3.
In some embodiments is a compound of a (I), or a ceutically acceptable salt or solvate f, wherein -X—R1 is —N(H)CH2CH2C(O)OCH3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or e thereof, wherein - X-R1 is -OCH2CH2CH2C(O)OCH3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein —X-R1 is — N(H)CH2CH2CH2C(O)OCH3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is - OCHZCH2C(CH3)2C(O)OCH3. In some embodiments is a compound of Formula (I), or a pharmaceutically able salt or e f, wherein -X-R1 is - N(H)CH2CH2C(CH3)2C(O)OCH3.
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or e f, wherein -X-R1 is -OCH2CH20CH2C(O)OH. In some embodiments is a compound of Formula (I), or a ceutically acceptable salt or solvate thereof, wherein -X-R1 is -N(H)CH2CH20CH2C(O)OH. In some ments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein - X-R1 is -OCH2CH2N(H)CH2C(O)OH. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is - N(H)CH2CH2N(S02CH3)CH2C(O)OH. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is - OCHZCHZCHZC(O)OCH(CH3)OC(O)OCH2CH3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is - N(H)CH2CH2CH2C(O)OCH(CH3)OC(O)OCH(CH3)2. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate f, wherein -X-R1 is - OCHZCHZCHZC(O)OCH20C(O)OC(CH3)3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or e thereof, wherein -X-R1 is - N(H)CH2CHZCH2C(O)OCH(CH3)OC(O)CH(CH3)2.
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or e thereof, wherein -X—R1 is -O—cyclopropyl-C(O)OH, In some embodiments is a nd of Formula (I), or a pharmaceutically acceptable salt or solvate f, wherein -X-R1 is -N(H)-cyclopropyl—C(O)OH. In some embodiments is a compound of a (I), or a pharmaceutically acceptable salt or solvate thereof, wherein - X-R1 is -O-cyclobutyl-C(O)OH. In some embodiments is a compound of Formula (I), or a pharmaceutically able salt or solvate thereof, wherein -X-R1 is -N(H)—cyclobutyl- C(O)OH.
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, l, 2, or 3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate f, wherein 11 is 0, 1, or 2. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 or 2. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or e thereof, wherein n is 0 or 1.
In some embodiments is a compound of Formula (I), or a ceutically acceptable salt or solvate thereof, wherein n is O. In some embodiments is a nd of Formula (I), or a ceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 4.
In some embodiments is a compound of Formula (I), or a pharmaceutically able salt or e thereof, wherein n is 1 and R2 is halogen, C1_6alkyl, C1-6haloalkyl, or -OR17. In some ments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R2 is halogen, C1-6alkyl, or C1- 6haloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, n n is 1 and R2 is halogen. In some embodiments is a compound of a (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R2 is -Cl. In some ments is a compound of Formula (I), or a pharmaceutically acceptable salt or e thereof, wherein n is 1 and R2 is -F. In some embodiments is a nd of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R2 is C1.6alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R2 is -CH3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or e thereof, wherein n is 1 and R2 is C1_6haloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or e thereof, wherein n is 1 and R2 is -CF3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate f, wherein n is 1 and R2 is C1_6alkoxy.
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate f, wherein n is 1 and R2 is -OCH3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R2 is C1_6haloalkoxy. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R2 is -OCF3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R2 is -OH. In some embodiments is a compound of a (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is l and R2 is -CN.
In some embodiments is a compound of a (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R2 is independently halogen, C1- 6alkyl, C1-6haloalkyl, or -OR17. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, n n is 2 and each R2 is independently halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1.6haloalkoxy, -OH, or -CN.
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R2 is independently halogen, C1-6alkyl, C1- shaloalkyl, C1-6alkoxy, -OCF3, or -CN. In some embodiments is a nd of Formula (I), or a pharmaceutically acceptable salt or e thereof, wherein n is 2 and each R2 is independently n, C1_6alkyl, C1_6haloalkyl, C1_6alkoxy, or -OCF3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or e thereof, wherein n is 2 and each R2 is independently halogen, C1-6alkyl, C1-6haloalkyl, or - OCF3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R2 is ndently n, C1- 6alkyl, or C1.6haloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R2 is independently halogen or loalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or e thereof, wherein n is 2 and each R2 is independently halogen or C1-6alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate f, wherein n is 2 and each R2 is independently halogen. In some embodiments is a compound of a (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R2 is independently C1-(,alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R2 is independently C1-6haloalkyl.
In some embodiments is a compound of a (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3 and each R2 is independently halogen, C1- 6alkyl, C1-6haloalkyl, or -OR17. In some ments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3 and each R2 is independently halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1.6haloalkoxy, -OH, or -CN.
In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3 and each R2 is independently halogen, C1-6alkyl, C1- 6haloalkyl, C1-6alkoxy, -OCF3, or -CN. In some embodiments is a nd of Formula (I), or a pharmaceutically acceptable salt or solvate f, wherein n is 3 and each R2 is independently halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, or -OCF3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3 and each R2 is independently halogen, C1-6alkyl, C1-6haloalkyl, or - OCF3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3 and each R2 is independently halogen, C1- 6alkyl, or C1.6haloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3 and each R2 is ndently halogen or loalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, n n is 3 and each R2 is independently halogen or C1_6alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3 and each R2 is independently halogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3 and each R2 is ndently C1-6alkyl. In some ments is a nd of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3 and each R2 is independently C1-6haloalkyl.
In some embodiments is a nd of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 4 and each R2 is independently halogen, C1- 6alkyl, C1-6haloalkyl, and —0R”.
In some ments is a compound of Formula (Ia): (R2)n fl 0 CF3 R1—x GOAOXCBN Formula (Ia), wherein: X is —o—, —s—, —soz—, -N(R3)-, or -CH2-, Y is -O- or -N(R7)-, R1 is -(CR4R5)m-R6, -(CR4R5)p-Y-(CR4R5)q-R6, or —(CR4R5)t—C3.6cycloalkyl—R6, each R2 is independently selected from halogen, -CN, kyl, loalkyl, -C1. 6alkyl(heterocycloalkyl), 011”, and —C(0)NR18R19; R3 is H or C1-6alkyl, each R4 and R5 is each independently selected from H, F, and C1.6alkyl, or R4 and R5, together with the carbon to which they are attached, form a C3-6cycloalkyl ring, R6 is , -C(O)R10, or -C(O)O-(CR12R13)-OC(O)R11; R7 is H, C1_6alkyl, or , R8 is C1-6alkyl, R9 is H or C1.5alkyl; R10 is C1_6alkyl or -NHSOZR21; R11 is C1.6alkyl or C1.6alkoxy; R12 and R13 is each independently H or C1.6alkyl, each R17 is independently selected from H, kyl, loalkyl, aminoalkyl, cycloalkyl, -C1-6alkyl(heterocycloalkyl), -C1-6alkyl-C(O)(heterocycloalkyl), ally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, each R18 and R19 is independently selected from H, C1-6alkyl, C1-6haloalkyl, cycloalkyl, aryl, and heteroaryl, or R18 and R19, together with the nitrogen to which they are attached, form a heterocycloalkyl ring optionally substituted with one, two, or three R20; each R20 is independently selected from halogen, kyl, C1-6haloalkyl, oxo, -CN, and C3-6cycloalkyl; R21 is C1_6alkyl, mis l, 2, 3 or4; n is 0,1, 2, 3, or4, p is 2, 3, or 4, q is l, 2, or 3, and t is O, l, or 2, or a pharrnaceutically acceptable salt or solvate f.
In some embodiments is a compound of Formula (Ia), or a pharrnaceutically acceptable salt or solvate thereof, wherein X is -O-, -S—, -SOz—, -N(R3)—, or -CH2-. In some embodiments is a compound of Formula (Ia), or a pharmaceutically able salt or solvate thereof, wherein X is —O-. In some embodiments is a compound of Formula (Ia), or a pharrnaceutically acceptable salt or solvate thereof, wherein X is -S-. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -SOz-. In some embodiments is a compound of Formula (Ia), or a pharrnaceutically acceptable salt or e thereof, wherein X is -. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or WO 93949 solvate thereof, wherein X is . In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —N(CH3)—. In some embodiments is a compound of Formula (Ia), or a ceutically acceptable salt or e thereof, wherein X is —N(CH2CH3)-. In some embodiments is a compound of Formula (Ia), or a pharmaceutically able salt or solvate thereof, wherein X is -CH2-.
In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6. In some embodiments is a nd of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6 and R6 is -C02R9. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate f, wherein R1 is -(CR4R5)m-R6 and R6 is -C02H. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, n R1 is -(CR4R5)m-R6 and R6 is - COzCH3. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m—R6 and R6 is -C02CH2CH3. In some embodiments is a compound of Formula (Ia), or a ceutically able salt or solvate thereof, wherein R1 is -(CR4R5)m-R6 and R6 is -C(O)R10, In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6 and R6 is -C(O)NHSOZCH3. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, n R1 is - (CR4R5)m-R6 and R6 is -C(O)O-(CR12R13)-OC(O)R11. In some ments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is — (CR4R5)m-R6 and R6 is CH20C(O)R”. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is - (CR4R5)m-R6 and R6 is -C(O)OCH20C(O)OCH2CH3. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is — (CR4R5)m-R6 and R6 is -C(O)OCH20C(O)OCH(CH3)2. In some embodiments is a compound of Formula (Ia), or a ceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6 and R6 is -C(O)OCH20C(O)OC(CH3)3. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is 5)m-R6 and R6 is -C(O)OCH20C(O)CH(CH3)2. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6 and m is 1. In some embodiments is a compound of a (Ia), or a ceutically acceptable salt or solvate thereof, wherein R1 is 5)m-R6 and m is 2.
In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6 and m is 3. In some ments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate f, wherein R1 is -(CR4R5)m-R6 and m is 4. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate f, wherein R1 is -(CR4R5)m-R6 and each R4 and R5 is each independently selected from H and C1-6alkyl. In some embodiments is a compound of Formula (Ia), or a pharmaceutically able salt or solvate thereof, wherein R1 is -(CR4R5)m-R6 and each R4 and R5 is H.
In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02H, m is 1, and R4 and R5 is independently selected from H and C1.6alkyl. In some ments is a nd of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02H, m is 2, and each R4 and R5 is each independently selected from H and C1-6alkyl. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is 5)m-R6, R6 is - COZH, m is 3, and each R4 and R5 is each independently ed from H and C1-6alky1. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02H, m is 4, and each R4 and R5 is each independently selected from H and C1-6alkyl.
In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02H, m is 1, and R4 and R5 are H. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, n R1 is -(CR4R5)m-R6, R6 is -C02H, m is 2, and each R4 and R5 is H. In some ments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is - COZH, m is 3, and each R4 and R5 is H. In some embodiments is a compound of Formula (Ia), or a pharmaceutically able salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02H, m is 4, and each R4 and R5 is H.
In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is 5)m-R6, R6 is -C02R9, R9 is ky1, m is 1, and R4 and R5 is independently selected from H and kyl. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate f, wherein R1 is -(CR4R5)m-R6, R6 is -C02R9, R9 is C1_6alkyl, m is 2, and each R4 and R5 is each independently selected from H and C1-6alkyl. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02R9, R9 is C1-6alkyl, m is 3, and each R4 and R5 is each independently selected from H and C1-6alkyl. In some embodiments is a nd of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is - (CR4R5)m-R6, R6 is -C02R9, R9 is C1_6alkyl, m is 4, and each R4 and R5 is each ndently selected from H and C1-6alkyl.
In some embodiments is a nd of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02R9, R9 is C1_6alkyl, m is 1, and R4 and R5 are H. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is - COzRg, R9 is C1-6alkyl, m is 2, and each R4 and R5 is H. In some embodiments is a compound of Formula (Ia), or a ceutically acceptable salt or e thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02R9, R9 is C1_6alkyl, m is 3, and each R4 and R5 is H. In some ments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is , R9 is C1-6alkyl, m is 4, and each R4 and R5 is H.
In some embodiments is a compound of Formula (Ia), or a ceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)10-Y-(CR4R5)q-R6. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p-Y-(CR4R5)q-R6 and R6 is -C02R9. In some embodiments is a nd of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, n R1 is -(CR4R5)p-Y-(CR4R5)q-R6 and R6 is -C02H. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p-Y-(CR4R5)q-R6 and R6 is -C02CH3. In some embodiments is a compound of a (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p-Y-(CR4R5)q-R6 and R6 is -C02CH2CH3. In some embodiments is a compound of Formula (Ia), or a ceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p-Y-(CR4R5)q-R6 and Y is -O-. In some embodiments is a compound of Formula (Ia), or a pharmaceutically able salt or solvate thereof, wherein R1 is -(CR4R5)p-Y-(CR4R5)q-R6 and Y is -N(R7)-. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or e thereof, wherein R1 is —(CR4R5)p-Y-(CR4R5)q-R6 and Y is -N(H)-. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is —(CR4R5)I,-Y-(CR4R5)q-R6 and Y is -N(S02Me)-. In some embodiments is a compound of a (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)10-Y-(CR4R5)q-R6 and p is 2. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)10-Y-(CR4R5)q-R6 and p is 3. In some embodiments is a compound of Formula (Ia), or a ceutically acceptable salt or solvate thereof, wherein R1 is - (CR4R5)10-Y-(CR4R5)q-R6 and p is 4. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, n R1 is —(CR4R5)p—Y- (CR4R5)q-R6 and q is 1. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p-Y—(CR4R5)q—R6 and q is 2. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p-Y-(CR4R5)q-R6 and q is 3. In some ments is a compound of a (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p-Y-(CR4R5)q-R6 and each R4 and R5 is each independently selected from H and kyl. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, n R1 is - (CR4R5)p-Y-(CR4R5)q-R6 and each R4 and R5 is H.
In some embodiments is a nd of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is 5)p-Y-(CR4R5)q-R6, R6 is -C02H, Y is —O-, p is 2, q is l, and R4 and R5 is independently selected from H and C1-6alkyl. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p-Y-(CR4R5)q-R6, R6 is -C02H, Y is -N(H)-, p is 2, q is l, and each R4 and R5 is each independently selected from H and C1.6alkyl. In some embodiments is a compound of Formula (Ia), or a ceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p-Y-(CR4R5)q-R6, R6 is -C02H, Y is -N(SOzMe)-, p is 2, q is l, and each R4 and R5 is each independently selected from H and C1-6alkyl.
In some embodiments is a nd of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p-Y-(CR4R5)q-R6, R6 is -C02H, Y is -O—, p is 2, q is l, and R4 and R5 are H. In some embodiments is a compound of a (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is 5)p-Y- (CR4R5)q-R6, R6 is -C02H, Y is -N(H)-, p is 2, q is l, and each R4 and R5 is H. In some embodiments is a compound of a (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is —(CR4R5)p-Y-(CR4R5)q-R6, R6 is —C02H, Y is -N(SOzMe)-, p is 2, q is l, and each R4 and R5 is H.
In some embodiments is a compound of Formula (Ia), or a pharmaceutically able salt or solvate thereof, wherein R1 is -(CR4R5)p-Y-(CR4R5)q-R6, R6 is -C02R9, R9 is kyl, Y is -O-, p is 2, q is l, and R4 and R5 is independently selected from H and C1- salkyl. In some embodiments is a compound of Formula (Ia), or a ceutically able salt or solvate thereof, wherein R1 is -(CR4R5)10-Y-(CR4R5)q-Ré, R6 is -C02R9, R9 is C1_6alkyl, Y is -N(H)-, p is 2, q is 1, and each R4 and R5 is each ndently selected from H and C1-6alkyl. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p-Y-(CR4R5)q—R6, R6 is -C02R9, R9 is C1_6alkyl, Y is -N(SOzMe)-, p is 2, q is l, and each R4 and R5 is each independently selected from H and C1.6alkyl.
In some embodiments is a compound of Formula (Ia), or a pharmaceutically able salt or solvate thereof, n R1 is -(CR4R5)p-Y-(CR4R5)q-R6, R6 is -C02R9, R9 is C1_6alkyl, Y is -O-, p is 2, q is l, and R4 and R5 are H. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p-Y-(CR4R5)q-R6, R6 is £02119, R9 is C1-6alkyl, Y is -N(H)-, p is 2, q is 1, and each R4 and R5 is H. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, n R1 is 5)p-Y-(CR4R5)q-R6, R6 is -C02R9, R9 is kyl, Y is -N(SOzMe)-, p is 2, q is 1, and each R4 and R5 is H.
In some embodiments is a compound of Formula (Ia), or a ceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)t-C3-6cycloalkyl-R6. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or e thereof, wherein R1 is -(CR4R5)t-cyclopropyl-R6. In some embodiments is a compound of Formula (Ia), or a pharmaceutically able salt or solvate thereof, wherein R1 is -(CR4R5)t-cyclobutyl-R6. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, n R1 is -(CR4R5)t-cyclopentyl-R6.
In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)t-cyclohexyl—R6. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or e thereof, wherein R1 is -(CR4R5)t-C3.6cycloalkyl-R6 and R6 is -C02R9, In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is - (CR4R5)t-C3.6cycloalkyl-R6 and R6 is —C02H. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is - (CR4R5)t-C3_6cycloalkyl-R6 and R6 is —C02CH3. In some embodiments is a compound of a (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is - (CR4R5)t-C3.6cycloalkyl-R6 and R6 is —C02CH2CH3. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is - (CR4R5)t-C3.6cycloalkyl-R6 and t is 0. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)t-C3_ (,cycloalkyl-R6 and t is 1. In some embodiments is a compound of Formula (Ia), or a pharmaceutically able salt or solvate f, wherein R1 is -(CR4R5)t-C3.6cycloalkyl- R6 and t is 2.
In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate f, n R1 is -(CR4R5)t-C3.6cycloalkyl-R6, R6 is -C02H, t is 0, and R4 and R5 is independently selected from H and C1.6alkyl. In some ments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)t-C3-6cycloalkyl-R6, R6 is -C02H, t is 1, and each R4 and R5 is each ndently selected from H and kyl. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is - (CR4R5)t-C3-6cycloalkyl-R6, R6 is -C02H, t is 2, and each R4 and R5 is each independently selected from H and C1-6alkyl.
In some embodiments is a compound of Formula (Ia), or a pharmaceutically able salt or solvate thereof, wherein R1 is -(CR4R5)t-C3-6cycloalkyl-Ré, R6 is -C02H, t is O, and R4 and R5 are H. In some ments is a compound of Formula (Ia), or a ceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)t-C3.6cycloalkyl- R6, R6 is -C02H, tis l, and each R4 and R5 is H. In some ments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is - (CR4R5)t-C3-6cycloalkyl-R6, R6 is -C02H, t is 2, and each R4 and R5 is H.
In some embodiments is a nd of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)t-C3_6cycloalkyl-R6, R6 is -C02R9, R9 is C1_6alkyl, t is O, and R4 and R5 is independently selected from H and C1-6alkyl. In some embodiments is a compound of Formula (Ia), or a ceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)t-C3.6cycloalkyl-R6, R6 is -C02R9, R9 is C1-6alkyl, t is l, and each R4 and R5 is each independently selected from H and C1-6alkyl. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)t-C3.6cycloalkyl-R6, R6 is -C02R9, R9 is kyl, t is 2, and each R4 and R5 is each independently selected from H and C1-6alkyl.
In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)t-C3.6cycloalkyl-R6, R6 is -C02R9, R9 is C1-6alkyl, tis 0, and R4 and R5 are H. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is - (CR4R5)t-C3.6cycloalkyl-R6, R6 is -C02R9, R9 is C1-6alkyl, tis l, and each R4 and R5 is H. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)t-C3.6cycloalkyl-R6, R6 is -COZR9, R9 is C1_6alkyl, t is 2, and each R4 and R5 is H.
In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein -X—R1 is -OCH2C(O)OH. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is -N(H)CH2C(O)OH. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is - 3)C(O)OH. In some embodiments is a nd of Formula (Ia), or a pharmaceutically able salt or solvate thereof, wherein -X-R1 is - N(H)CH(CH3)C(O)OH. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is -OCH2CH2C(O)OH.
In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is -N(H)CH2CH2C(O)OH. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate f, wherein -X-R1 is -OCH2CH2CH2C(O)OH. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is - N(H)CH2CH2CH2C(O)OH. In some embodiments is a compound of Formula (Ia), or a ceutically acceptable salt or solvate thereof, wherein -X-R1 is - OCHZCH2C(CH3)2C(O)OH. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate f, wherein -X-R1 is - N(H)CH2CH2C(CH3)2C(O)OH.
In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein -X—R1 is -OCH2C(O)OCH3. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is -N(H)CH2C(O)OCH3. In some embodiments is a compound of Formula (Ia), or a pharmaceutically able salt or solvate f, n -X-R1 is -OCH(CH3)C(O)OCH3. In some embodiments is a compound of Formula (Ia), or a pharmaceutically able salt or solvate thereof, wherein -X-R1 is - (CH3)C(O)OCH3, In some ments is a compound of Formula (Ia), or a ceutically acceptable salt or solvate thereof, n -X-R1 is —OCH2CH2C(O)OCH3.
In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is H2CH2C(O)OCH3. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, n -X-R1 is -OCH2CH2CH2C(O)OCH3. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is - N(H)CH2CH2CH2C(O)OCH3. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is - OCHZCH2C(CH3)2C(O)OCH3. In some embodiments is a compound of Formula (Ia), or a ceutically acceptable salt or solvate thereof, n -X-R1 is - N(H)CH2CH2C(CH3)2C(O)OCH3.
In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or e thereof, wherein -X-R1 is -OCH2CH20CH2C(O)OH. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is -N(H)CH2CH20CH2C(O)OH. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is -OCH2CH2N(H)CH2C(O)OH. In some embodiments is a compound of Formula (Ia), or a ceutically acceptable salt or solvate thereof, wherein —X-R1 is - N(H)CH2CH2N(SOZCH3)CH2C(O)OH, In some embodiments is a nd of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein —X-R1 is - OCH2CH2CH2C(O)OCH(CH3)OC(O)OCH2CH3. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate f, wherein -X-R1 is - N(H)CH2CH2CH2C(O)OCH(CH3)OC(O)OCH(CH3)2. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is - OCHZCHzCHzC(O)OCH20C(O)OC(CH3)3. In some ments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, n —X-R1 is - N(H)CH2CHZCH2C(O)OCH(CH3)OC(O)CH(CH3)2.
In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is -O-cyclopropyl-C(O)OH. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is -N(H)-cyclopropyl-C(O)OH. In some embodiments is a compound of Formula (Ia), or a ceutically acceptable salt or solvate thereof, wherein -X-R1 is -O—cyclobutyl-C(O)OH. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate f, wherein —X-R1 is cyclobutyl- C(O)OH.
In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate f, wherein n is O, l, 2, or 3. In some embodiments is a 2017/061870 compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate f, wherein n is 1 or 2. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0 or 1.
In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is O. In some ments is a compound of Formula (Ia), or a ceutically acceptable salt or solvate f, n n is 1. In some ments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or e thereof, wherein n is 3. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate f, n n is 4.
In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R2 is halogen, C1.6alkyl, C1.6haloalkyl, or -OR17. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R2 is n, C1_6alkyl, or C1- lkyl. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, n n is 1 and R2 is halogen. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R2 is -Cl, In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R2 is -F. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R2 is C1-6alkyl. In some embodiments is a compound of Formula (Ia), or a pharmaceutically able salt or solvate thereof, wherein n is 1 and R2 is -CH3. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R2 is C1-6haloalkyl. In some embodiments is a compound of a (Ia), or a pharmaceutically acceptable salt or solvate f, wherein n is 1 and R2 is -CF3. In some embodiments is a nd of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R2 is C1-6alkoxy. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R2 is -OCH3. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate f, wherein n is 1 and R2 is C1_6haloalkoxy. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R2 is - OCF3. In some embodiments is a compound of Formula (Ia), or a pharmaceutically WO 93949 acceptable salt or solvate thereof, wherein n is l and R2 is -OH. In some embodiments is a nd of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is l and R2 is -CN.
In some ments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R2 is independently halogen, C1- salkyl, C1.6haloalkyl, or -OR17. In some embodiments is a compound of a (Ia), or a pharmaceutically acceptable salt or e thereof, wherein n is 2 and each R2 is independently n, C1.6alkyl, C1.6haloalkyl, C1.6alkoxy, C1.6haloalkoxy, -OH, or -CN.
In some embodiments is a compound of Formula (Ia), or a ceutically acceptable salt or solvate thereof, wherein n is 2 and each R2 is independently halogen, C1.5alkyl, C1. 6haloalkyl, C1-6alkoxy, -OCF3, or -CN. In some embodiments is a compound of a (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R2 is independently halogen, C1-6alkyl, loalkyl, C1-6alkoxy, or -OCF3. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R2 is independently halogen, C1_6alkyl, C1- 6haloalkyl, or -OCF3. In some embodiments is a compound of Formula (Ia), or a ceutically acceptable salt or solvate thereof, wherein n is 2 and each R2 is independently halogen, C1-6alkyl, or C1.6haloalkyl. In some embodiments is a nd of Formula (Ia), or a ceutically acceptable salt or solvate thereof, wherein n is 2 and each R2 is independently halogen or C1-6haloalkyl. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R2 is independently halogen or C1-6alkyl. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, n n is 2 and each R2 is independently halogen. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R2 is independently C1-6alkyl. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R2 is independently C1-6haloalkyl.
] In some ments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3 and each R2 is independently halogen, C1- 6alkyl, C1_6haloalkyl, or -OR17. In some embodiments is a nd of Formula (Ia), or a pharmaceutically acceptable salt or e thereof, wherein n is 3 and each R2 is independently halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1_6haloalkoxy, -OH, or -CN.
In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3 and each R2 is ndently halogen, C1-6alkyl, C1- 6haloalkyl, C1_6alkoxy, -OCF3, or -CN. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3 and each R2 is independently halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, or —OCF3. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3 and each R2 is ndently halogen, C1.6alkyl, C1. 6haloalkyl, or -OCF3. In some embodiments is a compound of a (Ia), or a pharmaceutically acceptable salt or solvate f, wherein n is 3 and each R2 is independently halogen, C1-6alkyl, or C1.6haloalkyl. In some embodiments is a nd of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, n n is 3 and each R2 is independently halogen or C1-6haloalkyl. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3 and each R2 is independently halogen or C1-6alkyl. In some embodiments is a nd of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3 and each R2 is independently halogen. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3 and each R2 is independently kyl. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3 and each R2 is independently C1-6haloalkyl.
In some embodiments is a nd of Formula (Ia), or a pharmaceutically able salt or solvate thereof, wherein n is 4 and each R2 is independently halogen, C1- 6alkyl, C1-6haloalkyl, and OR”.
] In some embodiments is a compound of a (Iaa): (R2)n m o CF3 R1-X 00WN Formula (Iaa), wherein: X is -O- or -N(R3)-, R1 is —(CR4R5)m—R"; each R2 is independently selected from halogen, C1-6alkyl, or C1-6haloalkyl; R3 is H or C1_6alkyl, each R4 and R5 is each independently selected from H, F, and C1_6alkyl, R6 is -C02R9; R9 is H or C1-6alkyl, m is l, 2, 3 or 4; and n is O, l, or 2, or a pharmaceutically acceptable salt or solvate f.
In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -O-. In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein X is - . In some embodiments is a compound of Formula (Iaa), or a pharmaceutically able salt or solvate thereof, wherein X is -N(H)-. In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein X is )-. In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -N(CH2CH3)—.
