WO2010138901A1 - Carboxylic acid-containing compounds, derivatives thereof, and related methods of use - Google Patents

Carboxylic acid-containing compounds, derivatives thereof, and related methods of use Download PDF

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Publication number
WO2010138901A1
WO2010138901A1 PCT/US2010/036709 US2010036709W WO2010138901A1 WO 2010138901 A1 WO2010138901 A1 WO 2010138901A1 US 2010036709 W US2010036709 W US 2010036709W WO 2010138901 A1 WO2010138901 A1 WO 2010138901A1
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Prior art keywords
trifluoromethyl
methyl
fluorophenyl
biphenyl
acid
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PCT/US2010/036709
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French (fr)
Inventor
Hairuo Peng
Julio H. Cuervo
Alexey Ishchenko
Gnanasambandam Kumaravel
Wen-Cherng Lee
Alexey Lugovskoy
Tina Talreja
Arthur G. Taveras
Zhili Xin
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Biogen Idec Ma Inc
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Publication of WO2010138901A1 publication Critical patent/WO2010138901A1/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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
    • C07C59/56—Unsaturated compounds containing hydroxy or O-metal groups containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
    • C07C59/68—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/26—Oxygen atoms attached in position 2 with hetero atoms or acyl radicals directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to carboxylic acid-containing compounds and their use as pharmacologically active agents capable of modulating or inhibiting gamma secretase, a key enzyme in the formation of neurotoxic agents that result in dementia, Alzheimer's and related diseases.
  • AD Alzheimer's disease
  • a ⁇ is formed from amyloid precursor protein (APP) via separate intracellular proteolytic events involving the enzymes ⁇ -secretase and ⁇ -secretase.
  • APP amyloid precursor protein
  • Variability in the site of the proteolysis mediated by ⁇ -secretase results in A ⁇ of varying chain length, e.g. A ⁇ 38, A ⁇ 40 and A ⁇ 42.
  • a ⁇ After secretion into the extracellular medium, A ⁇ forms initially- soluble aggregates which are widely believed to be the key neurotoxic agents in AD, and which ultimately result in the insoluble deposits and dense neuritic plaques which are the pathological characteristics of AD.
  • Other dementing conditions associated with deposition of A ⁇ in the brain include cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), multi-infarct dementia, dementia pugilistica and Down syndrome.
  • AD Various interventions in the plaque-forming process have been proposed as therapeutic treatments for AD.
  • One such method of treatment that has been proposed is that of blocking or attenuating the production of A ⁇ , for example by inhibition of ⁇ - or ⁇ - secretase.
  • gamma secretase e.g., alter the cleavage pattern of gamma secretase.
  • Such compounds may be useful in the treatment and prevention of diseases such as Alzheimer's disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), multi-infarct dementia, dementia pugilistica and Down syndrome.
  • diseases such as Alzheimer's disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), multi-infarct dementia, dementia pugilistica and Down syndrome.
  • the present invention provides a compound having a general structure according to formula I:
  • W is -COOH , or a carboxylic acid mimic or bioisostere
  • Z is N, NR CR 17 Or CR 18 R 19 ; each R 1 and R 2 is independently H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, halo, haloalkyl, Ci-C 6 alkoxy, cyclyl, cyclylalkyl, halocyclyl or halocyclylalkyl; or R 1 and R 2 , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring; wherein either R or R are optionally taken together with R a or R a to form an optionally substituted, saturated or unsaturated 3-7 membered ring;
  • A is a bond, NR 10 , O, S, alkylenyl, amide, ester, carbamate, urea, thiourea or sulfonylurea;
  • B is N or O
  • R is aryl, heteroaryl, cyclyl or heterocyclyl, each of which is optionally substituted with 1-3 R 11 ; each R 4 and R 5 is independently H, Ci-Cs alkyl, haloalkyl, cyclyl, cyclylalkyl, aryl or heteroaryl, each of which is optionally substituted with 1-3 R 12 ; or R 4 and R 5 , together with the carbon to which they are attached, may form a 3-7 membered ring that is optionally saturated or unsaturated, and unsubstituted or substituted;
  • R 6 and R 7 are each independently H, Ci-Cs alkyl, cyclyl, aryl, heteroaryl, cyclylalkyl or arylalkyl, each of which is optionally substituted with 1 -3 R ; wherein when B is O, R 7 is absent; wherein when B is N, R 6 and R 7 , together with the nitrogen to which they are attached, may form a 3-7 membered ring that is optionally saturated or unsaturated, and unsubstituted or substituted with 1-3 R 14 ; and wherein R 4 and R 6 , together with the atoms to which they are attached, may form a 3-7 membered ring ring that is optionally saturated or unsaturated, and unsubstituted or substituted with 1 -3 R ;
  • R 8a , R 8b , R 9a and R 9b are each independently H, Ci-C 6 alkyl, hydroxy, halo, haloalkyl, or CN;
  • R 10 is hydrogen, Ci-C 6 alkyl or haloalkyl; each R 11 , R 12 , R 13 , R 14 and R 15 is independently Ci-C 6 alkyl, Ci-C 6 alkenyl, Ci-C 6 alkynyl, halo, haloalkyl, alkoxy, haloalkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, arylalkyl, hetero arylalkyl, cyclylalkyl, heterocyclylalkyl, carboxylate, cyano, oxo, nitro, amino, alkylamino, dialkylamino, mercapto, thioalkyl, aryloxy, thioalkoxy, amido, SO3H, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphate, or acyl, each of which is optionally substituted; wherein two R 11 , R 12
  • R 9b is attached, R 9b is absent; and wherein when represents the presence of a bond to
  • Z is N or CR 17 ; or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, tautomer, enantiomer, stereoisomer, analog or derivative thereof, including mixtures thereof in any ratios.
  • m is 1.
  • W is -COOH. In another embodiment, W is a carboxylic acid mimic or bioisostere, for example, -C(O)NHS(O) 2 CH 3 .
  • Z is CR 7 .
  • R 7 is H;
  • n O
  • n 1
  • each R and R is independently H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, haloalkyl, Ci-C 6 alkoxy, cyclyl, cyclylalkyl, halocyclyl or halocyclylalkyl; or R and R 2 , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • each R 1 and R 2 is independently H, Ci-C 6 alkyl, haloalkyl or Ci-C 6 alkoxy; or R 1 and R 2 , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • each R 1 and R 2 is independently H, Ci-C 6 alkyl or haloalkyl; or R 1 and R 2 , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • each R 1 and R 2 is independently H or Ci-C 6 alkyl; or R 1 and R 2 , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • R 1 and R 2 are both H. In some embodiments, R 1 and R 2 are both Ci-C 6 alkyl (e.g., methyl or ethyl). In some embodiments, one of R 1 and R 2 is methyl and the other is sec-butyl. In some embodiments, one of R 1 and R 2 is hydrogen and the other is Ci-C 6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, sec-butyl or neopentyl). In some embodiments, one of R 1 and R 2 is hydrogen and the other is methyl. In some embodiments, one of R 1 and R 2 is hydrogen and the other is ethyl. In some embodiments, one of R 1 and R 2 is hydrogen and the other is cyclylalkyl (e.g., cyclopropylmethyl) .
  • R 1 and R 2 together with the carbon to which they are attached, form a ring (e.g., a cyclopentyl, cyclobutyl, or cyclopropyl ring).
  • R 8a is taken with one of R 1 and R 2 , together with the carbons to which they are attached, to form a ring (e.g., a 5-membered ring or a 6- membered ring).
  • A is a bond. In another embodiment, A is O. In yet another embodiment, A is NR 10 . In some embodiments, R 10 is hydrogen.
  • R 3 is aryl, heteroaryl, each of which is optionally substituted with 1-3 R 11 . In some embodiments, R 3 is aryl optionally substituted with 1-3 R 11 . In some embodiments, R 3 is heteroaryl optionally substituted with 1-3 R 11 .
  • each R 11 is independently Ci-C 6 alkyl, Ci-C 6 alkenyl, halo, haloalkyl, haloalkoxy, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R 11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 11 is independently Ci-C 6 alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, amino or alkylamino, each of which is optionally substituted; or wherein two R 11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R is independently Ci-C 6 alkyl, halo, haloalkyl, haloalkoxy or alkoxy; or wherein two R 11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 11 is independently Ci-C 6 alkyl, halo, haloalkyl or haloalkoxy.
  • R is aryl, e.g., phenyl. In some embodiments, R is unsubstituted phenyl.
  • R 3 is phenyl substituted with one R 11 . In some embodiments, R 3 is substituted at the ortho position. In some embodiments, R 3 is substituted at the meta position. In some embodiments, R 3 is substituted at the para position. In some embodiments, R 11 is halo (e.g., fluoro or chloro). In some embodiments, R 11 is haloalkyl (e.g., trifluoro methyl). In some embodiments, R 11 is haloalkoxy (e.g., trifluoromethoxy). In some embodiments, R 11 is Ci-C 6 alkyl, e.g., C 3 alkyl (e.g., isopropyl) or C4 alkyl (e.g., tert-butyl).
  • R 11 is Ci-C 6 alkyl, e.g., C 3 alkyl (e.g., isopropyl) or C4 alkyl (e.g., tert-butyl).
  • R is phenyl substituted with 2 R .
  • both R 11 are Ci-C 6 alkyl (e.g., methyl).
  • both R 11 are halo (e.g., fluoro).
  • one R 11 is halo (e.g., fluoro) and the other is haloalkyl (e.g., trifluoromethyl).
  • R is phenyl substituted with 3 R . In some embodiments, all three R 11 are halo (e.g., fluoro).
  • R 3 is pyridyl. In some embodiments, R 3 is unsubstituted pyridyl. In some embodiments, R 3 is pyridyl substituted with 1 R 11 . In some embodiments, R 11 is haloalkyl (e.g., trifluoromethyl). In some embodiments, R 3 is pyrimidyl. In some embodiments, R 3 is unsubstituted pyrimidyl. In some embodiments, R 3 is pyrimidyl substituted with 1 R 11 . In some embodiments, R 11 is Ci-C 6 alkyl, e.g., C4 alkyl (e.g., tert-butyl).
  • each R 4 and R 5 is independently H, Ci-Cs alkyl, haloalkyl, hydroxy, cyclyl, cyclylalkyl, aryl or heteroaryl, each of which is optionally substituted with 1-3 R 12 .
  • R 4 and R 5 is independently H, Ci-Cs alkyl, haloalkyl, cyclylalkyl, cyclyl, aryl or heteroaryl.
  • each R 12 is independently Ci-C 6 alkyl, Ci-C 6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 12 is independently Ci-C 6 alkyl, halo, haloalkyl or alkoxy, each of which is optionally substituted; or wherein two R 12 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 12 is independently Ci-C 6 alkyl, halo or haloalkyl, each of which is optionally substituted.
  • R 4 is hydrogen or C 1-8 alkyl.
  • R 5 is aryl (e.g., phenyl). In some embodiments, R 5 is unsubstituted phenyl.
  • R 5 is phenyl substituted with one R 12 . In some embodiments, R 5 is substituted at the ortho position. In some embodiments, R 5 is substituted at the meta position. In some embodiments, R 5 is substituted at the para position.
  • R 12 is halo (e.g., fluoro or chloro). In some embodiments, R 12 is haloalkyl (e.g., trifluoromethyl). In some embodiments, R 12 is Ci-C 6 alkyl, e.g., C3 alkyl (e.g., isopropyl), or C4 alkyl (e.g., tert-butyl). In some embodiments, R 12 is -CN. In some embodiments, R 5 is phenyl substituted with 2 R . In some embodiments, both R 12 are halo (e.g., fluoro).
  • R 5 is heteroaryl
  • R 5 is pyridyl. In some embodiments, R 5 is unsubstituted pyridyl.
  • R 5 is pyridyl substituted with 1 R 12 .
  • R 12 is halo (e.g., fluoro).
  • R 12 is haloalkyl (e.g., trifluoromethyl).
  • R 5 is imidazolyl
  • R 5 is imidazolyl substituted with one R 12 .
  • R 12 is haloalkyl (e.g., trifluoromethyl).
  • R 5 is thiazolyl
  • R 5 is pyrazolyl. In some embodiments, R 5 is pyrazolyl substituted with 1-3 R 12 . In some embodiments, R 5 is pyrazolyl substituted with three R 12 . In some embodiments, one R 12 is Ci-C 6 alkyl (e.g., methyl), one is halo (e.g., fluoro) and one is haloalkyl (trifluoromethyl). In another embodiment, three R 12 are each independently Ci-C 6 alkyl (e.g., two are methyl and one is t-butyl).
  • R 5 is:
  • R 5 is pyrimidyl. In some embodiments, R 5 is unsubstituted pyrimidyl. In some embodiments, R 5 is pyrimidyl substituted with 1 R 12 . In some embodiments, R 12 is Ci-C 6 alkyl, e.g., C4 alkyl (e.g., tert-butyl).
  • R 5 is indolyl
  • R 5 is indazolyl. In some embodiments, R 5 is indazolyl substituted with 1 R 12 . In some embodiments, R 12 is Ci-C 6 alkyl (e.g., methyl).
  • R 5 is hydrogen. In some embodiments, R 5 is Ci-Cs alkyl. In some embodiments, R 5 is methyl. In some embodiments, R 5 is C 5 alkyl, e.g., isopentyl (3-methylbutyl) or neopentyl (2,2- dimethylpropyl). In some embodiments, R 5 is C 6 alkyl, e.g., neohexyl (3,3- dimethylbutyl).
  • R 5 is cyclyl, e.g., cycloalkyl (e.g., cyclohexyl). In some embodiments, R 5 is bicyclo[2.2.2]octanyl.
  • R 5 is cyclylalkyl, e.g., cyclohexylmethyl.
  • R 5 is haloalkyl (e.g., 2,2,2-trifluoroethoxy, 3,3,3- trifluoropropyl or 4,4,4-trifluorobutyl).
  • R 6 and R 7 are each independently H, Ci-Cs alkyl, cyclyl, aryl, heteroaryl, cyclylalkyl or arylalkyl, each of which is optionally substituted with 1-3 R 13 ; wherein when B is O, R 7 is absent; wherein when B is N, R 6 and R 7 , together with the nitrogen to which they are attached, may form a 3-7 membered ring that is optionally saturated or unsaturated, and unsubstituted or substituted with 1-3 R 14 ; and wherein R 4 and R 6 , together with the atoms to which they are attached, may form a 3-7 membered ring ring that is optionally saturated or unsaturated, and unsubstituted or substituted with 1-3 R 15 .
  • each R 13 , R 14 and R 15 is independently Ci-C 6 alkyl, Ci-C 6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two, R 13 , R 14 and R 15 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 13 , R 14 and R 15 is independently Ci-C 6 alkyl, halo, haloalkyl, alkoxy, hydroxy, cyano, amino or alkylamino, each of which is optionally substituted; or wherein two , R 13 , R 14 and R 15 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 13 , R 14 and R 15 is independently Ci-C 6 alkyl, halo, haloalkyl or hydroxy, each of which is optionally substituted; or wherein two , R 13 , R 14 and R 15 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • B is O and R 7 is absent.
  • R is aryl, e.g., phenyl. In some embodiments, R is phenyl substituted with one R . In some embodiments, R is substituted at the ortho position. In some embodiments, R is substituted at the meta position. In some embodiments, R is substituted at the para position. In some embodiments, R is haloalkyl (e.g., trifiuoromethyl).
  • B is N.
  • R and R together with the nitrogen to which they are attached, form a ring, e.g., a 4-membered ring (e.g., an azetidine ring).
  • R 6 and R 7 together with the nitrogen to which they are attached, form a 5-membered ring, e.g., a pyrrolidine ring. In some embodiments, R 6 and R 7 , together with the nitrogen to which they are attached, form a pyrrolidine ring that is substituted with one R 14 .
  • R 14 is halo (e.g., fluoro). In some embodiments, R 14 is Ci-C 6 alkyl (e.g., sec-butyl).
  • R and R 7 together with the nitrogen to which they are attached, form a pyrrolidine ring that is substituted with two R .
  • both R are Ci-C 6 alkyl (e.g., methyl).
  • both R are halo (e.g., fluoro).
  • two R together with the atoms to which they are attached, form a ring, e.g., a 3-membered ring, a 5-membered ring or a 6-membered ring (e.g., a phenyl ring).
  • R and R together with the nitrogen to which they are attached, form a 6-membered ring, e.g., a piperidine ring.
  • R and R 7 together with the nitrogen to which they are attached, form a piperidine ring that is unsubstituted.
  • R 6 and R 7 together with the nitrogen to which they are attached, form a piperidine ring that is substituted with one R 14 .
  • R 14 is halo (e.g., fluoro).
  • R 14 is Ci-C 6 alkyl, e.g., methyl.
  • R 14 is C3 alkyl (e.g., n-propyl).
  • R 14 is C4 alkyl (e.g., tert-butyl or isobutyl).
  • R 14 is haloalkyl (e.g., trifluoromethyl).
  • R is alkoxy (e.g., methoxy or ethoxy). In some embodiments, R is aryl (e.g., phenyl). In some embodiments, R is cyano. In some embodiments, R is a carboxylate. In some embodiments, R is -SO2CH3.
  • R and R 7 together with the nitrogen to which they are attached, form a piperidine ring that is substituted with two R .
  • both R 14 are halo (e.g., fluoro).
  • both R 14 are Ci-C 6 alkyl (e.g., methyl).
  • two R together with the carbons to which they are attached, form a ring, e.g., a 3-membered ring or a 6-membered ring.
  • R 6 and R 7 together with the nitrogen to which they are attached, form a piperazine ring. In some embodiments, R 6 and R 7 , together with the nitrogen to which they are attached, form a piperazine ring that is unsubstituted. In some embodiments, R 6 and R 7 , together with the nitrogen to which they are attached, form a piperazine ring that is substituted with one R 14 . In some embodiments, R 14 is Ci-C 6 alkyl (e.g., methyl).
  • R and R 7 together with the nitrogen to which they are attached, form a thiomorpholino.
  • R and R 7 together with the nitrogen to which they are attached, form a 7-membered ring.
  • R and R together with the nitrogen to which they are attached, form a bridged bicyclic ring (e.g., a 3-azabicyclo[3.2.1]octan-3-yl ring). In some embodiments, R and R , together with the nitrogen to which they are attached, form a fused bicyclic ring (e.g., 3-azabicyclo[3.1.0]hexan-3-yl). In some embodiments, R 6 and R 7 , together with the nitrogen to which they are attached, form a spirocyclic ring system (e.g., 6-azaspiro[2.5]octan-6-yl). In some embodiments, both R 6 and R 7 are Ci-Cs alkyl. In some embodiments, one of R 6 and R 7 is methyl and the other is n-heptyl.
  • both R 6 and R 7 are cyclyl. In some embodiments, one of R 6 and R 7 is cyclopropyl and the other is cyclohexyl.
  • R 6 is Ci-Cs alkyl (e.g., C5 alkyl) and R 7 is aryl (e.g., phenyl). In some embodiments, R 6 is isopentyl (3-methylbutyl) and R 7 is phenyl substituted with 1 R 13 . In some embodiments, R 13 is Ci-C 6 alkyl, e.g., C4 alkyl (e.g., tert- butyl). In some embodiments, R 13 is haloalkyl (e.g., trifluoromethyl).
  • R 6 is Ci-Cs alkyl and R 7 is cyclyl.
  • R 6 is methyl. In some embodiments, R 6 is C4 alkyl (e.g., n-butyl or sec-butyl). In some embodiments, R 6 is C5 alkyl (e.g., 2,2-dimethylpropyl, 3- methylbutyl or 2-methylbutyl). In some embodiments, R 6 is C 6 alkyl (e.g., 3,3- dimethylbutyl).
  • R 7 is cyclyl, e.g., cycloalkyl (e.g., cyclohexyl). In some embodiments, R 7 is cyclohexyl substituted with 1 R 13 . In some embodiments, R 13 is C 1 - C 6 alkyl (e.g., methyl). In some embodiments, R 13 is C3 alkyl (e.g., isopropyl). In some embodiments, R 13 is C 4 alkyl (e.g., tert-butyl). In some embodiments, R 13 is haloalkyl (e.g., trifluoromethyl). In some embodiments, R 13 is halo (e.g., fluoro). In some embodiments, R 13 is -CN.
  • R 13 is C 1 - C 6 alkyl (e.g., methyl). In some embodiments, R 13 is C3 alkyl (e.g., isopropyl). In some embodiments, R 13 is C 4 alky
  • R 7 is cyclohexyl substituted with 2 R 13 .
  • both R 13 are halo (e.g., fluoro).
  • both R 13 are Ci-C 6 alkyl (e.g., methyl).
  • R 7 is a bicyclic group, e.g., bicyclo[2.2.2]octane.
  • R 7 is bicyclo[2.2.2]octane substituted with I R 13 .
  • R 6 is arylalkyl (e.g., benzyl) and R 7 is cyclyl, e.g., cycloalkyl (e.g., cyclohexyl). In some embodiments, R 7 is cyclohexyl substituted with 1 R 13 . In some embodiments, R 13 is Ci-C 6 alkyl, e.g., C4 alkyl (e.g., tert-butyl).
  • R 6 is cyclylalkyl (e.g., cyclopentylmethyl or cyclohexylmethyl), and R 7 is cyclyl, e.g., cycloalkyl (e.g., cyclohexyl). In some embodiments, R 7 is cyclohexyl substituted with 1 R 13 . In some embodiments, R 13 is C 1 - C 6 alkyl, e.g., C 4 alkyl (e.g., tert-butyl).
  • R is hydrogen and R 7 is cyclyl, e.g., cycloalkyl (e.g., cyclohexyl). In some embodiments, R 7 is cyclohexyl substituted with 1-3 R 13 . In some embodiments, R 7 is cyclohexyl substituted with one R 13 . In some embodiments, R 13 is Ci-C 6 alkyl (e.g., methyl). In some embodiments, R 13 is C3 alkyl (e.g., isopropyl). In some embodiments, R 13 is C4 alkyl (e.g., tert-butyl). In some embodiments, R 13 is haloalkyl (e.g., trifluoromethyl). In some embodiments, R 13 is halo (e.g., fluoro). In some embodiments, R 13 is -CN.
  • R 7 is cyclohexyl substituted with two R 13 .
  • each R 13 is independently halo (e.g., fluoro).
  • each R 13 is independently Ci-C 6 alkyl (e.g., methyl).
  • R 7 is a bicyclic group, e.g., bicyclo[2.2.2]octane. In some embodiments, R 7 is bicyclo[2.2.2]octane substituted with one R 13 . In some embodiments, R 13 is haloalkyl (e.g., difluoromethyl).
  • R 6 is hydrogen and R 7 is Ci-Cs alkyl.
  • R 7 is C 6 alkyl (e.g., 4-methylpentyl).
  • R 7 is 4- methylpentyl that is substituted with one R 13 .
  • R 13 is aryl (e.g., phenyl).
  • R 13 is phenyl substituted with haloalkyl (e.g., trifluoromethyl).
  • R 4 and R 6 together with the atoms to which they are attached, form a ring, e.g., a 6-membered ring. In some embodiments, R 4 and R 6 , together with the atoms to which they are attached, form a 6-membered ring that is substituted with 1 R 15 .
  • R 15 is Ci-C 6 alkyl (e.g., methyl). In some embodiments, R 15 is haloalkyl (e.g., trifluoromethyl).
  • R 7 is Ci-C 6 alkyl, e.g., C4 alkyl (e.g., sec-butyl) or C5 alkyl (e.g., 2,2-dimethylpropyl). In some embodiments, R 7 is haloalkyl (e.g., 4,4,4- trifluorobutyl).
  • R 7 is aryl (e.g., phenyl). In some embodiments, R 7 is phenyl substituted with one R 13 . In some embodiments, R 13 is haloalkyl (e.g., trifluoromethyl).
  • R 7 is arylalkyl (e.g., benzyl). In some embodiments, R 7 is benzyl substituted with one R 13 . In some embodiments, R 13 is haloalkyl (e.g., trifluoromethyl).
  • R 8a , R 8b , R 9a and R 9b are each independently H, Ci-C 6 alkyl, halo, haloalkyl, or CN. In some embodiments, R 8a , R 8b , R 9a and R 9b are H.
  • Z is CR 17 . In some embodiments, R 17 is H.
  • each represents the presence of a bond. In some embodiments, each represents the absence of a bond.
  • the compound has the following formula:
  • m is 1.
  • W is -COOH. In another embodiment, W is a carboxylic acid mimic or bioisostere, for example, -C(O)NHS(O) 2 CHs.
  • Z is CR 17 .
  • R 17 is H;
  • n is O.
  • n is 1.
  • each R 1 and R 2 is independently H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, halo, haloalkyl, Ci-C 6 alkoxy, cyclyl, cyclylalkyl, halocyclyl or halocyclylalkyl; or R and R , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • each R 1 and R 2 is independently H, Ci-C 6 alkyl, haloalkyl or Ci-C 6 alkoxy; or R 1 and R 2 , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • each R 1 and R 2 is independently H, Ci-C 6 alkyl or haloalkyl; or R 1 and R 2 , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • each R 1 and R 2 is independently H or Ci-C 6 alkyl; or R 1 and R 2 , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • A is a bond. In another embodiment, A is O. In yet another embodiment, A is NR 10 . Also, R 10 is hydrogen in another embodiment.
  • R 3 is aryl or heteroaryl, each of which is optionally substituted with 1-3 R 11 . In some embodiments, R 3 is aryl optionally substituted with 1-3 R 11 . In some embodiments, R 3 is heteroaryl optionally substituted with 1-3 R 11 .
  • each R 11 is independently Ci-C 6 alkyl, Ci-C 6 alkenyl, halo, haloalkyl, haloalkoxy, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R 11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R is independently Ci-C 6 alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, amino or alkylamino, each of which is optionally substituted; or wherein two R together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 11 is independently Ci-C 6 alkyl, halo, haloalkyl, haloalkoxy or alkoxy; or wherein two R 11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 11 is independently Ci-C 6 alkyl, halo, haloalkyl or haloalkoxy.
  • each R and R 5 is independently H, Ci-Cs alkyl, haloalkyl, hydroxy, cyclyl, cyclylalkyl, aryl or heteroaryl, each of which is optionally substituted with 1-3 R .
  • R and R 5 is independently H, Ci-Cs alkyl, haloalkyl, cyclylalkyl, cyclyl, aryl or heteroaryl.
  • each R is independently Ci-C 6 alkyl, Ci-C 6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 12 is independently Ci-C 6 alkyl, halo, haloalkyl or alkoxy, each of which is optionally substituted; or wherein two R 12 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 12 is independently Ci-C 6 alkyl, halo or haloalkyl, each of which is optionally substituted.
  • R and R 7 are each independently H, Ci-Cs alkyl, cyclyl, aryl, heteroaryl, cyclylalkyl or arylalkyl, each of which is optionally substituted with 1-3 R ; wherein when B is O, R 7 is absent; wherein when B is N, R and R 7 , together with the nitrogen to which they are attached, may form a 3-7 membered ring that is optionally saturated or unsaturated, and unsubstituted or substituted with 1-3 R ; and wherein R and R , together with the atoms to which they are attached, may form a 3-7 membered ring ring that is optionally saturated or unsaturated, and unsubstituted or substituted with 1-3 R 15 .
  • each R 13 , R 14 and R 15 is independently Ci-C 6 alkyl, Ci-C 6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two, R 13 , R 14 and R 15 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 13 , R 14 and R 15 is independently Ci-C 6 alkyl, halo, haloalkyl, alkoxy, hydroxy, cyano, amino or alkylamino, each of which is optionally substituted; or wherein two , R 13 , R 14 and R 15 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 13 , R 14 and R 15 is independently Ci-C 6 alkyl, halo, haloalkyl or hydroxy, each of which is optionally substituted; or wherein two , R 13 , R 14 and R 15 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • B is O and R is absent.
  • B is N.
  • R 8a and R 9a are each independently H, Ci-C 6 alkyl, halo, haloalkyl or CN. In some embodiments, R 8a and R 9b are H.
  • Z is CR 17 . In some embodiments, R 17 is H.
  • the compound has the following formula:
  • m is 1.
  • W is -COOH. In another embodiment, W is a carboxylic acid mimic or bioisostere, for example, -C(O)NHS(O) 2 CHs.
  • Z is CR 17 .
  • R 17 is H;
  • n is O.
  • n is 1.
  • each R 1 and R 2 is independently H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, halo, haloalkyl, Ci-C 6 alkoxy, cyclyl, cyclylalkyl, halocyclyl or halocyclylalkyl; or R and R , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • each R 1 and R 2 is independently H, Ci-C 6 alkyl, haloalkyl or Ci-C 6 alkoxy; or R 1 and R 2 , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • each R 1 and R 2 is independently H, Ci-C 6 alkyl or haloalkyl; or R 1 and R 2 , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • each R 1 and R 2 is independently H or Ci-C 6 alkyl; or R 1 and R 2 , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • A is a bond. In another embodiment, A is O. In yet another embodiment, A is NR 10 . Also, R 10 is hydrogen in another embodiment.
  • R 3 is aryl, heteroaryl, each of which is optionally substituted with 1-3 R 11 . In some embodiments, R 3 is aryl optionally substituted with 1-3 R 11 . In some embodiments, R 3 is heteroaryl optionally substituted with 1-3 R 11 .
  • each R 11 is independently Ci-C 6 alkyl, Ci-C 6 alkenyl, halo, haloalkyl, haloalkoxy, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R 11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R is independently Ci-C 6 alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, amino or alkylamino, each of which is optionally substituted; or wherein two R together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 11 is independently Ci-C 6 alkyl, halo, haloalkyl, haloalkoxy or alkoxy; or wherein two R 11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 11 is independently Ci-C 6 alkyl, halo, haloalkyl or haloalkoxy.
  • each R and R 5 is independently H, Ci-Cs alkyl, haloalkyl, hydroxy, cyclyl, cyclylalkyl, aryl or heteroaryl, each of which is optionally substituted with 1-3 R .
  • R and R 5 is independently H, Ci-Cs alkyl, haloalkyl, cyclylalkyl, cyclyl, aryl or heteroaryl.
  • each R is independently Ci-C 6 alkyl, Ci-C 6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 12 is independently Ci-C 6 alkyl, halo, haloalkyl or alkoxy, each of which is optionally substituted; or wherein two R 12 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 12 is independently Ci-C 6 alkyl, halo or haloalkyl, each of which is optionally substituted.
  • R and R 7 are each independently H, Ci-Cs alkyl, cyclyl, aryl, heteroaryl, cyclylalkyl or arylalkyl, each of which is optionally substituted with 1-3 R ; wherein when B is O, R 7 is absent; wherein when B is N, R and R 7 , together with the nitrogen to which they are attached, may form a 3-7 membered ring that is optionally saturated or unsaturated, and unsubstituted or substituted with 1-3 R ; and wherein R and R , together with the atoms to which they are attached, may form a 3-7 membered ring ring that is optionally saturated or unsaturated, and unsubstituted or substituted with 1-3 R 15 .
  • each R 13 , R 14 and R 15 is independently Ci-C 6 alkyl, Ci-C 6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two, R 13 , R 14 and R 15 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 13 , R 14 and R 15 is independently Ci-C 6 alkyl, halo, haloalkyl, alkoxy, hydroxy, cyano, amino or alkylamino, each of which is optionally substituted; or wherein two , R 13 , R 14 and R 15 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 13 , R 14 and R 15 is independently Ci-C 6 alkyl, halo, haloalkyl or hydroxy, each of which is optionally substituted; or wherein two , R 13 , R 14 and R 15 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • B is O and R is absent.
  • B is N.
  • R 8a , R 8b , R 9b and R 9a are each independently H, Ci-C 6 alkyl, halo, haloalkyl, or CN. In some embodiments, R 8a and R 9b are H.
  • Z is CR 17 . In some embodiments, R 17 is H.
  • the compound has the following formula:
  • m is 1.
  • W is -COOH. In another embodiment, W is a carboxylic acid mimic or bioisostere, for example, -C(O)NHS(O) 2 CHs.
  • Z is CR 17 .
  • R 17 is H;
  • n is O.
  • n is 1.
  • each R 1 and R 2 is independently H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, halo, haloalkyl, Ci-C 6 alkoxy, cyclyl, cyclylalkyl, halocyclyl or halocyclylalkyl; or R and R , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • each R 1 and R 2 is independently H, Ci-C 6 alkyl, haloalkyl or Ci-C 6 alkoxy; or R 1 and R 2 , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • each R 1 and R 2 is independently H, Ci-C 6 alkyl or haloalkyl; or R 1 and R 2 , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • each R 1 and R 2 is independently H or Ci-C 6 alkyl; or R 1 and R 2 , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • A is a bond. In another embodiment, A is O. In yet another embodiment, A is NR 10 . Also, R 10 is hydrogen in another embodiment.
  • R 3 is aryl, heteroaryl, each of which is optionally substituted with 1-3 R 11 . In some embodiments, R 3 is aryl optionally substituted with 1-3 R 11 . In some embodiments, R 3 is heteroaryl optionally substituted with 1-3 R 11 .
  • each R 11 is independently Ci-C 6 alkyl, Ci-C 6 alkenyl, halo, haloalkyl, haloalkoxy, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R 11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R is independently Ci-C 6 alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, amino or alkylamino, each of which is optionally substituted; or wherein two R together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 11 is independently Ci-C 6 alkyl, halo, haloalkyl, haloalkoxy, or alkoxy; or wherein two R 11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 11 is independently Ci-C 6 alkyl, halo, haloalkyl or haloalkoxy.
  • each R and R 5 is independently H, Ci-Cs alkyl, haloalkyl, hydroxy, cyclyl, cyclylalkyl, aryl or heteroaryl, each of which is optionally substituted with 1-3 R .
  • R and R 5 is independently H, Ci-Cs alkyl, haloalkyl, cyclylalkyl, cyclyl, aryl or heteroaryl.
  • each R is independently Ci-C 6 alkyl, Ci-C 6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 12 is independently Ci-C 6 alkyl, halo, haloalkyl or alkoxy, each of which is optionally substituted; or wherein two R 12 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 12 is independently Ci-C 6 alkyl, halo or haloalkyl, each of which is optionally substituted.
  • R and R 7 are each independently H, Ci-Cs alkyl, cyclyl, aryl, heteroaryl, cyclylalkyl or arylalkyl, each of which is optionally substituted with 1-3 R ; wherein when B is O, R 7 is absent; wherein when B is N, R and R 7 , together with the nitrogen to which they are attached, may form a 3-7 membered ring that is optionally saturated or unsaturated, and unsubstituted or substituted with 1-3 R ; and wherein R and R , together with the atoms to which they are attached, may form a 3-7 membered ring ring that is optionally saturated or unsaturated, and unsubstituted or substituted with 1-3 R 15 .
  • each R 13 , R 14 and R 15 is independently Ci-C 6 alkyl, Ci-C 6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two, R 13 , R 14 and R 15 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 13 , R 14 and R 15 is independently Ci-C 6 alkyl, halo, haloalkyl, alkoxy, hydroxy, cyano, amino or alkylamino, each of which is optionally substituted; or wherein two , R 13 , R 14 and R 15 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 13 , R 14 and R 15 is independently Ci-C 6 alkyl, halo, haloalkyl or hydroxy, each of which is optionally substituted; or wherein two , R , R and R 5 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • R 8a and R 9a are each independently H, Ci-C 6 alkyl, halo, haloalkyl, or CN. In some embodiments, R 8a and R 9b are H.
  • Z is CR 17 . In some embodiments, R 17 is H.
  • the compound has the following formula:
  • s is 0, 1, 2 or 3.
  • m is 1.
  • W is -COOH. In another embodiment, W is a carboxylic acid mimic or bioisostere, for example, -C(O)NHS(O) 2 CH 3 .
  • Z is CR 17 .
  • R 17 is H;
  • n is O.
  • n is 1.
  • each R 1 and R 2 is independently H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, halo, haloalkyl, Ci-C 6 alkoxy, cyclyl, cyclylalkyl, halocyclyl or halocyclylalkyl; or R and R , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • each R 1 and R 2 is independently H, Ci-C 6 alkyl, haloalkyl or Ci-C 6 alkoxy; or R 1 and R 2 , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • each R 1 and R 2 is independently H, Ci-C 6 alkyl, or haloalkyl; or R 1 and R 2 , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • each R 1 and R 2 is independently H or Ci-C 6 alkyl; or R 1 and R 2 , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • each R 4 and R 5 is independently H, Ci-Cs alkyl, haloalkyl, hydroxy, cyclyl, cyclylalkyl, aryl or heteroaryl, each of which is optionally substituted with 1-3 R 12 .
  • R 4 and R 5 is independently H, Ci-Cs alkyl, haloalkyl, cyclylalkyl, cyclyl, aryl or heteroaryl.
  • each R 12 is independently Ci-C 6 alkyl, Ci-C 6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R is independently Ci-C 6 alkyl, halo, haloalkyl or alkoxy, each of which is optionally substituted; or wherein two R 12 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 12 is independently Ci-C 6 alkyl, halo or haloalkyl, each of which is optionally substituted.
  • R 6 and R 7 are each independently H, Ci-Cs alkyl, cyclyl, aryl, heteroaryl, cyclylalkyl or arylalkyl, each of which is optionally substituted with 1-3 R 13 ; wherein when B is O, R 7 is absent; wherein when B is N, R 6 and R 7 , together with the nitrogen to which they are attached, may form a 3-7 membered ring that is optionally saturated or unsaturated, and unsubstituted or substituted with 1-3 R ; and wherein R and R , together with the atoms to which they are attached, may form a 3-7 membered ring ring that is optionally saturated or unsaturated, and unsubstituted or substituted with 1-3 R 15 .
  • each R , R and R 5 is independently Ci-C 6 alkyl, Ci-C 6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two, R , R and R together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 13 , R 14 and R 15 is independently Ci-C 6 alkyl, halo, haloalkyl, alkoxy, hydroxy, cyano, amino or alkylamino, each of which is optionally substituted; or wherein two , R 13 , R 14 and R 15 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 13 , R 14 and R 15 is independently Ci-C 6 alkyl, halo, haloalkyl or hydroxy, each of which is optionally substituted; or wherein two , R , R and R 5 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • B is O and R 7 is absent.
  • B is N.
  • R a and R a are each independently H, Ci-C 6 alkyl, halo, haloalkyl, or CN. In some embodiments, R a and R are H.
  • Z is CR . In some embodiments, R is H.
  • the compound has the following formula:
  • s 0, 1, 2 or 3.
  • m is 1.
  • W is -COOH. In another embodiment, W is a carboxylic acid mimic or bioisostere, for example, -C(O)NHS(O) 2 CHs.
  • Z is CR 7 .
  • R 7 is H;
  • n 0.
  • n 1
  • each R 1 and R 2 is independently H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, halo, haloalkyl, Ci-C 6 alkoxy, cyclyl, cyclylalkyl, halocyclyl or halocyclylalkyl; or R 1 and R 2 , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • each R 1 and R 2 is independently H, Ci-C 6 alkyl, haloalkyl or Ci-C 6 alkoxy; or R 1 and R 2 , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • each R 1 and R 2 is independently H, Ci-C 6 alkyl or haloalkyl; or R and R , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • each R and R is independently H or Ci-C 6 alkyl; or R and R , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • each R and R is independently H, Ci-Cs alkyl, haloalk hydroxy, cyclyl, cyclylalkyl, aryl or heteroaryl, each of which is optionally substituted with 1-3 R 12 .
  • R 4 and R 5 is independently H, Ci-Cs alkyl, haloalkyl, cyclylalkyl, cyclyl, aryl or heteroaryl.
  • each R 12 is independently Ci-C 6 alkyl, Ci-C 6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R is independently Ci-C 6 alkyl, halo, haloalkyl or alkoxy, each of which is optionally substituted; or wherein two R 12 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 12 is independently Ci-C 6 alkyl, halo or haloalkyl, each of which is optionally substituted.
  • R 6 and R 7 are each independently H, Ci-Cs alkyl, cyclyl, aryl, heteroaryl, cyclylalkyl or arylalkyl, each of which is optionally substituted with 1-3 R 13 ; wherein when B is O, R 7 is absent; wherein when B is N, R 6 and R 7 , together with the nitrogen to which they are attached, may form a 3-7 membered ring that is optionally saturated or unsaturated, and unsubstituted or substituted with 1-3 R ; and wherein R and R 6 , together with the atoms to which they are attached, may form a 3-7 membered ring ring that is optionally saturated or unsaturated, and unsubstituted or substituted with 1-3 R 15 .
  • each R 13 , R 14 and R 15 is independently Ci-C 6 alkyl, Ci-C 6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two, R 13 , R 14 and R 15 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 13 , R 14 and R 15 is independently Ci-C 6 alkyl, halo, haloalkyl, alkoxy, hydroxy, cyano, amino or alkylamino, each of which is optionally substituted; or wherein two , R 13 , R 14 and R 15 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 13 , R 14 and R 15 is independently Ci-C 6 alkyl, halo, haloalkyl or hydroxy, each of which is optionally substituted; or wherein two , R , R and R 5 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • R 8a and R 9a are each independently H, Ci-C 6 alkyl, halo, haloalkyl, or CN. In some embodiments, R 8a and R 9b are H.
  • Z is CR 17 . In some embodiments, R 17 is H.
  • W is -COOH; n is 1; one of R 1 and R 2 is hydrogen and the other is lower alkyl; each of R 8a and R 9a is hydrogen; s is 1; R 11 is haloalkyl; R 4 is hydrogen; R 5 is optionally substituted aryl; R 6 and R 7 , together with the nitrogen to which they are attached, form an optionally substituted 6-membered ring; Z is CR 17 ; and R 17 is H.
  • W is -COOH; n is 1; R 1 and R 2 , together with the carbon to which they are attached, form a ring; each of R 8a and R 9a is hydrogen; s is 1 ; R 11 is haloalkyl; R 4 is hydrogen; R 5 is aryl; R 6 and R 7 , together with the nitrogen to which they are attached, form a 6-membered ring, or one of R 6 and R 7 is hydrogen while the other is lower alkyl; Z is CR 17 ; and R 17 is H.
  • the compound has the following formula:
  • m is 1.
  • W is -COOH. In another embodiment, W is a carboxylic acid mimic or bioisostere, for example, -C(O)NHS(O) 2 CH 3 . In some embodiments, Z is CR 17 . In some embodiments, R 17 is H;
  • n 0.
  • n 1
  • each R 1 and R 2 is independently H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, halo, haloalkyl, Ci-C 6 alkoxy, cyclyl, cyclylalkyl, halocyclyl or halocyclylalkyl; or R and R , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • each R 1 and R 2 is independently H, Ci-C 6 alkyl, haloalkyl or Ci-C 6 alkoxy; or R 1 and R 2 , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • each R 1 and R 2 is independently H, Ci-C 6 alkyl or haloalkyl; or R 1 and R 2 , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • each R 1 and R 2 is independently H or Ci-C 6 alkyl; or R 1 and R 2 , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • A is a bond. In another embodiment, A is O. In yet another embodiment, A is NR 10 . Also, R 10 is hydrogen in another embodiment.
  • R is aryl, heteroaryl, each of which is optionally substituted with 1-3 R 11 .
  • R 3 is aryl optionally substituted with 1-3 R 11 .
  • R 3 is heteroaryl optionally substituted with 1-3 R 11 .
  • each R 11 is independently Ci-C 6 alkyl, Ci-C 6 alkenyl, halo, haloalkyl, haloalkoxy, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R 11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 11 is independently Ci-C 6 alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, amino or alkylamino, each of which is optionally substituted; or wherein two R 11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 11 is independently Ci-C 6 alkyl, halo, haloalkyl, haloalkoxy or alkoxy; or wherein two R 11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 11 is independently Ci-C 6 alkyl, halo, haloalkyl or haloalkoxy.
  • each R and R 5 is independently H, Ci-Cs alkyl, haloalkyl, hydroxy, cyclyl, cyclylalkyl, aryl or heteroaryl, each of which is optionally substituted with 1-3 R .
  • R and R is independently H, Ci-Cs alkyl, haloalkyl, cyclylalkyl, cyclyl, aryl or heteroaryl.
  • each R is independently Ci-C 6 alkyl, Ci-C 6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R 12 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 12 is independently Ci-C 6 alkyl, halo, haloalkyl or alkoxy, each of which is optionally substituted; or wherein two R 12 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R is independently Ci-C 6 alkyl, halo or haloalkyl, each of which is optionally substituted.
  • R is H, Ci-Cs alkyl, cyclyl, aryl, heteroaryl, cyclylalkyl or arylalkyl, each of which is optionally substituted with 1-3 R .
  • each R is independently Ci-C 6 alkyl, Ci-C 6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted.
  • each R 13 is independently Ci-C 6 alkyl, halo, haloalkyl, alkoxy, hydroxy, cyano, amino or alkylamino, each of which is optionally substituted.
  • each R 13 is independently Ci-C 6 alkyl, halo, haloalkyl or hydroxy, each of which is optionally substituted.
  • R 8a and R 9a are each independently H, Ci-C 6 alkyl, halo, haloalkyl, or CN.
  • R 8a and R 9b are H.
  • Z is CR 17 . In some embodiments, R 17 is H. In one aspect, the invention features compound of formula (II):
  • n is O, 1 or 2;
  • W is -COOH, or a carboxylic acid mimic or bioisostere
  • R 1 and R 2 is independently H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, halo, haloalkyl, Ci-C 6 alkoxy, cyclyl, cyclylalkyl, halocyclyl or halocyclylalkyl; or R 1 and R 2 , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring; wherein either R 1 or R 2 is optionally taken together with R 8a or R 8b to form an optionally substituted, saturated or unsaturated 3-7 membered ring;
  • A is a bond, NR 10 , O, S, alkylenyl, amide, ester, carbamate, urea, thiourea or sulfonylurea;
  • R 3 is aryl, heteroaryl, cyclyl or heterocyclyl, each of which is optionally substituted with 1-3 R 11 ; each R 4 and R 5 is independently H, Ci-Cs alkyl, haloalkyl, cyclyl, cyclylalkyl, aryl or heteroaryl, each of which is optionally substituted with 1-3 R 12 ; or R 4 and R 5 , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring; R 6 and R 7 , together with the nitrogen to which they are attached, form a 3-7 membered ring that is optionally saturated or unsaturated, and substituted or unsubstituted with 1-3 R 14 ; each R 8a , R 8b , R 9a and R 9b is independently H, Ci-C 6 alkyl, hydroxy, halo, haloalkyl, or CN;
  • R is hydrogen, Ci-C 6 alkyl or haloalkyl; and each R 11 , R 12 , and R 14 is independently Ci-C 6 alkyl, Ci-C 6 alkenyl, Ci-C 6 alkynyl, halo, haloalkyl, alkoxy, haloalkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, carboxylate, cyano, oxo, nitro, amino, alkylamino, dialkylamino, mercapto, thioalkyl, aryloxy, thioalkoxy, amido, SO3H, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphate or acyl, each of which is optionally substituted; or wherein two R 11 , R 12 , or R 14 , together
  • W is -COOH. In another embodiment, W is a carboxylic acid mimic or bioisostere, for example, -C(O)NHS(O) 2 CH3.
  • n O
  • n 1
  • each R and R is independently H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, haloalkyl, Ci-C 6 alkoxy, cyclyl, cyclylalkyl, halocyclyl or halocyclylalkyl; or R 1 and R 2 , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • each R 1 and R 2 is independently H or Ci-C 6 alkyl; or R 1 and R 2 , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • R and R are both H. In some embodiments, R and R are both Ci-C 6 alkyl (e.g., methyl or ethyl). In some embodiments, one of R 1 and R 2 is methyl and the other is sec-butyl. In some embodiments, one of R and R is hydrogen and the other is Ci-C 6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, sec-butyl or neopentyl). In some embodiments, one of R and R is hydrogen and the other is C 2 -C 6 alkenyl (e.g., C3 alkenyl or ally 1) .
  • one of R and R is hydrogen and the other is cyclylalkyl (e.g., cyclopropylmethyl). In some embodiments, one of R 1 and R 2 is hydrogen and the other is cyclylalkyl (e.g., cyclopropylmethyl).
  • R 1 and R 2 together with the carbon to which they are attached, form a ring (e.g., a cyclopentyl, cyclobutyl, or cyclopropyl ring).
  • R 8a is taken with one of R 1 and R 2 , together with the carbons to which they are attached, to form a ring (e.g., a 5-membered ring or a 6- membered ring).
  • A is a bond. In another embodiment, A is O. In yet another embodiment, A is NR . Also, R is hydrogen in another embodiment.
  • R is aryl, heteroaryl, each of which is optionally substituted with 1 -3 R . In some embodiments, R is aryl optionally substituted with 1 -3 R 11 .
  • each R is independently Ci-C 6 alkyl, Ci-C 6 alkenyl, halo, haloalkyl, haloalkoxy, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 11 is independently Ci-C 6 alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, amino or alkylamino, each of which is optionally substituted; or wherein two R 11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 11 is independently Ci-C 6 alkyl, halo, haloalkyl, haloalkoxy or alkoxy; or wherein two R 11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and ooppttiioonnaallllyy ssuubbssttiittuutteedd rriinngg..
  • each R 11 is independently Ci-C 6 alkyl, halo, haloalkyl or haloalkoxy.
  • R is aryl, e.g., phenyl. In some embodiments, R is unsubstituted phenyl.
  • R is phenyl substituted with one R . In some embodiments, R is substituted at the ortho position. In some embodiments, R is substituted at the meta position. In some embodiments, R is substituted at the para position. In some embodiments, R 11 is halo (e.g., fluoro or chloro). In some embodiments, R 11 is haloalkyl (e.g., trifiuoromethyl). In some embodiments, R 11 is haloalkoxy (e.g., trifluoromethoxy).
  • R 11 is Ci-C 6 alkyl, e.g., C3 alkyl (e.g., isopropyl) or C 4 alkyl (e.g., tert-butyl). In some embodiments, R 11 is alkoxy (e.g., methoxy).
  • R 3 is phenyl substituted with two R 11 .
  • both R are Ci-C 6 alkyl (e.g., methyl).
  • both R are halo (e.g., fluoro).
  • one R is halo (e.g., fluoro) and the other is haloalkyl (e.g., trifiuoromethyl).
  • R is phenyl substituted with three R . In some embodiments, all three R are halo (e.g., fluoro).
  • R is pyridyl. In some embodiments, R is unsubstituted pyridyl. In some embodiments, R is pyridyl substituted with I R . In some embodiments, R is haloalkyl (e.g., trifiuoromethyl).
  • R 3 is pyrimidyl. In some embodiments, R 3 is unsubstituted pyrimidyl. In some embodiments, R 3 is pyrimidyl substituted with 1 R 11 . In some embodiments, R 11 is Ci-C 6 alkyl, e.g., C 4 alkyl (e.g., tert-butyl).
  • each R 4 and R 5 is independently H, Ci-Cs alkyl, haloalkyl, hydroxy, cyclyl, cyclylalkyl, aryl or heteroaryl, each of which is optionally substituted with 1-3 R 12 .
  • R 4 and R 5 is independently H, Ci-Cs alkyl, haloalkyl, cyclylalkyl, cyclyl, aryl or heteroaryl.
  • each R 12 is independently Ci-C 6 alkyl, Ci-C 6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R is independently Ci-C 6 alkyl, halo, haloalkyl or alkoxy, each of which is optionally substituted; or wherein two R 12 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 12 is independently Ci-C 6 alkyl, halo or haloalkyl, each of which is optionally substituted.
  • R 4 is hydrogen
  • R 5 is aryl (e.g., phenyl). In some embodiments, R 5 is unsubstituted phenyl.
  • R 5 is phenyl substituted with one R 12 . In some embodiments, R 5 is substituted at the ortho position. In some embodiments, R 5 is substituted at the meta position. In some embodiments, R 5 is substituted at the para position.
  • R 12 is halo (e.g., fluoro or chloro). In some embodiments, R 12 is haloalkyl (e.g., trifluoromethyl). In some embodiments, R 12 is Ci-C 6 alkyl, e.g., C3 alkyl (e.g., isopropyl), or C4 alkyl (e.g., tert-butyl). In some embodiments, R 12 is -CN.
  • R 5 is phenyl substituted with two R 12 .
  • both R 12 are halo (e.g., fluoro).
  • R 5 is heteroaryl. In some embodiments, R 5 is pyridyl. In some embodiments, R 5 is unsubstituted pyridyl.
  • R 5 is pyridyl substituted with one R 12 .
  • R 12 is halo (e.g., fluoro).
  • R 12 is haloalkyl (e.g., trifluoromethyl).
  • R 5 is imidazolyl
  • R 5 is imidazolyl substituted with one R 12 .
  • R 12 is haloalkyl (e.g., trifluoromethyl).
  • R 5 is thiazolyl
  • R 5 is pyrazolyl. In some embodiments, R 5 is pyrazolyl substituted with 1-3 R 12 . In some embodiments, R 5 is pyrazolyl substituted with three R 12 . In some embodiments, one R 12 is Ci-C 6 alkyl (e.g., methyl), one is halo (e.g., fluoro) and one is haloalkyl (trifluoromethyl). In some embodiments, three R 12 are each independently Ci-C 6 alkyl (e.g., two are methyl and one is t-butyl).
  • R 5 is:
  • R 5 is pyrimidyl. In some embodiments, R 5 is unsubstituted pyrimidyl. In some embodiments, R 5 is pyrimidyl substituted with one R 12 . In some embodiments, R 12 is Ci-C 6 alkyl, e.g., Ci alkyl (e.g., methyl) or C4 alkyl (e.g., tert-butyl).
  • R 5 is indolyl
  • R 5 is indazolyl. In some embodiments, R 5 is indazolyl substituted with one R 12 . In some embodiments, R 12 is Ci-C 6 alkyl (e.g., methyl).
  • R 5 is hydrogen
  • R 5 is Ci-Cs alkyl. In some embodiments, R 5 is methyl. In some embodiments, R 5 is C 5 alkyl, e.g., isopentyl (3-methylbutyl) or neopentyl (2,2- dimethylpropyl). In some embodiments, R 5 is C 6 alkyl, e.g., neohexyl (3,3- dimethylbutyl).
  • R 5 is cyclyl, e.g., cycloalkyl (e.g., cyclohexyl). In some embodiments, R 5 is bicyclo[2.2.2]octanyl.
  • R 5 is cyclylalkyl, e.g., cyclohexylmethyl.
  • R 5 is haloalkyl (e.g., 2,2,2-trifluoroethoxy, 3,3,3- trifluoropropyl or 4,4,4-trifluorobutyl).
  • R 6 and R 7 are each independently H, Ci-Cs alkyl, cyclyl, aryl, heteroaryl, cyclylalkyl or arylalkyl, each of which is optionally substituted with 1-3 R 13 ; wherein when B is O, R 7 is absent; wherein when B is N, R 6 and R 7 , together with the nitrogen to which they are attached, may form a 3-7 membered ring that is optionally saturated or unsaturated, and unsubstituted or substituted with 1-3 R 14 ; and wherein R 4 and R 6 , together with the atoms to which they are attached, may form a 3-7 membered ring ring that is optionally saturated or unsaturated, and unsubstituted or substituted with 1-3 R 15 .
  • each R 13 , R 14 and R 15 is independently Ci-C 6 alkyl, Ci-C 6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two , R 13 , R 14 and R 15 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 13 , R 14 and R 15 is independently Ci-C 6 alkyl, halo, haloalkyl, alkoxy, hydroxy, cyano, amino or alkylamino, each of which is optionally substituted; or wherein two , R 13 , R 14 and R 15 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 13 , R 14 and R 15 is independently Ci-C 6 alkyl, halo, haloalkyl or hydroxy, each of which is optionally substituted; or wherein two , R 13 , R 14 and R 15 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • R 6 and R 7 together with the nitrogen to which they are attached, form a 4-membered ring (e.g., an azetidine ring).
  • R 6 and R 7 together with the nitrogen to which they are attached, form a 5-membered ring, e.g., a pyrrolidine ring. In some embodiments, R 6 and R 7 , together with the nitrogen to which they are attached, form a pyrrolidine ring that is substituted with one R 14 .
  • R 14 is halo (e.g., fluoro). In some embodiments, R 14 is Ci-C 6 alkyl (e.g., sec-butyl).
  • R 6 and R 7 together with the nitrogen to which they are attached, form a pyrrolidine ring that is substituted with two R 14 .
  • both R 14 are Ci-C 6 alkyl (e.g., methyl).
  • both R 14 are halo (e.g., fluoro).
  • two R 14 together with the atoms to which they are attached, form a ring, e.g., a 3-membered ring, a 5-membered ring or a 6-membered ring (e.g., a phenyl ring).
  • R 6 and R 7 together with the nitrogen to which they are attached, form a 6-membered ring, e.g., a piperidine ring. In some embodiments, R 6 and R 7 , together with the nitrogen to which they are attached, form a piperidine ring that is unsubstituted.
  • R 6 and R 7 together with the nitrogen to which they are attached, form a piperidine ring that is substituted with one R .
  • R 14 is halo (e.g., fluoro).
  • R 14 is Ci-C 6 alkyl, e.g., methyl.
  • R 14 is C3 alkyl (e.g., n-propyl).
  • R 14 is C4 alkyl (e.g., tert-butyl or isobutyl).
  • R 14 is haloalkyl (e.g., trifluoromethyl).
  • R 14 is alkoxy (e.g., methoxy or ethoxy). In some embodiments, R 14 is aryl (e.g., phenyl). In some embodiments, R 14 is cyano. In some embodiments, R 14 is a carboxylate. In some embodiments, R 14 is -SO 2 CH 3 .
  • R 6 and R 7 together with the nitrogen to which they are attached, form a piperidine ring that is substituted with two R 14 .
  • both R 14 are halo (e.g., fluoro).
  • both R 14 are Ci-C 6 alkyl (e.g., methyl).
  • two R 14 together with the carbons to which they are attached, form a ring, e.g., a 3-membered ring or a 6-membered ring.
  • R 6 and R 7 together with the nitrogen to which they are attached, form a piperazine ring. In some embodiments, R 6 and R 7 , together with the nitrogen to which they are attached, form a piperazine ring that is unsubstituted. In some embodiments, R 6 and R 7 , together with the nitrogen to which they are attached, form a piperazine ring that is substituted with one R 14 . In some embodiments, R 14 is Ci-C 6 alkyl (e.g., methyl).
  • R 6 and R 7 together with the nitrogen to which they are attached, form a piperazine that is substituted with two R .
  • two R 14 together with the carbons to which they are attached, form an optionally substituted ring such as a heteroaryl.
  • the heteroaryl is a triazole.
  • the triazole is substituted with a haloalkyl substituent, (e.g., trifluoromethyl).
  • R 6 and R 7 together with the nitrogen to which they are attached, form a thiomorpholino.
  • R 6 and R 7 together with the nitrogen to which they are attached, form a 7-membered ring.
  • R 6 and R 7 together with the nitrogen to which they are attached, form a bridged bicyclic ring (e.g., a 3-azabicyclo[3.2.1]octan-3-yl ring). In some embodiments, R 6 and R 7 , together with the nitrogen to which they are attached, form a fused bicyclic ring (e.g., 3-azabicyclo[3.1.0]hexan-3-yl). In some embodiments, R and R , together with the nitrogen to which they are attached, form a spirocyclic ring system (e.g., 6-azaspiro[2.5]octan-6-yl).
  • Z is CH.
  • the compound has the following formula: wherein t is 0, 1 or 2 and u is 0, 1, 2 or 3.
  • t is 1.
  • m is 1.
  • W is -COOH. In another embodiment, W is a carboxylic acid mimic or bioisostere, for example, -C(O)NHS(O) 2 CHs.
  • Z is CR . In some embodiments, R is H;
  • n 0.
  • n 1
  • each R 1 and R 2 is independently H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, halo, haloalkyl, Ci-C 6 alkoxy, cyclyl, cyclylalkyl, halocyclyl or halocyclylalkyl; or R 1 and R 2 , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • each R 1 and R 2 is independently H, Ci-C 6 alkyl, haloalkyl or Ci-C 6 alkoxy; or R 1 and R 2 , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • each R 1 and R 2 is independently H, Ci-C 6 alkyl or haloalkyl; or R 1 and R 2 , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • each R and R is independently H or Ci-C 6 alkyl; or R and R , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • A is a bond. In another embodiment, A is O. In yet another embodiment, A is NR . Also, R is hydrogen in another embodiment. In some embodiments, R is aryl, heteroaryl, each of which is optionally substituted with 1-3 R 11 . In some embodiments, R 3 is aryl optionally substituted with 1-3 R 11 . In some embodiments, R 3 is heteroaryl optionally substituted with 1-3 R 11 .
  • each R 11 is independently Ci-C 6 alkyl, Ci-C 6 alkenyl, halo, haloalkyl, haloalkoxy, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R 11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 11 is independently Ci-C 6 alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, amino or alkylamino, each of which is optionally substituted; or wherein two R 11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 11 is independently Ci-C 6 alkyl, halo, haloalkyl, haloalkoxy or alkoxy; or wherein two R 11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 11 is independently Ci-C 6 alkyl, halo, haloalkyl or haloalkoxy.
  • each R 4 and R 5 is independently H, Ci-Cs alkyl, haloalkyl, hydroxy, cyclyl, cyclylalkyl, aryl or heteroaryl, each of which is optionally substituted with 1-3 R 12 .
  • R 4 and R 5 is independently H, Ci-Cs alkyl, haloalkyl, cyclylalkyl, cyclyl, aryl or heteroaryl.
  • each R 12 is independently Ci-C 6 alkyl, Ci-C 6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 12 is independently Ci-C 6 alkyl, halo, haloalkyl or alkoxy, each of which is optionally substituted; or wherein two R 12 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 12 is independently Ci-C 6 alkyl, halo or haloalkyl, each of which is optionally substituted.
  • each R 14 is independently Ci-C 6 alkyl, Ci-C 6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted.
  • each R 14 is independently Ci-C 6 alkyl, halo, haloalkyl, alkoxy, hydroxy, cyano, amino or alkylamino, each of which is optionally substituted.
  • each R 14 is independently Ci-C 6 alkyl, halo, haloalkyl or hydroxy, each of which is optionally substituted.
  • R 8a and R 9a are each independently H, Ci-C 6 alkyl, halo, haloalkyl, or CN. In some embodiments, R 8a and R 9b are H.
  • Z is CR 17 . In some embodiments, R 17 is H.
  • the compound has the following formula:
  • t is 0, 1 or 2 and u is 0, 1, 2 or 3. In some embodiments, t is 1.
  • W is -COOH. In another embodiment, W is a carboxylic acid mimic or bioisostere, for example, -C(O)NHS(O) 2 CH 3 .
  • Z is CR 17 .
  • R 17 is H;
  • n is O.
  • n is 1.
  • each R 1 and R 2 is independently H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, halo, haloalkyl, Ci-C 6 alkoxy, cyclyl, cyclylalkyl, halocyclyl or halocyclylalkyl; or R and R , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • each R 1 and R 2 is independently H, Ci-C 6 alkyl, haloalkyl or Ci-C 6 alkoxy; or R 1 and R 2 , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • each R 1 and R 2 is independently H, Ci-C 6 alkyl or haloalkyl; or R 1 and R 2 , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • each R 1 and R 2 is independently H or Ci-C 6 alkyl; or R 1 and R 2 , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • A is a bond. In another embodiment, A is O. In yet another embodiment, A is NR 10 . Also, R 10 is hydrogen in another embodiment.
  • R 3 is aryl, heteroaryl, each of which is optionally substituted with 1-3 R 11 . In some embodiments, R 3 is aryl optionally substituted with 1-3 R 11 . In some embodiments, R 3 is heteroaryl optionally substituted with 1-3 R 11 .
  • each R 11 is independently Ci-C 6 alkyl, Ci-C 6 alkenyl, halo, haloalkyl, haloalkoxy, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R 11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R is independently Ci-C 6 alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, amino or alkylamino, each of which is optionally substituted; or wherein two R together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 11 is independently Ci-C 6 alkyl, halo, haloalkyl, haloalkoxy or alkoxy; or wherein two R 11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 11 is independently Ci-C 6 alkyl, halo, haloalkyl or haloalkoxy.
  • each R and R 5 is independently H, Ci-Cs alkyl, haloalkyl, hydroxy, cyclyl, cyclylalkyl, aryl or heteroaryl, each of which is optionally substituted with 1-3 R .
  • R and R 5 is independently H, Ci-Cs alkyl, haloalkyl, cyclylalkyl, cyclyl, aryl or heteroaryl.
  • each R is independently Ci-C 6 alkyl, Ci-C 6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 12 is independently Ci-C 6 alkyl, halo, haloalkyl or alkoxy, each of which is optionally substituted; or wherein two R 12 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 12 is independently Ci-C 6 alkyl, halo or haloalkyl, each of which is optionally substituted.
  • each R is independently Ci-C 6 alkyl, Ci-C 6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted.
  • each R is independently Ci-C 6 alkyl, halo, haloalkyl, alkoxy, hydroxy, cyano, amino or alkylamino, each of which is optionally substituted.
  • each R is independently Ci-C 6 alkyl, halo, haloalkyl or hydroxy, each of which is optionally substituted.
  • R a and R are each independently H, Ci-C 6 alkyl, halo, haloalkyl, or CN. In some embodiments, R 8a and R 8b are H.
  • Z is CR 17 . In some embodiments, R 17 is H.
  • the compound has the following formula:
  • t is 1.
  • W is -COOH. In another embodiment, W is a carboxylic acid mimic or bioisostere, for example, -C(O)NHS(O) 2 CH 3 .
  • Z is CR 7 .
  • R 7 is H;
  • n 0.
  • n 1
  • each R and R is independently H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, halo, haloalkyl, Ci-C 6 alkoxy, cyclyl, cyclylalkyl, halocyclyl or halocyclylalkyl; or R 1 and R 2 , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • each R 1 and R 2 is independently H, Ci-C 6 alkyl, haloalkyl or Ci-C 6 alkoxy; or R 1 and R 2 , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • each R 1 and R 2 is independently H, Ci-C 6 alkyl or haloalkyl; or R 1 and R 2 , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • each R 1 and R 2 is independently H or Ci-C 6 alkyl; or R and R , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • each R and R 5 is independently H, Ci-Cs alkyl, haloalk hydroxy, cyclyl, cyclylalkyl, aryl or heteroaryl, each of which is optionally substituted with 1-3 R 12 .
  • R 4 and R 5 is independently H, Ci-Cs alkyl, haloalkyl, cyclylalkyl, cyclyl, aryl or heteroaryl.
  • each R 12 is independently Ci-C 6 alkyl, Ci-C 6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R is independently Ci-C 6 alkyl, halo, haloalkyl or alkoxy, each of which is optionally substituted; or wherein two R 12 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 12 is independently Ci-C 6 alkyl, halo or haloalkyl, each of which is optionally substituted.
  • each R 14 is independently Ci-C 6 alkyl, Ci-C 6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted.
  • each R 14 is independently Ci-C 6 alkyl, halo, haloalkyl, alkoxy, hydroxy, cyano, amino or alkylamino, each of which is optionally substituted.
  • each R 14 is independently Ci-C 6 alkyl, halo, haloalkyl or hydroxy, each of which is optionally substituted.
  • R 8a and R 8b are each independently H, Ci-C 6 alkyl, halo, haloalkyl, or CN. In some embodiments, R 8a and R 8b are H.
  • Z is CR 17 . In some embodiments, R 17 is H.
  • each R 14 is independently Ci-C 6 alkyl. In some embodiments, u and t are both 1 and R 14 is at the para position with respect to the nitrogen ring atom.
  • W is -COOH; n is O or 1 ; R 4 and R 5 are independently H, Ci-C 6 alkyl or haloalkyl; s is 1 or 2; u is O or 1; and t is 1.
  • W is - COOH; n is 1; each R 1 and R 2 are independently H or Ci-C 6 alkyl; R 4 and R 5 are each independently H, aryl or heteroaryl; each R 11 is independently Ci-C 6 alkyl, halo or haloalkyl; R 14 is methyl, ethyl, halomethyl or haloethyl; s is 1 or 2; u is 0 or 1 and t is 1.
