WO2016100555A1 - Boronic acid derivatives and uses thereof - Google Patents

Boronic acid derivatives and uses thereof Download PDF

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Publication number
WO2016100555A1
WO2016100555A1 PCT/US2015/066166 US2015066166W WO2016100555A1 WO 2016100555 A1 WO2016100555 A1 WO 2016100555A1 US 2015066166 W US2015066166 W US 2015066166W WO 2016100555 A1 WO2016100555 A1 WO 2016100555A1
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phenyl
naphthamido
alkyl
ring
cyclohexylpropanoyl
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PCT/US2015/066166
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French (fr)
Inventor
Jill Melissa BACCEI
Renata Marcella Oballa
David Andrew POWELL
Jeffrey Roger Roppe
Tao Sheng
Brian Stearns
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Inception 4, Inc.
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Publication of WO2016100555A1 publication Critical patent/WO2016100555A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents

Definitions

  • This invention is directed to novel boronic acid derivatives of Formula I, and pharmaceutically acceptable salts, solvate, solvate of the salt and prodrugs thereof, useful in the prevention (e.g., delaying the onset of or reducing the risk of developing) and treatment (e.g., controlling, alleviating, or slowing the progression of) of Age-related Macular Degeneration (AMD) and related diseases of the eye.
  • AMD Age-related Macular Degeneration
  • diseases include dry- AMD, Wet-AMD, geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, and degeneration of retinal or photoreceptor cells.
  • the invention disclosed herein is further directed to methods of prevention, slowing the progress of, and treatment of dry-AMD, Wet-AMD, and geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, and degeneration of retinal or photoreceptor cells, comprising: administration of a therapeutically effective amount of a compound of the invention.
  • the compounds of the invention are inhibitors of HTRA1.
  • the compounds of the invention are useful in the prevention and treatment of a wide range diseases mediated (in whole or in part) by HTRA1.
  • the compounds of the invention are also useful for inhibiting HtrAl protease activity in an eye or locus of an arthritis or related condition.
  • Age-related macular degeneration is the leading cause of severe loss of vision in people over the age of 60.
  • Age is the major risk factor for the onset of AMD: the likelihood of developing AMD triples after age 55. Many factors, however, contribute to the likelihood that an individual will develop AMD.
  • cataracts prevent excessive light exposure from falling on the macula, and are in some way prophylactic for AMD. While it is possible that dark iris pigmentation may protect the macula from light damage, it is difficult to distinguish between iris pigmentation alone and other, cosegregating genetic factors which may be actual risk factors.
  • HTRAl single nucleotide polymorphs have been found to be associated with an increased risk of AMD. See, for example, WO2008/013893A2, WO2008/067040A2 and WO2008/094370A2. These S P's include rsl 1200638, rsl0490924, rs3750848, rs3793917 and rs932275.
  • the risk allele rsl 1200638 was found to be associated with increased HTRAl mRNA and protein expression, and HtrAl is present in drusen in patients with AMD.
  • dry AMD In broad terms, there are two forms of AMD: dry AMD and wet AMD.
  • dry AMD also called non-neovascular AMD or non-exudative AMD
  • drusen appear in the macula of the eye, the cells in the macula die, and vision becomes blurry.
  • Dry AMD can progress in three stages: 1) early, 2) intermediate, and 3) advanced dry AMD. Dry AMD can also progress into wet AMD during any of these stages.
  • Wet AMD also called neovascular or exudative AMD
  • PSNV posterior segment neovascularization
  • Leakage from abnormal blood vessels forming in this process damages the macula and impairs vision, eventually leading to blindness.
  • the end stage of AMD is characterized by a complete degeneration of the neurosensory retina and of the underlying retinal pigment epithelium in the macular area.
  • Advanced stages of AMD can be subdivided into geographic atrophy (GA) and exudative AMD.
  • GA geographic atrophy
  • RPE retinal pigment epithelium
  • GA is typically considered less severe than the exudative AMD because its onset is less sudden, to date no treatment has been effective at halting or slowing its progression.
  • treatment of dry AMD includes the administration of antioxidant vitamins and/or zinc.
  • antioxidant vitamins and/or zinc For example, one study at the National Eye Institute assessed a composition comprising Vitamin C, Beta Carotene, zinc oxide and cupric oxide.
  • Treatment of AMD is also wanting.
  • Available drug therapies include: Bevacizumab (Avastin), Ranibizumab (Lucentis), Pegaptanib (Macugen), and Aflibercept (Eylea).
  • Bevacizumab Avastin
  • Ranibizumab Ranibizumab
  • Macugen Pegaptanib
  • Aflibercept Eylea
  • the medication is injected into the eye. Injections may be repeated every four weeks to maintain the beneficial effect of the medication. Those with a positive result, may partially recover vision as the blood vessels shrink and the fluid under the retina is absorbed, allowing retinal cells to regain some function.