In some ments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6. In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6 and R6 is -C02R9. In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is - (CR4R5)m-R6 and R6 is -C02H. In some embodiments is a compound of Formula (Iaa), or a ceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6 and R6 is - C02CH3. In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6 and R6 is -C02CH2CH3. In some ments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or e thereof, wherein R1 is -(CR4R5)m-R6 and m is 1. In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or e f, wherein R1 is 5)m-R6 and m is 2. In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m—R6 and m is 3. In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or e thereof, wherein R1 is -(CR4R5)m-R6 and m is 4. In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is —(CR4R5)m-R6 and each R4 and R5 is each ndently selected from H and C1-6alkyl. In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6 and each R4 and R5 is H.
] In some embodiments is a compound of Formula (Iaa), or a ceutically acceptable salt or solvate thereof, wherein R1 is 5)m-R6, R6 is -C02H, m is 1, and R4 and R5 is independently selected from H and C1-6alkyl. In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02H, m is 2, and each R4 and R5 is each independently selected from H and C1.6alkyl. In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is - COzH, m is 3, and each R4 and R5 is each ndently selected from H and kyl. In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or e thereof, wherein R1 is -(CR4R5)m-R6, R6 is -COzH, m is 4, and each R4 and R5 is each independently selected from H and C1-6alkyl.
In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02H, m is l, and R4 and R5 are H. In some embodiments is a compound of a (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02H, m is 2, and each R4 and R5 is H. In some embodiments is a compound of a (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is — COzH, m is 3, and each R4 and R5 is H. In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02H, m is 4, and each R4 and R5 is H.
In some embodiments is a compound of Formula (Iaa), or a pharmaceutically able salt or solvate thereof, wherein R1 is 5)m-R6, R6 is -C02R9, R9 is C1_6alkyl, m is l, and R4 and R5 is independently selected from H and C1_6alkyl. In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02R9, R9 is C1-6alkyl, m is 2, and each R4 and R5 is each independently selected from H and C1-6alkyl. In some embodiments is a compound of Formula (Iaa), or a ceutically acceptable salt or solvate thereof, n R1 is -(CR4R5)m-R6, R6 is , R9 is kyl, m is 3, and each R4 and R5 is each independently selected from H and C1-6alkyl. In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, n R1 is - (CR4R5)m-R6, R6 is -C02R9, R9 is Cmalkyl, m is 4, and each R4 and R5 is each independently selected from H and C1-6alkyl.
In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02R9, R9 is C1_6alkyl, WO 93949 2017/061870 m is 1, and R4 and R5 are H. In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is - C02R9, R9 is C1_6alkyl, m is 2, and each R4 and R5 is H. In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02R9, R9 is C1-6alkyl, m is 3, and each R4 and R5 is H.
In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02R9, R9 is C1_6alkyl, m is 4, and each R4 and R5 is H.
In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is (O)OH. In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, n -X-R1 is -N(H)CH2C(O)OH. In some embodiments is a compound of Formula (Iaa), or a ceutically acceptable salt or solvate thereof, wherein -X-R1 is - OCH(CH3)C(O)OH. In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is - N(H)CH(CH3)C(O)OH. In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is -OCH2CH2C(O)OH.
In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or e f, wherein -X-R1 is -N(H)CH2CH2C(O)OH. In some embodiments is a compound of a (Iaa), or a ceutically acceptable salt or solvate thereof, wherein -X-R1 is -OCH2CH2CH2C(O)OH. In some embodiments is a compound of Formula (Iaa), or a pharmaceutically able salt or solvate thereof, wherein -X-R1 is - N(H)CH2CH2CH2C(O)OH. In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is - OCHZCH2C(CH3)2C(O)OH. In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is - 2CH2C(CH3)2C(O)OH.
In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate f, n -X—R1 is -OCH2C(O)OCH3. In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is -N(H)CH2C(O)OCH3. In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or e thereof, wherein -X-R1 is -OCH(CH3)C(O)OCH3. In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is - N(H)CH(CH3)C(O)OCH3. In some embodiments is a compound of Formula (Iaa), or a pharmaceutically able salt or solvate thereof, wherein -X—R1 is —OCH2CH2C(O)OCH3, In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is -N(H)CH2CH2C(O)OCH3. In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, n -X-R1 is -OCH2CH2CH2C(O)OCH3. In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is - N(H)CH2CH2CH2C(O)OCH3. In some ments is a nd of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is - OCH2CH2C(CH3)2C(O)OCH3. In some embodiments is a nd of Formula (Iaa), or a pharmaceutically able salt or solvate thereof, wherein -X-R1 is - N(H)CH2CH2C(CH3)2C(O)OCH3.
In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 or 2. In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0 or 1. In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0. In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, n n is 2.
In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is l and R2 is halogen, C1_6alkyl, or C1- lkyl. In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate f, wherein n is l and R2 is halogen. In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or e thereof, wherein n is l and R2 is -Cl. In some embodiments is a compound of a (Iaa), or a pharmaceutically acceptable salt or e thereof, wherein n is l and R2 is -F. In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is l and R2 is C1-6alkyl. In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is l and R2 is —CH3. In some embodiments is a nd of Formula (Iaa), or a pharmaceutically acceptable salt or solvate f, wherein n is l and R2 is C1_6haloalkyl. In some embodiments is a compound of Formula (Iaa), or a ceutically acceptable salt or e thereof, wherein n is l and R2 is -CF3.
In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R2 is independently halogen, C1- , or C1_6haloalkyl. In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R2 is independently halogen or C1-6haloalkyl. In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, n n is 2 and each R2 is independently halogen or C1.6alkyl. In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate f, wherein n is 2 and each R2 is independently n. In some ments is a nd of a (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R2 is independently C1-6alkyl. In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, n n is 2 and each R2 is independently C1-6haloalkyl.
In some embodiments is a compound of Formula (Ib): o CF3 NAOXCFa (R2)n #516; Rl-X Formula (Ib); wherein: X is -o-, -s-, -s02-, -, or -CH2-; Y is -O- or -N(R7)-, R1 is —(CR4R5)m—R6, -(CR4R5)p—Y—(CR4R5)q-R6, or -(CR4R5)t-C3-6cycloalkyl-R6; each R2 is independently selected from halogen, -CN, kyl, C1.6haloalkyl, -C1. 6alkyl(heterocycloalkyl), -OR17, and -C(O)NR18R19; R3 is H or C1-6alkyl, each R4 and R5 is each independently selected from H, F, and C1_6alkyl, or R4 and R5, together with the carbon to which they are attached, form a C3-6cycloalkyl ring, R6 is £02119, -C(O)R1°, or -C(O)O-(CR12R13)-OC(O)R11; R7 is H, C1.6alkyl, or —s02R8; R8 is C1-6alkyl, R9 is H or C1_6alkyl, R10 is C1_6alkyl or -NHSOZR21; R11 is C1_6alkyl or C1-6alkoxy, R12 and R13 is each ndently H or kyl; each R17 is independently selected from H, C1-6alkyl, C1.6haloalkyl, aminoalkyl, cycloalkyl, -C1-6alkyl(heterocycloalkyl), —C1-6alkyl-C(O)(heterocycloalkyl), optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; each R18 and R19 is ndently selected from H, C1.6alkyl, C1.6haloalkyl, cycloalkyl, aryl, and heteroaryl; or R18 and R19, together with the en to which they are attached, form a heterocycloalkyl ring optionally substituted with one, two, or three R20; each R20 is independently selected from n, C1-6alkyl, C1-6haloalkyl, oxo, -CN, and C3.6cycloalkyl; R21 is C1_6alkyl; mis 1, 2, 3 or4; n is 0,1, 2, 3, or4; p is 2, 3, or 4; q is l, 2, or 3; and t is O, 1, or 2; or a pharrnaceutically acceptable salt or solvate thereof.
In some embodiments is a compound of a (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -O-, -S-, -SOz—, —, or -CH2-. In some embodiments is a compound of Formula (Ib), or a ceutically acceptable salt or solvate thereof, wherein X is -O-. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -S-. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -SOz-. In some embodiments is a compound of Formula (Ib), or a pharrnaceutically acceptable salt or solvate thereof, wherein X is —N(R3)-. In some ments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein X is —N(H)-. In some embodiments is a nd of Formula (Ib), or a pharrnaceutically acceptable salt or solvate thereof, n X is -N(CH3)-. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -N(CH2CH3)-. In some embodiments is a compound of Formula (Ib), or a pharrnaceutically acceptable salt or solvate thereof, wherein X is -CH2-.
In some embodiments is a compound of Formula (Ib), or a pharrnaceutically able salt or solvate thereof, wherein R1 is -(CR4R5)m-R6. In some embodiments is a compound of Formula (Ib), or a pharrnaceutically acceptable salt or solvate thereof, wherein R1 is 5)m-R6 and R6 is -C02R9. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, n R1 is -(CR4R5)m-R6 and R6 is -C02H. In some embodiments is a compound of Formula (Ib), or a ceutically acceptable salt or solvate thereof, wherein R1 is 5)m-R6 and R6 is - COzCH3. In some embodiments is a compound of a (Ib), or a pharmaceutically acceptable salt or solvate thereof, n R1 is -(CR4R5)m-R6 and R6 is -C02CH2CH3. In some embodiments is a compound of a (Ib), or a ceutically acceptable salt or solvate thereof, wherein R1 is —(CR4R5)m-R6 and R6 is —C(O)R10. In some embodiments is a compound of Formula (Ib), or a ceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6 and R6 is -C(O)NHSOZCH3. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is - (CR4R5)m-R6 and R6 is -C(O)O-(CR12R13)-OC(O)R11. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or e thereof, wherein R1 is - (CR4R5)m—R6 and R6 is -C(O)OCH20C(O)R”. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is - )m-R6 and R6 is -C(O)OCH20C(O)OCH2CH3. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is - (CR4R5)m—R6 and R6 is -C(O)OCH20C(O)OCH(CH3)2. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6 and R6 is -C(O)OCH20C(O)OC(CH3)3. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or e thereof, wherein R1 is -(CR4R5)m-R6 and R6 is -C(O)OCH20C(O)CH(CH3)2. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, n R1 is -(CR4R5)m-R6 and m is 1. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or e thereof, wherein R1 is -(CR4R5)m-R6 and m is 2.
In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6 and m is 3. In some ments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6 and m is 4. In some embodiments is a nd of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6 and each R4 and R5 is each independently selected from H and C1-6alkyl. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or e thereof, wherein R1 is —(CR4R5)m-R6 and each R4 and R5 is H.
In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, n R1 is -(CR4R5)m-R6, R6 is -C02H, m is 1, and R4 and R5 is independently ed from H and C1-6alkyl. In some embodiments is a compound of a (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02H, m is 2, and each R4 and R5 is each independently selected from H and C1.6alkyl. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is - COzH, m is 3, and each R4 and R5 is each independently selected from H and C1.6alkyl. In some embodiments is a nd of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02H, m is 4, and each R4 and R5 is each independently selected from H and C1-6alkyl.
In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02H, m is l, and R4 and R5 are H. In some embodiments is a nd of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02H, m is 2, and each R4 and R5 is H. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is — COzH, m is 3, and each R4 and R5 is H. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate f, wherein R1 is -(CR4R5)m-R6, R6 is -C02H, m is 4, and each R4 and R5 is H.
In some embodiments is a compound of Formula (Ib), or a ceutically acceptable salt or solvate thereof, wherein R1 is 5)m-R6, R6 is -C02R9, R9 is C1_6alkyl, m is l, and R4 and R5 is independently selected from H and C1_6alkyl. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02R9, R9 is C1-6alkyl, m is 2, and each R4 and R5 is each independently selected from H and C1-6alkyl. In some embodiments is a nd of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02R9, R9 is kyl, m is 3, and each R4 and R5 is each independently selected from H and C1-6alkyl. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is - (CR4R5)m-R6, R6 is -C02R9, R9 is Cmalkyl, m is 4, and each R4 and R5 is each independently selected from H and C1-6alkyl.
In some embodiments is a compound of a (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02R9, R9 is C1_6alkyl, m is 1, and R4 and R5 are H. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or e thereof, wherein R1 is -(CR4R5)m-R6, R6 is - C02R9, R9 is C1_6alkyl, m is 2, and each R4 and R5 is H. In some ments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02R9, R9 is C1-6alkyl, m is 3, and each R4 and R5 is H. In some embodiments is a compound of Formula (Ib), or a pharmaceutically able salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02R9, R9 is C1_6alkyl, m is 4, and each R4 and R5 is H.
In some embodiments is a compound of Formula (Ib), or a ceutically acceptable salt or solvate thereof, n R1 is -(CR4R5)p-Y-(CR4R5)q-R6. In some embodiments is a compound of Formula (Ib), or a ceutically acceptable salt or solvate thereof, n R1 is -(CR4R5)p-Y-(CR4R5)q-R6 and R6 is . In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p-Y—(CR4R5)q-R6 and R6 is -C02H. In some ments is a compound of Formula (Ib), or a pharmaceutically able salt or solvate thereof, wherein R1 is -(CR4R5)p-Y—(CR4R5)q—R6 and R6 is -C02CH3. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)lo-Y—(CRA'R5)q-R6 and R6 is -C02CH2CH3. In some embodiments is a nd of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)1£,-Y-(CR4R5)q-R6 and Y is -O-. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p-Y-(CR4R5)q-R6 and Y is -N(R7)-. In some embodiments is a compound of a (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)lo-Y-(CR4R5)q-R6 and Y is -N(H)-. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p-Y-(CR4R5)q-R6 and Y is -N(SOzMe)-. In some ments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p-Y-(CR4R5)q-R6 and p is 2. In some embodiments is a compound of Formula (lb), or a pharmaceutically able salt or solvate thereof, wherein R1 is -(CR4R5)p-Y-(CR4R5)q-R6 and p is 3. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is - (CR4R5)p-Y-(CR4R5)q-R6 and p is 4. In some embodiments is a nd of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is —(CR4R5)p-Y- (CR4R5)q-R6 and q is 1. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p—Y-(CR4R5)q-R6 and q is 2. In some embodiments is a compound of Formula (Ib), or a ceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p-Y-(CR4R5)q-R6 and q is 3. In some embodiments is a compound of Formula (lb), or a pharmaceutically acceptable salt or solvate f, wherein R1 is -(CR4R5)p-Y-(CR4R5)q-R6 and each R4 and R5 is each independently selected from H and C1.6alkyl. In some embodiments is a compound of Formula (lb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is - (CR4R5)p-Y-(CR4R5)q-R6 and each R4 and R5 is H.
In some embodiments is a compound of Formula (lb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p-Y-(CR4R5)q-R6, R6 is -C02H, Y is -O-, p is 2, q is l, and R4 and R5 is independently selected from H and C1-6alkyl. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p-Y-(CR4R5)q-R6, R6 is -C02H, Y is -N(H)-, p is 2, q is l, and each R4 and R5 is each ndently selected from H and C1.6alkyl. In some embodiments is a compound of Formula (lb), or a pharmaceutically acceptable salt or e thereof, wherein R1 is -(CR4R5)p-Y-(CR4R5)q-R6, R6 is -COZH, Y is —N(SOzMe)-, p is 2, q is l, and each R4 and R5 is each independently selected from H and C1-6alkyl.
In some embodiments is a compound of Formula (lb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p-Y-(CR4R5)q-R6, R6 is -C02H, Y is -O-, p is 2, q is l, and R4 and R5 are H. In some embodiments is a compound of Formula (lb), or a pharmaceutically acceptable salt or solvate thereof, n R1 is -(CR4R5)p-Y- (CR4R5)q-R6, R6 is -C02H, Y is -N(H)-, p is 2, q is 1, and each R4 and R5 is H. In some embodiments is a compound of Formula (lb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p-Y-(CR4R5)q-R6, R6 is -C02H, Y is -N(SOzMe)-, p is 2, q is l, and each R4 and R5 is H.
In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)10-Y-(CR4R5)q-R6, R6 is -C02R9, R9 is C1_6alkyl, Y is -O-, p is 2, q is l, and R4 and R5 is ndently selected from H and C1- salkyl. In some embodiments is a nd of a (lb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)10-Y-(CR4R5)q-Ré, R6 is -C02R9, R9 is kyl, Y is , p is 2, q is 1, and each R4 and R5 is each independently ed from H and C1_6alkyl. In some embodiments is a compound of Formula (lb), or a pharmaceutically acceptable salt or solvate f, n R1 is - CR4R5 p-Y—(CR4R5) —R6,q R6 is -C02R9, R9 is C1.6alkyl, Y is -N(SOzMe)-, p is 2, q is 1, and each R4 and R5 is each ndently selected from H and C1-6alkyl.
In some embodiments is a nd of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p-Y-(CR4R5)q—R6, R6 is -C02R9, R9 is C1-6alkyl, Y is -O-, p is 2, q is 1, and R4 and R5 are H. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p-Y-(CR4R5)q-R6, R6 is £02119, R9 is C1_6alkyl, Y is -N(H)-, p is 2, q is 1, and each R4 and R5 is H. In some embodiments is a compound of Formula (Ib), or a ceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p—Y-(CR4R5)q-R67 R6 is , R9 is C1-6alkyl, Y is -N(SOzMe)-, p is 2, q is 1, and each R4 and R5 is H.
In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)t-C3-6cycloalkyl-R6. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)t-cyclopropyl-R6. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is 5)t-cyclobutyl-R6. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)t-cyclopentyl-R6.
In some embodiments is a compound of Formula (Ib), or a pharmaceutically able salt or solvate thereof, wherein R1 is -(CR4R5)t-cyclohexyl-R6. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)t-C3.6cycloalkyl-R6 and R6 is -C02R9. In some embodiments is a compound of Formula (Ib), or a pharmaceutically able salt or solvate thereof, wherein R1 is - (CR4R5)t-C3_6cycloalkyl-R6 and R6 is —C02H. In some ments is a nd of Formula (Ib), or a pharmaceutically able salt or solvate thereof, wherein R1 is - (CR4R5)t-C3.6cycloalkyl-R6 and R6 is —C02CH3. In some ments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is - (CR4R5)t-C3_6cycloalkyl-R6 and R6 is —C02CH2CH3, In some ments is a compound of Formula (lb), or a pharmaceutically acceptable salt or solvate thereof, n R1 is - (CR4R5)t-C3.6cycloalkyl-R6 and t is 0. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)t-C3. alkyl-R6 and t is 1. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or e thereof, wherein R1 is -(CR4R5)t-C3_6cycloalkyl- R6 and t is 2.
In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or e thereof, wherein R1 is -(CR4R5)t-C3-6cycloalkyl-R6, R6 is -C02H, t is 0, and R4 and R5 is independently ed from H and C1-6alkyl. In some embodiments is a nd of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)t-C3-6cycloalkyl-R6, R6 is -C02H, tis l, and each R4 and R5 is each independently selected from H and C1.6alkyl. In some embodiments is a nd of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is - (CR4R5)t-C3.6cycloalkyl-R6, R6 is -C02H, t is 2, and each R4 and R5 is each independently selected from H and C1-6alkyl.
In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)t-C3.6cycloalkyl-R6, R6 is -C02H, t is 0, and R4 and R5 are H. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)t-C3.6cycloalkyl- R6, R6 is -C02H, t is l, and each R4 and R5 is H. In some embodiments is a compound of a (Ib), or a pharmaceutically acceptable salt or e thereof, wherein R1 is - (CR4R5)t-C3_6cycloalkyl-R6, R6 is -C02H, t is 2, and each R4 and R5 is H.
In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate f, wherein R1 is -(CR4R5)t-C3-6cycloalkyl-Rs, R6 is -C02R9, R9 is C1_6alkyl, t is 0, and R4 and R5 is independently selected from H and C1-6alkyl. In some embodiments is a compound of Formula (Ib), or a ceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)t-C3.6cycloalkyl-R6, R6 is -C02R9, R9 is C1-6alkyl, t is l, and each R4 and R5 is each independently selected from H and C1-6alkyl. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)t-C3.6cycloalkyl-R6, R6 is -C02R9, R9 is kyl, t is 2, and each R4 and R5 is each independently selected from H and C1-6alkyl.
In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)t-C3_6cycloalkyl-R6, R6 is -C02R9, R9 is C1_6alkyl, tis 0, and R4 and R5 are H. In some embodiments is a compound of Formula (Ib), or a ceutically acceptable salt or solvate thereof, wherein R1 is - )t-C3_6cycloalkyl-R6, R6 is -C02R9, R9 is C1-6all<yl, tis l, and each R4 and R5 is H. In some embodiments is a compound of a (Ib), or a ceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)t-C3.6cycloalkyl-R6, R6 is -C02R9, R9 is C1_6alkyl, t is 2, and each R4 and R5 is H.
In some embodiments is a compound of Formula (Ib), or a pharmaceutically able salt or solvate thereof, wherein -X—R1 is -OCH2C(O)OH. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is H2C(O)OH. In some embodiments is a compound of Formula (Ib), or a ceutically acceptable salt or solvate thereof, wherein -X-R1 is - OCH(CH3)C(O)OH. In some ments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is - N(H)CH(CH3)C(O)OH. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is -OCH2CH2C(O)OH.
In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is -N(H)CH2CH2C(O)OH. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is -OCH2CH2CH2C(O)OH. In some embodiments is a compound of a (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is - N(H)CH2CH2CH2C(O)OH. In some embodiments is a compound of Formula (Ib), or a pharmaceutically able salt or solvate thereof, wherein -X-R1 is - 2C(CH3)2C(O)OH. In some ments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, n -X-R1 is - N(H)CH2CH2C(CH3)2C(O)OH.
In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein -X—R1 is (O)OCH3. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or e thereof, wherein -X-R1 is -N(H)CH2C(O)OCH3. In some ments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is -OCH(CH3)C(O)OCH3. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or e thereof, wherein -X-R1 is - N(H)CH(CH3)C(O)OCH3. In some ments is a compound of Formula (lb), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is —OCH2CH2C(O)OCH3.
In some embodiments is a compound of a (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is -N(H)CH2CH2C(O)OCH3. In some embodiments is a compound of a (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is -OCH2CH2CH2C(O)OCH3. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is - N(H)CH2CH2CH2C(O)OCH3. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is - OCHzCH2C(CH3)2C(O)OCH3. In some ments is a compound of Formula (Ib), or a pharmaceutically able salt or solvate thereof, wherein -X-R1 is - N(H)CH2CH2C(CH3)2C(O)OCH3, ] In some ments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein -X—R1 is -OCH2CH20CH2C(O)OH. In some embodiments is a compound of a (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is -N(H)CH2CH20CH2C(O)OH. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is -OCH2CH2N(H)CH2C(O)OH. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is - N(H)CH2CH2N(S02CH3)CH2C(O)OH. In some embodiments is a compound of Formula (Ib), or a pharmaceutically able salt or solvate thereof, wherein —X-R1 is - OCH2CH2CH2C(O)OCH(CH3)OC(O)OCH2CH3. In some ments is a compound of Formula (Ib), or a pharmaceutically able salt or solvate thereof, wherein -X-R1 is - N(H)CH2CH2CH2C(O)OCH(CH3)OC(O)OCH(CH3)2. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is - OCH2CH2CH2C(O)OCH20C(O)OC(CH3)3. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is - N(H)CH2CH2CH2C(O)OCH(CH3)OC(O)CH(CH3)2.
In some embodiments is a compound of Formula (Ib), or a ceutically acceptable salt or solvate thereof, wherein -X-R1 is -O-cyclopropyl-C(O)OH. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is -N(H)—cyclopropyl-C(O)OH. In some embodiments is a nd of Formula (Ib), or a pharmaceutically acceptable salt or e thereof, wherein -X-R1 is -O—cyclobutyl-C(O)OH. In some embodiments is a compound of a (Ib), or a pharmaceutically acceptable salt or solvate f, wherein —X-R1 is —N(H)-cyclobutyl- C(O)OH.
In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, l, 2, or 3. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or e thereof, wherein n is 0, l, or 2. In some ments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is l or 2. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0 or 1.
In some ments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, n n is O. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate f, wherein n is 1. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a nd of a (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3. In some embodiments is a nd of Formula (Ib), or a ceutically acceptable salt or solvate thereof, wherein n is 4.
In some embodiments is a compound of Formula (Ib), or a ceutically acceptable salt or solvate thereof, wherein n is l and R2 is halogen, C1.6alkyl, C1.6haloalkyl, or -OR17. In some embodiments is a compound of Formula (Ib), or a ceutically acceptable salt or solvate thereof, wherein n is l and R2 is halogen, C1_6alkyl, or C1- lkyl. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is l and R2 is n. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, n n is l and R2 is -Cl. In some embodiments is a compound of Formula (Ib), or a ceutically acceptable salt or solvate thereof, n n is l and R2 is -F. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is l and R2 is C1-6alkyl. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is l and R2 is -CH3. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, whereinn is l and R2 is C1-6haloalkyl. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate f, wherein n is l and R2 is -CF3. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is l and R2 is C1-6alkoxy. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is l and R2 is -OCH3. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is l and R2 is C1_6haloalkoxy. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is l and R2 is - OCF3. In some embodiments is a compound of Formula (Ib), or a ceutically acceptable salt or solvate thereof, wherein n is l and R2 is -OH. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or e thereof, wherein n is l and R2 is -CN.
In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R2 is independently halogen, C1- 6alkyl, C1_6haloalkyl, or -OR17. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R2 is independently halogen, C1-6alkyl, loalkyl, C1-6alkoxy, C1.6haloalkoxy, -OH, or -CN.
In some embodiments is a compound of Formula (Ib), or a ceutically acceptable salt or e thereof, wherein n is 2 and each R2 is independently halogen, C1-6alkyl, C1- 6haloalkyl, C1.6alkoxy, -OCF3, or -CN. In some embodiments is a compound of Formula (Ib), or a pharmaceutically able salt or solvate thereof, wherein n is 2 and each R2 is independently halogen, C1.6alkyl, C1-6haloalkyl, C1-6alkoxy, or -OCF3. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R2 is independently halogen, C1-6alkyl, C1- 6haloalkyl, or -OCF3. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R2 is independently halogen, C1-6alkyl, or C1.6haloalkyl. In some embodiments is a nd of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R2 is independently halogen or C1-6haloalkyl. In some embodiments is a nd of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R2 is independently n or C1-6alkyl. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, n n is 2 and each R2 is independently halogen. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R2 is independently C1-6alkyl. In some embodiments is a compound of Formula (Ib), or a pharmaceutically able salt or solvate thereof, wherein n is 2 and each R2 is independently C1-6haloalkyl.
In some embodiments is a compound of Formula (Ib), or a pharmaceutically able salt or e thereof, wherein n is 3 and each R2 is independently halogen, C1- 6alkyl, C1_6haloalkyl, or -OR17. In some embodiments is a nd of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3 and each R2 is independently halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1.6haloalkoxy, -OH, or -CN.