  • the compound has the following formula:
  • v 0, 1 or 2.
  • m is 1.
  • W is -COOH. In another embodiment, W is a carboxylic acid mimic or bioisostere, for example, -C(O)NHS(O) 2 CHs.
  • Z is CR 17 .
  • R 17 is H;
  • A is a bond. In another embodiment, A is O. In yet another embodiment, A is NR 10 . Also, R 10 is hydrogen in another embodiment.
  • R is aryl, heteroaryl, each of which is optionally substituted with 1 -3 R . In some embodiments, R is aryl optionally substituted with 1 -3 R . In some embodiments, R is heteroaryl optionally substituted with 1-3 R .
  • each R is independently Ci-C 6 alkyl, Ci-C 6 alkenyl, halo, haloalkyl, haloalkoxy, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R is independently Ci-C 6 alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, amino or alkylamino, each of which is optionally substituted; or wherein two R 11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 11 is independently Ci-C 6 alkyl, halo, haloalkyl, haloalkoxy or alkoxy; or wherein two R 11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 11 is independently Ci-C 6 alkyl, halo, haloalkyl or haloalkoxy.
  • each R 4 and R 5 is independently H, Ci-Cs alkyl, haloalkyl, hydroxy, cyclyl, cyclylalkyl, aryl or heteroaryl, each of which is optionally substituted with 1-3 R 12 .
  • R 4 and R 5 is independently H, Ci-Cs alkyl, haloalkyl, cyclylalkyl, cyclyl, aryl or heteroaryl.
  • each R 12 is independently Ci-C 6 alkyl, Ci-C 6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 12 is independently Ci-C 6 alkyl, halo, haloalkyl or alkoxy, each of which is optionally substituted; or wherein two R 12 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 12 is independently Ci-C 6 alkyl, halo or haloalkyl, each of which is optionally substituted.
  • R 6 and R 7 are each independently H, Ci-Cs alkyl, cyclyl, aryl, heteroaryl, cyclylalkyl or arylalkyl, each of which is optionally substituted with 1-3 R 13 ; wherein when B is O, R 7 is absent; wherein when B is N, R 6 and R 7 , together with the nitrogen to which they are attached, may form a 3-7 membered ring that is optionally saturated or unsaturated, and unsubstituted or substituted with 1-3 R ; and wherein R and R 6 , together with the atoms to which they are attached, may form a 3-7 membered ring ring that is optionally saturated or unsaturated, and unsubstituted or substituted with 1-3 R 15 .
  • each R 13 , R 14 and R 15 is independently Ci-C 6 alkyl, Ci-C 6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two, R 13 , R 14 and R 15 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R , R and R 5 is independently Ci-C 6 alkyl, halo, haloalkyl, alkoxy, hydroxy, cyano, amino or alkylamino, each of which is optionally substituted; or wherein two , R , R and R 5 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R , R and R 5 is independently Ci-C 6 alkyl, halo, haloalkyl or hydroxy, each of which is optionally substituted; or wherein two , R , R and R together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • Z is CR 17 . In some embodiments, R 17 is H.
  • the compound has the following formula:
  • v is 0, 1 or 2 and s is 0, 1, 2 or 3.
  • m is 1.
  • W is -COOH. In another embodiment, W is a carboxylic acid mimic or bioisostere, for example, -C(O)NHS(O) 2 CHs.
  • Z is CR 17 .
  • R 17 is H;
  • each R 11 is independently Ci-C 6 alkyl, Ci-C 6 alkenyl, halo, haloalkyl, haloalkoxy, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R 11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R is independently Ci-C 6 alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, amino or alkylamino, each of which is optionally substituted; or wherein two R 11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R is independently Ci-C 6 alkyl, halo, haloalkyl, haloalkoxy or alkoxy; or wherein two R together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 11 is independently Ci-C 6 alkyl, halo, haloalkyl or haloalkoxy.
  • each R and R is independently H, Ci-Cs alkyl, haloalkyl, hydroxy, cyclyl, cyclylalkyl, aryl or heteroaryl, each of which is optionally substituted with 1-3 R 12 .
  • R 4 and R 5 is independently H, Ci-Cs alkyl, haloalkyl, cyclylalkyl, cyclyl, aryl or heteroaryl.
  • each R 12 is independently Ci-C 6 alkyl, Ci-C 6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R 12 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R is independently Ci-C 6 alkyl, halo, haloalkyl or alkoxy, each of which is optionally substituted; or wherein two R together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R is independently Ci-C 6 alkyl, halo or haloalkyl, each of which is optionally substituted.
  • R and R are each independently H, Ci-Cs alkyl, cyclyl, aryl, heteroaryl, cyclylalkyl or arylalkyl, each of which is optionally substituted with 1-3 R 13 ; wherein when B is O, R 7 is absent; wherein when B is N, R 6 and R 7 , together with the nitrogen to which they are attached, may form a 3-7 membered ring that is optionally saturated or unsaturated, and unsubstituted or substituted with 1-3 R 14 ; and wherein R 4 and R 6 , together with the atoms to which they are attached, may form a 3-7 membered ring ring that is optionally saturated or unsaturated, and unsubstituted or substituted with 1-3 R 15 .
  • each R , R and R 5 is independently Ci-C 6 alkyl, Ci-C 6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two, R , R and R 5 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R , R and R is independently Ci-C 6 alkyl, halo, haloalkyl, alkoxy, hydroxy, cyano, amino or alkylamino, each of which is optionally substituted; or wherein two , R , R and R together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 13 , R 14 and R 15 is independently Ci-C 6 alkyl, halo, haloalkyl or hydroxy, each of which is optionally substituted; or wherein two , R 13 , R 14 and R 15 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • Z is CR 17 . In some embodiments, R 17 is H.
  • the invention features a compound of formula (III):
  • W is -COOH, or a carboxylic acid mimic or bioisostere
  • Z is N, NR 16 , CR 17 or CR 18 R 19
  • each R 1 and R 2 is independently H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, halo, haloalkyl, Ci-C 6 alkoxy, cyclyl, cyclylalkyl, halocyclyl or halocyclylalkyl; or R 1 and R 2 , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring; wherein either R or R is optionally taken together with R or R to form an optionally substituted, saturated or unsaturated 3-7 membered ring;
  • A is a bond, NR 10 , O, S, alkylenyl, amide, ester, carbamate, urea, thiourea or sulfonylurea;
  • R is aryl, heteroaryl, cyclyl or heterocyclyl, each of which is optionally substituted with 1-3 R 11 ; each R 4 and R 5 is independently H, Ci-Cs alkyl, haloalkyl, cyclyl, cyclylalkyl, aryl or heteroaryl, each of which is optionally substituted with 1-3 R 12 ; or R 4 and R 5 , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring;
  • Y is an aryl, heteroaryl, cyclyl or heterocyclyl ring
  • R 8a , R 8b , R 9a and R 9b are each independently H, Ci-C 6 alkyl, hydroxy, halo, haloalkyl, or CN;
  • R 10 is hydrogen, Ci-C 6 alkyl or haloalkyl; and each R 11 and R 12 is independently Ci-C 6 alkyl, Ci-C 6 alkenyl, Ci-C 6 alkynyl, halo, haloalkyl, alkoxy, haloalkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, carboxylate, cyano, oxo, nitro, amino, alkylamino, dialkylamino, mercapto, thioalkyl, aryloxy, thioalkoxy, amido, SO3H, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphate or acyl, each of which is optionally substituted; or wherein two R 11 or R 12 , together with the atoms to which they are attached,
  • R is attached, R is absent; and wherein when represents the presence of a bond to
  • Z is N or CR 17 , or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, tautomer, enantiomer, stereoisomer, analog or derivative thereof, including mixtures thereof in any ratios.
  • W is -COOH.
  • W is a carboxylic acid mimic or bioisostere, for example, -C(O)NHS(O) 2 CHs.
  • n O
  • n 1
  • each R 1 and R 2 is independently H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, haloalkyl, Ci-C 6 alkoxy, cyclyl, cyclylalkyl, halocyclyl or halocyclylalkyl; or R 1 and R 2 , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • each R 1 and R 2 is independently H or Ci-C 6 alkyl; or R 1 and R 2 , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • R and R are both H. In some embodiments, R and R are both Ci-C 6 alkyl (e.g., methyl or ethyl). In some embodiments, one of R 1 and R 2 is methyl and the other is sec-butyl. In some embodiments, one of R and R is hydrogen and the other is Ci-C 6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, sec-butyl or neopentyl). In some embodiments, one of R and R is hydrogen and the other is C 2 -C 6 alkenyl (e.g., C 3 alkenyl or ally 1) . In some embodiments, one of R 1 and R 2 is hydrogen and the other is cyclylalkyl (e.g., cyclopropylmethyl).
  • R 1 and R 2 together with the carbon to which they are attached, form a ring (e.g., a cyclopentyl, cyclobutyl, or cyclopropyl ring).
  • R 8 is taken with one of R 1 and R 2 , together with the carbons to which they are attached, to form a ring (e.g., a 5-membered ring or a 6- membered ring).
  • A is a bond. In another embodiment, A is O. In yet another embodiment, A is NR 10 . In some embodiments, R 10 is hydrogent.
  • R is aryl, heteroaryl, each of which is optionally substituted with 1-3 R 11 .
  • R 3 is aryl optionally substituted with 1-3 R 11 .
  • each R 11 is independently Ci-C 6 alkyl, Ci-C 6 alkenyl, halo, haloalkyl, haloalkoxy, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R 11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 11 is independently Ci-C 6 alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, amino or alkylamino, each of which is optionally substituted; or wherein two R 11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R is independently Ci-C 6 alkyl, halo, haloalkyl, haloalkoxy or alkoxy; or wherein two R 11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and ooppttiioonnaallllyy ssuubbssttiittuutteedd rriinngg..
  • each R 11 is independently Ci-C 6 alkyl, halo, haloalkyl or haloalkoxy.
  • R 3 is aryl, e.g., phenyl. In some embodiments, R 3 is unsubstituted phenyl.
  • R 3 is phenyl substituted with one R 11 . In some embodiments, R 3 is substituted at the ortho position. In some embodiments, R 3 is substituted at the meta position. In some embodiments, R 3 is substituted at the para position. In some embodiments, R 11 is halo (e.g., fluoro or chloro). In some embodiments, R 11 is haloalkyl (e.g., trifiuoromethyl). In some embodiments, R 11 is haloalkoxy (e.g., trifluoromethoxy).
  • R 11 is Ci-C 6 alkyl, e.g., C3 alkyl (e.g., isopropyl) or C4 alkyl (e.g., tert-butyl). In some embodiments, R 11 is alkoxy (e.g., methoxy).
  • R is phenyl substituted with two R .
  • both R are Ci-C 6 alkyl (e.g., methyl).
  • both R are halo (e.g., fluoro).
  • one R is halo (e.g., fluoro) and the other is haloalkyl (e.g., trifluoromethyl).
  • R is phenyl substituted with three R . In some embodiments, all three R are halo (e.g., fluoro).
  • R is pyridyl. In some embodiments, R is unsubstituted pyridyl. In some embodiments, R 3 is pyridyl substituted with one R 11 . In some embodiments, R 11 is haloalkyl (e.g., trifluoromethyl).
  • R 3 is pyrimidyl. In some embodiments, R 3 is unsubstituted pyrimidyl. In some embodiments, R 3 is pyrimidyl substituted with one R 11 . In some embodiments, R 11 is Ci-C 6 alkyl, e.g., C4 alkyl (e.g., tert-butyl).
  • m is 1.
  • each R and R 5 is independently H, Ci-Cs alkyl, haloalkyl, hydroxy, cyclyl, cyclylalkyl, aryl or heteroaryl, each of which is optionally substituted with 1-3 R .
  • R and R 5 is independently H, Ci-Cs alkyl, haloalkyl, cyclylalkyl, cyclyl, aryl or heteroaryl.
  • each R is independently Ci-C 6 alkyl, Ci-C 6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 12 is independently Ci-C 6 alkyl, halo, haloalkyl or alkoxy, each of which is optionally substituted; or wherein two R 12 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 12 is independently Ci-C 6 alkyl, halo or haloalkyl, each of which is optionally substituted.
  • R 4 is hydrogen or Ci-Cs alkyl.
  • R 5 is aryl (e.g., phenyl). In some embodiments, R 5 is unsubstituted phenyl.
  • R 5 is phenyl substituted with one R 12 . In some embodiments, R 5 is substituted at the ortho position. In some embodiments, R 5 is substituted at the meta position. In some embodiments, R 5 is substituted at the para position.
  • R 12 is halo (e.g., fluoro or chloro). In some embodiments,
  • R 12 is haloalkyl (e.g., trifluoromethyl).
  • R 12 is Ci-C 6 alkyl, e.g., C3 alkyl (e.g., isopropyl), or C4 alkyl (e.g., tert-butyl).
  • R 12 is -CN.
  • R 5 is phenyl substituted with two R 12 .
  • both R 12 are halo (e.g., fluoro).
  • R 5 is heteroaryl
  • R 5 is pyridyl. In some embodiments, R 5 is unsubstituted pyridyl.
  • R 5 is pyridyl substituted with one R 12 .
  • R 12 is halo (e.g., fluoro).
  • R 12 is haloalkyl (e.g., trifluoromethyl).
  • R 5 is indolyl
  • R 5 is imidazolyl
  • R 5 is imidazolyl substituted with one R 12 .
  • R 12 is haloalkyl (e.g., trifluoromethyl).
  • R 5 is thiazolyl
  • R 5 is pyrazolyl. In some embodiments, R 5 is pyrazolyl substituted with 1-3 R 12 . In some embodiments, R 5 is pyrazolyl substituted with three R 12 . In some embodiments, one R 12 is Ci-C 6 alkyl (e.g., methyl), one is halo (e.g., fluoro) and one is haloalkyl (trifluoromethyl).
  • R 5 is:
  • R is pyrimidyl. In some embodiments, r R> 5 is unsubstituted pyrimidyl. In some embodiments, R 5 is pyrimidyl substituted with one R 12 . In some embodiments, R 12 is Ci-C 6 alkyl, e.g., C4 alkyl (e.g., tert-butyl).
  • R 5 is indazolyl. In some embodiments, R 5 is indazolyl substituted with one R 12 . In some embodiments, R 12 is Ci-C 6 alkyl (e.g., methyl).
  • R 5 is hydrogen
  • R 5 is Ci-Cs alkyl. In some embodiments, R 5 is methyl. In some embodiments, R 5 is C 5 alkyl, e.g., isopentyl (3-methylbutyl) or neopentyl (2,2- dimethylpropyl). In some embodiments, R 5 is C 6 alkyl, e.g., neohexyl (3,3- dimethylbutyl).
  • R 5 is cyclyl, e.g., cycloalkyl (e.g., cyclohexyl). In some embodiments, R 5 is bicyclo[2.2.2]octanyl.
  • R 5 is cyclylalkyl, e.g., cyclohexylmethyl.
  • R 5 is haloalkyl (e.g., 2,2,2 -trifluoroethoxy, 3,3,3- trifluoropropyl or 4,4,4-trifluorobutyl).
  • Y is heterocyclyl (e.g., piperidinyl, piperizinyl, pyrollidinyl or morpholinyl).
  • the compound has the following formula: wherein Y is cyclyl or aryl.
  • Y is cyclyl
  • Y is aryl
  • m is 1.
  • W is -COOH. In another embodiment, W is a carboxylic acid mimic or bioisostere, for example, -C(O)NHS(O) 2 CHs.
  • Z is CR 7 .
  • R 7 is H;
  • n O
  • n 1
  • each R and R is independently H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, halo, haloalkyl, Ci-C 6 alkoxy, cyclyl, cyclylalkyl, halocyclyl or halocyclylalkyl; or R 1 and R 2 , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • each R 1 and R 2 is independently H, Ci-C 6 alkyl, haloalkyl or Ci-C 6 alkoxy; or R 1 and R 2 , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • each R 1 and R 2 is independently H, Ci-C 6 alkyl or haloalkyl; or R 1 and R 2 , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • each R and R is independently H or Ci-C 6 alkyl; or R and R , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • A is a bond.
  • A is O.
  • A is NR 10 .
  • R 10 is hydrogen in another embodiment.
  • R 3 is aryl, heteroaryl, each of which is optionally substituted with 1-3 R 11 . In some embodiments, R 3 is aryl optionally substituted with 1-3 R 11 . In some embodiments, R 3 is heteroaryl optionally substituted with 1-3 R 11 .
  • each R 11 is independently Ci-C 6 alkyl, Ci-C 6 alkenyl, halo, haloalkyl, haloalkoxy, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R 11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 11 is independently Ci-C 6 alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, amino or alkylamino, each of which is optionally substituted; or wherein two R 11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 11 is independently Ci-C 6 alkyl, halo, haloalkyl, haloalkoxy or alkoxy; or wherein two R 11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 11 is independently Ci-C 6 alkyl, halo, haloalkyl or haloalkoxy.
  • each R 4 and R 5 is independently H, Ci-Cs alkyl, haloalkyl, hydroxy, cyclyl, cyclylalkyl, aryl or heteroaryl, each of which is optionally substituted with 1-3 R 12 .
  • R 4 and R 5 is independently H, Ci-Cs alkyl, haloalkyl, cyclylalkyl, cyclyl, aryl or heteroaryl.
  • each R 12 is independently Ci-C 6 alkyl, Ci-C 6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R 12 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 12 is independently Ci-C 6 alkyl, halo, haloalkyl or alkoxy, each of which is optionally substituted; or wherein two R > 12 .
  • each R is independently Ci-C 6 alkyl, halo or haloalkyl, each of which is optionally substituted.
  • R 8a , R 8b , R 9b and R 9a are each independently H, Ci-C 6 alkyl, halo, haloalkyl, or CN. In some embodiments, R 8a , R 8b , R 9b and R 9a are H.
  • Z is CR 7 . In some embodiments, R 7 is H.
  • the compound has the following formula:
  • Y is heterocyclyl (e.g., piperidinyl, pyrazolyl, pyrollidinyl, piperazinyl or morpholinyl).
  • m is 1.
  • W is -COOH. In another embodiment, W is a carboxylic acid mimic or bioisostere, for example, -C(O)NHS(O) 2 CHs.
  • Z is CR 17 .
  • R 17 is H;
  • n O
  • n 1
  • each R 1 and R 2 is independently H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, halo, haloalkyl, Ci-C 6 alkoxy, cyclyl, cyclylalkyl, halocyclyl or halocyclylalkyl; or R and R , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • each R and R 2 is independently H, Ci-C 6 alkyl, haloalkyl or Ci-C 6 alkoxy; or R 1 and R 2 , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • each R 1 and R 2 is independently H, Ci-C 6 alkyl or haloalkyl; or R 1 and R 2 , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • each R 1 and R 2 is independently H or Ci-C 6 alkyl; or R 1 and R 2 , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
  • A is a bond. In another embodiment, A is O. In yet another embodiment, A is NR 10 . Also, R 10 is hydrogen in another embodiment.
  • R 3 is aryl, heteroaryl, each of which is optionally substituted with 1-3 R 11 . In some embodiments, R 3 is aryl optionally substituted with 1-3 R 11 . In some embodiments, R 3 is heteroaryl optionally substituted with 1-3 R 11 .
  • each R 11 is independently Ci-C 6 alkyl, Ci-C 6 alkenyl, halo, haloalkyl, haloalkoxy, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R 11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R is independently Ci-C 6 alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, amino or alkylamino, each of which is optionally substituted; or wherein two R 11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R is independently Ci-C 6 alkyl, halo, haloalkyl, haloalkoxy or alkoxy; or wherein two R 11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 11 is independently Ci-C 6 alkyl, halo, haloalkyl or haloalkoxy.
  • each R 4 and R 5 is independently H, Ci-Cs alkyl, haloalkyl, hydroxy, cyclyl, cyclylalkyl, aryl or heteroaryl, each of which is optionally substituted with 1-3 R 12 .
  • R 4 and R 5 is independently H, Ci-Cs alkyl, haloalkyl, cyclylalkyl, cyclyl, aryl or heteroaryl.
  • each R 12 is independently Ci-C 6 alkyl, Ci-C 6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R is independently Ci-C 6 alkyl, halo, haloalkyl or alkoxy, each of which is optionally substituted; or wherein two R 12 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
  • each R 12 is independently Ci-C 6 alkyl, halo or haloalkyl, each of which is optionally substituted.
  • R 8a and R 9a are each independently H, Ci-C 6 alkyl, halo, haloalkyl, or CN. In some embodiments, R 8a and R 9a are H.
  • Z is CR 17 . In some embodiments, R 17 is H.
  • the invention features a compound of formula (IV):
  • n 0, 1 or 2;
  • W is -COOH, or a carboxylic acid mimic or bioisostere; each R 1 and R 2 is independently H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, halo, haloalkyl, Ci-C 6 alkoxy, cyclyl, cyclylalkyl, halocyclyl or halocyclylalkyl; or R 1 and R 2 , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring;
  • A is a bond, NR 10 , O, S, alkylenyl, amide, ester, carbamate, urea, thiourea or sulfonylurea;
  • B is N or O
  • R 3 is aryl, heteroaryl, cyclyl or heterocyclyl, each of which is optionally substituted with 1-3 R 11 ; each R 4 and R 5 is independently H, Ci-Cs alkyl, haloalkyl, cyclyl, cyclylalkyl, aryl or heteroaryl, each of which is optionally substituted with 1-3 R 12 ; or R 4 and R 5 , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring;
  • R 6 and R 7 are each independently H, Ci-Cs alkyl, cyclyl, aryl, heteroaryl, cyclylalkyl or arylalkyl, each of which is optionally substituted with 1-3 R 13 ; wherein when B is O, R 7 is absent; wherein when B is N, R 6 and R 7 , together with the nitrogen to which they are attached, may form a ring that is optionally substituted with 1-3 R 14 ; and wherein R 4 and R 6 , together with the atoms to which they are attached, optionally form ring that is optionally substituted with 1-3 R 15 ;
  • R 10 is hydrogen, Ci-C 6 alkyl or haloalkyl; and each R 11 , R 12 , R 13 , R 14 and R 15 is independently Ci-C 6 alkyl, Ci-C 6 alkenyl, Ci-C 6 alkynyl, halo, haloalkyl, alkoxy, haloalkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, arylalkyl, hetero arylalkyl, cyclylalkyl, hetero cyclylalkyl, carboxylate, cyano, oxo, nitro, amino, alkylamino, dialkylamino, mercapto, thioalkyl, aryloxy, thioalkoxy, amido, SO3H, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphate or acyl, each of which is optionally substituted; wherein two R 11 , R 12
  • W is -COOH.
  • W is a carboxylic acid mimic or bioisostere, for example, -C(O)NHS(O) 2 CHs.
  • n is 1. In some embodiments, R and R are both H.
  • A is a bond. In another embodiment, A is O. In yet another embodiment, A is NR . Also, R is hydrogen in another embodiment.
  • R is aryl, e.g., phenyl. In some embodiments, R is phenyl substituted with one R . In some embodiments, R is substituted at the ortho position. In some embodiments, R 3 is substituted at the meta position. In some embodiments, R 3 is substituted at the para position. In some embodiments, R 11 is halo (e.g., fluoro or chloro). In some embodiments, R 11 is haloalkyl (e.g., trifluoro methyl).
  • m is 1.
  • R 4 is hydrogen or Ci-Cs alkyl.
  • R 5 is aryl (e.g., phenyl). In some embodiments, R 5 is phenyl substituted with one R . In some embodiments, R is haloalkyl (e.g., trifluoromethyl).
  • B is N.
  • R and R 7 together with the nitrogen to which they are attached, form a 6-membered ring, e.g., a piperidine ring. In some embodiments, R and R , together with the nitrogen to which they are attached, form a piperidine ring that is substituted with one R . In some embodiments, R is haloalkyl (e.g., trifluoromethyl).
  • the invention features a compound of formula (V): wherein: m is 0, 1, 2, 3 or 4; n is 0, 1 or 2;
  • W is -COOH, or a carboxylic acid mimic or bioisostere
  • Z is N or CH; each R 1 and R 2 is independently H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, halo, haloalkyl, Ci-C 6 alkoxy, eye IyI or cyclylalkyl; or R 1 and R 2 , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring; wherein either R 1 or R 2 are optionally taken together with R 8 or R 9 to form an optionally substituted, saturated or unsaturated 3-7 membered ring;
  • A is a bond, NR 10 , O, S, alkylenyl, amide, ester, carbamate, urea, thiourea or sulfonylurea;
  • B is N or O
  • R is aryl, heteroaryl, cyclyl or heterocyclyl, each of which is optionally substituted with 1-3 R 11 ; each R and R is independently H, Ci-Cs alkyl, haloalkyl, cyclyl, cyclylalkyl, aryl or heteroaryl, each of which is optionally substituted with 1-3 R ; or R and R , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring;
  • R 6 and R 7 are each independently H, Ci-Cs alkyl, cyclyl, aryl, heteroaryl, cyclylalkyl or arylalkyl, each of which is optionally substituted with 1-3 R 13 ; wherein when B is O, R 7 is absent; wherein when B is N, R 6 and R 7 , together with the nitrogen to which they are attached, may form a ring that is optionally substituted with 1-3 R 14 ; and wherein R 4 and R 6 , together with the atoms to which they are attached, optionally form ring that is optionally substituted with 1-3 R 5 ;
  • R 8 and R 9 are each independently H, Ci-C 6 alkyl, hydroxy, halo, haloalkyl, or CN;
  • R 10 is hydrogen, Ci-C 6 alkyl or haloalkyl; and each R 11 , R 12 , R 13 , R 14 and R 15 is independently Ci-C 6 alkyl, Ci-C 6 alkenyl, Ci-C 6 alkynyl, halo, haloalkyl, alkoxy, haloalkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, carboxylate, cyano, oxo, nitro, amino, alkylamino, dialkylamino, mercapto, thioalkyl, aryloxy, thioalkoxy, amido, SO3H, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphate or acyl, each of which is optionally substituted; wherein two R 11 , R 12 ,
  • W is -COOH.
  • W is a carboxylic acid mimic or bioisostere, for example, -C(O)NHS(O) 2 CH3.
  • n O
  • n is 1.
  • R and R are both H.
  • R 1 and R 2 are both Ci-C 6 alkyl (e.g., methyl or ethyl).
  • one of R and R is methyl and the other is sec-butyl.
  • one of R 1 and R 2 is hydrogen and the other is Ci-C 6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, sec-butyl or neopentyl).
  • one of R 1 and R 2 is hydrogen and the other is C 2 -C 6 alkenyl (e.g., C 3 alkenyl or allyl).
  • one of R 1 and R 2 is hydrogen and the other is cyclylalkyl (e.g., cyclopropylmethyl). In some embodiments, one of R 1 and R 2 is hydrogen and the other is cyclylalkyl (e.g., cyclopropylmethyl).
  • R and R together with the carbon to which they are attached, form a ring (e.g., a cyclopentyl, cyclobutyl, or cyclopropyl ring).
  • R is taken with one of R and R , together with the carbons to which they are attached, to form a ring (e.g., a 5-membered ring or a 6- membered ring).
  • A is a bond. In another embodiment, A is O. In yet another embodiment, A is NR . Also, R is hydrogen in another embodiment.
  • R is aryl, e.g., phenyl. In some embodiments, R is unsubstituted phenyl.
  • R 3 is phenyl substituted with one R 11 . In some embodiments, R 3 is substituted at the ortho position. In some embodiments, R 3 is substituted at the meta position. In some embodiments, R 3 is substituted at the para position. In some embodiments, R 11 is halo (e.g., fluoro or chloro). In some embodiments, R 11 is haloalkyl (e.g., trifiuoromethyl). In some embodiments, R 11 is haloalkoxy (e.g., trifluoromethoxy).
  • R 11 is Ci-C 6 alkyl, e.g., C 3 alkyl (e.g., isopropyl) or C4 alkyl (e.g., tert-butyl). In some embodiments, R 11 is alkoxy (e.g., methoxy).
  • R is phenyl substituted with two R .
  • both R are Ci-C 6 alkyl (e.g., methyl).
  • both R are halo (e.g., fluoro).
  • one R is halo (e.g., fluoro) and the other is haloalkyl (e.g., trifiuoromethyl).
  • R is phenyl substituted with three R .
  • all three R i l l are halo (e.g., fluoro).
  • R 3 is pyridyl. In some embodiments, R 3 is unsubstituted pyridyl. In some embodiments, R 3 is pyridyl substituted with one R 11 . In some embodiments, R 11 is haloalkyl (e.g., trifiuoromethyl). In some embodiments, R 3 is pyrimidyl. In some embodiments, R 3 is unsubstituted pyrimidyl. In some embodiments, R 3 is pyrimidyl substituted with 1 R 11 . In some embodiments, R 11 is Ci-C 6 alkyl, e.g., C4 alkyl (e.g., tert-butyl).
  • m is 1.
  • R 4 is hydrogen or Ci-Cs alkyl.
  • R 5 is aryl (e.g., phenyl). In some embodiments, R 5 is unsubstituted phenyl.
  • R 5 is phenyl substituted with one R 12 .
  • R 12 is halo (e.g., fluoro or chloro). In some embodiments, R 12 is haloalkyl (e.g., trifluoromethyl). In some embodiments, R 12 is Ci-C 6 alkyl, e.g., C3 alkyl (e.g., isopropyl), or C4 alkyl (e.g., tert-butyl). In some embodiments, R 12 is -CN.
  • R 5 is phenyl substituted with two R 12 .
  • both R 12 are halo (e.g., fluoro).
  • R 5 is heteroaryl
  • R 5 is pyridyl. In some embodiments, R 5 is unsubstituted pyridyl.
  • R 5 is pyridyl substituted with one R 12 .
  • R 12 is halo (e.g., fluoro).
  • R 12 is haloalkyl (e.g., trifluoromethyl).
  • R 5 is imidazolyl
  • R 5 is imidazolyl substituted with one R 12 .
  • R 12 is haloalkyl (e.g., trifluoromethyl).
  • R 5 is thiazolyl
  • R 5 is pyrazolyl. In some embodiments, R 5 is pyrazolyl substituted with 1-3 R 12 . In some embodiments, R 5 is pyrazolyl substituted with three R 12 . In some embodiments, one R 12 is Ci-C 6 alkyl (e.g., methyl), one is halo (e.g., fluoro) and one is haloalkyl (trifluoromethyl).
  • R 5 is:
  • R 5 is pyrimidyl. In some embodiments, R 5 is unsubstituted pyrimidyl. In some embodiments, R 5 is pyrimidyl substituted with one R 12 . In some embodiments, R 12 is C 1 -C 6 alkyl, e.g., Ci alkyl (e.g., methyl) or C4 alkyl (e.g., tert-butyl).
  • R 5 is indolyl
  • R 5 is indazolyl. In some embodiments, R 5 is indazolyl substituted with one R 12 . In some embodiments, R 12 is Ci-C 6 alkyl (e.g., methyl).
  • R 5 is hydrogen
  • R 5 is Ci-Cs alkyl. In some embodiments, R 5 is methyl. In some embodiments, R 5 is C 5 alkyl, e.g., isopentyl (3-methylbutyl) or neopentyl (2,2- dimethylpropyl). In some embodiments, R 5 is C 6 alkyl, e.g., neohexyl (3,3- dimethylbutyl).
  • R 5 is cyclyl, e.g., cycloalkyl (e.g., cyclohexyl). In some embodiments, R 5 is bicyclo[2.2.2]octanyl.
  • R 5 is cyclylalkyl, e.g., cyclohexylmethyl.
  • R 5 is haloalkyl (e.g., 2,2,2 -trifluoroethoxy or 3,3,3- trifluoropropyl).
  • B is O and R 7 is absent.
  • R 6 is aryl, e.g., phenyl. In some embodiments, R 6 is phenyl substituted with one R 13 . In some embodiments, R 6 is substituted at the ortho position. In some embodiments, R 6 is substituted at the meta position. In some embodiments, R 6 is substituted at the para position. In some embodiments, R 13 is haloalkyl (e.g., trifluoromethyl).
  • B is N.
  • R 6 and R 7 together with the nitrogen to which they are attached, form a ring, e.g., a 4-membered ring (e.g., an azetidine ring).
  • R 6 and R 7 together with the nitrogen to which they are attached, form a 5-membered ring, e.g., a pyrrolidine ring. In some embodiments, R 6 and R 7 , together with the nitrogen to which they are attached, form a pyrrolidine ring that is substituted with one R 14 .
  • R 14 is halo (e.g., fluoro). In some embodiments, R 14 is Ci-C 6 alkyl (e.g., sec-butyl).
  • R 6 and R 7 together with the nitrogen to which they are attached, form a pyrrolidine ring that is substituted with two R 14 .
  • both R 14 are Ci-C 6 alkyl (e.g., methyl).
  • both R 14 are halo (e.g., fluoro).
  • two R 14 together with the atoms to which they are attached, form a ring, e.g., a 3-membered ring, a 5-membered ring or a 6-membered ring (e.g., a phenyl ring).
  • R 6 and R 7 together with the nitrogen to which they are attached, form a 6-membered ring, e.g., a piperidine ring. In some embodiments, R 6 and R 7 , together with the nitrogen to which they are attached, form a piperidine ring that is unsubstituted.
  • R 6 and R 7 together with the nitrogen to which they are attached, form a piperidine ring that is substituted with one R .
  • R 14 is halo (e.g., fluoro).
  • R 14 is Ci-C 6 alkyl, e.g., methyl.
  • R 14 is C3 alkyl (e.g., n-propyl).
  • R 14 is C4 alkyl (e.g., tert-butyl or isobutyl).
  • R 14 is haloalkyl (e.g., trifluoromethyl).
  • R 14 is alkoxy (e.g., methoxy or ethoxy). In some embodiments, R 14 is aryl (e.g., phenyl). In some embodiments, R 14 is cyano. In some embodiments, R 14 is a carboxylate. In some embodiments, R 14 is -SO 2 CH 3 .
  • R 6 and R 7 together with the nitrogen to which they are attached, form a piperidine ring that is substituted with two R 14 .
  • both R 14 are halo (e.g., fluoro).
  • both R 14 are Ci-C 6 alkyl (e.g., methyl).
  • two R 14 together with the carbons to which they are attached, form a ring, e.g., a 3-membered ring or a 6-membered ring.
  • R 6 and R 7 together with the nitrogen to which they are attached, form a piperazine ring. In some embodiments, R 6 and R 7 , together with the nitrogen to which they are attached, form a piperazine ring that is unsubstituted. In some embodiments, R 6 and R 7 , together with the nitrogen to which they are attached, form a piperazine ring that is substituted with one R 14 . In some embodiments, R 14 is Ci-C 6 alkyl (e.g., methyl).
  • R 6 and R 7 together with the nitrogen to which they are attached, form a piperazine that is substituted with two R 14 .
  • two R 14 together with the carbons to which they are attached, form an optionally substituted ring such as a heteroaryl.
  • the heteroaryl is a triazole.
  • the triazole is substituted with a haloalkyl substituent (e.g., trifluoromethyl).
  • R 6 and R 7 together with the nitrogen to which they are attached, form a thiomorpholino.
  • R 6 and R 7 together with the nitrogen to which they are attached, form a 7-membered ring.
  • R 6 and R 7 together with the nitrogen to which they are attached, form a bridged bicyclic ring (e.g., a 3-azabicyclo[3.2.1]octan-3-yl ring). In some embodiments, R 6 and R 7 , together with the nitrogen to which they are attached, form a fused bicyclic ring (e.g., 3-azabicyclo[3.1.0]hexan-3-yl). In some embodiments, R and R , together with the nitrogen to which they are attached, form a spirocyclic ring system (e.g., 6-azaspiro[2.5]octan-6-yl).
  • both R 6 and R 7 are Ci-Cs alkyl. In some embodiments, one of R 6 and R 7 is methyl and the other is n-heptyl.
  • both R 6 and R 7 are cyclyl. In some embodiments, one of R 6 and R 7 is cyclopropyl and the other is cyclohexyl.
  • R 6 is Ci-Cs alkyl (e.g., C5 alkyl) and R 7 is aryl (e.g., phenyl). In some embodiments, R 6 is isopentyl (3-methylbutyl) and R 7 is phenyl substituted with one R 13 .
  • R 13 is Ci-C 6 alkyl, e.g., C4 alkyl (e.g., tert-butyl). In some embodiments, R 13 is haloalkyl (e.g., trifluoromethyl).
  • R 6 is Ci-Cs alkyl and R 7 is cyclyl.
  • R 6 is methyl. In some embodiments, R 6 is C4 alkyl (e.g., n-butyl or sec-butyl). In some embodiments, R 6 is C 5 alkyl (e.g., 2,2-dimethylpropyl, 3- methylbutyl or 2-methylbutyl). In some embodiments, R 6 is C 6 alkyl (e.g., 3,3- dimethylbutyl).
  • R is cyclyl, e.g., cycloalkyl (e.g., cyclohexyl). In some embodiments, R 7 is cyclohexyl substituted with one R 13 .
  • R 13 is Ci-C 6 alkyl (e.g., methyl). In some embodiments, R 13 is C3 alkyl (e.g., isopropyl). In some embodiments, R 13 is C4 alkyl (e.g., tert-butyl). In some embodiments, R 13 is haloalkyl (e.g., trifluoromethyl). In some embodiments, R 13 is halo (e.g., fiuoro). In some embodiments, R 13 is -CN.
  • R 7 is cyclohexyl substituted with two R 13 .
  • both R 13 are halo (e.g., fluoro).
  • both R 13 are Ci-C 6 alkyl (e.g., methyl).
  • R 7 is a bicyclic group, e.g., bicyclo[2.2.2]octane.
  • R 7 is bicyclo[2.2.2]octane substituted with one R 13 .
  • R 6 is arylalkyl (e.g., benzyl) and R 7 is cyclyl, e.g., cycloalkyl (e.g., cyclohexyl). In some embodiments, R is cyclohexyl substituted with one R 13 . In some embodiments, R 13 is Ci-C 6 alkyl, e.g., C4 alkyl (e.g., tert-butyl).
  • R 6 is cyclylalkyl (e.g., cyclopentylmethyl or cyclohexylmethyl), and R 7 is cyclyl, e.g., cycloalkyl (e.g., cyclohexyl). In some embodiments, R 7 is cyclohexyl substituted with one R 13 . In some embodiments, R 13 is C 1 - C 6 alkyl, e.g., C 4 alkyl (e.g., tert-butyl). In some embodiments, R 6 is hydrogen and R 7 is cyclyl, e.g., cycloalkyl (e.g., cyclohexyl).
  • R 7 is cyclohexyl substituted with 1-3 R 13 . In some embodiments, R 7 is cyclohexyl substituted with one R 13 . In some embodiments, R 13 is Ci-C 6 alkyl (e.g., methyl). In some embodiments, R 13 is C3 alkyl (e.g., isopropyl). In some embodiments, R 13 is C4 alkyl (e.g., tert-butyl). In some embodiments, R 13 is haloalkyl (e.g., trifluoromethyl). In some embodiments, R 13 is halo (e.g., fluoro). In some embodiments, R 13 is -CN.
  • R 7 is cyclohexyl substituted with two R 13 .
  • both R 13 are halo (e.g., fluoro).
  • both R 13 are Ci-C 6 alkyl (e.g., methyl).
  • R 7 is a bicyclic group, e.g., bicyclo[2.2.2]octane. In some embodiments, R 7 is bicyclo[2.2.2]octane substituted with one R 13 . In some embodiments, R 13 is haloalkyl (e.g., difluoromethyl).
  • R 6 is hydrogen and R 7 is Ci-Cs alkyl.
  • R 7 is C 6 alkyl (e.g., 4-methylpentyl).
  • R 7 is A- methylpentyl that is substituted with one R 13 .
  • R 13 is aryl (e.g., phenyl).
  • R 13 is phenyl substituted with haloalkyl (e.g., trifluoromethyl).
  • R 4 and R 6 together with the atoms to which they are attached, form a ring, e.g., a 6-membered ring. In some embodiments, R 4 and R 6 , together with the atoms to which they are attached, form a 6-membered ring that is substituted with one R 15 .
  • R 15 is Ci-C 6 alkyl (e.g., methyl). In some embodiments, R 15 is haloalkyl (e.g., trifluoromethyl).
  • R 7 is Ci-C 6 alkyl, e.g., C4 alkyl (e.g., sec-butyl) or C 5 alkyl (e.g., 2,2-dimethylpropyl).
  • R 7 is haloalkyl (e.g., 4,4,4- trifluorobutyl).
  • R 7 is aryl (e.g., phenyl).
  • R 7 is phenyl substituted with one R 13 .
  • R 13 is haloalkyl (e.g., trifluoromethyl).
  • R 7 is arylalkyl (e.g., benzyl). In some embodiments, R 7 is benzyl substituted with one R 13 . In some embodiments, R 13 is haloalkyl (e.g., trifluoromethyl).
  • a compound described herein can be, for example, in a form of an achiral compound, a racemate, an optically active compound, a pure diastereomer, a mixture of diastereomers, or a pharmacologically acceptable salt.
  • the compound of formula (I), (II), (III), (IV) or (V) is produced as an S enantiomer in an enantiomeric excess (e.g., 10%, 50%, 75%, 85%, 90%, 95%, 97% or greater). In some embodiments, the compound of formula (I), (II), (III), (IV) or (V) is produced as an R enantiomer in an enantiomeric excess (e.g., 10%, 50%, 75%, 85%, 90%, 95%, 97% or greater).
  • the compound of formula (I), (II), (III), (IV) or (V) is produced in as an R,S diastereomer in a diastereomeric excess (e.g., 10%, 50%, 75%, 85%, 90%, 95%, 97% or greater). In some embodiments, the compound of formula (I), (II), (III), (IV) or (V) is produced in as an R,R diastereomer in a diastereomeric excess (e.g., 10%, 50%, 75%, 85%, 90%, 95%, 97% or greater).
  • the compound of formula (I), (II), (III), (IV) or (V) is produced in as an S,R diastereomer in a diastereomeric excess (e.g., 10%, 50%, 75%, 85%, 90%, 95%, 97% or greater). In some embodiments, the compound of formula (I), (II), (III), (IV) or (V) is produced in as an S,S diastereomer in a diastereomeric excess (e.g., 10%, 50%, 75%, 85%, 90%, 95%, 97% or greater).
  • the present invention is directed to a method of producing a compound of formula (I) or (II), the method comprising a condensation of a compound of formula (VII):
  • the method further comprising an asymmetric hydrogenation of a compound of formula (VIII) to produce a compound of formula (XIa) or (XIb);
  • the method further comprises a hydrolysis step.
  • the compound of formula (XIa) is produced in an enantiomeric excess (e.g., 10%, 50%, 75%, 85%, 90%, 95%, 97% or greater).
  • the compound of formula (XIb) is produced in an enantiomeric excess (e.g., 10%, 50%, 75%, 85%, 90%, 95%, 97% or greater).
  • Figure 1 is a table, Table 1, depicting representative compounds analytical data and synthetic methods and EC50 values. Synthetic methods correspond to those described in Schemes 1-7.
  • Figure 2 is a table, Table 2, depicting representative compounds, and EC50 values.
  • a compound described herein modulates gamma secretase (e.g., alters the cleavage pattern of gamma secretase), e.g., when administered to a subject.
  • the compounds described herein include the compounds of formula (I), (II), (III), (IV) or (V) wherein n, m, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , A and Z are as defined above.
  • the compounds described herein may also include the intermediate compounds of the formula (VI), (VII), (VIII) or (IX).
  • the compounds described herein can be used for a variety of purposes, e.g., therapeutic purposes. Many of the compounds modulate gamma-secretase activity and can be used, for example to alter the cleavage pattern of gamma secretase, e.g., in a subject.
  • a compound described herein can be, for example, an enantiomerically enriched isomer of a stereoisomer described herein.
  • the compound may have an enantiomeric excess of at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%.
  • Enantiomer refers to either of a pair of chemical compounds whose molecular structures have a mirror-image relationship to each other.
  • a preparation of a compound disclosed herein may be enriched for an isomer of the compound having a selected stereochemistry, e.g., R or S, corresponding to a selected stereocenter.
  • the compound may have a purity corresponding to a compound having a selected stereochemistry of a selected stereocenter of at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%.
  • a compound described herein can, for example, include a preparation of a compound disclosed herein that is enriched for a structure or structures having a selected stereochemistry, e.g., R or S, at a selected.
  • a preparation of a compound disclosed herein is enriched for isomers (subject isomers) which are diastereomers of the compound described herein.
  • the compound has a purity corresponding to a compound having a selected diastereomer of at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%.
  • Diastereomer when used herein, refers to a stereoisomer of a compound having two or more chiral centers that is not a mirror image of another stereoisomer of the same compound.
  • the compounds may be prepared in racemic form or as individual enantiomers or diastereomers by either stereospecific synthesis or by resolution.
  • the compounds may, for example, be resolved into their component enantiomers or diastereomers by standard techniques, such as the formation of stereoisomeric pairs by salt formation with an optically active base, followed by fractional crystallization and regeneration of the free acid.
  • the compounds may also be resolved by formation of stereoisomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
  • the enantiomers also may be obtained from kinetic resolution of the racemate of corresponding esters using lipase enzymes, e.g.
  • a compound described herein can also be modified by appending appropriate functionalities to enhance selective biological properties.
  • modifications are known in the art and include those that increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism, and/or alter rate of excretion. Examples of these modifications include, but are not limited to, esterification with polyethylene glycols, derivatization with pivolates or fatty acid substituents, conversion to carbamates, hydro xylation of aromatic rings, and hetero atom- substitution in aromatic rings.
  • Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms termed polymorphic forms. In general, all physical forms are of use in the methods contemplated by the present invention and are intended to be within the scope of the present invention.
  • “Compound or a pharmaceutically acceptable salt, hydrate, polymorph or solvate of a compound” intends the inclusive meaning of "or”, in that materials meeting more than one of the stated criteria are included, e.g., a material that is both a salt and a solvate is encompassed.
  • a compound described herein can be in the form of a metabolite.
  • a metabolite may be a compound that is related to a compound described herein, as a form of such compound obtained in a human or animal body by action of the body on the administered form of the compound.
  • a metabolite may be a de -methylated analogue of a compound bearing a methyl group, which is obtained in the body after administration of the methylated compound as a result of action by the body on the methylated compound.
  • a metabolite may also be a carboxylic-acid containing compound, which is obtained in the body after administration of the corresponding ester as a result of action by the body on the ester- containing compound.
  • the compounds of this invention may also be represented in multiple tautomeric forms.
  • the invention expressly includes all tautomeric forms of the compounds described herein, even though only a single tautomeric form may be represented. All such isomeric forms of such compounds are expressly included in the present invention.
  • an "alkyl” group is a saturated aliphatic hydrocarbon group.
  • An alkyl group can be straight or branched, and can have, for example, from 1 to 8 carbon atoms in a chain.
  • straight chain alkyl groups include, but are not limited to, ethyl and butyl.
  • branched alkyl groups include, but are not limited to, isopropyl and t-butyl.
  • aryl is an aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring system, wherein any ring atom capable of substitution can be substituted (e.g., by one or more substituents).
  • aryl moieties include, but are not limited to, phenyl, naphthyl, and anthracenyl.
  • a “substituted aryl” group is an aryl group that is substituted with one or more substituents such as alkyl, alkoxy, amino, nitro, carboxy, carboalkoxy, cyano, alkylamino, dialkylamino, halo, hydroxy, hydroxyalkyl, mercaptyl, alkylmercaptyl, trihaloalkyl, carboxyalkyl, sulfoxy, or carbamoyl.
  • aralkyl group is an alkyl group that is substituted with an aryl group.
  • An example of an aralkyl group is benzyl.
  • cycloalkyl or "cyclyl” as employed herein includes saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons, preferably 3 to 8 carbons, and more preferably 3 to 6 carbons, wherein the cycloalkyl group may be optionally substituted.
  • Cyclyl groups include monocyclic and polycyclic groups (e.g., a bicyclic group such as a fused bicyclic, spirocyclic and bridged bicyclic structure).
  • Preferred cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.
  • a “heteroaryl” group is an aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively). Any ring atom can be substituted (e.g., by one or more substituents).
  • a “carboxyl” group is a -COOH group.
  • alkoxy group is an alkyl-O- group in which "alkyl” is as previously described.
  • haloalkyl refers to an alkyl in which one or more hydrogen atoms are replaced by halo, and includes alkyl moieties in which all hydrogens have been replaced by halo (e.g., perfluoroalkyl).
  • halogen or "halo” group is fluorine, chlorine, bromine or iodine.
  • a “heterocyclyl” group is a 5 to about 10 membered ring structure, in which one or more of the atoms in the ring is an element other than carbon, e.g., N, O, S.
  • a heterocyclyl group can be aromatic or non-aromatic, i.e., can be saturated, or can be partially or fully unsaturated.
  • Heterocyclyl groups include monocyclic and polycyclic groups (e.g., a bicyclic group such as a fused bicyclic, spirocyclic and bridged bicyclic structure).
  • heterocyclyl groups include pyridyl, imidazolyl, furanyl, thienyl, thiazolyl, tetrahydro furanyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, indolyl, indolinyl, isoindolinyl, piperidinyl, pyrimidinyl, piperazinyl, isoxazolyl, isoxazolidinyl, tetrazolyl, and benzimidazolyl.
  • a “substituted heterocyclyl” group is a heterocyclyl group wherein one or more hydrogens are replaced by substituents such as alkoxy, alkylamino, dialkylamino, carbalkoxy, carbamoyl, cyano, halo, trihalomethyl, hydroxy, carbonyl, thiocarbonyl, hydroxyalkyl or nitro.
  • a “ring” is an aryl, heteroaryl, cyclyl or heterocyclyl group, each of which are defined herein.
  • Such groups include -COOR a , - CONR a R b , -CN, -PO 3 H 2 , -SO 3 H, -S(O) 2 NHR a , -S(O) 2 NHC(O)R a , -CH 2 S(O) 2 R a , - C(O)NHS(O) 2 R a , -C(O)NHOH, -C(O)NHCN, -CH(CF 3 )OH, -C(CF 3 ) 2 OH, -P(O)(OH) 2 and groups of sub-formulae (a)-(i') below:
  • substituent groups are specified by their conventional chemical formulae, written from left to right, they optionally encompass substituents resulting from writing the structure from right to left, e.g., -CH 2 O- optionally also recites -OCH 2 -.
  • fused ring system means at least two rings, wherein each ring has at least 2 atoms in common with another ring.
  • “Fused ring systems” may include aromatic as well as non aromatic rings. Examples of “fused ring systems” are naphthalenes, indoles, quinolines, chromenes, norbornanes, and the like.
  • treatment refers both to prevention of a particular disease or treatment of a pre-existing condition.
  • host 'or "patient in need thereof as used herein may be any mammalian species, for example a primate species, particularly humans.
  • Animal models are of interest for veterinary treatment and for experimental investigations, providing a model for treatment of human disease.
  • terapéuticaally effective amount means that amount of a compound, material, or composition comprising a compound of the present invention which is effective for producing some desired therapeutic effect by simultaneous blocking or inhibiting gamma secretase receptors in a mammal, thereby blocking the biological consequences of that pathway in the treated cells, at a reasonable benefit/risk ratio applicable to any medical treatment.
  • Drug dosage depends upon the specific compound used within a particular formulation, the specific disease, the patient status, etc.
  • a "therapeutically effective dose” is typically sufficient to reduce the undesired cell population in the target tissue while the viability of the patient is maintained.
  • the treatment is generally continued until a reduction in cell population has occurred, for example, at least about 50% reduction in the cell burden, and may be continued until essentially no more undesired cells are detected in the body.
  • enriched preparation is enriched for a selected stereoconfiguration of one, two, three or more selected stereocenters within the subject compound.
  • Exemplary selected stereocenters and exemplary stereoconfigurations thereof can be selected from those provided herein, e.g., in an example described herein.
  • enriched is meant at least 60%, e.g., of the molecules of compound in the preparation have a selected stereochemistry of a selected stereocenter. In preferred embodiments it is at least 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%.
  • Enriched refers to the level of a subject molecule(s) and does not connote a process limitation unless specified.
  • a compound described herein can be in the form of a salt, e.g., a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salt includes salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al, J. Pharma. Science 1977, 66: 1-19).
  • Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
  • the present invention provides compounds, which are in a prodrug form.
  • Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention.
  • prodrugs for carboxylic acid analogs of the invention include a variety of esters.
  • the pharmaceutical compositions of the invention include a carboxylic acid ester.
  • the prodrug is suitable for treatment /prevention of those diseases and conditions that require the drug molecule to cross the blood brain barrier.
  • the prodrug enters the brain, where it is converted into the active form of the drug molecule.
  • prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
  • a hydroxybenzaldehyde such as compound 1 may first be activated, e.g., by triflation. Subsequent coupling (e.g., via a Suzuki coupling) to install an aryl group (R 3 ) may be followed by reductive amination and hydrolysis to yield the desired compound 4.
  • a hydroxybenzaldehyde such as compound 1 may first be subjected to reductive amination to yield compound 5, and then activated, e.g., by triflation to yield compound 6. Subsequent coupling (e.g., via a Suzuki coupling) to install an aryl group (R 3 ) may be followed by hydrolysis to yield the desired compound 8.
  • starting materials 9 or 10 may be subjected to an aminoalkylation reaction (e.g., Petasis or Mannich reaction) to form compound 11, and then activated, e.g., by triflation, to yield compound 12.
  • an aminoalkylation reaction e.g., Petasis or Mannich reaction
  • activated e.g., by triflation
  • Subsequent coupling e.g., via a Suzuki coupling
  • an aryl group (R ) may be followed by hydrolysis to yield the desired compound 13.
  • starting material 14 may be acylated (e.g., via a Friedel-Crafts reaction) to yield compound 15, which may then be activated (e.g., via triflation). Subsequent coupling (e.g., Suzuki coupling) and reduction yields compound 21.
  • starting material 19 may be activated, e.g., by triflation, to yield compound 19. Subsequent coupling (e.g., via a Suzuki coupling) and reduction (e.g., via a Grignard reaction) yields compound 21.
  • halogenation followed by displacement and hydrolysis provides the desired compound 24.
  • compound 21 may be subjected to a coupling reaction (e.g., Mitsunobu) followed by hydrolysis to yield the desired compound 27.
  • a coupling reaction e.g., Mitsunobu
  • compound 28 may be subjected to an alkylation reaction followed by hydrolysis to yield the desired compound 30.
  • compounds 31 and 35 may be prepared by coupling of 2-(3- (benzyloxy)phenyl)acetic acid with either the R-isomer of 4-benzyl-oxazolidin-one or the S-isomer of 4-benzyl-oxazolidin-one by Evans's procedures.
  • Compounds 32 and 36 may be prepared by alkylation of compounds 31 and 35 respectively with an appropriate alkyl bromide.
  • Compounds 33 and 37 may be prepared from compounds 32 and 36 by debenzylation, for example, through Pd-catalyzed hydrogenation in an alcohol solvent.
  • Compounds 34 and 38 may be obtained from the removal of chiral auxiliary groups from compounds 33 and 37, respectively, followed by esterification.
  • Compounds 34 and 38 may be further derivatized using methods A, B, C, D, E, F, G, and H described above, to provide desired compounds.
  • compound 39 may be prepared by reacting methyl 2-(3- hydroxyphenyl)acetate with an amine and an aldehyde through Mannich reaction. Subsequent triflation followed by Suzuki coupling reaction can give compound 41. After hydrolysis of the ester into acid 42, Evan's chiral auxiliaries may be installed using standard conditions to give compounds 43 or 44, which may be alkylated respectively with an appropriate alkyl bromide to give compounds 45 or 46. Compounds 47 or 48 may be obtained by removal of chiral auxiliary from compounds 45 or 46, respectively.
  • step 1 gives rise to a racemic mixture, and isomers of the newly generated chiral center (i.e., stereoisomers of compound 39) can be separated by chiral chromatography (see, e.g., Example 42) or chiral resolution through diastereomeric salt (see, e.g., CRC Handbook of Optical Resolutions via Diastereomeric Salt Formation, edited by David Kozma, CRC press 2002).
  • the desired stereoisomer 39 can then go through the chiral synthetic method of Scheme 8 above (using Evan's chiral auxiliaries) or Scheme 9 below (using Noyori catalysts in asymmetric hydrogenation) to give rise to compounds of formula (I) with two specific chiral centers.
  • compound 49 may be generated through Aldol condensation of compound 41 with an appropriate aldehyde. After hydrolysis of the ester into an acid 50, the double bond may be saturated by asymmetric hydrogenation using appropriated Noyori condition and catalysts to give compounds 51 or 52.
  • Exemplary compounds may be found in Table 1 in Figure 1 , and Table 2 in Figure 2. Additional exemplary compounds are described in the Examples. In Table 1, the synthetic method corresponds to those described in Schemes 1-7. The synthetic method corresponds to those described in Schemes 1-7.
  • the compounds described herein can be used for the modulation of gamma- secretase activity.
  • modulation of ⁇ -secretase activity refers to an effect on the processing of APP by the ⁇ -secretase complex. Preferably it refers to an effect in which the overall rate of processing of APP remains essentially as without the application of said compounds, but in which the relative quantities of the processed products are changed, more preferably in such a way that the amount of the A ⁇ 42 -peptide produced is reduced.
  • a different A ⁇ species can be produced (e.g. A ⁇ 38, A ⁇ 40 or other A ⁇ peptide species of shorter amino acid sequence instead of A ⁇ 42) or the relative quantities of the products are different (e.g. the ratio of A ⁇ 40 to A ⁇ 42 is changed, preferably increased).
  • Gamma secretase activity can be measured, for example by determining APP processing, e.g. by determining the levels of A ⁇ peptide species produced, most importantly levels of A ⁇ 42 (see Examples section).
  • the invention features a pharmaceutical composition
  • a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, tautomer, enantiomer, stereoisomer, analog or derivative thereof, including mixtures thereof in any ratios, and a pharmaceutically acceptable carrier.
  • the compounds of the formulae described herein can, for example, be administered by injection, intravenously, intraarterially, subdermally, intraperitoneally, intramuscularly, or subcutaneously; or orally, buccally, nasally, transmucosally, topically, in an ophthalmic preparation, or by inhalation, with a dosage ranging from about 0.5 to about 100 mg/kg of body weight, alternatively dosages between 1 mg and 1000 mg/dose, every 4 to 120 hours, or according to the requirements of the particular drug.
  • the methods herein contemplate administration of an effective amount of compound or compound composition to achieve the desired or stated effect.
  • the pharmaceutical compositions of this invention will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion.
  • Such administration can be used as a chronic or acute therapy.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • a typical preparation will contain from about 5% to about 95% active compound (w/w).
  • such preparations contain from about 20% to about 80% active compound.
  • pharmaceutically acceptable carrier or adjuvant refers to a carrier or adjuvant that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.
  • Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d- ⁇ -tocopherol polyethyleneglycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene
  • Cyclodextrins such as ⁇ -, ⁇ -, and ⁇ -cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl- ⁇ -cyclodextrins, or other solubilized derivatives may also be advantageously used to enhance delivery of compounds of the formulae described herein.
  • compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection.
  • the pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles.
  • the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form.
  • parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • compositions of this invention comprise a combination of a compound of the formulae described herein and one or more additional therapeutic or prophylactic agents
  • both the compound and the additional agent should be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen.
  • the additional agents may be administered separately, as part of a multiple dose regimen, from the compounds of this invention. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition.
  • the invention features a method of modulating gamma-secretase activity in a subject, the method comprising administering to the subject a compound or pharmaceutical composition described herein.
  • the invention features a method of treating a disorder associated with elevated A ⁇ levels in a subject, the method comprising administering to the subject a compound or pharmaceutical composition described herein.
  • the invention features a method of reducing the levels of A ⁇ in a subject, the method comprising administering to the subject a compound or pharmaceutical composition described herein.
  • the invention features a method of reducing the deposition of A ⁇ in a subject, the method comprising administering to the subject a compound or pharmaceutical composition described herein.
  • the invention features a method of treating a neurodegenerative disorder in a subject, the method comprising administering to the subject a compound or pharmaceutical composition described herein.
  • the invention features a method of treating Alzheimer's disease in a subject, the method comprising administering to the subject a compound or pharmaceutical composition described herein.
  • the invention features a method of treating a subject at risk for developing Alzheimer's disease, the method comprising administering to the subject a compound or pharmaceutical composition described herein.
  • the invention features a method of delaying the progression of Alzheimer's disease in a subject, the method comprising administering to the subject a compound or pharmaceutical composition described herein.
  • the invention features a method of delaying the onset of Alzheimer's disease in a subject, the method comprising administering to the subject a compound or pharmaceutical composition described herein. In one aspect, the invention features a method of improving cognitive function in a subject, the method comprising administering to the subject a compound or pharmaceutical composition described herein.
  • the compound or pharmaceutical composition described herein is administered in combination with an additional therapeutic agent.
  • the additional therapeutic agent is a cholinesterase inhibitor.
  • the additional therapeutic agent is selected from the group consisting of donepezil, rivastigmine, galantamine and tacrine.
  • the additional therapeutic agent is an N-methyl-D-aspartate (NMDA) receptor modulator.
  • the additional therapeutic agent is memantine.
  • the compounds described herein may be administered in a composition described herein, for example by a dosage form or route described herein.
  • a compound described herein such as a gamma secretase modulator (e.g., a compound that alter the cleavage pattern of gamma secretase) can be useful in the prevention and/or treatment of numerous diseases, including Alzheimer's disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis- Dutch type (HCHWA-D), multi-infarct dementia, dementia pugilistica and Down syndrome.
  • a gamma secretase modulator e.g., a compound that alter the cleavage pattern of gamma secretase
  • HHCHWA-D hereditary cerebral hemorrhage with amyloidosis- Dutch type
  • multi-infarct dementia dementia pugilistica and Down syndrome.
  • a compound or composition described herein can be used in the treatment of Alzheimer's disease (AD).
  • AD Alzheimer's disease
  • AD is the most prevalent form of dementia. It is a neurodegenerative disorder, clinically characterized by progressive loss of memory and general cognitive function, and pathologically characterized by the deposition of extracellular proteinaceous plaques in the cortical and associative brain regions of sufferers. These plaques mainly comprise fibrillar aggregates of ⁇ -amyloid peptide (A ⁇ ).
  • a ⁇ is formed from amyloid precursor protein (APP) via separate intracellular proteolytic events involving the enzymes ⁇ -secretase and ⁇ -secretase.
  • APP amyloid precursor protein
  • a ⁇ Variability in the site of the proteolysis mediated by ⁇ -secretase results in A ⁇ of varying chain length, e.g. A ⁇ 38, A ⁇ 40 and A ⁇ 42. After secretion into the extracellular medium, A ⁇ forms initially-soluble aggregates which are widely believed to be the key neurotoxic agents in AD, and which ultimately result in the insoluble deposits and dense neuritic plaques which are the pathological characteristics of AD.
  • a compound or composition described herein can be used in the treatment of cerebral amyloid angiopathy.
  • cerebral amyloid angiopathy is a form of angiopathy in which ⁇ -amyloid deposits form in the walls of the blood vessels of the central nervous system, ⁇ -amyloid deposition predisposes these blood vessels to failure, increasing the risk of a hemorrhagic stroke. Since this can be caused by the same amyloid protein that is associated with Alzheimer's dementia, such brain hemorrhages are more common in people who suffer from Alzheimer's, however they can also occur in those who have no history of dementia.
  • the hemorrhage within the brain is usually confined to a particular lobe and this is slightly different compared to brain hemorrhages which occur as a consequence of high blood pressure (hypertension) - a more common cause of a hemorrhagic stroke (or cerebral hemorrhage).
  • a compound or composition described herein can be used in the treatment of hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D).
  • HCHWA-D is a rare autosomal dominant disorder autosomal dominant form of cerebral amyloidosis. It is caused by an amyloid precursor protein 693 mutation that clinically leads to recurrent hemorrhagic strokes and dementia.
  • the disease is pathologically characterized by the deposition of A ⁇ in cerebral blood vessels and as plaques in the brain parenchyma.
  • a compound or composition described herein can be used in the treatment of multi-infarct dementia.
  • vascular dementia also known as vascular dementia, it is the second most common form of dementia after Alzheimer disease (AD) in older adults.
  • AD Alzheimer disease
  • the term refers to a group of syndromes caused by different mechanisms all resulting in vascular lesions in the brain.
  • the main subtypes of this disease described at the moment are: mild cognitive impairment, multi-infarct dementia, vascular dementia due to a strategic single infarct (affecting the thalamus, the anterior cerebral artery, the parietal lobes or the cingulate gyrus), vascular dementia due to hemorrhagic lesions, small vessel disease (which includes vascular dementia due to lacunar lesions and Binswanger's disease), and mixed Alzheimer's and vascular dementia.
  • vascular lesions can be the result of diffuse cerebrovascular disease or focal lesions (or a combination of both, which is what is observed in the majority of cases).
  • Mixed dementia is diagnosed when patients have evidence of AD and cerebrovascular disease, either clinically or based on neuroimaging evidence of ischemic lesions. In fact multi-infarct dementia and Alzheimer's disease often coexist, especially in older patients with dementia.
  • a compound or composition described herein can be used in the treatment of dementia pugilistica (DP).
  • DP also called chronic traumatic encephalopathy (CTE), chronic boxer's encephalopathy, traumatic boxer's encephalopathy, boxer's dementia, and punch-drunk syndrome
  • CTE chronic traumatic encephalopathy
  • traumatic boxer's encephalopathy traumatic boxer's encephalopathy
  • boxer's dementia boxer's dementia
  • punch-drunk syndrome DP is a neurological disorder which may affect career boxers, wrestlers, mixed martial artists, and football players who receive multiple dazing blows to the head.
  • Dementia pugilistica the severe form of chronic traumatic brain injury, commonly manifests as declining mental and physical abilities such as dementia and parkinsonism.
  • the encephalopathy develops over a period of years, with the average time of onset being about 12-16 years after the start of a career in boxing.
  • the condition is thought to affect around 15% of professional boxers, but it may affect other types of athletes.
  • the condition may be caused by repeat concussions, or repeat subconcussive blows (blows that are below the threshold of force necessary to cause concussion), or both.
  • Loss of neurons, scarring of brain tissue, collection of proteinaceous, senile plaques, hydrocephalus, attenuation of corpus callosum, diffuse axonal injury, neurofibrillary tangles and damage to the cerebellum are implicated in the syndrome.
  • the condition may be etiologically related to Alzheimer's disease.
  • a compound or composition described herein can be used in the treatment of Down syndrome.
  • Down syndrome is a chromosomal disorder caused by the presence of all or part of an extra 21st chromosome. The condition is characterized by a combination of major and minor differences in structure. Often Down syndrome is associated with some impairment of cognitive ability and physical growth as well as facial appearance. Individuals with Down syndrome tend to have a lower than average cognitive ability, often ranging from mild to moderate developmental disabilities. A small number have severe to profound mental disability. Many of the common physical features of Down syndrome also appear in people with a standard set of chromosomes.
  • They may include a single transverse palmar crease (a single instead of a double crease across one or both palms, also called the Simian crease), an almond shape to the eyes caused by an epicanthic fold of the eyelid, upslanting palpebral fissures (the separation between the upper and lower eyelids), shorter limbs, poor muscle tone, a larger than normal space between the big and second toes, and protruding tongue.
  • Health concerns for individuals with Down syndrome include a higher risk for congenital heart defects, gastroesophageal reflux disease, recurrent ear infections, obstructive sleep apnea, and thyroid dysfunctions.
  • Parkinson's disease is a degenerative disease of the brain (central nervous system) that often impairs motor skills, speech, and other functions. It is characterized by muscle rigidity, tremor, a slowing of physical movement (bradykinesia) and, in extreme cases, a loss of physical movement (akinesia).
  • the primary symptoms are the results of decreased stimulation of the motor cortex by the basal ganglia, normally caused by the insufficient formation and action of dopamine, which is produced in the dopaminergic neurons of the brain. Secondary symptoms may include high level cognitive dysfunction and subtle language problems.
  • PD is both chronic and progressive.
  • Dementia is common and affects approximately 40% of PD patients during the course of the disease.
  • the risk for the development of dementia in PD patients is approximately 6 times higher than compared to non-PD age matched controls.