  • WO2012/078540 published December 6, 2012, also discloses this compound (identified therein as NVP-LB976) as an inhibitor of HtrAl, and claims the use of a composition "... comprising nanoparticles and peripheral blood cells, wherein the nanoparticles comprise an HTRAl/htral and/or a CIS/cish activator" in the prevention or treatment of a number of diseases, including age-related macular degeneration.
  • This invention is directed to novel boronic acid derivatives of Formula I,
  • ASD Age-related Macular Degeneration
  • diseases include dry- AMD, Wet-AMD, geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, and degeneration of retinal or photoreceptor cells.
  • the invention disclosed herein is further directed to methods of prevention, slowing the progress of, and treatment of dry-AMD, Wet-AMD, and geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, and degeneration of retinal or photoreceptor cells, comprising: administration of a therapeutically effective amount of a compound of the invention.
  • the compounds of the invention are inhibitors of HTRAl .
  • the compounds of the invention are useful in the prevention and treatment of a wide range diseases mediated (in whole or in part) by HTRAl .
  • the compounds of the invention are also useful for inhibiting HtrAl protease activity in an eye or locus of an arthritis or related condition,
  • the boronic acid derivative is a compound of Formula I
  • each n is independently selected from 0, 1, or 2;
  • X is selected from -C(O)-, -S0 2 - and -CHCH 3 , wherein 1, 2 or 3 of the CH 3 hydrogens may optionally be replaced with a halogen;
  • R 1 is selected from the group consisting of:
  • R 1 choices (a), (b), (c), (d) and (e) are optionally mono- or di- substituted with substituents independently selected from halogen, -CH 3 , -CF 3 , -
  • R 2 is selected from the group consisting of:
  • heteroaryl is a 5- or 6-membered monocyclic ring, having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
  • R 2 choices (a), (b) and (c) are optionally mono- or di- substituted with substituents independently selected from halogen, -CH 3 , -CF 3 , -OCH 3 and -OCF 3 ;
  • R 3a and R 3b are each independently selected from the group consisting of:
  • heteroaryl is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
  • heteroaryl is a 5- or 6- membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
  • heteroaryl is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
  • heterocycle is a 5- or 6- membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
  • R 3a and R 3b taken together with the atom to which they are attached form a carbonyl, with the proviso that at least one of R 3a and R 3b is other than hydrogen;
  • R 4a and R 4b are each independently hydrogen or or
  • R 3a and R 4a or R 3a and R 4b or R 3b and R 4a or R 3b and R 4b are j oined together to form a bond or joined together so that together with the atoms to which they are attached there is formed a ring selected from phenyl, Cs-ecycloalkyl, optionally mono- or di-substituted with substituents independently selected from hydroxyl, - CH 3 , -CF 3 , -OCH 3 and -OCF 3 ;
  • R 5 is selected from the group consisting of:
  • R 6 is selected from the group consisting of:
  • heterocycle is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
  • heterocycle is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O, wherein the alkyl of R 6 choices (a), (b), (e), (f), (g), (h), (i), (k) and (1), and the aryl of R 6 choices (a), (b), (c), (d), (e), (f), (g), (h), (k) and (1), and the heteroaryl of R 6 choice (e) and the heterocycle of R 6 choices (b), ,(g),(h) and (1), and the heterocycloalkyl of R 6 choice (f) are each optionally mono or di-substituted with substituents independently selected from halogen, hydroxyl, -CH 3 , -CF 3 , -OCH 3 and
  • X is selected from -C(O)- and -CHCF 3 .
  • R 1 is selected from the group consisting of:
  • R 1 choices (a), (b) and (c) are optionally mono- or di-substituted with substituents independently selected from halogen, -CH 3 , -CF 3 , -OCH 3 and -OCF 3 .
  • R 1 is naphthyl
  • R 2 is wherein the C seyeloalkyl is optionally mono- or di-substituted with substituents independently selected from halogen, -CH 3 , -CF 3 , -OC3 ⁇ 4 and -OCF 3 .
  • R 2 is
  • R ,a is hydrogen
  • R b is selected from the group consisting of:
  • R 3a and R 3b taken together with the atom to which they are attached form a carbonyl, or
  • R 3b and R 4a or R 3b and R 4b are joined together so that together with the atoms to which they are attached there is formed a ring selected from phenyl, C 5- 6 cycloalkyl, optionally mono- or di- substituted with substituents independently selected from hydroxyl, -CH 3 , -CF 3 , -OCH 3 and -OCF 3 .