In some embodiments is a compound of Formula (Ib), or a ceutically acceptable salt or solvate thereof, wherein n is 3 and each R2 is independently n, C1-6alkyl, C1- 6haloalkyl, koxy, -OCF3, or -CN. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate f, wherein n is 3 and each R2 is independently halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, or -OCF3. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3 and each R2 is independently halogen, C1_6alkyl, C1- 6haloalkyl, or —OCF3. In some embodiments is a nd of Formula (Ib), or a ceutically acceptable salt or solvate thereof, n n is 3 and each R2 is independently halogen, C1.6alkyl, or C1.6haloalkyl. In some ments is a nd of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3 and each R2 is independently halogen or C1.6haloalkyl. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3 and each R2 is independently halogen or C1.6alkyl. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3 and each R2 is independently halogen. In some embodiments is a compound of a (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3 and each R2 is independently C1-6alkyl. In some embodiments is a compound of Formula (lb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3 and each R2 is independently C1-6haloalkyl.
] In some ments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 4 and each R2 is independently halogen, C1- 6alkyl, C1_6haloalkyl, and 011”.
In some embodiments is a compound of Formula (Ibb): o CF3 NJJ\0)\CF3 (R2), MOO R1-X Formula (Ibb); wherein: X is -O- or -; R1 is -(CR4R5)m-R6, each R2 is independently selected from halogen, C1-6alkyl, or C1.6haloalkyl; R3 is H or C1_6alkyl, each R4 and R5 is each ndently selected from H, F, and C1_6alkyl; R6 is £02119; R9 is H or C1-6alkyl; mis l, 2, 3 or4, and 11 is O, 1, or 2, or a pharmaceutically acceptable salt or solvate thereof.
In some ments is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or e thereof, wherein X is —O-. In some embodiments is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein X is - N(R3)—. In some ments is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -N(H)-. In some embodiments is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -N(CH3)-. In some embodiments is a compound of a (Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -N(CH2CH3)-.
In some embodiments is a compound of Formula (Ibb), or a ceutically acceptable salt or e thereof, wherein R1 is -(CR4R5)m-R6. In some embodiments is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6 and R6 is -C02R9. In some embodiments is a compound of Formula (Ibb), or a ceutically able salt or solvate thereof, wherein R1 is - (CR4R5)m-R6 and R6 is -C02H. In some embodiments is a compound of Formula (Ibb), or a ceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6 and R6 is - COzCH3. In some embodiments is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof, n R1 is -(CR4R5)m-R6 and R6 is -C02CH2CH3. In some ments is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or e thereof, wherein R1 is -(CR4R5)m-R6 and m is 1. In some embodiments is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6 and m is 2. In some embodiments is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6 and m is 3, In some embodiments is a compound of a (Ibb), or a pharmaceutically acceptable salt or e thereof, wherein R1 is -(CR4R5)m-R6 and m is 4. In some embodiments is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is 5)m-R6 and each R4 and R5 is each independently selected from H and C1-6alkyl. In some embodiments is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6 and each R4 and R5 is H.
In some embodiments is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02H, m is 1, and R4 and R5 is independently selected from H and C1-6alkyl. In some embodiments is a WO 93949 compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is —(CR4R5)m-R6, R6 is -C02H, m is 2, and each R4 and R5 is each independently selected from H and C1-6alkyl. In some embodiments is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof, n R1 is -(CR4R5)m-R6, R6 is - COzH, m is 3, and each R4 and R5 is each independently selected from H and C1-6alkyl. In some embodiments is a compound of a (Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02H, m is 4, and each R4 and R5 is each independently selected from H and C1.6alkyl.
In some embodiments is a compound of Formula (Ibb), or a ceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02H, m is l, and R4 and R5 are H. In some embodiments is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02H, m is 2, and each R4 and R5 is H. In some embodiments is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate f, wherein R1 is -(CR4R5)m-R6, R6 is - COZH, m is 3, and each R4 and R5 is H. In some embodiments is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02H, m is 4, and each R4 and R5 is H.
In some ments is a compound of Formula (Ibb), or a ceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02R9, R9 is C1_6alkyl, m is 1, and R4 and R5 is independently selected from H and C1-6alkyl. In some embodiments is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or e thereof, n R1 is -(CR4R5)m-R6, R6 is -C02R9, R9 is C1-6alkyl, m is 2, and each R4 and R5 is each independently selected from H and C1-6alkyl. In some ments is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or e thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02R9, R9 is C1-6alkyl, m is 3, and each R4 and R5 is each independently selected from H and C1-6alkyl. In some ments is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof, n R1 is - (CR4R5)m-R6, R6 is -C02R9, R9 is C1_6alkyl, m is 4, and each R4 and R5 is each independently selected from H and C1-6alkyl.
In some embodiments is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is 5)m-R6, R6 is -C02R9, R9 is C1_6alkyl, m is l, and R4 and R5 are H. In some embodiments is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is - C02R9, R9 is kyl, m is 2, and each R4 and R5 is H. In some embodiments is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02R9, R9 is C1-6alkyl, m is 3, and each R4 and R5 is H.
In some ments is a compound of a (Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02R9, R9 is C1_6alkyl, m is 4, and each R4 and R5 is H.
In some embodiments is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or e thereof, wherein -X-R1 is -OCH2C(O)OH. In some embodiments is a nd of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is -N(H)CH2C(O)OH. In some embodiments is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is - OCH(CH3)C(O)OH. In some embodiments is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is - N(H)CH(CH3)C(O)OH. In some embodiments is a compound of Formula (Ibb), or a ceutically acceptable salt or solvate thereof, n -X-R1 is -OCH2CH2C(O)OH.
In some embodiments is a compound of a (Ibb), or a pharmaceutically acceptable salt or e thereof, wherein -X-Rl is -N(H)CH2CH2C(O)OH. In some embodiments is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is -OCH2CH2CH2C(O)OH. In some embodiments is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is - N(H)CH2CH2CH2C(O)OH. In some embodiments is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or e thereof, wherein -X-R1 is - OCH2CH2C(CH3)2C(O)OH. In some embodiments is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is - N(H)CH2CH2C(CH3)2C(O)OH.
In some embodiments is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is -OCH2C(O)OCH3. In some embodiments is a nd of a (Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is -N(H)CH2C(O)OCH3. In some embodiments is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof, n -X-R1 is -OCH(CH3)C(O)OCH3. In some ments is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate f, wherein —X-R1 is - (CH3)C(O)OCH3. In some embodiments is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or e thereof, wherein -X—R1 is —OCH2CH2C(O)OCH3.
In some embodiments is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-Rl is -N(H)CH2CH2C(O)OCH3. In some embodiments is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof, n -X-R1 is H2CH2C(O)OCH3. In some embodiments is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein —X-R1 is - N(H)CH2CH2CH2C(O)OCH3. In some embodiments is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is - OCHZCH2C(CH3)2C(O)OCH3. In some ments is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is - N(H)CH2CH2C(CH3)2C(O)OCH3.
In some embodiments is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is l or 2. In some ments is a nd of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is O or 1. In some embodiments is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0. In some ments is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some ments is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or e thereof, wherein n is 2.
In some ments is a compound of Formula (Ibb), or a pharmaceutically able salt or solvate thereof, wherein n is l and R2 is halogen, C1_6alkyl, or C1- 6haloalkyl. In some embodiments is a compound of Formula (Ibb), or a pharmaceutically able salt or solvate thereof, wherein n is l and R2 is halogen. In some embodiments is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is l and R2 is -Cl. In some embodiments is a compound of a (Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is l and R2 is -F. In some embodiments is a nd of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is l and R2 is C1-6alkyl. In some embodiments is a compound of Formula (Ibb), or a pharmaceutically able salt or solvate thereof, wherein n is l and R2 is -CH3. In some embodiments is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is l and R2 is C1-6haloalkyl. In some embodiments is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is l and R2 is -CF3.
In some embodiments is a nd of Formula (Ibb), or a pharmaceutically acceptable salt or e thereof, wherein n is 2 and each R2 is independently halogen, C1- 6alkyl, or C1.6haloalkyl. In some embodiments is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R2 is independently halogen or C1-6haloalkyl. In some embodiments is a compound of a (Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R2 is independently halogen or C1-6alkyl. In some embodiments is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R2 is independently halogen. In some ments is a nd of a (Ibb), or a ceutically acceptable salt or solvate thereof, wherein n is 2 and each R2 is independently ky1‘ In some embodiments is a compound of a (Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R2 is independently C1.6haloalkyl.
In some embodiments is a compound of Formula (Ic): o CF3 (Ron A A @VN N o CF3 R ~x1 Formula (Ic), wherein: X is —o—, —s—, —s02—, -N(R3)-, or -CH2-; Y is -O- or -N(R7)-, R1 is —(CR4R5)m—R", —(CR4R5)p—Y—(CR4R5)q—R6, or —(CR4R5)t—C3.6cycloalkyl—R6, each R2 is independently selected from halogen, -CN, C1-6alkyl, C1.6haloalkyl, -C1. 6alkyl(heterocycloalkyl), -OR17, and -C(O)NR18R19; R3 is H or C1-6alkyl, each R4 and R5 is each independently selected from H, F, and C1.6alkyl; or R4 and R5, together with the carbon to which they are attached, form a C3-6cycloalkyl ring, R6 is 4302119, -C(O)R10, or -C(O)O-(CR12R13)-OC(O)R11; R7 is H, C1.6alkyl, or -SOzR8, R8 is kyl; R9 is H or C1_6alkyl, R10 is C1_6alkyl or —NHs02R21; R11 is C1_6alkyl or C1-6alkoxy, R12 and R13 is each independently H or kyl; each R17 is independently selected from H, C1_6alkyl, C1_6haloalkyl, aminoalkyl, cycloalkyl, -C1-6alkyl(heterocycloalkyl), -C1-6alkyl-C(O)(heterocycloalkyl), optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, each R18 and R19 is independently selected from H, C1_6alkyl, C1_6haloalkyl, cycloalkyl, aryl, and heteroaryl; or R18 and R19, together with the nitrogen to which they are attached, form a heterocycloalkyl ring optionally substituted with one, two, or three R20, each R20 is independently selected from halogen, C1.6alkyl, C1.6haloalkyl, oxo, -CN, and C3-6cycloalkyl, R21 is C1.6alkyl; mis l, 2, 3 or4; n is 0,], 2, 3, or4, p is 2, 3, or 4, q is 1, 2, or 3; and tis O, l, or 2, or a pharrnaceutically acceptable salt or solvate thereof.
In some ments is a compound of Formula (Ic), or a pharrnaceutically acceptable salt or e thereof, wherein X is -O-, -S-, -SOz—, -N(R3)-, or -CH2-. In some embodiments is a compound of Formula (Ic), or a pharmaceutically able salt or solvate thereof, wherein X is -O-. In some embodiments is a nd of Formula (Ic), or a pharrnaceutically acceptable salt or solvate f, wherein X is -S-. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate f, wherein X is -SOz-. In some embodiments is a compound of Formula (Ic), or a pharrnaceutically acceptable salt or solvate thereof, wherein X is -N(R3)-. In some embodiments is a compound of Formula (Ic), or a ceutically able salt or solvate thereof, wherein X is -N(H)—. In some embodiments is a compound of Formula (Ic), or a pharrnaceutically acceptable salt or solvate thereof, wherein X is —N(CH3)—. In some embodiments is a compound of a (Ic), or a ceutically acceptable salt or solvate thereof, wherein X is —N(CH2CH3)-, In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -CH2-.
In some embodiments is a compound of Formula (Ic), or a pharrnaceutically acceptable salt or e thereof, wherein R1 is -(CR4R5)m-R6. In some embodiments is a compound of Formula (Ic), or a aceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6 and R6 is -C02R9. In some ments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6 and R6 is -C02H. In some embodiments is a nd of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6 and R6 is - . In some embodiments is a nd of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6 and R6 is -C02CH2CH3. In some embodiments is a compound of Formula (Ic), or a ceutically acceptable salt or solvate f, n R1 is -(CR4R5)m-R6 and R6 is -C(O)R10. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is 5)m-R6 and R6 is HSOZCH3. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is - (CR4R5)m-R6 and R6 is -C(O)O-(CR12R13)-OC(O)R11. In some embodiments is a compound of Formula (Ic), or a pharmaceutically able salt or solvate thereof, wherein R1 is - (CR4R5)m-R6 and R6 is -C(O)OCH20C(O)R“. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is - (CR4R5)m-R6 and R6 is -C(O)OCH20C(O)OCH2CH3. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is - (CR4R5)m-R6 and R6 is -C(O)OCH20C(O)OCH(CH3)2. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate f, wherein R1 is -(CR4R5)m-R6 and R6 is CH20C(O)OC(CH3)3. In some embodiments is a compound of Formula (Ic), or a pharmaceutically able salt or e thereof, wherein R1 is -(CR4R5)m-R6 and R6 is -C(O)OCH20C(O)CH(CH3)2. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6 and m is 1. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6 and m is 2.
In some embodiments is a compound of Formula (Ic), or a ceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6 and m is 3. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6 and m is 4. In some embodiments is a compound of Formula (Ic), or a ceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6 and each R4 and R5 is each independently selected from H and C1-6alkyl. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate f, wherein R1 is -(CR4R5)m-R6 and each R4 and R5 is H.
In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02H, m is l, and R4 and R5 is independently selected from H and C1-6alkyl. In some embodiments is a compound of a (Ic), or a pharmaceutically able salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02H, m is 2, and each R4 and R5 is each independently selected from H and C1_6alkyl. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate f, wherein R1 is -(CR4R5)m-R6, R6 is - COZH, m is 3, and each R4 and R5 is each independently ed from H and C1_6alkyl. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is —(CR4R5)m-R6, R6 is -C02H, m is 4, and each R4 and R5 is each independently selected from H and C1-6alkyl.
In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02H, m is l, and R4 and R5 are H. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or e thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02H, m is 2, and each R4 and R5 is H. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is — COzH, m is 3, and each R4 and R5 is H. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, n R1 is 5)m-R6, R6 is -C02H, m is 4, and each R4 and R5 is H.
In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02R9, R9 is C1_6alkyl, m is l, and R4 and R5 is independently selected from H and C1-6alkyl. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02R9, R9 is C1-6alkyl, m is 2, and each R4 and R5 is each independently selected from H and C1-6alkyl. In some embodiments is a compound of a (Ic), or a ceutically able salt or solvate thereof, n R1 is -(CR4R5)m-R6, R6 is -C02R9, R9 is kyl, m is 3, and each R4 and R5 is each ndently selected from H and C1-6alkyl. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is - (CR4R5)m-R6, R6 is -C02R9, R9 is C1_6alkyl, m is 4, and each R4 and R5 is each independently ed from H and kyl.
In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02R9, R9 is C1_6alkyl, m is l, and R4 and R5 are H. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is - C02R9, R9 is C1-6alkyl, m is 2, and each R4 and R5 is H. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02R9, R9 is C1-6alkyl, m is 3, and each R4 and R5 is H. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or e thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02R9, R9 is l<yl, m is 4, and each R4 and R5 is H.
In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p-Y-(CR4R5)q—R6. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is —(CR4R5)p-Y-(CR4R5)q-R6 and R6 is -C02R9. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p-Y-(CR4R5)q-R6 and R6 is -C02H. In some ments is a nd of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p-Y-(CR4R5)q-R6 and R6 is -C02CH3. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p-Y—(CR4R5)q-R6 and R6 is 2CH3. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p-Y—(CRA'R5)q-R6 and Y is -O-. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate f, wherein R1 is -(CR4R5)lo-Y—(CR4R5)q-R6 and Y is -N(R7)-. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is 5)1£,-Y-(CR4R5)q-R6 and Y is -N(H)-. In some embodiments is a compound of Formula (Ic), or a pharmaceutically able salt or solvate thereof, wherein R1 is -(CR4R5)p-Y-(CR4R5)q-R6 and Y is Me)-. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or e thereof, wherein R1 is -(CR4R5)p-Y-(CRlRSM-R6 and p is 2. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or e thereof, wherein R1 is -(CR4R5)p-Y-(CR4R5)q-R6 and p is 3. In some embodiments is a compound of a (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is - (CR4R5)p-Y-(CR4R5)q-R6 and p is 4. In some embodiments is a compound of a (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is —(CR4R5)p-Y- )q-R6 and q is 1. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p-Y—(CR4R5)q-R6 and q is 2. In some ments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is 5)1,-Y-(CR4R5).;l—R6 and q is 3. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)10-Y-(CR4R5)q-R6 and each R4 and R5 is each ndently selected from H and C1-6alkyl. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is - (CR4R5)p-Y-(CR4R5)q-R6 and each R4 and R5 is H.
] In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p-Y-(CR4R5)q—R6, R6 is —COZH, Y is -O-, p is 2, q is 1, and R4 and R5 is independently selected from H and C1-6alkyl. In some embodiments is a compound of Formula (Ic), or a ceutically acceptable salt or e thereof, wherein R1 is -(CR4R5)p-Y-(CR4R5)q-R6, R6 is -C02H, Y is -N(H)-, p is 2, q is 1, and each R4 and R5 is each independently selected from H and C1.6alkyl. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or e thereof, wherein R1 is -(CR4R5)p-Y-(CR4R5)q-R6, R6 is -C02H, Y is -N(SOzMe)-, p is 2, q is 1, and each R4 and R5 is each independently selected from H and C1-6alkyl.
In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p-Y-(CR4R5)q-R6, R6 is -C02H, Y is -O-, p is 2, q is 1, and R4 and R5 are H. In some embodiments is a nd of a (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p-Y- (CR4R5)q-R6, R6 is -C02H, Y is -N(H)-, p is 2, q is 1, and each R4 and R5 is H. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or e thereof, wherein R1 is -(CR4R5)p-Y-(CR4R5)q-R6, R6 is -C02H, Y is -N(SOzMe)-, p is 2, q is 1, and each R4 and R5 is H.
In some embodiments is a compound of a (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p-Y-(CR4R5)q-R6, R6 is -C02R9, R9 is C1_6alkyl, Y is -O-, p is 2, q is 1, and R4 and R5 is independently selected from H and C1- 6alkyl. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, n R1 is -(CR4R5)p-Y-(CR4R5)q-R6, R6 is -C02R9, R9 is C1_6alkyl, Y is -N(H)-, p is 2, q is 1, and each R4 and R5 is each independently selected from H and C1_6alkyl. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p-Y-(CR4R5)q-R6, R6 is -C02R9, R9 is C1.6alkyl, Y is -N(SOzMe)-, p is 2, q is 1, and each R4 and R5 is each independently selected from H and kyl.
In some ments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, n R1 is -(CR4R5)p-Y-(CR4R5)q—R6, R6 is -C02R9, R9 is C1-6alkyl, Y is -O-, p is 2, q is 1, and R4 and R5 are H. In some embodiments is a WO 93949 compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)p-Y-(CR4R5)q-R6, R6 is 4102119, R9 is kyl, Y is -N(H)-, p is 2, q is 1, and each R4 and R5 is H. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or e thereof, n R1 is -(CR4R5)p-Y-(CR4R5)q—R6, R6 is -C02R9, R9 is C1.6alkyl, Y is -N(SOzMe)-, p is 2, q is l, and each R4 and R5 is H.
In some embodiments is a compound of Formula (Ic), or a pharmaceutically able salt or solvate thereof, wherein R1 is -(CR4R5)t-C3-6cycloalkyl-R6. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)t-cyclopropyl-R6. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)t-cyclobutyl-R6. In some embodiments is a nd of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)t-cyclopentyl-R6.
In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)t-cyclohexyl-R6. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or e thereof, wherein R1 is -(CR4R5)t-C3.6cycloalkyl-R6 and R6 is -C02R9. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is - )t-C3.6cycloalkyl-R6 and R6 is -C02H. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is - (CR4R5)t-C3_6cycloalkyl-R6 and R6 is -C02CH3. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is - (CRA'R5)t-C3.6cycloalkyl-R6 and R6 is -C02CH2CH3. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is — (CR4R5)t-C3.6cycloalkyl-R6 and t is 0. In some ments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate f, n R1 is 5)t-C3. scycloalkyl-R6 and t is 1. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)t-C3_6cycloalkyl- R6 and t is 2.
In some embodiments is a compound of a (Ic), or a pharmaceutically acceptable salt or solvate f, wherein R1 is -(CR4R5)t-C3.6cycloalkyl-R6, R6 is -C02H, t is 0, and R4 and R5 is independently selected from H and C1-6alkyl. In some embodiments is a nd of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is —(CR4R5)t-C3-6cycloalkyl—R6, R6 is -C02H, tis l, and each R4 and R5 is each ndently selected from H and C1-6alkyl. In some embodiments is a compound of WO 93949 Formula (Ic), or a pharmaceutically able salt or solvate thereof, n R1 is - (CR4R5)t-C3-6cycloalkyl-R6, R6 is -C02H, t is 2, and each R4 and R5 is each independently selected from H and C1_6alkyl.
In some embodiments is a nd of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)t-C3.6cycloalkyl-R6, R6 is -C02H, t is 0, and R4 and R5 are H. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, n R1 is -(CR4R5)t-C3_6cycloalkyl- R6, R6 is -C02H, tis l, and each R4 and R5 is H. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is - (CR4R5)t-C3-6cycloalkyl-R6, R6 is -C02H, t is 2, and each R4 and R5 is H.
In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is 5)t-C3-6cycloalkyl-Rs, R6 is , R9 is C1-6alkyl, t is 0, and R4 and R5 is independently selected from H and C1-6alkyl. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, n R1 is -(CR4R5)t-C3.6cycloalkyl-R6, R6 is -C02R9, R9 is C1_6alkyl, t is l, and each R4 and R5 is each independently selected from H and C1_6alkyl. In some ments is a compound of Formula (Ic), or a pharmaceutically able salt or solvate thereof, wherein R1 is -(CR4R5)t-C3.6cycloalkyl-R6, R6 is -COzR9, R9 is C1-6alkyl, t is 2, and each R4 and R5 is each independently selected from H and C1-6alkyl.
In some ments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate f, wherein R1 is -(CR4R5)t-C3.6cycloalkyl-R6, R6 is -C02R9, R9 is C1-6alkyl, tis 0, and R4 and R5 are H. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is - (CR4R5)t-C3_6cycloalkyl-R6, R6 is -C02R9, R9 is C1_6alkyl, tis l, and each R4 and R5 is H. In some embodiments is a compound of a (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)t-C3.6cycloalkyl-R6, R6 is -C02R9, R9 is C1-6alkyl, t is 2, and each R4 and R5 is H.
In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein -X—R1 is -OCH2C(O)OH. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is -N(H)CH2C(O)OH. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, n -X-R1 is - OCH(CH3)C(O)OH. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate f, wherein -X-R1 is - N(H)CH(CH3)C(O)OH. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate f, wherein -X—R1 is —OCH2CH2C(O)OH.
In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein -X—R1 is —N(H)CH2CH2C(O)OH. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or e thereof, wherein -X-R1 is -OCH2CH2CH2C(O)OH. In some ments is a compound of Formula (Ic), or a pharmaceutically able salt or solvate thereof, wherein -X-R1 is - N(H)CH2CH2CH2C(O)OH. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, n -X-R1 is - OCH2CH2C(CH3)2C(O)OH. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is - N(H)CH2CH2C(CH3)2C(O)OH4 ] In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate f, wherein -X-R1 is -OCH2C(O)OCH3. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is -N(H)CH2C(O)OCH3A In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is -OCH(CH3)C(O)OCH3. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is - N(H)CH(CH3)C(O)OCH3. In some embodiments is a compound of Formula (Ic), or a ceutically acceptable salt or solvate thereof, wherein -X-R1 is -OCH2CH2C(O)OCH3.
In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is -N(H)CH2CH2C(O)OCH3. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is -OCH2CH2CH2C(O)OCH3. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is - N(H)CH2CH2CH2C(O)OCH3. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is - 2C(CH3)2C(O)OCH3. In some embodiments is a compound of a (Ic), or a ceutically able salt or solvate thereof, wherein -X-R1 is - N(H)CH2CH2C(CH3)2C(O)OCH3.
] In some ments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate f, wherein -X—R1 is -OCH2CH20CH2C(O)OH. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or 2017/061870 solvate f, wherein -X-R1 is -N(H)CH2CH20CH2C(O)OH. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is -OCH2CH2N(H)CH2C(O)OH. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is — N(H)CH2CH2N(S02CH3)CH2C(O)OH. In some embodiments is a compound of Formula (Ic), or a pharmaceutically able salt or solvate thereof, wherein -X-R1 is — ZCHZC(O)OCH(CH3)OC(O)OCH2CH3. In some embodiments is a compound of Formula (Ic), or a ceutically acceptable salt or solvate thereof, wherein —X-R1 is — N(H)CH2CH2CH2C(O)OCH(CH3)OC(O)OCH(CH3)2. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is - OCHZCHZCHZC(O)OCH20C(O)OC(CH3)3. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, n -X-R1 is - N(H)CH2CH2CH2C(O)OCH(CH3)OC(O)CH(CH3)2.
In some embodiments is a compound of a (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein -X—R1 is -O-cyclopropyl-C(O)OH. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is -N(H)—cyclopropyl-C(O)OH. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is lobutyl-C(O)OH. In some ments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is -N(H)-cyclobutyl- C(O)OH.
In some ments is a nd of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein n is O, 1, 2, or 3. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 or 2. In some embodiments is a compound of a (Ic), or a ceutically acceptable salt or solvate f, wherein n is 0 or 1.
In some embodiments is a compound of a (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein n is O. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of a (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3. In some embodiments is a compound of Formula (Ic), or a ceutically acceptable salt or solvate thereof, wherein n is 4.
] In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate f, wherein n is l and R2 is n, kyl, C1_6haloalkyl, or -OR17. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate f, n n is l and R2 is halogen, C1_6alkyl, or C1- 6haloalkyl. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein n is l and R2 is halogen. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein n is l and R2 is -Cl. In some embodiments is a nd of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein n is l and R2 is -F. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate f, wherein n is l and R2 is C1-6alkyl. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R2 is -CH3. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R2 is C1-6haloalkyl. In some embodiments is a compound of a (Ic), or a ceutically acceptable salt or solvate thereof, wherein n is l and R2 is -CF3. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein n is l and R2 is C1-6alkoxy. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein n is l and R2 is -OCH3. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein n is l and R2 is C1-6haloalkoxy. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein n is l and R2 is - OCF3. In some embodiments is a compound of Formula (Ic), or a pharmaceutically able salt or solvate thereof, n n is l and R2 is -OH. In some ments is a compound of Formula (Ic), or a ceutically acceptable salt or solvate thereof, wherein n is l and R2 is -CN.
In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R2 is independently halogen, C1- salkyl, C1-6haloalkyl, or -OR17. In some embodiments is a nd of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R2 is independently halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1_6haloalkoxy, -OH, or -CN.
In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R2 is independently halogen, C1-6alkyl, C1- 6haloalkyl, koxy, -OCF3, or -CN. In some embodiments is a compound of Formula WO 93949 (Ic), or a pharmaceutically acceptable salt or e thereof, wherein n is 2 and each R2 is independently halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, or —OCF3. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R2 is independently halogen, C1_6alkyl, C1- 6haloalkyl, or -OCF3. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R2 is independently halogen, C1-6alkyl, or C1.6haloalkyl. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R2 is independently halogen or C1-6haloalkyl. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R2 is ndently halogen or C1-6alkyl. In some embodiments is a nd of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R2 is independently halogen. In some embodiments is a nd of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R2 is independently C1-6alkyl. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R2 is independently C1-6haloalkyl.
In some ments is a nd of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3 and each R2 is independently halogen, C1- 6alkyl, C1_6haloalkyl, or -OR17. In some embodiments is a compound of a (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3 and each R2 is independently halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1.6haloalkoxy, -OH, or -CN.