  • the dementia associated with PD is characterized by dysexecutive syndrome affecting mainly executive and visuospatial functions while memory is relatively preserved.
  • a compound or composition described herein can be used in the treatment of memory loss associated with multiple sclerosis (MS).
  • MS also known as disseminated sclerosis or encephalomyelitis disseminate,is an autoimmune condition in which the immune system attacks the central nervous system, leading to demyelination.
  • MS affects the ability of nerve cells in the brain and spinal cord to communicate with each other. Nerve cells communicate by sending electrical signals called action potentials down long fibers called axons, which are wrapped in an insulating substance called myelin.
  • myelin insulating substance
  • multiple sclerosis refers to scars (scleroses - better known as plaques or lesions) in the white matter of the brain and spinal cord, which is mainly composed of myelin.
  • MS takes several forms, with new symptoms occurring either in discrete attacks (relapsing forms) or slowly accumulating over time (progressive forms). Between attacks, symptoms may go away completely, but permanent neurological problems often occur, especially as the disease advances. Almost any neurological symptom can appear with the disease, and often progresses to physical and cognitive disability.
  • the subject is being treated with an additional therapeutic agent.
  • additional agents include beta secretase inhibitors; muscarinic antagonists (e.g., m-i agonists or ITi2 antagonists); cholinesterase inhibitors (e.g., acetyl- and/or butyrylchlolinesterase inhibitors) (e.g., Donepezil, Tacrine, Galantamine, Rivastigmine); gamma secretase inhibitors; gamma secretase modulators; HMG-CoA reductase inhibitors; non-steroidal anti-inflammatory agents; N-methyl-D-aspartate receptor antagonists (e.g.
  • Memantine anti-amyloid antibodies
  • vitamin E nicotinic acetylcholine receptor agonists; CBl receptor inverse agonists or CB 1 receptor antagonists
  • antibiotics growth hormone secretagogues; histamine H3 antagonists; AMPA agonists; PDE4 inhibitors; GABAA inverse agonists; inhibitors of amyloid aggregation; glycogen synthase kinase beta inhibitors; promoters of alpha secretase activity; PDE-IO inhibitors; Tau kinase inhibitors (e.g., GSK3beta inhibitors, cdk5 inhibitors, or ERK inhibitors); anti-A ⁇ vaccine; APP ligands; agents that upregulate insulin cholesterol lowering agents (for example, statins such as Atorvastatin, Fluvastatin, Lovastatin, Mevastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin); cholesterol absorption inhibitors (such as E
  • the compounds and pharmaceutical compositions of this invention will be administered from about 1 to about 6 times per day, for example, once daily.
  • a compound or composition described herein may be administered at a dosage ranging from about 0.1 g/dose to about 10 g/dose, for example, from about 0.25 g/ dose to about 5 g/dose, or in a preferred embodiment, from about 0.6 g/dose to about 1.1 g/dose.
  • Such administration can be used as a chronic or acute therapy.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • a typical preparation will contain from about 5% to about 95% active compound (w/w). Alternatively, such preparations contain from about 20% to about 80% active compound.
  • treatment with a compound or composition described herein improves one or more clinical outcomes.
  • treatment with a compound or composition described herein may improve cognitive function. Elements of cognitive function include memory, orientation, attention, reasoning, language and praxis.
  • treatment with a compound or composition described herein may delay the progression of Alzheimer's disease, or reduce the rate of cognitive decline.
  • treatment with a compound or composition described herein may reduce the level of A ⁇ peptide(s) produced or reduce the deposition of A ⁇ peptide(s) in a subject.
  • clinical outcomes may be assessed using known methods.
  • One such method is the cognitive subscale of Alzheimer's Disease Assessment Scale (ADAS-cog), which examines selected aspects of cognitive performance including elements of memory, orientation, attention, reasoning, language and praxis.
  • ADAS-cog Alzheimer's Disease Assessment Scale
  • clinical outcomes may be assessed using the Clinician's Interview Based Impression of Change requiring the use of caregiver information (CIBIC plus).
  • CIBIC plus evaluates four major areas of patient function: General, Cognitive, Behavioral and Activities of Daily Living. It represents the assessment of a skilled clinician based upon his/her observations at an interview with the patient, in combination with information supplied by a caregiver familiar with the behavior of the patient over the interval rated.
  • clinical outcomes may be assessed using the Alzheimer's Disease Cooperative Study - Activities of Daily Living inventory (ADCS-ADL).
  • ADCS-ADL Alzheimer's Disease Cooperative Study - Activities of Daily Living inventory
  • This evaluation involves a comprehensive battery of ADL questions used to measure functional capabilities of patients, as determined via interview with a caregiver familiar with the behavior of the patient.
  • a modified version, ADCS-AD Lsev may be used for assessment of patients with moderate to severe dementia.
  • ADCS- ADLsev involves assessment of a subset of 19 items, including ratings of the patients' ability to eat, dress, bathe, telephone, travel, shop, and perform other household chores.
  • clinical outcomes may be assessed using the Severe Impairment Battery (SIB), a multi-item instrument that has been validated for the evaluation of patients with moderate to severe dementia. It evaluates the following domains: social interaction, orientation, attention, language, memory, praxis, constructional abilities and visuo spatial functions.
  • SIB Severe Impairment Battery
  • Chinese Hamster Ovary (CHO) cells expressing the APP V717F mutation were grown in ⁇ -MEM media containing 10% FBS, 2 mM L-Glutamine, and 1% pen/strep until nearly confluent. Cells were added to 96-well flat-bottom plates to a density of 25,000 cells per well in 80 ⁇ L of media and the plates were then incubated at 37°C in a 5% CO 2 atmosphere for 4 hours prior to challenging with compound. Immediately prior to adding diluted compound solution to the cells, the media was replaced with 80 ⁇ L of serum- free media ( ⁇ -MEM, 2mM L-Glutamine, 1% pen/strep supplemented with 2% B27).
  • 10 mM DMSO stock solutions of test compounds were further diluted with DMSO to yield nine, 3-fold serial dilutions. 5 ⁇ l of these diluted solutions were further diluted into 828 ⁇ L of serum- free media. 80 ⁇ L of these resulting dilutions with serum- free media were added to the previously plated cells containing 80 ⁇ L of serum- free media. The final concentration of DMSO on the cells was 0.3%.
  • the plates were incubated for 17 hours at 37°C in a 5% CO 2 atmosphere. Following incubation, conditioned media from the compound-challenged cells was transferred to new 96-well plates and centrifuged at 1,000 RPM at 4°C for 10 minutes.
  • a CellTiter-Blue Viability Assay (Promega) was used to determine the metabolic capacity of cells by their ability to reduce the indicator dye resazurin into resorufin.
  • 50 ⁇ L of CellTiter-Blue Reagent diluted 5-fold in FBS- containing media was added to compound-challenged cells after the removal of media, as described above. Cells were incubated with the reagent for 1 hour at 37° in a 5% CO 2 atmosphere and the fluorescence was recorded (560 Ex /590 Em ). Results are reported in Table 1.
  • mice and mouse models were utilized. Male CF-I mice or F344 rats from Charles River laboratories, over the age of 11 weeks, were used for testing compounds. Animals were dosed (10.0 ml/kg in mice and 5.0 ml/kg in rats) by oral gavage with experimental compounds in a vehicle consisting of ETOH (10%), propolenye glycol (10%) and a solution of water and solutol (20/80; v/v). A single oral dose (30 or 50 mg/kg) was given four hours before euthanasia.
  • mice were anesthetized with ketamine/xylazine (100/10 mg/kg, ip) at a volume of 10.0 ml/kg in mice and 1.0 ml/kg in rats.
  • Blood was collected via cardiac puncture into a sterile syringe and transferred to EDTA treated collection tubes. The blood was mixed and then kept at 4 degrees Celsius until spun in a centrifuge (10 minutes at 10,000 rpm); serum was collected and kept on ice until frozen at -80 degrees.
  • the brain was removed from the cranium and the hindbrain and forebrain were separated. The forebrain was divided evenly into left and right hemispheres by cutting along the sagital midline. Both sides were weighed and then quickly frozen on dry ice for analysis.
  • the resulting supernatant was further processed with a Waters 60 mg HLB Oasis column.
  • the column was treated with methanol and water prior to loading 0.8 mL of the supernatant.
  • the column was washed with 5% methanol and then 30% methanol prior to A ⁇ elution with 0.8 mL of an aqueous solution of 90% methanol and 2% ammonium hydroxide.
  • the eluate was collected and evaporated in a vacuum dryer.
  • the A ⁇ levels were quantified using a MesoScale Discovery ELISA kit which was able to measure A ⁇ 38, 40, and 42 simultaneously.
  • the residue of the dried elution buffer was resuspended in 0.4 mL of the blocking buffer provided in the MesoScale Discovery kit. 25 ⁇ L of this reconstituted mixture was added to the ELISA plate and the manufacturer's instructions were followed for analysis. Standard curves in the analysis were derived from A ⁇ 38, 40, and 42 peptides supplied in the kit.
  • Triethylamine (757 mL, 5.43 mol) was added to a solution of methyl 2-(3- hydroxyphenyl) acetate in acetonitrile (10L) over 10 minutes.
  • Magnesium chloride (516 g, 5.43 mol) was added over 15 minutes.
  • the temperature of the reaction increased to -40 0 C during this addition.
  • the reaction mixture was stirred for 1.5 h, during which time it went to a nearly homogeneous brown solution.
  • the reaction was heated to reflux and paraformaldehyde (326g, 10.9 mol) was added quickly.
  • the reaction was heated at reflux for an additional 4h, and was allowed to cool to room temperature and stir overnight.
  • Methyl 2-(3-(benzyloxy)phenyl)acetate (10 g, 39 mmol, 1.0 equiv.) was dissolved in dry THF (150 ml), and the solution was cooled to -78 0 C, then LiHMDS (40 ml, 39 mmol, 1.0 equiv.) was added dropwise to the solution, allowed to stirred for about 1 h. Then CH 3 I (2 ml, 39 mmol, 1.0 equiv.) was added in dropwise at -78 0 C. The mixture was stirred at -78 0 C for 1 h and then warmed to rt for 16 h.
  • Methyl 2-(3-hydroxyphenyl)propanoate (10.8 g, 60 mmol, 1.0 equiv.), MgCl 2 (8.55 g, 90 mmol, 1.5 equiv.), Et 3 N (1.11 g, 240 mmol, 4 equiv.) and paraformaldehyde (13 g, 420 mmol, 7 equiv.) were dissolved in THF (150 ml). The mixture was heated to 75 0 C for 4 h and then cooled to rt and quenched with HCl diluted solution. The mixture was extracted with EtOAc. The organic layer was dried over Na 2 SC ⁇ and concentrated in vacuum.
  • Methyl 2-(3-hydroxyphenyl)butanoate (11.6 g, 60 mmol, 1.0 equiv.), MgCl 2 (8.55 g, 90 mmol, 1.5 equiv.), Et 3 N (1.11 g, 240 mmol, 4 equiv.) and paraformaldehyde (13 g, 420 mmol, 7 equiv.) were dissolved in THF (150 ml). The mixture was heated to 80 0 C for 4 h and then cooled to rt and quenched with HCl diluted solution. The mixture was extracted with EtOAc. The organic layer was dried over Na 2 SC ⁇ and concentrated in vacuo.
  • Methyl 2-(3-(benzyloxy)phenyl)-3-cyclopropylpropanoate (3.5 g, 11.0 mmol, 1.0 eq) was dissolved in THF (20 mL). Pd/C (0.35 g, 0.1 eq) was added under N 2 atmosphere. The mixture was purged with H 2 for three times and stirred at rt for 16 h.
  • the vial was heated using microwave irradiation at 120 0 C for 5 min.
  • the reaction mixture was partitioned between ethyl acetate and brine.
  • the organic phase was dried over MgSO4, filtered and concentrated.
  • the residue was purified by flash chromatography on silica (EtOAc in hexane 5-10%) to collect methyl 2-(6-((benzyl((lr,4r)-4-tert- butylcyclohexyl)amino)methyl)-4'-fluorobiphenyl-3-yl)acetate as a colorless oil (22 mg, 100%). It was used as such for next step without taking NMR.
  • the reaction mixture was heated using microwave irradiation at 11O 0 C for 15 minutes. It was diluted with water, extracted with EtOAc. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica (5-10% EtOAc in hexane) to get the ester as a colorless oil (23 mg).
  • the above ester in THF (0.5 mL)/MeOH (0.5 mL) was treated with 3M NaOH in water (70 ⁇ L) using microwave irradiation at HO 0 C for 15 minutes. Added IM HCl (210 ⁇ L) and diluted with water, extracted with EtOAc.
  • Step 6 2-(6-(l-(4,4-Difluoropiperidin-l-yl)-4-methylpentyl)-4'-(trifluoromethyl)biphenyl-3- yl)acetic acid
  • Methyl 2-(6-formyl-4'-(trifluoromethyl)biphenyl-3-yl)acetate (900 mg, 2.79 mmol, 1.0 equiv) was dissolved in diethyl ether (10 mL) and cooled to between -30 to - 40 0 C.
  • a 0.5 M solution of methylcyclohexylmagnesium bromide in diethyl ether (14 mL, 6.97 mmol, 2.5 equiv) was added dropwise maintaining the temperature between -30 to - 40 0 C over 30 minutes. The reaction was then quenched with saturated ammonium chloride solution (25 mL).
  • the reaction mixture was purified by flash chromatography on silica (5-10% EtOAc in hexane) to get the ester as a colorless oil (9 mg, 17%).
  • the above ester in MeOH (500 ⁇ L) and THF (500 ⁇ L) was treated with IN NaOH (200 ⁇ L) at room temperature for 2 h.
  • Neutralized with IN HCl (200 ⁇ L) was diluted with water, extracted with EtOAc.
  • the organic phase was dried, filtered and concentrated to get 2-(6- (4-methyl-l-(4-(trifiuoromethyl)phenoxy)pentyl)-4'-(trifiuoromethyl)biphenyl-3-yl)acetic acid as colorless oil (3 mg, 6%).
  • Titanium tetrachloride (1.2 ml, 0.0109 mol) was added to (3-hydroxyphenyl) acetic acid methyl ester (1.662g, 0.001 mol). The resulting thick solution was stirred at room temperature for 15 minutes, then brought to 12O 0 C and let to stir at this temperature for an additional hour. After cooling to room temperature, 40 ml of dichloromethane was added followed by 40 ml of water. The aqueous layer was separated and extracted with dichloromethane (40 ml). The combined organic layer was washed with 1 N hydrochloric acid (100 ml) and brine (40 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated under high vacuum.
  • Methyl-2-(6-(l-aminoethyl)-4'-(trifluoromethyl)biphenyl-3-yl)acetate (0.052 g, 0.000153 mol) was added to a solution of 4-tertbutylcyclohexanone (0.029 g, 0.000184 mol) in methanol (0.5 ml). The mixture was stirred at room temperature for 45 minutes, cooled to -78 0 C, and treated with 2 M solution of lithium borohydride(0.092 ml, 0.00184) in tetrahydroborane. After Ih, the reaction mixture was brought up to room temperature and stirred for 16 h.

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Abstract

Compounds that modulate gamma secretase (e.g., alter the cleavage pattern of gamma secretase) are described herein. Also disclosed are pharmaceutical compositions, methods of modulating the activity of gamma secretase, and methods of treating Alzheimer's Disease using the compounds described herein.

Description

CARBOXYLIC ACID-CONTAINING COMPOUNDS, DERIVATIVES THEREOF, AND RELATED METHODS OF USE
CLAIM OF PRIORITY
This application claims priority from U.S. S.N. 61/182,448, filed May 29, 2009 and U.S.S.N. 61/302,796, filed February 9, 2010, each of which is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
The present invention relates to carboxylic acid-containing compounds and their use as pharmacologically active agents capable of modulating or inhibiting gamma secretase, a key enzyme in the formation of neurotoxic agents that result in dementia, Alzheimer's and related diseases.
BACKGROUND OF INVENTION
Alzheimer's disease (AD) is the most prevalent form of dementia. It is a neurodegenerative disorder, clinically characterized by progressive loss of memory and general cognitive function, and pathologically characterized by the deposition of extracellular proteinaceous plaques in the cortical and associative brain regions of sufferers. These plaques mainly comprise fibrillar aggregates of β-amyloid peptide (Aβ). Aβ is formed from amyloid precursor protein (APP) via separate intracellular proteolytic events involving the enzymes β-secretase and γ-secretase. Variability in the site of the proteolysis mediated by γ-secretase results in Aβ of varying chain length, e.g. Aβ38, Aβ40 and Aβ42. After secretion into the extracellular medium, Aβ forms initially- soluble aggregates which are widely believed to be the key neurotoxic agents in AD, and which ultimately result in the insoluble deposits and dense neuritic plaques which are the pathological characteristics of AD. Other dementing conditions associated with deposition of Aβ in the brain include cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), multi-infarct dementia, dementia pugilistica and Down syndrome.
Various interventions in the plaque-forming process have been proposed as therapeutic treatments for AD. One such method of treatment that has been proposed is that of blocking or attenuating the production of Aβ, for example by inhibition of β- or γ- secretase.
SUMMARY OF INVENTION
Described herein are compounds and compositions, which can be used, for example to modulate gamma secretase (e.g., alter the cleavage pattern of gamma secretase). Such compounds may be useful in the treatment and prevention of diseases such as Alzheimer's disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), multi-infarct dementia, dementia pugilistica and Down syndrome.
In one aspect, the present invention provides a compound having a general structure according to formula I:
Figure imgf000003_0001
wherein: m is 1, 2, 3 or 4; n is 0, 1 or ? •
W is -COOH , or a carboxylic acid mimic or bioisostere;
6
Z is N, NR CR17 Or CR18R19; each R1 and R2 is independently H, Ci-C6 alkyl, C2-C6 alkenyl, halo, haloalkyl, Ci-C6 alkoxy, cyclyl, cyclylalkyl, halocyclyl or halocyclylalkyl; or R1 and R2, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring; wherein either R or R are optionally taken together with R a or R a to form an optionally substituted, saturated or unsaturated 3-7 membered ring;
A is a bond, NR10, O, S, alkylenyl, amide, ester, carbamate, urea, thiourea or sulfonylurea;
B is N or O;
R is aryl, heteroaryl, cyclyl or heterocyclyl, each of which is optionally substituted with 1-3 R11; each R4 and R5 is independently H, Ci-Cs alkyl, haloalkyl, cyclyl, cyclylalkyl, aryl or heteroaryl, each of which is optionally substituted with 1-3 R12; or R4 and R5, together with the carbon to which they are attached, may form a 3-7 membered ring that is optionally saturated or unsaturated, and unsubstituted or substituted;
R6 and R7 are each independently H, Ci-Cs alkyl, cyclyl, aryl, heteroaryl, cyclylalkyl or arylalkyl, each of which is optionally substituted with 1 -3 R ; wherein when B is O, R7 is absent; wherein when B is N, R6 and R7, together with the nitrogen to which they are attached, may form a 3-7 membered ring that is optionally saturated or unsaturated, and unsubstituted or substituted with 1-3 R14; and wherein R4 and R6, together with the atoms to which they are attached, may form a 3-7 membered ring ring that is optionally saturated or unsaturated, and unsubstituted or substituted with 1 -3 R ;
R8a, R8b, R9a and R9b are each independently H, Ci-C6 alkyl, hydroxy, halo, haloalkyl, or CN;
R10 is hydrogen, Ci-C6 alkyl or haloalkyl; each R11, R12, R13, R14 and R15 is independently Ci-C6 alkyl, Ci-C6 alkenyl, Ci-C6 alkynyl, halo, haloalkyl, alkoxy, haloalkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, arylalkyl, hetero arylalkyl, cyclylalkyl, heterocyclylalkyl, carboxylate, cyano, oxo, nitro, amino, alkylamino, dialkylamino, mercapto, thioalkyl, aryloxy, thioalkoxy, amido, SO3H, sulfate, S(O)NH2, S(O)2NH2, phosphate, or acyl, each of which is optionally substituted; wherein two R11, R12, R13, R14 or R15, together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring; and each R16, R17, R18, and R19 is independently H, Ci-C6 alkyl, hydroxy, halo, haloalkyl or CN; each R20 is independently Ci-Cs alkyl; each independently represents the presence or absence of a bond; wherein when represents the presence of a bond to the carbon to which R is attached, R is absent; and wherein when represents the presence of a bond to the carbon to which
R9b is attached, R9b is absent; and wherein when represents the presence of a bond to
Z, then Z is N or CR17; or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, tautomer, enantiomer, stereoisomer, analog or derivative thereof, including mixtures thereof in any ratios.
In some embodiments, m is 1.
In some embodiments, W is -COOH. In another embodiment, W is a carboxylic acid mimic or bioisostere, for example, -C(O)NHS(O)2CH3.
In some embodiments, Z is CR 7. In some embodiments, R 7 is H;
In some embodiments, n is O.
In some embodiments, n is 1.
In some embodiments, each R and R is independently H, Ci-C6 alkyl, C2-C6 alkenyl, haloalkyl, Ci-C6 alkoxy, cyclyl, cyclylalkyl, halocyclyl or halocyclylalkyl; or R and R2, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring. In some embodiments, each R1 and R2 is independently H, Ci-C6 alkyl, haloalkyl or Ci-C6 alkoxy; or R1 and R2, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring. In some embodiments, each R1 and R2 is independently H, Ci-C6 alkyl or haloalkyl; or R1 and R2, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring. In some embodiments, each R1 and R2 is independently H or Ci-C6 alkyl; or R1 and R2, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
In some embodiments, R1 and R2 are both H. In some embodiments, R1 and R2 are both Ci-C6 alkyl (e.g., methyl or ethyl). In some embodiments, one of R1 and R2 is methyl and the other is sec-butyl. In some embodiments, one of R1 and R2 is hydrogen and the other is Ci-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, sec-butyl or neopentyl). In some embodiments, one of R1 and R2 is hydrogen and the other is methyl. In some embodiments, one of R1 and R2 is hydrogen and the other is ethyl. In some embodiments, one of R1 and R2 is hydrogen and the other is cyclylalkyl (e.g., cyclopropylmethyl) .
In some embodiments, R1 and R2, together with the carbon to which they are attached, form a ring (e.g., a cyclopentyl, cyclobutyl, or cyclopropyl ring).
In some embodiments, R8a is taken with one of R1 and R2, together with the carbons to which they are attached, to form a ring (e.g., a 5-membered ring or a 6- membered ring).
In some embodiments, A is a bond. In another embodiment, A is O. In yet another embodiment, A is NR10. In some embodiments, R10 is hydrogen.
In some embodiments, R3 is aryl, heteroaryl, each of which is optionally substituted with 1-3 R11. In some embodiments, R3 is aryl optionally substituted with 1-3 R11. In some embodiments, R3 is heteroaryl optionally substituted with 1-3 R11.
In some embodiments, each R11 is independently Ci-C6 alkyl, Ci-C6 alkenyl, halo, haloalkyl, haloalkoxy, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R11 is independently Ci-C6 alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, amino or alkylamino, each of which is optionally substituted; or wherein two R11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R is independently Ci-C6 alkyl, halo, haloalkyl, haloalkoxy or alkoxy; or wherein two R11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R11 is independently Ci-C6 alkyl, halo, haloalkyl or haloalkoxy.
In some embodiments, R is aryl, e.g., phenyl. In some embodiments, R is unsubstituted phenyl.
In some embodiments, R3 is phenyl substituted with one R11. In some embodiments, R3 is substituted at the ortho position. In some embodiments, R3 is substituted at the meta position. In some embodiments, R3 is substituted at the para position. In some embodiments, R11 is halo (e.g., fluoro or chloro). In some embodiments, R11 is haloalkyl (e.g., trifluoro methyl). In some embodiments, R11 is haloalkoxy (e.g., trifluoromethoxy). In some embodiments, R11 is Ci-C6 alkyl, e.g., C3 alkyl (e.g., isopropyl) or C4 alkyl (e.g., tert-butyl).
In some embodiments, R is phenyl substituted with 2 R . In some embodiments, both R11 are Ci-C6 alkyl (e.g., methyl). In some embodiments, both R11 are halo (e.g., fluoro). In some embodiments, one R11 is halo (e.g., fluoro) and the other is haloalkyl (e.g., trifluoromethyl).
In some embodiments, R is phenyl substituted with 3 R . In some embodiments, all three R11 are halo (e.g., fluoro).
In some embodiments, R3 is pyridyl. In some embodiments, R3 is unsubstituted pyridyl. In some embodiments, R3 is pyridyl substituted with 1 R11. In some embodiments, R11 is haloalkyl (e.g., trifluoromethyl). In some embodiments, R3 is pyrimidyl. In some embodiments, R3 is unsubstituted pyrimidyl. In some embodiments, R3 is pyrimidyl substituted with 1 R11. In some embodiments, R11 is Ci-C6 alkyl, e.g., C4 alkyl (e.g., tert-butyl).
In some embodiments, each R4 and R5 is independently H, Ci-Cs alkyl, haloalkyl, hydroxy, cyclyl, cyclylalkyl, aryl or heteroaryl, each of which is optionally substituted with 1-3 R12. In some embodiments, R4 and R5 is independently H, Ci-Cs alkyl, haloalkyl, cyclylalkyl, cyclyl, aryl or heteroaryl.
In some embodiments, each R12 is independently Ci-C6 alkyl, Ci-C6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R12 is independently Ci-C6 alkyl, halo, haloalkyl or alkoxy, each of which is optionally substituted; or wherein two R12 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R12 is independently Ci-C6 alkyl, halo or haloalkyl, each of which is optionally substituted.
In some embodiments, R4 is hydrogen or C1-8 alkyl.
In some embodiments, R5 is aryl (e.g., phenyl). In some embodiments, R5 is unsubstituted phenyl.
In some embodiments, R5 is phenyl substituted with one R12. In some embodiments, R5 is substituted at the ortho position. In some embodiments, R5 is substituted at the meta position. In some embodiments, R5 is substituted at the para position.
In some embodiments, R12 is halo (e.g., fluoro or chloro). In some embodiments, R12 is haloalkyl (e.g., trifluoromethyl). In some embodiments, R12 is Ci-C6 alkyl, e.g., C3 alkyl (e.g., isopropyl), or C4 alkyl (e.g., tert-butyl). In some embodiments, R12 is -CN. In some embodiments, R5 is phenyl substituted with 2 R . In some embodiments, both R12 are halo (e.g., fluoro).
In some embodiments, R5 is heteroaryl.
In some embodiments, R5 is pyridyl. In some embodiments, R5 is unsubstituted pyridyl.
In some embodiments, R5 is pyridyl substituted with 1 R12. In some embodiments, R12 is halo (e.g., fluoro). In some embodiments, R12 is haloalkyl (e.g., trifluoromethyl).
In some embodiments, R5 is imidazolyl.
In some embodiments, R5 is imidazolyl substituted with one R12. In some embodiments, R12 is haloalkyl (e.g., trifluoromethyl).
In some embodiments, R5 is thiazolyl.
In some embodiments, R5 is pyrazolyl. In some embodiments, R5 is pyrazolyl substituted with 1-3 R12. In some embodiments, R5 is pyrazolyl substituted with three R12. In some embodiments, one R12 is Ci-C6 alkyl (e.g., methyl), one is halo (e.g., fluoro) and one is haloalkyl (trifluoromethyl). In another embodiment, three R12 are each independently Ci-C6 alkyl (e.g., two are methyl and one is t-butyl).
In some embodiments, R5 is:
Figure imgf000009_0001
In some embodiments, R5 is pyrimidyl. In some embodiments, R5 is unsubstituted pyrimidyl. In some embodiments, R5 is pyrimidyl substituted with 1 R12. In some embodiments, R12 is Ci-C6 alkyl, e.g., C4 alkyl (e.g., tert-butyl).
In some embodiments, R5 is indolyl.
In some embodiments, R5 is indazolyl. In some embodiments, R5 is indazolyl substituted with 1 R12. In some embodiments, R12 is Ci-C6 alkyl (e.g., methyl).
In some embodiments, R5 is hydrogen. In some embodiments, R5 is Ci-Cs alkyl. In some embodiments, R5 is methyl. In some embodiments, R5 is C5 alkyl, e.g., isopentyl (3-methylbutyl) or neopentyl (2,2- dimethylpropyl). In some embodiments, R5 is C6 alkyl, e.g., neohexyl (3,3- dimethylbutyl).
In some embodiments, R5 is cyclyl, e.g., cycloalkyl (e.g., cyclohexyl). In some embodiments, R5 is bicyclo[2.2.2]octanyl.
In some embodiments, R5 is cyclylalkyl, e.g., cyclohexylmethyl.
In some embodiments, R5 is haloalkyl (e.g., 2,2,2-trifluoroethoxy, 3,3,3- trifluoropropyl or 4,4,4-trifluorobutyl).
In some embodiments, R6 and R7 are each independently H, Ci-Cs alkyl, cyclyl, aryl, heteroaryl, cyclylalkyl or arylalkyl, each of which is optionally substituted with 1-3 R13; wherein when B is O, R7 is absent; wherein when B is N, R6 and R7, together with the nitrogen to which they are attached, may form a 3-7 membered ring that is optionally saturated or unsaturated, and unsubstituted or substituted with 1-3 R14; and wherein R4 and R6, together with the atoms to which they are attached, may form a 3-7 membered ring ring that is optionally saturated or unsaturated, and unsubstituted or substituted with 1-3 R15.
In some embodiments, each R13, R14 and R15 is independently Ci-C6 alkyl, Ci-C6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two, R13, R14 and R15 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R13, R14 and R15 is independently Ci-C6 alkyl, halo, haloalkyl, alkoxy, hydroxy, cyano, amino or alkylamino, each of which is optionally substituted; or wherein two , R13, R14 and R15 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R13, R14 and R15 is independently Ci-C6 alkyl, halo, haloalkyl or hydroxy, each of which is optionally substituted; or wherein two , R13, R14 and R15 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
In some embodiments, B is O and R7 is absent.
In some embodiments, R is aryl, e.g., phenyl. In some embodiments, R is phenyl substituted with one R . In some embodiments, R is substituted at the ortho position. In some embodiments, R is substituted at the meta position. In some embodiments, R is substituted at the para position. In some embodiments, R is haloalkyl (e.g., trifiuoromethyl).
In some embodiments, B is N.
In some embodiments, R and R , together with the nitrogen to which they are attached, form a ring, e.g., a 4-membered ring (e.g., an azetidine ring).
In some embodiments, R6 and R7, together with the nitrogen to which they are attached, form a 5-membered ring, e.g., a pyrrolidine ring. In some embodiments, R6 and R7, together with the nitrogen to which they are attached, form a pyrrolidine ring that is substituted with one R14. In some embodiments, R14 is halo (e.g., fluoro). In some embodiments, R14 is Ci-C6 alkyl (e.g., sec-butyl).
In some embodiments, R and R7, together with the nitrogen to which they are attached, form a pyrrolidine ring that is substituted with two R . In some embodiments, both R are Ci-C6 alkyl (e.g., methyl). In some embodiments, both R are halo (e.g., fluoro). In some embodiments, two R , together with the atoms to which they are attached, form a ring, e.g., a 3-membered ring, a 5-membered ring or a 6-membered ring (e.g., a phenyl ring).
In some embodiments, R and R , together with the nitrogen to which they are attached, form a 6-membered ring, e.g., a piperidine ring. In some embodiments, R and R7, together with the nitrogen to which they are attached, form a piperidine ring that is unsubstituted.
In some embodiments, R6 and R7, together with the nitrogen to which they are attached, form a piperidine ring that is substituted with one R14. In some embodiments, R14 is halo (e.g., fluoro). In some embodiments, R14 is Ci-C6 alkyl, e.g., methyl. In some embodiments, R14 is C3 alkyl (e.g., n-propyl). In some embodiments, R14 is C4 alkyl (e.g., tert-butyl or isobutyl). In some embodiments, R14 is haloalkyl (e.g., trifluoromethyl). In some embodiments, R is alkoxy (e.g., methoxy or ethoxy). In some embodiments, R is aryl (e.g., phenyl). In some embodiments, R is cyano. In some embodiments, R is a carboxylate. In some embodiments, R is -SO2CH3.
In some embodiments, R and R7, together with the nitrogen to which they are attached, form a piperidine ring that is substituted with two R . In some embodiments, both R14 are halo (e.g., fluoro). In some embodiments, both R14 are Ci-C6 alkyl (e.g., methyl). In some embodiments, two R , together with the carbons to which they are attached, form a ring, e.g., a 3-membered ring or a 6-membered ring.
In some embodiments, R6 and R7, together with the nitrogen to which they are attached, form a piperazine ring. In some embodiments, R6 and R7, together with the nitrogen to which they are attached, form a piperazine ring that is unsubstituted. In some embodiments, R6 and R7, together with the nitrogen to which they are attached, form a piperazine ring that is substituted with one R14. In some embodiments, R14 is Ci-C6 alkyl (e.g., methyl).
In some embodiments, R and R7, together with the nitrogen to which they are attached, form a thiomorpholino.
In some embodiments, R and R7, together with the nitrogen to which they are attached, form a 7-membered ring.
In some embodiments, R and R , together with the nitrogen to which they are attached, form a bridged bicyclic ring (e.g., a 3-azabicyclo[3.2.1]octan-3-yl ring). In some embodiments, R and R , together with the nitrogen to which they are attached, form a fused bicyclic ring (e.g., 3-azabicyclo[3.1.0]hexan-3-yl). In some embodiments, R6 and R7, together with the nitrogen to which they are attached, form a spirocyclic ring system (e.g., 6-azaspiro[2.5]octan-6-yl). In some embodiments, both R6 and R7 are Ci-Cs alkyl. In some embodiments, one of R6 and R7 is methyl and the other is n-heptyl.
In some embodiments, both R6 and R7 are cyclyl. In some embodiments, one of R6 and R7 is cyclopropyl and the other is cyclohexyl.
In some embodiments, R6 is Ci-Cs alkyl (e.g., C5 alkyl) and R7 is aryl (e.g., phenyl). In some embodiments, R6 is isopentyl (3-methylbutyl) and R7 is phenyl substituted with 1 R13. In some embodiments, R13 is Ci-C6 alkyl, e.g., C4 alkyl (e.g., tert- butyl). In some embodiments, R13 is haloalkyl (e.g., trifluoromethyl).
In some embodiments, R6 is Ci-Cs alkyl and R7 is cyclyl.
In some embodiments, R6 is methyl. In some embodiments, R6 is C4 alkyl (e.g., n-butyl or sec-butyl). In some embodiments, R6 is C5 alkyl (e.g., 2,2-dimethylpropyl, 3- methylbutyl or 2-methylbutyl). In some embodiments, R6 is C6 alkyl (e.g., 3,3- dimethylbutyl).
In some embodiments, R7 is cyclyl, e.g., cycloalkyl (e.g., cyclohexyl). In some embodiments, R7 is cyclohexyl substituted with 1 R13. In some embodiments, R13 is C1- C6 alkyl (e.g., methyl). In some embodiments, R13 is C3 alkyl (e.g., isopropyl). In some embodiments, R13 is C4 alkyl (e.g., tert-butyl). In some embodiments, R13 is haloalkyl (e.g., trifluoromethyl). In some embodiments, R13 is halo (e.g., fluoro). In some embodiments, R13 is -CN.
In some embodiments, R7 is cyclohexyl substituted with 2 R13. In some embodiments, both R13 are halo (e.g., fluoro). In some embodiments, both R13 are Ci-C6 alkyl (e.g., methyl). In some embodiments, R7 is a bicyclic group, e.g., bicyclo[2.2.2]octane. In some embodiments, R7 is bicyclo[2.2.2]octane substituted with I R13.
In some embodiments, R6 is arylalkyl (e.g., benzyl) and R7 is cyclyl, e.g., cycloalkyl (e.g., cyclohexyl). In some embodiments, R7 is cyclohexyl substituted with 1 R13. In some embodiments, R13 is Ci-C6 alkyl, e.g., C4 alkyl (e.g., tert-butyl). In some embodiments, R6 is cyclylalkyl (e.g., cyclopentylmethyl or cyclohexylmethyl), and R7 is cyclyl, e.g., cycloalkyl (e.g., cyclohexyl). In some embodiments, R7 is cyclohexyl substituted with 1 R13. In some embodiments, R13 is C1- C6 alkyl, e.g., C4 alkyl (e.g., tert-butyl).
In some embodiments, R is hydrogen and R7 is cyclyl, e.g., cycloalkyl (e.g., cyclohexyl). In some embodiments, R7 is cyclohexyl substituted with 1-3 R13. In some embodiments, R7 is cyclohexyl substituted with one R13. In some embodiments, R13 is Ci-C6 alkyl (e.g., methyl). In some embodiments, R13 is C3 alkyl (e.g., isopropyl). In some embodiments, R13 is C4 alkyl (e.g., tert-butyl). In some embodiments, R13 is haloalkyl (e.g., trifluoromethyl). In some embodiments, R13 is halo (e.g., fluoro). In some embodiments, R13 is -CN.
In some embodiments, R7 is cyclohexyl substituted with two R13. In some embodiments, each R13 is independently halo (e.g., fluoro). In some embodiments, each R13 is independently Ci-C6 alkyl (e.g., methyl).
In some embodiments, R7 is a bicyclic group, e.g., bicyclo[2.2.2]octane. In some embodiments, R7 is bicyclo[2.2.2]octane substituted with one R13. In some embodiments, R13 is haloalkyl (e.g., difluoromethyl).
In some embodiments, R6 is hydrogen and R7 is Ci-Cs alkyl. In some embodiments, R7 is C6 alkyl (e.g., 4-methylpentyl). In some embodiments, R7 is 4- methylpentyl that is substituted with one R13. In some embodiments, R13 is aryl (e.g., phenyl). In some embodiments, R13 is phenyl substituted with haloalkyl (e.g., trifluoromethyl).
In some embodiments, R4 and R6, together with the atoms to which they are attached, form a ring, e.g., a 6-membered ring. In some embodiments, R4 and R6, together with the atoms to which they are attached, form a 6-membered ring that is substituted with 1 R15. In some embodiments, R15 is Ci-C6 alkyl (e.g., methyl). In some embodiments, R15 is haloalkyl (e.g., trifluoromethyl). In some embodiments, R7 is Ci-C6 alkyl, e.g., C4 alkyl (e.g., sec-butyl) or C5 alkyl (e.g., 2,2-dimethylpropyl). In some embodiments, R7 is haloalkyl (e.g., 4,4,4- trifluorobutyl).
In some embodiments, R7 is aryl (e.g., phenyl). In some embodiments, R7 is phenyl substituted with one R13. In some embodiments, R13 is haloalkyl (e.g., trifluoromethyl).
In some embodiments, R7 is arylalkyl (e.g., benzyl). In some embodiments, R7 is benzyl substituted with one R13. In some embodiments, R13 is haloalkyl (e.g., trifluoromethyl).
In some embodiments, R8a, R8b, R9a and R9b are each independently H, Ci-C6 alkyl, halo, haloalkyl, or CN. In some embodiments, R8a, R8b, R9a and R9b are H.
In some embodiments, Z is CR17. In some embodiments, R17 is H.
In some embodiments, each represents the presence of a bond. In some embodiments, each represents the absence of a bond.
In some embodiments, the compound has the following formula:
Figure imgf000015_0001
In some embodiments, m is 1.
In some embodiments, W is -COOH. In another embodiment, W is a carboxylic acid mimic or bioisostere, for example, -C(O)NHS(O)2CHs.
In some embodiments, Z is CR17. In some embodiments, R17 is H; In some embodiments, n is O. In some embodiments, n is 1. In some embodiments, each R1 and R2 is independently H, Ci-C6 alkyl, C2-C6 alkenyl, halo, haloalkyl, Ci-C6 alkoxy, cyclyl, cyclylalkyl, halocyclyl or halocyclylalkyl; or R and R , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring. In some embodiments, each R1 and R2 is independently H, Ci-C6 alkyl, haloalkyl or Ci-C6 alkoxy; or R1 and R2, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring. In some embodiments, each R1 and R2 is independently H, Ci-C6 alkyl or haloalkyl; or R1 and R2, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring. In some embodiments, each R1 and R2 is independently H or Ci-C6 alkyl; or R1 and R2, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
In some embodiments, A is a bond. In another embodiment, A is O. In yet another embodiment, A is NR10. Also, R10 is hydrogen in another embodiment.
In some embodiments, R3 is aryl or heteroaryl, each of which is optionally substituted with 1-3 R11. In some embodiments, R3 is aryl optionally substituted with 1-3 R11. In some embodiments, R3 is heteroaryl optionally substituted with 1-3 R11.
In some embodiments, each R11 is independently Ci-C6 alkyl, Ci-C6 alkenyl, halo, haloalkyl, haloalkoxy, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R is independently Ci-C6 alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, amino or alkylamino, each of which is optionally substituted; or wherein two R together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R11 is independently Ci-C6 alkyl, halo, haloalkyl, haloalkoxy or alkoxy; or wherein two R11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R11 is independently Ci-C6 alkyl, halo, haloalkyl or haloalkoxy.
In some embodiments, each R and R5 is independently H, Ci-Cs alkyl, haloalkyl, hydroxy, cyclyl, cyclylalkyl, aryl or heteroaryl, each of which is optionally substituted with 1-3 R . In some embodiments, R and R5 is independently H, Ci-Cs alkyl, haloalkyl, cyclylalkyl, cyclyl, aryl or heteroaryl.
In some embodiments, each R is independently Ci-C6 alkyl, Ci-C6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R12 is independently Ci-C6 alkyl, halo, haloalkyl or alkoxy, each of which is optionally substituted; or wherein two R12 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R12 is independently Ci-C6 alkyl, halo or haloalkyl, each of which is optionally substituted.
In some embodiments, R and R7 are each independently H, Ci-Cs alkyl, cyclyl, aryl, heteroaryl, cyclylalkyl or arylalkyl, each of which is optionally substituted with 1-3 R ; wherein when B is O, R7 is absent; wherein when B is N, R and R7, together with the nitrogen to which they are attached, may form a 3-7 membered ring that is optionally saturated or unsaturated, and unsubstituted or substituted with 1-3 R ; and wherein R and R , together with the atoms to which they are attached, may form a 3-7 membered ring ring that is optionally saturated or unsaturated, and unsubstituted or substituted with 1-3 R15.
In some embodiments, each R13, R14 and R15 is independently Ci-C6 alkyl, Ci-C6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two, R13, R14 and R15 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R13, R14 and R15 is independently Ci-C6 alkyl, halo, haloalkyl, alkoxy, hydroxy, cyano, amino or alkylamino, each of which is optionally substituted; or wherein two , R13, R14 and R15 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R13, R14 and R15 is independently Ci-C6 alkyl, halo, haloalkyl or hydroxy, each of which is optionally substituted; or wherein two , R13, R14 and R15 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
In some embodiments, B is O and R is absent.
In some embodiments, B is N.
In some embodiments, R8a and R9a are each independently H, Ci-C6 alkyl, halo, haloalkyl or CN. In some embodiments, R8a and R9b are H.
In some embodiments, Z is CR17. In some embodiments, R17 is H.
In some embodiments, the compound has the following formula:
Figure imgf000018_0001
In some embodiments, m is 1.
In some embodiments, W is -COOH. In another embodiment, W is a carboxylic acid mimic or bioisostere, for example, -C(O)NHS(O)2CHs.
In some embodiments, Z is CR17. In some embodiments, R17 is H; In some embodiments, n is O. In some embodiments, n is 1. In some embodiments, each R1 and R2 is independently H, Ci-C6 alkyl, C2-C6 alkenyl, halo, haloalkyl, Ci-C6 alkoxy, cyclyl, cyclylalkyl, halocyclyl or halocyclylalkyl; or R and R , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring. In some embodiments, each R1 and R2 is independently H, Ci-C6 alkyl, haloalkyl or Ci-C6 alkoxy; or R1 and R2, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring. In some embodiments, each R1 and R2 is independently H, Ci-C6 alkyl or haloalkyl; or R1 and R2, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring. In some embodiments, each R1 and R2 is independently H or Ci-C6 alkyl; or R1 and R2, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
In some embodiments, A is a bond. In another embodiment, A is O. In yet another embodiment, A is NR10. Also, R10 is hydrogen in another embodiment.
In some embodiments, R3 is aryl, heteroaryl, each of which is optionally substituted with 1-3 R11. In some embodiments, R3 is aryl optionally substituted with 1-3 R11. In some embodiments, R3 is heteroaryl optionally substituted with 1-3 R11.
In some embodiments, each R11 is independently Ci-C6 alkyl, Ci-C6 alkenyl, halo, haloalkyl, haloalkoxy, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R is independently Ci-C6 alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, amino or alkylamino, each of which is optionally substituted; or wherein two R together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R11 is independently Ci-C6 alkyl, halo, haloalkyl, haloalkoxy or alkoxy; or wherein two R11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R11 is independently Ci-C6 alkyl, halo, haloalkyl or haloalkoxy.
In some embodiments, each R and R5 is independently H, Ci-Cs alkyl, haloalkyl, hydroxy, cyclyl, cyclylalkyl, aryl or heteroaryl, each of which is optionally substituted with 1-3 R . In some embodiments, R and R5 is independently H, Ci-Cs alkyl, haloalkyl, cyclylalkyl, cyclyl, aryl or heteroaryl.
In some embodiments, each R is independently Ci-C6 alkyl, Ci-C6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R12 is independently Ci-C6 alkyl, halo, haloalkyl or alkoxy, each of which is optionally substituted; or wherein two R12 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R12 is independently Ci-C6 alkyl, halo or haloalkyl, each of which is optionally substituted.
In some embodiments, R and R7 are each independently H, Ci-Cs alkyl, cyclyl, aryl, heteroaryl, cyclylalkyl or arylalkyl, each of which is optionally substituted with 1-3 R ; wherein when B is O, R7 is absent; wherein when B is N, R and R7, together with the nitrogen to which they are attached, may form a 3-7 membered ring that is optionally saturated or unsaturated, and unsubstituted or substituted with 1-3 R ; and wherein R and R , together with the atoms to which they are attached, may form a 3-7 membered ring ring that is optionally saturated or unsaturated, and unsubstituted or substituted with 1-3 R15.
In some embodiments, each R13, R14 and R15 is independently Ci-C6 alkyl, Ci-C6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two, R13, R14 and R15 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R13, R14 and R15 is independently Ci-C6 alkyl, halo, haloalkyl, alkoxy, hydroxy, cyano, amino or alkylamino, each of which is optionally substituted; or wherein two , R13, R14 and R15 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R13, R14 and R15 is independently Ci-C6 alkyl, halo, haloalkyl or hydroxy, each of which is optionally substituted; or wherein two , R13, R14 and R15 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
In some embodiments, B is O and R is absent.
In some embodiments, B is N.
In some embodiments, R8a, R8b, R9b and R9a are each independently H, Ci-C6 alkyl, halo, haloalkyl, or CN. In some embodiments, R8a and R9b are H.
In some embodiments, Z is CR17. In some embodiments, R17 is H.
In some embodiments, the compound has the following formula:
Figure imgf000021_0001
In some embodiments, m is 1.
In some embodiments, W is -COOH. In another embodiment, W is a carboxylic acid mimic or bioisostere, for example, -C(O)NHS(O)2CHs.
In some embodiments, Z is CR17. In some embodiments, R17 is H; In some embodiments, n is O. In some embodiments, n is 1. In some embodiments, each R1 and R2 is independently H, Ci-C6 alkyl, C2-C6 alkenyl, halo, haloalkyl, Ci-C6 alkoxy, cyclyl, cyclylalkyl, halocyclyl or halocyclylalkyl; or R and R , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring. In some embodiments, each R1 and R2 is independently H, Ci-C6 alkyl, haloalkyl or Ci-C6 alkoxy; or R1 and R2, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring. In some embodiments, each R1 and R2 is independently H, Ci-C6 alkyl or haloalkyl; or R1 and R2, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring. In some embodiments, each R1 and R2 is independently H or Ci-C6 alkyl; or R1 and R2, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
In some embodiments, A is a bond. In another embodiment, A is O. In yet another embodiment, A is NR10. Also, R10 is hydrogen in another embodiment.
In some embodiments, R3 is aryl, heteroaryl, each of which is optionally substituted with 1-3 R11. In some embodiments, R3 is aryl optionally substituted with 1-3 R11. In some embodiments, R3 is heteroaryl optionally substituted with 1-3 R11.
In some embodiments, each R11 is independently Ci-C6 alkyl, Ci-C6 alkenyl, halo, haloalkyl, haloalkoxy, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R is independently Ci-C6 alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, amino or alkylamino, each of which is optionally substituted; or wherein two R together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R11 is independently Ci-C6 alkyl, halo, haloalkyl, haloalkoxy, or alkoxy; or wherein two R11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R11 is independently Ci-C6 alkyl, halo, haloalkyl or haloalkoxy.
In some embodiments, each R and R5 is independently H, Ci-Cs alkyl, haloalkyl, hydroxy, cyclyl, cyclylalkyl, aryl or heteroaryl, each of which is optionally substituted with 1-3 R . In some embodiments, R and R5 is independently H, Ci-Cs alkyl, haloalkyl, cyclylalkyl, cyclyl, aryl or heteroaryl.
In some embodiments, each R is independently Ci-C6 alkyl, Ci-C6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R12 is independently Ci-C6 alkyl, halo, haloalkyl or alkoxy, each of which is optionally substituted; or wherein two R12 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R12 is independently Ci-C6 alkyl, halo or haloalkyl, each of which is optionally substituted.
In some embodiments, R and R7 are each independently H, Ci-Cs alkyl, cyclyl, aryl, heteroaryl, cyclylalkyl or arylalkyl, each of which is optionally substituted with 1-3 R ; wherein when B is O, R7 is absent; wherein when B is N, R and R7, together with the nitrogen to which they are attached, may form a 3-7 membered ring that is optionally saturated or unsaturated, and unsubstituted or substituted with 1-3 R ; and wherein R and R , together with the atoms to which they are attached, may form a 3-7 membered ring ring that is optionally saturated or unsaturated, and unsubstituted or substituted with 1-3 R15.
In some embodiments, each R13, R14 and R15 is independently Ci-C6 alkyl, Ci-C6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two, R13, R14 and R15 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R13, R14 and R15 is independently Ci-C6 alkyl, halo, haloalkyl, alkoxy, hydroxy, cyano, amino or alkylamino, each of which is optionally substituted; or wherein two , R13, R14 and R15 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R13, R14 and R15 is independently Ci-C6 alkyl, halo, haloalkyl or hydroxy, each of which is optionally substituted; or wherein two , R , R and R 5 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
In some embodiments, R8a and R9a are each independently H, Ci-C6 alkyl, halo, haloalkyl, or CN. In some embodiments, R8a and R9b are H.
In some embodiments, Z is CR17. In some embodiments, R17 is H.
In some embodiments, the compound has the following formula:
Figure imgf000024_0001
wherein s is 0, 1, 2 or 3. In some embodiments, m is 1.
In some embodiments, W is -COOH. In another embodiment, W is a carboxylic acid mimic or bioisostere, for example, -C(O)NHS(O)2CH3.
In some embodiments, Z is CR17. In some embodiments, R17 is H; In some embodiments, n is O. In some embodiments, n is 1. In some embodiments, each R1 and R2 is independently H, Ci-C6 alkyl, C2-C6 alkenyl, halo, haloalkyl, Ci-C6 alkoxy, cyclyl, cyclylalkyl, halocyclyl or halocyclylalkyl; or R and R , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring. In some embodiments, each R1 and R2 is independently H, Ci-C6 alkyl, haloalkyl or Ci-C6 alkoxy; or R1 and R2, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring. In some embodiments, each R1 and R2 is independently H, Ci-C6 alkyl, or haloalkyl; or R1 and R2, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring. In some embodiments, each R1 and R2 is independently H or Ci-C6 alkyl; or R1 and R2, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
In some embodiments, each R4 and R5 is independently H, Ci-Cs alkyl, haloalkyl, hydroxy, cyclyl, cyclylalkyl, aryl or heteroaryl, each of which is optionally substituted with 1-3 R12. In some embodiments, R4 and R5 is independently H, Ci-Cs alkyl, haloalkyl, cyclylalkyl, cyclyl, aryl or heteroaryl.
In some embodiments, each R12 is independently Ci-C6 alkyl, Ci-C6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R is independently Ci-C6 alkyl, halo, haloalkyl or alkoxy, each of which is optionally substituted; or wherein two R12 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R12 is independently Ci-C6 alkyl, halo or haloalkyl, each of which is optionally substituted.
In some embodiments, R6 and R7 are each independently H, Ci-Cs alkyl, cyclyl, aryl, heteroaryl, cyclylalkyl or arylalkyl, each of which is optionally substituted with 1-3 R13; wherein when B is O, R7 is absent; wherein when B is N, R6 and R7, together with the nitrogen to which they are attached, may form a 3-7 membered ring that is optionally saturated or unsaturated, and unsubstituted or substituted with 1-3 R ; and wherein R and R , together with the atoms to which they are attached, may form a 3-7 membered ring ring that is optionally saturated or unsaturated, and unsubstituted or substituted with 1-3 R15.
In some embodiments, each R , R and R 5 is independently Ci-C6 alkyl, Ci-C6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two, R , R and R together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R13, R14 and R15 is independently Ci-C6 alkyl, halo, haloalkyl, alkoxy, hydroxy, cyano, amino or alkylamino, each of which is optionally substituted; or wherein two , R13, R14 and R15 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R13, R14 and R15 is independently Ci-C6 alkyl, halo, haloalkyl or hydroxy, each of which is optionally substituted; or wherein two , R , R and R 5 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
In some embodiments, B is O and R7 is absent.
In some embodiments, B is N.
In some embodiments, R a and R a are each independently H, Ci-C6 alkyl, halo, haloalkyl, or CN. In some embodiments, R a and R are H.
In some embodiments, Z is CR . In some embodiments, R is H.
In some embodiments, the compound has the following formula:
Figure imgf000027_0001
wherein s is 0, 1, 2 or 3.
In some embodiments, m is 1.
In some embodiments, W is -COOH. In another embodiment, W is a carboxylic acid mimic or bioisostere, for example, -C(O)NHS(O)2CHs.
In some embodiments, Z is CR 7. In some embodiments, R 7 is H;
In some embodiments, n is 0.
In some embodiments, n is 1.
In some embodiments, each R1 and R2 is independently H, Ci-C6 alkyl, C2-C6 alkenyl, halo, haloalkyl, Ci-C6 alkoxy, cyclyl, cyclylalkyl, halocyclyl or halocyclylalkyl; or R1 and R2, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring. In some embodiments, each R1 and R2 is independently H, Ci-C6 alkyl, haloalkyl or Ci-C6 alkoxy; or R1 and R2, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring. In some embodiments, each R1 and R2 is independently H, Ci-C6 alkyl or haloalkyl; or R and R , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring. In some embodiments, each R and R is independently H or Ci-C6 alkyl; or R and R , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
In some embodiments, each R and R is independently H, Ci-Cs alkyl, haloalk hydroxy, cyclyl, cyclylalkyl, aryl or heteroaryl, each of which is optionally substituted with 1-3 R12. In some embodiments, R4 and R5 is independently H, Ci-Cs alkyl, haloalkyl, cyclylalkyl, cyclyl, aryl or heteroaryl.
In some embodiments, each R12 is independently Ci-C6 alkyl, Ci-C6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R is independently Ci-C6 alkyl, halo, haloalkyl or alkoxy, each of which is optionally substituted; or wherein two R12 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R12 is independently Ci-C6 alkyl, halo or haloalkyl, each of which is optionally substituted.
In some embodiments, R6 and R7 are each independently H, Ci-Cs alkyl, cyclyl, aryl, heteroaryl, cyclylalkyl or arylalkyl, each of which is optionally substituted with 1-3 R13; wherein when B is O, R7 is absent; wherein when B is N, R6 and R7, together with the nitrogen to which they are attached, may form a 3-7 membered ring that is optionally saturated or unsaturated, and unsubstituted or substituted with 1-3 R ; and wherein R and R6, together with the atoms to which they are attached, may form a 3-7 membered ring ring that is optionally saturated or unsaturated, and unsubstituted or substituted with 1-3 R15.
In some embodiments, each R13, R14 and R15 is independently Ci-C6 alkyl, Ci-C6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two, R13, R14 and R15 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R13, R14 and R15 is independently Ci-C6 alkyl, halo, haloalkyl, alkoxy, hydroxy, cyano, amino or alkylamino, each of which is optionally substituted; or wherein two , R13, R14 and R15 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R13, R14 and R15 is independently Ci-C6 alkyl, halo, haloalkyl or hydroxy, each of which is optionally substituted; or wherein two , R , R and R 5 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
In some embodiments, R8a and R9a are each independently H, Ci-C6 alkyl, halo, haloalkyl, or CN. In some embodiments, R8a and R9b are H.
In some embodiments, Z is CR17. In some embodiments, R17 is H.
In some embodiments, W is -COOH; n is 1; one of R1 and R2 is hydrogen and the other is lower alkyl; each of R8a and R9a is hydrogen; s is 1; R11 is haloalkyl; R4 is hydrogen; R5 is optionally substituted aryl; R6 and R7, together with the nitrogen to which they are attached, form an optionally substituted 6-membered ring; Z is CR17; and R17 is H.
In some embodiments, W is -COOH; n is 1; R1 and R2, together with the carbon to which they are attached, form a ring; each of R8a and R9a is hydrogen; s is 1 ; R11 is haloalkyl; R4 is hydrogen; R5 is aryl; R6 and R7, together with the nitrogen to which they are attached, form a 6-membered ring, or one of R6 and R7 is hydrogen while the other is lower alkyl; Z is CR17; and R17 is H.
In some embodiments, the compound has the following formula:
Figure imgf000029_0001
In some embodiments, m is 1.
In some embodiments, W is -COOH. In another embodiment, W is a carboxylic acid mimic or bioisostere, for example, -C(O)NHS(O)2CH3. In some embodiments, Z is CR17. In some embodiments, R17 is H;
In some embodiments, n is 0.
In some embodiments, n is 1.
In some embodiments, each R1 and R2 is independently H, Ci-C6 alkyl, C2-C6 alkenyl, halo, haloalkyl, Ci-C6 alkoxy, cyclyl, cyclylalkyl, halocyclyl or halocyclylalkyl; or R and R , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring. In some embodiments, each R1 and R2 is independently H, Ci-C6 alkyl, haloalkyl or Ci-C6 alkoxy; or R1 and R2, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring. In some embodiments, each R1 and R2 is independently H, Ci-C6 alkyl or haloalkyl; or R1 and R2, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring. In some embodiments, each R1 and R2 is independently H or Ci-C6 alkyl; or R1 and R2, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
In some embodiments, A is a bond. In another embodiment, A is O. In yet another embodiment, A is NR10. Also, R10 is hydrogen in another embodiment.
In some embodiments, R is aryl, heteroaryl, each of which is optionally substituted with 1-3 R11. In some embodiments, R3 is aryl optionally substituted with 1-3 R11. In some embodiments, R3 is heteroaryl optionally substituted with 1-3 R11.
In some embodiments, each R11 is independently Ci-C6 alkyl, Ci-C6 alkenyl, halo, haloalkyl, haloalkoxy, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R11 is independently Ci-C6 alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, amino or alkylamino, each of which is optionally substituted; or wherein two R11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R11 is independently Ci-C6 alkyl, halo, haloalkyl, haloalkoxy or alkoxy; or wherein two R11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R11 is independently Ci-C6 alkyl, halo, haloalkyl or haloalkoxy.
In some embodiments, each R and R5 is independently H, Ci-Cs alkyl, haloalkyl, hydroxy, cyclyl, cyclylalkyl, aryl or heteroaryl, each of which is optionally substituted with 1-3 R . In some embodiments, R and R is independently H, Ci-Cs alkyl, haloalkyl, cyclylalkyl, cyclyl, aryl or heteroaryl.
In some embodiments, each R is independently Ci-C6 alkyl, Ci-C6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R12 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R12 is independently Ci-C6 alkyl, halo, haloalkyl or alkoxy, each of which is optionally substituted; or wherein two R12 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R is independently Ci-C6 alkyl, halo or haloalkyl, each of which is optionally substituted.
In some embodiments, R is H, Ci-Cs alkyl, cyclyl, aryl, heteroaryl, cyclylalkyl or arylalkyl, each of which is optionally substituted with 1-3 R .
In some embodiments, each R is independently Ci-C6 alkyl, Ci-C6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted. In some embodiments, each R13 is independently Ci-C6 alkyl, halo, haloalkyl, alkoxy, hydroxy, cyano, amino or alkylamino, each of which is optionally substituted. In some embodiments, each R13 is independently Ci-C6 alkyl, halo, haloalkyl or hydroxy, each of which is optionally substituted. In some embodiments, R8a and R9a are each independently H, Ci-C6 alkyl, halo, haloalkyl, or CN. In some embodiments, R8a and R9b are H.
In some embodiments, Z is CR17. In some embodiments, R17 is H. In one aspect, the invention features compound of formula (II):
Figure imgf000032_0001
wherein: m is 1, 2, 3 or 4; n is O, 1 or 2;
W is -COOH, or a carboxylic acid mimic or bioisostere;
Z is N or CH; each R1 and R2 is independently H, Ci-C6 alkyl, C2-C6 alkenyl, halo, haloalkyl, Ci-C6 alkoxy, cyclyl, cyclylalkyl, halocyclyl or halocyclylalkyl; or R1 and R2, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring; wherein either R1 or R2 is optionally taken together with R8a or R8b to form an optionally substituted, saturated or unsaturated 3-7 membered ring;
A is a bond, NR10, O, S, alkylenyl, amide, ester, carbamate, urea, thiourea or sulfonylurea;
R3 is aryl, heteroaryl, cyclyl or heterocyclyl, each of which is optionally substituted with 1-3 R11; each R4 and R5 is independently H, Ci-Cs alkyl, haloalkyl, cyclyl, cyclylalkyl, aryl or heteroaryl, each of which is optionally substituted with 1-3 R12; or R4 and R5, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring; R6 and R7, together with the nitrogen to which they are attached, form a 3-7 membered ring that is optionally saturated or unsaturated, and substituted or unsubstituted with 1-3 R14; each R8a, R8b, R9a and R9b is independently H, Ci-C6 alkyl, hydroxy, halo, haloalkyl, or CN;
R is hydrogen, Ci-C6 alkyl or haloalkyl; and each R11, R12, and R14 is independently Ci-C6 alkyl, Ci-C6 alkenyl, Ci-C6 alkynyl, halo, haloalkyl, alkoxy, haloalkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, carboxylate, cyano, oxo, nitro, amino, alkylamino, dialkylamino, mercapto, thioalkyl, aryloxy, thioalkoxy, amido, SO3H, sulfate, S(O)NH2, S(O)2NH2, phosphate or acyl, each of which is optionally substituted; or wherein two R11, R12, or R14, together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring; each R20 is independently Ci-Cs alkyl; wherein -A-R3 and -(CR4R5)mNR6R7 are each positioned at one of Z, R8a, R8b, R9a or R9b, or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, tautomer, enantiomer, stereoisomer, analog or derivative thereof, including mixtures thereof in any ratios.
In some embodiments, W is -COOH. In another embodiment, W is a carboxylic acid mimic or bioisostere, for example, -C(O)NHS(O)2CH3.
In some embodiments, n is O.
In some embodiments, n is 1.
In some embodiments, each R and R is independently H, Ci-C6 alkyl, C2-C6 alkenyl, haloalkyl, Ci-C6 alkoxy, cyclyl, cyclylalkyl, halocyclyl or halocyclylalkyl; or R1 and R2, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring. In some embodiments, each R1 and R2 is independently H or Ci-C6 alkyl; or R1 and R2, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
In some embodiments, R and R are both H. In some embodiments, R and R are both Ci-C6 alkyl (e.g., methyl or ethyl). In some embodiments, one of R1 and R2 is methyl and the other is sec-butyl. In some embodiments, one of R and R is hydrogen and the other is Ci-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, sec-butyl or neopentyl). In some embodiments, one of R and R is hydrogen and the other is C2-C6 alkenyl (e.g., C3 alkenyl or ally 1) . In some embodiments, one of R and R is hydrogen and the other is cyclylalkyl (e.g., cyclopropylmethyl). In some embodiments, one of R1 and R2 is hydrogen and the other is cyclylalkyl (e.g., cyclopropylmethyl).
In some embodiments, R1 and R2, together with the carbon to which they are attached, form a ring (e.g., a cyclopentyl, cyclobutyl, or cyclopropyl ring).
In some embodiments, R8a is taken with one of R1 and R2, together with the carbons to which they are attached, to form a ring (e.g., a 5-membered ring or a 6- membered ring).
In some embodiments, A is a bond. In another embodiment, A is O. In yet another embodiment, A is NR . Also, R is hydrogen in another embodiment.
In some embodiments, R is aryl, heteroaryl, each of which is optionally substituted with 1 -3 R . In some embodiments, R is aryl optionally substituted with 1 -3 R11.
In some embodiments, each R is independently Ci-C6 alkyl, Ci-C6 alkenyl, halo, haloalkyl, haloalkoxy, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R11 is independently Ci-C6 alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, amino or alkylamino, each of which is optionally substituted; or wherein two R11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R11 is independently Ci-C6 alkyl, halo, haloalkyl, haloalkoxy or alkoxy; or wherein two R11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and ooppttiioonnaallllyy ssuubbssttiittuutteedd rriinngg.. IInn some embodiments, each R11 is independently Ci-C6 alkyl, halo, haloalkyl or haloalkoxy.
IInn ssoommee eemmbbood< iments, R is aryl, e.g., phenyl. In some embodiments, R is unsubstituted phenyl.
In some embodiments, R is phenyl substituted with one R . In some embodiments, R is substituted at the ortho position. In some embodiments, R is substituted at the meta position. In some embodiments, R is substituted at the para position. In some embodiments, R11 is halo (e.g., fluoro or chloro). In some embodiments, R11 is haloalkyl (e.g., trifiuoromethyl). In some embodiments, R11 is haloalkoxy (e.g., trifluoromethoxy). In some embodiments, R11 is Ci-C6 alkyl, e.g., C3 alkyl (e.g., isopropyl) or C4 alkyl (e.g., tert-butyl). In some embodiments, R11 is alkoxy (e.g., methoxy).
In some embodiments, R3 is phenyl substituted with two R11. In some embodiments, both R are Ci-C6 alkyl (e.g., methyl). In some embodiments, both R are halo (e.g., fluoro). In some embodiments, one R is halo (e.g., fluoro) and the other is haloalkyl (e.g., trifiuoromethyl).
In some embodiments, R is phenyl substituted with three R . In some embodiments, all three R are halo (e.g., fluoro).
In some embodiments, R is pyridyl. In some embodiments, R is unsubstituted pyridyl. In some embodiments, R is pyridyl substituted with I R . In some embodiments, R is haloalkyl (e.g., trifiuoromethyl).
In some embodiments, R3 is pyrimidyl. In some embodiments, R3 is unsubstituted pyrimidyl. In some embodiments, R3 is pyrimidyl substituted with 1 R11. In some embodiments, R11 is Ci-C6 alkyl, e.g., C4 alkyl (e.g., tert-butyl).
In some embodiments, m is 1. In some embodiments, each R4 and R5 is independently H, Ci-Cs alkyl, haloalkyl, hydroxy, cyclyl, cyclylalkyl, aryl or heteroaryl, each of which is optionally substituted with 1-3 R12. In some embodiments, R4 and R5 is independently H, Ci-Cs alkyl, haloalkyl, cyclylalkyl, cyclyl, aryl or heteroaryl.
In some embodiments, each R12 is independently Ci-C6 alkyl, Ci-C6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R is independently Ci-C6 alkyl, halo, haloalkyl or alkoxy, each of which is optionally substituted; or wherein two R12 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R12 is independently Ci-C6 alkyl, halo or haloalkyl, each of which is optionally substituted.
In some embodiments, R4 is hydrogen.
In some embodiments, R5 is aryl (e.g., phenyl). In some embodiments, R5 is unsubstituted phenyl.
In some embodiments, R5 is phenyl substituted with one R12. In some embodiments, R5 is substituted at the ortho position. In some embodiments, R5 is substituted at the meta position. In some embodiments, R5 is substituted at the para position.