  • R 3a is hydrogen
  • R 3b is selected from the group consisting of:
  • R 3b is selected from the group consisting of:
  • R 4a and R 4b are each hydrogen, or
  • R 3b and R 4a or R 3b and R 4b are joined together so that together with the atoms to which they are attached there is formed a ring selected from phenyl, C,. 6Cycloalkyl, optionally mono- or di- substituted with substituents independently selected from hydroxyl, -CH 3 , -CF 3 , -OCH 3 and -OCF 3 .
  • R 4a and R ',a are each hydrogen.
  • t is selected from 3, 4 and 5;
  • R 5 is selected from the group consisting of:
  • R 5 is selected from the group consisting of:
  • R 5 is selected from the group consisting of:
  • the compound of the first embodiment is a compound of Formula la:
  • X is selected from -C(O)- and -CHCF 3 -;
  • R a is hydrogen
  • R 3b is selected from the group consisting of:
  • R a and R 3b taken together with the atom to which they are attached form a carbonyl
  • R 4 is hydrogen or Ci-ealkyl, or
  • R 3b and R 4 are joined to form a bond or joined so that together with the atoms to which they are attached there is formed a ring selected from phenyl and cyclopentyl;
  • R 5 is selected from the group consisting of:
  • R ,b is selected from the group consisting of:
  • R 5 is selected from the group consisting of:
  • the compound of the first embodiment is selected from the group consisting of:
  • a pharmaceutical composition comprising any one of the compounds of the first through eighteenth embodiments, or a pharmaceutically acceptable salt, solvate, solvate of the salt or prodrug thereof, and a pharmaceutically acceptable carrier.
  • a method of preventing, or treating a disease of the eye selected from dry-AMD, Wet-AMD, and geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, and degeneration of retinal or photoreceptor cells is provided, comprising: administration of a therapeutically effective amount of any one of the compounds of the first through eighteenth embodiments or a pharmaceutically acceptable salt, solvate, solvate of the salt or prodrug thereof.
  • the method of prevention is selected from delaying the onset of disease and reducing the risk of developing a disease of the eye, wherein the disease of the eye is selected from dry-AMD, Wet-AMD, and geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, and degeneration of retinal or photoreceptor cells.
  • the method of treating a disease of the eye is selected from controlling, alleviating, and slowing the progression of, wherein the disease is selected from dry-AMD, Wet-AMD, and geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, and degeneration of retinal or photoreceptor cells.
  • the disease is geographic atrophy.
  • a method of inhibiting HtrAl protease activity in an eye comprising administration of a therapeutically effective amount of any one of the compounds of the first through eighteenth embodiments or a pharmaceutically acceptable salt, solvate, solvate of the salt or prodrug thereof.
  • a method of preventing, or treating a disease of the eye selected from dry-AMD, Wet-AMD, and geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, and degeneration of retinal or photoreceptor cells comprising: administration of a therapeutically effective amount of a compound of Formula I:
  • each n is independently selected from 0, 1, or 2;
  • X is selected from -C(O)-, -S0 2 - and -CHCH 3 , wherein 1, 2 or 3 of the CH 3 hydrogens may optionally be replaced with a halogen;
  • R 1 is selected from the group consisting of:
  • R 1 choices (a), (b), (c), (d) and (e) are optionally mono- or di- substituted with substituents independently selected from halogen, -CH 3 , -CF 3 , -
  • R 2 is selected from the group consisting of:
  • heteroaryl is a 5- or 6-membered monocyclic ring, having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
  • R 2 choices (a), (b) and (c) are optionally mono- or di- substituted with substituents independently selected from halogen, -CH 3 , -CF 3 , -OCH 3 and -OCF 3 ;
  • R 3a and R 3b are each independently selected from the group consisting of:
  • heteroaryl is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
  • heteroaryl is a 5- or 6- membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
  • heteroaryl is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
  • heterocycle is a 5- or 6- membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
  • R 3a and R 3b taken together with the atom to which they are attached form a carbonyl, or
  • R 4a and R 4b are each independently hydrogen or or
  • R 3a and R 4a or R 3a and R 4b or R 3b and R 4a or R 3b and R 4b are j oined together to form a bond or joined together so that together with the atoms to which they are attached there is formed a ring selected from phenyl, Cs-ecycloalkyl, optionally mono- or di-substituted with substituents independently selected from hydroxyl, - CH 3 , -CF 3 , -OCH 3 and -OCF 3 ;
  • R 5 is selected from the group consisting of:
  • R 6 is selected from the group consisting of:
  • heterocycle is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
  • heterocycle is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O, wherein the alkyl of R 6 choices (a), (b), (e), (f), (g), (h), (i), (k) and (1), and the aryl of R 6 choices (a), (b), (c), (d), (e), (f), (g), (h), (k) and (1), and the heteroaryl of R 6 choice (e) and the heterocycle of R 6 choices (b), (g), (h) and (1), and the heterocycloalkyl of R 6 choice (f) are each optionally mono or di-substituted with substituents independently selected from halogen, hydroxyl, -CH 3 , -CF 3 , -OCH 3 and
  • any of the features of an embodiment is applicable to all embodiments identified herein. Moreover, any of the features of an embodiment is independently combinable, partly or wholly with other embodiments described herein in any way, e.g., one, two, or three or more embodiments may be combinable in whole or in part. Further, any of the features of an embodiment may be made optional to other embodiments. Any embodiment of a method can comprise another embodiment of a compound, and any embodiment of a compound can be configured to perform a method of another embodiment.