In some embodiments is a compound of Formula (Ic), or a ceutically acceptable salt or solvate thereof, n n is 3 and each R2 is independently halogen, C1-6alkyl, C1- lkyl, C1-6alkoxy, -OCF3, or -CN. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3 and each R2 is independently halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, or -OCF3. In some embodiments is a compound of Formula (Ic), or a pharmaceutically able salt or solvate thereof, wherein n is 3 and each R2 is independently halogen, C1-6alkyl, C1- 6haloalkyl, or -OCF3. In some ments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, n n is 3 and each R2 is independently halogen, C1-6alkyl, or C1.6haloalkyl. In some embodiments is a compound of Formula (Ic), or a pharmaceutically able salt or solvate thereof, wherein n is 3 and each R2 is ndently halogen or C1-6haloalkyl. In some embodiments is a compound of WO 93949 Formula (Ic), or a ceutically acceptable salt or solvate thereof, wherein n is 3 and each R2 is independently halogen or C1-6alkyl. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or e thereof, wherein n is 3 and each R2 is independently halogen. In some embodiments is a nd of Formula (Ic), or a ceutically acceptable salt or solvate f, wherein n is 3 and each R2 is independently C1.6alkyl. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, n n is 3 and each R2 is independently C1.6haloalkyl.
In some embodiments is a compound of a (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 4 and each R2 is independently halogen, C1. 6alkyl, C1_6haloalkyl, and OR”.
In some embodiments is a compound of Formula (Icc): o CF3 (R2)" tum?NAOACF‘g R1~X Formula (Icc), wherein: X is -O- or -N(R3)-, R1 is —(CR4R5)m—R"; each R2 is independently selected from halogen, C1_6alkyl, or C1_6haloalkyl; R3 is H or C1.6alkyl; each R4 and R5 is each independently selected from H, F, and C1.(,alkyl, R6 is -C02R9; R9 is H or C1_6alkyl, m is 1, 2, 3 or 4; and n is O, l, or 2, or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments is a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -O-. In some embodiments is a compound of Formula (Icc), or a ceutically acceptable salt or solvate thereof, wherein X is - N(R3)-. In some embodiments is a compound of Formula (Icc), or a pharmaceutically able salt or solvate f, wherein X is -N(H)—. In some embodiments is a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof, WO 93949 wherein X is -N(CH3)-. In some ments is a nd of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -N(CH2CH3)-.
In some embodiments is a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6. In some embodiments is a compound of Formula (Icc), or a pharmaceutically able salt or solvate thereof, wherein R1 is —(CR4R5)m-R6 and R6 is -C02R9. In some embodiments is a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is - (CR4R5)m-R6 and R6 is —C02H. In some embodiments is a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6 and R6 is - COzCH3. In some embodiments is a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate f, wherein R1 is -(CR4R5)m-R6 and R6 is -C02CH2CH3. In some embodiments is a compound of Formula (Icc), or a pharmaceutically able salt or solvate thereof, wherein R1 is -(CR4R5)m-R6 and m is 1. In some embodiments is a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof, n R1 is -(CR4R5)m-R6 and m is 2. In some embodiments is a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6 and m is 3. In some embodiments is a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6 and m is 4. In some embodiments is a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6 and each R4 and R5 is each independently selected from H and C1-6alkyl. In some ments is a compound of Formula (Icc), or a pharmaceutically acceptable salt or e thereof, wherein R1 is -(CR4R5)m—R6 and each R4 and R5 is H.
] In some ments is a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02H, m is l, and R4 and R5 is ndently selected from H and C1-6alkyl. In some ments is a compound of Formula (Icc), or a ceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02H, m is 2, and each R4 and R5 is each independently selected from H and C1-6alkyl. In some embodiments is a compound of a (Icc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is - COZH, m is 3, and each R4 and R5 is each independently selected from H and C1_6alkyl. In some embodiments is a compound of Formula (Icc), or a pharmaceutically able salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is —C02H, m is 4, and each R4 and R5 is each independently selected from H and C1-6alkyl.
In some embodiments is a compound of a (Icc), or a pharmaceutically acceptable salt or solvate f, wherein R1 is -(CR4R5)m-R6, R6 is -C02H, m is 1, and R4 and R5 are H. In some embodiments is a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate f, wherein R1 is -(CR4R5)m-R6, R6 is -C02H, m is 2, and each R4 and R5 is H. In some embodiments is a nd of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is - COzH, m is 3, and each R4 and R5 is H. In some embodiments is a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02H, m is 4, and each R4 and R5 is H.
In some embodiments is a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02R9, R9 is C1_6alkyl, m is l, and R4 and R5 is independently selected from H and C1-6alkyl. In some embodiments is a compound of Formula (Icc), or a pharmaceutically acceptable salt or e thereof, wherein R1 is -(CR4R5)m-R6, R6 is —C02R9, R9 is C1-6alkyl, m is 2, and each R4 and R5 is each independently selected from H and C1-6alkyl. In some embodiments is a compound of Formula (Icc), or a pharmaceutically acceptable salt or e f, wherein R1 is -(CR4R5)m-R6, R6 is -C02R9, R9 is C1-6alkyl, m is 3, and each R4 and R5 is each independently selected from H and C1-6alkyl. In some embodiments is a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is - (CR4R5)m-R6, R6 is -C02R9, R9 is C1_6alkyl, m is 4, and each R4 and R5 is each independently selected from H and C1-6alkyl.
In some embodiments is a nd of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is -C02R9, R9 is C1_6alkyl, m is l, and R4 and R5 are H. In some embodiments is a compound of a (Icc), or a pharmaceutically acceptable salt or solvate f, wherein R1 is -(CR4R5)m-R6, R6 is - C02R9, R9 is C1-6alkyl, m is 2, and each R4 and R5 is H. In some embodiments is a compound of a (Icc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -(CR4R5)m-R6, R6 is , R9 is C1_6alkyl, m is 3, and each R4 and R5 is H.
In some embodiments is a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate f, wherein R1 is -(CR4R5)m-R6, R6 is -C02R9, R9 is C1-6alkyl, m is 4, and each R4 and R5 is H.
In some embodiments is a nd of Formula (Icc), or a pharmaceutically able salt or solvate thereof, wherein -X—R1 is -OCH2C(O)OH. In some embodiments is a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is -N(H)CH2C(O)OH. In some embodiments is a compound of Formula (Icc), or a pharmaceutically acceptable salt or e thereof, wherein —X-R1 is — 3)C(O)OH. In some embodiments is a compound of Formula (Icc), or a pharmaceutically able salt or e thereof, n -X-R1 is - N(H)CH(CH3)C(O)OH. In some embodiments is a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof, wherein -X—R1 is —OCH2CH2C(O)OH.
In some embodiments is a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof, wherein —X-R1 is -N(H)CH2CH2C(O)OH. In some embodiments is a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is -OCH2CH2CH2C(O)OH. In some embodiments is a compound of Formula (Icc), or a ceutically acceptable salt or solvate thereof, wherein -X-R1 is - N(H)CH2CH2CH2C(O)OH. In some embodiments is a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is - OCH2CH2C(CH3)2C(O)OH. In some embodiments is a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof, n -X-R1 is - N(H)CH2CH2C(CH3)2C(O)OH.
In some embodiments is a compound of Formula (Icc), or a pharmaceutically acceptable salt or e f, wherein -X-R1 is -OCH2C(O)OCH3. In some embodiments is a compound of Formula (Icc), or a pharmaceutically able salt or solvate thereof, wherein -X-R1 is -N(H)CH2C(O)OCH3. In some embodiments is a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is -OCH(CH3)C(O)OCH3. In some embodiments is a nd of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is - N(H)CH(CH3)C(O)OCH3. In some embodiments is a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is H2C(O)OCH3.
In some embodiments is a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is -N(H)CH2CH2C(O)OCH3. In some embodiments is a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is -OCH2CH2CH2C(O)OCH3. In some embodiments is a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is - N(H)CH2CH2CH2C(O)OCH3. In some ments is a compound of Formula (Icc), or a pharmaceutically able salt or solvate thereof, wherein -X-R1 is - 2C(CH3)2C(O)OCH3. In some embodiments is a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof, wherein -X-R1 is - N(H)CH2CH2C(CH3)2C(O)OCH3.
In some embodiments is a compound of Formula (Icc), or a pharmaceutically acceptable salt or e thereof, wherein n is l or 2. In some embodiments is a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0 or 1. In some embodiments is a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate f, wherein n is 0. In some ments is a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2.
In some embodiments is a compound of a (Icc), or a pharmaceutically acceptable salt or solvate thereof, n n is 1 and R2 is halogen, C1_6alkyl, or C1- 6haloalkyl. In some embodiments is a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R2 is halogen. In some embodiments is a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof, n n is 1 and R2 is -Cl. In some embodiments is a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof, wherein n is l and R2 is -F. In some embodiments is a compound of Formula (Icc), or a pharmaceutically acceptable salt or e f, wherein n is 1 and R2 is C1-6alkyl. In some ments is a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R2 is -CH3. In some embodiments is a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate f, wherein n is l and R2 is C1_6haloalkyl. In some embodiments is a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof, wherein n is l and R2 is -CF3.
] In some embodiments is a compound of Formula (Icc), or a pharmaceutically acceptable salt or e thereof, n n is 2 and each R2 is independently halogen, C1- 6alkyl, or loalkyl. In some embodiments is a nd of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R2 is independently halogen or C1-6haloalkyl. In some embodiments is a compound of Formula (Icc), or a pharmaceutically acceptable salt or e thereof, wherein n is 2 and each R2 is independently halogen or C1-6alkyl. In some embodiments is a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof, n n is 2 and each R2 is independently halogen. In some embodiments is a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R2 is independently kyl. In some embodiments is a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2 and each R2 is independently C1-6haloalkyl. r embodiments provided herein include combinations of one or more of the particular embodiments set forth above.
In some embodiments, the compound disclosed herein has the structure provided in Table l. 4-((2-((8-((( l , 1, l ,3,3,3-Hexafluoropropan yl)oxy)carbonyl)-l,8-diazaspiro[4.5]decan—l - yl)methyl)-5 - (trifluoromethyl)phenyl)amino)butanoic acid 4-((2-((8-(((l,1,l,3,3,3-Hexafluoropropan )carbonyl)-2,8-diazaspiro[4.5]decan yl)methyl)-5 - (trifluoromethyl)phenyl)amino)butanoic acid 4-((2-((5 -(((1, 1,1,3 ,3 ,3 -Hexafluoropropan—2- yl)oxy)carbonyl)hexahydropyrrolo[3 ,4 - ol-2( 1H)—yl)methyl)-5 - (trifluoromethyl)phenyl)amino)butanoic acid 4-((3 -((8-((( l , l, l ,3,3,3-Hexafluoropropan yl)oxy)carbonyl)-1,8-diazaspiro[4.5]decan yl)methyl)-5 - (trifluoromethyl)phenyl)amino)butanoic acid 4-((3-((8-(((1, 3,3-Hexafluoropropan—2— y1)oxy)carbony1)-2,8-diazaspiro[4.5]decan hy1)-5 - (tiifluoromethyl)phenyl)amino)butanoic acid 4-(5-Chloro((8-(((1,1,1,3,3,3- hexafluoropropan-Z-y1)oxy)carbonyl)-1,8- diazaspiro[4.5]decan yl)methyl)phenoxy)butanoic acid 2-(2-((8-(((1,1,1,3,3,3-chafluoropropan y1)oxy)carbonyl)-1, 8-diazaspiro[4,5]decan y1)methy1)-5 -(trifluoromethyl)phenoxy)acetic acid 2-(5—Chloro—2-((8-(((1,1,1,3,3,3- hexafluoropropan-Z-y1)oxy)carbony1)- 1 ,8- diazaspiro[4.5]decan y1)methy1)phenoxy)acetic acid 4-(2-((8-(((1, 1,1,3 ,3 ,3 -Hexafluoropropan y1)oxy)carbony1)-1, aspiro[4.5]decan y1)methy1)-5 — (tiifluoromethyl)phenoxy)butanoic acid (2-((8-(((1,1,1,3,3,3-Hexafluoropropan y1)oxy)carbony1)-1, 8-diazaspiro[4.5]decan y1)methyl)-5 -(trifluoromethy1)phenyl)glycine 4-((2-((8-(((1, 1,1,3 ,3 ,3 -Hexafluoropropan-2— y1)oxy)carbony1)-1, 8-diazaspiro[4.5]decan y1)methy1)-5 -(trifluoromethy1)pheny1)amino)- 2,2—dimethylbutanoic acid 3-((3-Chloro((8-(((1,1,1,3,3,3- hexafluoropropan-Z-y1)oxy)carbony1)- 1 ,8- diazaspiro[4.5]decan hyl)pheny1)amino)propanoic acid (2-((8-(((1,1,1,3 ,3 ,3 -Hexafluoropropan y1)oxy)carbony1)-1, 8-diazaspiro[4.5]decan y1)methy1)-5 -(trifluoromethy1)phenyl)-L- alanine 4-(3-((8-(((1,1,1,3,3,3-Hexafluoropropan y1)oxy)carbony1)-1,8-diazaspiro[4.5]decan y1)methyl)-5 - (tiifluoromethy1)phenoxy)cyclohexane-1 - carboxylic acid 4-(2-((8-(((1,1,1,3,3,3-Hexafluoropropan—2— y1)oxy)carbony1)-1, 8-diazaspiro[4.5]decan y1)methy1)-5 - oromethy1)phenoxy)cyclohexane-1 — carboxylic acid 1, 1 , 1,3 ,3 ,3 uoropropan-2—yl 1-(2-((4- (methylsulfonamido)—4-oxobutyl)amino) (tIifluoromethyl)benzyl)-1,8- diazaspiro[4.5]decanecarboxylate 4-(3-Chloro((8-(((1,1,1,3,3,3- hexafluoropropan-Z-y1)oxy)carbony1)- 1 ,8- diazaspiro[4.5]dccan yl)methy1)phenoxy)butanoic acid 1, 1 , 1,3 ,3 ,3 -Hexafluoropropanyl 1-(2-(4— lsulfonamido)0X0butoxy) (tIifluoromethyl)benzyl)-1,8- diazaspiro[4.5]decane—8-carboxylate 1-(2-((8-(((1,1,1,3,3,3-chafluoropropan )carbonyl)-1,8—diazaspiro[4.5]decan-1 - y1)methyl)-5 - (trifluoromethyl)phenoxy)cyclopropane-1 - carboxylic acid 1-((5-Chloro((8-(((1,1,1,3,3,3- hexafluoropropan-Z-y1)oxy)carbony1)- 1 ,8- NO diazaspiro[4.5]decan yl)methy1)phenoxy)methyl)cyclopropanc carboxylic acid 3-((3-((8-(((1,1,1,3,3,3-Hexafluoropropan y1)oxy)carbony1)-1,8-diazaspiro[4.5]decan—1 - [Q y1)mcthyl)-5 - (trifluoromethyl)phenyl)amino)propanoic acid 1-((2-((8-(((1, 1,1,3 ,3 ,3 uoropropan—2- y1)oxy)carbonyl)-1, 8-diazaspiro[4.5]decan NN y1)methyl)-5 - (tiifluoromethyl)phenoxy)methyl)cyclopropane carboxy1ic acid oropropan-Z-yl)oxy)carbonyl)- 1 ,8- diazaspiro[4.5]decan- l - yl)methyl)phenoxy)methyl)cyclopropane- l - carboxylic acid 1-((5 o((8-(((1, 1,1,3 ,3 ,3- hexafluoropropan-Z-yl)oxy)carbonyl)- 1 ,8- diazaspiro[4.5]decan yl)methyl)phenoxy)methyl)cyclopropane— l - carboxylic acid l-((2-Fluoro-6—((8-(((l, 1,1,33,3- hexafluoropropan-Z-yl)oxy)carbonyl)-1,8- diazaspiro[4.5]decan yl)methyl)phenoxy)methyl)cyclopropane- l - carboxylic acid Preparation of the Compounds The compounds used in the reactions bed herein are made ing to known organic sis techniques, starting from commercially available chemicals and/or from compounds bed in the al literature. "Commercially available chemicals" are obtained from standard commercial sources including Acros Organics (Geel, Belgium), h Chemical (Milwaukee, WI, ing Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Ark Pharrn, Inc. (Libertyville, IL), Avocado Research (Lancashire, UK), BDH Inc. (Toronto, Canada), Bionet (Cornwall, UK), Chemservice Inc. (West r, PA), Combi—blocks (San Diego, CA), Crescent Chemical Co, (Hauppauge, NY), eMolecules (San Diego, CA), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedical s, Inc. (Costa Mesa, CA), Key Organics (Cornwall, UK), Lancaster Synthesis (Windham, NH), Matrix Scientific, (Columbia, SC), Maybridge Chemical Co. Ltd. (Cornwall, UK), Parish Chemical Co, (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), PolyorganiX (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Ryan Scientific, Inc.
(Mount Pleasant, SC), Spectrum Chemicals (Gardena, CA), Sundia Meditech, (Shanghai, China), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and WuXi hai, China).
Suitable reference books and treatises that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc, New York; S. R. r et al., "Organic Functional Group Preparations," 2nd Ed, Academic Press, New York, 1983, H. 0. House, "Modern Synthetic Reactions", 2nd Ed, W. A.
Benjamin, Inc. Menlo Park, Calif. 1972, T. L. Gilchrist, "Heterocyclic try", 2nd Ed, John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and ure", 4th Ed, Wiley-Interscience, New York, 1992. Additional le reference books and treatises that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that be the preparation, include for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, s, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 329074-5; Hoffman, RV. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0509618-5; Larock, R. C.
"Comprehensive Organic ormations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0—4714, March, J. ced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 060180-2, Otera, J. (editor) "Modern Carbonyl try" (2000) Wiley-VCH, ISBN: 329871-1, Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 093022-9, Solomons, T. W. G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 019095-0, Stowell, J.C., mediate Organic try" 2nd Edition (1993) Wiley-Interscience, ISBN: 0—4712, "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 329645-X, in 8 volumes, ic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and stry of Functional Groups" John Wiley & Sons, in 73 volumes.
Specific and analogous reactants are also identified through the s of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and sity libraries, as well as through on—line ses (the American Chemical Society, Washington, DC, may be contacted for more details).
Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g, those listed above) provide custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G.
Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.
Further Forms of Compounds Disclosed Herein Isomers Furthermore, in some embodiments, the compounds described herein exist as geometric isomers. In some ments, the compounds described herein possess one or more double bonds. The compounds ted herein include all cis, trans, syn, anti, en (E), and zusammen (D isomers as well as the corresponding mixtures thereof. In some situations, compounds exist as tautomers. The compounds described herein e all possible tautomers within the formulas described herein. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S ration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures f. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or reoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as optically pure enantiomers by chiral chromatographic resolution of the racemic mixture. In some embodiments, the nds described herein are prepared as their dual isomers by reacting a racemic mixture of the compound with an optically active ing agent to form a pair of diastereoisomeric compounds, ting the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable xes are preferred (e. g., crystalline diastereomeric salts). In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some ments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any cal means that would not result in racemization.
Labeled compounds In some embodiments, the compounds described herein exist in their isotopically—labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such ically-labeled compounds. In some embodiments, the methods disclosed herein include methods of ng diseases by administering such isotopically-labeled compounds as ceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those d herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number ent from the atomic mass or mass number usually found in nature. Examples of isotopes that are incorporated into nds of the invention e isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluonne and de, such as 2H, 3H, 13 C, 14C, 15N, 18O, 17O, 31F, 32F, 358, 18F, and 36Cl, respectively. Compounds described herein, and the ceutically acceptable salts, , solvate, hydrates or derivatives thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds, for example those into which radioactive es such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i. e., 3H and carbon-14, i. e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e., 2H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some embodiments, the isotopically labeled nds, pharmaceutically able salt, ester, solvate, hydrate or derivative thereof is prepared by any suitable method.
In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
Pharmaceutically acceptable salts In some embodiments, the compounds bed herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of ng diseases by administering such pharmaceutically able salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
In some ments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in silu during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed, Solvates In some embodiments, the compounds described herein exist as solvates. The invention provides for s of ng diseases by administering such solvates. The invention further provides for methods of treating diseases by stering such solvates as pharmaceutical compositions.
Solvates contain either stoichiometric or non-stoichiometric s of a solvent, and, in some embodiments, are formed during the process of crystallization with ceutically acceptable solvents such as water, ethanol, and the like es are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.
Solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds bed herein are iently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol. In addition, the nds provided herein exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the es of the compounds and methods provided herein.
Prodrugs In some embodiments, the nds described herein exist in prodrug form. The invention provides for methods of treating diseases by administering such prodrugs. The invention further provides for methods of treating diseases by administering such prodrugs as pharmaceutical compositions.
In some embodiments, prodrugs include compounds wherein an amino acid residue, or a ptide chain of two or more (e.g., two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of compounds of the present invention. The amino acid residues include but are not limited to the 20 naturally occurring amino acids and also includes 4-hydroxyproline, hydroxylysine, ne, isodemosine, 3-methylhistidine, norvaline, lanine, gamma-aminobutyric acid, cirtulline, homocysteine, homoserine, omithine and methionine sulfone. In other embodiments, prodrugs e compounds wherein a nucleic acid residue, or an oligonucleotide of two or more (e.g., two, three or four) nucleic acid residues is covalently joined to a compound of the present invention.
Pharrnaceutically acceptable gs of the compounds described herein also include, but are not limited to, , carbonates, thiocarbonates, N—acyl derivatives, N—acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N—Mannich bases, Schiff bases, amino acid conjugates, ate esters, metal salts and sulfonate esters. In some embodiments, compounds having free amino, amido, hydroxy or ylic groups are converted into prodrugs. For instance, free carboxyl groups are derivatized as amides or alkyl esters. In certain instances, all of these prodrug moieties incorporate groups including but not d to ether, amine and carboxylic acid functionalities.
Hydroxy prodrugs include esters, such as though not limited to, acyloxyalkyl (e. g. acyloxymethyl, acyloxyethyl) esters, alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters, phosphate esters, sulfonate esters, sulfate esters and disulflde containing esters, ethers, amides, ates, hemisuccinates, ylaminoacetates and phosphoryloxymethyloxycarbonyls, as outlined in AdvancedDrug ry Reviews 1996, 19, 115.
Amine derived prodrugs include, but are not limited to the following groups and combinations of groups: 0 o o s s R o R o _NJLR _IJLO,R —[JJ\S’R —|\|:JLo'R —I}IJJ\S’R _NJ\OJLR _NJ\OJLO,R H H H H H H H o s R R s R s R o —3% 121%] —N/)\R —N¢\RITJR —EJ\SJLR —EJ\0JLR —EJ\SJLR ”1‘ ”1‘ R s R‘ s R o R' s R o R o _NJ\OJJ\S,R —II\IJ\OJJ\O’R _NJ\OJJ\S,R _NJ\SJJ\O,R —r}1J\sJ\s’R _N/ks)l\o,R H H H H H H as well as sulfonamides and phosphonamides.
In certain instances, sites on any aromatic ring ns are tible to various metabolic reactions, therefore incorporation of appropriate substituents on the aromatic ring structures, , ze or eliminate this metabolic pathway.
Pharmaceutical Compositions In certain embodiments, the nd of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc) as described herein is administered as a pure chemical. In some embodiments, the compound of a (I), (la), (Iaa), (Ib), (Ibb), (Ic), or (Icc) described herein is combined with a pharmaceutically suitable or acceptable r (also referred to herein as a pharmaceutically suitable (or able) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for WO 93949 example, in Remington: The Science ctice ofPharmacy (Gennaro, 21St Ed. Mack Pub. Co., , PA (2005)).
Accordingly, provided herein is a pharmaceutical composition comprising at least one compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc) described herein, or a pharmaceutically acceptable salt or solvate f, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ients of the composition and not deleterious to the recipient (i.e., the subject) of the composition.
One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I), or a pharmaceutically able salt thereof.
One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (Ia), or a pharmaceutically acceptable salt thereof.
One embodiment provides a pharmaceutical composition comprising a pharmaceutically able excipient and a compound of Formula (lb), or a pharmaceutically acceptable salt f.
One ment provides a pharmaceutical ition comprising a pharmaceutically acceptable excipient and a compound of Formula (II), or a pharmaceutically acceptable salt thereof.
Another embodiment provides a pharmaceutical composition ting ially of a pharmaceutically able excipient and a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Another ment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable excipient and a compound of Formula (Ia), or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable excipient and a compound of Formula (lb), or a pharmaceutically able salt thereof. Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable excipient and a compound of Formula (II), or a pharmaceutically acceptable salt thereof.
In certain embodiments, the compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc) as described herein is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as contaminating intermediates or by-products that are created, for example, in one or more of the steps of a sis method.
These pharmaceutical compositions include those suitable for oral, , topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) vaginal, ophthalmic, or aerosol administration.
Exemplary pharmaceutical compositions are used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which includes one or more of a disclosed compound, as an active ingredient, in a mixture with an organic or inorganic r or excipient suitable for external, enteral or parenteral applications. In some embodiments, the active ingredient is compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, es, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active object nd is included in the ceutical composition in an amount sufficient to e the desired effect upon the process or condition of the disease.
In some embodiments for preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g, conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid mulation composition containing a homogeneous mixture of a disclosed compound or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the ition so that the composition is y subdivided into equally effective unit dosage forms such as tablets, pills and es.
In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the t ition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or ium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, cellulose, microcrystalline cellulose, silicifled microcrystalline cellulose, lactose, sucrose, e, mannitol, and/or silicic acid; (2) binders, such as, for e, carboxymethylcellulose, hypromellose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol, (4) disintegrating agents, such as crospovidone, croscarmellose , sodium starch glycolate, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, n silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds, (7) wetting agents, such WO 93949 2017/061870 as, for example, docusate sodium, cetyl alcohol and glycerol monostearate, (8) absorbents, such as kaolin and bentonite clay, (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) ng . In the case of capsules, tablets and pills, in some embodiments, the compositions comprise buffering . In some embodiments, solid compositions of a similar type are also employed as fillers in soft and hard—filled gelatin es using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene s and the like.
In some embodiments, a tablet is made by compression or molding, ally with one or more accessory ingredients. In some embodiments, compressed tablets are prepared using binder (for example, gelatin or ypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for e, sodium starch glycolate or cross- linked sodium carboxymethyl cellulose), surface-active or dispersing agent. In some embodiments, molded tablets are made by g in a le machine a mixture of the subject ition moistened with an inert liquid diluent. In some ments, s, and other solid dosage forms, such as dragees, capsules, pills and granules, are scored or prepared with coatings and shells, such as enteric coatings and other coatings.
Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or c solvents, or mixtures thereof, and powders.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the subject composition, in some embodiments, the liquid dosage forms contain inert diluents, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3—butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.
In some embodiments, suspensions, in addition to the subject composition, contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and an esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar- agar and tragacanth, and mixtures thereof.
] In some embodiments, formulations for rectal or vaginal administration are presented as a suppository, which are prepared by mixing a subject composition with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, WO 93949 polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body ature and, therefore, will melt in the body cavity and release the active agent.
Dosage forms for transdermal administration of a subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
In some embodiments, the active component is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants as required.