In some embodiments, R12 is halo (e.g., fluoro or chloro). In some embodiments, R12 is haloalkyl (e.g., trifluoromethyl). In some embodiments, R12 is Ci-C6 alkyl, e.g., C3 alkyl (e.g., isopropyl), or C4 alkyl (e.g., tert-butyl). In some embodiments, R12 is -CN.
In some embodiments, R5 is phenyl substituted with two R12. In some embodiments, both R12 are halo (e.g., fluoro).
In some embodiments, R5 is heteroaryl. In some embodiments, R5 is pyridyl. In some embodiments, R5 is unsubstituted pyridyl.
In some embodiments, R5 is pyridyl substituted with one R12. In some embodiments, R12 is halo (e.g., fluoro). In some embodiments, R12 is haloalkyl (e.g., trifluoromethyl).
In some embodiments, R5 is imidazolyl.
In some embodiments, R5 is imidazolyl substituted with one R12. In some embodiments, R12 is haloalkyl (e.g., trifluoromethyl).
In some embodiments, R5 is thiazolyl.
In some embodiments, R5 is pyrazolyl. In some embodiments, R5 is pyrazolyl substituted with 1-3 R12. In some embodiments, R5 is pyrazolyl substituted with three R12. In some embodiments, one R12 is Ci-C6 alkyl (e.g., methyl), one is halo (e.g., fluoro) and one is haloalkyl (trifluoromethyl). In some embodiments, three R12 are each independently Ci-C6 alkyl (e.g., two are methyl and one is t-butyl).
In some embodiments, R5 is:
Figure imgf000037_0001
In some embodiments, R5 is pyrimidyl. In some embodiments, R5 is unsubstituted pyrimidyl. In some embodiments, R5 is pyrimidyl substituted with one R12. In some embodiments, R12 is Ci-C6 alkyl, e.g., Ci alkyl (e.g., methyl) or C4 alkyl (e.g., tert-butyl).
In some embodiments, R5 is indolyl.
In some embodiments, R5 is indazolyl. In some embodiments, R5 is indazolyl substituted with one R12. In some embodiments, R12 is Ci-C6 alkyl (e.g., methyl).
In some embodiments, R5 is hydrogen.
In some embodiments, R5 is Ci-Cs alkyl. In some embodiments, R5 is methyl. In some embodiments, R5 is C5 alkyl, e.g., isopentyl (3-methylbutyl) or neopentyl (2,2- dimethylpropyl). In some embodiments, R5 is C6 alkyl, e.g., neohexyl (3,3- dimethylbutyl).
In some embodiments, R5 is cyclyl, e.g., cycloalkyl (e.g., cyclohexyl). In some embodiments, R5 is bicyclo[2.2.2]octanyl.
In some embodiments, R5 is cyclylalkyl, e.g., cyclohexylmethyl.
In some embodiments, R5 is haloalkyl (e.g., 2,2,2-trifluoroethoxy, 3,3,3- trifluoropropyl or 4,4,4-trifluorobutyl).
In some embodiments, R6 and R7 are each independently H, Ci-Cs alkyl, cyclyl, aryl, heteroaryl, cyclylalkyl or arylalkyl, each of which is optionally substituted with 1-3 R13; wherein when B is O, R7 is absent; wherein when B is N, R6 and R7, together with the nitrogen to which they are attached, may form a 3-7 membered ring that is optionally saturated or unsaturated, and unsubstituted or substituted with 1-3 R14; and wherein R4 and R6, together with the atoms to which they are attached, may form a 3-7 membered ring ring that is optionally saturated or unsaturated, and unsubstituted or substituted with 1-3 R15.
In some embodiments, each R13, R14 and R15 is independently Ci-C6 alkyl, Ci-C6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two , R13, R14 and R15 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R13, R14 and R15 is independently Ci-C6 alkyl, halo, haloalkyl, alkoxy, hydroxy, cyano, amino or alkylamino, each of which is optionally substituted; or wherein two , R13, R14 and R15 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R13, R14 and R15 is independently Ci-C6 alkyl, halo, haloalkyl or hydroxy, each of which is optionally substituted; or wherein two , R13, R14 and R15 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, R6 and R7, together with the nitrogen to which they are attached, form a 4-membered ring (e.g., an azetidine ring).
In some embodiments, R6 and R7, together with the nitrogen to which they are attached, form a 5-membered ring, e.g., a pyrrolidine ring. In some embodiments, R6 and R7, together with the nitrogen to which they are attached, form a pyrrolidine ring that is substituted with one R14. In some embodiments, R14 is halo (e.g., fluoro). In some embodiments, R14 is Ci-C6 alkyl (e.g., sec-butyl).
In some embodiments, R6 and R7, together with the nitrogen to which they are attached, form a pyrrolidine ring that is substituted with two R14. In some embodiments, both R14 are Ci-C6 alkyl (e.g., methyl). In some embodiments, both R14 are halo (e.g., fluoro). In some embodiments, two R14, together with the atoms to which they are attached, form a ring, e.g., a 3-membered ring, a 5-membered ring or a 6-membered ring (e.g., a phenyl ring).
In some embodiments, R6 and R7, together with the nitrogen to which they are attached, form a 6-membered ring, e.g., a piperidine ring. In some embodiments, R6 and R7, together with the nitrogen to which they are attached, form a piperidine ring that is unsubstituted.
In some embodiments, R6 and R7, together with the nitrogen to which they are attached, form a piperidine ring that is substituted with one R . In some embodiments, R14 is halo (e.g., fluoro). In some embodiments, R14 is Ci-C6 alkyl, e.g., methyl. In some embodiments, R14 is C3 alkyl (e.g., n-propyl). In some embodiments, R14 is C4 alkyl (e.g., tert-butyl or isobutyl). In some embodiments, R14 is haloalkyl (e.g., trifluoromethyl). In some embodiments, R14 is alkoxy (e.g., methoxy or ethoxy). In some embodiments, R14 is aryl (e.g., phenyl). In some embodiments, R14 is cyano. In some embodiments, R14 is a carboxylate. In some embodiments, R14 is -SO2CH3.
In some embodiments, R6 and R7, together with the nitrogen to which they are attached, form a piperidine ring that is substituted with two R14. In some embodiments, both R14 are halo (e.g., fluoro). In some embodiments, both R14 are Ci-C6 alkyl (e.g., methyl). In some embodiments, two R14, together with the carbons to which they are attached, form a ring, e.g., a 3-membered ring or a 6-membered ring.
In some embodiments, R6 and R7, together with the nitrogen to which they are attached, form a piperazine ring. In some embodiments, R6 and R7, together with the nitrogen to which they are attached, form a piperazine ring that is unsubstituted. In some embodiments, R6 and R7, together with the nitrogen to which they are attached, form a piperazine ring that is substituted with one R14. In some embodiments, R14 is Ci-C6 alkyl (e.g., methyl).
In some embodiments, R6 and R7, together with the nitrogen to which they are attached, form a piperazine that is substituted with two R . In some embodiments, two R14, together with the carbons to which they are attached, form an optionally substituted ring such as a heteroaryl. In some embodiments, the heteroaryl is a triazole. In some embodiments, the triazole is substituted with a haloalkyl substituent, (e.g., trifluoromethyl).
In another embodiment, R6 and R7, together with the nitrogen to which they are attached, form a thiomorpholino.
In some embodiments, R6 and R7, together with the nitrogen to which they are attached, form a 7-membered ring.
In some embodiments, R6 and R7, together with the nitrogen to which they are attached, form a bridged bicyclic ring (e.g., a 3-azabicyclo[3.2.1]octan-3-yl ring). In some embodiments, R6 and R7, together with the nitrogen to which they are attached, form a fused bicyclic ring (e.g., 3-azabicyclo[3.1.0]hexan-3-yl). In some embodiments, R and R , together with the nitrogen to which they are attached, form a spirocyclic ring system (e.g., 6-azaspiro[2.5]octan-6-yl).
In some embodiments, Z is CH.
In yet another embodiment, the compound has the following formula:
Figure imgf000041_0001
wherein t is 0, 1 or 2 and u is 0, 1, 2 or 3.
In some embodiments, t is 1.
In some embodiments, m is 1.
In some embodiments, W is -COOH. In another embodiment, W is a carboxylic acid mimic or bioisostere, for example, -C(O)NHS(O)2CHs.
In some embodiments, Z is CR . In some embodiments, R is H;
In some embodiments, n is 0.
In some embodiments, n is 1.
In some embodiments, each R1 and R2 is independently H, Ci-C6 alkyl, C2-C6 alkenyl, halo, haloalkyl, Ci-C6 alkoxy, cyclyl, cyclylalkyl, halocyclyl or halocyclylalkyl; or R1 and R2, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring. In some embodiments, each R1 and R2 is independently H, Ci-C6 alkyl, haloalkyl or Ci-C6 alkoxy; or R1 and R2, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring. In some embodiments, each R1 and R2 is independently H, Ci-C6 alkyl or haloalkyl; or R1 and R2, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring. In some embodiments, each R and R is independently H or Ci-C6 alkyl; or R and R , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
In some embodiments, A is a bond. In another embodiment, A is O. In yet another embodiment, A is NR . Also, R is hydrogen in another embodiment. In some embodiments, R is aryl, heteroaryl, each of which is optionally substituted with 1-3 R11. In some embodiments, R3 is aryl optionally substituted with 1-3 R11. In some embodiments, R3 is heteroaryl optionally substituted with 1-3 R11.
In some embodiments, each R11 is independently Ci-C6 alkyl, Ci-C6 alkenyl, halo, haloalkyl, haloalkoxy, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R11 is independently Ci-C6 alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, amino or alkylamino, each of which is optionally substituted; or wherein two R11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R11 is independently Ci-C6 alkyl, halo, haloalkyl, haloalkoxy or alkoxy; or wherein two R11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R11 is independently Ci-C6 alkyl, halo, haloalkyl or haloalkoxy.
In some embodiments, each R4 and R5 is independently H, Ci-Cs alkyl, haloalkyl, hydroxy, cyclyl, cyclylalkyl, aryl or heteroaryl, each of which is optionally substituted with 1-3 R12. In some embodiments, R4 and R5 is independently H, Ci-Cs alkyl, haloalkyl, cyclylalkyl, cyclyl, aryl or heteroaryl.
In some embodiments, each R12 is independently Ci-C6 alkyl, Ci-C6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R12 is independently Ci-C6 alkyl, halo, haloalkyl or alkoxy, each of which is optionally substituted; or wherein two R12 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R12 is independently Ci-C6 alkyl, halo or haloalkyl, each of which is optionally substituted.
In some embodiments, each R14 is independently Ci-C6 alkyl, Ci-C6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted. In some embodiments, each R14 is independently Ci-C6 alkyl, halo, haloalkyl, alkoxy, hydroxy, cyano, amino or alkylamino, each of which is optionally substituted. In some embodiments, each R14 is independently Ci-C6 alkyl, halo, haloalkyl or hydroxy, each of which is optionally substituted.
In some embodiments, R8a and R9a are each independently H, Ci-C6 alkyl, halo, haloalkyl, or CN. In some embodiments, R8a and R9b are H.
In some embodiments, Z is CR17. In some embodiments, R17 is H.
In still another embodiment, the compound has the following formula:
Figure imgf000043_0001
wherein t is 0, 1 or 2 and u is 0, 1, 2 or 3. In some embodiments, t is 1.
In some embodiments, W is -COOH. In another embodiment, W is a carboxylic acid mimic or bioisostere, for example, -C(O)NHS(O)2CH3.
In some embodiments, Z is CR17. In some embodiments, R17 is H; In some embodiments, n is O. In some embodiments, n is 1. In some embodiments, each R1 and R2 is independently H, Ci-C6 alkyl, C2-C6 alkenyl, halo, haloalkyl, Ci-C6 alkoxy, cyclyl, cyclylalkyl, halocyclyl or halocyclylalkyl; or R and R , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring. In some embodiments, each R1 and R2 is independently H, Ci-C6 alkyl, haloalkyl or Ci-C6 alkoxy; or R1 and R2, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring. In some embodiments, each R1 and R2 is independently H, Ci-C6 alkyl or haloalkyl; or R1 and R2, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring. In some embodiments, each R1 and R2 is independently H or Ci-C6 alkyl; or R1 and R2, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
In some embodiments, A is a bond. In another embodiment, A is O. In yet another embodiment, A is NR10. Also, R10 is hydrogen in another embodiment.
In some embodiments, R3 is aryl, heteroaryl, each of which is optionally substituted with 1-3 R11. In some embodiments, R3 is aryl optionally substituted with 1-3 R11. In some embodiments, R3 is heteroaryl optionally substituted with 1-3 R11.
In some embodiments, each R11 is independently Ci-C6 alkyl, Ci-C6 alkenyl, halo, haloalkyl, haloalkoxy, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R is independently Ci-C6 alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, amino or alkylamino, each of which is optionally substituted; or wherein two R together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R11 is independently Ci-C6 alkyl, halo, haloalkyl, haloalkoxy or alkoxy; or wherein two R11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R11 is independently Ci-C6 alkyl, halo, haloalkyl or haloalkoxy.
In some embodiments, each R and R5 is independently H, Ci-Cs alkyl, haloalkyl, hydroxy, cyclyl, cyclylalkyl, aryl or heteroaryl, each of which is optionally substituted with 1-3 R . In some embodiments, R and R5 is independently H, Ci-Cs alkyl, haloalkyl, cyclylalkyl, cyclyl, aryl or heteroaryl.
In some embodiments, each R is independently Ci-C6 alkyl, Ci-C6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R12 is independently Ci-C6 alkyl, halo, haloalkyl or alkoxy, each of which is optionally substituted; or wherein two R12 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R12 is independently Ci-C6 alkyl, halo or haloalkyl, each of which is optionally substituted.
In some embodiments, each R is independently Ci-C6 alkyl, Ci-C6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted. In some embodiments, each R is independently Ci-C6 alkyl, halo, haloalkyl, alkoxy, hydroxy, cyano, amino or alkylamino, each of which is optionally substituted. In some embodiments, each R is independently Ci-C6 alkyl, halo, haloalkyl or hydroxy, each of which is optionally substituted.
In some embodiments, R a and R are each independently H, Ci-C6 alkyl, halo, haloalkyl, or CN. In some embodiments, R8a and R8b are H.
In some embodiments, Z is CR17. In some embodiments, R17 is H.
Alternatively, the compound has the following formula:
Figure imgf000046_0001
wherein s is 0, 1, 2 or 3; t is 0, 1 or 2 and u is 0, 1, 2 or 3.
In some embodiments, t is 1.
In some embodiments, W is -COOH. In another embodiment, W is a carboxylic acid mimic or bioisostere, for example, -C(O)NHS(O)2CH3.
In some embodiments, Z is CR 7. In some embodiments, R 7 is H;
In some embodiments, n is 0.
In some embodiments, n is 1.
In some embodiments, each R and R is independently H, Ci-C6 alkyl, C2-C6 alkenyl, halo, haloalkyl, Ci-C6 alkoxy, cyclyl, cyclylalkyl, halocyclyl or halocyclylalkyl; or R1 and R2, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring. In some embodiments, each R1 and R2 is independently H, Ci-C6 alkyl, haloalkyl or Ci-C6 alkoxy; or R1 and R2, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring. In some embodiments, each R1 and R2 is independently H, Ci-C6 alkyl or haloalkyl; or R1 and R2, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring. In some embodiments, each R1 and R2 is independently H or Ci-C6 alkyl; or R and R , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
In some embodiments, each R and R5 is independently H, Ci-Cs alkyl, haloalk hydroxy, cyclyl, cyclylalkyl, aryl or heteroaryl, each of which is optionally substituted with 1-3 R12. In some embodiments, R4 and R5 is independently H, Ci-Cs alkyl, haloalkyl, cyclylalkyl, cyclyl, aryl or heteroaryl.
In some embodiments, each R12 is independently Ci-C6 alkyl, Ci-C6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R is independently Ci-C6 alkyl, halo, haloalkyl or alkoxy, each of which is optionally substituted; or wherein two R12 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R12 is independently Ci-C6 alkyl, halo or haloalkyl, each of which is optionally substituted.
In some embodiments, each R14 is independently Ci-C6 alkyl, Ci-C6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted. In some embodiments, each R14 is independently Ci-C6 alkyl, halo, haloalkyl, alkoxy, hydroxy, cyano, amino or alkylamino, each of which is optionally substituted. In some embodiments, each R14 is independently Ci-C6 alkyl, halo, haloalkyl or hydroxy, each of which is optionally substituted.
In some embodiments, R8a and R8b are each independently H, Ci-C6 alkyl, halo, haloalkyl, or CN. In some embodiments, R8a and R8b are H.
In some embodiments, Z is CR17. In some embodiments, R17 is H.
In some embodiments, each R14 is independently Ci-C6 alkyl. In some embodiments, u and t are both 1 and R14 is at the para position with respect to the nitrogen ring atom.
In some embodiments, W is -COOH; n is O or 1 ; R4 and R5 are independently H, Ci-C6 alkyl or haloalkyl; s is 1 or 2; u is O or 1; and t is 1. In some embodiments, W is - COOH; n is 1; each R1 and R2 are independently H or Ci-C6 alkyl; R4 and R5 are each independently H, aryl or heteroaryl; each R11 is independently Ci-C6 alkyl, halo or haloalkyl; R14 is methyl, ethyl, halomethyl or haloethyl; s is 1 or 2; u is 0 or 1 and t is 1. In another embodiment, the compound has the following formula:
Figure imgf000048_0001
wherein v is 0, 1 or 2.
In some embodiments, m is 1.
In some embodiments, W is -COOH. In another embodiment, W is a carboxylic acid mimic or bioisostere, for example, -C(O)NHS(O)2CHs.
In some embodiments, Z is CR17. In some embodiments, R17 is H;
In some embodiments, A is a bond. In another embodiment, A is O. In yet another embodiment, A is NR10. Also, R10 is hydrogen in another embodiment.
In some embodiments, R is aryl, heteroaryl, each of which is optionally substituted with 1 -3 R . In some embodiments, R is aryl optionally substituted with 1 -3 R . In some embodiments, R is heteroaryl optionally substituted with 1-3 R .
In some embodiments, each R is independently Ci-C6 alkyl, Ci-C6 alkenyl, halo, haloalkyl, haloalkoxy, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R is independently Ci-C6 alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, amino or alkylamino, each of which is optionally substituted; or wherein two R11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R11 is independently Ci-C6 alkyl, halo, haloalkyl, haloalkoxy or alkoxy; or wherein two R11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R11 is independently Ci-C6 alkyl, halo, haloalkyl or haloalkoxy.
In some embodiments, each R4 and R5 is independently H, Ci-Cs alkyl, haloalkyl, hydroxy, cyclyl, cyclylalkyl, aryl or heteroaryl, each of which is optionally substituted with 1-3 R12. In some embodiments, R4 and R5 is independently H, Ci-Cs alkyl, haloalkyl, cyclylalkyl, cyclyl, aryl or heteroaryl.
In some embodiments, each R12 is independently Ci-C6 alkyl, Ci-C6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R12 is independently Ci-C6 alkyl, halo, haloalkyl or alkoxy, each of which is optionally substituted; or wherein two R12 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R12 is independently Ci-C6 alkyl, halo or haloalkyl, each of which is optionally substituted.
In some embodiments, R6 and R7 are each independently H, Ci-Cs alkyl, cyclyl, aryl, heteroaryl, cyclylalkyl or arylalkyl, each of which is optionally substituted with 1-3 R13; wherein when B is O, R7 is absent; wherein when B is N, R6 and R7, together with the nitrogen to which they are attached, may form a 3-7 membered ring that is optionally saturated or unsaturated, and unsubstituted or substituted with 1-3 R ; and wherein R and R6, together with the atoms to which they are attached, may form a 3-7 membered ring ring that is optionally saturated or unsaturated, and unsubstituted or substituted with 1-3 R15.
In some embodiments, each R13, R14 and R15 is independently Ci-C6 alkyl, Ci-C6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two, R13, R14 and R15 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R , R and R 5 is independently Ci-C6 alkyl, halo, haloalkyl, alkoxy, hydroxy, cyano, amino or alkylamino, each of which is optionally substituted; or wherein two , R , R and R 5 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R , R and R 5 is independently Ci-C6 alkyl, halo, haloalkyl or hydroxy, each of which is optionally substituted; or wherein two , R , R and R together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
In some embodiments, Z is CR17. In some embodiments, R17 is H.
In yet another embodiment, the compound has the following formula:
Figure imgf000050_0001
wherein v is 0, 1 or 2 and s is 0, 1, 2 or 3.
In some embodiments, m is 1.
In some embodiments, W is -COOH. In another embodiment, W is a carboxylic acid mimic or bioisostere, for example, -C(O)NHS(O)2CHs.
In some embodiments, Z is CR17. In some embodiments, R17 is H;
In some embodiments, each R11 is independently Ci-C6 alkyl, Ci-C6 alkenyl, halo, haloalkyl, haloalkoxy, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R is independently Ci-C6 alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, amino or alkylamino, each of which is optionally substituted; or wherein two R11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R is independently Ci-C6 alkyl, halo, haloalkyl, haloalkoxy or alkoxy; or wherein two R together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R11 is independently Ci-C6 alkyl, halo, haloalkyl or haloalkoxy.
In some embodiments, each R and R is independently H, Ci-Cs alkyl, haloalkyl, hydroxy, cyclyl, cyclylalkyl, aryl or heteroaryl, each of which is optionally substituted with 1-3 R12. In some embodiments, R4 and R5 is independently H, Ci-Cs alkyl, haloalkyl, cyclylalkyl, cyclyl, aryl or heteroaryl.
In some embodiments, each R12 is independently Ci-C6 alkyl, Ci-C6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R12 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R is independently Ci-C6 alkyl, halo, haloalkyl or alkoxy, each of which is optionally substituted; or wherein two R together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R is independently Ci-C6 alkyl, halo or haloalkyl, each of which is optionally substituted.
In some embodiments, R and R are each independently H, Ci-Cs alkyl, cyclyl, aryl, heteroaryl, cyclylalkyl or arylalkyl, each of which is optionally substituted with 1-3 R13; wherein when B is O, R7 is absent; wherein when B is N, R6 and R7, together with the nitrogen to which they are attached, may form a 3-7 membered ring that is optionally saturated or unsaturated, and unsubstituted or substituted with 1-3 R14; and wherein R4 and R6, together with the atoms to which they are attached, may form a 3-7 membered ring ring that is optionally saturated or unsaturated, and unsubstituted or substituted with 1-3 R15.
In some embodiments, each R , R and R 5 is independently Ci-C6 alkyl, Ci-C6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two, R , R and R 5 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R , R and R is independently Ci-C6 alkyl, halo, haloalkyl, alkoxy, hydroxy, cyano, amino or alkylamino, each of which is optionally substituted; or wherein two , R , R and R together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R13, R14 and R15 is independently Ci-C6 alkyl, halo, haloalkyl or hydroxy, each of which is optionally substituted; or wherein two , R13, R14 and R15 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring.
In some embodiments, Z is CR17. In some embodiments, R17 is H.
In one aspect, the invention features a compound of formula (III):
Figure imgf000052_0001
wherein: m is 1, 2 , 3 or 4; n is 0, 1 or ? •
W is -COOH, or a carboxylic acid mimic or bioisostere; Z is N, NR16, CR17 or CR18R19; each R1 and R2 is independently H, Ci-C6 alkyl, C2-C6 alkenyl, halo, haloalkyl, Ci-C6 alkoxy, cyclyl, cyclylalkyl, halocyclyl or halocyclylalkyl; or R1 and R2, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring; wherein either R or R is optionally taken together with R or R to form an optionally substituted, saturated or unsaturated 3-7 membered ring;
A is a bond, NR10, O, S, alkylenyl, amide, ester, carbamate, urea, thiourea or sulfonylurea;
R is aryl, heteroaryl, cyclyl or heterocyclyl, each of which is optionally substituted with 1-3 R11; each R4 and R5 is independently H, Ci-Cs alkyl, haloalkyl, cyclyl, cyclylalkyl, aryl or heteroaryl, each of which is optionally substituted with 1-3 R12; or R4 and R5, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring;
Y is an aryl, heteroaryl, cyclyl or heterocyclyl ring;
R8a, R8b, R9a and R9b are each independently H, Ci-C6 alkyl, hydroxy, halo, haloalkyl, or CN;
R10 is hydrogen, Ci-C6 alkyl or haloalkyl; and each R11 and R12 is independently Ci-C6 alkyl, Ci-C6 alkenyl, Ci-C6 alkynyl, halo, haloalkyl, alkoxy, haloalkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, carboxylate, cyano, oxo, nitro, amino, alkylamino, dialkylamino, mercapto, thioalkyl, aryloxy, thioalkoxy, amido, SO3H, sulfate, S(O)NH2, S(O)2NH2, phosphate or acyl, each of which is optionally substituted; or wherein two R11 or R12, together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring, each R16, R17, R18, and R19 is independently H, Ci-C6 alkyl, hydroxy, halo, haloalkyl, or CN; each R20 is independently Ci-Cs alkyl; and each independently represents the presence or absence of a bond; wherein when represents the presence of a bond to the carbon to which R8b is attached, R8b is absent; and wherein when represents the presence of a bond to the carbon to which
R is attached, R is absent; and wherein when represents the presence of a bond to
Z, then Z is N or CR17, or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, tautomer, enantiomer, stereoisomer, analog or derivative thereof, including mixtures thereof in any ratios.
In a preferred embodiment, W is -COOH. In another embodiment, W is a carboxylic acid mimic or bioisostere, for example, -C(O)NHS(O)2CHs.
In some embodiments, n is O.
In some embodiments, n is 1.
In some embodiments, each R1 and R2 is independently H, Ci-C6 alkyl, C2-C6 alkenyl, haloalkyl, Ci-C6 alkoxy, cyclyl, cyclylalkyl, halocyclyl or halocyclylalkyl; or R1 and R2, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring. In some embodiments, each R1 and R2 is independently H or Ci-C6 alkyl; or R1 and R2, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
In some embodiments, R and R are both H. In some embodiments, R and R are both Ci-C6 alkyl (e.g., methyl or ethyl). In some embodiments, one of R1 and R2 is methyl and the other is sec-butyl. In some embodiments, one of R and R is hydrogen and the other is Ci-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, sec-butyl or neopentyl). In some embodiments, one of R and R is hydrogen and the other is C2-C6 alkenyl (e.g., C3 alkenyl or ally 1) . In some embodiments, one of R1 and R2 is hydrogen and the other is cyclylalkyl (e.g., cyclopropylmethyl).
In some embodiments, R1 and R2, together with the carbon to which they are attached, form a ring (e.g., a cyclopentyl, cyclobutyl, or cyclopropyl ring). In some embodiments, R8 is taken with one of R1 and R2, together with the carbons to which they are attached, to form a ring (e.g., a 5-membered ring or a 6- membered ring).
In some embodiments, A is a bond. In another embodiment, A is O. In yet another embodiment, A is NR10. In some embodiments, R10 is hydrogent.
In some embodiments, R is aryl, heteroaryl, each of which is optionally substituted with 1-3 R11. In some embodiments, R3 is aryl optionally substituted with 1-3 R11.
In some embodiments, each R11 is independently Ci-C6 alkyl, Ci-C6 alkenyl, halo, haloalkyl, haloalkoxy, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R11 is independently Ci-C6 alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, amino or alkylamino, each of which is optionally substituted; or wherein two R11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R is independently Ci-C6 alkyl, halo, haloalkyl, haloalkoxy or alkoxy; or wherein two R11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and ooppttiioonnaallllyy ssuubbssttiittuutteedd rriinngg.. IInn some embodiments, each R11 is independently Ci-C6 alkyl, halo, haloalkyl or haloalkoxy.
IInn ssoommee eemmbbood< iments, R3 is aryl, e.g., phenyl. In some embodiments, R3 is unsubstituted phenyl.
In some embodiments, R3 is phenyl substituted with one R11. In some embodiments, R3 is substituted at the ortho position. In some embodiments, R3 is substituted at the meta position. In some embodiments, R3 is substituted at the para position. In some embodiments, R11 is halo (e.g., fluoro or chloro). In some embodiments, R11 is haloalkyl (e.g., trifiuoromethyl). In some embodiments, R11 is haloalkoxy (e.g., trifluoromethoxy). In some sembodiments, R11 is Ci-C6 alkyl, e.g., C3 alkyl (e.g., isopropyl) or C4 alkyl (e.g., tert-butyl). In some embodiments, R11 is alkoxy (e.g., methoxy).
In some embodiments, R is phenyl substituted with two R . In some embodiments, both R are Ci-C6 alkyl (e.g., methyl). In some embodiments, both R are halo (e.g., fluoro). In some embodiments, one R is halo (e.g., fluoro) and the other is haloalkyl (e.g., trifluoromethyl).
In some embodiments, R is phenyl substituted with three R . In some embodiments, all three R are halo (e.g., fluoro).
In some embodiments, R is pyridyl. In some embodiments, R is unsubstituted pyridyl. In some embodiments, R3 is pyridyl substituted with one R11. In some embodiments, R11 is haloalkyl (e.g., trifluoromethyl).
In some embodiments, R3 is pyrimidyl. In some embodiments, R3 is unsubstituted pyrimidyl. In some embodiments, R3 is pyrimidyl substituted with one R11. In some embodiments, R11 is Ci-C6 alkyl, e.g., C4 alkyl (e.g., tert-butyl).
In some embodiments, m is 1.
In some embodiments, each R and R5 is independently H, Ci-Cs alkyl, haloalkyl, hydroxy, cyclyl, cyclylalkyl, aryl or heteroaryl, each of which is optionally substituted with 1-3 R . In some embodiments, R and R5 is independently H, Ci-Cs alkyl, haloalkyl, cyclylalkyl, cyclyl, aryl or heteroaryl.
In some embodiments, each R is independently Ci-C6 alkyl, Ci-C6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R12 is independently Ci-C6 alkyl, halo, haloalkyl or alkoxy, each of which is optionally substituted; or wherein two R12 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R12 is independently Ci-C6 alkyl, halo or haloalkyl, each of which is optionally substituted.
In some embodiments, R4 is hydrogen or Ci-Cs alkyl.
In some embodiments, R5 is aryl (e.g., phenyl). In some embodiments, R5 is unsubstituted phenyl.
In some embodiments, R5 is phenyl substituted with one R12. In some embodiments, R5 is substituted at the ortho position. In some embodiments, R5 is substituted at the meta position. In some embodiments, R5 is substituted at the para position.
IInn some embodiments, R12 is halo (e.g., fluoro or chloro). In some embodiments,
R12 is haloalkyl (e.g., trifluoromethyl). In some embodiments, R12 is Ci-C6 alkyl, e.g., C3 alkyl (e.g., isopropyl), or C4 alkyl (e.g., tert-butyl). In some embodiments, R12 is -CN.
In some embodiments, R5 is phenyl substituted with two R12. In some embodiments, both R12 are halo (e.g., fluoro).
In some embodiments, R5 is heteroaryl.
In some embodiments, R5 is pyridyl. In some embodiments, R5 is unsubstituted pyridyl.
In some embodiments, R5 is pyridyl substituted with one R12. In some embodiments, R12 is halo (e.g., fluoro). In some embodiments, R12 is haloalkyl (e.g., trifluoromethyl).
In some embodiments, R5 is indolyl.
In some embodiments, R5 is imidazolyl.
In some embodiments, R5 is imidazolyl substituted with one R12. In some embodiments, R12 is haloalkyl (e.g., trifluoromethyl).
In some embodiments, R5 is thiazolyl.
In some embodiments, R5 is pyrazolyl. In some embodiments, R5 is pyrazolyl substituted with 1-3 R12. In some embodiments, R5 is pyrazolyl substituted with three R12. In some embodiments, one R12 is Ci-C6 alkyl (e.g., methyl), one is halo (e.g., fluoro) and one is haloalkyl (trifluoromethyl).
In some embodiments, R5 is:
Figure imgf000058_0001
In some embodiments, R is pyrimidyl. In some embodiments, r R> 5 is unsubstituted pyrimidyl. In some embodiments, R5 is pyrimidyl substituted with one R12. In some embodiments, R12 is Ci-C6 alkyl, e.g., C4 alkyl (e.g., tert-butyl).
In some embodiments, R5 is indazolyl. In some embodiments, R5 is indazolyl substituted with one R12. In some embodiments, R12 is Ci-C6 alkyl (e.g., methyl).
In some embodiments, R5 is hydrogen.
In some embodiments, R5 is Ci-Cs alkyl. In some embodiments, R5 is methyl. In some embodiments, R5 is C5 alkyl, e.g., isopentyl (3-methylbutyl) or neopentyl (2,2- dimethylpropyl). In some embodiments, R5 is C6 alkyl, e.g., neohexyl (3,3- dimethylbutyl).
In some embodiments, R5 is cyclyl, e.g., cycloalkyl (e.g., cyclohexyl). In some embodiments, R5 is bicyclo[2.2.2]octanyl.
In some embodiments, R5 is cyclylalkyl, e.g., cyclohexylmethyl.
In some embodiments, R5 is haloalkyl (e.g., 2,2,2 -trifluoroethoxy, 3,3,3- trifluoropropyl or 4,4,4-trifluorobutyl).
In some embodiments, Y is heterocyclyl (e.g., piperidinyl, piperizinyl, pyrollidinyl or morpholinyl).
In yet another embodiment, the compound has the following formula:
Figure imgf000059_0001
wherein Y is cyclyl or aryl.
In some embodiments, Y is cyclyl.
In some embodiments, Y is aryl.
In some embodiments, m is 1.
In some embodiments, W is -COOH. In another embodiment, W is a carboxylic acid mimic or bioisostere, for example, -C(O)NHS(O)2CHs.
In some embodiments, Z is CR 7. In some embodiments, R 7 is H;
In some embodiments, n is O.
In some embodiments, n is 1.
In some embodiments, each R and R is independently H, Ci-C6 alkyl, C2-C6 alkenyl, halo, haloalkyl, Ci-C6 alkoxy, cyclyl, cyclylalkyl, halocyclyl or halocyclylalkyl; or R1 and R2, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring. In some embodiments, each R1 and R2 is independently H, Ci-C6 alkyl, haloalkyl or Ci-C6 alkoxy; or R1 and R2, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring. In some embodiments, each R1 and R2 is independently H, Ci-C6 alkyl or haloalkyl; or R1 and R2, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring. In some embodiments, each R and R is independently H or Ci-C6 alkyl; or R and R , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring. In some embodiments, A is a bond. In another embodiment, A is O. In yet another embodiment, A is NR10. Also, R10 is hydrogen in another embodiment.
In some embodiments, R3 is aryl, heteroaryl, each of which is optionally substituted with 1-3 R11. In some embodiments, R3 is aryl optionally substituted with 1-3 R11. In some embodiments, R3 is heteroaryl optionally substituted with 1-3 R11.
In some embodiments, each R11 is independently Ci-C6 alkyl, Ci-C6 alkenyl, halo, haloalkyl, haloalkoxy, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R11 is independently Ci-C6 alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, amino or alkylamino, each of which is optionally substituted; or wherein two R11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R11 is independently Ci-C6 alkyl, halo, haloalkyl, haloalkoxy or alkoxy; or wherein two R11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R11 is independently Ci-C6 alkyl, halo, haloalkyl or haloalkoxy.
In some embodiments, each R4 and R5 is independently H, Ci-Cs alkyl, haloalkyl, hydroxy, cyclyl, cyclylalkyl, aryl or heteroaryl, each of which is optionally substituted with 1-3 R12. In some embodiments, R4 and R5 is independently H, Ci-Cs alkyl, haloalkyl, cyclylalkyl, cyclyl, aryl or heteroaryl.
In some embodiments, each R12 is independently Ci-C6 alkyl, Ci-C6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R12 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R12 is independently Ci-C6 alkyl, halo, haloalkyl or alkoxy, each of which is optionally substituted; or wherein two R > 12 . together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R is independently Ci-C6 alkyl, halo or haloalkyl, each of which is optionally substituted.
In some embodiments, R8a, R8b, R9b and R9a are each independently H, Ci-C6 alkyl, halo, haloalkyl, or CN. In some embodiments, R8a, R8b, R9b and R9a are H.
In some embodiments, Z is CR 7. In some embodiments, R 7 is H.
In still another embodiment, the compound has the following formula:
Figure imgf000061_0001
wherein Y is heterocyclyl (e.g., piperidinyl, pyrazolyl, pyrollidinyl, piperazinyl or morpholinyl).
In some embodiments, m is 1.
In some embodiments, W is -COOH. In another embodiment, W is a carboxylic acid mimic or bioisostere, for example, -C(O)NHS(O)2CHs.
In some embodiments, Z is CR17. In some embodiments, R17 is H;
In some embodiments, n is O.
In some embodiments, n is 1.
In some embodiments, each R1 and R2 is independently H, Ci-C6 alkyl, C2-C6 alkenyl, halo, haloalkyl, Ci-C6 alkoxy, cyclyl, cyclylalkyl, halocyclyl or halocyclylalkyl; or R and R , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring. In some embodiments, each R and R2 is independently H, Ci-C6 alkyl, haloalkyl or Ci-C6 alkoxy; or R1 and R2, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring. In some embodiments, each R1 and R2 is independently H, Ci-C6 alkyl or haloalkyl; or R1 and R2, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring. In some embodiments, each R1 and R2 is independently H or Ci-C6 alkyl; or R1 and R2, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring.
In some embodiments, A is a bond. In another embodiment, A is O. In yet another embodiment, A is NR10. Also, R10 is hydrogen in another embodiment.
In some embodiments, R3 is aryl, heteroaryl, each of which is optionally substituted with 1-3 R11. In some embodiments, R3 is aryl optionally substituted with 1-3 R11. In some embodiments, R3 is heteroaryl optionally substituted with 1-3 R11.
In some embodiments, each R11 is independently Ci-C6 alkyl, Ci-C6 alkenyl, halo, haloalkyl, haloalkoxy, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R is independently Ci-C6 alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, amino or alkylamino, each of which is optionally substituted; or wherein two R11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R is independently Ci-C6 alkyl, halo, haloalkyl, haloalkoxy or alkoxy; or wherein two R11 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R11 is independently Ci-C6 alkyl, halo, haloalkyl or haloalkoxy.
In some embodiments, each R4 and R5 is independently H, Ci-Cs alkyl, haloalkyl, hydroxy, cyclyl, cyclylalkyl, aryl or heteroaryl, each of which is optionally substituted with 1-3 R12. In some embodiments, R4 and R5 is independently H, Ci-Cs alkyl, haloalkyl, cyclylalkyl, cyclyl, aryl or heteroaryl.
In some embodiments, each R12 is independently Ci-C6 alkyl, Ci-C6 alkenyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, cyano, oxo, nitro, amino, alkylamino or acyl, each of which is optionally substituted; or wherein two R together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R is independently Ci-C6 alkyl, halo, haloalkyl or alkoxy, each of which is optionally substituted; or wherein two R12 together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring. In some embodiments, each R12 is independently Ci-C6 alkyl, halo or haloalkyl, each of which is optionally substituted.
In some embodiments, R8a and R9a are each independently H, Ci-C6 alkyl, halo, haloalkyl, or CN. In some embodiments, R8a and R9a are H.
In some embodiments, Z is CR17. In some embodiments, R17 is H.
In one aspect, the invention features a compound of formula (IV):
Figure imgf000063_0001
wherein: m is 0, 1, 2, 3 or 4; n is 0, 1 or 2;
W is -COOH, or a carboxylic acid mimic or bioisostere; each R1 and R2 is independently H, Ci-C6 alkyl, C2-C6 alkenyl, halo, haloalkyl, Ci-C6 alkoxy, cyclyl, cyclylalkyl, halocyclyl or halocyclylalkyl; or R1 and R2, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring;
A is a bond, NR10, O, S, alkylenyl, amide, ester, carbamate, urea, thiourea or sulfonylurea;
B is N or O;
R3 is aryl, heteroaryl, cyclyl or heterocyclyl, each of which is optionally substituted with 1-3 R11; each R4 and R5 is independently H, Ci-Cs alkyl, haloalkyl, cyclyl, cyclylalkyl, aryl or heteroaryl, each of which is optionally substituted with 1-3 R12; or R4 and R5, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring;
R6 and R7 are each independently H, Ci-Cs alkyl, cyclyl, aryl, heteroaryl, cyclylalkyl or arylalkyl, each of which is optionally substituted with 1-3 R13; wherein when B is O, R7 is absent; wherein when B is N, R6 and R7, together with the nitrogen to which they are attached, may form a ring that is optionally substituted with 1-3 R14; and wherein R4 and R6, together with the atoms to which they are attached, optionally form ring that is optionally substituted with 1-3 R15;
R10 is hydrogen, Ci-C6 alkyl or haloalkyl; and each R11, R12, R13, R14 and R15 is independently Ci-C6 alkyl, Ci-C6 alkenyl, Ci-C6 alkynyl, halo, haloalkyl, alkoxy, haloalkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, arylalkyl, hetero arylalkyl, cyclylalkyl, hetero cyclylalkyl, carboxylate, cyano, oxo, nitro, amino, alkylamino, dialkylamino, mercapto, thioalkyl, aryloxy, thioalkoxy, amido, SO3H, sulfate, S(O)NH2, S(O)2NH2, phosphate or acyl, each of which is optionally substituted; wherein two R11, R12, R13, R14 or R15, together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring, each R20 is independently Ci-Cs alkyl, or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, tautomer, enantiomer, stereoisomer, analog or derivative thereof, including mixtures thereof in any ratios.
In a preferred embodiment, W is -COOH. In another embodiment, W is a carboxylic acid mimic or bioisostere, for example, -C(O)NHS(O)2CHs.
In some embodiments, n is 1. In some embodiments, R and R are both H.
In one embodiment, A is a bond. In another embodiment, A is O. In yet another embodiment, A is NR . Also, R is hydrogen in another embodiment.
In some embodiments, R is aryl, e.g., phenyl. In some embodiments, R is phenyl substituted with one R . In some embodiments, R is substituted at the ortho position. In some embodiments, R3 is substituted at the meta position. In some embodiments, R3 is substituted at the para position. In some embodiments, R11 is halo (e.g., fluoro or chloro). In some embodiments, R11 is haloalkyl (e.g., trifluoro methyl).
In some embodiments, m is 1.
In some embodiments, R4 is hydrogen or Ci-Cs alkyl.
In some embodiments, R5 is aryl (e.g., phenyl). In some embodiments, R5 is phenyl substituted with one R . In some embodiments, R is haloalkyl (e.g., trifluoromethyl).
In some embodiments, B is N.
In some embodiments, R and R7, together with the nitrogen to which they are attached, form a 6-membered ring, e.g., a piperidine ring. In some embodiments, R and R , together with the nitrogen to which they are attached, form a piperidine ring that is substituted with one R . In some embodiments, R is haloalkyl (e.g., trifluoromethyl).
In one aspect, the invention features a compound of formula (V):
Figure imgf000066_0001
wherein: m is 0, 1, 2, 3 or 4; n is 0, 1 or 2;
W is -COOH, or a carboxylic acid mimic or bioisostere;
Z is N or CH; each R1 and R2 is independently H, Ci-C6 alkyl, C2-C6 alkenyl, halo, haloalkyl, Ci-C6 alkoxy, eye IyI or cyclylalkyl; or R1 and R2, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring; wherein either R1 or R2 are optionally taken together with R8 or R9 to form an optionally substituted, saturated or unsaturated 3-7 membered ring;
A is a bond, NR10, O, S, alkylenyl, amide, ester, carbamate, urea, thiourea or sulfonylurea;
B is N or O;
R is aryl, heteroaryl, cyclyl or heterocyclyl, each of which is optionally substituted with 1-3 R11; each R and R is independently H, Ci-Cs alkyl, haloalkyl, cyclyl, cyclylalkyl, aryl or heteroaryl, each of which is optionally substituted with 1-3 R ; or R and R , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring;
R6 and R7 are each independently H, Ci-Cs alkyl, cyclyl, aryl, heteroaryl, cyclylalkyl or arylalkyl, each of which is optionally substituted with 1-3 R13; wherein when B is O, R7 is absent; wherein when B is N, R6 and R7, together with the nitrogen to which they are attached, may form a ring that is optionally substituted with 1-3 R14; and wherein R4 and R6, together with the atoms to which they are attached, optionally form ring that is optionally substituted with 1-3 R 5;
R8 and R9 are each independently H, Ci-C6 alkyl, hydroxy, halo, haloalkyl, or CN;
R10 is hydrogen, Ci-C6 alkyl or haloalkyl; and each R11, R12, R13, R14 and R15 is independently Ci-C6 alkyl, Ci-C6 alkenyl, Ci-C6 alkynyl, halo, haloalkyl, alkoxy, haloalkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, carboxylate, cyano, oxo, nitro, amino, alkylamino, dialkylamino, mercapto, thioalkyl, aryloxy, thioalkoxy, amido, SO3H, sulfate, S(O)NH2, S(O)2NH2, phosphate or acyl, each of which is optionally substituted; wherein two R11, R12, R13, R14 or R15, together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring, each R20 is independently Ci-Cs alkyl, or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, tautomer, enantiomer, stereoisomer, analog or derivative thereof, including mixtures thereof in any ratios.
In a preferred embodiment, W is -COOH. In another embodiment, W is a carboxylic acid mimic or bioisostere, for example, -C(O)NHS(O)2CH3.
In some embodiments, n is O.
In some embodiments, n is 1. In some embodiments, R and R are both H. In some embodiments, R1 and R2 are both Ci-C6 alkyl (e.g., methyl or ethyl). In some embodiments, one of R and R is methyl and the other is sec-butyl. In some embodiments, one of R1 and R2 is hydrogen and the other is Ci-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, sec-butyl or neopentyl). In still another embodiment, one of R1 and R2 is hydrogen and the other is C2-C6 alkenyl (e.g., C3 alkenyl or allyl). In some embodiments, one of R1 and R2 is hydrogen and the other is cyclylalkyl (e.g., cyclopropylmethyl). In some embodiments, one of R1 and R2 is hydrogen and the other is cyclylalkyl (e.g., cyclopropylmethyl).
In some embodiments, R and R , together with the carbon to which they are attached, form a ring (e.g., a cyclopentyl, cyclobutyl, or cyclopropyl ring).
In some embodiments, R is taken with one of R and R , together with the carbons to which they are attached, to form a ring (e.g., a 5-membered ring or a 6- membered ring).
In one embodiment, A is a bond. In another embodiment, A is O. In yet another embodiment, A is NR . Also, R is hydrogen in another embodiment.
In some embodiments, R is aryl, e.g., phenyl. In some embodiments, R is unsubstituted phenyl.
In some embodiments, R3 is phenyl substituted with one R11. In some embodiments, R3 is substituted at the ortho position. In some embodiments, R3 is substituted at the meta position. In some embodiments, R3 is substituted at the para position. In some embodiments, R11 is halo (e.g., fluoro or chloro). In some embodiments, R11 is haloalkyl (e.g., trifiuoromethyl). In some embodiments, R11 is haloalkoxy (e.g., trifluoromethoxy). In some embodiments, R11 is Ci-C6 alkyl, e.g., C3 alkyl (e.g., isopropyl) or C4 alkyl (e.g., tert-butyl). In some embodiments, R11 is alkoxy (e.g., methoxy).
In some embodiments, R is phenyl substituted with two R . In some embodiments, both R are Ci-C6 alkyl (e.g., methyl). In some embodiments, both R are halo (e.g., fluoro). In some embodiments, one R is halo (e.g., fluoro) and the other is haloalkyl (e.g., trifiuoromethyl).
In some embodim neents, R is phenyl substituted with three R . In some embodiments, all three R i l l are halo (e.g., fluoro).
In some embodiments, R3 is pyridyl. In some embodiments, R3 is unsubstituted pyridyl. In some embodiments, R3 is pyridyl substituted with one R11. In some embodiments, R11 is haloalkyl (e.g., trifiuoromethyl). In some embodiments, R3 is pyrimidyl. In some embodiments, R3 is unsubstituted pyrimidyl. In some embodiments, R3 is pyrimidyl substituted with 1 R11. In some embodiments, R11 is Ci-C6 alkyl, e.g., C4 alkyl (e.g., tert-butyl).
In some embodiments, m is 1.
In some embodiments, R4 is hydrogen or Ci-Cs alkyl.
In some embodiments, R5 is aryl (e.g., phenyl). In some embodiments, R5 is unsubstituted phenyl.
In some embodiments, R5 is phenyl substituted with one R12.
In some embodiments, R12 is halo (e.g., fluoro or chloro). In some embodiments, R12 is haloalkyl (e.g., trifluoromethyl). In some embodiments, R12 is Ci-C6 alkyl, e.g., C3 alkyl (e.g., isopropyl), or C4 alkyl (e.g., tert-butyl). In some embodiments, R12 is -CN.
In some embodiments, R5 is phenyl substituted with two R12. In some embodiments, both R12 are halo (e.g., fluoro).
In some embodiments, R5 is heteroaryl.
In some embodiments, R5 is pyridyl. In some embodiments, R5 is unsubstituted pyridyl.
In some embodiments, R5 is pyridyl substituted with one R12. In some embodiments, R12 is halo (e.g., fluoro). In some embodiments, R12 is haloalkyl (e.g., trifluoromethyl).
In some embodiments, R5 is imidazolyl.
In some embodiments, R5 is imidazolyl substituted with one R12. In some embodiments, R12 is haloalkyl (e.g., trifluoromethyl).
In some embodiments, R5 is thiazolyl.
In some embodiments, R5 is pyrazolyl. In some embodiments, R5 is pyrazolyl substituted with 1-3 R12. In some embodiments, R5 is pyrazolyl substituted with three R12. In some embodiments, one R12 is Ci-C6 alkyl (e.g., methyl), one is halo (e.g., fluoro) and one is haloalkyl (trifluoromethyl).
In some embodiments, R5 is:
Figure imgf000070_0001
In some embodiments, R5 is pyrimidyl. In some embodiments, R5 is unsubstituted pyrimidyl. In some embodiments, R5 is pyrimidyl substituted with one R12. In some embodiments, R12 is C1-C6 alkyl, e.g., Ci alkyl (e.g., methyl) or C4 alkyl (e.g., tert-butyl).
In some embodiments, R5 is indolyl.
In some embodiments, R5 is indazolyl. In some embodiments, R5 is indazolyl substituted with one R12. In some embodiments, R12 is Ci-C6 alkyl (e.g., methyl).
In some embodiments, R5 is hydrogen.
In some embodiments, R5 is Ci-Cs alkyl. In some embodiments, R5 is methyl. In some embodiments, R5 is C5 alkyl, e.g., isopentyl (3-methylbutyl) or neopentyl (2,2- dimethylpropyl). In some embodiments, R5 is C6 alkyl, e.g., neohexyl (3,3- dimethylbutyl).
In some embodiments, R5 is cyclyl, e.g., cycloalkyl (e.g., cyclohexyl). In some embodiments, R5 is bicyclo[2.2.2]octanyl.
In some embodiments, R5 is cyclylalkyl, e.g., cyclohexylmethyl.
In some embodiments, R5 is haloalkyl (e.g., 2,2,2 -trifluoroethoxy or 3,3,3- trifluoropropyl).
In some embodiments, B is O and R7 is absent.
In some embodiments, R6 is aryl, e.g., phenyl. In some embodiments, R6 is phenyl substituted with one R13. In some embodiments, R6 is substituted at the ortho position. In some embodiments, R6 is substituted at the meta position. In some embodiments, R6 is substituted at the para position. In some embodiments, R13 is haloalkyl (e.g., trifluoromethyl).
In some embodiments, B is N. In some embodiments, R6 and R7, together with the nitrogen to which they are attached, form a ring, e.g., a 4-membered ring (e.g., an azetidine ring).
In some embodiments, R6 and R7, together with the nitrogen to which they are attached, form a 5-membered ring, e.g., a pyrrolidine ring. In some embodiments, R6 and R7, together with the nitrogen to which they are attached, form a pyrrolidine ring that is substituted with one R14. In some embodiments, R14 is halo (e.g., fluoro). In some embodiments, R14 is Ci-C6 alkyl (e.g., sec-butyl).
In some embodiments, R6 and R7, together with the nitrogen to which they are attached, form a pyrrolidine ring that is substituted with two R14. In some embodiments, both R14 are Ci-C6 alkyl (e.g., methyl). In some embodiments, both R14 are halo (e.g., fluoro). In some embodiments, two R14, together with the atoms to which they are attached, form a ring, e.g., a 3-membered ring, a 5-membered ring or a 6-membered ring (e.g., a phenyl ring).
In some embodiments, R6 and R7, together with the nitrogen to which they are attached, form a 6-membered ring, e.g., a piperidine ring. In some embodiments, R6 and R7, together with the nitrogen to which they are attached, form a piperidine ring that is unsubstituted.
In some embodiments, R6 and R7, together with the nitrogen to which they are attached, form a piperidine ring that is substituted with one R . In some embodiments, R14 is halo (e.g., fluoro). In some embodiments, R14 is Ci-C6 alkyl, e.g., methyl. In some embodiments, R14 is C3 alkyl (e.g., n-propyl). In some embodiments, R14 is C4 alkyl (e.g., tert-butyl or isobutyl). In some embodiments, R14 is haloalkyl (e.g., trifluoromethyl). In some embodiments, R14 is alkoxy (e.g., methoxy or ethoxy). In some embodiments, R14 is aryl (e.g., phenyl). In some embodiments, R14 is cyano. In some embodiments, R14 is a carboxylate. In some embodiments, R14 is -SO2CH3.
In some embodiments, R6 and R7, together with the nitrogen to which they are attached, form a piperidine ring that is substituted with two R14. In some embodiments, both R14 are halo (e.g., fluoro). In some embodiments, both R14 are Ci-C6 alkyl (e.g., methyl). In some embodiments, two R14, together with the carbons to which they are attached, form a ring, e.g., a 3-membered ring or a 6-membered ring.
In some embodiments, R6 and R7, together with the nitrogen to which they are attached, form a piperazine ring. In some embodiments, R6 and R7, together with the nitrogen to which they are attached, form a piperazine ring that is unsubstituted. In some embodiments, R6 and R7, together with the nitrogen to which they are attached, form a piperazine ring that is substituted with one R14. In some embodiments, R14 is Ci-C6 alkyl (e.g., methyl).
In some embodiments, R6 and R7, together with the nitrogen to which they are attached, form a piperazine that is substituted with two R14. In yet another embodiment, two R14, together with the carbons to which they are attached, form an optionally substituted ring such as a heteroaryl. In some embodiments, the heteroaryl is a triazole. In some embodiments, the triazole is substituted with a haloalkyl substituent (e.g., trifluoromethyl).
In some embodiments, R6 and R7, together with the nitrogen to which they are attached, form a thiomorpholino.
In some embodiments, R6 and R7, together with the nitrogen to which they are attached, form a 7-membered ring.
In some embodiments, R6 and R7, together with the nitrogen to which they are attached, form a bridged bicyclic ring (e.g., a 3-azabicyclo[3.2.1]octan-3-yl ring). In some embodiments, R6 and R7, together with the nitrogen to which they are attached, form a fused bicyclic ring (e.g., 3-azabicyclo[3.1.0]hexan-3-yl). In some embodiments, R and R , together with the nitrogen to which they are attached, form a spirocyclic ring system (e.g., 6-azaspiro[2.5]octan-6-yl).
In some embodiments, both R6 and R7 are Ci-Cs alkyl. In some embodiments, one of R6 and R7 is methyl and the other is n-heptyl.
In some embodiments, both R6 and R7 are cyclyl. In some embodiments, one of R6 and R7 is cyclopropyl and the other is cyclohexyl. In some embodiments, R6 is Ci-Cs alkyl (e.g., C5 alkyl) and R7 is aryl (e.g., phenyl). In some embodiments, R6 is isopentyl (3-methylbutyl) and R7 is phenyl substituted with one R13. In some embodiments, R13 is Ci-C6 alkyl, e.g., C4 alkyl (e.g., tert-butyl). In some embodiments, R13 is haloalkyl (e.g., trifluoromethyl).
In some embodiments, R6 is Ci-Cs alkyl and R7 is cyclyl.
In some embodiments, R6 is methyl. In some embodiments, R6 is C4 alkyl (e.g., n-butyl or sec-butyl). In some embodiments, R6 is C5 alkyl (e.g., 2,2-dimethylpropyl, 3- methylbutyl or 2-methylbutyl). In some embodiments, R6 is C6 alkyl (e.g., 3,3- dimethylbutyl).
In some embodiments, R is cyclyl, e.g., cycloalkyl (e.g., cyclohexyl). In some embodiments, R7 is cyclohexyl substituted with one R13. In some embodiments, R13 is Ci-C6 alkyl (e.g., methyl). In some embodiments, R13 is C3 alkyl (e.g., isopropyl). In some embodiments, R13 is C4 alkyl (e.g., tert-butyl). In some embodiments, R13 is haloalkyl (e.g., trifluoromethyl). In some embodiments, R13 is halo (e.g., fiuoro). In some embodiments, R13 is -CN.
In some embodiments, R7 is cyclohexyl substituted with two R13. In some embodiments, both R13 are halo (e.g., fluoro). In some embodiments, both R13 are Ci-C6 alkyl (e.g., methyl). In some embodiments, R7 is a bicyclic group, e.g., bicyclo[2.2.2]octane. In some embodiments, R7 is bicyclo[2.2.2]octane substituted with one R13.
In some embodiments, R6 is arylalkyl (e.g., benzyl) and R7 is cyclyl, e.g., cycloalkyl (e.g., cyclohexyl). In some embodiments, R is cyclohexyl substituted with one R13. In some embodiments, R13 is Ci-C6 alkyl, e.g., C4 alkyl (e.g., tert-butyl).
In some embodiments, R6 is cyclylalkyl (e.g., cyclopentylmethyl or cyclohexylmethyl), and R7 is cyclyl, e.g., cycloalkyl (e.g., cyclohexyl). In some embodiments, R7 is cyclohexyl substituted with one R13. In some embodiments, R13 is C1- C6 alkyl, e.g., C4 alkyl (e.g., tert-butyl). In some embodiments, R6 is hydrogen and R7 is cyclyl, e.g., cycloalkyl (e.g., cyclohexyl). In some embodiments, R7 is cyclohexyl substituted with 1-3 R13. In some embodiments, R7 is cyclohexyl substituted with one R13. In some embodiments, R13 is Ci-C6 alkyl (e.g., methyl). In some embodiments, R13 is C3 alkyl (e.g., isopropyl). In some embodiments, R13 is C4 alkyl (e.g., tert-butyl). In some embodiments, R13 is haloalkyl (e.g., trifluoromethyl). In some embodiments, R13 is halo (e.g., fluoro). In some embodiments, R13 is -CN.
In some embodiments, R7 is cyclohexyl substituted with two R13. In some embodiments, both R13 are halo (e.g., fluoro). In some embodiments, both R13 are Ci-C6 alkyl (e.g., methyl).
In some embodiments, R7 is a bicyclic group, e.g., bicyclo[2.2.2]octane. In some embodiments, R7 is bicyclo[2.2.2]octane substituted with one R13. In some embodiments, R13 is haloalkyl (e.g., difluoromethyl).
In some embodiments, R6 is hydrogen and R7 is Ci-Cs alkyl. In some embodiments, R7 is C6 alkyl (e.g., 4-methylpentyl). In some embodiments, R7 is A- methylpentyl that is substituted with one R13. In some embodiments, R13 is aryl (e.g., phenyl). In some embodiments, R13 is phenyl substituted with haloalkyl (e.g., trifluoromethyl).
In some embodiments, R4 and R6, together with the atoms to which they are attached, form a ring, e.g., a 6-membered ring. In some embodiments, R4 and R6, together with the atoms to which they are attached, form a 6-membered ring that is substituted with one R15. In some embodiments, R15 is Ci-C6 alkyl (e.g., methyl). In some embodiments, R15 is haloalkyl (e.g., trifluoromethyl).
In some embodiments, R7 is Ci-C6 alkyl, e.g., C4 alkyl (e.g., sec-butyl) or C5 alkyl (e.g., 2,2-dimethylpropyl). In some embodiments, R7 is haloalkyl (e.g., 4,4,4- trifluorobutyl). In some embodiments, R7 is aryl (e.g., phenyl). In some embodiments, R7 is phenyl substituted with one R13. In some embodiments, R13 is haloalkyl (e.g., trifluoromethyl).
In some embodiments, R7 is arylalkyl (e.g., benzyl). In some embodiments, R7 is benzyl substituted with one R13. In some embodiments, R13 is haloalkyl (e.g., trifluoromethyl).
A compound described herein can be, for example, in a form of an achiral compound, a racemate, an optically active compound, a pure diastereomer, a mixture of diastereomers, or a pharmacologically acceptable salt.
In some embodiments, the compound of formula (I), (II), (III), (IV) or (V) is produced as an S enantiomer in an enantiomeric excess (e.g., 10%, 50%, 75%, 85%, 90%, 95%, 97% or greater). In some embodiments, the compound of formula (I), (II), (III), (IV) or (V) is produced as an R enantiomer in an enantiomeric excess (e.g., 10%, 50%, 75%, 85%, 90%, 95%, 97% or greater).
In some embodiments, the compound of formula (I), (II), (III), (IV) or (V) is produced in as an R,S diastereomer in a diastereomeric excess (e.g., 10%, 50%, 75%, 85%, 90%, 95%, 97% or greater). In some embodiments, the compound of formula (I), (II), (III), (IV) or (V) is produced in as an R,R diastereomer in a diastereomeric excess (e.g., 10%, 50%, 75%, 85%, 90%, 95%, 97% or greater). In some embodiments, the compound of formula (I), (II), (III), (IV) or (V) is produced in as an S,R diastereomer in a diastereomeric excess (e.g., 10%, 50%, 75%, 85%, 90%, 95%, 97% or greater). In some embodiments, the compound of formula (I), (II), (III), (IV) or (V) is produced in as an S,S diastereomer in a diastereomeric excess (e.g., 10%, 50%, 75%, 85%, 90%, 95%, 97% or greater).
In another aspect, the present invention is directed to a method of producing a compound of formula (I) or (II), the method comprising a condensation of a compound of formula (VII):
Figure imgf000076_0001
to produce a compound of formula (VIII):
Figure imgf000076_0002
the method further comprising an asymmetric hydrogenation of a compound of formula (VIII) to produce a compound of formula (XIa) or (XIb);
Figure imgf000076_0003
16 wherein W, R1, R2, R3, R4, R5, R6, R7, R8a, R8b, R9a, R9b, R10, R11, R12, R13, R14, R15, R R17, R18, R19, R20, A, Z, W and m are as defined for a compound of formula (I) or (II).
In some embodiments, the method further comprises a hydrolysis step.
In certain embodiments, the compound of formula (XIa) is produced in an enantiomeric excess (e.g., 10%, 50%, 75%, 85%, 90%, 95%, 97% or greater). In some embodiments, the compound of formula (XIb) is produced in an enantiomeric excess (e.g., 10%, 50%, 75%, 85%, 90%, 95%, 97% or greater).
BRIEF DESCRIPTION OF DRAWINGS
Figure 1 is a table, Table 1, depicting representative compounds analytical data and synthetic methods and EC50 values. Synthetic methods correspond to those described in Schemes 1-7.
Figure 2 is a table, Table 2, depicting representative compounds, and EC50 values.
DETAILED DESCRIPTION
Compounds, compositions comprising those compounds, and related methods of use are described herein. In some embodiments, a compound described herein modulates gamma secretase (e.g., alters the cleavage pattern of gamma secretase), e.g., when administered to a subject.
Compounds
The compounds described herein include the compounds of formula (I), (II), (III), (IV) or (V) wherein n, m, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, A and Z are as defined above. The compounds described herein may also include the intermediate compounds of the formula (VI), (VII), (VIII) or (IX). The compounds described herein can be used for a variety of purposes, e.g., therapeutic purposes. Many of the compounds modulate gamma-secretase activity and can be used, for example to alter the cleavage pattern of gamma secretase, e.g., in a subject.
A compound described herein can be, for example, an enantiomerically enriched isomer of a stereoisomer described herein. For example, the compound may have an enantiomeric excess of at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%. Enantiomer, as used herein, refers to either of a pair of chemical compounds whose molecular structures have a mirror-image relationship to each other. A preparation of a compound disclosed herein may be enriched for an isomer of the compound having a selected stereochemistry, e.g., R or S, corresponding to a selected stereocenter. For example, the compound may have a purity corresponding to a compound having a selected stereochemistry of a selected stereocenter of at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%. A compound described herein can, for example, include a preparation of a compound disclosed herein that is enriched for a structure or structures having a selected stereochemistry, e.g., R or S, at a selected.
In one embodiment, a preparation of a compound disclosed herein is enriched for isomers (subject isomers) which are diastereomers of the compound described herein. For example, the compound has a purity corresponding to a compound having a selected diastereomer of at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%. Diastereomer, when used herein, refers to a stereoisomer of a compound having two or more chiral centers that is not a mirror image of another stereoisomer of the same compound.
The compounds may be prepared in racemic form or as individual enantiomers or diastereomers by either stereospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers or diastereomers by standard techniques, such as the formation of stereoisomeric pairs by salt formation with an optically active base, followed by fractional crystallization and regeneration of the free acid. The compounds may also be resolved by formation of stereoisomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column. The enantiomers also may be obtained from kinetic resolution of the racemate of corresponding esters using lipase enzymes, e.g. AmanoAk, Amano lipase PS, Amano lipaseA, Amano lipase M, Amano lipase F- 15 Amano lipase G (from Biocatalytics Inc) in aqueous organic solvents. A compound described herein can also be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and include those that increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism, and/or alter rate of excretion. Examples of these modifications include, but are not limited to, esterification with polyethylene glycols, derivatization with pivolates or fatty acid substituents, conversion to carbamates, hydro xylation of aromatic rings, and hetero atom- substitution in aromatic rings.
Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms termed polymorphic forms. In general, all physical forms are of use in the methods contemplated by the present invention and are intended to be within the scope of the present invention. "Compound or a pharmaceutically acceptable salt, hydrate, polymorph or solvate of a compound" intends the inclusive meaning of "or", in that materials meeting more than one of the stated criteria are included, e.g., a material that is both a salt and a solvate is encompassed.
A compound described herein can be in the form of a metabolite. A metabolite may be a compound that is related to a compound described herein, as a form of such compound obtained in a human or animal body by action of the body on the administered form of the compound. For example, a metabolite may be a de -methylated analogue of a compound bearing a methyl group, which is obtained in the body after administration of the methylated compound as a result of action by the body on the methylated compound. A metabolite may also be a carboxylic-acid containing compound, which is obtained in the body after administration of the corresponding ester as a result of action by the body on the ester- containing compound. The compounds of this invention may also be represented in multiple tautomeric forms. In such instances, the invention expressly includes all tautomeric forms of the compounds described herein, even though only a single tautomeric form may be represented. All such isomeric forms of such compounds are expressly included in the present invention.
Definitions
As used herein, an "alkyl" group is a saturated aliphatic hydrocarbon group. An alkyl group can be straight or branched, and can have, for example, from 1 to 8 carbon atoms in a chain. Examples of straight chain alkyl groups include, but are not limited to, ethyl and butyl. Examples of branched alkyl groups include, but are not limited to, isopropyl and t-butyl.
An "aryl" group is an aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring system, wherein any ring atom capable of substitution can be substituted (e.g., by one or more substituents). Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, and anthracenyl. A "substituted aryl" group is an aryl group that is substituted with one or more substituents such as alkyl, alkoxy, amino, nitro, carboxy, carboalkoxy, cyano, alkylamino, dialkylamino, halo, hydroxy, hydroxyalkyl, mercaptyl, alkylmercaptyl, trihaloalkyl, carboxyalkyl, sulfoxy, or carbamoyl.
An "aralkyl" group is an alkyl group that is substituted with an aryl group. An example of an aralkyl group is benzyl.