  • the invention is directed to compounds of Formula I
  • each n is independently selected from 0, 1, or 2;
  • X is selected from -C(O)-, -S0 2 - and -CHCH 3 , wherein 1, 2 or 3 of the CH 3 hydrogens may optionally be replaced with a halogen;
  • R 1 is selected from the group consisting of:
  • R 1 choices (a), (b), (c), (d) and (e) are optionally mono- or di- substituted with substituents independently selected from halogen, -CH 3 , -CF 3 , -OCH 3 and -OCF 3 ;
  • R 2 is selected from the group consisting of:
  • heteroaryl is a 5- or 6-membered monocyclic ring, having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
  • R 2 choices (a), (b) and (c) are optionally mono- or di-substituted with substituents independently selected from halogen, -CH 3 , -CF 3 , -OCH 3 and -OCF 3 ;
  • R a and R are each independently selected from the group consisting of:
  • heteroaryl is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
  • heteroaryl is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
  • heterocycle is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
  • R 3a and R 3b taken together with the atom to which they are attached form a carbonyl, with the proviso that at least one of R 3a and R 3b is other than hydrogen;
  • R 4a and R 4b are each independently hydrogen or or
  • R 3a and R 4a or R 3a and R 4b or R 3b and R 4a or R 3b and R 4b are joined together to form a bond or joined together so that together with the atoms to which they are attached there is formed a ring selected from phenyl, Cs-ecycloalkyl, optionally mono- or di-substituted with substituents independently selected from hydroxyl, -CH 3 , -CF 3 , -OCH 3 and -OCF 3 ;
  • R 5 is selected from the group consisting of:
  • R 6 is selected from the group consisting of:
  • heterocycle is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
  • (k) - H-S0 2 - H 2 optionally substituted with Ci -3 alkyl, phenyl, naphthyl, Ci -3 alkyl- phenyl, Ci -3 alkyl-naphthyl, heterocycle, C 3-6 -cycloalkyl or Ci -3 alkyl-heterocycle, wherein the heterocycle is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
  • alkyl of R 6 choices (a), (b), (e), (f), (g), (h), (i), (k) and (1)
  • aryl of R 6 choices (a), (b), (c), (d), (e), (f), (g), (h), (k) and (1)
  • heterocycloalkyl of R 6 choice (f) are each optionally mono or di- substituted with substituents independently selected from halogen, hydroxyl, -CH 3 , -CF 3 , -OCH 3 and -OCF 3 .
  • X is selected from -C(O)- and -CHCF 3 .
  • X is -C(O)- .
  • R 1 is selected from the group consisting of:
  • R 1 choices (a), (b) and (c) are optionally mono- or di-substituted with substituents independently selected from halogen, -CH 3 , -CF 3 , -OCH 3 and -OCF 3 .
  • R 1 is naphthyl
  • R 2 is -(CH 2 )n-C 3-8 cycloalkyl
  • C 3-8 cycloalkyl is optionally mono- or di-substituted with substituents independently selected from halogen, -CH 3 , -CF 3 , -OCH 3 and -OCF 3 .
  • R 2 is -(CH 2 )-cyclohexyl.
  • R 3a is hydrogen
  • R 3b is selected from the group consisting of:
  • R 3a and R 3b taken together with the atom to which they are attached form a carbonyl, or
  • R 3 and R 4a or R 3b and R 4b are joined together so that together with the atoms to which they are attached there is formed a ring selected from phenyl, Cs-ecycloalkyl, optionally mono- or di-substituted with substituents independently selected from hydroxyl, - CH 3 , -CF 3 , -OCH 3 and -OCF 3 .
  • R 3a is hydrogen
  • R ,b is selected from the group consisting of:
  • R 3 is hydrogen
  • R ,b is selected from the group consisting of:
  • R 4a and R 4b are each hydrogen, or
  • R 3b and R 4a or R 3b and R 4b are joined together so that together with the atoms to which they are attached there is formed a ring selected from phenyl, Cs-ecycloalkyl, optionally mono- or di-substituted with substituents independently selected from hydroxyl, - CH 3 , -CF 3 , -OCH 3 and -OCF 3 .