In some ments, the ointments, pastes, creams and gels contain, in addition to a subject composition, excipients, such as animal and ble fats, oils, waxes, paraffins, starch, anth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
In some embodiments, powders and sprays contain, in addition to a t composition, excipients such as lactose, talc, silicic acid, aluminum ide, calcium silicates and polyamide powder, or mixtures of these substances. In some embodiments, sprays additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
In some embodiments, the compounds described herein are formulated as eye drops for ophthalmic administration, Compositions and compounds disclosed herein alternatively are stered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. In some embodiments, a ueous (e.g., fluorocarbon propellant) suspension is used. In some ments, sonic nebulizers are used because they minimize exposing the agent to shear, which results in degradation of the compounds contained in the subject compositions. Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and izers. The carriers and stabilizers vary with the requirements of the ular subject composition, but typically include non—ionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum n, an esters, oleic acid, in, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols generally are prepared from ic solutions.
Pharmaceutical compositions suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, sions or ons, or sterile powders which are reconstituted into sterile injectable solutions or dispersions just prior to use, which, in some ments, contain antioxidants, s, bacteriostats, solutes which render the formulation isotonic with the blood of the ed recipient or suspending or thickening agents.
Examples of suitable aqueous and non—aqueous carriers which are employed in the ceutical compositions include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, ble oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins. Proper fluidity is maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants Also contemplated are enteral pharmaceutical formulations including a disclosed compound and an c material; and a pharmaceutically acceptable carrier or excipient thereof. Enteric als refer to polymers that are substantially insoluble in the acidic environment of the stomach, and that are predominantly soluble in intestinal fluids at specific pHs. The small intestine is the part of the gastrointestinal tract (gut) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum. The pH of the duodenum is about 5.5, the pH of the jejunum is about 6.5 and the pH of the distal ileum is about 7.5. ingly, enteric materials are not soluble, for example, until a pH of about .0, of about 5.2, of about 5.4, of about 5.6, of about 5.8, of about 6.0, of about 6.2, of about 6.4, of about 6.6, of about 6.8, of about 7.0, of about 7.2, of about 7.4, of about 7.6, of about 7.8, of about 8.0, of about 8.2, of about 8.4, of about 8.6, of about 8.8, of about 9.0, of about 9.2, of about 9.4, of about 9.6, of about 9.8, or of about 10.0. Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl cellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, ose e succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, ose acetate butyrate, cellulose acetate propionate, copolymer of methacrylic acid and methyl methacrylate, copolymer of methyl acrylate, methylmethacrylate and methacrylic acid, copolymer of methylvinyl ether and maleic anhydride (Gantrez ES series), ethyl methyacrylate-methylmethacrylate- chlorotrimethylammonium ethyl acrylate mer, natural resins such as zein, shellac and copal collophorium, and several commercially available enteric dispersion systems (e.g., Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit 8100, Kollicoat EMIVB 0D, Estacryl 30D, Coateric, and Aquateric). The solubility of each of the above materials is either known or is readily determinable in vitro.
The dose of the composition comprising at least one compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc) as described herein differs, depending upon the patient's (e.g., human) condition, that is, stage of the disease, general health status, age, and other factors.
Pharmaceutical compositions are administered in a manner appropriate to the disease to be d (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's e, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and ent regimen es the composition(s) in an amount ient to provide therapeutic and/or prophylactic benefit (e.g., an ed clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and/or clinical trials. In some embodiments, the optimal dose s upon the body mass, weight, or blood volume of the patient.
Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day.
Methods Disclosed herein are methods of modulating the activity of MAGL. Contemplated methods, for example, se exposing said enzyme to a compound described herein. In some embodiments, the compound utilized by one or more of the foregoing methods is one of the generic, subgeneric, or specific compounds described herein, such as a compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc), or a pharmaceutically able salt or e f. The ability of compounds described herein to modulate or inhibit MAGL is evaluated by procedures known in the art and/or described herein. Another aspect of this disclosure provides methods of treating a disease associated with expression or activity of MAGL in a patient.
Also disclosed herein are s of treating and/or preventing in a patient in need thereof a disorder such as one or more of acute or chronic pain and athy.
Disclosed methods e administering a pharmaceutically effective amount of a nd described herein.
In another embodiment is a method of ng pain in a patient, sing administering a therapeutically effective amount of a compound of a (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc) described herein, or a pharmaceutically acceptable salt or solvate thereof, to a patient in need thereof to treat said pain. In another embodiment is a method of ng neuropathic pain in a patient, comprising administering a therapeutically effective amount of a compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc) described herein, or a ceutically acceptable salt or solvate thereof, to a patient in need thereof to treat said neuropathic pain. In another embodiment is a method of treating inflammatory pain in a patient, comprising administering a eutically ive amount of a compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc) described herein, or a pharmaceutically acceptable salt or solvate thereof, to a patient in need thereof to treat said inflammatory pain. In another embodiment is a method of treating complex regional pain syndrome in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc) described herein, or a pharmaceutically acceptable salt or solvate thereof.
In r embodiment is a method of treating a disease or disorder in a patient sing administering to the patient in need thereof a therapeutically effective amount of a compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc) described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein the disease or disorder is selected from the group consisting of epilepsy/seizure disorder, multiple sclerosis, neuromyelitis optica (NMO), Tourette syndrome, mer’s e, and abdominal pain associated with irritable bowel syndrome. In another embodiment is a method of treating sy/seizure disorder in a patient comprising administering to the patient in need thereof a therapeutically effective amount of a compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc) described herein, or a pharmaceutically acceptable salt or e thereof. In another embodiment is a method of treating multiple sclerosis in a t comprising administering to the patient in need thereof a therapeutically effective amount of a compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc) described herein, or a pharmaceutically acceptable salt or solvate f. In another embodiment is a method of treating neuromyelitis optica (NMO) in a patient comprising administering to the patient in need thereof a therapeutically effective amount of a compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc) described herein, or a pharmaceutically acceptable salt or e f. In another embodiment is a method of treating te syndrome in a patient comprising stering to the patient in need thereof a therapeutically effective amount of a nd of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc) described herein, or a ceutically acceptable salt or solvate f, In another embodiment is a method of treating Alzheimer’s disease in a t comprising administering to the patient in need thereof a therapeutically effective amount of a compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc) described herein, or a pharmaceutically acceptable salt or solvate thereof.
In another embodiment is a method of treating abdominal pain associated with irritable bowel syndrome in a patient comprising administering to the patient in need thereof a therapeutically effective amount of a compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc) described herein, or a pharmaceutically acceptable salt or solvate thereof.
In another embodiment is a method of treating acute pain, inflammatory pain, cancer pain, pain caused by peripheral neuropathy, central pain, f1bromyalgia, migraine, vasoocclussive painful crises in sickle cell disease, spasticity or pain associated with multiple sclerosis, functional chest pain, rheumatoid arthritis, osteoarthritis, or onal dyspepsia in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc) described herein, or a pharmaceutically acceptable salt or solvate f. In another embodiment is a method of ng acute pain in a patient in need f, sing administering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc) described , or a pharmaceutically able salt or solvate thereof. In r embodiment is a method of treating inflammatory pain in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc) described herein, or a ceutically acceptable salt or e thereof. In another embodiment is a method of treating cancer pain in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc) described herein, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment is a method of treating pain caused by peripheral neuropathy in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (la), (Iaa), (Ib), (Ibb), (Ic), or (Icc) described herein, or a pharmaceutically acceptable salt or solvate thereof.
In another embodiment is a method of treating central pain in a patient in need thereof, comprising stering to the patient a therapeutically effective amount of a nd of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc) described , or a pharmaceutically acceptable salt or solvate thereof. In another embodiment is a method of treating frbromyalgia in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc) described herein, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment is a method of treating migraine in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc) described herein, or a ceutically acceptable salt or solvate thereof. In another embodiment is a method of treating vasoocclussive painful crises in sickle cell disease in a t in need thereof, comprising administering to the t a therapeutically effective amount of a compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc) described herein, or a ceutically acceptable salt or e thereof. In another embodiment is a method of treating spasticity or pain associated with multiple sclerosis in a patient in need f, comprising administering to the patient a eutically effective amount of a compound of Formula (I), (la), (Iaa), (Ib), (Ibb), (Ic), or (Icc) described herein, or a pharmaceutically acceptable salt or solvate thereof.
In another embodiment is a method of treating functional chest pain in a patient in need thereof, sing administering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc) described herein, or a pharmaceutically acceptable salt or solvate f. In r embodiment is a method of treating rheumatoid arthritis in a patient in need thereof, comprising administering to the t a therapeutically effective amount of a nd of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc) described herein, or a pharmaceutically acceptable salt or solvate thereof.
In r embodiment is a method of treating osteoarthritis in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc) described herein, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment is a method of treating functional sia in a patient in need thereof, comprising stering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc) bed herein, or a pharmaceutically acceptable salt or solvate thereof.
] In some embodiments, disclosed herein is a method of treating Persistent Motor Tic Disorder in a t in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc) described herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, disclosed herein is a method of ng Persistent Vocal Tic Disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective 2017/061870 amount of a compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc) described , or a pharmaceutically able salt or solvate thereof.
In some embodiments, disclosed herein is a method of treating attention deficit and ctivity disorder (ADHD) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc) described herein, or a pharmaceutically acceptable salt or solvate f.
In some embodiments, disclosed herein is a method of treating obsessive—compulsive disorder (OCD) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc) described herein, or a pharmaceutically acceptable salt or solvate f.
In r embodiment is a method of lowering intraocular eye pressure (IOP) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc) described herein, or a ceutically acceptable salt or solvate thereof. In r embodiment is a method of treating glaucoma in a t in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc) described , or a pharmaceutically acceptable salt or solvate thereof.
In another embodiment is a method of treating atopic dermatitis in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc) described herein, or a pharmaceutically able salt or solvate thereof.
In another embodiment is a method of ng pruritis in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc) described herein, or a pharmaceutically acceptable salt or solvate f.
In another embodiment is a method of treating Down’s syndrome in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc) described herein, or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, disclosed herein is a method of synergistically potentiating the ty of an opioid analgesic in a patient being treated with an opioid analgesic, comprising administering to the patient a eutically effective amount of a compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc) described herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, disclosed herein is a method of reducing the acute side-effects associated with an opioid analgesic in a patient being treated with an opioid analgesic, comprising administering to the patient a therapeutically ive amount of a compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc) described herein, or a pharmaceutically acceptable salt or solvate thereof.
In another embodiment is a method of treating dystonia in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc) described herein, or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, disclosed herein is a method of ng Amyotrophic Lateral Sclerosis (ALS) or ALS-related symptoms in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc) described herein, or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, disclosed herein is a method of treating agitation in autism in a t in need thereof, comprising stering to the patient a therapeutically effective amount of a nd of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc) described herein, or a pharmaceutically acceptable salt or solvate thereof.
] In another embodiment is a method of treating sleep disturbance or bladder dysfunction associated with multiple sclerosis in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc) described herein, or a pharmaceutically acceptable salt or e thereof.
In some embodiments, disclosed herein is a method of treating Huntington’s Disease in a patient in need thereof, comprising administering to the patient a eutically effective amount of a compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc) described herein, or a pharmaceutically able salt or solvate thereof.
In some embodiments, sed herein is a method of Parkinson’s e in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc) described herein, or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, disclosed herein is a method of improving onal outcome following stroke in a patient in need thereof, sing administering to the patient a therapeutically effective amount of a compound of a (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc) bed herein, or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, disclosed herein is a method of treating traumatic brain injury in a patient in need thereof, comprising stering to the patient a therapeutically effective amount of a nd of a (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc) described herein, or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, disclosed herein is a method of treating trigeminal gia in a patient in need thereof, comprising administering to the patient a therapeutically ive amount of a compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc) described herein, or a pharmaceutically acceptable salt or solvate thereof. In some ments, disclosed herein is a method of treating glossopharyngeal gia in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), (Iaa), (Ib), (Ibb), (Ic), or (Icc) described herein, or a pharmaceutically acceptable salt or solvate thereof.
In certain embodiments, a sed compound utilized by one or more of the foregoing methods is one of the generic, subgeneric, or specific compounds described herein, such as a compound of Formula (I), (la), (Iaa), (Ib), (Ibb), (Ic), or (Icc).
Disclosed compounds are administered to patients (animals and humans) in need of such ent in dosages that will provide optimal pharmaceutical efficacy. It will be appreciated that the dose required for use in any particular application will vary from patient to patient, not only with the ular compound or composition selected, but also with the route of administration, the nature of the condition being treated, the age and condition of the patient, concurrent medication or special diets then being followed by the patient, and other factors, with the appropriate dosage ultimately being at the discretion of the attendant physician. For treating clinical conditions and diseases noted above, a contemplated compound sed herein is administered orally, subcutaneously, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non- toxic pharmaceutically acceptable carriers, nts and vehicles. Parenteral administration include aneous injections, intravenous or intramuscular injections or infusion techniques.
Also contemplated herein are combination therapies, for example, co— administering a disclosed compound and an onal active agent, as part of a ic treatment regimen intended to provide the beneficial effect from the co—action of these therapeutic agents. The beneficial effect of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents. Administration of these eutic agents in ation typically is carried out over a defined time period (usually weeks, months or years depending upon the combination selected). Combination therapy is intended to embrace stration of multiple therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner.
Substantially simultaneous administration is accomplished, for example, by administering to the subject a single formulation or composition, (e.g., a tablet or capsule having a fixed ratio of each therapeutic agent or in multiple, single formulations (e.g., capsules) for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent is effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous ne tissues. The therapeutic agents are administered by the same route or by different routes. For e, a first therapeutic agent of the combination ed is administered by intravenous injection while the other eutic agents of the combination are administered orally. atively, for e, all therapeutic agents are administered orally or all therapeutic agents are stered by intravenous injection.
Combination therapy also embraces the administration of the therapeutic agents as described above in further combination with other biologically active ingredients and non- drug therapies. Where the ation therapy further comprises a non-drug treatment, the non-drug treatment is conducted at any suitable time so long as a ial effect from the co-action of the combination of the therapeutic agents and non-drug treatment is achieved.
For example, in appropriate cases, the beneficial effect is still achieved when the non—drug treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks.
The components of the combination are administered to a t simultaneously or sequentially. It will be iated that the components are t in the same pharmaceutically acceptable carrier and, therefore, are administered simultaneously.
Alternatively, the active ients are present in separate pharmaceutical carriers, such as conventional oral dosage forms, that are administered either simultaneously or tially.
] For example, e.g., for contemplated treatment of pain, a disclosed compound is co- stered with another therapeutic for pain such as an opioid, a cannabinoid receptor (CB-l or CB-2) modulator, a COX-2 inhibitor, acetaminophen, and/or a non-steroidal anti- inflammatory agent. Additional therapeutics e.g., for the treatment of pain that are co- administered, include morphine, e, hydromorphone, hydrocodone, oxymorphone, fentanyl, tramadol, and levorphanol.
Other contemplated therapeutics for co-administration include aspirin, naproxen, ibuprofen, salsalate, diflunisal, dexibuprofen, fenoprofen, ketoprofen, oxaprozin, loxoprofen, indomethacin, tolmetin, sulindac, etodolac, ketorolac, piroxicam, meloxicam, tenoxicam, am, lomoxicam, celecoxib, parecoxib, rimonabant, and/or etoricoxib.
] The following examples are ed merely as illustrative of various embodiments and shall not be construed to limit the invention in any way.
EXAMPLES List of iations As used above, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings: ACN or MeCN acetonitrile Bn benzyl BOC or Boc tert-butyl carbamate CD1 1, bonyldiimidazole Cy cyclohexyl DCE dichloroethane CHzCl) DCM dichloromethane (CHzClz) DIPEA or DIEA diisopropylethylamine DMAP 4-(N,N—dimethylamino)pyn'dine DMF dimethylformamide DMA MN—dimethylacetamide DMSO dimethylsulfoxide equiv equivalent(s) Et ethyl EtOH ethanol EtOAc ethyl acetate HATU l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5- b]pyridinium 3-oxid orophosphate HFIP l, 1, 1,3,3 ,3 -hexafluoropropanol HPLC high performance liquid chromatography LAH m aluminum hydiide LCMS liquid chromatography-mass ometry Me methyl MeOH methanol MS mass oscopy NMM N—methylmorpholine NMR nuclear magnetic resonance PlVfl3 para-methoxybenzyl rt room temperature TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography 1. Chemical Synthesis Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Anhydrous solvents and oven-dried glassware were used for synthetic transformations sensitive to moisture and/or oxygen. Yields were not optimized.
Reaction times are approximate and were not optimized. Column chromatography and thin layer tography (TLC) were performed on silica gel unless otherwise noted. Spectra are given in ppm (6) and coupling nts (J) are reported in Hertz, For proton spectra the solvent peak was used as the reference peak.
Example 1: 4-((2-((8-(((1,1,1,3,3,3-Hexafluoropropanyl)0xy)carbonyl)—l,8- diazaspiro[4.5]decanyl)methyl)(triflu0r0methyl)phenyl)amin0)butanoic acid Step 1: Preparation of tert-butyl meth0xybenzyl)amin0)butan0ate HzN/\/\n,0\'< PMB’ /O NaBH4, EtOH 0 O 70 °C to rt, overnight + A flask was charged with 4—methoxybenzaldehyde (4.27 g, 31.4 mmol, 1.00 equiv), EtOH (30 mL), and utyl 4-aminobutanoate (5.00 g, 31.4 mmol, 1.00 equiv).
The resulting solution was stirred for 5 h at 70 CC and cooled to rt. Sodium borohydride (0.718 g, 18.9 mmol, 0.60 equiv) was added. The resulting solution was stirred overnight at rt and concentrated. The residue was chromatographed on a silica gel column with EtOAc/petroleum ether (2/1) to provide 4.55 g (52% yield) of lerl—butyl 4-((4- methoxybenzyl)amino)butanoate as a yellow oil. LCMS (ESI, m/z): 280 [M+H]+.
Step 2: Preparation of tert-butyl 4-((2-formyl(trifluoromethyl)phenyl)(4— methoxybenzyl)amin0)butan0ate m“, e,m ’PerEt, DMSO mi 110 °C, overnight 0 0 A flask was charged with tert—butyl 4-((4-methoxybenzyl)amino)butanoate (3.00 g, 10.7 mmol, 1.00 equiv), DMSO (35 mL), 2-fluoro—4-(trifluoromethyl)benzaldehyde (2.07 g, 10.7 mmol, 1.00 equiv), and DIPEA (4.18 g, 32.3 mmol, 3.00 equiv) under en. The resulting solution was stirred overnight at 110 oC and quenched with water (50 mL). The ing solution was ted with DCM (2 X 80 mL) and the organic layers were combined, washed with brine (2 X 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was chromatographed on a silica gel column with EtOAc/petroleum ether (l/l2) to e 2.20 g (45% yield) of terl-butyl 4-((2-formyl (trifluoromethyl)phenyl)(4-methoxybenzyl)amino)butanoate as a yellow oil. LCMS (ESI, m/z): 452 [M+H]+.
Step 3: Preparation of 1-(tert-butyl) 8-(1,1,1,3,3,3-hexafluoropropan-Z-yl) 1,8- diazaspiro[4.5]decane-1,8-dicarb0xylate ,J\ O CF3 \N HO CF3 Boc\N NACACFa sgene, ’PerEt, DCM rt, overnight A flask was charged with triphosgene (1.73 g, 5.82 mmol, 0.70 equiv), DCM (60 mL), and HFIP (2.80 g, 16.7 mmol, 2.00 equiv) under nitrogen. DIPEA (4.28 g, 33.2 mmol, 4.00 equiv) was added at 0 CC, and then the reaction mixture was allowed to stir for 2 h at rt. terl-Butyl l,8-diazaspiro[4.5]decane-l-carboxylate (2.00 g, 8.32 mmol, 1.00 equiv) was added and the mixture was stirred overnight. The mixture was then quenched with water (50 mL), extracted with DCM (2 x 80 mL) and the organic layers were combined, washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was chromatographed on a silica gel column with EtOAc/petroleum ether (1/5) to provide 2.56 g (71% yield) of 1-(lert—butyl) ,l,3,3,3-hexafluoropropanyl) 1,8— diazaspiro[4.5]decane-1,8-dicarboxylate as a yellow solid. LCMS (ESI, m/z): 435 [M+H]+.
Step 4: Preparation of 1,1,1,3,3,3-hexafluoropropan-Z-yl 1,8-diazaspir0[4.5]decane carboxylate, 2,2,2-trifluor0acetate salt 3°C“ N o CF3 —*DCM n N o CF3 rt, 3h TFA ] A flask was d with 1—(lerZ—butyl) 8-(1,l,l,3,3,3—hexafluoropropanyl) 1,8- diazaspiro[4.5]decane-1,8-dicarboxylate (200 mg, 0.460 mmol, 1.00 equiv), DCM (10 mL), and TFA (2 mL). The resulting solution was stirred for 3 h at rt and concentrated to e 250 mg (crude) of 1,1,1,3,3,3-hexafluoropropanyl l,8-diazaspiro[4.5]decane carboxylate, 2,2,2-trifluoroacetate salt as a white solid. LCMS (ESI, m/z): 335 [M+H]+.
Step 5: ation of 1,1,1,3,3,3-hexafluoropropan-Z-yl 1-(2-((4-(tert-but0xy)—4- oxobutyl)(4—methoxybenzyl)amin0)—4-(trifluoromethyl)benzyl)—1,8- diazaspiro [4.5] decane—8-carb0xylate :1?” 0 >4 i E3 O {pT o CF3 TFA N ‘PMB N BH OAa ( 0):: EtN, DCE3 rt, overnight wOACFa 0% A flask was charged with 1,1,1,3,3,3-hexafluoropropanyl 1,8- diazaspiro[4.5]decane—8-carboxylate, trifluoroacetate salt (154 mg, 0.460 mmol, 1.20 equiv), DCE (10 mL), TEA (115 mg, 1.14 mmol, 3.00 equiv), and lert—butyl 4-((2-formyl (trifluoromethyl)phenyl)(4-methoxybenzyl)amino)butanoate (171 mg, 0.380 mmol, 1.00 . The resulting solution was stirred 1 h at rt and sodium toxyborohydride (243 mg, 1.15 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at rt and quenched with water (30 mL). The resulting solution was extracted with DCM (2 x 50 mL) and the organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was chromatographed on a silica gel column with DCM/MeOH (97/3) to provide 250 mg (86% yield) of 1,1,1,3,3,3- hexafluoropropanyl 1-(2-((4-(lert—butoxy)—4-oxobutyl)(4-methoxybenzyl)amino)—4- (trifluoromethyl)benzyl)-1,8-diazaspiro[4.5]decanecarboxylate as a yellow oil. LCMS (ESI, m/Z): 770 [M+H]+.
Step 6: Preparation of 4-((2—((8-(((1,1,1,3,3,3-hexafluor0pr0panyl)0xy)carbonyl)—1,8- diazaspiro[4.5]decanyl)methyl)(triflu0r0methyl)phenyl)amino)butanoic acid 0% o 0 OH N\PMB DCM NH F30\©\\ o CF3 rt.5h F30\©\\ i 5:3 GO1%,, GO 0 N N A flask was charged with 1,1,1,3,3,3-hexafluoropropanyl 1-(2-((4-(tert- butoxy)—4-oxobutyl)(4-methoxybenzyl)amino)(trifluoromethyl)benzyl)- 1 , 8- diazaspiro[4.5]decanecarboxylate (250 mg, 0.320 mmol, 1.00 equiv), DCM (10 mL), and TFA (2 mL). The resulting solution was d 5 h at rt and concentrated. The crude product (400 mg) was purified by ative HPLC to provide 13.4 mg (7% yield) of 4- ((2-((8-(((1,1,1,3,3,3-hexafluoropropany1)oxy)carbony1)—1,8-diazaspiro[4.5]decan y1)methy1)(trifluoromethyl)pheny1)amino)butanoic acid as a white solid. 1H NMR (400 MHz, Methanol-d4) 5 7.15 (d, J: 7.6 Hz, 1H), 6.82 (d, J: 80 Hz, 1H), 6.77 (s, 1H), 6.08 - 6.16 (m, 1H), 4.15 - 4.21 (m, 2H), 3.71 - 3.79 (m, 2H), 3.01 - 3.19 (m, 4H), 2.64 (t, J: 6.8 Hz, 2H), 2.43 (t, J: 7.2 Hz, 2H), 1.84 - 1.97 (m, 8H), 1.48 - 1.57 (m, 2H). LCMS (ESI, m/z): 594 [M+H]+.
Example 2: 4-((2-((8-(((1,1,1,3,3,3-Hexafluoropropanyl)0xy)carbonyl)-2,8- diazaspiro[4.5]decanyl)methyl)(triflu0r0methyl)phenyl)amin0)butanoic acid ii “3 N 0J\CF3 The title compound was sized according to the representative procedure of Example 1 using commercially available 2-fluoro(trifluoromethyl)benzaldehyde in Step 2 and tert—butyl 2,8-diazaspiro[4.5]decane-2—carboxylate in Step 3 to provide 4-((2-((8- (((1,1, 1,3 ,3 ,3-hexafluoropropanyl)oxy)carbonyl)-2,8-diazaspiro[4.5]decanyl)methyl)— -(trifluoromethyl)phenyl)amino)butanoic acid as a white solid. 1H NMR (300 MHz, Methanol-d4) 5 7.24 (d, J = 7.5 Hz, 1H), 6.84 — 6.87 (m, 2H), 6.09 — 6.18 (m, 1H), 3.86 (s, 2H), 3.47 = 6.3 Hz, 2H), 2.88 — 3.63 (m, 4H), 3.27 (t, J (t, J = 7.2 Hz, 2H), 2.74 (s, 2H), 2.40 (t, J = 6.9 Hz, 2H), 1.95 = 7.0 Hz, 2H), 1.66 — 2.04 (m, 2H), 1.86 (t, J — 1.67 (m, 4H). LCMS (ESI, m/Z): 594 [M+H]+.
Example 3: 4-((2-((5-(((1,1,1,3,3,3-Hexafluoropropan-Z- yl)0xy)carbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl) (trifluoromethyl)phenyl)amino)butanoic acid 0 CF3 F3Cma»NJLoXCFa O OH The title compound was synthesized according to the representative procedure of Example 1 using commercially available tert—butyl dropyrrolo[3,4-c]pyrrole-2(1H)- carboxylate in Step 3 and hloric acid and l,4-dioxane in Step 6 to provide 60.1 mg (32% yield) of ((5-(((1, l,1,3,3,3-hexaf1uoropropan yl)oxy)carbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl)—5- (trifluoromethyl)pheny1)amino)butanoic acid as a white solid. 1H NMR (300 MHz, Methanol-d4) 6 7.15 (d, J: 7.8 Hz, 1H), 6.80 - 6.83 (m, 2H), 6.08 - 6.16 (m, 1H), 3.66 - 3.74 (m, 4H), 3.34 - 3.42 (m, 2H), 3.18 (t, J= 6.9 Hz, 2H), 2.98 (br, 2H), 2.65 - 2.67 (m, 2H), 2.43 - 2.50 (m, 2H), 2.33 (t, J: 7.2 Hz, 2H), 1.90 - 1.97 (m, 2H). LCMS (ESI, m/z): 566 [M+H]+.