The terms "cycloalkyl" or "cyclyl" as employed herein includes saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons, preferably 3 to 8 carbons, and more preferably 3 to 6 carbons, wherein the cycloalkyl group may be optionally substituted. Cyclyl groups include monocyclic and polycyclic groups (e.g., a bicyclic group such as a fused bicyclic, spirocyclic and bridged bicyclic structure). Preferred cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. A "heteroaryl" group is an aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively). Any ring atom can be substituted (e.g., by one or more substituents).
A "carboxyl" group is a -COOH group.
An "alkoxy" group is an alkyl-O- group in which "alkyl" is as previously described.
The term "haloalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced by halo, and includes alkyl moieties in which all hydrogens have been replaced by halo (e.g., perfluoroalkyl).
A "halogen" or "halo" group is fluorine, chlorine, bromine or iodine.
A "heterocyclyl" group is a 5 to about 10 membered ring structure, in which one or more of the atoms in the ring is an element other than carbon, e.g., N, O, S. A heterocyclyl group can be aromatic or non-aromatic, i.e., can be saturated, or can be partially or fully unsaturated. Heterocyclyl groups include monocyclic and polycyclic groups (e.g., a bicyclic group such as a fused bicyclic, spirocyclic and bridged bicyclic structure). Examples of heterocyclyl groups include pyridyl, imidazolyl, furanyl, thienyl, thiazolyl, tetrahydro furanyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, indolyl, indolinyl, isoindolinyl, piperidinyl, pyrimidinyl, piperazinyl, isoxazolyl, isoxazolidinyl, tetrazolyl, and benzimidazolyl.
A "substituted heterocyclyl" group is a heterocyclyl group wherein one or more hydrogens are replaced by substituents such as alkoxy, alkylamino, dialkylamino, carbalkoxy, carbamoyl, cyano, halo, trihalomethyl, hydroxy, carbonyl, thiocarbonyl, hydroxyalkyl or nitro.
A "ring" is an aryl, heteroaryl, cyclyl or heterocyclyl group, each of which are defined herein. The terms "carboxylic acid mimic" and "bioisostere," as used herein, refer to a group as defined in The Practice of Medicinal Chemistry, Wermuth CG. Ed.: Academic Press: New York, 1996, p. 203. Particular examples of such groups include -COORa, - CONRaRb, -CN, -PO3H2, -SO3H, -S(O)2NHRa, -S(O)2NHC(O)Ra, -CH2S(O)2Ra, - C(O)NHS(O)2Ra, -C(O)NHOH, -C(O)NHCN, -CH(CF3)OH, -C(CF3)2OH, -P(O)(OH)2 and groups of sub-formulae (a)-(i') below:
Figure imgf000082_0001
(I) (I) (m) (n) (P)
Figure imgf000082_0002
(q) (D (t)
Figure imgf000082_0003
(y) (a') (b1) (C) (d1) (e1)
Figure imgf000082_0004
(f) (g1) (h1) (0 wherein Ra and R are each independently Ci-C6 alkyl, aryl or heteroaryl; and Rc is hydrogen or C1-C4 alkyl. It will be understood that in the above sub-formulae (a) to (i'), keto-enol tautomerism may be possible and that the sub-formulae (a) to (i') should be taken to encompass all tautomers thereof. As used herein, a description of the compounds of the invention in every case includes a pharmaceutically acceptable salt, solvate, hydrate, prodrug, tautomer, enantiomer, stereoisomer, analog or derivative thereof, including mixtures thereof in any ratios.
Where substituent groups are specified by their conventional chemical formulae, written from left to right, they optionally encompass substituents resulting from writing the structure from right to left, e.g., -CH2O- optionally also recites -OCH2-.
As used herein, the term "fused ring system" means at least two rings, wherein each ring has at least 2 atoms in common with another ring. "Fused ring systems" may include aromatic as well as non aromatic rings. Examples of "fused ring systems" are naphthalenes, indoles, quinolines, chromenes, norbornanes, and the like.
The term "treatment" as used herein refers both to prevention of a particular disease or treatment of a pre-existing condition.
The term "host 'or "patient in need thereof as used herein may be any mammalian species, for example a primate species, particularly humans. Animal models are of interest for veterinary treatment and for experimental investigations, providing a model for treatment of human disease.
The phrase "therapeutically effective amount" as used herein means that amount of a compound, material, or composition comprising a compound of the present invention which is effective for producing some desired therapeutic effect by simultaneous blocking or inhibiting gamma secretase receptors in a mammal, thereby blocking the biological consequences of that pathway in the treated cells, at a reasonable benefit/risk ratio applicable to any medical treatment.
Drug dosage depends upon the specific compound used within a particular formulation, the specific disease, the patient status, etc. A "therapeutically effective dose" is typically sufficient to reduce the undesired cell population in the target tissue while the viability of the patient is maintained. The treatment is generally continued until a reduction in cell population has occurred, for example, at least about 50% reduction in the cell burden, and may be continued until essentially no more undesired cells are detected in the body.
An "enriched preparation," as used herein, is enriched for a selected stereoconfiguration of one, two, three or more selected stereocenters within the subject compound. Exemplary selected stereocenters and exemplary stereoconfigurations thereof can be selected from those provided herein, e.g., in an example described herein. By enriched is meant at least 60%, e.g., of the molecules of compound in the preparation have a selected stereochemistry of a selected stereocenter. In preferred embodiments it is at least 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%. Enriched refers to the level of a subject molecule(s) and does not connote a process limitation unless specified.
A compound described herein can be in the form of a salt, e.g., a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" includes salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al, J. Pharma. Science 1977, 66: 1-19). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
In addition to salt forms, the present invention provides compounds, which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. For instance, prodrugs for carboxylic acid analogs of the invention include a variety of esters. In an exemplary embodiment, the pharmaceutical compositions of the invention include a carboxylic acid ester. In another exemplary embodiment, the prodrug is suitable for treatment /prevention of those diseases and conditions that require the drug molecule to cross the blood brain barrier. In a preferred embodiment, the prodrug enters the brain, where it is converted into the active form of the drug molecule. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
Synthetic Methods A compound described herein may be prepared via a variety of synthetic methods. Representative syntheses are shown in Schemes 1-7 below.
Scheme 1. Exemplary synthetic method A.
Figure imgf000086_0001
reductive amination Hydrolysis
Figure imgf000086_0002
In method A of Scheme 1, a hydroxybenzaldehyde such as compound 1 may first be activated, e.g., by triflation. Subsequent coupling (e.g., via a Suzuki coupling) to install an aryl group (R3) may be followed by reductive amination and hydrolysis to yield the desired compound 4.
Scheme 2. Exemplary synthetic method B.
Figure imgf000086_0003
Suzuki coupling
Figure imgf000086_0004
In method B of Scheme 2, a hydroxybenzaldehyde such as compound 1 may first be subjected to reductive amination to yield compound 5, and then activated, e.g., by triflation to yield compound 6. Subsequent coupling (e.g., via a Suzuki coupling) to install an aryl group (R3) may be followed by hydrolysis to yield the desired compound 8.
Scheme 3. Exemplary synthetic methods C and D.
Figure imgf000087_0001
10
In methods C and D of Scheme 3, starting materials 9 or 10 may be subjected to an aminoalkylation reaction (e.g., Petasis or Mannich reaction) to form compound 11, and then activated, e.g., by triflation, to yield compound 12. Subsequent coupling (e.g., via a Suzuki coupling) to install an aryl group (R ) may be followed by hydrolysis to yield the desired compound 13.
Scheme 4. Exemplary synthetic methods E and F.
Figure imgf000088_0001
In method E of Scheme 4, starting material 14 may be acylated (e.g., via a Friedel-Crafts reaction) to yield compound 15, which may then be activated (e.g., via triflation). Subsequent coupling (e.g., Suzuki coupling) and reduction yields compound 21. In method F, starting material 19 may be activated, e.g., by triflation, to yield compound 19. Subsequent coupling (e.g., via a Suzuki coupling) and reduction (e.g., via a Grignard reaction) yields compound 21. In either method, halogenation followed by displacement and hydrolysis provides the desired compound 24.
Scheme 5. Exemplary synthetic method G. Hydrolysis
Mitsunobu
Figure imgf000089_0003
Figure imgf000089_0001
Figure imgf000089_0002
21 26 27
In method G of Scheme 5, compound 21 may be subjected to a coupling reaction (e.g., Mitsunobu) followed by hydrolysis to yield the desired compound 27.
Scheme 6. Exemplary synthetic method H.
Hydrolysis
Alkylation
Figure imgf000089_0006
Figure imgf000089_0004
Figure imgf000089_0005
In method H of Scheme 6, compound 28 may be subjected to an alkylation reaction followed by hydrolysis to yield the desired compound 30.
Scheme 7. Exemplary chiral synthesis method.
Figure imgf000089_0007
In Scheme 7, compounds 31 and 35 may be prepared by coupling of 2-(3- (benzyloxy)phenyl)acetic acid with either the R-isomer of 4-benzyl-oxazolidin-one or the S-isomer of 4-benzyl-oxazolidin-one by Evans's procedures. Compounds 32 and 36 may be prepared by alkylation of compounds 31 and 35 respectively with an appropriate alkyl bromide. Compounds 33 and 37 may be prepared from compounds 32 and 36 by debenzylation, for example, through Pd-catalyzed hydrogenation in an alcohol solvent. Compounds 34 and 38 may be obtained from the removal of chiral auxiliary groups from compounds 33 and 37, respectively, followed by esterification.
Compounds 34 and 38 may be further derivatized using methods A, B, C, D, E, F, G, and H described above, to provide desired compounds.
Scheme 8. Exemplary Chiral Synthetic Method J
Figure imgf000090_0001
In Scheme 8, compound 39 may be prepared by reacting methyl 2-(3- hydroxyphenyl)acetate with an amine and an aldehyde through Mannich reaction. Subsequent triflation followed by Suzuki coupling reaction can give compound 41. After hydrolysis of the ester into acid 42, Evan's chiral auxiliaries may be installed using standard conditions to give compounds 43 or 44, which may be alkylated respectively with an appropriate alkyl bromide to give compounds 45 or 46. Compounds 47 or 48 may be obtained by removal of chiral auxiliary from compounds 45 or 46, respectively. It should be noted that the Mannich reaction in step 1 above gives rise to a racemic mixture, and isomers of the newly generated chiral center (i.e., stereoisomers of compound 39) can be separated by chiral chromatography (see, e.g., Example 42) or chiral resolution through diastereomeric salt (see, e.g., CRC Handbook of Optical Resolutions via Diastereomeric Salt Formation, edited by David Kozma, CRC press 2002). The desired stereoisomer 39 can then go through the chiral synthetic method of Scheme 8 above (using Evan's chiral auxiliaries) or Scheme 9 below (using Noyori catalysts in asymmetric hydrogenation) to give rise to compounds of formula (I) with two specific chiral centers.
Scheme 9. Exemplary Chiral Synthetic Method K
Aldol condensation Hydrolysis
Figure imgf000091_0001
Figure imgf000091_0002
Noyori asymmetric hydrogenation
Figure imgf000091_0003
Figure imgf000091_0004
51 52 In method K of scheme 9, compound 49 may be generated through Aldol condensation of compound 41 with an appropriate aldehyde. After hydrolysis of the ester into an acid 50, the double bond may be saturated by asymmetric hydrogenation using appropriated Noyori condition and catalysts to give compounds 51 or 52.
Exemplary compounds may be found in Table 1 in Figure 1 , and Table 2 in Figure 2. Additional exemplary compounds are described in the Examples. In Table 1, the synthetic method corresponds to those described in Schemes 1-7. The synthetic method corresponds to those described in Schemes 1-7.
The compounds described herein can be used for the modulation of gamma- secretase activity. As used herein, the term "modulation of γ-secretase activity" refers to an effect on the processing of APP by the γ-secretase complex. Preferably it refers to an effect in which the overall rate of processing of APP remains essentially as without the application of said compounds, but in which the relative quantities of the processed products are changed, more preferably in such a way that the amount of the Aβ42 -peptide produced is reduced. For example a different Aβ species can be produced (e.g. Aβ38, Aβ40 or other Aβ peptide species of shorter amino acid sequence instead of Aβ42) or the relative quantities of the products are different (e.g. the ratio of Aβ40 to Aβ42 is changed, preferably increased).
Gamma secretase activity can be measured, for example by determining APP processing, e.g. by determining the levels of Aβ peptide species produced, most importantly levels of Aβ42 (see Examples section).
Pharmaceutical compositions
In one aspect, the invention features a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, tautomer, enantiomer, stereoisomer, analog or derivative thereof, including mixtures thereof in any ratios, and a pharmaceutically acceptable carrier. The compounds of the formulae described herein can, for example, be administered by injection, intravenously, intraarterially, subdermally, intraperitoneally, intramuscularly, or subcutaneously; or orally, buccally, nasally, transmucosally, topically, in an ophthalmic preparation, or by inhalation, with a dosage ranging from about 0.5 to about 100 mg/kg of body weight, alternatively dosages between 1 mg and 1000 mg/dose, every 4 to 120 hours, or according to the requirements of the particular drug. The methods herein contemplate administration of an effective amount of compound or compound composition to achieve the desired or stated effect. Typically, the pharmaceutical compositions of this invention will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w/w). Alternatively, such preparations contain from about 20% to about 80% active compound.
The term "pharmaceutically acceptable carrier or adjuvant" refers to a carrier or adjuvant that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.
Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopherol polyethyleneglycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene -polyoxypropylene-block polymers, polyethylene glycol and wool fat. Cyclodextrins such as α-, β-, and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives may also be advantageously used to enhance delivery of compounds of the formulae described herein.
The pharmaceutical compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection. The pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
When the compositions of this invention comprise a combination of a compound of the formulae described herein and one or more additional therapeutic or prophylactic agents, both the compound and the additional agent should be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen. The additional agents may be administered separately, as part of a multiple dose regimen, from the compounds of this invention. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition.
Methods of treatment In one aspect, the invention features a method of modulating gamma-secretase activity in a subject, the method comprising administering to the subject a compound or pharmaceutical composition described herein.
In one aspect, the invention features a method of treating a disorder associated with elevated Aβ levels in a subject, the method comprising administering to the subject a compound or pharmaceutical composition described herein.
In one aspect, the invention features a method of reducing the levels of Aβ in a subject, the method comprising administering to the subject a compound or pharmaceutical composition described herein.
In one aspect, the invention features a method of reducing the deposition of Aβ in a subject, the method comprising administering to the subject a compound or pharmaceutical composition described herein.
In one aspect, the invention features a method of treating a neurodegenerative disorder in a subject, the method comprising administering to the subject a compound or pharmaceutical composition described herein.
In one aspect, the invention features a method of treating Alzheimer's disease in a subject, the method comprising administering to the subject a compound or pharmaceutical composition described herein.
In one aspect, the invention features a method of treating a subject at risk for developing Alzheimer's disease, the method comprising administering to the subject a compound or pharmaceutical composition described herein.
In one aspect, the invention features a method of delaying the progression of Alzheimer's disease in a subject, the method comprising administering to the subject a compound or pharmaceutical composition described herein.
In one aspect, the invention features a method of delaying the onset of Alzheimer's disease in a subject, the method comprising administering to the subject a compound or pharmaceutical composition described herein. In one aspect, the invention features a method of improving cognitive function in a subject, the method comprising administering to the subject a compound or pharmaceutical composition described herein.
In some embodiments, the compound or pharmaceutical composition described herein is administered in combination with an additional therapeutic agent. In some embodiments, the additional therapeutic agent is a cholinesterase inhibitor. In some embodiments, the additional therapeutic agent is selected from the group consisting of donepezil, rivastigmine, galantamine and tacrine. In some embodiments, the additional therapeutic agent is an N-methyl-D-aspartate (NMDA) receptor modulator. In some embodiments, the additional therapeutic agent is memantine.
The compounds described herein may be administered in a composition described herein, for example by a dosage form or route described herein.
The compounds and compositions described herein can be administered to a subject, for example using a method described herein, who is suffering from a disorder described herein. For example, a compound described herein such as a gamma secretase modulator (e.g., a compound that alter the cleavage pattern of gamma secretase) can be useful in the prevention and/or treatment of numerous diseases, including Alzheimer's disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis- Dutch type (HCHWA-D), multi-infarct dementia, dementia pugilistica and Down syndrome.
In some embodiments, a compound or composition described herein can be used in the treatment of Alzheimer's disease (AD). AD is the most prevalent form of dementia. It is a neurodegenerative disorder, clinically characterized by progressive loss of memory and general cognitive function, and pathologically characterized by the deposition of extracellular proteinaceous plaques in the cortical and associative brain regions of sufferers. These plaques mainly comprise fibrillar aggregates of β-amyloid peptide (Aβ). Aβ is formed from amyloid precursor protein (APP) via separate intracellular proteolytic events involving the enzymes β-secretase and γ-secretase. Variability in the site of the proteolysis mediated by γ-secretase results in Aβ of varying chain length, e.g. Aβ38, Aβ40 and Aβ42. After secretion into the extracellular medium, Aβ forms initially-soluble aggregates which are widely believed to be the key neurotoxic agents in AD, and which ultimately result in the insoluble deposits and dense neuritic plaques which are the pathological characteristics of AD.
In some embodiments, a compound or composition described herein can be used in the treatment of cerebral amyloid angiopathy. Also known as congophilic angiopathy, cerebral amyloid angiopathy is a form of angiopathy in which β-amyloid deposits form in the walls of the blood vessels of the central nervous system, β-amyloid deposition predisposes these blood vessels to failure, increasing the risk of a hemorrhagic stroke. Since this can be caused by the same amyloid protein that is associated with Alzheimer's dementia, such brain hemorrhages are more common in people who suffer from Alzheimer's, however they can also occur in those who have no history of dementia. The hemorrhage within the brain is usually confined to a particular lobe and this is slightly different compared to brain hemorrhages which occur as a consequence of high blood pressure (hypertension) - a more common cause of a hemorrhagic stroke (or cerebral hemorrhage).
In some embodiments, a compound or composition described herein can be used in the treatment of hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D). HCHWA-D is a rare autosomal dominant disorder autosomal dominant form of cerebral amyloidosis. It is caused by an amyloid precursor protein 693 mutation that clinically leads to recurrent hemorrhagic strokes and dementia. The disease is pathologically characterized by the deposition of Aβ in cerebral blood vessels and as plaques in the brain parenchyma.
In some embodiments, a compound or composition described herein can be used in the treatment of multi-infarct dementia. Also known as vascular dementia, it is the second most common form of dementia after Alzheimer disease (AD) in older adults. The term refers to a group of syndromes caused by different mechanisms all resulting in vascular lesions in the brain. The main subtypes of this disease described at the moment are: mild cognitive impairment, multi-infarct dementia, vascular dementia due to a strategic single infarct (affecting the thalamus, the anterior cerebral artery, the parietal lobes or the cingulate gyrus), vascular dementia due to hemorrhagic lesions, small vessel disease (which includes vascular dementia due to lacunar lesions and Binswanger's disease), and mixed Alzheimer's and vascular dementia. Vascular lesions can be the result of diffuse cerebrovascular disease or focal lesions (or a combination of both, which is what is observed in the majority of cases). Mixed dementia is diagnosed when patients have evidence of AD and cerebrovascular disease, either clinically or based on neuroimaging evidence of ischemic lesions. In fact multi-infarct dementia and Alzheimer's disease often coexist, especially in older patients with dementia.
In some embodiments, a compound or composition described herein can be used in the treatment of dementia pugilistica (DP). Also called chronic traumatic encephalopathy (CTE), chronic boxer's encephalopathy, traumatic boxer's encephalopathy, boxer's dementia, and punch-drunk syndrome, DP is a neurological disorder which may affect career boxers, wrestlers, mixed martial artists, and football players who receive multiple dazing blows to the head. Dementia pugilistica, the severe form of chronic traumatic brain injury, commonly manifests as declining mental and physical abilities such as dementia and parkinsonism. The encephalopathy develops over a period of years, with the average time of onset being about 12-16 years after the start of a career in boxing. The condition is thought to affect around 15% of professional boxers, but it may affect other types of athletes. The condition may be caused by repeat concussions, or repeat subconcussive blows (blows that are below the threshold of force necessary to cause concussion), or both. Loss of neurons, scarring of brain tissue, collection of proteinaceous, senile plaques, hydrocephalus, attenuation of corpus callosum, diffuse axonal injury, neurofibrillary tangles and damage to the cerebellum are implicated in the syndrome. The condition may be etiologically related to Alzheimer's disease. In some embodiments, a compound or composition described herein can be used in the treatment of Down syndrome. Down syndrome is a chromosomal disorder caused by the presence of all or part of an extra 21st chromosome. The condition is characterized by a combination of major and minor differences in structure. Often Down syndrome is associated with some impairment of cognitive ability and physical growth as well as facial appearance. Individuals with Down syndrome tend to have a lower than average cognitive ability, often ranging from mild to moderate developmental disabilities. A small number have severe to profound mental disability. Many of the common physical features of Down syndrome also appear in people with a standard set of chromosomes. They may include a single transverse palmar crease (a single instead of a double crease across one or both palms, also called the Simian crease), an almond shape to the eyes caused by an epicanthic fold of the eyelid, upslanting palpebral fissures (the separation between the upper and lower eyelids), shorter limbs, poor muscle tone, a larger than normal space between the big and second toes, and protruding tongue. Health concerns for individuals with Down syndrome include a higher risk for congenital heart defects, gastroesophageal reflux disease, recurrent ear infections, obstructive sleep apnea, and thyroid dysfunctions.
In some embodiments, a compound or composition described herein can be used in the treatment of Parkinson's-related dementia. Parkinson's disease (PD) is a degenerative disease of the brain (central nervous system) that often impairs motor skills, speech, and other functions. It is characterized by muscle rigidity, tremor, a slowing of physical movement (bradykinesia) and, in extreme cases, a loss of physical movement (akinesia). The primary symptoms are the results of decreased stimulation of the motor cortex by the basal ganglia, normally caused by the insufficient formation and action of dopamine, which is produced in the dopaminergic neurons of the brain. Secondary symptoms may include high level cognitive dysfunction and subtle language problems. PD is both chronic and progressive. Dementia is common and affects approximately 40% of PD patients during the course of the disease. The risk for the development of dementia in PD patients is approximately 6 times higher than compared to non-PD age matched controls. The dementia associated with PD is characterized by dysexecutive syndrome affecting mainly executive and visuospatial functions while memory is relatively preserved.
In some embodiments, a compound or composition described herein can be used in the treatment of memory loss associated with multiple sclerosis (MS). MS, also known as disseminated sclerosis or encephalomyelitis disseminate,is an autoimmune condition in which the immune system attacks the central nervous system, leading to demyelination. MS affects the ability of nerve cells in the brain and spinal cord to communicate with each other. Nerve cells communicate by sending electrical signals called action potentials down long fibers called axons, which are wrapped in an insulating substance called myelin. In MS, the body's immune system attacks and damages the myelin. When myelin is lost, the axons can no longer effectively conduct signals. The name multiple sclerosis refers to scars (scleroses - better known as plaques or lesions) in the white matter of the brain and spinal cord, which is mainly composed of myelin. MS takes several forms, with new symptoms occurring either in discrete attacks (relapsing forms) or slowly accumulating over time (progressive forms). Between attacks, symptoms may go away completely, but permanent neurological problems often occur, especially as the disease advances. Almost any neurological symptom can appear with the disease, and often progresses to physical and cognitive disability.
In some embodiments, the subject is being treated with an additional therapeutic agent. Such additional agents include beta secretase inhibitors; muscarinic antagonists (e.g., m-i agonists or ITi2 antagonists); cholinesterase inhibitors (e.g., acetyl- and/or butyrylchlolinesterase inhibitors) (e.g., Donepezil, Tacrine, Galantamine, Rivastigmine); gamma secretase inhibitors; gamma secretase modulators; HMG-CoA reductase inhibitors; non-steroidal anti-inflammatory agents; N-methyl-D-aspartate receptor antagonists (e.g. Memantine); anti-amyloid antibodies; vitamin E; nicotinic acetylcholine receptor agonists; CBl receptor inverse agonists or CB 1 receptor antagonists; antibiotics; growth hormone secretagogues; histamine H3 antagonists; AMPA agonists; PDE4 inhibitors; GABAA inverse agonists; inhibitors of amyloid aggregation; glycogen synthase kinase beta inhibitors; promoters of alpha secretase activity; PDE-IO inhibitors; Tau kinase inhibitors (e.g., GSK3beta inhibitors, cdk5 inhibitors, or ERK inhibitors); anti-Aβ vaccine; APP ligands; agents that upregulate insulin cholesterol lowering agents (for example, statins such as Atorvastatin, Fluvastatin, Lovastatin, Mevastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin); cholesterol absorption inhibitors (such as Ezetimibe); fibrates (such as, for example, for example, clofibrate, Clofibride, Etofibrate, and Aluminium Clofibrate); LXR agonists; LRP mimics; nicotinic receptor agonists; H3 receptor antagonists; histone deacetylase inhibitors; hsp90 inhibitors; ml muscarinic receptor agonists; 5-HT6 receptor antagonists; mGluRI ; mGluRδ; positive allosteric modulators or agonists; mGluR2/3 antagonists; anti-inflammatory agents that can reduce neuro inflammation; Prostaglandin EP2 receptor antagonists; PAI-I inhibitors; agents that can induce Aβ efflux such as gelsolin; glutaminyl cyclase inhibitors; or any other drug known to a person skilled in the art suitable to treat or prevent Alzheimer's disease.
Dosages
Typically, the compounds and pharmaceutical compositions of this invention will be administered from about 1 to about 6 times per day, for example, once daily. For example, a compound or composition described herein may be administered at a dosage ranging from about 0.1 g/dose to about 10 g/dose, for example, from about 0.25 g/ dose to about 5 g/dose, or in a preferred embodiment, from about 0.6 g/dose to about 1.1 g/dose. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w/w). Alternatively, such preparations contain from about 20% to about 80% active compound.
Clinical outcomes
In some embodiments, treatment with a compound or composition described herein, for example, using a method described herein, improves one or more clinical outcomes. For example, in some embodiments, treatment with a compound or composition described herein may improve cognitive function. Elements of cognitive function include memory, orientation, attention, reasoning, language and praxis. In some embodiments, treatment with a compound or composition described herein may delay the progression of Alzheimer's disease, or reduce the rate of cognitive decline. In some embodiments, treatment with a compound or composition described herein may reduce the level of Aβ peptide(s) produced or reduce the deposition of Aβ peptide(s) in a subject.
In some embodiments, clinical outcomes may be assessed using known methods. One such method is the cognitive subscale of Alzheimer's Disease Assessment Scale (ADAS-cog), which examines selected aspects of cognitive performance including elements of memory, orientation, attention, reasoning, language and praxis.
In some embodiments, clinical outcomes may be assessed using the Clinician's Interview Based Impression of Change requiring the use of caregiver information (CIBIC plus). CIBIC plus evaluates four major areas of patient function: General, Cognitive, Behavioral and Activities of Daily Living. It represents the assessment of a skilled clinician based upon his/her observations at an interview with the patient, in combination with information supplied by a caregiver familiar with the behavior of the patient over the interval rated.
In some embodiments, clinical outcomes may be assessed using the Alzheimer's Disease Cooperative Study - Activities of Daily Living inventory (ADCS-ADL). This evaluation involves a comprehensive battery of ADL questions used to measure functional capabilities of patients, as determined via interview with a caregiver familiar with the behavior of the patient. A modified version, ADCS-AD Lsev, may be used for assessment of patients with moderate to severe dementia. ADCS- ADLsev involves assessment of a subset of 19 items, including ratings of the patients' ability to eat, dress, bathe, telephone, travel, shop, and perform other household chores.
In some embodiments, clinical outcomes may be assessed using the Severe Impairment Battery (SIB), a multi-item instrument that has been validated for the evaluation of patients with moderate to severe dementia. It evaluates the following domains: social interaction, orientation, attention, language, memory, praxis, constructional abilities and visuo spatial functions.
EXAMPLES Example 1. Screening for γ-Secretase Modulation in a Cell-based Assay
Chinese Hamster Ovary (CHO) cells expressing the APP V717F mutation were grown in α-MEM media containing 10% FBS, 2 mM L-Glutamine, and 1% pen/strep until nearly confluent. Cells were added to 96-well flat-bottom plates to a density of 25,000 cells per well in 80μL of media and the plates were then incubated at 37°C in a 5% CO2 atmosphere for 4 hours prior to challenging with compound. Immediately prior to adding diluted compound solution to the cells, the media was replaced with 80 μL of serum- free media (α-MEM, 2mM L-Glutamine, 1% pen/strep supplemented with 2% B27).
10 mM DMSO stock solutions of test compounds were further diluted with DMSO to yield nine, 3-fold serial dilutions. 5 μl of these diluted solutions were further diluted into 828 μL of serum- free media. 80 μL of these resulting dilutions with serum- free media were added to the previously plated cells containing 80 μL of serum- free media. The final concentration of DMSO on the cells was 0.3%. The plates were incubated for 17 hours at 37°C in a 5% CO2 atmosphere. Following incubation, conditioned media from the compound-challenged cells was transferred to new 96-well plates and centrifuged at 1,000 RPM at 4°C for 10 minutes. 20 μL of the collected media was measured for Aβ42, 40 and 38 levels using Human/Rodent Aβ Triplex Elisa plates according to the manufacturers protocol (Meso Scale Discovery). Nonlinear regression analysis (sigmoidal dose-response, variable slope) was used to fit curves for Aβ42, 40 and 38, and calculate EC50 values for Aβ42 inhibition (GraphPad by Prism). Typically, data are expressed as a percent of control.
To measure cell viability, a CellTiter-Blue Viability Assay (Promega) was used to determine the metabolic capacity of cells by their ability to reduce the indicator dye resazurin into resorufin. 50 μL of CellTiter-Blue Reagent diluted 5-fold in FBS- containing media was added to compound-challenged cells after the removal of media, as described above. Cells were incubated with the reagent for 1 hour at 37° in a 5% CO2 atmosphere and the fluorescence was recorded (560Ex/590Em). Results are reported in Table 1.
Example 2. Measurement of Aβ from brain of wild-type mice and rats
To determine whether acute administration of an Aβ42 lowering agent would reduce Aβ42 levels in vivo, rat and mouse models were utilized. Male CF-I mice or F344 rats from Charles River laboratories, over the age of 11 weeks, were used for testing compounds. Animals were dosed (10.0 ml/kg in mice and 5.0 ml/kg in rats) by oral gavage with experimental compounds in a vehicle consisting of ETOH (10%), propolenye glycol (10%) and a solution of water and solutol (20/80; v/v). A single oral dose (30 or 50 mg/kg) was given four hours before euthanasia. At the appointed time, animals were anesthetized with ketamine/xylazine (100/10 mg/kg, ip) at a volume of 10.0 ml/kg in mice and 1.0 ml/kg in rats. Blood was collected via cardiac puncture into a sterile syringe and transferred to EDTA treated collection tubes. The blood was mixed and then kept at 4 degrees Celsius until spun in a centrifuge (10 minutes at 10,000 rpm); serum was collected and kept on ice until frozen at -80 degrees. The brain was removed from the cranium and the hindbrain and forebrain were separated. The forebrain was divided evenly into left and right hemispheres by cutting along the sagital midline. Both sides were weighed and then quickly frozen on dry ice for analysis.
To measure brain Aβ levels, these previously weighed and excised frozen hemispheres in a 5 mL tubes were used. An ice-cold aqueous solution of 50 mM NaCl, 0.4% diethylamine, and EDTA-free protease inhibitors was added to the tube at 1 mL solution per 100 mg of wet brain weight. The brain tissue was homogenized using a tip sonicator and then 1.2 mL was centrifuged at 44,000 x g for 30 minutes at 4°C.
The resulting supernatant was further processed with a Waters 60 mg HLB Oasis column. The column was treated with methanol and water prior to loading 0.8 mL of the supernatant. The column was washed with 5% methanol and then 30% methanol prior to Aβ elution with 0.8 mL of an aqueous solution of 90% methanol and 2% ammonium hydroxide. The eluate was collected and evaporated in a vacuum dryer.
The Aβ levels were quantified using a MesoScale Discovery ELISA kit which was able to measure Aβ 38, 40, and 42 simultaneously. The residue of the dried elution buffer was resuspended in 0.4 mL of the blocking buffer provided in the MesoScale Discovery kit. 25 μL of this reconstituted mixture was added to the ELISA plate and the manufacturer's instructions were followed for analysis. Standard curves in the analysis were derived from Aβ 38, 40, and 42 peptides supplied in the kit.
Example 3. Synthesis of Intermediate 1 Methyl 2-(4-formyl-3-hydroxyphenyl)acetate
Figure imgf000105_0001
Triethylamine (757 mL, 5.43 mol) was added to a solution of methyl 2-(3- hydroxyphenyl) acetate in acetonitrile (10L) over 10 minutes. Magnesium chloride (516 g, 5.43 mol) was added over 15 minutes. The temperature of the reaction increased to -400C during this addition. The reaction mixture was stirred for 1.5 h, during which time it went to a nearly homogeneous brown solution. The reaction was heated to reflux and paraformaldehyde (326g, 10.9 mol) was added quickly. The reaction was heated at reflux for an additional 4h, and was allowed to cool to room temperature and stir overnight. After cooling in an ice-salt bath, a 1.2N solution of HCl (8L) was added and the mixture stirred until all the solids dissolved. The reaction was poured into a 50 L separatory funnel and diluted with a 60% ethyl acetate/heptane solution (20L). The organic layer was washed with water (5L) and saturated brine (5L), dried over sodium sulfate and concentrated under reduced pressure. It was purified by flash chromatography on silica gel (5-20% EtOAc in heptane). The fractions were collected and concentrated. The material was allowed to solidify overnight in a freezer and the resulting solid was triturated at -300C with a 1 : 1 hexane:MTBE mixture to give the desired product with a purity >95% (82.9g, 9% ). 1H NMR (300MHz ,CDCl3) δ = 11.04 (s, 1 H), 9.87 (s, 1 H), 7.52 (d, J= 7.9 Hz, 1 H), 6.95 (d, J= 7.9 Hz, 1 H), 6.91 (s, 1 H), 3.71 (s, 3 H), 3.65 (s, 2 H); LCMS m/z 195.1 [M+l]+.
Example 4. Synthesis of Intermediate 2
Methyl 2-(4-formyl-3-(trifluoromethylsulfonyloxy)phenyl)acetate
Figure imgf000106_0001
Pyridine (13.5 mL, 167 mmol) and DMAP (0.4g, 3.3 mmol) was added to a solution of methyl 2-(4-formyl-3-hydroxyphenyl)acetate (10.8g, 55.7 mmol) in dichloromethane (20OmL) in an ice/methanol bath (-120C). Triflic anhydride (18.7 mL, 111 mmol) was added dropwise to the solution at such a rate that the temperature did not exceed 0 0C. The reaction was stirred for an additional 2 h at between -10 to -5 0C. TLC indicated that the reaction was complete. Water (100 mL) was added. The organic layer was washed with IN HCl (10OmL), saturated brine (100 mL), dried over sodium sulfate and concentrated under reduced pressure. The oil was purified by flash chromatography on silica gel (20-25% EtOAc in heptane) to give methyl 2-(4-formyl-3- (trifluoromethylsulfonyloxy)phenyl)acetate as a colorless oil (14. Ig, 78%); LCMS m/z 327.1 [M+l]+.
Example 5. Synthesis of Intermediate 3
Methyl 2-(6-formyl-4'-(trifluoromethyl)biphenyl-3-yl)acetate
Figure imgf000107_0001
To a mixture of 4-(trifluoromethyl)phenylboronic acid (456 mg, 2.40 mmol), methyl 2- (4-formyl-3-(trifluoromethylsulfonyloxy)phenyl)acetate (652 mg, 2.00 mmol), Tetrakis(triphenylphosphine)palladium(0) (92 mg, 0.080 mmol) in 1 ,2-dimethoxyethane (8 mL) was added ethanol (4 mL), followed by saturated aqueous sodium bicarbonate solution (1.2 mL). The reaction mixture was heated using microwave reactor at 100 0C for 10 min. It was partitioned between EtOAc and brine. The organic phase was dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography on silica (10-15% EtOAc in hexane) to get methyl 2-(6-formyl-4'- (trifluoromethyl)biphenyl-3-yl)acetate as a colorless oil (583 mg, 90%); LCMS m/z 323.2 [M+ 1]+.
Example 6. Synthesis of Intermediate 4 psi
Figure imgf000108_0001
Figure imgf000108_0002
Methyl 2-(3 -hydroxyphenyl)-4-methylpentanoate
Figure imgf000108_0003
Step l
Methyl 2-(3-(benzyloxy)phenyl)-4-methylpent-4-enoate
Figure imgf000108_0004
In a 20 L vessel with mechanical stir, nitrogen inlet and cooling bath (ethanol, liquid nitrogen, dry ice) was brought THF (1OL) and under stirring was added 3-benzyloxy- phenylacetic acid methyl ester (200 g, 0.78 mol). When all was dissolved, the solution was cooled to -78 0C. A solution of LiHMDS (1014 ml, 1.0 M solution in THF, 1.01 mol) was added drop-wise, keeping the temperature at -78 0C. The mixture was stirred for 1 hour (dry ice was added to the ethanol cooling bath). 3-bromo-2-methyl-l-propene (110.6 g, 0.82 mol) was added drop-wise while keeping the temperature at -78 0C. The cooling bath was removed after the addition and the mixture was allowed to warm up to room temperature overnight. The mixture was quenched with a saturated solution of NH4CI in water (4 L) and the solution was extracted with ethyl acetate (2 L x2). The organic layers were dried over Na2SC^, filtered and concentrated to give methyl 2-(3-hydroxyphenyl)-4- methylpentanoate as a yellow oil (242g, 100%). NMR (300 MHz, CDCl3): δ 1.25: s, IH; δ 1.6: s, 2H; δ 2.25: dd, IH; δ 2.7: dd, IH; δ 3.5: s, 3H; δ 3.6: dd, IH; δ 4.4-4.7: dd, 2H; δ 4.9: s, 2H; δ 6.6-6.8: m, 2H; δ 7.1: m, 2H; δ 7.2-7.3: m, 5H. Step 2
Methyl 2-(3-(benzyloxy)phenyl)-4-methylpent-4-enoate
Figure imgf000109_0001
To a 5 L steel PARR vessel, methyl 2-(3-(benzyloxy)phenyl)-4-methyl pent-4-enoate (120 gram, 0.387 mol, 1 eq.) was dissolved in a mixture of methanol (1.5 L) and ethyl acetate (1.5 L). A suspension of palladium on carbon (10% Pd, 15.0 g) in ethyl acetate was added to the solution in the steel vessel and the vessel was brought under nitrogen atmosphere. Hydrogen gas (5 bar) was added and refilled twice. No hydrogen gas was consumed anymore and TLC showed that the reaction was completed. The solution was filtered over Celite 535 coarse (about 50 gram) and washed with ethyl acetate (150 ml). The filtrate was concentrated, and purification was done with column chromatography over silica te give a yellow oil (86.3 g, 100%). CDCl3: δ 0.9: d, 6H; δ 1.5: m, IH; δ 1.7: m, IH; δ 1.9: m, IH; δ 3.7: s, 3H; δ 5.2: s, OH; δ 6.8: dd, IH; δ 6.9: m, 2H; δ 7.2: t, 1 H
Example 7. Synthesis of Intermediate 4a
Methyl 2-(4-formyl-3-hydroxyphenyl)-4-methylpentanoate
Figure imgf000109_0002
Same procedure utilized for intermediate 1.
To a 3-neck vessel of 2 L, with magnetic stir and nitrogen inlet, crude methyl 2-(3- (benzyloxy)phenyl)-4-methylpent-4-enoate (86.3 g, 0.388 mol, 1 eq.) was dissolved in THF (IL) and cooled to 0 0C (ice bath). To the solution was drop wise added an ethyl magnesium-bromide solution (1.0 m in THF, 387 ml, 0.387 mol, 1 eq.) and the temperature rose from -1.5 to 3.2 0C. After addition the mixture was stirred for 30 minutes and then concentrated. A yellow solid was obtained which was dissolved in toluene (IL) in a 2 L flask. Under stirring was added paraformaledehyde (30 g, 1.00 mol, 2.5 eq.) and triethylamine (61 g, 0.60 mol, 1.5 eq.). The mixture was heated to reflux and refluxed for 3 hours, then cooled down to room temperature overnight. The mixture was quenched with water (2.5 L) and acidified with a 2 M HCl solution. The mixture was extracted with TBME, dried over sodium sulfate, filtered and concentrated, and purification was done with column chromatography over silica (ethyl acetate/heptane = 1/9) to give desired compound as a yellow oil (19 g, 20%). NMR in CDCl3: δ 0.9: d, 6H; δ 1.5: m, IH; δ 1.7: m, IH; δ 1.9: m, IH; δ 3.7: s, 3H; δ 6.9: dd, 2H; δ 7.5: d, IH; δ 9.9: s, 1 H; δ 11.0: s, IH.
Example 8. Synthesis of Intermediate 6 Methyl 2-(3-hydroxyphenyl)propanoate
Figure imgf000110_0001
6
Step l
Figure imgf000110_0002
3-Hydroxyphenylacetic acid (15.2 g, 0.1 mol, 1.0 equiv.) and concentrated H2SO4 (392 mg, 4 mmol, 0.04 equiv.) were dissolved in MeOH (100 ml). The mixture was stirred at rt for 1 h, then quenched with NaOH solution, extracted with EtOAc. The organic layer was dried with Na2SO4 and concentrated in vacuo. The residue was purified with a silica gel column chromatography (eluting with PE/EtOAc=5:l). Methyl 2-(3- hydroxyphenyl)acetate was obtained as a yellow oil (14.2 g, 86 %). 1H NMR (400 MHz, CDCl3) δ = 7.15-7.19 (m, IH), 6.81 (d, IH), 6.72-6.76 (m, 2H), 5.88 (s, IH), 3.70 (s, 3H), 3.58 (s, 2H); LCMS m/z 167 [M+l]+. Step 2
Figure imgf000111_0001
Methyl 2-(3-hydroxyphenyl)acetate (33 g, 0.2 mol, 1.0 equiv.), BnBr (24 ml, 0.2 mol, 1.0 equiv.) and K2CO3 (80 g, 0.58 mol, 2.9 equiv.) were dissolved in CH3CN (200 ml). The mixture was stirred at rt for 6 h; then removed the solvent, partitioned between water and EtOAc. The organic layer was dried with Na2Sθ4 and concentrated in vacuum. Purified with a silica gel column chromatography (PE/EtOAc = 10:1) to obtain methyl 2-(3- (benzyloxy)phenyl)acetate (44.2 g, 87%). 1H NMR (400 MHz, CDCl3) δ = 7.30-7.44 (m, 5H), 7.22 (d, IH), 6.92 (s, IH), 6.88 (d, 2H), 5.05 (s, 2H), 3.68 (s, 3H), 3.59 (s, 2H); LCMS m/z 257 [M+l]+.
Step 3
Figure imgf000111_0002
Methyl 2-(3-(benzyloxy)phenyl)acetate (10 g, 39 mmol, 1.0 equiv.) was dissolved in dry THF (150 ml), and the solution was cooled to -78 0C, then LiHMDS (40 ml, 39 mmol, 1.0 equiv.) was added dropwise to the solution, allowed to stirred for about 1 h. Then CH3I (2 ml, 39 mmol, 1.0 equiv.) was added in dropwise at -78 0C. The mixture was stirred at -78 0C for 1 h and then warmed to rt for 16 h. The mixture was quenched with NaHCO3 solution, extracted with EtOAc and H2O. The organic layer was dried over Na2Sθ4 and concentrated in vacuo. Purified with a silica gel column chromatography (PE/EtOAc= 100: 1) to obtain methyl 2-(3-(benzyloxy)phenyl)propanoate (8 g, 76 %). 1H NMR (400 MHz, CDCl3): 7.34-7.47 (m, 5H), 7.25 (d, IH), 6.96 (s, IH), 6.91-6.93 (t, 2H), 5.07 (s, 2H) 3.69-3.75 (q, IH), 3.67 (s, 3H), 1.50 (d, 3H); LCMS m/z 271 [M+l]+.
Step 4
Figure imgf000112_0001
To a solution of methyl 2-(3-(benzyloxy)phenyl)propanoate (15.6 g, 43 mmol, 1.0 equiv.) in methanol (150 ml) was added palladium charcoal (2.2 g, 10%wt), and the mixture was stirred under balloon pressure H2 for 3 h. The solution was filtered through Celite and concentrated under reduced pressure. Then passed through a short silica gel column, eluted with PE/EtOAc=10:l to afford methyl 2-(3-hydroxyphenyl)propanoate (9 g, 87 %). 1H NMR ^OO MHZ5 CDCI3) O = 7.16-7.20 (t, IH), 6.84 (d, IH), 6.81 (s, IH), 6.74 (d, IH), 3.67 (s, 3H), 3.67-3.72 (q, IH), 1.48 (d, 3H); LCMS m/z 181 [M+l]+.
Example 9. Synthesis of Intermediate 6a Methyl 2-(4-formyl-3-hydroxyphenyl)propanoate
Figure imgf000112_0002
Methyl 2-(3-hydroxyphenyl)propanoate (10.8 g, 60 mmol, 1.0 equiv.), MgCl2 (8.55 g, 90 mmol, 1.5 equiv.), Et3N (1.11 g, 240 mmol, 4 equiv.) and paraformaldehyde (13 g, 420 mmol, 7 equiv.) were dissolved in THF (150 ml). The mixture was heated to 750C for 4 h and then cooled to rt and quenched with HCl diluted solution. The mixture was extracted with EtOAc. The organic layer was dried over Na2SC^ and concentrated in vacuum. The residue was purified with a silica gel column chromatography (eluting with PE/EtOAc =100: 1). Methyl 2-(4-formyl-3-hydroxyphenyl)propanoate was obtained as colorless viscous oil (6.5 g, 52 %). 1H NMR (400 MHz, CDCl3) δ = 11.04 (s, IH), 9.86 (s, IH), 7.51 (d, IH), 6.96 (d, IH), 6.92 (s, IH), 3.69-3.74 (q, IH), 3.67 (s, 3H), 1.50 (d, 3H); LCMS m/z 209 [M+ 1]+. Example 10. Synthesis of Intermediates 7-10
Figure imgf000113_0001
7 8 9 10
Intermediate 7 was synthesized using the same condition and reagents as for intermediate 6, except that 5 equivalent of MeI was used. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.19 (t, J = 7.91 Hz, IH), 6.90 (d, J = 7.78 Hz, IH), 6.82 (t, J = 2.13 Hz, IH), 6.71 (dd, J = 2.01, 7.53 Hz, IH), 1.54 - 1.60 (m, 6H); LCMS m/z 195.2 [M+l]+ Intermediates 8-10 were synthesized using the corresponding alkyl iodide with same condition as for intermediate 6. Analytical for intermediate 8: H NMR (400 MHz, CDCl3) δ = 7.15-7.19 (t, IH), 6.83 (d, 2H), 6.76 (d, IH), 6.20 (b, IH), 3.67 (s, 3H), 3.40- 3.44 (t, IH), 1.99-2.12 (m, IH), 1.73-1.84 (m, IH), 0.86-0.90 (t, 3H); LCMS m/z 195 [M+ 1]+.
Analytical for intermediate 9: 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.04 - 7.34 (m, 2H), 6.61 - 6.86 (m, 2H), 3.55 (s, 3H), 3.36 - 3.51 (m, IH), 1.56 - 1.75 (m, 2H), 1.47 - 1.56 (m, 2H), 1.16 (br. s., 3H); LCMS m/z 195.2 [M+l]+.
Analytical for intermediate 10: 1H NMR (400 MHz, DMSO-d6) δ = 9.37 (s, IH), 7.09 (t, J = 7.78 Hz, IH), 6.61 - 6.73 (m, 3H), 3.55 (s, 3H), 3.11 (d, J = 10.54 Hz, IH), 2.09 - 2.23 (m, IH), 0.94 (d, J = 6.53 Hz, 3H), 0.64 (d, J = 6.78 Hz, 3H); LCMS m/z 209.2 [M+ 1]+.
Example 11. Synthesis of Intermediate 7a and 8a
Figure imgf000113_0002
7a 8a
Methyl 2-(3-hydroxyphenyl)butanoate (11.6 g, 60 mmol, 1.0 equiv.), MgCl2 (8.55 g, 90 mmol, 1.5 equiv.), Et3N (1.11 g, 240 mmol, 4 equiv.) and paraformaldehyde (13 g, 420 mmol, 7 equiv.) were dissolved in THF (150 ml). The mixture was heated to 800C for 4 h and then cooled to rt and quenched with HCl diluted solution. The mixture was extracted with EtOAc. The organic layer was dried over Na2SC^ and concentrated in vacuo. The residue was purified with a silica gel column chromatography (eluting with PE/EtOAc =100: 1). Methyl 2-(4-formyl-3-hydroxyphenyl)butanoate (8a)was obtained as a colorless viscous oil (7.7 g, 58 %). 1H NMR (400 MHz, CDCl3) δ = 11.03 (s, IH), 9.87 (s, IH), 7.52 (d, IH), 6.94-6.99 (t, 2H), 3.68 (s, 3H), 3.46-3.50 (t, IH), 2.05-2.16 (m, IH), 1.75- 1.86 (m, IH), 0.88-0.92 (t, 3H).
Intermediate 7a was synthesized using similar conditions. ^H NMR (400 MHz, DMSO- d6) δ = 10.69 (s, IH), 10.20 (s, IH), 7.61 (d, J= 8.03 Hz, IH), 6.80 - 6.99 (m, 2H), 3.60 (s, 3H), 1.48 (s, 6H); LCMS m/z 223.1 [M+l]+.
Example 12: Synthesis of Intermediate 11
Methyl 1 -(3-hydroxyphenyl)cyclopentanecarboxylate
Figure imgf000114_0001
Step l
Methyl 1 -(3-(benzyloxy)phenyl)cyclopentanecarboxylate
Figure imgf000114_0002
A solution of methyl 2-(3-(benzyloxy)phenyl)acetate (4.90 g, 19.14 mmol, 1.0 eq) in dry THF was cooled to -78 0C. To this solution was added dropwise LiHMDS (36.0 mL, 38.28 mmol, 2.0 eq) and 1 ,4-dibromobutane (2.29 mL, 19.14 mmol, 1.0 eq) at this temperature under argon. After 10 mins, the reaction mixture was warmed up to r.t. for 1.5 h. The resulting mixture was then quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure, to give a crude product, which was purified using column chromatography to obtain methyl l-(3-(benzyloxy)phenyl)cyclopentanecarboxylate (3.09 g , 52%), as a white solid. LCMS m/z 311.0 [M+H] +; 1H NMR (400 MHz, CDCl3) δ: 7.44-7.29 (m, 5H), 7.24-7.19 (m, IH), 7.00-6.94 (m, 2H), 6.84 (dd, J= 8.0, 2.0 Hz, IH), 5.04 (s, 2H), 3.59 (s, 3H), 2.63-2.57 (m, 2H), 1.93-1.86 (m, 2H), 1.74-1.69 (m, 4H).
Step 2
Methyl 1 -(S-hydroxypheny^cyclopentanecarboxylate
Figure imgf000115_0001
A solution of methyl l-(3-(benzyloxy)phenyl)cyclopentanecarboxylate (3.08 g, 9.94 mmol, 1.0 eq) in MeOH (100 mL) was flushed with N2, and Pd/C (616 mg, 20% w/w) was added. The mixture was flushed with H2 for three times, and then stirred at r.t. for 72 h. The resulting mixture was filtered and the filtrate was evaporated to give the crude product, which was purified by column chromatography (PE/EA = 20/1 , and 5/1) to obtain methyl l-(3-hydroxyphenyl)cyclopentanecarboxylate (1.64 g, 75%) as a white solid. LCMS m/z 221.0 [M+H] +;!H NMR (400 MHz, MeOH-d4) δ: 7.13-7.10 (m, IH), 6.83-6.79 (m, 2H), 6.67-6.65 (m, IH), 3.61 (s, 3H), 2.62-2.56 (m, 2H), 1.93-1.86 (m, 2H), 1.78-1.68 (m, 4H).
Example 13: Synthesis of Intermediate 12
Methyl 3-cyclopropyl-2-(3-hydroxyphenyl)propanoate
Figure imgf000115_0002
Methyl 2-(3-(benzyloxy)phenyl)-3-cyclopropylpropanoate
Figure imgf000116_0001
2-(3-(benzyloxy)phenyl)acetate (6.0 g, 23.0 mmol, 1.0 eq) was dissolved in THF (300 mL). KHMDS (4.5 g, 23.0 mmol, 1.0 eq) was added dropwise at -78 0C with N2. The mixture was stirred at -78 0C for 1 h and (bromomethyl)cyclopropane (3.1 g, 23.0 mmol, 1.0 eq) was added dropwise at -78 0C . The mixture was stirred from -78 0C to rt for 16 h. The mixture was extracted with ethyl acetate and water (150 mL X 3), and the organic layer was dried over Na2SO^ The solvent was removed and the residue was purified by column to give methyl 2-(3-(benzyloxy)phenyl)-3-cyclopropylpropanoate as yellow oil (3.5 g, 42%). LCMS m/z 311.2 [M+l] +; 1H NMR (400 MHz, CDCl3) δ: 7.41-7.39 (m, 2H), 7.36-7.33 (m, 2H), 7.30-7.27 (m, IH), 7.21-7.18 (m, IH), 6.94 (bs, IH), 6.89-6.88 (m, IH), 6.85-6.83 (m, IH), 5.12 (bs, 2H), 3.64-3.61 (m, 4H), 1.87-1.68 (m, 2H), 0.60- 0.56 (m, IH), 0.39-0.33 (m, 2H), 0.07-0.02 (m, 2H).
Step 2
Methyl 3-cyclopropyl-2-(3-hydroxyphenyl)propanoate
Figure imgf000116_0002
Methyl 2-(3-(benzyloxy)phenyl)-3-cyclopropylpropanoate (3.5 g, 11.0 mmol, 1.0 eq) was dissolved in THF (20 mL). Pd/C (0.35 g, 0.1 eq) was added under N2 atmosphere. The mixture was purged with H2 for three times and stirred at rt for 16 h. The reaction mixture was filtered through celite, the filtrate was concentrated in vacuo, and the residue was purified by column chromatography to give methyl 3-cyclopropyl-2-(3- hydroxyphenyl)propanoate as yellow oil (2.0 g, 81%); LCMS m/z 221.0 [M+l] +; 1H NMR (400 MHz, DMSO-d6) δ: 9.33 (bs, IH), 7.07-7.03 (m, IH), 6.66-6.64 (m, 2H), 6.60-6.58 (m, IH), 3.57-3.53 (m, 4H), 1.78-1.49 (m, 2H), 0.59-0.49 (m, IH), 0.35-0.26 (m, 2H), 0.05-0.04 (m, 2H).
Example 14: Synthesis of Intermediate 13
Methyl 2-(3-hydroxyphenyl)-2,4-dimethylpentanoate
Figure imgf000117_0001
Step l
Methyl 2-(3-(benzyloxy)phenyl)-2,4-dimethylpent-4-enoate
Figure imgf000117_0002
A solution of methyl 2-(3-(benzyloxy)phenyl)propanoate (2.14 g, 7.90 mmol, 1.0 eq) in THF (40 mL ) was cooled to -78 0C, LiHMDS (1.06 N, 8.96 mL, 9.50 mmol, 1.2 eq) was added dropwise, after addition, the solution was stirred at -78 0C for 1 h. 3-bromo-2- methylprop- 1 -ene (1.27 g, 9.50 mmol, 1.2 eq) in THF (10 mL) was added slowly, after addition, the mixture was warmed to rt and stirred for Ih. The reaction was quenched with aqueous NH4CI (10%, 15 mL), water layer was extracted with ethyl acetate. The combined organic layer was dried over Na2SC^, the solvent was removed in vacuo, and the residue was purified using column chromatography to give methyl 2-(3- (benzyloxy)phenyl)-2,4-dimethylpent-4-enoate as colorless oil (2.12 g, 83%). LCMS m/z 347.0 [M+Na] +; 1H NMR (400 MHz, CDCl3) δ: 7.44-7.30 (m, 5H), 7.25-7.21 (m, IH), 6.99-6.94 (m, 2H), 6.88-6.84 (m, IH), 5.05 (s, 2H), 4.81 (bs, IH), 4.64 (bs, IH), 3.63 (s, 3H), 2.94-2.91 (m, IH), 2.62-2.58 (m, IH), 1.52 (s, 3H), 1.47 (s, 3H).
Step 2 Methyl 2-(3-hydroxyphenyl)-2,4-dimethylpentanoate
Figure imgf000118_0001
A solution of methyl 2-(3-(benzyloxy)phenyl)-2,4-dimethylpent-4-enoate (2.12 g, 6.54 mmol, 1.0 eq) in MeOH (100 mL) was purged with N2 for 3 times, Pd/C (10%, 400 mg, w% = 20%) was added and the mixture was purged with H2 for 3 times, stirred at rt for 16 h. Pd/C was filtered, the solvent was removed in vacuo to give methyl 2-(3- hydroxyphenyl)-2,4-dimethylpentanoate as a colorless oil (1.61 g, 100%). LCMS m/z = 237.2 [M+H] +; 1H NMR (400 MHz, CDCl3) δ: 7.20-7.16 (m, IH), 6.91-6.89 (m, IH), 6.85-6.84 (m, IH), 6.72-6.70 (m, IH), 3.64 (s, 3H), 2.07-2.02 (m, IH), 1.85-1.81 (m, IH), 1.67-1.61 (m, IH), 1.54 (s, 3H), 0.87-0.86 (m, 3H), 0.83-0.81 (m, 3H).
Example 15: Synthesis of Intermediate 14
Methyl 2-(3-hydroxyphenyl)-4,4-dimethylpentanoate
Figure imgf000118_0002
Step l
2-(3-methoxyphenyl)-4,4-dimethylpentanoic acid
Figure imgf000118_0003
To a solution of l-methoxy-3-vinylbenzene (1.34 g, 10.0 mmol, 1.0 eq.) in dry Et2O (20 mL) cooled to -78 0C in a dry-ice/acetone bath, a solution of t-BuLi (768 mg, 12.0 mmol, 1.2 eq.) in pentane (7.0 mL) was added dropwise. The resulting solution turned orange, and was stirred at -78 0C for 30 mins. Dry CO2 (gas) was bubbled into the solution for 5 min at this temperature, the orange solution turned colorless quickly, and the reaction was warmed to r.t. for another 30 min. The resulting mixture was quenched with sat. aq. NH4CI (20 mL), extracted with EtOAc (50 mL x 3), washed with brine, dried over Na2SO4, and concentrated in vacuo to give the crude product, which was purified by column chromatography to obtain 2-(3-methoxyphenyl)-4,4-dimethylpentanoic acid (2.20 g, 90%), as a yellow oil. LCMS m/z 237.0 [M+H] +; 1H NMR (400 MHz, CDCl3) δ: 7.27- 7.21 (m, IH), 6.94 (d, J= 8.0 Hz, IH), 6.90 (bs, IH), 6.80 (dd, J= 8.0, 2.4 Hz, IH), 3.81 (s, 3H), 3.64 (dd, J= 8.8, 4.0 Hz, IH), 2.26 (dd, J= 14.0, 8.8 Hz, IH), 1.63 (dd, J= 14.0, 4.0 Hz, IH), 0.92 (bs, 9H).
Step 2
2-(3-hydroxyphenyl)-4,4-dimethylpentanoic acid
Figure imgf000119_0001
A solution of 2-(3-methoxyphenyl)-4,4-dimethylpentanoic acid (2.2 g, 9.3 mmol, 1.0 eq.) in DCM (60 mL) was cooled to -78 0C, and a solution OfBBr3 (2.16 mL, 23.3 mmol, 2.5 eq.) in DCM (10 mL) was then added dropwise. The reaction mixture was stirred for 10 min at this temperature, then slowly warmed to r.t. and stirred for 2.0 h. The resulting mixture was quenched with water at 00C, extracted with DCM, washed with brine, dried over Na2SO4, and concentrated in vacuo to give the crude product, which was purified by column chromatography to obtain 2-(3-hydroxyphenyl)-4,4-dimethylpentanoic acid (1.60 g, 80%), as a yellow oil. LCMS m/z 223.0 [M+H] +; 1H NMR (400 MHz, CDCl3) δ: 7.18- 7.14 (m, IH), 6.88 (d, J= 8.0 Hz, IH), 6.83 (bs, IH), 6.71 (dd, J= 8.0, 2.1 Hz, IH), 3.60 (dd, J= 8.8, 4.0 Hz, IH), 2.22 (dd, J= 14.0, 8.8 Hz, IH), 1.59 (dd, J= 14.0, 4.0 Hz, IH), 0.89 (bs, 9H).
Step 3 Methyl 2-(3-hydroxyphenyl)-4,4-dimethylpentanoate
Figure imgf000120_0001
A solution of 2-(3-hydroxyphenyl)-4,4-dimethylpentanoic acid (1.41 g, 6.4 mmol, 1.0 eq.) in SOCl2 (3.0 mL) was warmed to reflux for 1.0 h. The reaction solution was concentrated in vacuo to give the carbonyl chloride, which was re-dissolved in DCM (10 mL) and MeOH (3.0 mL) was added. The mixture was heated to reflux for another 1.0 h, and evaporated in vacuo again, to give the crude product, which was purified by column chromatography to yield methyl 2-(3-hydroxyphenyl)-4,4-dimethylpentanoate (1.20 g, 80%), as a yellow oil. LCMS m/z 237.0 [M+H] +; 1H NMR (400 MHz, CDCl3) ^: 7.18- 7.14 (m, IH), 6.88-6.85 (m, 2H), 6.72 (dd, J= 8.0, 2.1 Hz, IH), 3.65 (s, 3H), 3.61 (dd, J = 8.8, 4.0 Hz, IH), 2.26 (dd, J= 14.0, 8.8 Hz, IH), 1.56 (dd, J= 14.0, 4.0 Hz, IH), 0.88 (bs, 9H).
Example 16. Synthesis of Intermediate 15
Figure imgf000120_0002
Step 1:
4-(difluoromethyl)bicyclo [2.2.2] octane- 1 -carboxylic acid
Figure imgf000120_0003
To a solution of Diethylaminosulfur trifluoride (2.69 mL, 0.0204 mol) in methylene chloride (187.8 mL, 2.929 mol) , cooled to -50 0C was added a solution of 4-formyl- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester (2.00 g, 0.0102 mol) in methylene chloride and reaction stirred overnight. The reaction is quenched with water and extracted with DCM. The organic is dried over MgSO4 and concentrated. The residue purified by flash chromatography (0-50% ethyl acetate/hexanes) to give methyl 4- (difluoromethyl)bicyclo[2.2.2]octane-l-carboxylate. LCMS m/z 219.2 [M+ 1]+ The ester was dissolved in isopropyl alcohol (20.00 mL) and 4 M of sodium hydroxide in water (6.00 mL, 0.0240 mol) was added to it. Solution stirred overnight. Quench with 1 M of hydrogen chloride in water (20.38 mL, 0.02038 mol). The precipitated solid is filtered to give the acid (1.45g, 70%). 1H NMR (400 MHz, DMSOd6) δ 11.92 - 12.21 (m, IH), 5.69 (m, IH), 1.63 - 1.74 (m, 6H), 1.41 - 1.54 (m, 6H); LCMS m/z 205.1 [M+ 1]+.
Step 2:
4-(difluoromethyl)-N-isopentylbicyclo[2.2.2]octan-l -amine
Figure imgf000121_0001
To a solution of 4-difluoromethyl-bicyclo[2.2.2]octane-l-carboxylic acid (0.345 g, 0.00169 mol) in toluene (6.900 mL,0.06478 mol) was added diphenylphosphonic azide (0.35 mL, 0.0016 mol) and triethylamine (0.27 mL, 0.0020 mol) and stirred for 1 h at room temperature. The solution of the azide was then heated to reflux for Ih. The isocyanate solution was cooled and treated with excess of benzyl alcohol (13.4 mL, 0.130 mol) and refluxed overnight (18h). The resulting solution was cooled and washed with 5% citric acid, sat NaHCCβ and NaCl. The organic layer was dried over MgSO4 and concentrated. The resulting residue was purified by flash chromatography (0-50% ethyl acetate in hexanes) to give benzyl 4-(difluoromethyl)bicyclo[2.2.2]octan-l-ylcarbamate as an oily solid.
To a solution of benzyl 4-(difluoromethyl)bicyclo[2.2.2]octan-l-ylcarbamate in MeOH was added 10% palladium on carbon (10 mol %) and solution hydrogenated at 50 psi for 18 h. The solution was filtered through celite and concentrated to give A- (difluoromethyl)bicyclo[2.2.2]octan-l-amine as a colorless oil.
To a solution of 4-difluoromethyl-bicyclo[2.2.2]oct-l-ylamine (0.100 g, 0.000571 mol) and isovaleraldehyde (0.0617 mL, 0.000571 mol) in 1,2-dichloroethane (3.00 mL, 0.0381 mol) was added sodium triacetoxyborohydride (0.121 g, 0.000571 mol) and solution stirred for 2 h. LCMS shows reaction complete. The reaction was quenched with sodium bicarbonate and extracted with ethyl acetate. The organics were concentrated to give the desired product (140 mg, 100%). LCMS m/z 246.3 [M+l]+.
Example 17. Synthesis of 2-(6-((Butyl((lr.4r)-4-tert-butylcvclohexyl)amino)methyl)-4'- (trifluoromethyl)biphenyl-3-yl)acetic acid (Method A)
Figure imgf000122_0001
Step l
Methyl 2-(6-((( 1 r,4r)-4-tert-butylcyclohexylamino)methyl)-4'-(trifluoromethyl)biphenyl- 3-yl)acetate
Figure imgf000122_0002
Methyl 2-(6-formyl-4'-(trifluoromethyl)biphenyl-3-yl)acetate (intermediate 3, 90 mg, 0.3 mmol), 4-tert-butylcyclohexanamine (140 mg, 0.9 mmol), NaBH(OAc)3 (126 mg, 0.6 mmol) and CH3COOH (54 mg, 0.9 mmol) were dissolved in dichloromethane (5 ml). The mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated NaHCO3, extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated to yield a crude product. The residue was purified by flash chromatography on silica to afford methyl 2-(6-(((lr,4r)-4-tert-butylcyclohexylamino) methyl)-4'-(trifiuoromethyl)biphenyl-3-yl)acetate (65 mg, 50%). 1H-NMR (CDCl3, 300MHz) δ = 7.66 (d, 2H), 7.60 (d, 2H), 7.47 (d, IH), 7.26-7.31 (m, IH), 7.16 (d, IH), 3.70 (s, 3H), 3.65 (s, 2H), 3.62 (s, 2H), 2.73-2.75 (m, IH), 1.64-1.68 (m, 2H), 1.61 (b, IH), 1.39 (d, 2H), 1.27-1.34 (m, 2H), 1.05-1.14 (m, 2H), 0.91-0.97 (m, IH), 0.81 (s, 9H); LCMS m/z 462 [M+ 1]+.
Step 2
Methyl 2-(6-((butyl(( 1 r,4r)-4-tert-butylcyclohexyl)amino)methyl)-4'- (trifluoromethyl)biphenyl-3-yl)acetate
Figure imgf000123_0001
2-(6-(((lr,4r)-4-tert-butylcyclohexylamino) methyl)-4'-(trifluoromethyl)biphenyl-3- yl)acetate (70 mg, 0.15 mmol), butyraldehyde (32 mg, 0.45 mmol), NaBH(OAc)3 (63 mg, 0.3 mmol) and CH3COOH (27 mg, 0.45 mmol) were dissolved in dichloromethane (5 ml). The mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated NaHCO3, extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated to yield methyl 2-(6-((butyl((lr,4r)-4-tert- butylcyclohexyl)amino)methyl)-4'-(trifluoromethyl)biphenyl-3-yl)acetate. LCMS m/z 518 [M+l]+.