  • t is selected from 3, 4 or 5;
  • R 5 is selected from the group consisting of:
  • R 5 is selected from the group consisting of:
  • R 5 is selected from the group consisting of:
  • X is selected from -C(O)- and -CHCF 3 -;
  • R ,a is hydrogen
  • R 3b is selected from the group consisting of:
  • R a and R 3b taken together with the atom to which they are attached form a carbonyl, R 4 is hydrogen or C ⁇ alkyl, or
  • R 3b and R 4 are joined together to form a bond or joined so that together with the atomsh they are attached there is formed a ring selected from phenyl and cyclopentyl;
  • R 5 is selected from the group consisting of:
  • R 3b is selected from the group consisting of:
  • R 5 is selected from the group consisting of:
  • the invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt, solvate, solvate of the salt or prodrug thereof, and a pharmaceutically acceptable carrier.
  • the invention is directed to a method of preventing, or treating a disease of the eye selected from dry-AMD, Wet-AMD, and geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, diabetic macula edema (DME), other retinopathies such as choroidal neovascularisation (CNV), choroidal neovascular membrane (CNVM), cystoid macular edema (CME), epi-retmal membrane (ERM) and macular hole, hypertrophic changes of the retina!
  • a disease of the eye selected from dry-AMD, Wet-AMD, and geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, diabetic macula edema (DME), other retinopathies such as choroidal neovascularisation (CNV), choroidal neovascular membrane (CNVM), cystoi
  • RPE pigment epithelium
  • atrophic changes of the retinal pigment epithelium atrophic changes of the retinal pigment epithelium, retinal detachment, choroidal vein occlusion, retinal vein occlusion, corneal angiogenesis following, for example, keratitis, cornea transplantation or keratoplasty, corneal angiogenesis due to hypoxia (e.g., induced by extensive contact lens wearing), pterygium conjunctivae, subretinal edema, intraretinai edema, stargardt disease and degeneration of retinal or photoreceptor cells, comprising: administration of a therapeutically effective amount of compound of Formula I or a pharmaceutically acceptable salt, solvate, solvate of the salt or prodrug thereof.
  • a genus directed to a method of preventing a disease of the eye wherein the method of prevention is selected from delaying the onset of disease and reducing the risk of developing a disease of the eye, wherein the disease of the eye is selected from dry-AMD, Wet-AMD, and geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, diabetic macula edema (DME), other retinopathies such as choroidal neovascularisation (CNV), choroidal neovascular membrane (CNVM), cystoid macular edema (CME), epi-retinal membrane (ERM) and macular hole, hypertrophic changes of the retinal pigment epithelium (RPE), atrophic changes of the retinal pigment epithelium, retinal detachment, choroidal vein occlusion, retinal vein occlusion, corneal angiogenesis following, for example
  • a genus directed to a method treating a disease of the eye wherein the method is selected from controlling, alleviating, and slowing the progression of, wherein the disease is selected from dry-AMD, Wet-AMD, and geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, diabetic macula edema (DME), other retinopathies such as choroidal neovasculari sation (CNV), choroidal neovascular membrane (CNVM), cystoid macular edema (CME), epi -retinal membrane (ERM) and macular hole, hypertrophic changes of the retinal pigment epithelium (RPE), atrophic changes of the retinal pigment epithelium, retinal detachment, choroidal vein occlusion, retinal vein occlusion, corneal angiogenesis following, for example, keratitis, cornea transplantation or ker
  • AMD age-related macular degeneration
  • CNV choroidal neovascularisation
  • DME diabetic macula edema
  • the invention is directed to a method of inhibiting Htr Al protease activity in an eye comprising administration of a therapeutically effective amount of compound of Formula I or a pharmaceutically acceptable salt, solvate, solvate of the salt or prodrug thereof.
  • the invention is directed to a method of preventing, or treating a disease of the eye selected from dry-AMD, Wet-AMD, and geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, diabetic macula edema (DME), other retinopathies such as choroidal neovascularisation (CNV), choroidal neovascular membrane (CNVM), cystoid macular edema (CME), epi-retinal membrane (ERM) and macular hole, hypertrophic changes of the retinal pigment epithelium (RPE), atrophic changes of the retina!