Example 4: 4-((3-((8-(((1,1,1,3,3,3-Hexafluoropropanyl)oxy)carb0nyl)—1,8- diazaspiro[4.5]decanyl)methyl)(trifluoromethyl)phenyl)amin0)butan0ic acid HO O Step 1: Preparation of tert-butyl 4-((3-formyl(trifluoromethyl)phenyl)(4- methoxybenzyl)amin0)butan0ate F C3 I F C3 PMB’N O PMB’N O O Pd2(dba)3, BlNAP, C82CO3 toluene 0 #O\ 100 °C, overnight ] A flask was charged with 3-bromo(trifluoromethyl)benzaldehyde (3 74 mg, 1.48 mmol, 1.00 equiv), tert—butyl 4-((4-methoxybenzyl)amino)butanoate (500 mg, 1.79 mmol, 1.20 equiv, prepared as described in Example 1, Step 1), tris(dibenzylideneacetone)dipalladium (68.0 mg, 0.070 mmol, 0.05 equiv), 2,2“- bis(diphenylphosphino)-1,1'-binaphthyl (139 mg, 0.220 mmol, 0.15 equiv), cesium carbonate (1.46 g, 4.48 mmol, 3.00 equiv), and toluene (10 mL). The reaction mixture was stirred ght at 100 oC and ed with water (30 mL). The resulting solution was extracted with EtOAc (2 x 50 mL) and the organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The e was chromatographed on a silica gel column with EtOAc/petroleum ether (1/6) to provide 320 mg (48% yield) of utyl 4-((3 -formyl—5-(trifluoromethyl)phenyl)(4- methoxybenzyl)amino)butanoate as a yellow oil. LCMS (ESI, m/z): 452 [M+H]+.
Step 2: Preparation of 1,1,1,3,3,3-hexafluor0pr0panyl 1-(3-((4-(tert—but0xy)—4- oxobutyl)(4-meth0xybenzyl)amin0)(trifluoromethyl)benzyl)—1,8- diazaspiro [4.5] decane—8-carboxylate F30P\©/\OH >< 0 o OACFs Phi; PMB\N Ac)3,Et3N,DCE Q i i=3 rt,ovemight <9 0 F C CF3 3 N A flask was charged with tert—butyl 4-((3 -formyl(trifluoromethyl)phenyl)(4— methoxybenzyl)amino)butanoate (300 mg, 0.660 mmol, 1.00 equiv), DCE (10 mL), TEA (200 mg, 1.98 mmol, 3.00 equiv), and 1,1,1,3,3,3-hexafluoropropan-2—yl 1,8- diazaspiro[4.5]decanecarboxylate, 2,2,2-trifluoroacetate salt (267 mg, 0.800 mmol, 1.20 equiv, prepared as described in e 1, Steps 3-4). The e was stirred for 1 h at rt and then sodium triacetoxyborohydride (420 mg, 1.98 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at rt and quenched with water (30 mL). The resulting solution was extracted with DCM (2 x 50 mL) and the organic layers were combined, washed with brine (2 x 30 mL), dried over ous sodium sulfate, filtered and concentrated. The residue was chromatographed on a silica gel column with EtOAc/petroleum ether (1/6) to provide 320 mg (63% yield) of 1,1,1,3,3,3- hexafluoropropanyl 1-(3 -((4-(Zert—butoxy)—4-oxobutyl)(4-methoxybenzyl)amino)—5 - uoromethyl)benzyl)-1,8-diazaspiro[4.5]decanecarboxylate as a yellow oil. LCMS (ESI, m/Z): 770 [M+H]+.
Step 3: Preparation of 4-((3-((8-(((1,l,1,3,3,3-hexafluoropr0panyl)0xy)carbonyl)-1,8- diazaspiro[4.5]decanyl)methyl)(triflu0r0methyl)phenyl)amino)butanoic acid 0 o F TFA PMB\N DCM rt, 3h 0 F3 i CF3 NJKOiCF 3 N 0 CF Fac N F3C {DO 3 A flask was charged with 1,l,1,3,3,3-hexafluoropropanyl l-(3 -((4-(z‘erl— butoxy)oxobuty1)(4-methoxybenzyl)amino)(trifluoromethy1)benzyl)- 1 , 8- diazaspiro[4.5]decanecarboxylate (320 mg, 0.420 mmol, 1.00 equiv), DCM (10 mL), and TFA (10 mL). The resulting solution was stirred for 3 h at rt and concentrated. The crude product was purified by preparative HPLC to provide 23.8 mg (10% yield) of 4-((3 -((8- (((1,1,1,3 ,3 ,3 -hexafluoropropanyl)oxy)carbonyl)- 1 , 8-diazaspiro[4.5]decanyl)methyl)— -(trifluoromethyl)phenyl)amino)butanoic acid as a white solid. 1H NMR (300 MHz, ol-d4) 5 6.84 (s, 2H), 6.76 (s, 1H), 6.12 - 6.18 (m, 1H), 4.22 (br, 2H), 3.78 (s, 2H), 3.06 — 3.12 (m, 4H), 2.93 (t, J: 6.0 Hz, 2H), 2.35 (t, J: 6.0 Hz, 2H), 2.00 - 2.05 (m, 2H), 1.84 - 1.93 (m, 6H), 1.64 - 1.68 (m, 2H). LCMS (ESI, m/z): 594 [M+H]+.
Example 5: ((8-(((1,1,1,3,3,3-Hexafluor0propan-Z-yl)0xy)carb0nyl)—2,8- diazaspiro[4.5]decan-Z-yl)methyl)—5-(triflu0r0methyl)phenyl)amin0)butanoic acid ] The title compound was prepared according to the representative procedure of Example 4 using 1,1,1,3,3,3-hexafluoropropanyl 2,8-diazaspiro[4.5]decane—8- carboxylate (prepared as described in Example 1, Steps 3-4 using commercially available lert-butyl 2,8-diazaspiro[4.5]decanecarboxylate) in Step 2 to provide 4-((3 -((8- ((( 1 , 1 , 1,3 ,3 ,3-hexafluoropropanyl)oxy)carbonyl)—2,8-diazaspiro[4.5]decan—2-yl)methyl)— -(trifluoromethyl)phenyl)amino)butanoic acid as a white solid. 1H NMR (300 MHz, Methanol-d4) 6 6.83 - 6.90 (m, 3H), 6.08 - 6.16 (m, 1H), 4.00 (br, 2H), 3.43 - 3.63 (m, 4H), 3.12 - 3.20 (m, 4H), 2.96 (br, 2H), 2.32 (t, J: 7.0 Hz, 2H), 1.84 - 1.94 (m, 4H), 1.66 - 1.68 (m, 4H). LCMS (ESI, m/Z): 594 [M+H]+.
Example 6: 4-(5-Chlor0((8-(((1,l,1,3,3,3—hexafluoropropanyl)0xy)carb0nyl)—1,8- diazaspir0[4.5]decanyl)methyl)phen0xy)butanoic acid mm EL CF3 <50N 0 CF3 Step 1: Preparation of tert-butyl 4-(5-chloro-Z-formylphenoxy)butan0ate 2017/061870 ("fl Br\/\/u\o>< \ O o Kicoa’ DMF CI 100 C, overnight A flask was charged with 4-chlorohydroxybenzaldehyde (250 mg, 1.60 mmol, 1.00 , DMF (10 mL), utyl 4-bromobutanoate (710 mg, 3.20 mmol, 2.00 equiv), and potassium carbonate (662 mg, 4.80 mmol, 3.00 equiv). The resulting solution was stirred overnight at 100 oC and quenched with water (30 mL). The resulting solution was extracted with DCM (2 X 50 mL) and the organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was chromatographed on a silica gel column with EtOAc/petroleum ether (1/8) to e 400 mg (84% yield) of lerl—butyl 4-(5—chloro—2-formylphenoxy)butanoate as a light yellow oil. 1H NMR (300 MHz, Chloroform-d) 5 10.4 (s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.00 — 7.04 (m, 2H), 4.14 (t, J: 6.0 Hz, 2H), 2.46 — 2.48 (m, 2H), 2.15 — 2.20 (m, 2H), 1.47 (s, 9H).
Step 2: Preparation of 1,1,1,3,3,3-hexafluoropropan-Z-yl 1-(2-(4-(tert—butoxy)—4- oxobutoxy)—4-chlorobenzyl)—1,8-diazaspir0[4.5]decanecarboxylate 0% 0% o CF3 0 H NJLOACFs TFA O 0 Cl 0 CF3 0' NaBH(OAc)3.Et3N,DCE A A \ rt,overnight 0 w0 A flask was charged with l,l,1,3,3,3-hexafluoropropanyl 1,8- diazaspiro[4.5]decane—8-carboxylate, 2,2,2-trifluoroacetate salt (224 mg, 0.670 mmol, 1.00 equiv, prepared as described in Example 1, Steps 3-4), DCE (10 mL), TEA (203 mg, 2.01 mmol, 3,00 equiv), tert—butyl 4—(5-chloroformylphenoxy)butanoate (200 mg, 0.670 mmol, 1.00 . The mixture was stirred for l h at rt and sodium triacetoxyborohydride (426 mg, 2.01 mmol, 3.00 equiv) was added. The ing solution was stirred overnight at rt and quenched with water (30 mL). The resulting solution was extracted with DCM (2 x 50 mL) and the organic layers were combined, washed with brine (2 x 30 mL), dried over ous sodium sulfate, filtered and concentrated. The residue was chromatographed on a silica gel column with DCM/MeOH (95/5) to provide 350 mg (85% yield) of 1,1,1,3,3,3- hexafluoropropanyl 1-(2-(4-(lerl—butoxy)—4-oxobutoxy)—4-chlorob enzyl)— 1 , 8- diazaspiro[4.5]decane—8-carboxylate as a yellow oil. LCMS (ESI, m/z): 617 [M+H]+.
Step 3: Preparation of 4-(5-chloro((8-(((1,1,1,3,3,3-hexafluoropropan-Z- yl)oxy)carbonyl)—1,8-diazaspiro[4.5]decan-l-yl)methyl)phenoxy)butanoic acid 0% o O OH O —’ O um 1 xane i ACFa O rt.overnight Cl\©\\ CF3 {:0 o CF3 wo CF3 A flask was charged with 1,1,1,3,3,3-hexafluoropropanyl 1-(2-(4—(terZ-butoxy)- 4-oxobutoxy)—4-chlorobenzyl)—1,8-diazaspiro[4.5]decanecarboxylate (300 mg, 0.490 mmol, 1.00 equiv), 1,4-dioxane (10 mL), and hloric acid (3 mL). The resulting solution was stirred overnight at rt and concentrated. The crude product (300 mg) was purified by preparative HPLC to e 123.0 mg (45% yield) of 4-(5-chloro((8- (((1,1,1,3,3,3—hexaf1uoropropanyl)oxy)carbonyl)—1,8—diazaspiro[4.5]decan-1— yl)methyl)phenoxy)butanoic acid as a white solid. 1H NMR (300 MHz, Methanol-d4) 5 7.33 (d, J: 8.1 Hz, 1H), 7.08 (s, 1H), 6.95 - 6.98 (m, 1H), 6.12 - 6.21 (m, 1H), 4.21 - 4.29 (m, 2H), 4.12 (t, J: 6.0 Hz, 2H), 4.04 (s, 2H), 3.05 - 3.22 (m, 4H), 2.38 (t, J: 6.8 Hz, 2H), 2.01 - 2.21 (m, 8H), 1.79 - 1.89 (m, 2H). LCMS (ESI, m/z): 561 [M+H]+.
Example 7: 2-(2-((8-(((1,1,1,3,3,3-Hexafluoropropanyl)0xy)carbonyl)—1,8- diazaspiro[4.5]decanyl)methyl)(trifluor0methyl)phenoxy)acetic acid 0&0?‘ F30GEOAOACEo CF3 Step 1: Preparation of 2-hydr0xy-4—(triflu0r0methyl)benzaldehyde F3C F30 K2C03, H20, DMSO /0 /0 100 °C, overnight F OH A flask was d with o-4—(trifluoromethyl)benzaldehyde (1.00 g, 5.21 mmol, 1.00 equiv), water (2 mL), DMSO (10 mL), and potassium carbonate (2.16 g, 15.6 mmol, 3.00 equiv) under nitrogen. The resulting solution was stirred overnight at 100 °C and quenched with water (50 mL). The resulting solution was extracted with EtOAc (2 X 80 mL) and the organic layers were combined, washed with brine (2 X 50 mL), dried over anhydrous sodium sulfate, d and concentrated. The residue was chromatographed on a silica gel column with EtOAc/petroleum ether (1/ 19) to e 500 mg (51% yield) of 2- hydroxy(trifluoromethyl)benzaldehyde as a light yellow oil.
Step 2: Preparation of tert-butyl 1-(2-hydroxy(trifluoromethyl)benzyl)-1,8- diazaspir0[4.5]decane-S-carboxylate N CH /O N,Boc OH NaBH(OAC)3. DCE rt, ght A flask was d with 2-hydroxy(trifluoromethyl)benzaldehyde (150 mg, 0.790 mmol, 1.00 equiv), DCE (10 mL), and tert—butyl 1,8-diazaspiro[4.5]decane carboxylate (227 mg, 0.940 mmol, 1.20 equiv). The mixture was stirred for 1 h at rt and sodium triacetoxyborohydride (502 mg, 3.00 equiv) was added. The resulting solution was stirred overnight at It and quenched with water (30 mL). The resulting solution was extracted with DCM (2 x 50 mL) and the organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous sodium e, filtered and concentrated. The residue was chromatographed on a silica gel column with DCM/MeOH (97/3) to provide 180 mg (55% yield) of lerl—butyl 1-(2-hydroxy(trifluoromethyl)benzyl)-1,8— diazaspiro[4.5]decanecarboxylate as a colorless oil. LCMS (ESI, m/z): 415 [M+H]+.
Step 3: Preparation of tert-butyl 1-(2-(2-(tert-butoxy)oxoethoxy)—4- (trifluoromethyl)benzyl)—1,8-diazaspiro[4.5]decane—S-carboxylate F30 Brfir >< 0}>4 Bcc 0 N K2C03, DMF NIB°° 100 °C, overnight N ] A flask was charged with tert—butyl 1-(2-hydroxy(trifluoromethyl)benzyl)—1,8- diazaspiro[4.5]decanecarboxylate (180 mg, 0.430 mmol, 1.00 equiv), DMF (10 mL), lert—butyl 2-bromoacetate (90.0 mg, 0.460 mmol, 1.10 equiv), and potassium carbonate (174 mg, 1.26 mmol, 3.00 equiv). The resulting on was stirred overnight at 100 oC and quenched with water (30 mL). The resulting solution was extracted with EtOAc (2 x 50 mL) and the organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, d and concentrated. The residue was chromatographed on a silica gel column with DCM/MeOH (96/4) to provide 160 mg (70% yield) of tert—butyl 1- (terl-butoxy)oxoethoxy)—4-(trifluoromethyl)benzyl)—1,8-diazaspiro[4.5]decane carboxylate as a yellow oil. LCMS (ESI, m/z): 529 [M+H]+.
Step 4: Preparation of 2-(2-((1,8-diazaspiro[4.5]decan-l-yl)methyl)—5- (trifluoromethyl)phenoxy)acetic acid hydrochloride 0 >4 o O\)\0 HCI O\)\\OH F3C —’ F30 1 ,4-dioxane ’ Bee N NH ] A flask was charged with ZerZ-butyl 2-(Zerl—butoxy)oxoethoxy) (trifluoromethyl)benzyl)-1,8—diazaspiro[4.5]decane-8—carboxylate (160 mg, 0.300 mmol, 1.00 equiv), 1,4-dioxane (10 mL), and concentrated hydrochloric acid (2 mL). The resulting solution was stirred for 3 h at rt and concentrated to provide 170 mg (crude) of 2-(2-((1,8- diazaspiro[4.5]decan—1-yl)methyl)—5-(trifluoromethyl)phenoxy)acetic acid hydrochloride as a yellow oil. LCMS (ESI, m/z): 373 [M+H]+.
Step 5: Preparation of 2-(2—((8-(((1,1,1,3,3,3-hexafluoropropanyl)oxy)carbonyl)—1,8- diazaspiro[4.5]decanyl)methyl)(trifluoromethyl)phenoxy)acetic acid 020+! HOKCF, 03LOH F30 o HCI Jk x triphosgene N O CF3 NH N N iPerEt, DCM rt, 3h A flask was charged with triphosgene (45.0 mg, 0.152 mmol, 0.50 equiv), DCM (10 mL), and HFIP (77.0 mg, 0.456 mmol, 1.50 equiv) under nitrogen. DIPEA (117 mg, 0.910 mmol, 3.00 equiv) was added at 0 OC. The mixture was stirred for 1 h at rt and 2-(2- ((1,8-diazaspiro[4.5]decan-1—yl)methyl)(trifluoromethyl)phenoxy)acetic acid hydrochloride (113 mg, 0.304 mmol, 1.00 equiv) was added. The resulting solution was stirred for 3 h at rt and quenched with water (30 mL). The resulting solution was extracted with DCM (2 x 50 mL) and the organic layers were combined, washed with brine (2 X 30 mL), dried over ous sodium sulfate, filtered and trated. The crude product (130 mg) was purified by preparative HPLC to provide 44.6 mg (33% yield) of 2-(2-((8- ((( l , 1 , 1,3 ,3 ,3-hexafluoropropanyl)oxy)carbonyl)- l ,8-diazaspiro[4.5]decanyl)methyl)— -(trifluoromethyl)phenoxy)acetic acid as a white solid. 1H NMR (300 MHz, Methanol-d4) 7.59 (d, J: 7.8 Hz, 1H), 7.48 (s, 1H), 7.35 (d, J: 7.8 Hz, 1H), 6.14 — 6.25 (m, 1H), 4.99 (s, 1H), 4.80 (br, 3H), 4.26 - 4.34 (m, 2H), 3.07 - 3.27 (m, 4H), 2.10 (br, 6H), 1.89 - 1.93 (m, 2H). LCMS (ESI, m/Z): 567 [M+H]+.
Example 8: 2-(5-Chlor0((8-(((1,1,1,3,3,3-hexafluoropropanyl)0xy)carb0nyl)—1,8- piro[4.5]decanyl)methyl)phenoxy)acetic acid o\)\OH Cl\QILJO‘AOACHo CF3 ] The title compound was prepared according to the entative procedure of Example 7 using 4-ch1orohydroxybenzaldehyde in Step 2 to provide 2-(5-chloro-2—((8- (((1,1,1,3,3,3 -hexafluoropropanyl)oxy)carbonyl)- 1 ,8-diazaspiro[4.5]decan yl)methyl)phenoxy)acetic acid as a white solid. 1H NMR (300 MHz, Methanol-d4) 5 7.38 (d, J: 8.1 Hz, 1H), 7.26 (s, 1H), 7.06 - 7.09 (m, 1H), 6.13 - 6.21 (m, 1H), 4.65 - 4.77 (m, 4H), 4.25 - 4.33 (m, 2H), 3.15 - 3.30 (m, 4H), 2.11 - 2.51(m,6H), 1.88 - 1.92 (m, 2H).
LCMS (ESI, m/Z): 533 [M+H]+.
Example 9: 4-(2-((8-(((1,1,1,3,3,3-Hexafluor0propanyl)0xy)carbonyl)—1,8- diazaspiro[4.5]decanyl)methyl)—5-(triflu0r0methyl)phen0xy)butan0ic acid “fl )1 CF3 <50N 0 CF3 Step 1: Preparation of tert-butyl 4-(2-f0rmyl(trifluoromethyl)phen0xy)butanoate O O BrMo Q; 0 >< 0 K2C03, DMF OH 100 °C. overnight OO>< A flask was charged with 2-hydroxy(trifluoromethyl)benzaldehyde (110 mg, 0.580 mmol, 1.00 equiv, prepared as described in Example 7, Step 1), DMF (10 mL), tert- butyl 4-bromobutanoate (258 mg, 1.16 mmol, 2.00 , and potassium carbonate (240 mg, 1.74 mmol, 3.00 equiv). The resulting solution was stirred overnight at rt and quenched with water (30 mL). The resulting solution was extracted with EtOAc (2 x 50 mL) and the c layers were combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, d and concentrated. The residue was chromatographed on a silica gel column with EtOAc/petroleum ether (1/9) to e 120 mg (62% yield) of tert—butyl 4-(2- formyl-S-(trifluoromethyl)phenoxy)butanoate as a yellow oil.
Step 2: Preparation of 1,1,1,3,3,3-hexafluoropropan-Z-yl 1-(2-(4-(tert—but0xy)—4- 0x0but0xy)(triflu0r0methyl)benzyl)—1,8-diazaspir0[4.5]decanecarb0xylate F30 i CF3 /0 w OACF3 TFA 0 >< NaBH(0Ac)3, EtsN, DCE NiOXCFS O 0 rt.overnight {DC} A flask was charged with terZ-butyl 4—(2-formyl (trifluoromethyl)phenoxy)butanoate (200 mg, 0.600 mmol, 1.00 equiv), DCE (10 mL), TEA (182 mg, 1.80 mmol, 3.00 equiv), and 1,1,1,3,3,3-hexafluoropropan-2—yl 1,8- diazaspiro[4.5]decanecarboxylate, 2,2,2-trifluoroacetate salt (201 mg, 0.600 mmol, 1.00 equiv, ed as bed in e 1, Steps 3—4). The mixture was stirred for 1 h at rt and then sodium triacetoxyborohydride (3 82 mg, 1.80 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at rt and quenched with water (30 mL). The resulting solution was extracted with DCM (2 x 50 mL) and the organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was tographed on a silica gel column with EtOAc/petroleum ether (3/17) to provide 250 mg (64% yield) of 1,1,1,3,3,3- hexafluoropropanyl 1-(2-(4-(lerZ-butoxy)oxobutoxy)(trifluoromethyl)benzyl)— 1 , 8 - diazaspiro[4.5]decanecarboxylate as a colorless oil. LCMS (ESI, m/z): 651 [M+H]+.
Step 3: Preparation of 4-(2-((8-(((1,1,1,3,3,3-hexaflu0r0pr0panyl)0xy)carb0nyl)-1,8- diazaspiro[4.5]decanyl)methyl)(trifluoromethyl)phenoxy)butanoic acid OK OH 0 DCM F3C\©\\ o CF3 O CF3 rt, overnight F3C\@\ A A wkoxcfi <Nj©q O CF3 A flask was charged with 1,1,1,3,3,3—hexafluoropropanyl 1—(2-(4-(lerZ-butoxy)- 4-oxobutoxy)—4-(trifluoromethyl)benzyl)—1,8-diazaspiro[4.5]decanecarboxylate (250 mg, 2017/061870 0.380 mmol, 1.00 , DCM (10 mL), and TFA (2 mL). The resulting solution was stirred overnight at rt and concentrated. The crude product (3 00 mg) was purified by preparative HPLC to provide 93.6 mg (41% yield) of 4-(2-((8-(((1 1 1 3 3 3- hexafluoropropan-Z—yl)oxy)carbonyl)—1,8-diazaspiro[4.5]decanyl)methyl) (trifluoromethyl)phenoxy)butanoic acid as a white solid. 1H NMR (3 00 MHz, ol-d4) 6 7.53 — 7.56 (m, 1H), 7.24 - 7.26 (m, 2H), 6.09 — 6.22 (m, 1H), 4.11 - 4.34 (m, 4H), 4.02 (br, 2H), 3.04 - 3.31 (m, 4H), 2.42 (t, J: 6.9 Hz, 2H), 2.12 - 2.18 (m, 4H), 1.92 - 2.10 (m, 4H), 1.75 - 1.87 (m, 2H). LCMS (ESI, m/z): 595 [M+H]+. e 10: (2-((8-(((1,1,1,3,3,3-Hexafluoropropanyl)oxy)carbonyl)—1,8- piro [4.5] decanyl)methyl)(trifluoromethyl)phenyl)glycine N\)\\OHH FacmwioxcaO CF3 Step 1: Preparation of tert-butyl 1-(2-nitro—4-(trifluoromethyl)benzyl)—1,8- diazaspiro [4.5]decanecarboxylate H N02 F30 N /o N,Boc N02 NaBH(OAc)3, DCE rt, overnight A flask was charged with 2-nitro(trifluoromethyl)benzaldehyde (500 mg, 2.28 mmol, 1.00 equiv), DCE (15 mL), and tert—butyl 1,8—diazaspiro[4.5]decanecarboxylate (547 mg, 2.28 mmol, 1.00 equiv). The mixture was stirred for 1 h at rt and sodium triacetoxyborohydride (1450 mg, 6.84 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at rt and quenched with water (30 mL). The ing solution was extracted with DCM (2 X 50 mL) and the organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was chromatographed on a silica gel column with DCM/MeOH (97/3) to provide 400 mg (40% yield) of lerl—butyl 1-(2-nitro(trifluoromethyl)benzyl)—1,8-diazaspiro[4.5]decane carboxylate as a yellow oil. LCMS (ESI, m/z): 444 [M+H]+.
Step 2: Preparation of tert-butyl 1-(2-amino(trifluoromethyl)benzyl)—1,8- diazaspiro [4.5] decane—8-carboxylate N02 NH2 F3C\©\\ H2. Pd/C N’ EtOAc Facfl BOG N rt, 2h N ] A flask was charged with tert—butyl 1-(2-nitro(trifluoromethyl)benzyl)-l,8- diazaspiro[4.5]decanecarboxylate (400 mg, 0.900 mmol, 1.00 equiv), EtOAc (10 mL), and 10% palladium on carbon (200 mg). Hydrogen was introduced into the reaction mixture and it was allowed to stir for 2 h at rt. The solids were filtered, and the filtrate was concentrated to provide 300 mg (80% yield) of lert—butyl 1-(2-amino (trifluoromethyl)benzyl)—l,8—diazaspiro[4.5]decane-8—carboxylate as a yellow solid. LCMS (ESI, m/Z): 414 [M+H]+.
Step 3: ation of tert-butyl 1-(2-((2-(tert—butoxy)—2-oxoethyl)amino) (trifluoromethyl)benzyl)—1,8-diazaspir0[4.5]decane—8-carboxylate F3C t—BuOOCABr H\3\\>LN /300—» N K2C03, DMF ,Boc 120 °C, overnight <9 A flask was charged with tert—butyl mino-4—(trifluoromethyl)benzyl)—l,8- diazaspiro[4.5]decanecarboxylate (150 mg, 0.360 mmol, 1.00 equiv), DMF (10 mL), potassium carbonate (150 mg, 1.09 mmol, 3.00 equiv), and utyl 2-bromoacetate (77.0 mg, 0.390 mmol, 1.10 equiv). The resulting solution was stirred overnight at 100 oC and ed with water (30 mL). The resulting solution was extracted with DCM (2 x 50 mL) and the organic layers were combined, washed with brine (2 X 30 mL), dried over anhydrous sodium sulfate, d and concentrated. The residue was chromatographed on a silica gel column with DCM/MeOH (98/2) to provide 100 mg (52% yield) of terZ-butyl 1- (2-((2-(z‘ert—butoxy)oxoethyl)amino)—4-(trifluoromethy1)benzyl)-l, 8- diazaspiro[4.5]decanecarboxylate as a yellow oil. LCMS (ESI, m/z): 528 [M+H]+.