Step 3 2-(6-((Butyl((lr,4r)-4-tert-butylcyclohexyl)amino)methyl)-4'-(trifluoromethyl)biphenyl- 3-yl)acetic acid
Figure imgf000124_0001
The above ester (30 mg, 0.07 mmol) was dissolved in MeOH (5 ml) and IN NaOH (140 μL, 0.14 mmol) was added. The mixture was heated to reflux for 30 minutes. The reaction mixture was adjusted pH to about 7.0; concentrated to yield a crude product. The residue was purified with pre-HPLC (ACN/H2O with 0.05% TFA as mobile phase) (15 mg, yield 20% in two steps). IH-NMR (CDCl3, 300MHz) δ: 7.76 (d, IH), 7.71 (d, 2H), 7.41 (d, 2H), 7.35 (d, IH), 7.20 (s, IH), 4.30 (b, 2H), 3.65 (s, 2H), 3.18 (b, IH), 2.77 (b, 2H), 1.77 (b, 2H), 1.40-1.47 (m, 5H), 1.21-1.30 (m, 4H), 1.07-1.10 (m, 3H), 0.75-0.81 (m, 12H). LCMS m/z 504 [M+l]+.
Example 18. Synthesis of 2-(6-((Benzyl((lr,4r)-4-tert-buMcvclohexyl)amino)methyl)- 4'-fluorobiphenyl-3-yl)acetic acid (Method B)
Figure imgf000124_0002
Step l
Methyl 2-(4-((benzyl(( 1 r,4r)-4-tert-butylcyclohexyl)amino)methyl)-3- hydroxyphenyl)acetate
Figure imgf000125_0001
To a mixture of (3-hydroxy-phenyl)-acetic acid methyl ester (42 mg, 0.25 mmol), paraformaldehyde (9.0 mg, 0.30 mmol) in α,α,α-trifluorotoluene (1 mL) was added amine (74 mg, 0.30 mmol). The reaction mixture was heated in a microwave reactor at 12O0C for 1 h. It was concentrated and purified by flash chromatography on silica (EtOAc in hexane 10-25%) to collect methyl 2-(4-((benzyl((lr,4r)-4-tert- butylcyclohexyl)amino)methyl)-3-hydroxyphenyl)acetate as a colorless oil (61mg, 58%). 1H NMR (300MHz ,DMSO-d6) δ = 10.56 (br. s., 1 H), 7.22 - 6.95 (m, 5 H), 6.84 (d, J = 7.6 Hz, 1 H), 6.39 (d, J = 7.6 Hz, 1 H), 6.35 (s, 1 H), 3.48 (s, 2 H), 3.38 (s., 2 H), 3.35 (s, 3 H), 3.30 (s, 2 H), 2.23 - 2.10 (m, 1 H), 1.72 - 0.59 (m, 9 H), 0.56 (s, 9 H); LCMS m/z 424.4 [M+l]+.
Step 2
Methyl 2-(4-((benzyl((lr,4r)-4-tert-butylcyclohexyl)amino)methyl)-3- (trifluoromethylsulfonyloxy)phenyl)acetate
Figure imgf000125_0002
To a mixture of methyl 2-(4-((benzyl((lr,4r)-4-tert-butylcyclohexyl)amino)methyl)-3- hydroxyphenyl)acetate (48 mg, 0.11 mmol), N-phenylbis(trifluoromethane- sulphonimide) (48 mg, 0.14 mmol) in methylene chloride (1 mL ) was added triethylamine (47 μL, 0.34 mmol), followed by 4-dimethylaminopyridine (1 mg, 0.008 mmol) . The reaction mixture was stirred at room temperature for 2 h. It was concentrated and purified by flash chromatography on silica (EtOAc in hexane 5-10%) to collect methyl 2-(4-((benzyl((lr,4r)-4-tert-butylcyclohexyl)amino)methyl)-3- (trifluoromethylsulfonyloxy)phenyl)acetate as a colorless oil (48 mg, 76%). It was used as such without taking NMR.
Step 3
Methyl 2-(6-((benzyl((lr,4r)-4-tert-butylcyclohexyl)amino)methyl)-4'-fluorobiphenyl-3- yl)acetate
Figure imgf000126_0001
To a microwave vial was added (4-{[benzyl-(4-tert-butyl-cyclohexyl)-amino]-methyl}-3- trifluoromethanesulfonyloxy-phenyl)-acetic acid methyl ester (24 mg, 0.043 mmol), A- fluoroboronic acid (11.5 mg, 0.0605 mmol), tetrakis(triphenylphosphine)palladium(0) (3 mg, 0.002 mmol) and 1 ,2-dimethoxyethane (300 μL), followed by ethanol (100 uL) and saturated aqueous sodium bicarbonate solution (40 μL). The vial was heated using microwave irradiation at 1200C for 5 min. The reaction mixture was partitioned between ethyl acetate and brine. The organic phase was dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography on silica (EtOAc in hexane 5-10%) to collect methyl 2-(6-((benzyl((lr,4r)-4-tert- butylcyclohexyl)amino)methyl)-4'-fluorobiphenyl-3-yl)acetate as a colorless oil (22 mg, 100%). It was used as such for next step without taking NMR.
Step 4
2-(6-((Benzyl((lr,4r)-4-tert-butylcyclohexyl)amino)methyl)-4'-fluorobiphenyl-3-yl)acetic acid
Figure imgf000127_0001
To a solution of above ester (22 mg, 0.0438 mmol) in THF (0.5 mL) and MeOH (0.5 ml) was added 3 M of sodium hydroxide in water (60 μL). The reaction mixture was heated at 1000C for 5 min. It was added IN HCl (180 μL) and diluted with more water, extracted with EtOAc. The organic phase was washed with water, dried over MgSO4, concentrated to get 2-(6-((benzyl((lr,4r)-4-tert-butylcyclohexyl)amino) methyl)-4'-fluorobiphenyl-3- yl)acetic acid as a white solid (19 mg, 89%). 1H NMR (400MHz ,DMSO-d6) δ = 12.27 (br. s., 1 H), 7.58 (d, J = 7.8 Hz, 1 H), 7.37 - 7.13 (m, 10 H), 7.03 (d, J = 1.3 Hz, 1 H), 3.56 (s, 2 H), 3.50 (s, 2 H), 3.44 (s, 2 H), 2.27 - 2.14 (m, 1 H), 1.76 - 1.52 (m, 4 H), 1.30 - 1.07 (m, 2 H), 0.95 - 0.64 (m, 3 H), 0.76 (s, 9 H); LCMS m/z 488.4 [M+ 1]+.
Example 19. Synthesis of 2-(4'-tert-butyl-6-((4-fruorophenyl)(4- (trifluoromethyl)piperidin-l-yl)methyl)biphenyl-3-yl)acetic acid (Method C)
Figure imgf000127_0002
Step l
Methyl 2-(4-((4-fluorophenyl)(4-(trifluoromethyl)piperidin- 1 -yl)methyl)-3- hydroxyphenyl)acetate
Figure imgf000128_0001
The mixture methyl 2-(4-formyl-3-hydroxyphenyl)acetate (intermediate 1) (930 mg, 4.79 mmol), 4-fluorophenylboronic acid (737 mg, 5.26 mmol), 4-trifluoromethyl-piperidine (115 mg, 7.18 mmol) in 5 mL of trifluoro-toluene was heated using microwave irradiation at 12O0C for 10 minutes. The organic solvent was then removed to give a crude product, which was purified by flash chromatography on silica (15-25% EtOAc in hexane) to give the desired methyl 2-(4-((4-fluorophenyl)(4-(trifluoromethyl)piperidin-l- yl)methyl)-3-hydroxyphenyl)acetate as a colorless oil (1.67 g, 82%). 1H NMR (400MHz ,DMSO-de) δ = 10.36 (s, 1 H), 7.42 (dd, J= 5.6, 8.4 Hz, 2 H), 7.22 - 7.05 (m, 3 H), 6.72 - 6.59 (m, 2 H), 4.69 (s, 1 H), 3.58 (s, 3 H), 3.51 (s, 2 H), 3.05 - 2.94 (m, 1 H), 2.81 - 2.71 (m, 1 H), 2.40 - 2.31 (m, 1 H), 2.02 - 1.86 (m, 2 H), 1.85 - 1.72 (m, 2 H), 1.59 - 1.39 (m, 2 H); LCMS m/z 426.2 [M+ 1]+.
Step 2
Methyl 2-(4-((4-fluorophenyl)(4-(trifluoromethyl)piperidin- 1 -yl)methyl)-3- (trifluoromethylsulfonyloxy)phenyl)acetate
Figure imgf000128_0002
To a solution of methyl 2-(4-((4-fluorophenyl)(4-(trifluoromethyl)piperidin-l-yl)methyl)- 3-hydroxyphenyl)acetate (1.61 g, 3.78 mmol) and Tf2O (1.28 g, 4.53 mmol) in 20 mL methylene chloride was slowly added Et3N (763 mg, 7.56 mmol). The mixture was stirred at room temperature for 2 hours. The organic solvent was removed and the residue was purified by flash chromatography on silica (10-20% EtOAc in hexane) to give methyl 2-(4-((4-fluorophenyl)(4-(trifiuoromethyl)piperidin- 1 -yl)methyl)-3- (trifluoromethylsulfonyloxy)phenyl)acetate as a colorless oil (1.75 g, 83%). 1H NMR (400MHz ,DMSOd6) δ = 7.83 (d, J= 8.0 Hz, 1 H), 7.43 (d, J= 8.0 Hz, 1 H), 7.35 (dd, J = 5.5, 8.5 Hz, 2 H), 7.28 (s, 1 H), 7.17 (t, J= 8.8 Hz, 2 H), 4.58 (s, 1 H), 3.78 (s, 2 H), 3.61 (s, 3 H), 3.30 (d, J= 9.5 Hz, 3 H), 2.92 - 2.82 (m, 1 H), 2.77 - 2.68 (m, 1 H), 1.91 (q, J= 9.8 Hz, 2 H), 1.77 (d, J= 12.0 Hz, 2 H), 1.62 - 1.41 (m, 2 H); LCMS m/z 558.2 [M+ 1]+.
Step 3
2-(4'-tert-butyl-6-((4-fluorophenyl)(4-(trifluoromethyl)piperidin-l-yl)methyl)biphenyl-3- yl)acetic acid
Figure imgf000129_0001
To a mixture of methyl 2-(4-((4-fluorophenyl)(4-(trifluoromethyl)piperidin-l-yl)methyl)- 3-(trifluoromethylsulfonyloxy)phenyl)acetate (35 mg, 0.063 mmol), 4-tert- butylphenylboronic acid (17 mg, 0.094 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II),complex with dichloromethane (1: 1) (3.1 mg, 0.0038 mmol) in 1,2-dimethoxyethane (0.6 mL) was added saturated aqueous sodium bicarbonate (80 μL, 2 mmol). The reaction mixture was heated using microwave irradiation at 11O0C for 15 minutes. It was diluted with water, extracted with EtOAc. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica (5-10% EtOAc in hexane) to get the ester as a colorless oil (23 mg). The above ester in THF (0.5 mL)/MeOH (0.5 mL) was treated with 3M NaOH in water (70 μL) using microwave irradiation at HO0C for 15 minutes. Added IM HCl (210 μL) and diluted with water, extracted with EtOAc. The organic phase was washed with water, dried over MgSO4, filtered and concentrated to get 2-(4'-tert-butyl-6-((4- fluorophenyl)(4-(trifluoromethyl)piperidin-l-yl)methyl)biphenyl-3-yl)acetic acid as a white powder (17 mg, 51% for two steps). 1H NMR (400MHz ,DMSO-d6) δ = 12.29 (br. s., 1 H), 7.68 (d, J = 8.3 Hz, 1 H), 7.48 (d, J= 8.3 Hz, 2 H), 7.27 (dd, J= 1.5, 8.0 Hz, 1 H), 7.08 (d, J= 8.0 Hz, 2 H), 7.03 (d, J= 7.3 Hz, 4 H), 6.98 (d, J= 1.5 Hz, 1 H), 4.44 (s, 1 H), 3.54 (s, 2 H), 3.11 - 2.90 (m, 1 H), 2.63 - 2.57 (m, 1 H), 2.31 - 2.15 (m, 1 H), 2.01 - 1.81 (m, 1 H), 1.82 - 1.57 (m, 3 H), 1.56 - 1.39 (m, 2 H), 1.36 (s, 9 H); LCMS m/z 528.4 [M+ 1]+.
Example 20. Synthesis of 4-methyl-2-(6-(phenyl(piperidin-l-yl)methyl)-4'- (trifluoromethyl)biphenyl-3-yl)pentanoic acid (Method D)
Figure imgf000130_0001
Step l
Methyl 2-(4-((4-fluorophenyl)(4-(trifluoromethyl)piperidin- 1 -yl)methyl)-3- hydroxyphenyl)acetate
Figure imgf000130_0002
To a mixture of methyl 2-(3-hydroxyphenyl)-4-methylpentanoate (intermediate 4) (110 mg, 0.50 mmol), piperidine (59 μL, 0.60 mmol) in trifluoro-toluene (1 mL) was added benzaldehyde (61 μL, 0.60 mmol). The mixture was heated using microwave irradiation at 12O0C for 1 hour. It was partitioned between EtOAc and brine. The organic phase was dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography on silica (10-15% EtOAc in hexane) to get Methyl 2-(4-((4- fluorophenyl)(4-(trifluoromethyl)piperidin- 1 -yl)methyl)-3-hydroxyphenyl)acetate as a colorless oil. (120 mg, 61%). 1H NMR (300MHz ,DMSO-de) δ = 11.36 (s, 1 H), 7.44 - 7.35 (m, 2 H), 7.31 (t, J= 7.4 Hz, 2 H), 7.23 (d, J= 6.8 Hz, 1 H), 6.66 (s, 1 H), 6.63 (d, J = 7.6 Hz, 1 H), 4.59, 4.58 (s, s, 1 H), 3.56, 3.55 (s, s, 3 H), 3.54 - 3.49 (m, 1 H), 2.44 - 2.21 (m, 4 H), 1.88 - 1.70 (m, 1 H), 1.63 - 1.22 (m, 8 H), 0.84 (d, J = 6.4 Hz, 6 H); LCMS m/z 396.3 [M+l]+.
Step 2
Methyl 5-methyl-2-oxo-3-(4-(phenyl(piperidin- 1 -yl)methyl)-3- (trifluoromethylsulfonyloxy)phenyl)hexanoate
Figure imgf000131_0001
To a mixture of methyl 2-(4-((4-fluorophenyl)(4-(trifluoromethyl)piperidin-l-yl)methyl)- 3-hydroxyphenyl)acetate (120 mg, 0.30 mmol), N-(5-chloro-2-pyridyl)triflimide (131 mg, 0.334 mmol) in methylene chloride (2 mL) was added triethylamine (46.5 μL, 0.334 mmol), followed by 4-dimethylaminopyridine (1 mg, 0.008 mmol). The reaction mixture was stirred at room temperature for Ih. It was concentrated and purified by flash chromatography on silica (10% EtOAc in hexane) to get methyl methyl 5-methyl-2-oxo- 3-(4-(phenyl(piperidin- 1 -yl)methyl)-3-(trifluoromethylsulfonyloxy)phenyl)hexanoate as a colorless oil (128 mg, 80%).
Step 3
4-Methyl-2-(6-(phenyl(piperidin-l-yl)methyl)-4'-(trifluoromethyl)biphenyl-3- yl)pentanoic acid
Figure imgf000132_0001
To a mixture of 4-(trifluoromethyl)phenylboronic acid (58.0 mg, 0.306 mmol), methyl 5- methyl-2-oxo-3-(4-(phenyl(piperidin-l-yl)methyl)-3-(trifluoromethylsulfonyloxy) phenyl)hexanoate (129 mg, 0.244 mmol), and tetrakis(triphenylphosphine)palladium(0) (14 mg, 0.012 mmol) in 1,2-dimethoxyethane (1 mL) was added ethanol (0.5 mL), followed by saturated aqueous sodium bicarbonate solution (0.2 mL). The mixture was heated using microwave irradiation at 12O0C for 30 min. The reaction mixture was diluted with water, extracted with EtOAc. The organic phase was dried over MgSθ4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica (5-10% EtOAc in hexane) to get the ester as a colorless oil (68 mg, 53%). The above ester in THF (1 mL)/MeOH (1 mL) was treated with 3M NaOH in water (0.2 mL, 0.6 mmol) using microwave irradiation at 1000C for 10 minutes. Added IM HCl (0.6 mL) and diluted with water, extracted with EtOAc. The organic phase was washed with water, dried over MgSO4, filtered and concentrated to get 4-Methyl-2-(6- (phenyl(piperidin-l-yl)methyl)-4'-(trifluoromethyl)biphenyl-3-yl)pentanoic acid as a white powder (66 mg, 100%). IH NMR (300MHz ,DMSO-d6) d = 12.21 (br. s., 1 H), 7.77 (d, J = 7.9 Hz, 2 H), 7.71 (dd, J = 2.1, 8.1 Hz, 1 H), 7.31 (d, J = 7.9 Hz, 3 H), 7.18 - 7.01 (m, 3 H), 6.99 - 6.88 (m, 3 H), 4.19 (s, 1 H), 3.57 - 3.45 (m, 1 H), 2.26 - 1.99 (m, 4 H), 1.88 - 1.70 (m, 1 H), 1.50 - 1.22 (m, 8 H), 0.78 (d, J = 6.4 Hz, 6 H); LCMS m/z 510.3 [M+ 1]+.
Example 21. Synthesis of 2-(6-(l-(4,4-Difluoropiperidin-l-yl)-4-methylpentyl)-4'- (trifluoromethyl)biphenyl-3-vP)acetic acid (Method E)
Figure imgf000133_0001
Step l
Methyl 2-(3-hydroxy-4-(4-methylpentanoyl)phenyl)acetate
Figure imgf000133_0002
To (3-hydroxy-phenyl)-acetic acid methyl ester (6.64 g, 40.0 mmol) in a flask was added boron trifluoride etherate (7.60 mL, 60.0 mmol) at room temperature under N2. The mixture was stirred at room temperature for 10 minutes. 4-methyl-pentanoyl chloride (8.08 g, 60.0 mmol) was added slowly. The reaction mixture was stirred at room temperature for another 10 minutes. It was then heated with an oil bath (12O0C) until almost all the O-acylated intermediate was converted to C-acylated product (monitored by LC-MS). The reaction was quenched carefully with saturated NaHCO3, diluted with brine, extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography on silica eluting with 5-10% EtOAc in hexane to give the ketone as a pale brown oil (2.65 g, 25%). 1H NMR (300MHz ,DMSO-d6) δ = 12.01 (s, 1 H), 7.88 (d, J= 8.7 Hz, 1 H), 6.90 - 6.82 (m, 3 H), 3.72 (s, 2 H), 3.63 (s, 3 H), 3.10 - 3.00 (m, 2 H), 1.69 - 1.46 (m, 3 H), 0.91 (d, J= 6.4 Hz, 6 H); LCMS m/z 265.2 [M+l]+.
Step 2
Methyl 2-(4-(4-methylpentanoyl)-3-(trifluoromethylsulfonyloxy)phenyl)acetate
Figure imgf000134_0001
To a solution of methyl 2-(3-hydroxy-4-(4-methylpentanoyl)phenyl)acetate (2.65 g, 10.0 mmol) in dichloromethane (50 mL), cooled by ice-water bath, was added pyridine (3.24 mL, 40.1 mmol), followed by trifluoromethanesulfonic anhydride (3.37 mL, 20.0 mmol). The mixture was then allowed to warm to room temperature and stirred for 1 hour. The mixture was diluted with dichloromethane, washed with IN HCl aqueous solution (x2), water, NaHCO3 aqueous solution. The organic phase was dried over MgSC>4, filtered and concentrated to get methyl 2-(4-(4-methylpentanoyl)-3- (trifluoromethylsulfonyloxy) phenyl) acetate as a pale brown oil (3.85 g, 97%). H NMR (300MHz ,DMSOd6) δ = 8.08 (d, J= 7.9 Hz, 1 H), 7.55 (d, J= 7.9 Hz, 1 H), 7.46 (s, 1 H), 3.91 (s, 2 H), 3.64 (s, 3 H), 3.01 (t, J= 7.4 Hz, 2 H), 1.72 - 1.39 (m, 3 H), 0.89 (d, J = 6.4 Hz, 6 H); LCMS m/z 397.1 [M+l]+.
Step 3
Methyl 2-(6-(4-methylpentanoyl)-4'-(trifluoromethyl)biphenyl-3-yl)acetate
Figure imgf000135_0001
To a mixture of 2-(4-(4-methylpentanoyl)-3-(trifluoromethylsulfonyloxy) phenyl) acetate (2.94 g, 7.42 mmol), 4-(trifluoromethyl)phenylboronic acid (1.69 g, 8.90 mmol), and tetrakis(triphenylphosphine)palladium(0) (428 mg, 0.371 mmol) in a 200 ml flask was added 1 ,2-dimethoxyethane (15 mL), followed by ethanol (10 mL) and saturated aqueous sodium bicarbonate solution (4 mL). The reaction mixture was heated with a 100 0C oil bath until the reaction was complete. It was diluted with EtOAc, washed with brine. The organic phase was dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography on silica eluting with 10-15% EtOAc in hexane to give methyl 2-(6-(4-methylpentanoyl)-4'-(trifluoromethyl)biphenyl-3-yl)acetate as an oil (2.26 g, 77%). 1H NMR (300MHz ,DMSO-d6) δ = 7.61 (d, J= 7.9 Hz, 2 H), 7.44 (d, J= 7.9 Hz, 1 H), 7.33 - 7.22 (m, 3 H), 7.18 (s, 1 H), 3.64 (s, 2 H), 3.45 (s, 3 H), 1.25 - 1.03 (m, 3 H), 0.51 (d, J= 6.0 Hz, 6 H); LCMS m/z 393.2 [M+l]+.
Step 4
Methyl 2-(6-(l-hydroxy-4-methylpentyl)-4'-(trifluoromethyl)biphenyl-3-yl)acetate
Figure imgf000135_0002
To a solution of methyl 2-(6-(4-methylpentanoyl)-4'-(trifluoromethyl)biphenyl-3- yl)acetate (2.73 g, 6.96 mmol) in methanol (30 mL) was added sodium tetrahydroborate (1.13 g, 29.9 mmol) portion-wise. The reaction mixture was stirred at room temperature for 10 minutes. It was quenched with satd. NH4CI, added IN HCl, extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic phases were washed with brine, dried, filtered and concentrated. The residue was purified by flash chromatography on silica (25% EtOAc in hexane) to collect methyl 2- (6-(l -hydro xy-4-methylpentyl)-4'-(trifluoromethyl)biphenyl-3-yl)acetate as a colorless oil (2.39 g, 87%). 1H NMR (300MHz ,DMSOd6) δ = 7.81 (d, J= 8.3 Hz, 2 H), 7.56 (t, J = 8.3 Hz, 3 H), 7.33 (dd, J= 1.9, 7.9 Hz, 1 H), 7.07 (d, J= 1.5 Hz, 1 H), 5.07 (d, J= 4.2 Hz, 1 H), 4.56 - 4.43 (m, 1 H), 3.71 (s, 2 H), 3.61 (s, 3 H), 1.61 - 0.79 (m, 5 H), 0.68 (dd, J= 6.4, 18.9 Hz, 6 H); LCMS m/z 377.2 [MH-I-H2O]+.
Step 5
Methyl 2-(6-(l-bromo-4-methylpentyl)-4'-(trifluoromethyl)biphenyl-3-yl)acetate
Figure imgf000136_0001
To a solution of methyl 2-(6-(l-hydroxy-4-methylpentyl)-4'-(trifluoromethyl)biphenyl-3- yl)acetate (730 mg, 1.8 mmol) in THF under N2 was added 1 M of phosphorus tribromide in methylene chloride drop-wise at room temperature. The reaction mixture was stirred for 20 minutes. It was diluted with ether and washed with water. The organic phase was dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography on silica (2-5% EtOAc in hexane) to collect 449 mg oil as a mixture of desired methyl 2-(6-(l -bromo-4-methylpentyl)-4'-(trifluoromethyl)biphenyl-3-yl)acetate and eliminated olefin by-product.
Step 6 2-(6-(l-(4,4-Difluoropiperidin-l-yl)-4-methylpentyl)-4'-(trifluoromethyl)biphenyl-3- yl)acetic acid
Figure imgf000137_0001
To a mixture of 2-(6-(l-bromo-4-methylpentyl)-4'-(trifluoromethyl)biphenyl-3-yl)acetate (18 mg, 0.040 mmol) and 4,4-difluoro-piperidine (13 mg, 0.080 mmol) in N,N- dimethylformamide (0.4 mL) was added potassium carbonate (11 mg, 0.080 mmol). The reaction mixture was stirred at room temperature for 6 hour. The reaction mixture was quenched with water, extracted with EtOAc. The organic phase was washed with water, dried over MgSO4, filtered and concentrated. The residue was purified flash chromatography on silica (10% EtOAC in hexane) to get 8 mg ester as colorless oil. It was dissolved in THF/MeOH, and treated with 3 M of sodium hydroxide in water (60 μL) at room temperature overnight. Added IM HCl (180 μL) and diluted with water, extracted with EtOAc. The organic phase was washed with water, dried over MgSO4, filtered and concentrated to get 2-(6-(l-(4,4-difluoropiperidin-l-yl)-4-methylpentyl)-4'- (trifluoromethyl)biphenyl-3-yl)acetic acid as a white powder (8 mg, 40%). 1H NMR (400MHz ,DMSO-d6) δ = 12.33 (br. s., 1 H), 7.80 (d, J= 7.8 Hz, 2 H), 7.52 (d, J= 7.8 Hz, 2 H), 7.42 (d, J= 8.0 Hz, 1 H), 7.32 (d, J= 7.8 Hz, 1 H), 7.10 (s, 1 H), 3.61 (s, 2 H), 3.56 - 3.48 (m, 1 H), 2.39 - 2.26 (m, 4 H), 1.95 - 0.59 (m, 15 H); LCMS m/z 484.3 [M+ 1]+.
Example 22. Synthesis of 2-(6-(2-cvclohexyl-l-(4-(trifluoromethyl)piperidin-l-yl)ethyl)- 4'-(trifluoromethyl)biphenyl-3-yl)acetic acid (Method F)
Step l
Figure imgf000138_0001
Into a mixture of intermediate 2 (4.3 g, 0.013 mol, 1.0 eq), 4-(trifluoromethyl)phenyl- boronic acid (4.37 g, 0.0195 mol, 1.5 eq), Pd(PPh3)4 (750 mg, 0.65 mmol, 0.05 eq), LiCl (1.42 g, 0.039 mol, 3 eq) and Na2CO3 (3.6 g, 0.034 mol, 2.6 eq) were added 32 ml of mixture solvent (toluene/EtOH/EtO = 5: 2: 1). The mixture was stirred at 90°C for 16 h.
The solvent was removed in vacuo and the residue was purified on silica gel column (PE/EA = 20: 1) to give desired product methyl 2-(6-formyl-4'-(trifluoromethyl)biphenyl- 3-yl)acetate as oil (3.80 g, 89% yield). 1H NMR (400 MHz, CDCl3) δ: 9.93 (s, IH), 8.02 (d, J= 8.0 Hz, IH), 7.34 (d, J= 8.0 Hz, 2H), 7.47-7.53 (m, 3H), 7.35 (s, IH), 3.75 (s, 2H), 3.73 (s, 3H); LCMS m/z 323.0 (M+H) +.
Figure imgf000138_0002
Methyl 2-(6-formyl-4'-(trifluoromethyl)biphenyl-3-yl)acetate (900 mg, 2.79 mmol, 1.0 equiv) was dissolved in diethyl ether (10 mL) and cooled to between -30 to - 40 0C. A 0.5 M solution of methylcyclohexylmagnesium bromide in diethyl ether (14 mL, 6.97 mmol, 2.5 equiv) was added dropwise maintaining the temperature between -30 to - 40 0C over 30 minutes. The reaction was then quenched with saturated ammonium chloride solution (25 mL). The solvent was removed in vacuo and the residue was was purified on silica gel column (PE/EA = 20: 1) to give desired product methyl 2-(6-(2-cyclohexyl-l- hydroxyethyl)-4'-(trifluoromethyl)biphenyl-3-yl)acetate as yellow oil (560 mg, 48% yield). 1H NMR (400 MHz, CDCl3) δ: 7.66 (d, J= 8.0 Hz, 2H), 7.61 (d, J= 8.4 Hz, IH), 7.41 (d, J= 8.0 Hz, 2 H), 7.35 (d, J= 10.0 Hz, IH), 7.09 (s, IH), 4.79-4.83 (m, IH), 3.69 (s, 3H), 3.64 (s, 2H), 1.40-1.71 (m, 9H), 1.07-1.16 (m, 3H), 0.79-0.85 (m, IH), 0.57-0.63 (m, IH); LCMS m/z 403.0 (M-OH) +.
Step 3
Figure imgf000139_0001
Into a mixture of methyl 2-(6-(2-cyclohexyl-l -hydroxy ethyl)-4'- (trifluoromethyl)biphenyl-3-yl)acetate (300 mg, 0.71 mmol, 1.0 eq) and tribromophosphine (380 mg, 1.42 mmol, 2.0 eq) were added to THF(IO ml), the mixture was reacted at room temperature for 30 minutes. TLC shows that the start material disappeared, the reaction was therefore quenched with H2O (10 mL). The solvent was removed in vacuo and the residue (crude 118 mg, 32% yield) was used in the next step without further purification.
Figure imgf000140_0001
Into a mixture of methyl 2-(6-(l-bromo-2-cyclohexylethyl)-4'-(trifiuoromethyl)biphenyl- 3-yl)acetate (80 mg,0.166 mmol, 1.0 eq), 4-(trifluoromethyl) piperidine hydrochloride (63 mg, 0.332 mmol, 2.0 eq) and Et3N (67 mg, 0.664 mmol, 4.0 eq) were added to acetonitrile (5 ml), the mixture was reacted at 80 0C for 1 h. The solvent was removed in vacuo and the residue was was purified on silica gel column (PE/EA = 20: 1) to give methyl 2-(6-(2-cyclohexyl- 1 -(4-(trifluoromethyl)piperidin- 1 -yl)ethyl)-4'- (trifluoromethyl)biphenyl-3-yl)acetate as colorless oil. LCMS m/z 556.0 (M+H) +, crude 37 mg, (40% yield)
The above mentioned ester (37 mg, 0.077 mmol, 1.0 eq)and NaOH (9.2 mg,0.23 mmol, 3 eq) were dissolved in EtOH (5 ml). The mixture was stirred at 80 0C for 30 min. Then neutralized with diluted HCl to pH ~ 3. The mixture was extracted with CH2Cl2 (15 ml * 3), the organic solvent was removed in vacuo and the residue was purified on prep-TLC (PE/EA = 1 : 1) to give desired product as brown oil (29 mg, 81% yield): 1H NMR (400 MHz, DMSO-d6) δ: 7.79 (d, J= 8.0 Hz, 2H), 7.52 (d, J= 7.6 Hz, 2H), 7.42 (d, J= 8.0 Hz, IH), 7.32 (d, J= 8.4 Hz, IH), 7.11 (s, IH), 3.63-3.65 (m, IH), 3.61 (s, 2H), 2.71-2.74 (m, IH), 2.59-2.62 (m, IH), 2.03-2.12 (m, 2H), 1.87-1.93 (m, IH), 1.62-1.71 (m, 3H), 1.51-1.55 (m, 5H), 1.23-1.29 (m, 3H), 1.03 (bs, 4H), 0.67-0.82 (m, 2H); LCMS m/z 542.0 (M+H)+.
Example 23. Synthesis of 2-(6-(4-methyl-l-(4-(trifluoromethyl)phenoxy)pentyl)-4'- (trifluoromethyl)biphenyl-3-yl)acetic acid
Figure imgf000141_0001
To a mixture of methyl 2-(6-(l-hydroxy-4-methylpentyl)-4'-(trifluoromethyl)biphenyl-3- yl)acetate (Example 21, step 4, 39 mg, 0.10 mmol), 3-(trifluoromethyl)phenol (18 mg, 0.11 mmol), triphenylphosphine (34 mg, 0.13 mmol) in tetrahydrofuran (500 μL) was added diisopropyl azodicarboxylate (30 μL, 0.15 mmol). The mixture was stirred at room temperature for Ih. The reaction mixture was purified by flash chromatography on silica (5-10% EtOAc in hexane) to get the ester as a colorless oil (9 mg, 17%). The above ester in MeOH (500 μL) and THF (500 μL) was treated with IN NaOH (200 μL) at room temperature for 2 h. Neutralized with IN HCl (200 μL), diluted with water, extracted with EtOAc. The organic phase was dried, filtered and concentrated to get 2-(6- (4-methyl-l-(4-(trifiuoromethyl)phenoxy)pentyl)-4'-(trifiuoromethyl)biphenyl-3-yl)acetic acid as colorless oil (3 mg, 6%). IH NMR (300MHz ,MeOD) δ = 7.70 (d, J = 7.9 Hz, 2 H), 7.52 - 7.30 (m, 5 H), 7.23 (d, J = 8.3 Hz, 1 H), 7.07 (s, 1 H), 6.70 (d, J = 8.7 Hz, 2 H), 5.04 (dd, J = 3.6, 8.5 Hz, 1 H), 3.54 (s, 2 H), 1.89 - 1.63 (m, 2 H), 1.42 - 0.76 (m, 3 H), 0.70 (dd, J = 6.4, 10.6 Hz, 6 H).
Example 24. Synthesis of 2-(6-(l-(4-terbutylcvclohexylamino)ethyl)-4'- (trifluomethyl)biphenyl)-3yl-)acetic acid.
Figure imgf000141_0002
Methyl 2-4-acetyl-3-hydroxyphenyl) acetate.
Figure imgf000142_0001
Titanium tetrachloride (1.2 ml, 0.0109 mol) was added to (3-hydroxyphenyl) acetic acid methyl ester (1.662g, 0.001 mol). The resulting thick solution was stirred at room temperature for 15 minutes, then brought to 12O0C and let to stir at this temperature for an additional hour. After cooling to room temperature, 40 ml of dichloromethane was added followed by 40 ml of water. The aqueous layer was separated and extracted with dichloromethane (40 ml). The combined organic layer was washed with 1 N hydrochloric acid (100 ml) and brine (40 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated under high vacuum. The residue was purified on silica gel (40 g) using hexane/ethyl acetate = 80/20 as eluent to give 0.51 g (22.8%) of the title compound as an oil. LCMS m/z 209.1 [M+ 1]+; IH NMR (300MHz ,CHLOROFORM-d) δ = 12.27 (s, 1 H), 7.38 - 7.30 (m, 1 H), 7.16 (d, J = 7.6 Hz, 1 H), 7.05 (br. s., 1 H), 3.70 (s, 3 H), 3.64 (s, 2 H), 2.30 (s, 3 H).
Step 2
Methyl-2-(4-acethyl-3-trifluoromethysulfonyloxy) phenyl) acetate
Figure imgf000142_0002
A stirred solution of methyl 2-4-acetyl-3-hydroxyphenyl) acetate (0.208 g, 0.001 mol) and pyridine (0.5 ml, 0.006 mol) in dry dichloromethane (3 ml) was treated with triflic anhydride (0.40 ml, 0.0024 mol) at O0C. The reaction mixture was kept at O0C for 18h. The resulting mixture was diluted with ethyl acetate, washed with 2 N hydrochloric acid, saturated sodium bicarbonate and brine, dried over magnesium sulfate, and concentrated under vacuum. The residue was purified on silica gel (40 g) using hexane/ethyl acetate = 80/20 as eluent to give 0.3g (100%) g of the title compound. LCMS m/z 341.03 [M+l]+
Step 3
Methyl-2-(6-acetyl-4'-(trifluoromethyl)byphenyl-3-yl) acetate.
Figure imgf000143_0001
A stirred suspension of methyl-2-(4-acethyl-3-trifluoromethysulfonyloxy) phenyl) acetate (0.3 g, 0.001 mol), 4-(trifluoromethyl) phenylboronic acid (0.21 g, 0.0011 mol), saturated aqueous solution of sodium bicarbonate (1.0 ml, 0.0012 mol), and [1,1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane(l :l) (0.04 g, 0.00005 mol) in 1 ,2-dimethoxyethane was purged with nitrogen for 10 min. The resulting reaction mixture was heated in a microwave at 650C for 10 minutes. After cooling at room temperature, the reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated under vacuum. The residue was purified on silica gel (40 g) using hexane/ethyl acetate = 80/20 as eluent to give 0.139 g (41%) of the title compound. LCMS m/z 337.2 [M+l]+
Step 4
(Z)-methyl-2-(6-(l-(hydroxyimino)ethyl)-4'-(trifluoromethyl)biphenyl-3-yl)acetate
Figure imgf000144_0001
A stirred solution of methyl-2-(6-acetyl-4'-(trifluoromethyl)biphenyl-3-yl) acetate (0.14 g, 0.000413 mol), hydroxylamine (0.020 g, 0.00062 mol) and sodium acetate trihydrate ( 0.102 g, 0.000748 mol) in methanol/water = 1/0.3 (1.3 ml) was refiuxed at 70-750C for 1.5h. After cooling at room temperature, the reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was concentrated under vacuum and the residue was purified on silica gel (40 g) using hexane/ethyl acetate = 70/30 as eluent to give 0.139 g (41%) of the title compound. LCMS m/z 352.1 [M+l]+.
Step 5
Methyl-2-(6-(l-aminoethyl)-4'-(trifluoromethyl)biphenyl-3-yl)acetate.
Figure imgf000144_0002
A stirred solution of (Z)-methyl-2-(6-(l-(hydroxyimino)ethyl)-4'- (trifiuoromethyl)biphenyl-3-yl)acetate (0.1 g, 0.0003 mol) and zinc ( 0.045 g, 0.000635 mol) in methanol/water = 0.8/0.34 ( 1.14 ml) was treated with acetic acid (0.1ml, 0.002 mol at 0 0C. The reaction mixture was then placed in an oil bath and heated at 3O0C for 2Oh. After cooling at room temperature, the reaction mixture was placed in an ice-water bath and methanol (0.5 ml) was added. The resulting mixture was filtered through a cartridge of celite. Ammonium hydroxide (.3 ml) and water (0.3 ml) was added, extracted with ethyl acetate and dried over magnesium sulfate. The solvent was removed under high vacuum and the residue (0.082 g, 80%) was taken to the next step without purification. 1H NMR (300MHz ,CHLOROFORM-d) δ = 7.69 (s, 1 H), 7.68 - 7.62 (m, 2 H), 7.44 (d, J = 7.9 Hz, 2 H), 7.36 (dd, J = 1.7, 8.1 Hz, 1 H), 7.09 (d, 1 H), 4.17 (d, J = 6.4 Hz, 1 H), 3.71 (s, 3 H), 3.65 (s, 2 H), 1.32 (d, J = 6.8 Hz, 3 H).
Step 6
Methyl-2-(6-(l-(4-terbutylcyclohexylamino)ethyl)-4'-(trifluomethyl)biphenyl)-3yl) acetate.
Figure imgf000145_0001
Methyl-2-(6-(l-aminoethyl)-4'-(trifluoromethyl)biphenyl-3-yl)acetate (0.052 g, 0.000153 mol) was added to a solution of 4-tertbutylcyclohexanone (0.029 g, 0.000184 mol) in methanol (0.5 ml). The mixture was stirred at room temperature for 45 minutes, cooled to -780C, and treated with 2 M solution of lithium borohydride(0.092 ml, 0.00184) in tetrahydroborane. After Ih, the reaction mixture was brought up to room temperature and stirred for 16 h. The reaction mixture was extracted with ethyl acetate, washed with saturated sodium bicarbonate, brine, dried over magnesium sulfate and concentrated under high vacuum. The residue was purified on silica gel (4 g) using hexane/ethyl acetate = 80/20 as eluent to give 0.06g of the title compound. LCMS m/z 476.3 [M+l]+
Step 7
2-(6-(l-(4-terbutylcyclohexylamino)ethyl)-4'-(trifluomethyl)biphenyl)-3yl-)acetic acid.
Figure imgf000146_0001
A solution of Methyl-2-(6-(l-(4-terbutylcyclohexylamino)ethyl)-4'- (trifluomethyl)biphenyl)-3yl-)acetate (0.02 g, 0.00042 mol) and sodium hydroxide (0.00168 mol) in methanol/water = 1.5/0.1 (1.6 ml) was heated in a microwave at 12O0C for ten minutes After cooling the mixture was diluted with dichloromethane and the pH adjusted with 2 N hydrochloric acid until a white precipitate was observed. The mixture was spun down and the pellet washed with water. The solid was dried under high vacuum. LCMS m/z 462.3 [M+l]+; 1H NMR (300MHz ,CHLOROFORM-d) δ = 7.64 (dd, J= 3.4, 7.9 Hz, 3 H), 7.25 (t, J= 6.8 Hz, 2 H), 7.08 (d, J= 5.3 Hz, 2 H), 4.21 (br. s., 1 H), 3.63 (s, 2 H), 2.83 (br. s., 1 H), 2.05 (s, 1 H), 1.67 - 1.61 (m, 4 H), 1.22 - 1.11 (m, 5 H), 0.93 - 0.89 (m, 3 H), 0.77 (s, 9 H); LCMS m/z; LCMS m/z 462.3 [M+H]+
Example 25. Synthesis of -(5-(piperidin-l-yl(4-(trifluoromethyl)phenyl)methyl)-4-(4-
(trifluoromethyl)phenyl)thiazol-2-yl)acetic acid
Figure imgf000146_0002
Step l ethyl 2-(4-(trifluoromethylsulfonyloxy)thiazol-2-yl)acetate
Figure imgf000147_0001
To a solution of ethyl 2-(4-hydroxythiazol-2-yl)acetate (1.0 g, 5.35 mmol, 1.0 eq), Et3N (1.08 g, 10.7 mmol, 2.0 eq) in DCM (6 mL) was slowly added triflic anhydride (1.81 g, 6.42 mmol, 1.2 eq) at 0 0C. The mixture was allowed to warm to room temperature and stirred for 16 hs, and then purified on silica gel (PE/EA=10/l) to obtain the desired product, 1.40 g (82 %), as a yellow oil. 1B NMR (400 MHz, CDCl3) δ: 7.09 (s, IH), 4.25 (q, J= 7.2 Hz, 2H), 4.04 (s, 2H), 1.31 (t, J= 7.2 Hz, 3H). LCMS: m/z 319.8 [M+H]+.
Step 2
Ethyl 2-(4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)acetate
Figure imgf000147_0002
To a pressure tube was introduced into ethyl 2-(4-hydroxythiazol-2-yl)acetate (1.40 g, 4.39 mmol, 1.0 eq), 4-(trifluoromethyl)phenylboronic acid (1.00 g, 5.27 mmol, 1.2 eq), Pd(dppf)Cl2 (358 mg, 0.439 mmol, 0.1 eq), LiCl (553 mg, 13.17 mmol, 3.0 eq), K2CO3 (1.21 g, 8.78 mmol, 2.0 eq), and also water (1.0 mL), EtOH (2.0 mL), and toluene (10.0 mL) under Ar atmosphere. After microwaving 4.0 hs at 12O0C, the resulting mixture was evaporated to dryness, which was purified by flash CC. (P/E: 0 - 10 % / in 30 mins), to give the desired compound, 700 mg (51%), as a yellow oil. 1H NMR (400 MHz, CDCl3) δ: 7.99 (d, J= 8.8 Hz, 2H), 7.66 (d, J= 8.8 Hz, 2H), 7.57 (s, IH), 4.26 (q, J= 7.2 Hz, 2H), 4.14 (s, 2H), 1.32 (t, J= 7.2 Hz, 3H). LCMS: m/z 315.8 [M+H]+. Ethyl 2-(5-(hydroxy(4-(trifluoromethyl)phenyl)methyl)-4-(4- (trifluoromethyl)phenyl)thiazol-2-yl)acetate
Figure imgf000148_0001
To a solution of Ethyl 2-(4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)acetate (315 mg, 1.0 mmol, 1.0 eq.) in dry THF (3.0 mL) was cooled to -780C, a solution of LDA in hexane (2.0 M, 1.2 mmol, 0.60 mL, 1.2 eq.) was then added dropwise under Ar atmosphere. The solution was stirred for 30 mins at this temperature, and a solution of TBSCl (301 mg, 2.0 mmol, 2.0 eq.) in THF (1.0 mL) was slowly added and stirred for another 1.0 h. The reaction system was cooled to -780C again. A solution of S-BuLi in hexane (1.3 M, 2.4 mmol, 1.85 mL, 2.4 eq.) was added dropwise and stirred for 30 mins, the solution of 4- (trifluoromethyl)benzaldehyde (418 mg , 2.4 mmol, 2.4 eq.) in THF (1.0 mL) was then introduced and stirred for 30 mins. Water (2.0 mL) was injected into the solution to quench the reaction, extracted with EtOAc (5.0 mL*3), dried over Na2SC^, and evaporated in vacuo, to give the red residue, which was purified by flash CC. (PE/EA: 0- 10%/in 40 mins) and further subjected to Pre-HPLC (MeOH/H2O: 50%-80%/in 30 mins), to obtain the target molecular, 200 mg (41 %), as a white solid. 1H NMR (400 MHz, CDCl3) δ: 7.76 (d, J= 8.4 Hz, 2H), 7.69 (d, J= 8.4 Hz, 2H), 7.60 (d, J= 8.0 Hz, 2H), 7.49 (d, J= 8.0 Hz, 2H), 6.16 (s, IH), 4.21 (q, J= 7.2 Hz, 2H), 4.04 (s, 2H), 1.29 (t, J = 7.2 Hz, 3H). LCMS: m/z 489.7 [M+H]+.
Step 4
Ethyl 2-(5-(bromo(4-(trifluoromethyl)phenyl)methyl)-4-(4- (trifluoromethyl)phenyl)thiazol-2-yl)acetate
Figure imgf000149_0001
To a solution of b Ethyl 2-(5-(hydroxy(4-(trifluoromethyl)phenyl)methyl)-4-(4- (trifluoromethyl)phenyl)thiazol-2-yl)acetate (0.22 mmol, 108 mg, 1.0 eq.) in dry THF (3.0 mL) was cooled to O0C, a solution of PBr3 (1.10 mmol, 298 mg, 5.0 eq.) in THF (1.0 mL) was then added dropwise. The mixture was stirred for 30 mins at this temperature and then poured into ice water (5.0 mL), extracted with EtOAc, washed by water, dried over Na2SC^, and evaporated in vacuo, to give the yellow oil, 118 mg (crude), which was applied to next step without further purification.
Step 5
Ethyl 2-(5-(piperidin- 1 -yl(4-(trifluoromethyl)phenyl)methyl)-4-(4- (trifluoromethyl)phenyl)thiazol-2-yl)acetate
Figure imgf000149_0002
To a solution of Ethyl 2-(5-(bromo(4-(trifluoromethyl)phenyl)methyl)-4-(4- (trifluoromethyl)phenyl)thiazol-2-yl)acetate (0.214 mmol, 118 mg, 1.0 eq., crude) in MeCN (3.0 mL) was added DIPEA (0.428 mmol, 36 mg, 2.0 eq.) at room temperature, piperidine (0.428 mmol, 55 mg, 2.0 eq.) was then added. The resulting mixture was stirred for 5.0 mins, and evaporated in vacuo, to give a yellow residue, which was purified by Pre-TLC (DCM/MeOH = 20/1), to yield the desired compound, 15 mg (13%), as a yellow oil. 1H NMR (400 MHz, CDCl3) δ: 7.71 (d, J= 8.0 Hz, 2H), 7.58 (d, J= 8.0 Hz, 2H), 7.54 (d, J= 8.0 Hz, 2H), 7.43 (d, J= 8.0 Hz, 2H), 4.76 (s, IH), 4.24 (q, J= 7.2 Hz, 2H), 4.04 (s, 2H), 2.38-2.27 (m, 4H), 1.56-1.50 (m, 4H), 1.45-1.40 (m, 2 H), 1.29 (t, J= 7.2 Hz, 3 H). LCMS: m/z 557.2 [M+H]+.
Step 6
2-(5-(piperidin- 1 -yl(4-(trifluoromethyl)phenyl)methyl)-4-(4- (trifluoromethyl)phenyl)thiazol-2-yl)acetic acid
Figure imgf000150_0001
To a solution of ethyl 2-(5-(piperidin-l-yl(4-(trifluoromethyl)phenyl)methyl)-4-(4- (trifluoromethyl)phenyl)thiazol-2-yl)acetate (0.027 mmol, 15 mg, 1.0 eq.) in EtOH (1.0 mL) was added 1.0 N aq. NaOH solution (0.0540 mmol, 0.054 mL, 2.0 eq.). The solution was stirred at room temperature for 1.0 h, adjusted pH to 7.0 with deluted HCl solution, extracted with EtOAc (3.0 mL*3), dried, and evaporated in vacuo, to give the residue, which was purified by Pre-TLC (DCM/MeOH = 10/1), to obtain the final product, 10 mg (71 %), as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 7.78 (d, J= 8.0 Hz, 2H), 7.69 (d, J= 8.0 Hz, 2H), 7.66 (d, J= 8.0 Hz, 2H), 7.51 (d, J= 8.0 Hz, 2H), 4.97 (s, IH), 3.97 (bs, 2H), 2.32-2.20 (m, 4H), 1.46 (bs, 4H), 1.34 (bs, 2H). LCMS: m/z 528.7 [M+H]+.
Example 26. Synthesis of 2-(6-((isopenM(4-(trifluoromethyl)phenyl)amino)methvP)-4'- (trifluoromethyl)biphenyl-3-yl)propanoic acid. (Method H).
Figure imgf000151_0001
To a mixture of methyl 2-(6-((isopentyl(4-(trifluoromethyl)phenyl)amino)methyl)-4'- (trifluoromethyl)biphenyl-3-yl)acetate (27 mg, 0.050 mmol) and sodium hydride (4.0 mg, 0.10 mmol) in a flask under N2 with ice-salt bath was added tetrahydrofuran (1 mL). The resulting mixture was stirred at room temperature for 1 h. It was cooled down again with ice-salt bath. Methyl iodide (4.7 μL, 0.075 mmol) was added. The mixture was stirred at room temperature for another hour. It was quenched with water, extracted with EtOAc. The organic phase was dried over MgS O4, filtered and concentrated. The residue was treated with 3N NaOH in a mixed solvent of THF and MeOH at 1000C for 10 min, acidified with IN HCl, extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated. It was purified by reverse phase HPLC (TFA method) to get desired acid as a white powder (2.5 mg, 9%). 1H NMR (300MHz ,DMSO- d6) δ = 12.37 (br. s., 1 H), 7.81 (d, J = 8.3 Hz, 2 H), 7.66 (d, J = 7.9 Hz, 2 H), 7.37 (d, J = 8.7 Hz, 2 H), 7.28 (d, J = 8.3 Hz, 1 H), 7.18 (d, J = 1.5 Hz, 1 H), 7.12 (d, J = 8.3 Hz, I H), 6.60 (d, J = 8.7 Hz, 2 H), 4.47 (s, 2 H), 3.86 - 3.52 (m, 3 H), 1.98 - 1.45 (m, 3 H), 1.37 (d, J = 6.8 Hz, 3 H), 0.86 (d, J = 6.8 Hz, 6 H); LCMS m/z 538.3 [M+l]+.
Example 27. Synthesis of l-(6-((4-fluorophenyl)(4-methylpiperidin-l-yl)methyl)-4'- (trifluoromethyl)biphenyl-3-yl)cvclopentanecarboxylic acid
Figure imgf000151_0002
Step l
Methyl 1 -(S-methoxypheny^cyclopentanecarboxylate
Figure imgf000152_0001
To a solution of (3-methoxy-phenyl)-acetic acid methyl ester (901 mg, 5.00 mmol) in tetrahydrofuran (10 mL) at -780C under N2 was added 1.0 M of lithium hexamethyldisilazide in tetrahydrofuran (6.25 mL, 6.25 mmol) drop-wise. The reaction mixture was stirred for 20 min at -780C and then 1,4-diiodobutane (674 μL, 5.00 mmol) was added drop-wise. The solution was stirred at -780C for 30 min before adding another portion of 1.0 M of lithium hexamethyldisilazide in tetrahydrofuran (6.25 mL). The mixture was stirred at -780C for 1 hour and then was allowed to warm to room temperature and stirred at room temperature for Ih. It was quenched with saturated NH4CI, extracted with EtOAc. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography on silica (EtOAc in hexane 5-10%) to collect methyl l-(3-methoxyphenyl) cyclopentanecarboxylate as a colorless oil (545 mg, 47%). 1H NMR (300MHz ,DMSO- d6) δ = 7.31 - 7.18 (m, 1 H), 6.96 - 6.77 (m, 3 H), 3.74 (s, 3 H), 3.55 (s, 3 H), 2.53 - 2.35 (m, 2 H), 1.96 - 1.76 (m, 2 H), 1.77 - 1.48 (m, 4 H); LCMS m/z 235.1 [M+l]+.
Step 2
Methyl 1 -(3-hydroxyphenyl)cyclopentanecarboxylate
Figure imgf000152_0002
To a solution of l-(3-methoxy-phenyl)-cyclopentanecarboxylic acid methyl ester (538 mg, 2.30 mmol) in methylene chloride (5 mL) was added 1 M of boron tribromide in methylene chloride (2.76 mL, 2.76 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with water, extracted with EtOAc. The organic phase was washed with satd.NELiCl, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography on silica (EtOAc in hexane 10-20%) to get methyl l-(3-hydroxyphenyl)cyclopentanecarboxylate as white solid (266 mg, 53%) solid. 1H NMR (SOOMHZ ,DMSO-d6) δ = 9.34 (s, IH), 7.31 - 7.18 (m, 1 H), 6.96 - 6.77 (m, 3 H), 3.55 (s, 3 H), 2.48 - 2.35 (m, 2 H), 1.96 - 1.76 (m, 2 H), 1.77 - 1.48 (m, 4 H); LCMS m/z 221.1 [M+ 1]+.
Step 3
1 -(6-((4-Fluorophenyl)(4-methylpiperidin- 1 -yl)methyl)-4'-(trifluoromethyl)biphenyl-3- yl)cyclopentanecarboxylic acid
Figure imgf000153_0001
Using methyl l-(3-hydroxyphenyl)cyclopentanecarboxylate as starting material and followed the procedure of method D (Example 20), the titled compound was synthesized (48 mg, 24% combined yield for 4 steps). 1H NMR (300MHz, DMSO-d6) δ = 12.28 (br. s., 1 H), 7.83 (d, J = 8.3 Hz, 2 H), 7.76 (d, J = 8.3 Hz, 1 H), 7.43 (dd, J = 1.9, 8.4 Hz, 1 H), 7.40 - 7.34 (m, 2 H), 7.07 - 6.94 (m, 4 H), 4.27 (s, 1 H), 3.33 - 2.45 (m, 4 H), 1.88 - 1.39 (m, 10 H), 1.39 - 1.01 (m, 3 H), 0.86 (d, J = 6.5 Hz, 3 H); LCMS m/z 540. 3 [M+ 1]+.
Example 28. Synthesis of 5-((4-fluorophenyl)(4-methylpiperidin-l-yl)methyl)-6-(4- (trifluoromethyl)phenyl)-2.3-dihvdro-lH-indene-l-carboxylic acid
Figure imgf000154_0001
Step l
Methyl 6-methoxy-2,3-dihydro- 1 H-indene- 1 -carboxylate
Figure imgf000154_0002
To a solution of 6-methoxy-indan- 1 -carboxylic acid (3.84 g, 20.0 mmol; Supplier = Anichem H12739) in methanol (15 mL) was added sulfuric acid (20 mL, 0.4 mmol) . The mixture was stirred at room temperature overnight. The reaction mixture was concentrated to remove most of methanol and partitioned between ethyl acetate and water. The organic phase was washed with satd. NaHCO3, dried over MgSθ4, filtered and concentrated to get methyl 6-methoxy-2,3-dihydro-l H-indene- 1 -carboxylate as a pale brown oil (4.07g, 99%). 1H NMR (300MHz ,DMSO-d6) δ = 7.15 (d, J = 8.3 Hz, 1 H), 6.89 - 6.74 (m, 2 H), 4.04 (t, J = 7.6 Hz, 1 H), 3.71 (s, 3 H), 3.67 (s, 3 H), 3.00 - 2.69 (m, 2 H), 2.38 - 2.15 (m, 2 H); LCMS m/z 207.1 [M+l]+.
Step 2
Methyl 6-hydroxy-2,3-dihydro- 1 H-indene- 1 -carboxylate
Figure imgf000154_0003
To a solution of 6-methoxy-2,3-dihydro-l H-indene- 1 -carboxylate (2.06 g, 10.0 mmol) in methylene chloride (20 mL), cooled with ice-water bath, was added 1 M of boron tribromide in methylene chloride(15.00 mL) drop- wise. The reaction mixture was stirred for 30 minutes and then allowed to warm to room temperature and stirred for 1 hour. The reaction was quenched with water, extracted with EtOAc. The organic phase was washed with satd. NH4CI, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography on silica (EtOAc in hexane 10-25-100%) to collect methyl 6- hydroxy-2,3-dihydro-lH-indene-l-carboxylate as colorless oil (290 mg, 15%). 1H NMR (300MHz ,DMSO-d6) δ = 9.17 (s, 1 H), 7.02 (d, J = 7.9 Hz, 1 H), 6.69 (d, J = 1.9 Hz, 1 H), 6.60 (dd, J = 2.3, 8.3 Hz, 1 H), 4.09 - 3.93 (m, 1 H), 3.66 (s, 3 H), 2.96 - 2.64 (m, 2 H), 2.24 (q, J = 7.3 Hz, 2 H); LCMS m/z 193.1 [M+l]+.
Step 3
5-((4-Fluorophenyl)(4-methylpiperidin-l-yl)methyl)-6-(4-(trifluoromethyl)phenyl)-2,3- dihydro- 1 H-indene- 1 -carboxylic acid
Figure imgf000155_0001
Using methyl 6-hydroxy-2,3-dihydro-l H-indene- 1-carboxylate and followed the procedure of method D (Example 20), the titled compound was synthesized (69 mg, 47% combined yield for 4 steps). 1H NMR (300MHz ,DMSO-d6) δ = 12.43 (s, 1 H), 7.82 (d, J = 7.8 Hz, 2 H), 7.67 (d, J = 14.8 Hz, 1 H), 7.47 - 7.27 (m, 2 H), 7.12 - 6.84 (m, 5 H), 4.29, 4.26 (s, s, 1 H), 4.06 - 3.91 (m, 1 H), 3.12 - 2.80 (m, 3 H), 2.45 - 2.40 (m, 1 H), 2.38 - 2.20 (m, 2 H), 1.97 - 1.71 (m, 1 H), 1.70 - 1.40 (m, 3 H), 1.34 - 1.22 (m, 1 H), 1.20 - 1.02 (m, 2 H), 0.93 - 0.79 (m, 3 H); LCMS m/z 512.2 [M+l]+.
Example 29. Synthesis of 2-(6-hydroxy-5-(piperidin-l-yl(4- (trifluoromethyl)phenyl)methyl)-4' (trifluoromethyl)biphenyl-3-yl)acetic acid
Figure imgf000156_0001
Step 1:
Methyl 2-(3-bromo-4-hydroxyphenyl)acetate
Figure imgf000156_0002
3-Bromo-4-hydroxyphenylacetic acid (0.3 g, 1.3 mmol, 1.0 equiv.) and concentrated H2SO4 (2.77 μL, 0.05 mmol, 0.04 equiv.) were dissolved in MeOH (10 ml). The mixture was stirred at room temperature for 1 h, and then quenched with NaOH solution, extracted with EtOAc. The organic layer was dried with Na2SO4 and concentrated in vacuum. The residue was purified with silica gel column chromatography (eluting with hexanes/EtOAc = 5: 1), to give the ester (0.2 g , 63%). LCMS m/z 245.0 [M+l]+
Step 2:
Methyl 2-(6-hydroxy-4'-(trifluoromethyl)biphenyl-3-yl)acetate
Figure imgf000156_0003
To a solution of Methyl 2-(3-bromo-4-hydroxyphenyl)acetate (185 mg, 0.75 mmol) in dioxane (3 mL) was added 4-(trifluoromethyl)phenylboronic acid (200 mg, 1.05 mmol), bis(tricyclohexylphosphine)palladium (0) (50 mg, 0.07 mmol) and saturated aqueous sodium bicarbonate (370 uL, 3.8 mmol). The reaction mixture was heated using microwave irradiation at HO0C for 15 minutes. LC-MS shows the reaction has completed. The reaction mixture was diluted with water, extracted with EtOAc. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica (10-30% EtOAc in hexane) to get the ester as a colorless oil (195 mg, 83%). LCMS m/z 311.2 [M+l]+.
Step 3:
2-(6-hydroxy-5-(piperidin-l-yl(4-(trifluoromethyl)phenyl)methyl)-4'- (trifluoromethyl)biphenyl-3-yl)acetic acid
Figure imgf000157_0001
To a mixture Methyl 2-(6-hydroxy-4'-(trifluoromethyl)biphenyl-3-yl)acetate (195 mg, 0.63 mmol), piperidine (93 μL, 0.94 mmol) in trifluoro -toluene (1 mL, 8 mmol) was added 4-trifluoromethylbenzaldehyde (126 μL, 0.94 mmol). The mixture was heated using microwave irradiation at 12O0C for 1 hour. It was partitioned between EtOAc and brine. The organic phase was dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography on silica (10-30% EtOAc in hexane) to get methyl 2-(6-hydroxy-5-(piperidin-l-yl(4-(trifluoromethyl)phenyl)methyl)-4'- (trifluoromethyl)biphenyl-3-yl)acetate (90 mg, 26%). LCMS m/z 552.3 [M+ 1]+ The above ester in THF (1 mL)/MeOH (1 mL) was treated with 4M NaOH in water (5 eq.) and heated using microwave irradiation at 1000C for 10 minutes. Added IM HCl and diluted with water, extracted with EtOAc. The organic phase was washed with water, dried over MgSO4, filtered and concentrated. The residue purified using silica gel chromatography (0-10% MeOH/DCM) to give the desired product. 1H NMR (400 MHz, DMSO-d6) δ 12.93 (br. s., IH), 8.80 (br. s., IH), 7.60 - 7.64 (m, 3H), 7.26 (s, 2H), 7.10 (s, IH), 7.14 (s, 2H), 6.99 (s, 2H), 4.86 (s, IH), 3.53 (s, 2H), 2.40 (br. s., 3H), 1.57 (m, 5H), 1.43 (br. s., 2H); LCMS m/z 538.2 [M+l]+
Example 30: Synthesis of (6-((4-fluorophenyl)(4-methylpiperidin-l-yl)methyl)-4'- (trifluoromethyl)biphenyl-3-yl)methanol
Figure imgf000158_0001
Step l
2-((4-fiuorophenyl)(4-methylpiperidin-l-yl)methyl)-5-(hydroxymethyl)phenol
Figure imgf000158_0002
A mixture of 3-(hydroxymethyl)phenol (500 mg, 2.8 mmol, 1.0 eq), 4-methylpiperidine (302 mg, 3.1 mmol, 1.1 eq) and 4-fluorobenzaldehyde (380 mg, 3.1 mmol, 1.1 eq) was added to toluene (10 mL). The mixture was heated at 120 0C for 16 h. The solvent was removed in vacuo and the residue was purified by column chromatography to give 2-((4- fluorophenyl)(4-methylpiperidin-l-yl)methyl)-5-(hydroxymethyl)phenol (1.18 g, 20%) as a yellow oil. LCMS m/z 330.0 [M+l] +; 1H-NMR (400 MHz, CDCl3) δ: 7.35 (bs, 2H), 6.99-6.95 (m, 2H), 6.85-6.83 (m, 2H), 6.71-6.69 (m, IH), 4.57 (s, 2H), 4.46 (s, IH), 3.12- 3.09 (m, IH), 2.70-2.67 (m, IH), 2.09-2.07 (m, IH), 1.93-1.88 (m, 1H),1.69-1.61 (m, 2H), 1.38-1.32 (m, 2H), 1.20-1.17 (m, IH), 0.91 (d, J= 4.0 Hz, 3H). Step 2
5-((tert-butyldimethylsilyloxy)methyl)-2-((4-fluorophenyl)(4-methylpiperidin-l- yl)methyl)phenol
Figure imgf000159_0001
A solution of 2-((4-fiuorophenyl)(4-methylpiperidin- 1 -yl)methyl)-5- (hydroxymethyl)phenol (1.0 g, 3.0 mmol, 1.0 eq), imidazole (268 mg, 0.39 mmol, 1.3 eq), DMAP (38 mg, 0.30 mmol, 0.1 eq) in THF (10 mL) was stirred for 30 min. TBSCl (498 mg, 3.3 mmol, 1.1 eq) was added at 0 0C. The mixture was stirred at rt for 1 h, diluted by saturated aq. solution of NH4CI. It was partitioned between ethyl acetate (100 mL) and water (50 mL) twice. The combined organic layer was washed with brine, and dried over Na2SC^, then filtered and concentrated in vacuo. The residue was purified by a column chromatography to obtain 5-((tert-butyldimethylsilyloxy)methyl)-2-((4- fluorophenyl)(4-methylpiperidin-l-yl)methyl)phenol. (400 mg, 30%) as a yellow oil. LCMS m/z 443.27 [M+l] +;Η-NMR (400 MHz, CDCl3) δ: 12.27 (bs, IH), 7.26 (bs, 2H), 6.88-6.84 (m, 2H), 6.76 (bs, IH), 6.76-6.71 (m, IH), 6.58-6.56 (m, IH), 4.56 (s, 2H),4.35 (s, IH), 3.04-3.02 (m, IH), 2.62-2.59 (m, IH), 1.99-1.93 (m, IH), 1.82-1.77 (m, IH), 1.58-1.50 (m, 2H), 1.15-1.11 (m, 3H), 0.85 (s, 9 H), 0.81 (d, J= 8.0 Hz, 3H), 0.00 (s, 6 H).
Step 3
5-((tert-butyldimethylsilyloxy)methyl)-2-((4-fluorophenyl)(4-methylpiperidin-l- yl)methyl)phenyl trifluoromethanesulfonate
Figure imgf000160_0001
To a solution of 5-((tert-butyldimethylsilyloxy)methyl)-2-((4-fluorophenyl)(4- methylpiperidin-l-yl)methyl)phenol (800 mg , 2.1 mmol, 1.0 eq) and Et3N (626 mg, 6.2 mmol, 3.0 eq) in DCM (20 mL) was slowly added Tf2O (586 mg, 2.1 mmol, 1.0 eq). The mixture was stirred at 0 0C for 1 h. The solvent was removed in vacuo and the residue was purified using column chromatography to yield 5-((tert- butyldimethylsilyloxy)methyl)-2-((4-fluorophenyl)(4-methylpiperidin-l- yl)methyl)phenyl trifluoromethanesulfonate (234 mg, 45%) as a yellow oil. LCMS m/z 576.0 [M+l] +; 1H-NMR (400 MHz, CDCl3) δ: 7.82 (d, J= 6.0 Hz, IH), 7.42- 7.34 (m, 2H), 7.31 (d, J= 6.0 Hz, IH), 7.28 (s, IH), 7.00-6.96 (m, 2H), 4.75 (s, 2H), 4.67 (s, IH), 2.92-2.83 (m, IH), 2.78-2.76 (m, IH), 1.97-1.88 (m, 3H), 1.62-1.59 (m, 3H), 1.58-1.50 (m, IH), 0.98 (s, 9H), 0.95 (d, J= 6.0 Hz, 3H), 0.14 (s, 6H).