  • a disease of the eye selected from dry-AMD, Wet-AMD, and geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, diabetic macula edema (DME), other retinopathies such as choroidal neovascularisation (C
  • corneal angiogenesis following, for example, keratitis, cornea transplantation or keratoplasty, corneal angiogenesis due to hypoxia (e.g., induced by extensive contact lens wearing), pterygium conjunctivae, subretinal edema, intraretinai edema, stargardt disease and degeneration of retinal or photoreceptor cells, comprising: administration of a therapeuticall effective amount of a compound of Formula I
  • each n is independently selected from 0, 1, or 2;
  • X is selected from -C(O)-, -S0 2 - and -CHCH 3 , wherein 1, 2 or 3 of the CH 3 hydrogens may optionally be replaced with a halogen;
  • R 1 is selected from the group consisting of:
  • R 1 choices (a), (b), (c), (d) and (e) are optionally mono- or di- substituted with substituents independently selected from halogen, -CH 3 , -CF 3 , -OCH 3 and -OCF 3 ;
  • R 2 is selected from the group consisting of: (a) -(CH 2 )n-C 3 - 8 cycloalkyl,
  • heteroaryl is a 5- or 6-membered monocyclic ring, having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
  • R 2 choices (a), (b) and (c) are optionally mono- or di-substituted with substituents independently selected from halogen, -CH 3 , -CF 3 , -OCH 3 and -OCF 3 ;
  • R 3a and R 3b are each independently selected from the group consisting of:
  • heteroaryl is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
  • heteroaryl is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
  • heterocycle is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
  • R 3a and R 3b taken together with the atom to which they are attached form a carbonyl, or
  • R 4a and R 4b are each independently hydrogen or or
  • R 3a and R 4a or R 3a and R 4b or R 3b and R 4a or R 3b and R 4b are joined together to form a bond or joined together so that together with the atoms to which they are attached there is formed a ring selected from phenyl, Cs-ecycloalkyl, optionally mono- or di-substituted with substituents independently selected from hydroxyl, -CH 3 , -CF 3 , -OCH 3 and -OCF 3 ;
  • R 5 is selected from the group consisting of:
  • R 6 is selected from the group consisting of:
  • heterocycle is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
  • (k) - H-S0 2 - H 2 optionally substituted with Ci -3 alkyl, phenyl, naphthyl, Ci -3 alkyl- phenyl, Ci -3 alkyl-naphthyl, heterocycle, C 3-6 -cycloalkyl or Ci -3 alkyl-heterocycle, wherein the heterocycle is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
  • alkyl of R 6 choices (a), (b), (e), (f), (g), (h), (i), (k) and (1)
  • aryl of R 6 choices (a), (b), (c), (d), (e), (f), (g), (h), (k) and (1)
  • heterocycloalkyl of R 6 choice (f) are each optionally mono or di- substituted with substituents independently selected from halogen, hydroxyl, -CH 3 , -CF 3 , -OCH 3 and -OCF 3 .
  • patient includes mammals such as mice, rats, cows, sheep, pigs, rabbits, goats, horses, monkeys, dogs, cats, and humans.
  • halo or halogen refers to any radical of fluorine, chlorine, bromine or iodine.
  • alkyl refers to a saturated hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms.
  • Ci -6 alkyl indicates that the group may have from 1 to 6 (inclusive) carbon atoms in it.
  • an alkyl is a which represents a straight-chain or branched saturated hydrocarbon radical having 1 to 6 carbon atoms. Examples include methyl, ethyl, ⁇ -propyl, isopropyl, «-butyl, isobutyl, sec-butyl, tert-butyl. Any atom can be optionally substituted, e.g., by one or more substituents. Examples of alkyl groups include without limitation methyl, ethyl, ⁇ -propyl, isopropyl, «-butyl, sec-butyl and tert-butyl.
  • haloalkyl refers to an alkyl group, in which at least one hydrogen atom is replaced by halo. In some embodiments, more than one hydrogen atom (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) are replaced by halo. In these embodiments, the hydrogen atoms can each be replaced by the same halogen (e.g., fluoro) or the hydrogen atoms can be replaced by a combination of different halogens (e.g., fluoro and chloro).
  • Haloalkyl also includes alkyl moieties in which all hydrogens have been replaced by halo (sometimes referred to herein as perhaloalkyl, e.g., perfluoroalkyl, such as trifluoromethyl). Any atom can be optionally substituted, e.g., by one or more substituents.
  • a haloalkyl is a Ci-6haloalkyl.
  • a fluoroalkyl is a Ci. 6 fluoroalkyl.
  • alkoxy refers to a group of formula -O- (alkyl).
  • Alkoxy can be, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso- butoxy, sec-butoxy, pentoxy, 2-pentoxy, 3-pentoxy, or hexyloxy.
  • thioalkoxy refers to a group of formula -S-(alkyl).
  • haloalkoxy and thiohaloalkoxy refer to -O-(haloalkyl) and -S-(haloalkyl), respectively.
  • sulfhydryl refers to -SH.
  • aralkyl refers to an alkyl moiety in which an alkyl hydrogen atom is replaced by an aryl group. One of the carbons of the alkyl moiety serves as the point of attachment of the aralkyl group to another moiety. Any ring or chain atom can be optionally substituted e.g., by one or more substituents.