Step 4: Preparation of (2-((1,8-diazaspiro[4.5]decan-l-yl)methyl)—5- (trifluoromethyl)phenyl)glycine hydochloride H\)\\O>L HNVCOOH Fgcfl HCI F3C\©\\ HCI W3“ oxane .1, overnight {30% A flask was charged with terZ-butyl 1-(2-((2-(z‘erZ-butoxy)-2—oxoethyl)amino)—4- (trifluoromethyl)benzyl)-1,8—diazaspiro[4.5]decane-8—carboxylate (100 mg, 0.234 mmol, 1.00 , 1,4-dioxane (10 mL), and hloric acid (3 mL). The ing solution was d overnight at rt and trated to e 150 mg (crude) of (2—((1,8- diazaspiro[4.5]decanyl)methyl)(trifluoromethyl)phenyl)glycine hydrochloride as a yellow solid. LCMS (ESI, m/z): 372 [M+H]+.
Step 5: Preparation of (2-((8-(((1,1,1,3,3,3-hexafluoropropanyl)0xy)carb0nyl)—1,8- diazaspiro[4.5]decanyl)methyl)(trifluoromethyl)phenyl)glycine HVCOOH E3 “$0H ”fl “0' “° “3 (L i f3 NH .triphosgene N O CF3 N N ’PerEt, DCM rt, overnight A flask was charged with triphosgene (45.0 mg, 0.150 mmol, 0.70 equiv), DCM (10 mL), and HFIP (73.0 mg, 0.430 mmol, 2.00 equiv) under nitrogen. DIPEA (84.0 mg, 0.650 mmol, 3.00 equiv) was added at 0 oC and the mixture was stirred for 1 h at rt. (2— ((1,8-Diazaspiro[4.5]decanyl)methyl)-5 -(t1ifluoromethyl)phenyl)glycine hydrochloride (80.0 mg, 0.220 mmol, 1.00 equiv) was added. The resulting solution was stirred overnight at rt and quenched with water (30 mL). The resulting solution was extracted with DCM (2 X 50 mL) and the organic layers were combined, washed with brine (2 X 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product (3 00 mg) was purified by preparative HPLC to provide 21.9 mg (18% yield) of (2-((8-(((1,1,l,3,3,3- hexafluoropropan-Z—yl)oxy)carbonyl)- 1 , 8-diazaspiro[4. 5]decanyl)methyl) (tiifluoromethyl)phenyl)glycine as a white solid. 1H NMR (3 00 MHZ, Methanol—d4) 5 7.30 (d, J: 7.5 Hz, 1H), 6.94 (d, J: 8.4 Hz, 1H), 6.88 (br, 1H), 6.09 - 6.19 (m, 1H), 4.20 - 4.28 (m, 2H),4.05 (s, 2H), 3.84 (s, 2H), 3.04 - 3.23 (m, 2H), 2.87 - 2.90 (m, 2H), 2.09 — 2.12 (m, 2H), 1.92 - 2.03 (m, 4H), 1.78 - 1.82 (m, 2H). LCMS (ESI, m/z): 566 [M+H]+.
Example 11: 4-((2-((8-(((1,1,1,3,3,3-Hexaflu0ropropanyl)oxy)carbonyl)-1,8- diazaspiro[4.5]decanyl)methyl)(trifluoromethyl)phenyl)amino)—2,2- dimethylbutanoic acid F3Cflwkoxmo CF3 WO 93949 Step 1: Preparation of tert-butyl 1-(2-bromo(trifluoromethyl)benzyl)—1,8- piro [4.5] —S-carboxylate H Br FaC N F30 N-Boc /O N, NaBH(OAc)3, DCE N rt, overnight A 250-mL round-bottom flask was charged with 2-bromo-4— oromethyl)benzaldehyde (2.00 g, 7.90 mmol, 1.00 equiv), DCE (30 mL), and tert— butyl 1,8-diazaspiro[4.5]decanecarboxylate (2.28 g, 9.48 mmol, 1.20 equiv). The mixture was stirred for 1 h at room temperature before the addition of sodium triacetoxyborohydride (5.04 g, 23.7 mmol, 3.00 equiv). The ing solution was stirred overnight at room temperature and quenched with water (50 mL). The mixture was extracted with DCM (2 x 80 mL) and the c layers were combined, washed with brine (2 x 80 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with OH (97/3) to provide (58% yield) of tert—butyl 1—(2-bromo—4-(tn'fluoromethyl)benzyl)—1,8—diazaspiro[4.5]decane-8— carboxylate as a light yellow oil. LCMS (ESI, m/z): 477 [M+H]+.
Step 2: Preparation of tert-butyl 1-(2-((4-(tert-butoxy)-3,3—dimethyl oxobutyl)amino)—4-(trifluoromethyl)benzyl)—1,8-diazaspir0[4.5]decanecarb0xylate 0 >4 Br O H2N o Fscfl N’B°° O ZI N Pd2(dba)3, BINAP, Cszcoa toluene <Nj©, Boc 100 °C, overnight A 50-mL round-bottom flask was d with lert—butyl 1-(2-bromo—4- (trifluoromethyl)benzyl)-1,8—diazaspiro[4.5]decanecarboxylate (400 mg, 0.840 mmol, 1.00 equiv), toluene (10 mL), tris(dibenzylideneacetone)dipalladium (115 mg, 0.130 mmol, 0.15 equiv), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (235 mg, 0.390 mmol, 0.45 equiv), cesium carbonate (822 mg, 2.52 mmol, 3.00 equiv), and lerl—butyl 4-amino-2,2- ylbutanoate (189 mg, 1.01 mmol, 1.20 equiv) under nitrogen. The resulting solution was stirred overnight at 100 °C and quenched with water (30 mL). The mixture was extracted with DCM (2 x 50 mL) and the organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with EtOAc/hexane (1/5) to provide 300 mg (61% yield) of Zert-butyl l-(2-((4-(tert-butoxy)-3,3-dimethyl oxobutyl)amino)—4-(trifluoromethyl)benzyl)-1,8-diazaspiro[4.5]decane—8-carboxylate as a yellow oil. LCMS (ESI, m/z): 584 [M+H]+.
Step 3: Preparation of 4-((2—((1,8-diazaspiro[4.5]decan-l-yl)methyl)—5- (trifluoromethyl)phenyl)amino)—2,2—dimethylbutanoic acid hydrochloride 0 >4 COOH H HCI N:j N F30 HC' F3C 1,4—dioxane rt, overnight NH , Boc A 50-mL round-bottom flask was charged with Zert-butyl 1-(2-((4-(tert-butoxy)— 3,3-dimethyloxobutyl)amino)(trifluoromethyl)benzyl)-l,8-diazaspiro[4.5]decane carboxylate (300 mg, 0.510 mmol, 1.00 equiv), 1,4-dioxane (10 mL), and concentrated hydrochloric acid (3 mL). The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure to provide 400 mg (crude) of 4-[(2-[1,8- diazaspiro[4. 5 ] decanylmethyl]-5 uoromethyl)phenyl)amino] -2,2-dimethylbutanoic acid hydrochloride as a light yellow solid. LCMS (ESI, m/z): 428 .
Step 4: Preparation of 4-((2—((8-(((1,1,1,3,3,3-hexafluoropropanyl)oxy)carbonyl)—1,8- diazaspiro[4.5]decanyl)methyl)(trifluoromethyl)phenyl)amino)—2,2- dimethylbutanoic acid COOH COOH S CF3 H H N A N : :5 FaC ”0 HCI CF3 F30 0 CF3 wk. triphosgene, t, DCM rt, overnight WAOXCF‘Q, A 50-mL round-bottom flask was d with triphosgene (97.0 mg, 0.330 mmol, 0.70 equiv), DCM (10 mL), and 1,1,1,3,3,3-hexafluoropropan—2-ol (157 mg, 0.930 mmol, 2.00 equiv) under nitrogen. N,N—Diisopropylethylamine (181 mg, 1.40 mmol, 3.00 equiv) was added at 0 °C, and the mixture was stirred for 1 h at room ature. [1,8- Diazaspiro[4. 5 ] decanylmethyl]-5 -(trifluoromethyl)phenyl)amino] -2,2-dimethylbutanoic acid hydrochloride (200 mg, 0.470 mmol, 1.00 equiv) was then added and the resulting solution was stirred overnight at room temperature before quenching with water (30 mL).
The mixture was extracted with DCM (2 x 50 mL) and the organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product (300 mg) was purified by preparative HPLC to afford 51.7 mg (18% yield) of 4-((2-((8-(((1,1,1,33,3- hexafluoropropan-2—yl)oxy)carbonyl)- 1 , 8-diazaspiro[4. 5]decanyl)methyl) (trifluoromethyl)phenyl)amino)-2,2-dimethylbutanoic acid as a white solid, 1H NMR (300 MHz, Methanol-d4) 6 7.15 (d, J: 7.8 Hz, 1H), 6.77 - 6.82 (m, 2H), 6.08 - 6.16 (m, 1H), 4.17 (br, 2H), 3.73 (s, 2H), 3.00 - 3.16 (m, 4H), 2.63 (t, J: 6.9 Hz, 2H), 1.76 - 1.97 (m, 8H), 1.51 - 1.55 (m, 2H), 1.25 (s, 6H). LCMS (ESI, m/z): 622 [M+H]+.
Example 12: 3-((3-Chlor0((8-(((1,1,1,3,3,3-hexafluoropr0panyl)oxy)carbonyl)- 1,8-diazaspiro[4.5]decanyl)methyl)phenyl)amin0)pr0pan0ic acid HOOC\/\NH Cl/©\<\r\:,©qJLOJ\CF3o CF3 The title compound was prepared according to the representative procedure of Example 11 using o(trifluoromethyl)benzaldehyde in Step 1 and lert—butyl 4— amino-2,2-dimethylbutanoate in Step 2 to provide 3-((3-chloro((8-(((1 1 1 3 3 3- hexafluoropropanyl)oxy)carbonyl)- 1 , 8-diazaspiro[4. 5]decan yl)methyl)phenyl)amino)propanoic acid as a white solid. 1H NMR (3 00 MHz, Methanol-d4) 6 6.87 (br, 2H), 6.79 (br, 1H), 6.08 - 6.21 (m, 1H), 4.20 - 4.22 (m, 2H), 3.81 (s, 2H), 3.40 (t, J: 6.9 Hz, 2H), 3.02 - 3.19 (m, 2H), 2.94 - 2.98 (m, 2H), 2.52 (t, J: 648 Hz, 2H), 1.88 - 2.06 (m, 6H), 1.56 - 1.72 (m, 2H). LCMS (ESI, m/z): 546 [M+H]+. e 13: (2-((8-(((1,1,1,3,3,3-Hexafluoropropanyl)oxy)carbonyl)—1,8- diazaspiro[4.5]decanyl)methyl)(triflu0r0methyl)phenyl)—L-alanine COOH F30Umloxm0 CF3 Step 1: Synthesis of (2-((8-(tert-butoxycarbonyl)—1,8-diazaspir0[4.5]decan yl)methyl)(trifluoromethyl)phenyl)—L-alanine COOH 3' Y F3C HZNY NH COOH F3C , Boc N Cul, , DMSO <50“, Boc 100 °C, overnight A 50-mL bottom flask was d with lert—butyl l-(2-bromo—4- uoromethyl)benzyl)—l,8—diazaspiro[4.5]decanecarboxylate (Example 11, Step 1, 300 mg, 0.630 mmol, 1.00 equiv), DMSO (10 mL), (2S)aminopropanoic acid (168 mg, 1.89 mmol, 3.00 equiv), cesium carbonate (821 mg, 2.52 mmol, 4.00 equiv), and copper (I) iodide (48.0 mg, 0.250 mmol, 0.40 equiv) under nitrogen. The resulting solution was stirred overnight at 100 °C and quenched with water (1 mL). The residue was chromatographed on a silica gel column with DCM/MeOH (4/1) to e 200 mg (66% yield) of (2-((8-(terz‘- butoxycarbonyl)—1,8—diazaspiro[4.5]decanyl)methyl)—5-(trifluoromethyl)phenyl)—L- alanine as a light yellow solid. LCMS (ESI, m/z): 486 [M+H]+.
Step 2: Preparation of (2-((8-(tert-butoxycarbonyl)—1,8-diazaspiro[4.5]decan-l- yl)methyl)—5-(trifluor0methyl)phenyl)—L-alanine The title compound was prepared according to the representative procedure of Example 11, Steps 3—4, using (2-((8-(terl—butoxycarbonyl)-1,8—diazaspiro[4.5]decan-1— yl)methyl)(trifluoromethyl)phenyl)-L-alanine in Step 3 to provide (2-((8-(tert- butoxycarbonyl)—1,8—diazaspiro[4.5]decanyl)methyl)(trifluoromethyl)phenyl)-L- alanine as a white solid. 1H NMR (300 MHz, Methanol-d4) 5 7.32 (d, J = 7.8 Hz, 1H), 6.96 - 7.30 (m, 2H), 6.12 — 6.21 (m, 1H), 4.37 - 4.46 (m, 1H), 4.22 — 4.25 (m, 2H), 4.09 - 4.16 (m, 1H), 3.80 - 3.84 (m, 1H), 3.04 - 3.30 (m, 2H), 2.90 - 2.93 (m, 2H), 2.08 - 2.23 (m, 2H), 1.76 - 2.03 (m, 6H), 1.48 (d, J: 6.9 Hz, 3H),.LCMS (ESI, m/z): 580 [M+H]+.
Example 14: 4-(3-((8-(((1,1,1,3,3,3-Hexafluoropropanyl)0xy)carb0nyl)—1,8- diazaspiro[4.5]decanyl)methyl)(trifluor0methyl)phenoxy)cyclohexane ylic acid HOOC Q i CF3 \O‘o \p‘ OXCFa N Step 1: Synthesis of ethyl 4-((methylsulfonyl)0xy)cyclohexanecarboxylate O O meow MsCl, Et3N, DCM m meow, A 40-mL round-bottom flask was charged with ethyl 4-hydroxycyclohexane carboxylate (200 mg, 1.16 mmol, 1.00 , TEA (351 mg, 3.47 mmol, 3.00 equiv), and DCM (10 mL). Methanesulfonyl chloride (158 mg, 1.38 mmol, 1.20 equiv) was added dropwise at 0 oC. The resulting solution was stirred for 2 h at room ature and quenched with water (10 mL). The mixture was extracted with DCM (3 x 10 mL) and the c layers were combined, washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield 280 mg (96% yield) of ethyl 4-(methanesulfonyloxy)cyclohexanecarboxylate as a light yellow oil.
Step 2: Synthesis of utyl 1-(3-hydroxy(trifluoromethyl)benzyl)-1,8- diazaspiro [4.5] decane—S-carboxylate ,Boc F C3 F30 {50 /0 Q N,Boc HO Et3N, NaBH(OAc)3, DCE rt, overnight ] A 40-mL round-bottom flask was charged with 3-hydroxy (trifluoromethyl)benzaldehyde (300 mg, 1.58 mmol, 1.00 equiv), tert-butyl 1,8- diazaspiro[4.5]decanecarboxylate (379 mg, 1.58 mmol, 1.00 equiv), and TEA (479 mg, 4.73 mmol, 3.00 equiv) in DCE (10 mL). The resulting solution was d for 0.5 h at room temperature. Sodium triacetoxyborohydride (1.00 g, 4.72 mmol, 3.00 equiv) was added, and the mixture was stirred overnight at room temperature and quenched with water (10 mL). The resulting solution was extracted with DCM (3 x 10 mL) and the organic layers were combined, washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, d and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with DCM/MeOH (10/1) to yield 520 mg (80% yield) of tert—butyl 1-(3- hydroxy(trifluoromethyl)benzyl)-1,8-diazaspiro[4.5]decanecarboxylate as a light yellow oil. LCMS (ESI, m/z): 415 [M+H]*.
Step 3: sis of tert-butyl 1-(3-((4-(ethoxycarbonyl)cyclohexyl)oxy)—5- (trifluoromethyl)benzyl)—1,8-diazaspir0[4.5]decane—S-carboxylate F3C O F3C Q S EtoocflQ N,Boc N,Boc HO o N C52CO3, DMF N 90 °C, overnight A 100-mL round—bottom flask was charged with tert—butyl 1-(3 -hydroxy (trifluoromethyl)benzyl)-1,8—diazaspiro[4.5]decane-8—carboxylate (3 80 mg, 0.920 mmol, 1.00 equiv), ethyl 4—(methanesulfonyloxy)cyclohexanecarboxylate (344 mg, 1.37 mmol, 1.50 equiv), cesium ate (898 mg, 2.76 mmol, 3.00 equiv), and N,N— dimethylformamide (10 mL). The resulting solution was stirred overnight at 90 CC and quenched with water (10 mL). The resulting solution was extracted with EtOAc (3 x 10 mL) and the organic layers were combined, washed with brine (2 X 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with petroleum ether (1/4) to provide 180 mg (35% yield) of utyl 1-(3 —((4-(ethoxycarbonyl)cyclohexyl)oxy)-5— oromethyl)benzyl)—1,8-diazaspiro[4.5]decanecarboxylate as a light yellow oil.
LCMS (ESI, m/z): 569 .
Step 4: Synthesis of 4-(3-((8-(tert—but0xycarbonyl)-1,8-diazaspiro[4.5]decan yl)methyl)(trifluoromethyl)phenoxy)cycl0hexane-l-carboxylic acid F30 F3C EtOOC LiOH, THF, H20 HOOC , Boc , Boc O {30“ rt, overnight 0 <50“ A 100-mL round-bottom flask was charged with teri—butyl 1—(3 -((4- (ethoxycarbonyl)cyclohexyl)oxy)(trifluoromethyl)benzyl)-1,8-diazaspiro[4.5]decane carboxylate (180 mg, 0.320 mmol, 1.00 equiv), lithium hydroxide (760 mg, 3.17 mmol, .0 equiv), tetrahydrofuran (5 mL), and water (3 mL). The ing solution was stirred overnight at room temperature and quenched with water (10 mL). The pH value of the solution was ed to 6 with hydrochloric acid (1M). The resulting solution was extracted with DCM (3 x 10 mL) and the organic layers were combined, washed with brine (2 X 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide 170 mg (99% yield) of 4-(3-((8-(tert-butoxycarbonyl)-1,8-diazaspiro[4.5]decan- 1-yl)methyl)(trifluoromethyl)phenoxy)cyclohexanecarboxylic acid as a solid. LCMS (ESI, m/z): 541 [M+H]+.
Step 5: Synthesis of 4-(3-((1,8-diazaspiro[4.5]decan-l-yl)methyl)—5— (trifluoromethyl)phenoxy)cyclohexane—1-carb0xylic acid hloride F3C F30 HCI, 1,4-dloxane HCI HOOC HOOC oc —> N’ NH ° <50 B "'2“ ° <50 A 50—mL round-bottom flask was charged with 4-(3—((8-(ter2‘—butoxycarbonyl)—1,8- diazaspiro[4. 5 ] decanyl)methyl)-5 —(trifluoromethyl)phenoxy)cyclohexanecarboxylic acid (170 mg, 0.310 mmol, 1.00 equiv), 1,4-dioxane (10 mL), and hydrochloric acid (2 mL).
The resulting solution was stirred for 2 h at room temperature and concentrated under WO 93949 reduced pressure to provide 180 mg (crude) of 4-(3-((1,8-diazaspiro[4.5]decan yl)methyl)(trifluoromethyl)phenoxy)cyclohexane-1—carboxylic acid hydrochloride as a light yellow oil. LCMS (ESI, m/Z): 441 [M+H]+.
Step 6: Synthesis of 4-(3-((8-(((1,1,1,3,3,3-hexafluor0propanyl)0xy)carbonyl)—1,8- diazaspiro[4.5]decanyl)methyl)(triflu0r0methyl)phenoxy)cyclohexane carboxylic acid HOOC HOOC CF3 NH sgene, ’PerEt ACFs CH2C|2 0 °C. 5h A 40-mL round-bottom flask was charged with 1,1,1,3,3,3-hexafluoropropan—2-ol (79.0 mg, 0.470 mmol, 1.50 equiv), and triphosgene (47.0 mg, 0.160 mmol, 0.50 equiv) in DCM (5 mL) under en. N,N—Diisopropylethylamine (121 mg, 0.940 mmol, 3.00 equiv) was added dropwise at 0 °C. The ing solution was stirred for 2 h at 0 °C before 4-(3—[1,8-diazaspiro[4.5]decanylmethyl]-5—(trifluoromethyl)phenoxy)cyclohexane-l— carboxylic acid hydrochloride (138 mg, 0.310 mmol, 1.00 equiv) was added. The resulting solution was stirred for 3 h at 0 °C and quenched with water (10 mL). The mixture was extracted with DCM (3 X 10 mL) and the organic layers were combined, washed with brine (2 X 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product (200 mg) was purified by preparative HPLC to afford 12.1 mg (6% yield) of4-(3-((8—(((1,1,l,3,3,3-heXafluoropropan—2-yl)oxy)carbonyl)-1,8— diazaspiro[4. 5 ] decanyl)methyl)-5 —(trifluoromethyl)phenoxy)cyclohexanecarboxylic acid as a white solid. 1H NMR (400 MHz, Methanol-d4) 8 7.06 — 7.54 (m, 3H), 6.15 - 6.19 (m, 1H), 4.31 - 4.89 (m, 1H), 4.20 - 4.23 (m, 2H), 3.34 - 3.82 (m, 2H), 3.07 - 3.32 (m, 2H), 2.95 (br, 1H), 2.72 - 2.76 (m, 1H), 2.20 - 2.23 (m, 1H), 2.07 - 2.10 (m, 1H), 1.73 - 2.00 (m, 11H), 1.52 - 1.68 (m, 4H). LCMS (ESI, m/z): 635 [M+H]+.
Example 15: (8-(((1,1,1,3,3,3-Hexafluor0propanyl)oxy)carb0nyl)—1,8- diazaspiro[4.5]decanyl)methyl)(triflu0r0methyl)phenoxy)cyclohexane carboxylic acid HOOC fig l CF3 N O CF3 The title compound was prepared according to the representative procedure of Example 14 using 2-hydroxy—4-(trifluoromethyl)benzaldehyde in Step 2 to provide 4-(2—((8- (((1,1, 1,3 ,3 ,3 -heXafluoropropanyl)oxy)carbonyl)- 1 , 8-diazaspiro[4.5]decan- l -yl)methyl)— -(trifluoromethyl)phenoxy)cyclohexanecarboxylic acid as a white solid. 1H NMR (400 MHz, Methanol-d4) 6 7.19 - 7.22 (m, 2H), 7.02 - 7.08 (m, 1H), 6.13 - 6.17 (m, 1H), 4.89 (br, 0.2H), 4.35 - 4.39 (m, 0.8H), 4.15 — 4.26 (m, 2H), 3.74 - 3.75 (m, 2H), 3.07 — 3.18 (m, 2H), 2.77 - 2.80 (m, 2H), 2.20 - 2.35 (m, 1H), 2.07 - 2.19 (m, 3H), 1.76 - 1.99 (m, 8H), 1.51 — 1.66 (m, 5H). LCMS (ESI, m/z): 635 [M+H]+. e 16: 1,1,1,3,3,3-Hexafluoropropan-Z-yl (4-(methylsulfonamid0) oxobutyl)amino)—4-(triflu0r0methyl)benzyl)-1,8-diazaspir0[4.5]decane-S-carboxylate ,SOzMe F30\©\\ O CF3 <50NJJ\O CF3 The title compound was prepared according to the representative procedure of Example 11 using lerZ-butyl 4-aminobutanoate in Step 2 to provide 1,1,1,3,3,3- hexafluoropropanyl 1-(2-((4-(methylsulfonamido)oxobutyl)amino) oromethyl)benzyl)—l,8-diazaspiro[4.5]decane-8—carboxylate as a white solid. 1H NMR (400 MHz, Methanol-d4) 5 7.16 (d, J= 7.6 Hz, 1H), 6.83 (d, J= 7.6 Hz, 1H), 6.77 (s, 1H), 6.08 - 6.18 (m, 1H), 4.16 - 4.22 (m, 2H), 3.72 - 3.83 (m, 2H), 3.01 - 3.24 (m, 7H), 2.64 (t, J = 7.0 Hz, 2H), 2.45 (t, J: 7.2 Hz, 2H), 1.91 - 1.99 (m, 5H), 1.75 - 1.90 (m, 3H), 154 - 1.56 (m, 2H). LCMS (ESI, m/Z): 671 [M+H]+.
Example 17: 4-(3-Chlor0-5—((8-(((1,1,1,3,3,3-hexafluor0propan-Z-yl)0xy)carb0nyl)-1,8- diazaspiro[4.5]decanyl)methyl)phen0xy)butanoic acid HOOC Q 0 CF3 Cl 00% CPS N Step 1: Synthesis of utyl 4-(3-chlor0f0rmylphenoxy)butanoate HO 0 BerOX K2003, DMF 0 100 °C, overnight A 50-mL round-bottom flask was charged with 3-chlorohydroxybenzaldehyde (1.00 g, 6.39 mmol, 1.00 equiv), N,N—dimethylformamide (10 mL), potassium carbonate (2.65 g, 19.2 mmol, 3.00 equiv), and terl-butyl 4-bromobutanoate (2.84 g, 12.7 mmol, 2.00 equiv), The resulting solution was stirred ght at 100 °C and quenched with water (30 mL). The resulting solution was ted with EtOAc (2 X 50 mL) and the organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and trated under reduced re. The residue was chromatographed on a silica gel column with DCM/MeOH (98/2) to provide 1.10 g (58%) of tert—butyl 4-(3- chloroformylphenoxy)butanoate as a light yellow oil.
Step 2: Synthesis of 1,1,1,3,3,3-hexafluoropropan-Z-yl 1-(3-(4-(tert-butoxy) 0x0but0xy)chlorobenzyl)—1,8-diazaspir0[4.5]decane-S-carboxylate CFO CF3 o n NJJ\0)\CF3 NaBH(OAc)3, Et3N, DCE 0 CFa /O rt, overnight Cl <j©lkOACF3N CI A 50-mL round-bottom flask was charged with tert—butyl 4-(3-chloro—5- formylphenoxy)butanoate (150 mg, 0.500 mmol, 1.00 , DCE (10 mL), TEA (153 mg, 1.50 mmol, 3.00 equiv), and 1,1,1,3,3,3-hexafluoropropanyl 1,8-diazaspiro[4,5]decane carboxylate, trifluoroacetate salt (Example 1, Step 4, 168 mg, 0.500 mmol, 1.00 equiv), The mixture was stirred for 1 h at room temperature before sodium triacetoxyborohydride (320 mg, 1.50 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature and quenched with water (30 mL). The mixture was extracted with DCM (2 x 50 mL) and the organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and trated under d pressure. The residue was chromatographed on a silica gel column with DCM/MeOH (98/2) to provide 240 mg (77% yield) of 1,1,1,3,3,3-hexafluoropropanyl 1- (3 -(4—(lert-butoxy)-4—oxobutoxy)—5 -chlorob enzyl)— 1 , 8—diazaspiro[4 , 5]decane-8—carboxylate as yellow oil. LCMS (ESI, m/z): 617 [M+H]+.
Step 3: sis of 4-(3-chloro((8-(((1,1,1,3,3,3-hexafluoropropan-Z- yl)oxy)carbonyl)—1,8-diazaspir0[4.5]decan-l-yl)methyl)phen0xy)butan0ic acid X HOOC HCI 3 O 1,4-dioxane rt, overnight o CF3 i E3 A A N o C' CF3 A 50-mL round-bottom flask was charged with 1,1,1,3,3,3-hexafluoropropan—2-yl 1-(3-(4-(lert-butoxy)—4-oxobutoxy)chlorobenzyl)-1,8-diazaspiro[4.5]decane—8- carboxylate (240 mg, 0.390 mmol, 1.00 equiv), 1,4-dioxane (10 mL), and hydrochloric acid (3 mL). The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure. The residue was dissolved in saturated NaHC03 solution (30 mL).