Step 4 l-((5-((tert-butyldimethylsilyloxy)methyl)-4'-(trifluoromethyl)biphenyl-2-yl)(4- fluorophenyl)methyl)-4-methylpiperidine
Figure imgf000160_0002
To 5-((tert-butyldimethylsilyloxy)methyl)-2-((4-fluorophenyl)(4-methylpiperidin- 1 - yl)methyl)phenyl trifluoromethanesulfonate (800 mg,1.6 mmol, 1.0 eq), A- (trifluoromethyl)phenyl boronic acid (441 mg, 2.3 mmol, 1.5 eq), Pd(PPh3^ (89 mg, 0.077 mmol, 0.05 eq), LiCl (195 mg, 4.7 mmol, 3.0 eq), Na2CO3 (427 mg, 4.0 mmol, 2.6 eq) was added solvent (toluene/EtOH/H2θ = 5:2: 1, 8 mL). The reaction was stirred at 90 0C for 16 h. The solvent was removed in vacuo and the residue was purified by column chromatography to give l-((5-((tert-butyldimethylsilyloxy)methyl)-4'- (trifluoromethyl)biphenyl-2-yl)(4-fluorophenyl)methyl)-4-methylpiperidine ( 140 mg, 61%) as a yellow oil. LCMS m/z 572.0 [M+ 1] +; 1H-NMR (400 MHz, CDCl3) δ: 7.76 (d, J= 6.0 Hz, IH), 7.57 (d, J= 6.0 Hz, 2H), 7.28 (d, J= 6.0 Hz, IH), 7.16-7.14 (m, 2H), 6.93 (s, IH), 6.90-6.87 (m, 2H), 6.76-6.72 (m, 2H), 4.63 (s, 2H), 4.17 (s, IH), 2.90 (bs, IH), 2.44 (bs, IH), 1.75-1.69 (m, IH), 1.60-1.55 (m, IH), 1.48-1.38 (m, 2H), 1.24-1.06 (m, 3H), 0.83 (s, 9H), 0.80 (d, J= 8.0 Hz, 3H), 0.00 (s, 6H).
Step 5
(6-((4-fluorophenyl)(4-methylpiperidin-l-yl)methyl)-4'-(trifluoromethyl)biphenyl-3- yl)methanol
Figure imgf000161_0001
l-((5-((tert-butyldimethylsilyloxy)methyl)-4'-(trifluoromethyl)biphenyl-2-yl)(4- fluorophenyl)methyl)-4-methylpiperidine (140 mg, 0.25 mmol, 1.0 eq), and TBAF (128 mg, 0.5 mmol, 2.0 eq) were dissolved in THF (5 mL). The mixture was stirred at rt for 2 h, diluted with ethyl acetate and washed with water, concentrated to give the desired product 6-((4-fluorophenyl)(4-methylpiperidin- 1 -yl)methyl)-4'-
(trifluoromethyl)biphenyl-3-yl)methanol (90 mg, 79%) as a white solid. LCMS m/z 458.0 [M+ 1] +; 1H-NMR (400 MHz, DMSOd6) δ: 7.83 (d, J= 8.0 Hz, 2H), 7.74 (d, J= 8.0 Hz, IH), 7.40-7.36 (m, 3H), 7.05 (s, IH), 7.02-7.00 (m, 4H), 5.18 (bs, IH), 4.48 (s, 2H), 4.29 (s, IH), 2.91-2.88 (m, IH), 2.47-2.45 (m, IH), 1.85-1.80 (m, IH), 1.66-1.61 (m, IH), 1.56-1.46 (m, 2H), 1.31-1.23 (m, IH), 1.18-1.09 (m, 2H), 0.86 (d, J= 8.0 Hz, 3H). Example 31: Synthesis of 2-(6-((4-fluorophenyl¥4-methylpiperidin-l-vπmethylV4'- (trifluoromethyl)biphenyl-3-yl)-N-(methylsulfonyl)propanamide
Figure imgf000162_0001
Stepl
Methyl 2-(4-((4-fluorophenyl)(4-methylpiperidin- 1 -yl)methyl) hydroxyphenyl)propanoate.
Figure imgf000162_0002
The desired product was obtained following the condition of Step 1 in Example 20 (Method D) using methyl 2-(3-hydroxyphenyl)propanoate, 6, 4-methylpiperidine and 4- fiuorobenzaldehyde. LCMS m/z = 386.1 [M+H] +; 1H NMR (400 MHz, CDCl3) δ: 12.46 (bs, IH), 7.34 (bs, 2H), 7.01-6.96 (m, 2H), 6.79-6.77 (m, 2H), 6.62 (d, J = 8.0 Hz, IH), 4.45 (s, IH), 3.64 (s, 3H), 3.63-3.59 (m, IH), 3.13 (bs, IH), 2.68 (bs, IH), 2.06-2.04 (m, IH), 1.89 (bs, IH), 1.69-1.60 (m, 2H), 1.44 (d, J= 7.6 Hz, 3H), 1.37-1.34 (m, 2H), 1.25- 1.24 (m, IH), 0.91 (d, J= 6.0 Hz, 3H).
Step 2
Methyl-2-(4-((4-fluorophenyl)(4-methylpiperidin-l-yl)methyl)-3- (trifluoromethylsulfonyloxy)phenyl)propanoate
Figure imgf000163_0001
The desired product was obtained following the condition of Step 2 in Example 20 using methyl 2-(4-((4-fluorophenyl)(4-methylpiperidin- 1 -yl)methyl) hydroxyphenyl)propanoate, Tf2O, NEt3 and DCM. LCMS m/z = 518.2 [M+H] +; 1H NMR (400 MHz, CDCl3) δ: 7.79 (d, J= 8.0 Hz, IH), 7.35-7.29 (m, 3H), 7.12 (s, IH), 6.97-6.91 (m, 2H), 4.57 (s, IH), 3.72-3.69 (m, IH), 3.66 (s, 3H), 2.83 (bs, IH), 2.68 (bs, IH), 1.90-1.82 (m, 2H), 1.55-1.52 (m, 2H), 1.47 (d, J= 7.6 Hz, 3H), 1.40-1.34 (m, IH), 1.27-1.17 (m, 2H), 0.91 (d, J= 6.8 Hz, 3H).
Step 3
Methyl 2-(6-((4-fluorophenyl)(4-methylpiperidin- 1 -yl)methyl)-4'- (trifluoromethyl)biphenyl-3-yl)propanoate
Figure imgf000163_0002
The desired product was obtained following the condition of Step 3 in Example 20 using methyl2-(4-((4-fluorophenyl)(4-methylpiperidin- 1 -yl)methyl)-3- (trifluoromethylsulfonyloxy)phenyl)propanoate, tetrakis(triphenylphosphine)palladium(O), 4-(trifluoromethyl)phenylboronic acid dimethoxy ethane, ethanol and saturated aqueous sodium bicarbonate. LCMS m/z = 514.3 [M+ 1] +; 1B NMR (400 MHz, CDCl3) δ: 7.83-7.80 (m, IH), 7.66 (d, J= 8.4 Hz, IH), 7.33-7.12 (m, 5H), 6.97-6.94 (m, 3H), 6.86-6.82 (m, IH), 4.23 (s, IH), 3.72-3.68 (m, IH), 3.64 (s, 3H), 2.85-2.81 (m, IH), 2.52 (bs, IH), 1.90-1.77 (m, IH), 1.67-1.54 (m, 3H), 1.47 (d, J= 7.6 Hz, 3H), 1.32-1.14 (m, 3H), 0.91-0.88 (m, 3H).
Step 4
2-(6-((4-fluorophenyl)(4-methylpiperidin-l-yl)methyl)-4'-(trifluoromethyl)biphenyl-3- yl)propanoic acid
Figure imgf000164_0001
To methyl 2-(6-((4-fluorophenyl)(4-methylpiperidin- 1 -yl)methyl)-4'- (trifluoromethyl)biphenyl-3-yl)propanoate (1.44 g, 2.80 mmol) was added 1: 1 MeOH/THF (20 mL) and 4 M of sodium hydroxide in water (3.50 mL, 14.0 mmol). Reaction heated in microwave for 10 mins at 100 0C. Hydrolysis complete. Quench with equivalent amount of 1 N HCl. Concentrate to remove MeOH. Extract with ethyl acetate. Concentrate. Purify using 0-10% MeOH in DCM to give 2-(6-((4-fluorophenyl)(4- methylpiperidin-l-yl)methyl)-4'-(trifluoromethyl)biphenyl-3-yl)propanoic acid. (1.2 g, 86%) LCMS m/z 500.2 [M+l]+; 1H NMR (400 MHz, DMSO-d6) δ 12.50 (bs, IH), 9.68 (bs, IH), 8.16 (d, J = 7.6 Hz, IH), 7.84 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 7.6 Hz, IH), 7.01- 7.29 (m, 7H), 5.13 (d, J = 9.2 Hz, IH), 3.74-3.79 (m, IH), 3.38 (d, J = 7.2 Hz, IH), 3.05 (d, J = 10.0 Hz, IH), 2.76-2.88 (m, 2H), 1.69-1.80 (m, 2H), 1.24-1.39 (m, 6H).
Step 5
2-(6-((4-fiuorophenyl)(4-methylpiperidin-l-yl)methyl)-4'-(trifluoromethyl)biphenyl-3- yl)-N-(methylsulfonyl)propanamide
Figure imgf000165_0001
A mixture of methanesulfonamide (28 mg, 0.28 mmol, 1.0 eq), 2-(6-((4-fluorophenyl)(4- methylpiperidin-l-yl)methyl)-4'-(trifluoromethyl)biphenyl-3-yl)propanoic acid (200 mg, 0.40 mmol, 1.4 eq), DMAP (12 mg, 0.08 mmol, 0.2 eq) and EDCI (64 mg, 0.34 mmol, 1.2 eq) was added to DCM (8 mL). The mixture was reacted at room temperature for 16 h. The solvent was removed in vacuo and the residue was purified by column chromatography to give desired product as white solid. (100 mg, 60%). LCMS m/z 576.9 [M+l] +; 1H NMR (400 MHz, CD3OD) δ: 7.90 (d, J = 8.0 Hz, IH), 7.75 (d, J = 8.4 Hz, 2H), 7.48 (bs, IH), 7.31 (bs, 2H), 7.12-7.06 (m, 3H), 6.97-6.93 (m, 2H), 4.50 (s, IH), 3.68 (q, J = 6.8 Hz, IH), 3.11 (bs, 4H), 2.67 (bs, IH), 2.12-1.98 (m, 2H), 1.66-1.55 (m, 2H), 1.43-1.18 (m, 6H), 0.91 (d, J= 6.4 Hz, 3H).
Example 32 : 6-((4-methyrpiperidin- 1 -vl)(4-(trifluoromethvl)phenvl)methyl)-N- (methylsulfonyl)-4'-(trifluoromethyl)biphenyl-3-carboxamide
Figure imgf000165_0002
Step l
Methyl 3-hydroxy-4-((4-methylpiperidin- 1 -yl)(4-(trifluoromethyl)phenyl)methyl)benzoate
Figure imgf000166_0001
The desired product was obtained following the condition of step 1 in Example 21 (Method D) using 3-hydroxybenzoic acid, 4-methylpiperidine and A- (trifiuoromethyl)benzaldehyde. LCMS m/z 408.2 [M+ 1] +; 1H-NMR (400 MHz, CDCl3) δ: 9.83 (bs, IH), 7.54-7.52 (m, 2H), 7.45 (bs, IH), 7.32-7.30 (m, 3H), 7.00 (bs, IH), 5.19 (s, IH), 3.88 (s, 3H), 2.29-2.19 (m, 4H), 1.67-1.59 (m, 3H), 1.48-1.34 (m, 2H), 1.06 (d, J = 6.0 Hz, 3H).
Step 2
Methyl 4-((4-methylpiperidin- 1 -yl)(4-(trifluoromethyl)phenyl)methyl)-3- (trifluoromethylsulfonyloxy)benzoate
Figure imgf000166_0002
The desired product was obtained following the condition of step 2 in Example 21 using methyl 3-hydroxy-4-((4-methylpiperidin- 1 -yl)(4-
(trifluoromethyl)phenyl)methyl)benzoate, Tf2O, NEt3 and DCM. LCMS m/z 540.0 [M+ 1] VH-NMR (400 MHz, CDCl3) δ: 7.82 (d, J= 6.0 Hz, IH), 7.42-7.39 (m, 2H), 7.31 (d, J= 6.0 Hz, IH), 7.28 (s, IH), 7.00-6.96 (m, 2H), 4.75 (s, 3H), 4.67 (s, IH), 2.92-2.83 (m, IH), 2.78-2.76 (m, IH), 1.97-1.88 (m, 2H), 1.62-1.59 (m, 2H), 1.44-1.38 (m, IH), 1.30-1.23 (m, 2H), 0.98 ((L J= 8.0 Hz, 3H).
Step 3
Methyl 6-((4-methylpiperidin- 1 -yl)(4-(trifluoromethyl)phenyl)methyl)- 4'-(trifluoromethyl)biphenyl-3-carboxylate
Figure imgf000167_0001
The desired product was obtained following the condition of step 3 Example 21 using methyl 4-((4-methylpiperidin- 1 -yl)(4-(trifiuoromethyl)phenyl)methyl)-3- (trifluoromethylsulfonyloxy)benzoate, tetrakis(triphenylphosphine)palladium(O), 4- (trifluoromethyl)phenylboronic acid dimethoxy ethane, ethanol and saturated aqueous sodium bicarbonate. LCMS m/z 536.0 [M+l] +; 1H-NMR (400 MHz, CDCl3) δ: 8.06-8.05 (m, IH), 8.02 (bs, IH), 7.78-7.77 (m, IH), 7.72-7.69 (m, 2H), 7.52 (bs, IH), 7.46 (d, J = 8.0 Hz, IH), 7.43-7.41 (m, 2H), 7.13-7.10 (m, 2H), 4.43 (s, IH), 3.88 (s, 3H), 2.98-2.95 (m, IH), 2.54-2.51 (m, IH), 1.91-1.85 (m, IH), 1.75-1.68 (m, 1H),1.6O-1.58 (m, IH), 1.53-1.50 (m, IH), 1.37-1.30 (m, 2H), 1.22-1.18 (m, IH), 0.91 (d, J= 8.0 Hz, 3H).
Step 4
6-((4-methylpiperidin-l-yl)(4-(trifluoromethyl)phenyl)methyl)-4'- (trifluoromethyl)biphenyl-3-carboxylic acid
Figure imgf000167_0002
The desired product was obtained following the condition of step 4 Example 21 using methyl 6-((4-methylpiperidin- 1 -yl)(4-(trifiuoromethyl)phenyl)methyl)- 4'- (trifluoromethyl)biphenyl-3-carboxylate, MeOH/THF and 4 M of sodium hydroxide in water. LCMS m/z 522.0 [M+l] +;Η-NMR (400 MHz, CDCl3) δ: 8.06-7.92 (m, 2H), 7.76 (bs, IH), 7.63 (d, J= 8.0 Hz, IH), 7.50-7.42 (m, IH), 7.35-7.32 (m, IH), 7.27-7.17 (m, 2H), 7.07-7.04 (m, 2H), 6.92-6.76 (m, IH), 3.41 (s, IH), 2.94-2.91 (m, IH), 2.51-2.48 (m, IH), 1.87-1.82 (m, IH), 1.71-1.66 (m, IH), 1.53-1.43 (m, 2H), 1.27-1.23 (m, 2H), 1.18-1.13 (m, IH), 0.83 (d, J= 4.0 Hz, 3H).
Step 5
6-((4-methylpiperidin-l-yl)(4-(trifluoromethyl)phenyl)methyl)-N-(methylsulfonyl)-4'- (trifluoromethyl)biphenyl-3-carboxamide
Figure imgf000168_0001
The desired product was obtained following the condition of step 5 Example 21 using 6- ((4-methylpiperidin-l-yl)(4-(trifluoromethyl)phenyl)methyl)-4'- (trifluoromethyl)biphenyl-3-carboxylic acid, methanesulfonamide, DMAP and DCM. LCMS m/z 599.2 [M+l] +; 1H-NMR (400 MHz, DMSOd6) δ: 8.46 (bs, IH), 8.19 (bs, IH), 7.91-7.79 (m, 5H), 7.51-7.44 (m, 4H), 5.29 (bs, IH), 3.37 (s, 3H), 3.19 (bs, IH), 2.97-2.79 (m, 3H), 2.52 (bs, IH), 1.76-1.68 (m, 2H), 1.55-1.43 (m, 3H), 0.89 (s, 3H).
Example 33. Synthesis of 2-(4-((4-Fluorophenyl)(4-methylpiperidin-l-yl)methyl)-3-(4- (trifluoromethyl)phenoxy) phenvDpropanoic acid
Figure imgf000168_0002
Step l Methyl 2-(4-((4-fluorophenyl)(4-methylpiperidin- 1 -yl)methyl)-3-(4-(trifluoromethyl) phenoxy)phenyl)propanoate
Figure imgf000169_0001
To a 25 mL three-necked rounded-bottom flask was charged with methyl 2-(4-((4- fluorophenyl)(4-methylpiperidin-l-yl)methyl)-3-hydroxyphenyl)propanoate (200 mg, 0.5 mmol), 4-(trifluoromethyl)phenylboronic acid (175 mg, 0.8 mmol), and anhydrous Cu(OAc)2 (94 mg, 0.5 mmol). The flask was flushed with Argon for 10 mins, and dry DCM (3.0 mL) was then injected by syringe. To this mixture was treated with dry Et3N (0.2 mL, 1.6 mmol) and stirred at r.t. for 2 days. The resulting mixture was filtered and the filtrate was concentrated in vacuo to give the crude product, which was applied to flash column chromatography (PE/ EtOAc: 0-10%) to yield the desired ester as a yellow oil (50 mg, 18%). IH NMR (400 MHz, CDCl3) δ: 7.75 (d, J = 8.4 Hz, IH), 7.50 (d, J = 8.4 Hz, 2H), 7.23-7.20 (m, 2H), 7.15 (d, J = 8.0 Hz, IH), 6.87-6.80 (m, 5H), 4.48 (s, IH), 3.64 (s, 3H), 3.63 (q, J = 7.2 Hz, IH), 2.92 (d, J = 11.2 Hz, IH), 2.66 (d, J = 11.2 Hz, IH), 1.77-1.71 (m, 2H), 1.58-1.50 (m, 2H), 1.42 (d, J = 7.2 Hz, 3H), 1.35-1.28 (m, IH), 1.25-1.15 (m, 2H), 0.90 (d, J = 6.4 Hz, 3H). LCMS m/z 530.0 [M+H]+.
Step 2
2-(4-((4-Fluorophenyl)(4-methylpiperidin-l-yl)methyl)-3-(4-(trifluoromethyl)phenoxy) phenyl)propanoic acid
Figure imgf000170_0001
Methyl 2-(4-((4-fluorophenyl)(4-methylpiperidin- 1 -yl)methyl)-3-(4- (trifluoromethyl)phenoxy)phenyl)propanoate from Step 1 (50 mg, 0.095 mmol) and IM NaOH (0.95 mL, 0.95 mmol) were suspended in THF (2.0 mL). The mixture was stirred at 800C for 5 h and then adjusted pH~5 with diluted HCl. The solution was extracted with EtOAc (5.0 mLx3), dried over Na2SO^ and evaporated in vacuo to obtain the final product as a white solid (47 mg, 96%). IH NMR (400 MHz, DMSO-d6) δ: 7.72 (d, J = 8.4 Hz, IH), 7.67 (d, J = 8.8 Hz, 2H), 7.27-7.22 (m, 3H), 7.01 (dd, J = 9.2, 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 6.89 (bs, IH), 4.43 (s, IH), 3.63 (q, J = 7.2 Hz, IH), 2.84 (d, J = 10.0 Hz, IH), 2.56 (d, J = 10.8 Hz, IH), 1.69 (dd, J = 11.2, 10.8 Hz, 2H), 1.51 (dd, J = 13.2, 12.4 Hz, 2H), 1.30 (d, J = 7.2 Hz, 3H), 1.29-1.22 (m, IH), 1.20-1.05 (m, 2H), 0.85 (d, J = 6.4 Hz, 3H). LCMS m/z 516.0 [M+H] +.
Example 34. Synthesis of 2-(4-((4-fluorophenyl)(4-methylpiperidin-l-yl)methyl)-3-(4- (trifluoromethyl) phenylamino)phenyl)propanoic acid
Figure imgf000170_0002
Steo l
Methyl 2-(4-((4-fluorophenyl)(4-methylpiperidin- 1 -yl)methyl)-3-(4-(trifluoromethyl) phenylamino)phenyl)propanoate
Figure imgf000171_0001
To a 10 mL pressure tube was charged with methyl 2-(4-((4-fluorophenyl)(4- methylpiperidin- 1 -yl)methyl)-3-(trifluoromethylsulfonyloxy)phenyl)propanoate (367 mg, 0.7 mmol), 4-(trifluoromethyl)benzenamine (137 mg, 0.85 mmol), CS2CO3 (347 mg, 1.1 mmol), Pd(OAc)2 (16 mg, 0.07 mmol), BINAP (89 mg, 0.14 mmol), and toluene (5 mL) under argon atmosphere. After microwaving at 15O0C for 2 h, the resulting mixture was cooled down and filtered. The filtrate was evaporated under reduced pressure to give the crude residue, which was purified by flash column chromatography (MeOHZH2O: 60% -
80%, containing 0.5% TFA) to yield the desired compound as a yellow oil (60 mg, 16%).
IH NMR (400 MHz, CDCl3) δ: 8.15 (d, J = 6.8 Hz, IH), 7.55 (bs, 2H), 7.33 (d, J = 8.4 Hz, 2H), 7.27-7.22 (m, 2H), 6.96-6.92 (m, 2H), 6.65 (m, 2H), 5.57 (s, IH), 3.68-3.64 (m, 4H), 3.58 (bs, IH), 3.39 (bs, IH), 2.76-2.67 (m, IH), 1.90-1.50 (m, 5H), 1.42 (d, J = 7.2 Hz, 3H), 1.35-1.25 (m, IH), 0.94 (d, J = 6.0 Hz, 3H). LCMS m/z 529.0 [M+H] +
Step 2
2-(4-((4-fluorophenyl)(4-methylpiperidin-l-yl)methyl)-3-(4-(trifluoromethyl) phenylamino)phenyl)propanoic acid
Figure imgf000171_0002
Methyl 2-(4-((4-fluorophenyl)(4-methylpiperidin- 1 -yl)methyl)-3-(4-(trifluoromethyl) phenylamino)phenyl)propanoate from Step 1 (32 mg, 0.06 mmol, 1.0 eq.) and aq. NaOH (0.6 mL, 0.6 mmol, 10.0 eq, IM) were suspended in THF (2.0 mL). The mixture was stirred at 8O0C for 6 h and then adjusted pH~5 with diluted HCl. The solution was extracted with EtOAc (5.0 mLx3), dried over Na2SO^ and evaporated in vacuo to give the crude product, which was purified by prep-TLC (DCM/MeOH = 20/1) to give the final product as a yellow solid (21 mg, 68%). IH NMR (400 MHz, DMSO-d6) δ: 9.04 (bs, IH), 7.49-7.46 (m, 2H), 7.43 (d, J = 7.2 Hz, IH), 7.35-7.32 (m, 2H), 7.14 (bs, IH), 7.03-6.96 (m, 3H), 6.89 (d, J = 8.4 Hz, 2H), 4.59 (s, IH), 3.57 (q, J = 7.2 Hz, IH), 2.83 (d, J = 10.0 Hz, IH), 2.67 (d, J = 11.2 Hz, IH), 1.89-1.78 (m, 2H), 1.63-1.54 (m, 2H), 1.40-1.30 (m, IH), 1.29 (d, J = 7.2 Hz, 3H), 1.28-1.15 (m, 2H), 0.90 (d, J = 6.0 Hz, 3H). LCMS m/z 515.0 [M+H] +
Example 35. Synthesis of 4-Methyl-6-((4-methylpiperidin-l-yl)(4- (trifluoromethyl)phenyl)methyl)-4'-(trifluoromethyl)biphenyl-3-carboxylic acid
Figure imgf000172_0001
Step l
Methyl 5 -hydro xy-2-methylbenzoate
Figure imgf000172_0002
5-Hydroxy-2-methylbenzoic acid (457 mg, 3.0 mmol, 1.0 eq), Cone. H2SO4 (12 mg, 0.1 mmol, 0.04 eq) were dissolved in MeOH (4 mL). The mixture was refluxed for 3 h, adjusted pH to 7.0 with 2 M NaOH solution. The mixture was extracted with EtOAc for three times. The combined organic layers were dried over Na2SO^ concentrated in vacuo. The residue was purified through silica gel column (PE/EtOAc = 50/1) to give the desired compound as a white solid (400 mg, yield 80%). IH-NMR (400MHz, CDCl3) δ: 9.83 (bs, IH), 7.32 (s, IH), 7.00 (d, J = 8.0 Hz, IH), 6.82 (d, J = 8.0 Hz, IH), 3.88 (s, 3H), 2.53 (s, 3H); LCMS m/z 167.0 [M+H] +.
Step 2
4-Methyl-6-((4-methylpiperidin-l-yl)(4-(trifluoromethyl)phenyl)methyl)-4'- (trifluoromethyl)biphenyl-3-carboxylic acid
Figure imgf000173_0001
Using Methyl 5-hydroxy-2-methylbenzoate as starting material and Method D (Example 20), the titled compound was synthesized (76 mg, 9% combined yield for 4 steps). 1H- NMR (400MHz, DMSO-d6) δ: 12.89 (bs, IH), 7.84 (d, J = 8.0 Hz, 2H), 7.72 (s, IH), 7.58 (d, J = 8.0 Hz, 2H), 7.55 (s, IH), 7.41 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 4.46 (s, IH), 2.92 (bs, IH), 2.58 (s, 3H), 2.45 (bs, IH), 1.92-1.87 (m, IH), 1.71-1.66 (m, IH), 1.58 (bs, IH), 1.49 (bs, IH), 1.33-1.27 (m, IH), 1.20-1.13 (m, 2H), 0.87 (d, J = 6.0 Hz, 3H); LCMS m/z 535.9 [M+H] +.
Example 36. Synthesis of 2(6-(4-methyl-l-(3-methylbutyl)piperidin-2-yl)-4'- (trifluoromethyl)biphenyl-3-yl)acetic acid
Figure imgf000173_0002
Step l Ethyl 2-(6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-4'-(trifluoromethyl)biphenyl-3- yl)acetate and 5-(2-ethoxy-2-oxoethyl)-4'-(trifluoromethyl)biphenyl-2-ylboronic acid
Figure imgf000174_0001
A mixture of ethyl 2-(6-iodo-4'-(trifluoromethyl)biphenyl-3-yl)acetate (prepared according to the procedure described in WO2006008558) (868 mg, 2.00 mmol, 1.0 eq.), bis(pinacolato)diboron (559 mg, 2.20 mmol, 1.1 eq.), KOAc (588 mg, 6.00 mmol, 3.0 eq.), Pd(dppf)Cl2 (163 mg, 0.20 mmol, 0.1 eq.), and DMF (15 mL) was degassed for 10 min, and then flushed with N2 for three times. The system was heated at 850C overnight, cooled to rt, poured into water (50 mL), extracted with EtOAc(50 mLx3), washed with brine, dried over Na2SO4, and the organic solvent was removed in vacuo to give the crude product, which was purified by flash column chromatography (PE/EtOAc = 0-10%) on silica gel to give a mixture of boronicc acid and its ester as a colorless oil (558 mg, yield 64%). LCMS m/z 435.0 [M+H] + (boronic ester) and 353.0 [M+H] + (boronic acid)
Step 2
Ethyl 2-(6-(4-methylpyridin-2-yl)-4'-(trifluoromethyl)biphenyl-3-yl)acetate
Figure imgf000174_0002
To a 25 -mL rounded-bottom flask was charged with boronic acid and ester from Step 1 (330 mg, 0.76 mmol, 1.0 eq.), 2-bromo-4-methylpyridine (157 mg, 0.91 mmol, 1.2 eq.), Pd(PPh3)4 (90 mg, 0.076 mmol, 0.01 eq.), K2CO3 (210 mg, 1.52 mmol, 2.0 eq.), LiCl (96 mg, 2.28 mmol, 3.0 eq.), and dioxane (5.0 mL) and water (1.0 mL). The mixture was desgassed for 10 min, flushed with N2 for 3 times, and then heated to reflux overnight. The resulting mixture was poured into water, extracted with EtOAc (5 mLx3), washed with brine, dried over Na2SC^, filtered, and the organic solvent was removed in vacuo to give the crude product, which was purified by flash column chromatography (EtOAc/PE = 0-20%) on silica gel to obtain the desired compound as a yellow oil (121 mg, 40%). IH NMR (400 MHz, CDC13) δ: 8.42 (d, J = 4.8 Hz, IH), 7.63 (d, J = 8.0 Hz, IH), 7.49 (d, J = 8.0 Hz, 2H), 7.42 (dd, J = 8.0, 1.6 Hz, IH), 7.35 (d, J = 1.6 Hz, IH), 7.27 (d, J = 8.0 Hz, 2H), 6.95 (d, J = 8.0 Hz, IH), 6.76 (s, IH), 4.18 (q, J = 6.8 Hz, 2H), 3.71 (s, 2H), 2.15 (s, 3H), 1.28 (t, J = 6.8 Hz, 3H). LCMS m/z 400.0 [M+H] +.
Step 3
Ethyl 2-(6-(4-methylpiperidin-2-yl)-4'-(trifluoromethyl)biphenyl-3-yl)acetate
Figure imgf000175_0001
A solution of ethyl 2-(6-(4-methylpyridin-2-yl)-4'-(trifluoromethyl)biphenyl-3-yl)acetate (118 mg, 0.30 mmol, 1.0 eq.) in EtOH (3.0 mL) was flushed with N2 for 3 times, and PtO2 (24 mg, 20% w/w) was then added, and followed by adding a few drops solution of HCl in EtOH. The mixture was flushed with H2 for 3 times, and stirred at rt for 6 h under H2 atmoshphere. The resulting mixture was filtered and the filtrate was evaporated in vacuo to give the crude product, which was resolved in water, adjusted pH to 9, extracted with EtOAc (5 mLx3), washed with brine, dried over Na2Sθ4, filtered, and the organic solvent was removed in vacuo to give the desired compound as a yellow oil (81 mg, 68%). IH NMR (400 MHz, CDCl3) δ: 7.61-7.57 (m, 3H), 7.37 (d, J = 8.0 Hz, 2H), 7.25 (dd, J = 8.0, 1.6 Hz, IH), 7.01 (d, J = 1.6 Hz, IH), 4.08 (q, J = 6.8 Hz, 2H), 3.56-3.52 (m, 3H), 3.06-3.01 (m, IH), 2.54-2.47 (m, IH), 1.58-1.50 (m, 2H), 1.38-1.23 (m, IH), 1.20- 1.08 (m, 5H), 0.83 (t, J = 6.8 Hz, 3H). LCMS m/z 406.0 [M+H] +.
Step 4
Ethyl 2-(6-(l-isopentyl-4-methylpiperidin-2-yl)-4'-(trifluoromethyl)biphenyl-3-yl)acetate
Figure imgf000176_0001
To a solution of ethyl 2-(6-(4-methylpiperidin-2-yl)-4'-(trifluoromethyl)biphenyl-3- yl)acetate (75 mg, 0.19 mmol, 1.0 eq.) and 3-methylbutanal (19 mg, 0.22 mmol, 1.2 eq) in dry DCM (5.0 mL) was added NaBH(OAc)3 (78 mg, 0.37 mmol, 2.0 eq.) at rt. After the addition was completed, the mixture was stirred at rt for 2 h, quenched with saturated NaHCO3 solution, extracted with EtOAc (5 mLx3), washed with brine, dried over Na2SO^ filtered, and the organic solvent was removed in vacuo to give the crude product, which was applied to flash column chromatography (EtOAc/PE = 0-10%) on silica gel to obtain the desired compound as a yellow oil (74 mg, yield 84%) IH NMR (400 MHz, CDCl3) δ: 7.67-7.62 (m, 3H), 7.36 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.0 Hz, IH), 7.04 (bs, IH), 4.15 (q, J = 7.2 Hz, 2H), 3.61 (s, 2H), 3.08-3.04 (m, 2H), 2.47-2.40 (m, IH), 1.88-1.82 (m, IH), 1.77-1.70 (m, IH), 1.64-1.58 (m, 2H), 1.40-1.30 (m, IH), 1.28-1.15 (m, 7H), 1.13-1.05 (m, IH), 0.86 (d, J = 6.0 Hz, 3H), 0.74 (d, J = 6.8 Hz, 3H), 0.69 (d, J = 6.8 Hz, 3H). LCMS m/z 476.1 [M+H] +.
Step 5
2-(6-( 1 -Isopentyl-4-methylpiperidin-2-yl)-4'-(trifluoromethyl)biphenyl-3-yl)acetic acid
Figure imgf000177_0001
Ethyl 2-(6-(l-isopentyl-4-methylpiperidin-2-yl)-4'-(trifluoromethyl)biphenyl-3-yl)acetate (74 mg, 0.16 mmol, 1.0 eq.) and NaOH (19 mg, 0.48 mmol, 3.0 eq) were suspended in THF (4.0 mL) and water (1.0 mL). The mixture was stirred at 8O0C for 5.O h under N2 atmosphere and then neutralized with diluted HCl to pH~5. The solution was extracted with EtOAc (5 mLx3), and the organic solvent was removed in vacuo to obtain a crude residue, which was purified by Prep-TLC (DCM/MeOH = 20: 1) to give the final product as a white solid (60 mg, 86%). IH NMR (400 MHz, DMSO-d6) δ: 7.80 (d, J = 8.0 Hz, 2H), 7.53 (d, J = 8.0 Hz, IH), 7.45 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.0 Hz, IH), 7.04 (bs, IH), 3.52 (s, 2H), 3.03-2.97 (m, 2H), 2.39-2.36 (m, IH), 1.67-1.65 (m, IH), 1.64-1.60 (m, 2H), 1.58-1.55 (m, IH), 1.40-1.30 (m, IH), 1.25-1.08 (m, 4H), 1.01-0.93 (m, IH), 0.83 (d, J = 6.0 Hz, 3H), 0.71 (d, J = 6.8 Hz, 3H), 0.63 (d, J = 6.8 Hz, 3H). LCMS m/z 448.1 [M+H] +.
Example 37. Synthesis of (6-(4-Methyl-l-(4-(trifluoromethyl)benzyl)piperidin-2-yl)-4'- (trifluoromethyl) biphenyl-3-vP)acetic acid
Figure imgf000177_0002
Ethyl 2-(6-(4-methylpiperidin-2-yl)-4'-(trifluoromethyl)biphenyl-3-yl)acetate (50 mg, 0.12 mmol, 1.0 eq.), l-(bromomethyl)-4-(trifluoromethyl) benzene (32 mg, 0.14 mmol, 1.0 eq.) and NaHCO3 (31 mg, 0.37 mmol, 3.0 eq.) were added to a mixture of THF (4 mL) and DMF (1 mL). The resulting mixture was heated to reflux for 4 h. After cooled to rt, the THF was removed under reduced pressure and the residue was partitioned between EtOAc and brine, the organic extracts combined, washed with brine, dried over Na2SO^ and concentrated in vacuo. The residue was purified by prep-TLC (PE/EtOAc = 20: 1) on silica gel to obtain the desired compound as a colorless oil (31 mg, 45%).
The ester (31 mg, 0.055 mmol, 1.0 eq.) andNaOH (7 mg, 0.17 mmol, 3.0 eq) were suspended in THF (4.0 mL) and water (1.0 mL). The mixture was stirred at 8O0C for 5.0 h under N2 atmosphere and then neutralized with diluted HCl to pH~5-6. The solution was extracted with EtOAc (5 mLx3), washed with brine, dried over Na2SO^ and the organic solvent was removed in vacuo to obtain a crude residue, which was purified by Prep-TLC (DCM/MeOH = 15:1) to give the final product as a white solid (26 mg, yield 92%). IH NMR (400 MHz, MeOH-d4) δ: 7.84 (d, J = 8.0 Hz, IH), 7.78 (d, J = 8.0 Hz, 2H), 7.56 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 8.0 Hz, 2H), 7.45-7.41 (m, 3H), 7.16 (bs, IH), 3.86 (d, J = 13.6 Hz, IH), 3.64 (s, 2H), 3.40-3.35 (m, IH), 2.90-2.85 (m, 2H), 2.05-1.97 (m, IH), 1.85-1.82 (m, IH), 1.60-1.57 (m, IH), 1.45-1.30 (m, 3H), 0.92 (d, J = 6.0 Hz, 3H). LCMS m/z 536.0 [M+H] +.
Example 38. Synthesis of l-(6-((4-Fluorophenyl)(4-methylpiperidin-l-yl)methyl)-4'- (trifluoromethyl)biphenyl-3-yl)cvclobutanecarboxylic acid
Figure imgf000178_0001
Step l
Methyl 1 -(3-hydroxyphenyl)cyclobutanecarboxylate
Figure imgf000179_0001
To a solution of l-(3-Methoxy-phenyl)-cyclobutanecarboxylic acid (2.96 g, 14.4 mmol; Supplier = Chemizon) in methylene chloride (18 mL, 280 mmol) was added 1 M of boron tribromide in methylene chloride (18.0 mL, 18.0 mmol), cooled with an ice-water bath. The reaction mixture was stirred at that temperature for 20 minutes. The reaction was quenched with ice and IN HCl, extracted with EtOAc. The organic phase was dried, filtered and concentrated to get ~3.3g oil as the acid intermediate (crude yield 120%). It was dissolved in methanol (10 ml), added 20 mL concentrated H2SO4, heated with oil bath at 8O0C overnight. It was partitioned between EtOAc and water. The organic phase was washed with brine, dried over MgSθ4, filtered and concentrated. Column purified (4Og, EtOAc in hex 10-15%) to get methyl l-(3-hydroxyphenyl)cyclobutanecarboxylate as a white solid (2.76 g, 93%).
Step 2
1 -(6-((4-Fluorophenyl)(4-methylpiperidin- 1 -yl)methyl)-4'-(trifluoromethyl)biphenyl-3- yl)cyclobutanecarboxylic acid
Figure imgf000179_0002
Using Methyl 5-hydroxy-2-methylbenzoate as starting material and Method D (Example 20), the titled compound was synthesized (76 mg, 9% combined yield for 4 steps). IH NMR (300 MHz, DMSO-d6) δ ppm 12.34 (s, 1 H) 7.83 (d, J=8.31 Hz, 2 H) 7.78 (d, J=8.31 Hz, 1 H) 7.30 - 7.46 (m, 3 H) 6.91 - 7.08 (m, 5 H) 4.29 (s, 1 H) 2.89 (d, J=9.82 Hz, 1 H) 2.60 - 2.77 (m, 2 H) 2.32 - 2.46 (m, 2 H) 1.69 - 2.01 (m, 3 H) 1.42 - 1.69 (m, 3 H) 1.02 - 1.38 (m, 3 H) 0.86 (d, J=6.42 Hz, 3 H); LCMS m/z 526.3 [M+H]+
Example 39. Synthesis of 2-(6-((4-Fluorophenyl)(piperidin-l-vP)methvP)-4'- (trifluoromethyl)biphenyl-3-yl)-4-methylpentanamide
Figure imgf000180_0001
To a mixture of , 2-{6-[(4-Fluoro-phenyl)-piperidin-l-yl-methyl]-4'-trifluoromethyl- biphenyl-3-yl}-4-methyl-pentanoic acid (43 mg, 0.082 mmol), ammonium chloride ( 8.7 mg, 0.16 mmol) and TBTU (38 mg, 0.12 mmol) in N,N-Dimethylformamide (2.0 mL, 26 mmol) was added N,N-Diisopropylethylamine (85 μL, 0.49 mmol). The reaction mixture was stirred at room temperature overnight. Reaction mixture was extracted with ethyl acetate, washed with brine and water, then dried and concentrated to give a crude oil. It was purified by flash chromatography on silica gel column to get desired product as a white solid (17 mg, yield 39%). LCMS m/z 527.3 [M+H]+.
Example 40. Synthesis of 2-(6-(bis(4-fluorophenyl)methyl)-4'- (trifluoromethyl)biphenyl-3-yl)acetic acid
Figure imgf000180_0002
Step l
Methyl 2-(4-formyl-3-(trifluoromethylsulfonyloxy)phenyl)acetate
Figure imgf000181_0001
To a solution of methyl 2-(4-formyl-3-hydroxyphenyl)acetate (582 mg, 3.00 mmol, 1.0 eq) and Et3N (758 mg, 7.50 mmol, 2.5 eq) in DCM (10.0 mL) was slowly added triflic anhydride (1.01 g, 3.60 mmol, 1.2 eq) at -78 0C for 2 h. After the mixture was washed with brine, the water layer was extracted with DCM twice (15 mL x 2). The organic layer was dried over Na2SO4, and evaporated under reduced pressure. The residue was purified on silica gel column chromatography (PE/ EtOAc = 10: 1) to obtain the desired product as a red oil (684 mg, Y: 70%). LC-MS m/z 327.2 [M+H] +; 1H NMR (400 MHz, CDCl3) δ: 10.25 (bs, IH), 7.96 (d, J= 8.0 Hz, IH), 7.47 (d, J= 8.0 Hz, IH), 7.38 (s, IH), 3.76-3.70 (m, 5H).
Step 2
Methyl 2-(6-formyl-4'-(trifluoromethyl)biphenyl-3-yl)acetate
Figure imgf000181_0002
Methyl 2-(4-formyl-3-(trifluoromethylsulfonyloxy)phenyl)acetate (652 mg, 2.00 mmol, 1.0 eq), 4-(trifiuoromethyl)phenylboronic acid (456 mg, 2.4 mmol, 1.2 eq), Na2CO3 (636 mg, 6.00 mmol, 3.0 eq), LiCl (123 mg, 6.00 mmol, 3.0 eq), and Pd(PPh3)4 (112 mg, 0.10 mmol, 0.1 eq) were dissolved in toluene/EtOH/H2θ = 5: 1:0.5 (5.0 mL). The mixture was purged with N2 for 3 times. The mixture was stirred at 95 0C for 16 h. After the mixture was washed with brine, the water layer was extracted with EtOAc twice (15 mL x 2). The organic layer was dried over Na2SO4, and evaporated under reduced pressure. Then the residue was purified on silica gel column chromatography (PE/ EtOAc = 20: 1) to obtain the desired product (258 mg, Y: 40%, red oil). LC-MS m/z 323.2 [M+H] +; 1H NMR (400 MHz, CDCl3) δ: 9.94 (bs, IH), 8.03 (d, J= 8.0 Hz, IH), 7.75 (d, J= 8.0 Hz, 2H), 7.54- 7.50 (m, 3H), 7.36 (s, IH), 3.77-3.71 (m, 5H).
Step 3
Methyl 2-(6-((4-fluorophenyl)(hydroxy)methyl)-4'-(trifluoromethyl)biphenyl-3-yl)acetate
Figure imgf000182_0001
To a solution of l-bromo-4-fluorobenzene (770 mg, 4.40 mmol, 4.4 eq) and TMEDA (465 mg, 4.00 mmol, 4.0 eq) in anhydrous THF (5.0 mL), a solution of butyllithium (1.6 mL, 2.5 M, 4.0 eq) in dry THF (2.0 mL) was added dropwise at -78 0C. The mixture was stirred at this temperature for 30 min, added dropwise into the solution of methyl 2-(6- formyl-4'-(trifluoromethyl)biphenyl-3-yl)acetate (322 mg, 1.00 mmol, 1.0 eq). Then the mixture was stirred at -78 0C for 2 h, quenched with saturated NH4CI aqueous solution, extracted with DCM. The organic layer was dried over Na2SO^ and evaporated under reduced pressure. The crude product was purified with Prep-TLC (PE/ EtOAc = 10: 1) to give the desired compound as a colorless oil (561 mg, 35% yield),. LC-MS m/z 401.0 [M-OH] +; 1H NMR (400 MHz, CDCl3) δ: 7.61-7.60 (m, 2H), 7.56-7.54 (m, IH), 7.36- 7.33 (m, 3H), 7.17-7.10 (m, 3H), 6.95-6.85 (m, 2H), 6.72-6.69 (m, IH), 5.79 (s, IH), 3.70-3.65 (m, 5H).
Step 4
Methyl 2-(6-(4-fluorobenzoyl)-4'-(trifluoromethyl)biphenyl-3-yl)acetate
Figure imgf000183_0001
To a solution of oxalyl dichloride (508 mg, 4.60 mmol, 1.6 eq) in dry DCM (5.0 mL), DMSO (719 mg, 9.22 mmol, 3.0 eq) was added dropwise at -78 0C. The mixture was stirred at this temperature for 30 min, and the solution of methyl 2-(6-((4- fluorophenyl)(hydroxy)methyl)-4'-(trifluoromethyl)biphenyl-3-yl)acetate (1.2 g. 2.88 mmol, 1.0 eq) in anhydrous DCM (3.0 ml) was added dropwise. Then the mixture was stirred at -78 0C for 2 h. To this mixture, Et3N (750 mg, 17.28 mmol, 6.0 eq) was added, and the mixture was allowed to warm to room temperature for 1 h. After the reaction mixture was washed with brine, the aqueous layer was extracted with DCM twice. The organic layer was dried over Na2SO^ and evaporated under reduced pressure. The crude product was purified with silica gel column chromatography (PE/ EtOAc = 10:1) to give the desired product as a colorless oil (745 mg, 62% yield). LCMS m/z 417.0 [M+H] +; 1H NMR (400 MHz, CDCl3) δ: 7.71-7.68 (m, 2H), 7.50-7.42 (m, 4H), 7.39-7.35 (m, 3H), 6.99-6.97 (m, 2H), 3.77-3.73 (m, 5H).
Step 5
Methyl 2-(6-((4-fluorophenyl)(hydroxy)methyl)-4'-(trifluoromethyl)biphenyl-3-yl)acetate
Figure imgf000183_0002
To a solution of methyl 2-(6-(4-fluorobenzoyl)-4'-(trifluoromethyl)biphenyl-3-yl)acetate (700 mg, 1.68 mmol, 1.0 eq) in anhydrous THF (1.0 mL) cooled to -780C, a solution of LDA in hexane (1.0 mL, 2.0 M, 1.2 eq) was added dropwise under Ar atmosphere. The solution was stirred for 30 min at this temperature, and a solution of TBSCl (390 mg, 3.36 mmol, 2.0 eq) in THF (0.5 mL) was slowly added at -780C. The mixture was warmed up to rt and stirred for another 3 h. The reaction system was cooled to -780C again. A solution of (4-fluorophenyl)lithium in THF (1.0 mL, 6.72 mmol, 4.0 eq) prepared as described in the Step 3 above was added dropwise and stirred for 30 min at rt. Then saturated NH4CI aqueous solution (2.0 mL) was injected into the mixture to quench the reaction. Then the mixture was extracted with EtOAc (5 mL x 3), dried over Na2SO4, and evaporated in vacuo, to give a red residue, which was purified by silica gel column chromatography (PE/ EtOAc = 10: 1) to obtain the desired product as a colorless oil ( 250 mg, 25% yield). LCMS: m/z 495.1 [M-OH] +; 1H NMR (400 MHz, CDCl3) δ: 7.42-7.40 (m, 2H), 7.19-7.16 (m, IH), 7.12-6.85 (m, HH), 6.80-6.75 (m, IH), 3.71 (s, 3H), 3.63 (s, 2H).
Step 6
Methyl 2-(6-(bis(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl-3-yl)acetate
Figure imgf000184_0001
To a solution of methyl 2-(6-((4-fluorophenyl)(hydroxy)methyl)-4'- (trifluoromethyl)biphenyl-3-yl)acetate (100 mg, 0. 20 mmol, 1.0 eq) in THF (5.0 mL) NaBH4 (38 mg, 1.0 mmol, 5.0 eq) and AlCl3 (67 mg, 0.50 mmol, 2.5 eq) were added. The mixture was heated at reflux for 3 h. After the reaction mixture was washed with brine, the water layer was extracted with EtOAc (10 mL x 2). Then the organic layer was dried over Na2SO4, and evaporated under reduced pressure. The crude product was purified with silica gel column chromatography (PE/ EtOAc = 20: 1) to give the product as a colorless oil (42 mg, 43% yield). LCMS m/z 497.0 [M H] +, 519.2 [M+Na] +; 1H NMR (400 MHz, CDCl3) δ: 7.55 (d, J= 8.0 Hz, 2H), 7.27-7.24 (m, IH), 7.17 (d, J= 8.0 Hz, 2H), 7.13-7.12 (m, IH), 7.01-6.99 (m, IH), 6.95-6.85 (m, 8H), 5.39 (s, IH), 3.71 (s, 3H), 3.64 (s, 2H).
Step 7
2-(6-(Bis(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl-3-yl)acetic acid
Figure imgf000185_0001
To a solution of methyl 2-(6-(bis(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl-3- yl)acetate (15 mg, 0.03 mmol, 1.0 eq) in MeOH (2.0 mL), aq. NaOH solution (0.15 mmol, 1.5 mL, 5.0 eq) was added. The solution was heated at reflux for 2 h, adjusted pH to 7.0 with diluted HCl solution, extracted with EtOAc (10 mLx3). The organic layer was dried, and evaporated in vacuo to give the residue which was purified by Prep-TLC (DCM/MeOH = 20: 1) to obtain the final product as a white solid (10 mg, 80% yield). LCMS: m/z 504.9 [M+Na] +; 1H NMR (400 MHz, DMSO-d6) δ: 7.68 (d, J= 8.0 Hz, 2H), 7.32-7.26 (m, 3H), 7.12-7.07 (m, 5H), 6.94-6.90 (m, 5H), 5.49 (s, IH), 3.59 (s, 2H).
Example 41. Synthesis of 2-(6-(bis(4-fluorophenyl)(hvdroxy)methyl)-4'- (trifluoromethyl)biphenyl-3-yl)acetic acid
Figure imgf000185_0002
To a solution of methyl 2-(6-((4-fluorophenyl)(hydroxy)methyl)-4'- (trifluoromethyl)biphenyl-3-yl)acetate(10 mg, 0.02 mmol, 1.0 eq) in MeOH (2.0 mL), aq. NaOH solution (0.10 mmol, 1.0 mL, 5.0 eq) was added. The solution was heated at reflux for 2 h, adjusted pH to 7.0 with diluted HCl solution, extracted with EtOAc (10 mL x 3). The organic layer was dried with Na2SC^ and evaporated in vacuo to give the residue which was purified by Prep-TLC (DCM/MeOH = 20: 1) to obtain the final product as a white solid (7 mg, 80% yield). LCMS: m/z 480.9 [M-OH] +; 1H NMR (400 MHz, DMSO-d6) δ: 7.37 (d, J= 8.0 Hz, 2H), 7.18 (d, J= 8.0 Hz, IH), 7.11-7.07 (m, 4H), 7.01- 6.94 (m, 7H), 6.85 (d, J= 8.0 Hz, IH), 6.45 (s, IH), 3.56 (s, 2H).
Example 42. Chiral separation.
Chiral separation of diastereomers was performed using SFC technology. The following 2-step SFC separation of racemic 2-(6-((4-fluorophenyl)(piperidin-l- yl)methyl)-4'-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid (condition listed below) yielded four individual diastereomers.
Step-1 preparative method (separated diastereomer-1 and diastereomer-4 from the mixture):
Chiralpak AD-H (2x15 cm) 407301; 10% isopropanol(0.1% DEA)/CO2, 100 bar; 50 mL/min, 220 nM. Inj vol.: 0.5 mL, 20 mg/ mL methanol
Analytical method:
Chiralpak AD-H (25 x 0.46 cm)
10% isopropanol (DEA)/CO2, lOObar
3 ml/min, 254 nM
Step-2 preparative method (separated diastereomer-2 and diastereomer-3 from the remaining mixture):
Chiralpak IC (3x15 cm) 806271; 10% 1: 1 heptane: isopropanol (0.1% DEA)/CO2, 100 bar; 50 mL/min, 220 nM. Inj vol.: 0.75 mL
Analytical method:
Chiralpak IC (15 x 0.46 cm)
10% 1: 1 heptane: isopropanol (DEA)/CO2, lOObar
3 ml/min, 254 nM. Exemplary compounds in Figure 1 can be chirally separated using similar conditions by modification of solvent gradients and flow rate as necessary.
Example 43. Synthesis of (2R)-2-(6-((4-fluorophenyl)(piperidin-l-yl)methyl)-4'- (trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid
Figure imgf000187_0001
Step l
Methyl 2-(4-((4-fluorophenyl)(piperidin- 1 -yl)methyl)-3-hydroxyphenyl)acetate
Figure imgf000187_0002
A mixture of methyl 2-(3-hydroxyphenyl)acetate (10 g, 60.0 mmol, 1.0 eq), piperidine (6.66 g, 78.3 mmol, 1.3 eq) and 4-fluorobenzaldehyde (9.71 g, 78.3 mmol, 1.3 eq) were dissolved in toluene (50 mL). The mixture was heated to 115 0C for 16 h. TLC showed the reaction was completed. The solvent was removed in vacuo, and the residue was purified with a silica gel column (petroleum ether/ EtOAc = 20: 1) to give desired product as yellow oil (6.8 g, yield 33%); 1H NMR (400 MHz, CDCl3) δ: 7.34 (bs, 2H), 7.01-6.96 (m, 2H), 6.80-6.77 (m, 2H), 6.61 (d, J= 8.0 Hz, IH), 4.45 (s, IH), 3.67 (s, 3H), 3.52 (s, 2H), 2.37 (bs, 3H), 1.64-1.60 (m, 5H), 1.45(m, 2H); LCMS m/z 358.1 [M+H] +.
Step 2
Methyl 2-(4-((4-fluorophenyl)(piperidin- 1 -yl)methyl)-3- (trifluoromethylsulfonyloxy)phenyl)acetate
Figure imgf000188_0001
To a solution of methyl 2-(4-((4-fluorophenyl)(piperidin-l-yl)methyl)-3- hydroxyphenyl)acetate (2.88 g, 7.47 mmol, 1.0 eq), Et3N (0.52 mL, 3.74 mmol, 0.5 eq) in DCM (30 mL) was slowly added triflic anhydride (1.9 mL, 11.2 mmol, 1.5 eq) at 0 0C. The solution was allowed to warm to room temperature for 60 mins. The reaction mixture was than diluted with water and washed with saturated Na2CO3 solution. The organic layer was separated and dried over Na2SO^ The solvent was removed to give the desired product as a brown oil (3.6 g, yield 98%); 1B NMR (400 MHz, CDCl3) δ: 7.80 (d, J= 8.4 Hz, IH), 7.35-7.28 (m, 3H), 7.13 (s, IH), 6.97-6.92 (m, 2H), 4.59 (s, IH), 3.69 (s, 3H), 3.60 (s, 2H), 2.32-2.27 (m, 4H), 1.57-1.52 (m, 4H), 1.45-1.44 (m, 2H); LCMS m/z 489.9 [M+H] +.
Step 3
Methyl 2-(6-((4-fluorophenyl)(piperidin- 1 -yl)methyl)-4'-(trifluoromethyl)biphenyl-3- yl)acetate
Figure imgf000188_0002
To a solution of methyl 2-(4-((4-fluorophenyl)(piperidin-l-yl)methyl)-3- (trifluoromethylsulfonyloxy)phenyl)acetate (1.5 g, 3.06 mmol, 1.0 eq), 4-trifluoro- methylphenylboronic acid (0.76 g, 3.98 mmol, 1.3 eq) in DME/H2O = 4: 1 (12.5 mL) was added Na2CO3 (0.974g, 9.2 mmol, 3.0 eq). The reaction mixture was degassed and purged with nitrogen. To this was added (PPh3)2PdCl2 (0.215 g, 0.31 mmol, 0.1 eq.) and reaction heated to 70 0C for 2 h. The reaction mixture was diluted with ethyl acetate and water. The organic phase was separated and dried over Na2SC^ and concentrated. The residue was purified on a silica gel column (hexanes/ EtOAc 0-30%) to give desired product as a white foam (1.1 g, yield 67 % yield); 1H NMR (400 MHz, CDCl3) δ: 7.85 (d, J= 8.0 Hz, IH), 7.66 (d, J= 8.4 Hz, 2H), 7.33 (d, J= 8.0 Hz, IH), 7.26-7.23 (m, 2H), 6.99-6.95 (m, 3H), 6.85-6.81 (m, 2H), 4.26 (s, IH), 3.68 (s, 3H), 3.59 (s, 2H), 2.31 (bs, 2H), 2.17-2.14 (m, 2H), 1.54-1.48 (m, 4H), 1.41-1.39 (m, 2H); LCMS m/z 486.0 [M+H] +.
Step 4
2-(6-((4-fiuorophenyl)(piperidin-l-yl)methyl)-4'-(trifluoromethyl)biphenyl-3-yl)acetic acid
Figure imgf000189_0001
Methyl 2-(6-((4-fluorophenyl)(piperidin- 1 -yl)methyl)-4'-(trifluoromethyl)biphenyl-3- yl)acetate (1.06 g, 2.1 mmol, 1.0 eq.) and NaOH (247 mg, 6.2 mmol, 3.0 eq) were suspended in EtOH (10.0 mL) and water (2.0 mL). The mixture was stirred at 80 0C for 5.O h under N2 atmosphere and then neutralized with diluted HCl to pH~5. The solution was extracted with EtOAc (10 mLx3). The combined organic phase was dried over Na2SO^ and the solvent was removed in vacuo to obtain the desired compound as a white solid (1.00 g, 97 % yield); 1H NMR (400 MHz, CDCl3) δ: 8.21 (bs, IH), 7.67 (d, J= 8.0 Hz, 2H), 7.48 (d, J= 8.0 Hz, IH), 7.26-7.23 (m, 2H), 7.13-7.08 (m, 3H), 6.84-6.80 (m, 2H), 4.50 (s, IH), 3.60 (s, 2H), 2.70-2.40 (m, 2H), 1.78-1.60 (m, 4H), 1.43 (bs, 2H); LCMS m/z 472.0 [M+H] +. (4R)-4-benzyl-3-(2-(6-((4-fluorophenyl)(piperidin-l-yl)methyl)-4'- (trifluoromethyl)biphenyl-3-yl)acetyl)oxazolidin-2-one
Figure imgf000190_0001
To a solution of 2-(6-((4-fluorophenyl)(piperidin-l-yl)methyl)-4'-
(trifluoromethyl)biphenyl-3-yl)acetic acid (1.00 g, 2.1 mmol, 1.0 eq.) in anhydrous THF (20 mL) at -78 0C was added 4-methylmorpholine (NMM, 257 uL, 2.3 mmol, 1.1 eq.) and pivaloyl chloride (TMAC, 288 uL, 2.3 mmol, 1.1 eq.) under argon. The mixture was stirred at this temperature for 15 min and at 0 0C for 1.0 h, to form a mixed anhydride solution.
A solution of (i?)-4-benzyloxazolidin-2-one (414 mg, 2.3 mmol, 1.1 eq.) in dry THF (5 mL) was cooled to -78 0C, and a solution of n-BuLi (149 mg, 2.3 mmol, 1.1 eq.) in hexane (934 uL) was then added dropwise. The mixture was stirred at this temperature for 45 min. Then the chiral auxiliary reagent was added dropwise to the mixed anhydride solution at -78 0C, and stirred at 0 0C for 1.0 h. The resulting mixture was quenched with sat. aq. NH4CI solution, extracted with EtOAc (50 mLx3). The combined organic phase was washed with sat. aq. NaHCO3 solution and brine, dried over Na2SO^ The solvent was removed in vacuo to give the crude product, which was purified by column chromatography (Petroleum ether/ EtOAc = 10:1) on silica gel to obtain the desired compound as a white solid (993 mg, 74% yield). 1B NMR (400 MHz, CDCl3) δ: 7.88 (d, J= 8.0 Hz, IH), 7.66 (d, J= 8.0 Hz, 2H), 7.39 (d, J= 8.0 Hz, IH), 7.31-7.24 (m, 2H), 7.23-7.19 (m, 3H), 7.12-7.08 (m, 2H), 7.06 (bs, IH), 7.01-6.98 (m, 2H), 6.86-6.82 (m, 2H), 4.69-4.65 (m, IH), 4.33-4.22 (m, 3H), 4.21-4.13 (m, 2H), 3.23 (dd, J= 13.6, 3.2 Hz, IH), 2.78 (dd, J= 13.6, 8.8 Hz, IH), 2.38-2.28 (m, 2H), 2.21-2.15 (m, 2H), 1.55-1.48 (m, 4H), 1.43-1.36 (m, 2H); LCMS m/z 631.0 [M+H] +. Step 5
(4R)-4-benzyl-3-((2R)-2-(6-((4-fluorophenyl)(piperidin-l-yl)methyl)-4'- (trifluoromethyl)biphenyl-3-yl)-4-methylpent-4-enoyl)oxazolidin-2-one
Figure imgf000191_0001
A solution of (4R)-4-benzyl-3-(2-(6-((4-fluorophenyl)(piperidin- 1 -yl)methyl)-4'- (trifluoromethyl)biphenyl-3-yl)acetyl)oxazolidin-2-one (993 mg, 1.6 mmol, 1.0 eq.) in anhydrous THF (20 mL) was cooled to -78 0C, and a solution of NaHMDS (317 mg, 1.7 mmol, 1.1 eq.) in THF (891 uL) was then added dropwise. The resulting red solution was stirred at -78 0C for 30 min, and 3-bromo-2-methylprop-l-ene (851 mg, 6.3 mmol, 4.0 eq.) was added dropwise. When the addition was almost completed, the reaction mixture turned green. At this point, the dry-ice bath was removed and replaced with water-ice bath and stirred at 0 0C for another 30 min. The resulting mixture was quenched with sat. aq. NH4CI solution, extracted with EtOAc (20 mLx3). The combined organic phase was washed with brine, dried over Na2SO^ The solvent was removed in vacuo to give the crude product, which was purified by column chromatography (Petroleum ether/ EtOAc = 20: 1) on silica gel to give the desired compound as a white solid (443 mg, 41% yield). 1H NMR (400 MHz, CDCl3) δ: 7.82 (d, J= 8.0 Hz, IH), 7.66 (d, J= 8.0 Hz, 2H), 7.45 (d, J= 8.0 Hz, IH), 7.34-7.20 (m, 7H), 7.10 (dd, J= 8.0, 2.0 Hz, IH), 7.00-6.95 (m, 2H), 6.87-6.82 (m, 2H), 5.46-5.40 (m, IH), 4.77 (d, J= 12.0 Hz, 2H), 4.64-4.60 (m, IH), 4.25 (d, J= 4.0 Hz, IH), 4.09-4.07 (m, 2H), 3.29 (dd, J= 13.6, 3.2 Hz, IH), 3.01 (dd, J= 14.4, 10.4 Hz, IH), 2.70 (dd, J= 13.6, 10.0 Hz, IH), 2.38 (dd, J= 14.4, 4.8 Hz, IH), 2.35-2.25 (m, 2H), 2.20-2.12 (m, 2H), 1.78 (s, 3H), 1.55-1.48 (m, 4H), 1.43-1.36 (m, 2H); LCMS m/z 685.0 [M+H] +.
Step 6 (4R)-4-benzyl-3-((2R)-2-(6-((4-fluorophenyl)(piperidin-l-yl)methyl)-4'- (trifluoromethyl)biphenyl-3-yl)-4-methylpentanoyl)oxazolidin-2-one
Figure imgf000192_0001
A solution of (4R)-4-benzyl-3-((2R)-2-(6-((4-fluorophenyl)(piperidin- 1 -yl)methyl)-4'- (trifluoromethyl)biphenyl-3-yl)-4-methylpent-4-enoyl)oxazolidin-2-one (400 mg, 0.59 mmol, 1.0 eq.) in MeOH (10 mL) was degassed for 10 min, and then flushed with N2 for 3 times. Pd/C (40 mg, 10% w/w) was then added, and the system was flushed with H2 for 3 times and stirred at r.t. overnight. The resulting mixture was filtered, and the filtrate was evaporated in vacuo to give the crude product, which was purified by column chromatography (Petroleum ether/ EtOAc = 40:1) on silica gel to give the desired compound as a white solid (200 mg, 50% yield). 1H NMR (400 MHz, CDCl3) δ: 7.80 (d, J= 8.0 Hz, IH), 7.66 (d, J= 8.0 Hz, 2H), 7.42 (dd, J= 8.4, 2.0 Hz, IH), 7.34-7.20 (m, 7H), 7.08 (dd, J= 8.0, 2.0 Hz, IH), 7.00-6.95 (m, 2H), 6.87-6.82 (m, 2H), 5.23-5.19 (m, IH), 4.63-4.60 (m, IH), 4.25 (d, J= 4.0 Hz, IH), 4.11-4.08 (m, 2H), 3.34 (dd, J= 13.2, 3.6 Hz, IH), 2.74 (dd, J= 13.2, 10.0 Hz, IH), 2.32-2.26 (m, 2H), 2.20-2.10 (m, 3H), 1.66-1.60 (m, IH), 1.55-1.50 (m, 5H), 1.43-1.36 (m, 2H), 0.93 (d, J= 6.8 Hz, 6H); LCMS m/z 687.0 [M+H] +;
Step 6
(2R)-2-(6-((4-fluorophenyl)(piperidin-l-yl)methyl)-4'-(trifluoromethyl)biphenyl-3-yl)-4- methylpentanoic acid
Figure imgf000192_0002
A solution of (4R)-4-benzyl-3-((2R)-2-(6-((4-fluorophenyl)(piperidin- 1 -yl)methyl)-4'- (trifluoromethyl)biphenyl-3-yl)-4-methylpentanoyl)oxazolidin-2-one (161 mg, 0.24 mmol, 1.0 eq.) and LiOH (6 mg, 0.24 mmol, 1.0 eq.) in THF (6 mL) and water (2 mL) was cooled to 0 0C, and 30% H2O2 (89 uL, 0.94 mmol, 4.0 eq.) were added dropwise. The mixture was stirred at 0 0C for 15 min, quenched with excess sat. aq. Na2SO3 solution, stirred at r.t. for another 30 min. The pH was adjusted to 6-7 with IN HCl. The mixture was extracted with EtOAc (10 mLx3). The combined organic phase was washed with brine, dried over Na2SO^ The solvent was removed in vacuo to give the crude product, which was purified by column chromatography (Petroleum ether/ EtOAc = 2: 1) on silica gel to yield the final product as a white solid (100 mg, 80% yield). 1H NMR (400 MHz, DMSO-de) δ: 7.83 (d, J= 8.0 Hz, 2H), 7.73 (dd, J= 8.0, 3.2 Hz, IH), 7.40-7.36 (m, 3H), 7.03-7.00 (m, 5H), 4.27 (s, IH), 3.58-3.55 (m, IH), 2.28-2.18 (m, 2H), 2.17-2.08 (m, 2H), 1.90-1.83 (m, IH), 1.50-1.35 (m, 8H), 0.84 (d, J= 6.4 Hz, 6H); LCMS m/z 528.0 [M+H] +; LCMS m/z 528.0 [M+H] +. The stereoselectivity at the target chiral center was determined using chiral HPLC to be > 98% for the desired chirality. Column: RegisPack 783104; Mobile phase: Heptane/IP A/Ethanol (94%:5%:1%, v/v) + 0.1% v/v TFA; flowrate: 1 mL/min.
Example 44. Synthesis of 2-(6-((4-fluorophenyl)(piperidin-l-yl)methyl)-4'- (trifluoromethyl)biphenyl-3-yl)propanoic acid:
Step l
Methyl 2-(6-((4-fluorophenyl)(piperidin- 1 -yl)methyl)-4'- (trifluoromethyl)biphenyl-3-yl)acrylate:
Figure imgf000194_0001
To a solution of methyl 2-(6-((4-fluorophenyl)(piperidin-l-yl)methyl)-4'- (trifluoromethyl)biphenyl-3-yl)acetate (0.31 g, 0.64 mmol, step 3, Example 43) in toluene (6 mL) were added paraformaldehyde (0.22 g), cesium carbonate (0.85 g, 2.6 mmol) and tris(2-(2-methoxyethoxy)ethyl)amine (20 mg, 0.064 mmol). The reaction was heated at 85 0C for 2 h. Upon completion, the reaction was cooled to room temperature and diluted with ethyl acetate (50 mL). The mixture was washed with water (20 mL). The organic layer was separated, washed with saturated brine (3 x 20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography on silica (ethyl acetate in heptane 0-30%) to collect methyl 2-(6-((4-fluorophenyl)(piperidin- 1 -yl)methyl)-4'-(trifluoromethyl)biphenyl-3- yl)acrylate (0.13 g, 41% yield). 1H NMR (300MHz ,CDCl3) δ = 7.90 (d, J = 8.1 Hz, 1 H), 7.66 (d, J = 7.8 Hz, 2 H), 7.49 (dd, J = 8.4 Hz, 2.1 Hz, 1 H), 7.31 - 7.24 (m, 2 H), 7.16 (d, J = 1.8 Hz, IH), 7.0 - 6.8 (m, 4 H), 6.32 (d, J = 0.9 Hz, 1 H), 5.91 (d, J = 1.2 Hz, I H), 4.28 (s, 1 H), 3.80 (s, 3 H), 2.36-2.14 (m, 4 H), 1.56 - 1.40 (m, 6 H); LCMS m/z 498.0 [M+ 1]+.