  • aralkyl include benzyl, 2-phenylethyl, and 3-phenylpropyl groups.
  • alkenyl refers to a straight or branched hydrocarbon chain containing the indicated number of carbon atoms and having one or more carbon-carbon double bonds. Any atom can be optionally substituted, e.g., by one or more substituents. Alkenyl groups can include, e.g., vinyl, allyl, 1-butenyl, and 2-hexenyl. In some embodiments, an alkenyl is a C2- 6 alkenyl.
  • heterocycle or “heterocyclic” includes heterocycloalkyls and heteroaryls.
  • heterocycloalkyl represents a stable 3-, 4-, 5-, 6- or 7-membered monocyclic- or stable 6-, 7-, 8-, 9-, 10-, 11-, or 12- membered fused bicyclic heterocyclic ring system which comprises at least one non-aromatic (i.e. saturated or partially unsaturated) ring which consists of carbon atoms and from one to four, preferably up to three, heteroatoms selected from the group consisting of N, O and S, wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and wherein the nitrogen heteroatom may optionally be quaternized.
  • non-aromatic i.e. saturated or partially unsaturated
  • a heterocycloalkyl is a C 2- ioheterocycloalkyl. In other embodiments, a heterocycloalkyl is a C 2- 6heterocycloalkyl. In some embodiments, a heterocycloalkyl is monocyclic preferably having a total number of 4 to 7, more preferably 4 to 6 ring atoms, including 3 to 6, preferably 3 to 5 carbon atoms and up to 2 heteroatoms and/or hetero-groups independently selected from the group consisting of N, O, S, SO and S0 2 , which ring system can be bonded via a ring carbon atom or, if possible, via a ring nitrogen atom.
  • a heterocycloalkyl is bicyclic.
  • the second ring may also be a non-aromatic ring which consists of carbon atoms and from one to four, preferably up to three, heteroatoms selected from the group consisting of N, O and S, as defined above, or the second ring may be a benzene ring, or a "cycloalkyl", or a “cycloalkenyl", as defined immediately below.
  • heterocyclic groups include, but are not limited to, aziridine, azetidine, chroman, dihydrofuran, dihydropyran, dioxane, dioxolane, hexahydroazepine, imidazolidine, imidazoline, indoline, isochroman, isoindoline, isothiazoline, isothiazolidine, isoxazoline, isoxazolidine, morpholine, oxazoline, oxazolidine, oxetane, piperazine, piperidine, pyran, pyrazolidine, pyrazoline, pyrrolidine, pyrroline, tetrahydrofuran, tetrahydropyran, thiamorpholine, thiazoline, thiazolidine, thiomorpholine, thietane, thiolane, sulfolane, 1,3-dioxolane, 1,3-oxa
  • 5- or 6-membered monocyclic heterocycloalkyl radicals having up to 2 heteroatoms selected from the group consisting of N, O and S, such as illustratively and preferably tetrahydrofuran, 1,3-dioxolane, pyrrolidine, tetrahydropyran, 1,4-dioxane, piperidine, piperazine, morpholine, and thiomorpholine.
  • cycloalkyl refers to a fully saturated monocyclic, bicyclic, tricyclic, or other polycyclic hydrocarbon groups. Any atom can be optionally substituted, e.g., by one or more substituents. A ring carbon serves as the point of attachment of a cycloalkyl group to another moiety. Cycloalkyl moieties can include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and norbornyl (bicyclo[2.2.1]heptyl).
  • a cycloalkyl is a C3.i 0 cycloalkyl. In other embodiments, a cycloalkyl is a C3- 6 cycloalkyl. In some embodiments, a cycloalkyl is monocyclic. In some embodiments, a cycloalkyl is bicyclic.
  • cycloalkenyl refers to partially unsaturated monocyclic, bicyclic, tricyclic, or other polycyclic hydrocarbon groups.
  • a ring carbon e.g., saturated or unsaturated
  • Any atom can be optionally substituted e.g., by one or more substituents.
  • Cycloalkenyl moieties can include, e.g., cyclopentenyl, cyclohexenyl, cyclohexadienyl, or norbornenyl.
  • a cycloalkenyl is a C4-iocycloalkenyl.
  • a cycloalkenyl is a C 4 . 6Cycloalkenyl. In some embodiments, a cycloalkenyl is monocyclic. In some embodiments, a cycloalkenyl is bicyclic.
  • cycloalkylene refers to a divalent monocyclic cycloalkyl group having the indicated number of ring atoms.
  • heterocycloalkylene refers to a divalent monocyclic heterocycloalkyl group having the indicated number of ring atoms.