The resulting solution was ted with DCM (2 X 50 mL) and the organic layers were combined, washed with brine (2 X 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under d pressure. The crude product (300 mg) was purified by preparative HPLC to afford 44.7 mg (20% yield) of 4-(3-chloro((8-(((1,1,1,3,3,3- oropropanyl)oxy)carbonyl)- 1 , 8-diazaspiro[4. 5]decan hyl)phenoxy)butanoic acid as a white solid. 1H NMR (300 MHz, Methanol-d4) 6.95 (s, 1H), 6.84-6.87 (m, 2H), 6.09 — 6.17 (m, 1H), 4.17 — 4.19 (m, 2H), 4.01 (t, J: 6.3 Hz, 2H), 3.68 (s, 2H), 3.05 - 3.12 ( m, 2H), 2.81 (t, J= 7.0 Hz, 2H), 2.43 (t, J: 7.4 Hz, 2H), 1.94 — 2.11 (m, 4H), 1.71 — 1.90 (m, 4H), 1.59 — 1.61 (m, 2H). LCMS (ESI, m/z): 561 [M+H]+.
Example 18: 1,1,1,3,3,3-hexafluoropropan-Z-yl 1-(2-(4-(methylsulf0namid0) 0x0but0xy)(trifluoromethyl)benzyl)—1,8-diazaspir0[4.5]decane—8-carboxylate HO HN,502Me H2N_fi— O O F30\©\‘ O i )\CFs EDCI, DMAP, DCM F3Cfl 0 cF3 rt,overnight A 50-mL round-bottom flask was charged with 4-(2-((8-(((1,l,1,3,3,3- hexafluoropropan-Z—yl)oxy)carbonyl)—1,8-diazaspiro[4.5]decanyl)methyl) (trifluoromethyl)phenoxy)butanoic acid (Example 6, Steps 1-3, 200 mg, 0.340 mmol, 1.00 , DCM (10 mL), methanesulfonamide (96.0 mg, 1.01 mmol, 3.00 equiv), 4— ylaminopyridine (123 mg, 1.01 mmol, 3.00 equiv), and N—(3-dimethylaminopropyl)- N’-ethylcarbodiimide hydrochloride (129 mg, 0.670 mmol, 2.00 equiv). The resulting solution was d overnight at room temperature and quenched with water (30 mL). The mixture was extracted with DCM (2 x 50 mL) and the organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product (300 mg) was purified by preparative HPLC to afford 52.0 mg (23% yield) of (2-((8-(((1,1,1,3,3,3-hexafluoropropan- xy)carbonyl)- 1 , 8 -diazaspiro[4. 5]decan- l -yl)methyl)-5 —(trifluoromethyl)phenyl)-L- alanine as a white solid. 1H NMR (300 MHz, Methanol-d4) 6 7.06 (d, J = 8.1 Hz, 1H), 7.26 - .28 (m, 2H), 6.12 - 6.20 (m, 1H), 4.23 - 4.31 (m, 2H), 4.16 (t, J: 6.0 Hz, 2H), 4.08 - 4.11 (m, 2H), 3.06 - 3.21 (m, 7H), 2.46 (t, J: 6.9 Hz, 2H), 1.97 - 2.20 (m, 8H), 1.76 - 1.80 (m, 2H). LCMS (ESI, m/z): 672 [M+H]+.
Example 19: (8-(((1,1,1,3,3,3—hexafluoropropan-Z-yl)oxy)carbonyl)-1,8- diazaspiro[4.5]decanyl)methyl)(trifluor0methyl)phenoxy)cyclopropane carboxylic acid AVCOOH F30%AOACF30 CF3 Step 1: Synthesis of methyl 1-(2-formyl-S-(trifluor0methyl)phenoxy)cyclopropane carboxylate / O F NaH,THF rt, 1h \ A flask was charged with methyl 1-hydroxycyclopropanecarboxylate (1.36 g, 11.7 mmol, 1.50 equiv) and THF (10 mL). Sodium hydride (0.780 g, 19.5 mmol, 2.50 equiv, 60% in mineral oil) was added at 0 0C1 The e was stirred for 20 min at room temperature. 2—Fluoro—4-(tn'fluoromethyl)benzaldehyde (1.50 g, 7.81 mmol, 1.00 equiv) was added. The resulting solution was stirred for 1 h at room temperature and quenched with water (30 mL). The resulting on was extracted with DCM (2 X 50 mL) and the organic layers were combined, washed with brine (2 x 30 mL), dried over ous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to provide 530 mg (24% yield) of methyl 1-(2-formyl (tIifluoromethyl)phenoxy)cyclopropanecarboxylate as a yellow oil. 1H NMR (300 MHZ, Chloroform-d) 6 10.50 (s, 1H), 8.00 - 7.97 (m, 1H), 7.38 - 7.27 (m, 2H), 3.79 (s, 3H), 1.82 - 1.70 (m, 2H), 1.52 — 1.44 (m, 2H).
Step 2: Synthesis of utyl 1-(methoxycarbonyl)cyclopropoxy)—4— (trifluoromethyl)benzyl)—1,8-diazaspir0[4.5]decane—S-carboxylate AV n DON-Boo 0 o F3C F3C — NaBH(OAc)3. DCE N,B°c \o rt, overnight <50 ] A flask was charged with methyl 1-(2-formyl (trifluoromethyl)phenoxy)cyclopropanecarboxylate (530 mg, 1.84 mmol, 1.00 equiv), DCE (10 mL), and tert-butyl l,8-diazaspiro[4.5]decanecarboxylate (530 mg, 2.21 mmol, 1.20 equiv). The mixture was stirred for 1 h at room temperature. Sodium triacetoxyborohydride (1.17 g, 5.52 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature and quenched with water (50 mL), as described in Example 7, Step 2. The residue was chromatographed on a silica gel column to provide 350 mg (37% yield) of tert-butyl 1-(2-(1-(methoxycarbonyl)cyclopropoxy) (trifluoromethyl)benzyl)—1,8—diazaspiro[4.5]decanecarboxylate as a yellow oil. LCMS (ESI, m/Z): 513 [M+H]+.
Step 3: Synthesis of 1-(2-((8-(tert-but0xycarb0nyl)—1,8-diazaspiro[4.5]decan-l- yl)methyl)(triflu0romethyl)phenoxy)cyclopr0pane-l-carboxylic acid 2017/061870 M /0 4cm O LiOH —.F3C Fae H20, THF , Boc rt, overnight fl<9,Boc A flask was charged with tert-butyl 1-(2-(1-(methoxycarbonyl)cyclopropoxy)—4- (trifluoromethyl)benzyl)-1,8—diazaspiro[4.5]decanecarboxylate (350 mg, 0.680 mmol, 1.00 equiv), water (5 mL), THF and (5 mL), lithium hydroxide (246 mg, 10.2 mmol, 15.0 equiv). The resulting solution was stirred overnight at room temperature. The pH value of the solution was adjusted to 5 with hydrochloric acid (1 mol/L), as described in Example 14, Step 4 to provide 330 mg (97% yield) of 1-(2-((8-(tert-butoxycarbonyl)-1,8- diazaspiro[4.5]decan—1-yl)methy1)-5—(trifluoromethyl)phenoxy)cyclopropane-1—carboxylic acid as a yellow oil. LCMS (ESI, m/z): 499 [M+H]+.
Step 4: Synthesis of 1-(2-((1,8-diazaspiro[4.5]decan-l-yl)methyl)—5— (trifluoromethyl)phen0xy)cyclopropanecarb0xylic acid AgCOOH COOH \GENJOQ’BW HC' A; F30 F3C 1,4—dioxane rt, 3h @610“ ] A flask was charged with 1-(2-((8-(tert-butoxycarbonyl)—1,8—diazaspiro[4.5]decan- ethy1)—5-(trifluoromethyl)phenoxy)cyclopropanecarboxylic acid (330 mg, 0.660 mmol, 1.00 equiv), 1,4-dioxane (10 mL), and trated hydrochloric acid (2 mL). The resulting solution was stirred for 3 h at room temperature and concentrated under reduced pressure to provide 264 mg (quantitative) of 1-(2-((1,8-diazaspiro[4.5]decanyl)methyl)— -(trifluoromethyl)phenoxy)cyc1opropanecarboxylic acid as a yellow oil. LCMS (ESI, m/z): 399 .
Step 5: Synthesis of (8-(((1,1,1,3,3,3-hexafluor0pr0panyl)0xy)carbonyl)—1,8- diazaspiro[4.5]decanyl)methyl)(trifluor0methyl)phenoxy)cyclopr0pane carboxylic acid A(COOH cu:3 X AVCOOH o 0 Ho CF3 F30 F3C o CF3 triphosgene NH NJkOACF3 N DIPEA, DCM N rt, overnight WO 93949 A flask was charged with triphosgene (137 mg, 0.462 mmol, 0.70 equiv), DCM (10 mL), and 3,3,3-hexafluoropropan-2—ol (222 mg, 1.32 mmol, 2.00 . DIPEA (255 mg, 1.98 mmol, 3.00 equiv) was added dropwise at 0 °C. The mixture was stirred for 1 h at room temperature. 1-(2-((1,8-Diazaspiro[4.5]decan—1-yl)methyl)-5— (trifluoromethyl)phenoxy)cyclopropanecarboxylic acid (264 mg, 0.660 mmol, 1.00 equiv) was added. The resulting solution was stirred overnight at room temperature and quenched with water (30 mL), as described in Example 1, Step 3. The crude product (300 mg) was purified by preparative HPLC to provide 268.6 mg (68% yield) of 1-(2-((8- ((( 1 , 1 , 1,3 ,3 ,3 -hexafluoropropanyl)oxy)carbonyl)- 1 , 8-diazaspiro[4.5]decanyl)methyl)— -(trifluoromethyl)phenoxy)cyclopropanecarboxylic acid as a white solid. 1H NMR (400 MHz, Methanol-d4) 6 7.65 - 7.58 (m, 2H), 7.36 (d, J: 8.0 Hz, 1H), 6.22 - 6.15 (m, 1H), 4.84 (br, 1H), 4.33 — 4.26 (m, 2H), 3.84 (br, 1H), 3.48 (br, 1H), 3.31 (br, 1H), 3.31 — 3.13 (m, 2H), 2.54 - 2.31 (m, 2H), 2.26 - 2.19 (m, 3H), 2.10 - 1.90 (m, 3H), 1.90 - 1.76 (m, 1H), 1.45 - 1.43 (m, 1H), 1.28 - 1.15 (m, 2H). LCMS (ESI, m/z): 593 [M+H]+.
Example 20: 1-((5-chlor0-2—((8-(((l,1,1,3,3,3-hexafluor0propanyl)0xy)carb0nyl)—1,8- piro[4.5]decanyl)methyl)phenoxy)methyl)cyclopropane-l-carboxylic acid Hooc CI\©/\\ o CF3 Step 1: Synthesis of ethyl 1-(((methylsulfonyl)0xy)methyl)cyclopr0pane-l-carboxylate O MsCLEQN O AOXOH DCM rt, 1h Aokom A flask was charged with ethyl 1-(hydroxymethyl)cyclopropanecarboxylate (1.20 g, 8.33 mmol, 1.00 equiv), DCM (10 mL), and TEA (2.52 g, 25.0 mmol, 3.00 equiv).
Methanesulfonyl chloride (1.42 g, 12.5 mmol, 1.50 equiv) was added at 0 oC. The resulting on was stirred for 1 h at room temperature and quenched with saturated NH4C1 solution (30 mL), as described in Example 14, Step 1, to provide 1.84 g of ethyl 1- (((methylsulfonyl)oxy)methyl)cyclopropanecarboxy1ate as a yellow oil.
Step 2: Synthesis of ethyl chl0roformylphenoxy)methyl)cyclopropane—1- carboxylate Akm” IQ m: C82C03, DMF 80 °C, ght 0 A flask was charged with ethyl l-(((methylsulfonyl)oxy)methyl)cyclopropane-l- carboxylate (1.07 g, 4.80 mmol, 1.50 equiv), DMF (10 mL), cesium carbonate (3.14 g, 9.60 mmol, 3.00 equiv), and 4-chlorohydroxybenzaldehyde (500 mg, 3.20 mmol, 1.00 .
The resulting solution was d overnight at 80 °C and quenched with water (50 mL), as described in Example 14, Step 3. The residue was chromatographed on a silica gel column to e 800 mg (89% yield) of ethyl 1-((5-chloro formylphenoxy)methyl)cyclopropane—l-carboxylate as a yellow oil. LCMS (ESI, m/z): 283 [M+H]+.
Step 3: Synthesis of tert-butyl 1-(4-chloro((1- (ethoxycarbonyl)cyclopr0pyl)methoxy)benzyl)—1,8—diazaspir0[4.5]decane carboxylate 0'mo w EtOOC BOG 0J<I 0 fl ,Boc QWOJ N NaBH(OAc)3, DCE rt, ght 0 {:0 A flask was charged with ethyl l-((5-chloro formylphenoxy)methyl)cyclopropane—l—carboxylate (0.800 g, 2.83 mmol, 1.00 equiv), DCE (10 mL), and tert-butyl l,8-diazaspiro[4.5]decanecarboxylate (0.816 g, 3.40 mmol, 1.20 equiv). The mixture was stirred for l h at room temperature. Sodium triacetoxyborohydride (1.80 g, 8.49 mmol, 3.00 equiv). The resulting solution was stirred overnight at room temperature and quenched with water (50 mL), as described in Example 7, Step 2. The residue was chromatographed on a silica gel column to provide 0.800 g (56% yield) of tert- butyl 1-(4-chloro((1-(ethoxycarbonyl)cyclopropyl)methoxy)benzyl)-1,8- diazaspiro[4.5]decanecarboxylate as a yellow oil. LCMS (ESI, m/z): 507 [M+H]+.
Step 4: Synthesis of 1-((2-((8-(tert-butoxycarbonyl)—1,8-diazaspir0[4.5]decan-l- yl)methyl)chlorophenoxy)methyl)cyclopr0pane—l-carboxylic acid EtOOC HOOC ON 0 Cl NaOH, THF, H20 CI Q’Bm rt, overnight N A flask was charged with tert-butyl 1-(4-chloro((1- (ethoxycarbonyl)cyclopropyl)methoxy)benzyl)—1,8-diazaspiro[4.5]decanecarboxylate (350 mg, 0.690 mmol, 1.00 equiv), THF (5 mL), water (5 mL), and sodium ide (277 mg, 6.92 mmol, 10.0 equiv). The resulting solution was d overnight at room temperature. The pH value of the solution was ed to 5 with hydrochloric acid (1 mol/L). The resulting solution was extracted with DCM (2 x 50 mL) and the organic layers were combined, washed with brine (2 X 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide 270 mg (82% yield) of 1-((2- ((8-(tert-butoxycarbonyl)-1,8-diazaspiro[4.5]decanyl)methyl) chlorophenoxy)methyl)cyclopropane-l-carboxylic acid as a yellow oil. LCMS (ESI, m/z): 479 [M+H]+.
Step 5: Synthesis of ((1,8-diazaspiro[4.5]decan-l-yl)methyl) chlorophenoxy)methyl)cyclopr0pane-l-carboxylic acid HOOC HOOC ON 0 Cl HCI, 1,4-dioxane CI l1, 3h NH A flask was charged with 1-[2-([8-[(tert-butoxy)carbonyl]-1,8- diazaspiro[4. 5 ] decan— 1 -yl]methyl)-5 -chlorophenoxymethyl]cyclopropanecarboxylic acid (270 mg, 0.560 mmol, 1.00 equiv), trated hloric acid (5 mL), and 1,4-dioxane (5 mL). The resulting solution was stirred for 3 h at room temperature filtered and concentrated under reduced pressure to provide 211 mg (quantitative) of ((l,8- diazaspiro[4. 5 ] decan— 1 -yl)methyl)-5 -chlorophenoxy)methyl)cyclopropanecarboxylic acid as a brown oil. LCMS (ESI, m/z): 379 [M+H]+.
Step 6: Synthesis of 1-((5-chloro-2—((8-(((l,1,1,3,3,3-hexafluoropropan-Z- yl)oxy)carbonyl)—1,8-diazaspiro[4.5]decanyl)methyl)phenoxy)methyl)cyclopropane- 1-carb0xylic acid HOOC HOOC 0N E3 0% NH triphosgene,D|PEA,DCM N O CF3 N . N rt, overnight A flask was charged with triphosgene (118 mg, 0.400 mmol, 0.70 equiv), DCM (10 mL), and 1,1,1,3,3,3-hexafluoropropanol (190 mg, 1.13 mmol, 2.00 equiv). DIPEA (220 mg, 1.71 mmol, 3.00 equiv) was added at 0 oC. The mixture was stirred for 1 h at room temperature. 1-((2-((1,8-Diazaspiro[4.5]decanyl)methyl) chlorophenoxy)methyl)cyclopropane—1-carboxylic acid (214 mg, 0.560 mmol, 1.00 equiv) was added. The resulting solution was stirred overnight at room temperature and quenched with ted NaHC03 on (30 mL), as described in Example 1, Step 3. The crude product (3 00 mg) was purified by preparative HPLC to provide 86.1 mg (27% yield) of 1- ((5 -chloro-2—((8-((( 1 , 1 , 1,3 ,3,3 —hexafluoropropanyl)oxy)carbonyl)- 1 , 8— diazaspiro[4.5]decanyl)methyl)phenoxy)methyl)cyclopropanecarboxylic acid as a white solid. 1H NMR (300 MHz, Chloroform-d) 6 7.18 (d, J: 8.1 Hz, 1H), 6.94 - 6.89 (m, 2H), 5.81 — 5.57 (m, 1H), 4.30 — 4.15 (m, 2H), 4.12 — 4.05 (m, 2H), 3.84 — 3.74 (m, 2H), 3.00 - 2.92 (m, 4H), 2.21 - 2.16 (m, 2H), 2.04 - 1.08 (m, 6H), 1.36 - 1.34 (m, 2H), 0.86 — 0.82 (m, 2H). LCMS (ESI, m/Z): 573 [M+H]+.
Examples 21-25: Examples 21-25 were prepared by similar procedures as described in Examples 1-20 (Table 2).
Table2 .—3--((3-((8- NMR (1H NMR, 300 MS MHz or 400 MHz) [M+H]+ (Methanol-d4) 8 6.97 - 6.89 (((1,1,1,3,3,3- (m, 2H), 6.83 (s, 1H), 6.20 - hexafluoropropan 6.16 (m, 1H), 4.26 (br, 2H), )carbonyl)--1,8- 3.85 (s, 2H), 3.46 - 3.32 (m, diazaspiro[4.5]decan— 2H), 3.18 - 2.98 (m, 4H), 580. 5 1-yl)methyl) 2.58 - 2.54 (m, 2H), 2.10 - (trifluoromethyl)phen 1.96 (m, 6H), 1.72 - 1.67 (m yl)amin0)propanoic 2H) acid 1-((2-((8- (Methanol- d4) 8 7.59 - 7.56 (((L1 1,33,3- (m, 1H), 7.30 - 7.29 (m, 2H) oropropan—2- 6.21 - 6.13 (m, 1H), 4.26 - yl)oxy)carbonyl)- l ,8- 4.18 (m, 6H), 3.27 - 3.08 (m diazaspiro [4 . 5] decan- 4H), 2.38 - 2.33 (m, 2H), 607. 5 1-yl)methyl) -5 - 2.15 -1.87(m,6H), 1.26 - (trifluoromethyl)phen 1.22 (m, 2H), 0.90 - 0.89 (m oxy)methyl)cyclopro 2H) panecarboxylic acid 1-((4-fluoro - (Chloroform-d) 5 7.06 - 6.94 (((1,1 1,333- (m, 2H), 6.85 - 6.80 (m, 1H) oropropan—2- 5.79 - 5.70 (m, 1H), 4.29 - yl)oxy)carbonyl)-1,8- 4.21 (m, 2H), 4.14 - 4.02 (m diazaspiro [4 . 5] decan- 2H), 3.84 - 3.73 (m, 2H), 557.1 1 _ 3.07 - 2.92 (m, 4H), 2.18 - yl)methyl)phenoxy)m 2.13 (m, 2H), 2.03 - 1.80 (m, ethyl)cyclopropane- 6H), 1.36 - 1.33 (m, 2H), l-carboxylic acid 0.87 - 0.83 (m, 2H) 1-((5-fluoro((8- (Chloroform— d) 8 7.34 -7 .26 (((1,1,1,3,3,3- (m, 1H), 6.69 - 6.63 (m, 2H), oropropan—2- 5.80 - 5.72 (m, 1H), 4.36 - yl)oxy)carbonyl)-1,8- 4.26 (m, 2H), 4.14 - 4.06 (m, diazaspiro[4.5]decan— 2H), 3.95 (br, 2H), 3.14 - 1- 3.00 (m, 4H), 2.38 - 2.33 (m, y1)methyl)phenoxy)m 2H), 2.15 - 1.87 (m, 6H), ethyl)cyclopropane- 1.37 (br, 2H), 0.86 - 0.85 (br, l-carboxylic acid 2H) 1-((2-fluoro((8- (Chloroform— d) 5 7.12 - 7.00 (((1,1,1,3,3,3- (m, 2H), 6.99 - 6.93 (m, 1H), hexafluoropropan—2- 5.80 - 5.72 (m, 1H), 4.38 - y1)oxy)carbonyl)-l,8- 4.01 (m, 4H), 3.97 (br, 1H), piro[4.5]decan— 3.80 (br, 1H), 3.06 - 2.96 (m, 1- 4H), 2.23 - 2.17 (m, 2H), yl)methyl)phenoxy)m 2.06 - 1.97 (m, 3H), 1.85 (br, ethyl)cyclopropane- 3H), 1.41 - 1.35 (m, 2H), 1-carboxylic acid 0.96 - 0.93 (m, 2H) II. Biological Evaluation Compounds were tested to assess their MAGL and serine hydrolase activity using the following in vitro and in vivo assays.
In vitro competitive activity-based protein profiling (human).
Proteomes (human prefrontal cortex or cell membrane fractions) (50 pL, 1.0-2.0 mg/mL total protein tration) were preincub ated with varying concentrations of inhibitors at 37 °C. After 30 min, FP-Rh or JW912 (10 [LL 50 uM in DMSO) was added and the mixture was incubated for another 30 min at room temperature. Reactions were quenched with SDS loading buffer (15 uL - 4X) and run on GE. Following gel imaging, serine hydrolase activity was determined by ing cent intensity of gel bands corresponding to MAGL using ImageJ 1.49k software. IC50 data from this assay is shown in Table 3.
In vitro competitive activity-based protein profiling (mouse). ] mes (mouse brain membrane fraction or cell lysates) (50 uL, 1.0 mg/mL total protein concentration) were preincubated with varying concentrations of tors at 37 °C. After 30 min, FP-Rh (1.0 uL, 50 M in DMSO) was added and the mixture was incubated for another 30 min at 37 °C. Reactions were quenched with SDS loading buffer (50 pL - 4X) and run on SDS-PAGE. Following gel imaging, serine hydrolase activity was determined by measuring fluorescent intensity of gel bands corresponding to MAGL using ImageJ 1.49k software.
Preparation of Mouse Brain mes from inhibitor treated mice.
Inhibitors were stered to wild-type C57Bl/6J by oral gavage in a vehicle of polyethylene glycol. Each animal was sacrificed 4 h following administration and brain proteomes were prepared and analyzed according to previously ished methods (See Niphakis, M. J., et al. (2011) ACS Chem. Neurosci. and Long, J. 2., et al. Nat. Chem. Biol. :37-44). Percent inhibition data from this assay is shown in Table 3.
TABLE 3 *** IC50 is less than ** ICSO is greater or equal to 100 nM; than 100 nM and less than 1 HM; * IC50 is greater than or equal to 1 HM and less than or equal to 10 MM.
A = % inhibition is r than or equal to 75%; B = % inhibition is greater than or equal to 50% and less than 75%; C = % inhibition is greater than or equal to 25% and less than 50%; D = % inhibition is greater than or equal to 0% and less than 25%.

Claims (26)

1. A compound having the structure of Formula (I): (R2)n R1 X Formula (I); wherein: is ; X is -O- or -N(R3)-; R1 is -(CR4R5)m-R6; each R2 is independently selected from halogen, C1-6alkyl, and C1-6haloalkyl; R3 is H or C1-6alkyl; each R4 and R5 is each independently selected from H and C1-6alkyl; or R4 and R5, together with the carbon to which they are ed, form a C3-6cycloalkyl ring; R6 is -CO2R9; R9 is H or C1-6alkyl; m is 1, 2, 3 or 4; and n is 1; or a pharmaceutically able salt thereof.
2. The compound of claim 1, or a ceutically acceptable salt thereof, wherein m is 1, 2, or 3.
3. The compound of any one of claims 1-2, or a pharmaceutically acceptable salt thereof, wherein m is 1.
4. The compound of any one of claims 1-2, or a pharmaceutically acceptable salt thereof, wherein m is 2.
5. The nd of any one of claims 1-2, or a pharmaceutically acceptable salt thereof, wherein m is 3.
6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein each R4 and R5 is H.
7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R9 is H.
8. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R9 is C1-6alkyl.
9. The compound of any one of claims 1-8, or a ceutically acceptable salt thereof, wherein X is -O-.
10. The compound of any one of claims 1-8, or a ceutically acceptable salt thereof, wherein X is -N(R3)- and R3 is H.
11. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein X is -N(R3)- and R3 is C1-6alkyl.
12. The compound of any one of claims 1-11, or a pharmaceutically able salt thereof, wherein R2 is -Cl.
13. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein R2 is -CF3.
14. A compound according to claim 1 selected from: HO O O CF3 F3C N O CF3 , , , , , , and ; or a pharmaceutically acceptable salt thereof.
15. A compound according to claim 1, wherein the compound is , or a pharmaceutically acceptable salt thereof.
16. A compound according to claim 1, wherein the nd is , or a pharmaceutically acceptable salt thereof.
17. A compound according to claim 1, n the compound is , or a pharmaceutically able salt thereof.
18. A pharmaceutical composition comprising a nd of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically able excipient.
19. Use of a nd according to any one of claims 1-17, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, in the manufacture of a medicament for treating pain.
20. The use according to claim 19, wherein the pain is neuropathic pain.
21. The use according to claim 19, n the pain is inflammatory pain.
22. Use of a compound according to any one of claims 1-17, or a pharmaceutically acceptable salt thereof, or a pharmaceutical ition ing to claim 18, in the manufacture of a medicament for treating a disease or disorder selected from the group consisting of epilepsy/seizure disorder, multiple sclerosis, Alzheimer’s disease, and abdominal pain associated with irritable bowel syndrome.
23. The use according to claim 22, wherein the disease or disorder is epilepsy/seizure disorder.
24. The use according to claim 22, wherein the disease or disorder is le sclerosis.
25. The use according to claim 22, wherein the disease or disorder is Alzheimer’s disease.
26. The use according to claim 22, wherein the disease or disorder is abdominal pain associated with irritable bowel syndrome.
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