Step 2 (Method one)
2-(6-((4-Fluorophenyl)(piperidin-l-yl)methyl)-4'-(trifluoromethyl)biphenyl-3- yl)acrylic acid:
Figure imgf000194_0002
To a solution of methyl 2-(6-((4-fluorophenyl)(piperidin-l-yl)methyl)-4'- (trifluoromethyl)biphenyl-3-yl)acrylate (0.13 g, 0.26 mmol) in THF (10 mL) was added potassium trimethylsilanolate (40 mg, 0.31 mmol). The reaction was heated to reflux for 3 h. Upon completion, the reaction was diluted with ethyl acetate (50 mL) and water (20 mL). The pH value of the aqueous phase was adjusted to 5-6 with 0.1 N HCl. The organic layer was separated, washed with saturated brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography on silica (ethyl acetate in heptane 5-30%) to collect 2-(6-((4-fiuorophenyl)(piperidin- 1 -yl)methyl)-4'-(trifluoromethyl)biphenyl-3- yl)acrylic acid (70 mg, 56% yield).
Step 2 (Method two)
2-(6-((4-Fluorophenyl)(piperidin-l-yl)methyl)-4'-(trifluoromethyl)biphenyl-3- yl)acrylic acid:
To a solution of methyl 2-(6-((4-fluorophenyl)(piperidin-l-yl)methyl)-4'- (trifluoromethyl)biphenyl-3-yl)acrylate (0.27 g, 0.54 mmol) in THF (10 mL) and water (2 mL) was added an aqueous 2N LiOH solution (0.6 mL, 1.2 mmol). The reaction was allowed to stir at room temperature overnight. Additional 2N LiOH solution (0.6 mL, 1.2 mmol) was added and the reaction was allowed to stir at room temperature for another 16 h. Upon completion, the reaction was diluted with ethyl acetate (50 mL). The pH value of the aqueous phase was adjusted to 5-6 with 0.1 N HCl. The organic layer was separated, washed with saturated brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography on silica (ethyl acetate in heptane 5-30%) to collect 2-(6-((4- fluorophenyl)(piperidin- 1 -yl)methyl)-4'-(trifluoromethyl)biphenyl-3-yl)acrylic acid (0.17 g, 65% yield). 1H NMR (300MHz ,CDCl3) δ = 8.07 (d, J = 8.4 Hz, 1 H), 7.70 (d, J = 8.4 Hz, 2 H), 7.60 (dd, J = 8.1 Hz, 2.1 Hz, 1 H), 7.28 - 7.06 (m, 5 H), 6.89- 6.83 (m, 2 H), 6.34 (d, J = 0.9 Hz, 1 H), 6.34 (bs, 1 H), 5.88 (d, J = 0.9 Hz, 1 H), 4.45 (s, 1 H), 2.53-2.39 (m, 4 H), 1.67 - 1.43 (m, 6 H); LCMS m/z 484.2 [M+ 1]+.
Step 3
(2R)-2-(6-((4-fluorophenyl)(piperidin-l-yl)methyl)-4'-(trifluoromethyl)biphenyl- 3-yl)propanoic acid:
Figure imgf000196_0001
A mixture of 2-(6-((4-fluorophenyl)(piperidin- 1 -yl)methyl)-4'-(trifluoromethyl)biphenyl- 3-yl)acrylic acid (70 mg, 0.14 mmol) and Diacetato[(R)-(+)-2,2'-bis(diphenylphosphino)- 5,5',6,6',7,7',8,8'-octahydro-l,l '-binaphthyl]ruthenium(II) (7 mg, 0.008 mmol) in methanol (20 mL) was hydrogenated @ 60 psi for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure. The resulting crude product was purified by flash chromatography on silica (ethyl acetate in heptane 0-30%) to collect 2- (6-((4-fluorophenyl)(piperidin-l-yl)methyl)-4'-(trifiuoromethyl)biphenyl-3-yl)propanoic acid (57 mg, 81% yield). 1H NMR (300MHz ,CDCl3) δ = 7.89 (m, 1 H), 7.67 (d, J = 8.4 Hz, 2 H), 7.45 (dd, J = 8.1 Hz, 2.1 Hz, 1 H), 7.29 - 7.21 (m, 2 H), 7.03 - 6.68 (m, 5 H), 4.31 (s, 1 H), 3.75 (m, 1 H), 2.40-2.05 (m, 4 H), 1.60 - 1.26 (m, 9 H); LCMS m/z 486.0 [M+ 1]+. The stereoselectivity at the target chiral center was determined using chiral HPLC to be > 95% for the desired chirality. Column: Diacel Chiralpak AD-H; Mobile phase: n-Hexane/IPA/Ethanol (90%:9%:l%, v/v) + 0.2% v/v TFA + 0.1% v/v TEA; flowrate: 0.3 mL/min.
Exemplary compounds in Figure 1 can be chirally separated using similar conditions by modification of solvent gradients and flow rate as necessary.
The phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of "including," "comprising," or "having," "containing," "involving," and variations thereof herein, is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.
Having thus described several aspects of at least one embodiment of this invention, it is to be appreciated various alterations, modifications, and improvements will readily occur to those skilled in the art. Such alterations, modifications, and improvements are intended to be part of this disclosure, and are intended to be within the spirit and scope of the invention. Accordingly, the foregoing description and drawings are by way of example only.

Claims

Claims
1. A compound of formula (I):
Figure imgf000198_0001
wherein: m is 0, 1 , 2, 3 or 4; n is 0, 1 or 2;
W is -COOH or a carboxylic acid mimic or bioisostere;
Z is N, NR16, CR17 Or CR18R19; each R1 and R2 is independently H, Ci-C6 alkyl, C2-C6 alkenyl, halo, haloalkyl, Ci-C6 alkoxy, eye IyI or cyclylalkyl; or R1 and R2, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring; wherein either R1 or R2 are optionally taken together with R8a or R9ato form an optionally substituted, saturated or unsaturated 3-7 membered ring;
A is a bond, NR10, O, S, alkylenyl, amide, ester, carbamate, urea, thiourea or sulfonylurea;
B is N or O;
R3 is aryl, heteroaryl, cyclyl or heterocyclyl, each of which is optionally substituted with 1-3 R11; each R4 and R5 is independently H, Ci-Cs alkyl, haloalkyl, cyclyl, cyclylalkyl, aryl or heteroaryl, each of which is optionally substituted with 1-3 R12; or R4 and R5, together with the carbon to which they are attached, may form a 3-7 membered ring that is optionally saturated or unsaturated, and unsubstituted or substituted; R6 and R7 are each independently H, Ci-Cs alkyl, cyclyl, aryl, heteroaryl, cyclylalkyl or arylalkyl, each of which is optionally substituted with 1-3 R13; wherein when B is O, R7 is absent; wherein when B is N, R6 and R7, together with the nitrogen to which they are attached, may form a 3-7 membered ring that is optionally saturated or unsaturated, and unsubstituted or substituted with 1-3 R14; and wherein R4 and R6, together with the atoms to which they are attached, may form a 3-7 membered ring ring that is optionally saturated or unsaturated, and unsubstituted or substituted with 1-3 R 5;
R8a, R8b, R9a and R9b are each independently H, Ci-C6 alkyl, hydroxy, halo, haloalkyl, or CN;
R10 is hydrogen, Ci-C6 alkyl or haloalkyl; each R11, R12, R13, R14 and R15 is independently Ci-C6 alkyl, Ci-C6 alkenyl, Ci-C6 alkynyl, halo, haloalkyl, alkoxy, haloalkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, arylalkyl, hetero arylalkyl, cyclylalkyl, heterocyclylalkyl, carboxylate, cyano, oxo, nitro, amino, alkylamino, dialkylamino, mercapto, thioalkyl, aryloxy, thioalkoxy, amido, SO3H, sulfate, S(O)NH2, S(O)2NH2, phosphate or acyl, each of which is optionally substituted; wherein two R11, R12, R13, R14 or R15, together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring; and each R16, R17, R18, and R19 is independently H, Ci-C6 alkyl, hydroxy, halo, haloalkyl or CN; each independently represents the presence or absence of a bond; wherein when represents the presence of a bond to the carbon to which R8b is attached, R8b is absent; and wherein when represents the presence of a bond to the carbon to which
R9b is attached, R9b is absent; and wherein when represents the presence of a bond to
Z, then Z is N or CR17; or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, tautomer, enantiomer, stereoisomer, analog or derivative thereof, including mixtures thereof in any ratios.
2. The compound of claim 1 , wherein the compound has the following formula:
Figure imgf000200_0001
3. The compound of claim 1 , wherein the compound has the following formula:
Figure imgf000200_0002
4. The compound of claim 1 , wherein the compound has the following formula:
Figure imgf000200_0003
5. The compound of claim 1 , wherein the compound has the following formula:
Figure imgf000201_0001
6. The compound of claim 1 , wherein the compound has the following formula:
Figure imgf000201_0002
7. The compound of claim 1 , wherein the compound has the following formula:
Figure imgf000201_0003
8. A compound of formula (II):
Figure imgf000202_0001
wherein: m is O, 1, 2, 3 or 4; n is O, 1 or 2;
W is -COOH, or a carboxylic acid mimic or bioisostere;
Z is N or CH; each R1 and R2 is independently H, Ci-C6 alkyl, C2-C6 alkenyl, halo, haloalkyl, Ci-C6 alkoxy, eye IyI or cyclylalkyl; or R1 and R2, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring; wherein either R1 or R2 is optionally taken together with R8a or R8b to form an optionally substituted, saturated or unsaturated 3-7 membered ring;
A is a bond, NR10, O, S, alkylenyl, amide, ester, carbamate, urea, thiourea or sulfonylurea;
R is aryl, heteroaryl, cyclyl or heterocyclyl, each of which is optionally substituted with 1-3 R11; each R and R is independently H, Ci-Cs alkyl, haloalkyl, cyclyl, cyclylalkyl, aryl or heteroaryl, each of which is optionally substituted with 1-3 R ; or R and R , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring;
R6 and R7, together with the nitrogen to which they are attached, form a 3-7 membered ring that is optionally saturated or unsaturated, and substituted or unsubstituted with 1-3 R14; each R8a, R8b, R9a and R9b is independently H, Ci-C6 alkyl, hydroxy, halo, haloalkyl, or CN; R10 is hydrogen, Ci-C6 alkyl or haloalkyl; and each R11, R12, and R14 is independently selected Ci-C6 alkyl, Ci-C6 alkenyl, Ci-C6 alkynyl, halo, haloalkyl, alkoxy, haloalkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, carboxylate, cyano, oxo, nitro, amino, alkylamino, dialkylamino, mercapto, thioalkyl, aryloxy, thioalkoxy, amido, SO3H, sulfate, S(O)NH2, S(O)2NH2, phosphate, and acyl, each of which is optionally substituted; wherein two R , R , or R , together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring; wherein -A-R3 and -(CR4R5)mNR6R7 are each positioned at one of Z, R8a, R8b, R9a or R9b, or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, tautomer, enantiomer, stereoisomer, analog or derivative thereof, including mixtures thereof in any ratios.
9. The compound of claim 8, wherein the compound has the following formula:
Figure imgf000203_0001
10. The compound of claim 8, wherein the compound has the following formula:
Figure imgf000204_0001
11. The compound of claim 8, wherein the compound has the following formula:
Figure imgf000204_0002
12. The compound of claim 11 , wherein W is -COOH; n is O or 1 ; R4 and R5 are independently H, Ci-C6 alkyl or haloalkyl; s is 1 or 2; u is O or 1; and t is 1.
13. The compound of claim 11, wherein W is -COOH; n is 1; each R and R are independently H or Ci-C6 alkyl; R and R5 are each independently H, aryl or heteroaryl; each R is independently Ci-C6 alkyl, halo or haloalkyl; R is methyl, ethyl, halomethyl or haloethyl; s is 1 or 2; u is O or 1 and t is 1.
14. The compound of claim 8, wherein the compound has the following formula:
Figure imgf000205_0001
15. The compound of claim 8, wherein the compound is:
)s
Figure imgf000205_0002
16. A compound of formula (III) :
Figure imgf000205_0003
wherein: m is 0, 1, 2, 3 or 4; n is 0, 1 or 2;
W is -COOH, or a carboxylic acid mimic or bioisostere; each R and R is independently H, Ci-C6 alkyl, C2-C6 alkenyl, halo, haloalkyl, Ci-C6 alkoxy, eye IyI or cyclylalkyl; or R and R , together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring; wherein either R or R is optionally taken together with R or R to form an optionally substituted, saturated or unsaturated 3-7 membered ring;
A is a bond, NR10, O, S, alkylenyl, amide, ester, carbamate, urea, thiourea or sulfonylurea;
R is aryl, heteroaryl, cyclyl or heterocyclyl, each of which is optionally substituted with 1-3 R11; each R4 and R5 is independently H, Ci-Cs alkyl, haloalkyl, cyclyl, cyclylalkyl, aryl or heteroaryl, each of which is optionally substituted with 1-3 R12; or R4 and R5, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring;
Y is a heterocyclic ring;
R8 and R9 are each independently H, Ci-C6 alkyl, hydroxy, halo, haloalkyl, or CN;
R10 is hydrogen, Ci-C6 alkyl or haloalkyl; and each R11 and R12 is independently Ci-C6 alkyl, Ci-C6 alkenyl, Ci-C6 alkynyl, halo, haloalkyl, alkoxy, haloalkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, carboxylate, cyano, oxo, nitro, amino, alkylamino, dialkylamino, mercapto, thioalkyl, aryloxy, thioalkoxy, amido, SO3H, sulfate, S(O)NH2, S(O)2NH2, phosphate or acyl, each of which is optionally substituted; wherein two R or R , together with the atoms to which they are attached, may form a 3- 7 membered, saturated or unsaturated, and optionally substituted ring, or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, tautomer, enantiomer, stereoisomer, analog or derivative thereof, including mixtures thereof in any ratios.
17. A compound of formula (IV) :
Figure imgf000207_0001
wherein: m is 0, 1, 2, 3 or 4; n is 0, 1 or 2;
W is -COOH , or a carboxylic acid mimic or bioisostere; each R1 and R2 is independently H, Ci-C6 alkyl, C2-C6 alkenyl, halo, haloalkyl, Ci-C6 alkoxy, eye IyI or cyclylalkyl; or R1 and R2, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring;
A is a bond, NR10, O, S, alkylenyl, amide, ester, carbamate, urea, thiourea or sulfonylurea;
B is N or O;
R3 is aryl, heteroaryl, cyclyl or heterocyclyl, each of which is optionally substituted with 1-3 R11; each R4 and R5 is independently H, Ci-Cs alkyl, haloalkyl, cyclyl, cyclylalkyl, aryl or heteroaryl, each of which is optionally substituted with 1-3 R12; or R4 and R5, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring;
R6 and R7 are each independently H, Ci-Cs alkyl, cyclyl, aryl, heteroaryl, cyclylalkyl or arylalkyl, each of which is optionally substituted with 1-3 R13; wherein when B is O, R7 is absent; wherein when B is N, R6 and R7, together with the nitrogen to which they are attached, may form a ring that is optionally substituted with 1-3 R14; and wherein R4 and R6, together with the atoms to which they are attached, optionally form ring that is optionally substituted with 1-3 R15;
R10 is hydrogen, Ci-C6 alkyl or haloalkyl; and each R11, R12, R13, R14 and R15 is independently Ci-C6 alkyl, Ci-C6 alkenyl, Ci-C6 alkynyl, halo, haloalkyl, alkoxy, haloalkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, arylalkyl, heteroarylalkyl, cyclylalkyl, heterocyclylalkyl, carboxylate, cyano, oxo, nitro, amino, alkylamino, dialkylamino, mercapto, thioalkyl, aryloxy, thioalkoxy, amido, SO3H, sulfate, S(O)NH2, S(O)2NH2, phosphate or acyl, each of which is optionally substituted; wherein two R11, R12, R13, R14 or R15, together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring, or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, tautomer, enantiomer, stereoisomer, analog or derivative thereof, including mixtures thereof in any ratios.
18. A compound of formula (V):
Figure imgf000208_0001
wherein: m is O, 1, 2, 3 or 4; n is 0, 1 or 2;
W is -COOH, or a carboxylic acid mimic or bioisostere; Z is N or CH; each R1 and R2 is independently H, Ci-C6 alkyl, C2-C6 alkenyl, halo, haloalkyl, Ci-C6 alkoxy, eye IyI or cyclylalkyl; or R1 and R2, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring; wherein either R1 or R2 are optionally taken together with R8 or R9 to form an optionally substituted, saturated or unsaturated 3-7 membered ring;
A is a bond, NR10, O, S, alkylenyl, amide, ester, carbamate, urea, thiourea or sulfonylurea;
B is N or O;
R is aryl, heteroaryl, cyclyl or heterocyclyl, each of which is optionally substituted with 1-3 R11; each R4 and R5 is independently H, Ci-Cs alkyl, haloalkyl, cyclyl, cyclylalkyl, aryl or heteroaryl, each of which is optionally substituted with 1-3 R12; or R4 and R5, together with the carbon to which they are attached, may form an optionally substituted, saturated or unsaturated 3-7 membered ring;
R6 and R7 are each independently H, Ci-Cs alkyl, cyclyl, aryl, heteroaryl, cyclylalkyl or arylalkyl, each of which is optionally substituted with 1 -3 R ; wherein when B is O, R7 is absent; wherein when B is N, R and R7, together with the nitrogen to which they are attached, may form a ring that is optionally substituted with 1 -3 R ; and wherein R and R , together with the atoms to which they are attached, optionally form ring that is optionally substituted with 1-3 R 5;
R8 and R9 are each independently H, Ci-C6 alkyl, hydroxy, halo, haloalkyl, or CN;
R10 is hydrogen, Ci-C6 alkyl or haloalkyl; and each R11, R12, R13, R14 and R15 is independently selected Ci-C6 alkyl, Ci-C6 alkenyl, Ci-C6 alkynyl, halo, haloalkyl, alkoxy, haloalkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, hydroxy, arylalkyl, hetero arylalkyl, cyclylalkyl, heterocyclylalkyl, carboxylate, cyano, oxo, nitro, amino, alkylamino, dialkylamino, mercapto, thioalkyl, aryloxy, thioalkoxy, amido, SO3H, sulfate, S(O)NH2, S(O)2NH2, phosphate, and acyl, each of which is optionally substituted; wherein two R11, R12, R13, R14 or R15, together with the atoms to which they are attached, may form a 3-7 membered, saturated or unsaturated, and optionally substituted ring, or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, tautomer, enantiomer, stereoisomer, analog or derivative thereof, including mixtures thereof in any ratios.
19. A pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, tautomer, enantiomer, stereoisomer, analog or derivative thereof, including mixtures thereof in any ratios, and a pharmaceutically acceptable carrier.
20. A method of modulating gamma-secretase activity in a subject, the method comprising administering to the subject a compound or pharmaceutical composition described herein.
21. A method of treating a disorder associated with elevated Aβ levels in a subject, the method comprising administering to the subject a compound or pharmaceutical composition described herein.
22. A method of reducing the levels of Aβ in a subject, the method comprising administering to the subject a compound or pharmaceutical composition described herein.
23. A method of reducing the deposition of Aβ in a subject, the method comprising administering to the subject a compound or pharmaceutical composition described herein.
24. A method of treating a neurodegenerative disorder in a subject, the method comprising administering to the subject a compound or pharmaceutical composition described herein.
25. A method of treating Alzheimer's disease in a subject, the method comprising administering to the subject a compound or pharmaceutical composition described herein.
26. A method of treating a subject at risk for developing Alzheimer's disease, the method comprising administering to the subject a compound or pharmaceutical composition described herein.
27. A method of delaying the progression of Alzheimer's disease in a subject, the method comprising administering to the subject a compound or pharmaceutical composition described herein.
28. A method of delaying the onset of Alzheimer's disease in a subject, the method comprising administering to the subject a compound or pharmaceutical composition described herein.
29. A method of improving cognitive function in a subject, the method comprising administering to the subject a compound or pharmaceutical composition described herein.
30. The method of any one of claims 20-29, wherein the compound or pharmaceutical composition described herein is administered in combination with an additional therapeutic agent.
31. The method of claim 30, wherein the additional therapeutic agent is a cholinesterase inhibitor.
32. The method of claim 30, wherein the additional therapeutic agent is selected from the group consisting of donepezil, rivastigmine, galantamine and tacrine.
33. The method of claim 30, wherein the additional therapeutic agent is an N-methyl- D-aspartate (NMDA) receptor modulator.
34. The method of claim 30, wherein the additional therapeutic agent is memantine.
35. A compound selected from the group consisting of
2-(6-((3,5-dimethylpiperidin-l-yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl- methylpentanoic acid;
2-(6-((4-fluorophenyl)(6-azaspiro[2.5]octan-6-yl)methyl)-4'-(trifluoromethyl)biphenyl-2 methylpentanoic acid;
2-(6-((4-fluorophenyl)(piperidin-l-yl)methyl)-5-(4-(trifluoromethyl)phenyl)pyridin-3-y] methylpentanoic acid;
2-(6-((3,3-dimethylpiperidin-l-yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl- methylpentanoic acid;
2-(6-((4-fluorophenyl)(hexahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl)-4'-(trifluoromet 4-methylpentanoic acid;
2-(3'-fluoro-6-((4-fluorophenyl)(piperidin-l-yl)methyl)-4'-(trifluoromethyl)biphenyl-3-> methylpentanoic acid;
2-(6-((3,3-difluoropiperidin-l-yl)(4-fiuorophenyl)methyl)-4'-(trifluoromethyl)biphenyl-. methylpentanoic acid;
2-(6-((4-fluorophenyl)(5-azaspiro[2.5]octan-5-yl)methyl)-4'-(trifluoromethyl)biphenyl-2 methylpentanoic acid;
4-methyl-2-(3',4',5'-trifluoro-6-((4-fiuorophenyl)(piperidin-l-yl)methyl)biphenyl-3-yl)p( 2-(6-((4-fluorophenyl)(4-(trifluoromethyl)piperidin-l-yl)methyl)-4'-(trifiuoromethyl)bip methylpentanoic acid;
2-(6-(3-azabicyclo[3.2.1]octan-3-yl(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphen}' methylpentanoic acid;
2-(6-((3,3-difluoropyrrolidin-l-yl)(4-fiuorophenyl)methyl)-4'-(trifluoromethyl)biphenyl methylpentanoic acid;
2-(6-((4,4-difluoropiperidin-l-yl)(4-fiuorophenyl)methyl)-4'-(trifluoromethyl)biphenyl-. methylpentanoic acid; 2-(6-((3,4-difluorophenyl)(piperidin-l-yl)methyl)-4'-(trifluoromethyl)biphenyl-3-yl)-4-r acid;
2-(6-((3,3-dimethylpyrrolidin-l-yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)bipheny methylpentanoic acid;
2-(6-((3,5-dimethylpiperidin-l-yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl- 2-(6-((4-fluorophenyl)(6-azaspiro[2.5]octan-6-yl)methyl)-4'-(trifluoromethyl)biphenyl-2 2-(6-((4-fluorophenyl)(piperidin-l-yl)methyl)-5-(4-(trifluoromethyl)phenyl)pyridin-3-y]
2-(6-((3,3-dimethylpiperidin-l-yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl- 2-(6-((4-fluorophenyl)(hexahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl)-4'-(trifluoromet yl)butanoic acid;
2-(3'-fluoro-6-((4-fluorophenyl)(piperidin-l-yl)methyl)-4'-(trifluoromethyl)biphenyl-3-> 2-(6-((3,3-difluoropiperidin-l-yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl-. 2-(6-((4-fluorophenyl)(5-azaspiro[2.5]octan-5-yl)methyl)-4'-(trifluoromethyl)biphenyl-2 2-(3',4',5'-trifluoro-6-((4-fluorophenyl)(piperidin- 1 -yl)methyl)biphenyl-3-yl)butanoic ac
2-(6-((3,3-difluoropiperidin-l-yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl-.
2-(6-(3-azabicyclo[3.2.1]octan-3-yl(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphen}' acid;
2-(6-((3,3-difluoropyrrolidin-l-yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl acid;
2-(6-((4,4-difluoropiperidin-l-yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl-.
2-(6-((3,4-difluorophenyl)(piperidin-l-yl)methyl)-4'-(trifluoromethyl)biphenyl-3-yl)buti 2-(6-((3,3-dimethylpyrrolidin-l-yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)bipheny acid;
3-cyclopropyl-2-(6-((3,5-dimethylpiperidin-l-yl)(4-fluorophenyl)methyl)-4'-(trifluorom yl)propanoic acid;
3-cyclopropyl-2-(6-((4-fluorophenyl)(6-azaspiro[2.5]octan-6-yl)methyl)-4'-(trifluoromei yl)propanoic acid;
3-cyclopropyl-2-(6-((4-fluorophenyl)(piperidin-l-yl)methyl)-5-(4-(trifluoromethyl)pheπ yl)propanoic acid;
3-cyclopropyl-2-(6-((3,3-dimethylpiperidin-l-yl)(4-fluorophenyl)methyl)-4'-(trifluorom yl)propanoic acid;
3-cyclopropyl-2-(6-((4-fluorophenyl)(hexahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl)-z (trifluoromethyl)biphenyl-3-yl)propanoic acid; 3-cyclopropyl-2-(3'-fluoro-6-((4-fluorophenyl)(piperidin-l-yl)methyl)-4'-(trifluorometh; yl)propanoic acid;
3-cyclopropyl-2-(6-((3,3-difluoropiperidin-l-yl)(4-fluorophenyl)methyl)-4'-(trifluorome yl)propanoic acid;
3-cyclopropyl-2-(6-((4-fluorophenyl)(5-azaspiro[2.5]octan-5-yl)methyl)-4'-(trifluoromei yl)propanoic acid;
3-cyclopropyl-2-(3',4',5'-trifluoro-6-((4-fluorophenyl)(piperidin-l-yl)methyl)biphenyl-3
3-cyclopropyl-2-(6-((4-fluorophenyl)(4-(trifluoromethyl)piperidin-l-yl)methyl)-4'-
(trifluoromethyl)biphenyl-3-yl)propanoic acid;
2-(6-(3-azabicyclo[3.2.1]octan-3-yl(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphen}' cyclopropylpropanoic acid;
3-cyclopropyl-2-(6-((3,3-difluoropyrrolidin-l-yl)(4-fluorophenyl)methyl)-4'-(trifluorom yl)propanoic acid;
3-cyclopropyl-2-(6-((4,4-difluoropiperidin-l-yl)(4-fluorophenyl)methyl)-4'-(trifluorome yl)propanoic acid;
3-cyclopropyl-2-(6-((3,4-difluorophenyl)(piperidin-l-yl)methyl)-4'-(trifluoromethyl)bip yl)propanoic acid;
3-cyclopropyl-2-(6-((3,3-dimethylpyrrolidin-l-yl)(4-fluorophenyl)methyl)-4'-(trifluoroπ yl)propanoic acid;
1 -(6-((3,5-dimethylpiperidin- 1 -yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl- yl)cyclopentanecarboxylic acid; l-(6-((4-fluorophenyl)(6-azaspiro[2.5]octan-6-yl)methyl)-4'-(trifluoromethyl)biphenyl-2 yl)cyclopentanecarboxylic acid;
1 -(6-((4-fluorophenyl)(piperidin- 1 -yl)methyl)-5-(4-(trifluoromethyl)phenyl)pyridin-3- yl)cyclopentanecarboxylic acid;
1 -(6-((3,3-dimethylpiperidin- 1 -yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl- yl)cyclopentanecarboxylic acid; l-(6-((4-fluorophenyl)(hexahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl)-4'-(trifluoromet yl)cyclopentanecarboxylic acid;
1 -(3'-fluoro-6-((4-fluorophenyl)(piperidin- 1 -yl)methyl)-4'-(trifluoromethyl)biphenyl-3- yl)cyclopentanecarboxylic acid;
1 -(6-((3,3-difluoropiperidin- 1 -yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl-. yl)cyclopentanecarboxylic acid; l-(6-((4-fluorophenyl)(5-azaspiro[2.5]octan-5-yl)methyl)-4'-(trifluoromethyl)biphenyl-2 yl)cyclopentanecarboxylic acid;
1 -(3',4',5'-trifluoro-6-((4-fluorophenyl)(piperidin- 1 -yl)methyl)biphenyl-3-yl)cyclopentai 1 -(6-((4,4-difluoropiperidin- 1 -yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl-. yl)cyclopentanecarboxylic acid;
1 -(6-((4-fluorophenyl)(4-(trifluoromethyl)piperidin- 1 -yl)methyl)-4'-(trifluoromethyl)bip yl)cyclopentanecarboxylic acid; 1 -(6-((3,3-difluoropyrrolidin- 1 -yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl yl)cyclopentanecarboxylic acid;
1 -(6-((4,4-difluoropiperidin- 1 -yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl-; yl)cyclopentanecarboxylic acid;
1 -(6-((3,4-difluorophenyl)(piperidin- 1 -yl)methyl)-4'-(trifluoromethyl)biphenyl-3- yl)cyclopentanecarboxylic acid;
1 -(6-((3,3-dimethylpyrrolidin- 1 -yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)bipheny yl)cyclopentanecarboxylic acid;
1 -(6-((3,5-dimethylpiperidin- 1 -yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl- yl)cyclobutanecarboxylic acid; l-(6-((4-fluorophenyl)(6-azaspiro[2.5]octan-6-yl)methyl)-4'-(trifluoromethyl)biphenyl-2 yl)cyclobutanecarboxylic acid;
1 -(6-((4-fluorophenyl)(piperidin- 1 -yl)methyl)-5-(4-(trifluoromethyl)phenyl)pyridin-3- yl)cyclobutanecarboxylic acid;
1 -(6-((3,3-dimethylpiperidin- 1 -yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl- yl)cyclobutanecarboxylic acid;
1 -(6-((4-fluorophenyl)(hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)methyl)-4'-(trifluoromet yl)cyclobutanecarboxylic acid;
1 -(3'-fluoro-6-((4-fluorophenyl)(piperidin- 1 -yl)methyl)-4'-(trifluoromethyl)biphenyl-3- yl)cyclobutanecarboxylic acid;
1 -(6-((3,3-difluoropiperidin- 1 -yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl-; yl)cyclobutanecarboxylic acid; l-(6-((4-fluorophenyl)(5-azaspiro[2.5]octan-5-yl)methyl)-4'-(trifluoromethyl)biphenyl-2 yl)cyclobutanecarboxylic acid;
1 -(3',4',5'-trifluoro-6-((4-fluorophenyl)(piperidin- 1 -yl)methyl)biphenyl-3-yl)cyclobutans
1 -(6-((4-fluorophenyl)(4-(trifluoromethyl)piperidin- 1 -yl)methyl)-4'-(trifluoromethyl)bip yl)cyclobutanecarboxylic acid; l-(6-(3-azabicyclo[3.2.1]octan-3-yl(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphen}' yl)cyclobutanecarboxylic acid;
1 -(6-((3,3-difluoropyrrolidin- 1 -yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl yl)cyclobutanecarboxylic acid;
1 -(6-((4,4-difluoropiperidin- 1 -yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl-; yl)cyclobutanecarboxylic acid; l-(6-((3,4-difluorophenyl)(piperidin-l-yl)methyl)-4'-(trifluoromethyl)biphenyl-3-yl)cyc acid;
1 -(6-((3,3-dimethylpyrrolidin- 1 -yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)bipheny yl)cyclobutanecarboxylic acid;
1 -(6-((3,5-dimethylpiperidin- 1 -yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl- yl)cyclopropanecarboxylic acid; l-(6-((4-fluorophenyl)(6-azaspiro[2.5]octan-6-yl)methyl)-4'-(trifluoromethyl)biphenyl-2 yl)cyclopropanecarboxylic acid; 1 -(6-((4-fluorophenyl)(piperidin- 1 -yl)methyl)-5-(4-(trifluoromethyl)phenyl)pyridin-3- yl)cyclopropanecarboxylic acid;
1 -(6-((3,3-dimethylpiperidin- 1 -yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl- yl)cyclopropanecarboxylic acid;
1 -(6-((4-fluorophenyl)(hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl)methyl)-4'-(trifluoromet yl)cyclopropanecarboxylic acid;
1 -(3'-fluoro-6-((4-fluorophenyl)(piperidin- 1 -yl)methyl)-4'-(trifluoromethyl)biphenyl-3- yl)cyclopropanecarboxylic acid;
1 -(6-((3,3-difluoropiperidin- 1 -yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl-. yl)cyclopropanecarboxylic acid; l-(6-((4-fluorophenyl)(5-azaspiro[2.5]octan-5-yl)methyl)-4'-(trifluoromethyl)biphenyl-2 yl)cyclopropanecarboxylic acid;
1 -(3',4',5'-trifluoro-6-((4-fluorophenyl)(piperidin- 1 -yl)methyl)biphenyl-3-yl)cyclopropa]
1 -(6-((4-fluorophenyl)(4-(trifluoromethyl)piperidin- 1 -yl)methyl)-4'-(trifluoromethyl)bip yl)cyclopropanecarboxylic acid; l-(6-(3-azabicyclo[3.2.1]octan-3-yl(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphen}' yl)cyclopropanecarboxylic acid;
1 -(6-((3,3-difluoropyrrolidin- 1 -yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl yl)cyclopropanecarboxylic acid;
1 -(6-((4,4-difluoropiperidin- 1 -yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl-. yl)cyclopropanecarboxylic acid;
1 -(6-((3,4-difluorophenyl)(piperidin- 1 -yl)methyl)-4'-(trifluoromethyl)biphenyl-3- yl)cyclopropanecarboxylic acid;
1 -(6-((3,3-dimethylpyrrolidin- 1 -yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)bipheny yl)cyclopropanecarboxylic acid;
2-(6-((3,5-dimethylpiperidin-l-yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl- methylpropanoic acid;
2-(6-((4-fluorophenyl)(6-azaspiro[2.5]octan-6-yl)methyl)-4'-(trifluoromethyl)biphenyl-2 methylpropanoic acid;
2-(6-((4-fluorophenyl)(piperidin-l-yl)methyl)-5-(4-(trifluoromethyl)phenyl)pyridin-3-y] methylpropanoic acid;
2-(6-((3,3-dimethylpiperidin-l-yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl- methylpropanoic acid;
2-(3'-fluoro-6-((4-fluorophenyl)(piperidin-l-yl)methyl)-4'-(trifluoromethyl)biphenyl-3-> methylpropanoic acid;
2-(6-((4-fluorophenyl)(hexahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl)-4'-(trifluoromet
2-methylpropanoic acid;
2-(6-((3,3-difluoropiperidin-l-yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl-. acid;
2-(6-((4-fluorophenyl)(5-azaspiro[2.5]octan-5-yl)methyl)-4'-(trifluoromethyl)biphenyl-2 methylpropanoic acid; 2-methyl-2-(3',4',5'-trifluoro-6-((4-fluorophenyl)(piperidin-l-yl)methyl)biphenyl-3-yl)pi 2-(6-((4-fluorophenyl)(4-(trifluoromethyl)piperidin-l-yl)methyl)-4'-(trifluoromethyl)bip methylpropanoic acid;
2-(6-(3-azabicyclo[3.2.1]octan-3-yl(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphen}' methylpropanoic acid;
2-(6-((3,3-difluoropyrrolidin-l-yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl methylpropanoic acid;
2-(6-((4,4-difluoropiperidin-l-yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl-. methylpropanoic acid;
2-(6-((3,4-difluorophenyl)(piperidin-l-yl)methyl)-4'-(trifluoromethyl)biphenyl-3-yl)-2-r acid;
2-(6-((3,3-dimethylpyrrolidin-l-yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)bipheny methylpropanoic acid;
2-(6-((3,5-dimethylpiperidin-l-yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl- dimethylpentanoic acid;
2-(6-((4-fluorophenyl)(6-azaspiro[2.5]octan-6-yl)methyl)-4'-(trifluoromethyl)biphenyl-2 dimethylpentanoic acid;
2-(6-((4-fluorophenyl)(piperidin-l-yl)methyl)-5-(4-(trifluoromethyl)phenyl)pyridin-3-y] dimethylpentanoic acid;
2-(6-((3,3-dimethylpiperidin-l-yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl- dimethylpentanoic acid;
2-(6-((4-fluorophenyl)(hexahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl)-4'-(trifluoromet 4,4-dimethylpentanoic acid;
2-(3'-fluoro-6-((4-fluorophenyl)(piperidin-l-yl)methyl)-4'-(trifluoromethyl)biphenyl-3-> dimethylpentanoic acid;
2-(6-((3,3-difluoropiperidin-l-yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl-. dimethylpentanoic acid;
2-(6-((4-fluorophenyl)(5-azaspiro[2.5]octan-5-yl)methyl)-4'-(trifluoromethyl)biphenyl-2 dimethylpentanoic acid;
4,4-dimethyl-2-(3',4',5'-trifluoro-6-((4-fluorophenyl)(piperidin-l-yl)methyl)biphenyl-3-} 2-(6-((4-fluorophenyl)(4-(trifluoromethyl)piperidin-l-yl)methyl)-4'-(trifluoromethyl)bip dimethylpentanoic acid;
2-(6-(3-azabicyclo[3.2.1]octan-3-yl(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphen}' dimethylpentanoic acid;
2-(6-((3,3-difluoropyrrolidin-l-yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl dimethylpentanoic acid;
2-(6-((4,4-difluoropiperidin-l-yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl-. dimethylpentanoic acid;
2-(6-((3,4-difluorophenyl)(piperidin-l-yl)methyl)-4'-(trifluoromethyl)biphenyl-3-yl)-4,4 dimethylpentanoic acid; 2-(6-((3,3-dimethylpyrrolidin-l-yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)bipheny dimethylpentanoic acid;
2-(6-((3,3-dimethylpyrrolidin-l-yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)bipheny dimethylpentanoic acid;
2-(6-((4-fluorophenyl)(6-azaspiro[2.5]octan-6-yl)methyl)-4'-(trifluoromethyl)biphenyl-2 acid;
2-(6-((4-fluorophenyl)(piperidin-l-yl)methyl)-5-(4-(trifluoromethyl)phenyl)pyridin-3-y] 2-(6-((3,3-dimethylpiperidin-l-yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl- acid;
2-(6-((4-fluorophenyl)(hexahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl)-4'-(trifluoromet yl)propanoic acid;
2-(3'-fluoro-6-((4-fluorophenyl)(piperidin-l-yl)methyl)-4'-(trifluoromethyl)biphenyl-3->
2-(6-((3,3-difluoropiperidin-l-yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl-; acid;
2-(6-((4-fluorophenyl)(5-azaspiro[2.5]octan-5-yl)methyl)-4'-(trifluoromethyl)biphenyl-2 acid;
2-(3',4',5'-trifluoro-6-((4-fluorophenyl)(piperidin- 1 -yl)methyl)biphenyl-3-yl)propanoic a
2-(6-((4-fluorophenyl)(4-(trifluoromethyl)piperidin-l-yl)methyl)-4'-(trifluoromethyl)bip yl)propanoic acid;
2-(6-(3-azabicyclo[3.2.1]octan-3-yl(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphen}' acid;
2-(6-((3,3-difluoropyrrolidin-l-yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl acid;
2-(6-((4,4-difluoropiperidin-l-yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl-; acid;
2-(6-((3,4-difluorophenyl)(piperidin-l-yl)methyl)-4'-(trifluoromethyl)biphenyl-3-yl)pro] 2-(6-((3,3-dimethylpyrrolidin-l-yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)bipheny acid
2-(6-((4,4-dimethylpiperidin-l-yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl- methylpentanoic acid;
2-(6-((4,4-dimethylpiperidin-l-yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl- 2-(6-((4,4-dimethylpiperidin-l-yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl- dimethylpentanoic acid;
2-(6-((4-chlorophenyl)(4-methylpiperidin-l-yl)methyl)-4'-(trifluoromethyl)biphenyl-3-}' 2-(6-((4-fluorophenyl)(piperidin-l-yl)methyl)-4'-(trifluoromethoxy)biphenyl-3-yl)-4,4-d acid; 3-cyclopropyl-2-(6-((4,4-dimethylpiperidin-l-yl)(4-fluorophenyl)methyl)-4'-(trifluorom yl)propanoic acid;
2-(6-((4-fluorophenyl)(4-methylpiperidin-l-yl)methyl)-4'-(trifluoromethoxy)biphenyl-3-
1 -(6-((4,4-dimethylpiperidin- 1 -yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl- yl)cyclopropanecarboxylic acid;
3-cyclopropyl-2-(6-((4-fluorophenyl)(piperidin-l-yl)methyl)-4'-(trifluoromethoxy)biphe acid;
1 -(6-((4,4-dimethylpiperidin- 1 -yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl- yl)cyclopentanecarboxylic acid;
1 -(6-((4-fluorophenyl)(4-propylpiperidin- 1 -yl)methyl)-4'-(trifluoromethyl)biphenyl-3- yl)cyclopropanecarboxylic acid;
1 -(6-((4-chlorophenyl)(4-methylpiperidin- 1 -yl)methyl)-4'-(trifluoromethyl)biphenyl-3- yl)cyclopropanecarboxylic acid;
1 -(6-((4,4-dimethylpiperidin- 1 -yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl- yl)cyclobutanecarboxylic acid;
1 -(6-((4-methylpiperidin- 1 -yl)(4-(trifluoromethyl)phenyl)methyl)-4'-(trifluoromethyl)bi yl)cyclopropanecarboxylic acid;
1 -(6-((4-fluorophenyl)(4-methylpiperidin- 1 -yl)methyl)-4'-(trifluoromethoxy)biphenyl-3- yl)cyclopropanecarboxylic acid;
2-(6-((4-fluorophenyl)(piperidin-l-yl)methyl)-4'-(trifluoromethyl)biphenyl-3-yl)-2,4-dir acid;
2-(6-((4-fluorophenyl)(pyrrolidin-l-yl)methyl)-4'-(trifluoromethyl)biphenyl-3-yl)-2,4-di acid;
2-(6-(azepan-l-yl(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl-3-yl)-2,4-dimetl 5-((4-fluorophenyl)(piperidin- 1 -yl)methyl)-6-(4-(trifluoromethyl)phenyl)-2,3-dihydro- 1 carboxylic acid;
2-(6-((4-chlorophenyl)(piperidin-l-yl)methyl)-4'-(trifluoromethyl)biphenyl-3-yl)-2,4-dii acid;
5-((4,4-dimethylpiperidin-l-yl)(4-fluorophenyl)methyl)-6-(4-(trifluoromethyl)phenyl)-2 indene-1 -carboxylic acid;
2-(6-((4,4-dimethylpiperidin-l-yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl- ethylbutanoic acid;
2-ethyl-2-(6-((4-fluorophenyl)(4-methylpiperidin-l-yl)methyl)-4'-(trifluoromethyl)biph( acid;
5-((3,3-dimethylpiperidin-l-yl)(4-fluorophenyl)methyl)-6-(4-(trifluoromethyl)phenyl)-2 indene- 1 -carboxylic acid;
2-ethyl-2-(6-((4-fluorophenyl)(piperidin-l-yl)methyl)-4'-(trifluoromethyl)biphenyl-3-yr 1 -(6-(3 ,3-dimethyl- 1 -(4-(trifluoromethyl)piperidin- 1 -yl)butyl)-4'-(trifluoromethyl)biphe yl)cyclopropanecarboxylic acid; 2-(6-((4-chlorophenyl)(3,3-dimethylpiperidin-l-yl)methyl)-4'-(trifluoromethyl)biphenyl ethylbutanoic acid;
2-(6-(3,3-dimethyl-l-(4-(trifluoromethyl)piperidin-l-yl)butyl)-4'-(trifluoromethyl)biphe acid;
2-(6-(3,3-dimethyl-l-(4-(trifluoromethyl)piperidin-l-yl)butyl)-4'-(trifluoromethyl)biphe acid;
2-(6-(3,3-dimethyl-l-(4-(trifluoromethyl)piperidin-l-yl)butyl)-4'-(trifluoromethyl)biphe methylpropanoic acid;
2-(6-(4-methyl- 1 -(4-(trifluoromethyl)piperidin- 1 -yl)pentyl)-4'-(trifluoromethyl)bipheny acid;
2-(6-(bicyclo[2.2.2]octan-l-yl(4-(trifluoromethyl)piperidin-l-yl)methyl)-4'-(trifluorome yl)acetic acid;
1 -(6-(4,4-dimethyl- 1 -(4-(trifluoromethyl)piperidin- 1 -yl)pentyl)-4'-(trifluoromethyl)biph yl)cyclopropanecarboxylic acid;;
2-(6-(4,4-dimethyl- 1 -(4-(trifluoromethyl)piperidin- 1 -yl)pentyl)-4'-(trifluoromethyl)biph yl)propanoic acid;
2-(6-(4,4-dimethyl- 1 -(4-(trifluoromethyl)piperidin- 1 -yl)pentyl)-4'-(trifluoromethyl)biph methylpropanoic acid;
2-(6-(4,4-dimethyl- 1 -(4-(trifluoromethyl)piperidin- 1 -yl)pentyl)-4'-(trifluoromethyl)biph acid;
2-(6-(cyclohexyl(4-(trifluoromethyl)piperidin-l-yl)methyl)-4'-(trifluoromethyl)biphenyl acid;
2-(6-(cyclohexyl(4-(trifluoromethyl)piperidin-l-yl)methyl)-4'-(trifluoromethyl)biphenyl acid;
2-(6-(cyclohexyl(4-(trifluoromethyl)piperidin-l-yl)methyl)-4'-(trifluoromethyl)biphenyl methylpropanoic acid;
1 -(6-(cyclohexyl(4-(trifluoromethyl)piperidin- 1 -yl)methyl)-4'-(trifluoromethyl)biphenyl yl)cyclopropanecarboxylic acid;
2-(6-(2-cyclohexyl- 1 -(4-(trifluoromethyl)piperidin- 1 -yl)ethyl)-4'-(trifluoromethyl)biphe acid;
2-methyl-2-(6-(piperidin- 1 -yl(5-(trifluoromethyl)- 1 H-imidazol-2-yl)methyl)-4'-(trifluor(
3-yl)propanoic acid;
2-(6-(piperi din- 1 -yl(5-(trifluoro methyl)- 1 H-imidazol-2-yl)methyl)-4'-(trifluoromethyl)b yl)propanoic acid;
2-(6-(piperidin-l-yl(5-(trifluoromethyl)-lH-imidazol-2-yl)methyl)-4'-(trifluoromethyl)b yl)butanoic acid; l-(6-(piperidin-l-yl(5-(trifluoromethyl)-lH-imidazol-2-yl)methyl)-4'-(trifluoromethyl)b yl)cyclopropanecarboxylic acid;
2-(6-((cyclohexyl(methyl)amino)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl-; acid;
2-(6-((cyclohexyl(methyl)amino)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl-; methylpentanoic acid; 2-(6-((cyclohexyl(methyl)amino)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl-;
2-(6-((cyclohexyl(cyclopropyl)amino)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biph( acid;
2-(6-((cyclohexyl(isobutyl)amino)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl acid;
2-(6-((cyclohexyl(neopentyl)amino)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphen; 2-(6-((cyclohexyl(cyclopropyl)amino)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biph( acid;
2-(6-((cyclohexyl(isobutyl)amino)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl 6-((4-fluorophenyl)(piperidin- 1 -yl)methyl)-7-(4-(trifluoromethyl)phenyl)- 1 ,2,3,4-tetralr carboxylic acid;
6-((4-fluorophenyl)(4-methylpiperidin- 1 -yl)methyl)-7-(4-(trifluoromethyl)phenyl)- 1 ,2,3 tetrahydro naphthalene- 1 -carboxylic acid;
6-((4,4-dimethylpiperidin- 1 -yl)(4-fluorophenyl)methyl)-7-(4-(trifluoromethyl)phenyl)- 1 tetrahydro naphthalene- 1 -carboxylic acid
6-((3,3-dimethylpiperidin- 1 -yl)(4-fluorophenyl)methyl)-7-(4-(trifluoromethyl)phenyl)- 1 tetrahydro naphthalene- 1 -carboxylic acid;
2-(6-((4-fluorophenyl)(4-methylpiperidin-l-yl)methyl)-4'-(trifluoromethyl)biphenyl-3-y
(methylsulfonyl)acetamide;
2-(6-((4-fluorophenyl)(4-methylpiperidin-l-yl)methyl)-4'-(trifluoromethyl)biphenyl-3-y
(methylsulfonyl)propanamide;
6-((4-fluorophenyl)(4-methylpiperidin-l-yl)methyl)-N-(methylsulfonyl)-4'-(trifluoromei carboxamide;
2-(6-(l-isobutylpiperidin-2-yl)-4'-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic ac 4-methyl-2-(6-(l-(4,4,4-trifluorobutyl)piperidin-2-yl)-4'-(trifluoromethyl)biphenyl-3-yl)
4-methyl-2-(6-(l-neopentylpiperidin-2-yl)-4'-(trifluoromethyl)biphenyl-3-yl)pentanoic i
4-methyl-2-(4'-(trifluoromethyl)-6-(l-(4-(trifluoromethyl)phenyl)piperidin-2-yl)biphen}' acid;
4-methyl-2-(4'-(trifluoromethyl)-6-(l-(2-(trifluoromethyl)phenyl)piperidin-2-yl)biphen}' acid;
4-methyl-2-(4'-(trifluoromethyl)-6-(l-(3-(trifluoromethyl)phenyl)piperidin-2-yl)biphen}' acid;
2-(4'-(trifluoromethyl)-6-(l-(4-(trifluoromethyl)benzyl)piperidin-2-yl)biphenyl-3-yl)but 2-(4'-(trifluoromethyl)-6-(l-(3-(trifluoromethyl)benzyl)piperidin-2-yl)biphenyl-3-yl)but 2-(4'-(trifluoromethyl)-6-(l-(2-(trifluoromethyl)benzyl)piperidin-2-yl)biphenyl-3-yl)but 2-(6-(l-isobutylpiperidin-3-yl)-4'-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic ac
4-methyl-2-(6-(l-neopentylpiperidin-3-yl)-4'-(trifluoromethyl)biphenyl-3-yl)pentanoic i 4-methyl-2-(4'-(trifluoromethyl)-6-(l-(3-(trifluoromethyl)phenyl)piperidin-3-yl)biphen}' acid;
4-methyl-2-(6-(l-(4,4,4-trifluorobutyl)piperidin-3-yl)-4'-(trifluoromethyl)biphenyl-3-yl)
4-methyl-2-(4'-(trifluoromethyl)-6-(l-(4-(trifluoromethyl)phenyl)piperidin-3-yl)biphen}' acid;
4-methyl-2-(4'-(trifluoromethyl)-6-(l-(2-(trifluoromethyl)phenyl)piperidin-3-yl)biphen}' acid;
2-(4'-(trifluoromethyl)-6-(l-(3-(trifluoromethyl)benzyl)piperidin-3-yl)biphenyl-3-yl)but 2-(4'-(trifluoromethyl)-6-(l-(2-(trifluoromethyl)benzyl)piperidin-3-yl)biphenyl-3-yl)but
2-(4'-(trifluoromethyl)-6-(l-(4-(trifluoromethyl)benzyl)piperidin-3-yl)biphenyl-3-yl)but
2-(6-(l-isobutyl-4-(trifluoromethyl)piperidin-2-yl)-4'-(trifluoromethyl)biphenyl-3-yl)-4- acid;
4-methyl-2-(6-(4-methyl-l-(4,4,4-trifluorobutyl)piperidin-2-yl)-4'-(trifluoromethyl)biph yl)pentanoic acid;
4-methyl-2-(6-(l-neopentyl-4-(trifluoromethyl)piperidin-2-yl)-4'-(trifluoromethyl)biphe acid;
(R)-2-(6-((4-fluorophenyl)(4-(trifluoromethyl)piperidin-l-yl)methyl)-4'-(trifluoromethy] yl)acetic acid;
(R)-2-(6-((S)-(4-fluorophenyl)(4-(trifluoromethyl)piperidin-l-yl)methyl)-4'-(trifluorome yl)-4-methylpentanoic acid;
(S)-2-(6-((4-fluorophenyl)(4-(trifluoromethyl)piperidin-l-yl)methyl)-4'-(trifluoromethyl yl)acetic acid;
(R)-2-(6-((R)-(4-fluorophenyl)(4-(trifluoromethyl)piperidin-l-yl)methyl)-4'-(trifluorom< yl)-4-methylpentanoic acid;
(S)-2-(6-((R)-(4-fluorophenyl)(4-(trifluoromethyl)piperidin-l-yl)methyl)-4'-(trifluorome yl)-4-methylpentanoic acid;
(S)-2-(6-((S)-(4-fluorophenyl)(4-(trifluoromethyl)piperidin-l-yl)methyl)-4'-(trifluorome yl)-4-methylpentanoic acid;
2-(5-((4-fluorophenyl)(4-methylpiperidin-l-yl)methyl)-4'-(trifluoromethyl)biphenyl-3-y methylpropanoic acid;
2-(5-((4-methylpiperidin-l-yl)(4-(trifluoromethyl)phenyl)methyl)-4'-(trifluoromethyl)bi yl)propanoic acid; 2-(5-((3,4-difluorophenyl)(4-methylpiperidin-l-yl)methyl)-4'-(trifluoromethyl)biphenyl- acid;
2-(5-((4-fluorophenyl)(5-azaspiro[2.5]octan-5-yl)methyl)-4'-(trifluoromethyl)biphenyl-2 methylpentanoic acid;
2-(5-((4-fluorophenyl)(piperidin-l-yl)methyl)-4'-(trifluoromethyl)biphenyl-3-yl)-4-metl"
2-(5-((3,4-difluorophenyl)(piperidin-l-yl)methyl)-4'-(trifluoromethyl)biphenyl-3-yl)-4-r acid;
2-(5-((4,4-dimethylpiperidin-l-yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl- methylpentanoic acid;
2-(5-((4-fluorophenyl)(hexahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl)-4'-(trifluoromet
4-methylpentanoic acid;
4-methyl-2-(3',4',5'-trifluoro-5-((4-fluorophenyl)(piperidin-l-yl)methyl)biphenyl-3-yl)p< 2-(5-((4-fluorophenyl)(6-azaspiro[2.5]octan-6-yl)methyl)-4'-(trifluoromethyl)biphenyl-2 methylpentanoic acid;
2-(5-((4-fluorophenyl)(pyrrolidin-l-yl)methyl)-4'-(trifluoromethyl)biphenyl-3-yl)-4-met 2-(3'-fluoro-5-((4-fluorophenyl)(piperidin-l-yl)methyl)-4'-(trifluoromethyl)biphenyl-3-> methylpentanoic acid;
2-(5-((3,5-dimethylpiperidin-l-yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl- methylpentanoic acid;
2-(5-((3,3-dimethylpyrrolidin-l-yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)bipheny methylpentanoic acid;
2-(5-((4-fluorophenyl)(4-methylpiperidin-l-yl)methyl)-4'-(trifluoromethyl)biphenyl-3-y 2-(5-((4-fluorophenyl)(4-(trifluoromethyl)piperidin-l-yl)methyl)-4'-(trifluoromethyl)bip yl)propanoic acid;
2-(5-((3,3-difluoropyrrolidin-l-yl)(4-fluorophenyl)methyl)-4'-(trifluoromethyl)biphenyl methylpentanoic acid; and
2-(5-((4-fluorophenyl)(4-methylpiperidin-l-yl)methyl)-4'-(trifluoromethyl)biphenyl-3-y methylpentanoic acid.
36. A compound selected from the group consisting of:
(R)-2-(6-((4-fiuorophenyl)(4-(trifluoromethyl)piperidin-l-yl)methyl)-4'- (trifluoromethyl)biphenyl-3-yl)acetic acid;
(S)-2-(6-((4-fluorophenyl)(4-(trifiuoromethyl)piperidin-l-yl)methyl)-4'- (trifluoromethyl)biphenyl-3-yl)acetic acid;
(R)-2-(6-((S)-(4-fluorophenyl)(4-(trifluoromethyl)piperidin-l-yl)methyl)-4'- (trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid; (R)-2-(6-((R)-(4-fluorophenyl)(4-(trifluoromethyl)piperidin-l-yl)methyl)-4?- (trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid; (S)-2-(6-((R)-(4-fluorophenyl)(4-(trifluoromethyl)piperidin-l-yl)methyl)-4?- (trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid; (S)-2-(6-((S)-(4-fluorophenyl)(4-(trifluoromethyl)piperidin-l-yl)methyl)-4?- (trifluoromethyl)biphenyl-3-yl)-4-methylpentanoic acid;
(S)-4-methyl-2-(3',4',5'-trifluoro-6-((S)-(4-fluorophenyl)(piperidin-l-yl)methyl)biphenyl- 3-yl)pentanoic acid;
(S)-4-methyl-2-(3',4',5'-trifluoro-6-((R)-(4-fluorophenyl)(piperidin-l-yl)methyl)biphenyl- 3-yl)pentanoic acid;
(R)-4-methyl-2-(3',4',5'-trifluoro-6-((R)-(4-fluorophenyl)(piperidin-l-yl)methyl)biphenyl- 3-yl)pentanoic acid;
(R)-4-methyl-2-(3',4',5'-trifluoro-6-((S)-(4-fluorophenyl)(piperidin-l-yl)methyl)biphenyl- 3-yl)pentanoic acid;
(R)-2-(6-((S)-(4-fluorophenyl)(piperidin-l-yl)methyl)-4'-(trifluoromethyl)biphenyl-3-yl)- 4-methylpentanoic acid;
(R)-2-(6-((R)-(4-fluorophenyl)(piperidin-l-yl)methyl)-4'-(trifluoromethyl)biphenyl-3-yl)- 4-methylpentanoic acid;
(S)-2-(6-((R)-(4-fluorophenyl)(piperidin-l-yl)methyl)-4'-(trifluoromethyl)biphenyl-3-yl)- 4-methylpentanoic acid;
(S)-2-(6-((S)-(4-fluorophenyl)(piperidin-l-yl)methyl)-4'-(trifluoromethyl)biphenyl-3-yl)- 4-methylpentanoic acid;
(R)- 1 -(6-((4-fluorophenyl)(4-methylpiperidin- 1 -yl)methyl)-4'-(trifluoromethyl)biphenyl- 3-yl)cyclobutanecarboxylic acid;
(S)-I -(6-((4-fluorophenyl)(4-methylpiperidin- 1 -yl)methyl)-4'-(trifluoromethyl)biphenyl- 3-yl)cyclobutanecarboxylic acid;
(R)- 1 -(6-((4-fluorophenyl)(piperidin- 1 -yl)methyl)-4'-(trifluoromethyl)biphenyl-3- yl)cyclobutanecarboxylic acid;
(S)- 1 -(6-((4-fluorophenyl)(piperidin- 1 -yl)methyl)-4'-(trifluoromethyl)biphenyl-3- yl)cyclobutanecarboxylic acid;
(R)- 1 -(3'-fluoro-6-((4-fluorophenyl)(4-methylpiperidin- 1 -yl)methyl)-4'- (trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylic acid; (S)- 1 -(3'-fluoro-6-((4-fluorophenyl)(4-methylpiperidin- 1 -yl)methyl)-4'- (trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylic acid;
(R)-2-(6-((R)-(4-fluorophenyl)(4-methylpiperidin-l-yl)methyl)-4'- (trifluoromethyl)biphenyl-3-yl)propanoic acid; (R)-2-(6-((S)-(4-fluorophenyl)(4-methylpiperidin-l-yl)methyl)-4?- (trifluoromethyl)biphenyl-3-yl)propanoic acid; (S)-2-(6-((S)-(4-fluorophenyl)(4-methylpiperidin-l-yl)methyl)-4?- (trifluoromethyl)biphenyl-3-yl)propanoic acid; (S)-2-(6-((R)-(4-fluorophenyl)(4-methylpiperidin-l-yl)methyl)-4?- (trifluoromethyl)biphenyl-3-yl)propanoic acid; (R)-2-(6-((R)-(4-fluorophenyl)(4-methylpiperidin-l-yl)methyl)-4?- (trifluoromethyl)biphenyl-3-yl)butanoic acid; (R)-2-(6-((S)-(4-fluorophenyl)(4-methylpiperidin-l-yl)methyl)-4?- (trifluoromethyl)biphenyl-3-yl)butanoic acid; (S)-2-(6-((S)-(4-fluorophenyl)(4-methylpiperidin-l-yl)methyl)-4?- (trifluoromethyl)biphenyl-3-yl)butanoic acid; (S)-2-(6-((R)-(4-fluorophenyl)(4-methylpiperidin-l-yl)methyl)-4?- (trifluoromethyl)biphenyl-3-yl)butanoic acid;
(R)-2-(6-((R)-(4-fluorophenyl)(4-(trifluoromethyl)piperidin-l-yl)methyl)-4?- (trifluoromethyl)biphenyl-3-yl)propanoic acid;
(R)-2-(6-((S)-(4-fluorophenyl)(4-(trifluoromethyl)piperidin-l-yl)methyl)-4?- (trifluoromethyl)biphenyl-3-yl)propanoic acid;
(S)-2-(6-((S)-(4-fluorophenyl)(4-(trifluoromethyl)piperidin-l-yl)methyl)-4?- (trifluoromethyl)biphenyl-3-yl)propanoic acid;
(S)-2-(6-((R)-(4-fluorophenyl)(4-(trifluoromethyl)piperidin-l-yl)methyl)-4?- (trifluoromethyl)biphenyl-3-yl)propanoic acid; (R)-2-(6-((R)-(4-fluorophenyl)(4-methylpiperidin-l-yl)methyl)-4?- (trifluoromethyl)biphenyl-3-yl)-4,4-dimethylpentanoic acid; (R)-2-(6-((S)-(4-fluorophenyl)(4-methylpiperidin-l-yl)methyl)-4?- (trifluoromethyl)biphenyl-3-yl)-4,4-dimethylpentanoic acid; (S)-2-(6-((S)-(4-fluorophenyl)(4-methylpiperidin-l-yl)methyl)-4?- (trifluoromethyl)biphenyl-3-yl)-4,4-dimethylpentanoic acid; (S)-2-(6-((R)-(4-fluorophenyl)(4-methylpiperidin-l-yl)methyl)-4?- (trifluoromethyl)biphenyl-3-yl)-4,4-dimethylpentanoic acid; (R)-3-cyclopropyl-2-(6-((R)-(4-fluorophenyl)(4-methylpiperidin-l-yl)methyl)-4'- (trifluoromethyl)biphenyl-3-yl)propanoic acid;
(R)-3-cyclopropyl-2-(6-((S)-(4-fluorophenyl)(4-methylpiperidin-l-yl)methyl)-4'- (trifluoromethyl)biphenyl-3-yl)propanoic acid;
(S)-3-cyclopropyl-2-(6-((S)-(4-fluorophenyl)(4-methylpiperidin-l-yl)methyl)-4'- (trifluoromethyl)biphenyl-3-yl)propanoic acid;
(S)-3-cyclopropyl-2-(6-((R)-(4-fluorophenyl)(4-methylpiperidin-l-yl)methyl)-4'- (trifluoromethyl)biphenyl-3-yl)propanoic acid;
(R)-2-(6-((R)-(4-methylpiperidin-l-yl)(4-(trifluoromethyl)phenyl)methyl)-4?- (trifluoromethyl)biphenyl-3-yl)propanoic acid;
(S)-2-(6-((R)-(4-methylpiperidin-l-yl)(4-(trifluoromethyl)phenyl)methyl)-4?- (trifluoromethyl)biphenyl-3-yl)propanoic acid;
(S)-2-(6-((S)-(4-methylpiperidin-l-yl)(4-(trifluoromethyl)phenyl)methyl)-4?- (trifluoromethyl)biphenyl-3-yl)propanoic acid;
(R)-2-(6-((S)-(4-methylpiperidin-l-yl)(4-(trifluoromethyl)phenyl)methyl)-4?- (trifluoromethyl)biphenyl-3-yl)propanoic acid; 2-(6-( 1 -(4-fluorophenyl)- 1 -(4-(trifluoromethyl)piperidin- 1 -yl)ethyl)-4'-
(trifluoromethyl)biphenyl-3-yl)propanoic acid;
2-(6-( 1 -(4-fluorophenyl)- 1 -(4-methylpiperidin- 1 -yl)ethyl)-4'-(trifluoromethyl)biphenyl-3- yl)propanoic acid;
2-(6-(l -(3, 4-difluorophenyl)-l -(4-methylpiperidin- l-yl)ethyl)-4'-
(trifluoromethyl)biphenyl-3-yl)propanoic acid;
2-(6-( 1 -(4-fluorophenyl)- 1 -(4-methylpiperidin- 1 -yl)ethyl)-4'-(trifluoromethyl)biphenyl-3- yl)butanoic acid;
1 -(6-( 1 -(4-fluorophenyl)- 1 -(piperidin- 1 -yl)ethyl)-4'-(trifluoromethyl)biphenyl-3- yl)cyclobutanecarboxylic acid;
2-(6-( 1 -(4-fluorophenyl)- 1 -(piperidin- 1 -yl)ethyl)-4'-(trifluoromethyl)biphenyl-3- yl)propanoic acid;
2-(6-( 1 -(4-fluorophenyl)- 1 -(piperidin- 1 -yl)ethyl)-4'-(trifluoromethyl)biphenyl-3-yl)-4- methylpentanoic acid;
(S)-2-(6-(4-methyl- 1 -(4-(trifluoromethyl)piperidin- 1 -yl)pentyl)-4'-
(trifluoromethyl)biphenyl-3-yl)acetic acid;
(R)-2-(6-(4-methyl- 1 -(4-(trifluoromethyl)piperidin- 1 -yl)pentyl)-4'-
(trifluoromethyl)biphenyl-3-yl)acetic acid;
(S)-2-(6-(3,3-dimethyl-l-(4-(trifluoromethyl)piperidin-l-yl)butyl)-4'-
(trifluoromethyl)biphenyl-3-yl)acetic acid;
(R)-2-(6-(3,3-dimethyl- 1 -(4-(trifluoromethyl)piperidin- 1 -yl)butyl)-4'-
(trifluoromethyl)biphenyl-3-yl)acetic acid;
2-(6-(3 ,3-dimethyl- 1 -(4-(trifluoromethyl)piperidin- 1 -yl)butyl)-4'-
(trifluoromethyl)biphenyl-3-yl)propanoic acid;
1 -(6-(3 ,3-dimethyl- 1 -(4-(trifluoromethyl)piperidin- 1 -yl)butyl)-4'-
(trifluoromethyl)biphenyl-3-yl)cyclopropanecarboxylic acid;
2-(6-(3 ,3-dimethyl- 1 -(4-(trifluoromethyl)piperidin- 1 -yl)butyl)-4'-
(trifluoromethyl)biphenyl-3-yl)butanoic acid;
2-(6-(3 ,3-dimethyl- 1 -(4-(trifluoromethyl)piperidin- 1 -yl)butyl)-4'-
(trifluoromethyl)biphenyl-3-yl)-2-methylpropanoic acid;
1 -(6-(3 ,3-dimethyl- 1 -(4-(trifluoromethyl)piperidin- 1 -yl)butyl)-4'-
(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylic acid;
2-(6-(cyclohexyl(4-(trifluoromethyl)piperidin-l-yl)methyl)-4'-(trifluoromethyl)biphenyl-
3-yl)acetic acid;
2-(6-(4,4-dimethyl- 1 -(4-(trifluoromethyl)piperidin- 1 -yl)pentyl)-4'-
(trifluoromethyl)biphenyl-3-yl)acetic acid; and
2-(6-(2-cyclohexyl- 1 -(4-(trifluoromethyl)piperidin- 1 -yl)ethyl)-4'-
(trifluoromethyl)biphenyl-3-yl)acetic acid.
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