  • aryl as used herein, is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, or biphenyl.
  • heteroaryl represents a stable 5-, 6- or 7-membered monocyclic- or stable 9 or 10-membered fused bicyclic ring system which comprises at least one aromatic ring, -which consists of carbon atoms and from one to four, preferably up to three, heteroatoms selected from the group consisting of N, O and S wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
  • the second ring need not be aromatic and need not comprise a heteroatom.
  • heteroaryl includes, for example, a stable 5-, 6- or 7-membered monocyclic aromatic ring consisting of carbon atoms and from one to four, preferably up to three , heteroatoms, as defined immediately above, fused to a benzene ring, or fused to a "heterocycloalkyl", a “cycloalkyl”, or a “cycloalkenyl”, as defined above.
  • heteroaryl groups include, but are not limited to, benzimidazole, benzisothiazole, benzisoxazole, benzofuran, isobenzofuran, benzothiazole, benzothiophene, benzotriazole, benzoxazole, carboline, cinnoline, furan, furazan, imidazole, indazole, indole, indolizine, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, phthalazine, pteridine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazine, triazole, triazole, benzimidazole,
  • 6-membered heteroaryl radicals having up to 2 nitrogen atoms such as pyridyl, pyrimidyl, pyridazinyl and pyrazinyl
  • 5-membered heteroaryl radicals having up to 2 heteroatoms selected from the group consisting of N, O and S such as illustratively and preferably thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isothiazolyl, and isoxazolyl.
  • acyl refers to those groups derived from an organic acid by removal of the hydroxy portion of the acid. Accordingly, acyl is meant to include, for example, acetyl, propionyl, butyryl, decanoyl, pivaloyl, benzoyl and the like.
  • Compound Forms And Salts [0083] The compounds of this invention may contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, enantiomerically enriched mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures.
  • the compounds of this invention include all cis, trans, syn, anti,
  • E
  • Z
  • 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.
  • the compounds of this invention include the compounds themselves, as well as their salts, solvate, solvate of the salt and their prodrugs, if applicable.
  • Salts for the purposes of the present invention are preferably pharmaceutically acceptable salts of the compounds according to the invention (for example, see S. M. Berge et al, "Pharmaceutical Salts", J. Pharm. Sci. 1977, 66, 1-19). Salts which are not themselves suitable for pharmaceutical uses but can be used, for example, for isolation or purification of the compounds according to the invention are also included.
  • a salt for example, can be formed between an anion and a positively charged substituent (e.g., amino) on a compound described herein.
  • Suitable anions include chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, and acetate.
  • a salt can also be formed between a cation and a negatively charged substituent (e.g., carboxylate) on a compound described herein.
  • Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion.
  • pharmaceutically acceptable salts refer to derivatives wherein the parent compound is modified by making acid or base salts thereof.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfonic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2- acetoxybenzoic, fumaric, benzenesulfonic, toluenesulfonic, naphthalenedisulfonic, methanesulfonic, ethanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
  • inorganic acids such as hydrochloric, hydrobromic, sulfonic, sulfuric, sulfamic
  • salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include acetic, benzenesulfonic, benzoic, naphthalenedisulfonic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, ⁇ -toluenesulfonic acid, and the like.
  • the salts are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids.
  • salts may be prepared from pharmaceutically acceptable non-toxic bases, including inorganic and organic acids.
  • Such salts that may be prepared include lithium salt, sodium salt, potassium salt, magnesium salt, calcium salt, dicyclohexylamine salt, N-methyl-D-glucamine salt, tris(hydroxymethyl)methylamine salt, arginine salt, lysine salt, and the like.
  • Solvates in the context of the invention are designated as those forms of the compounds according to the invention which form a complex in the solid or liquid state by stoichiometric coordination with solvent molecules. Hydrates are a specific form of solvates, in which the coordination takes place with water. Hydrates are preferred solvates in the context of the present invention.
  • the compounds of this invention may, either by nature of asymmetric centers or by restricted rotation, be present in the form of isomers (enantiomers, diastereomers). Any isomer may be present in which the asymmetric center is in the (R)-, (S)-, or (R,S)-configuration.
  • the present invention also encompasses all suitable isotopic variants of the compounds according to the invention.
  • An isotopic variant of a compound according to the invention is understood to mean a compound in which at least one atom within the compound according to the invention has been exchanged for another atom of the same atomic number, but with a different atomic mass than the atomic mass which usually or predominantly occurs in nature.
  • isotopes which can be incorporated into a compound according to the invention are those of hydrogen, carbon, nitrogen, oxygen, fluorine, chlorine, bromine and iodine, such as 2H (deuterium), 3H (tritium), 13C, 14C, 15N, 170, 180, 18F, 36C1, 82Br, 1231, 1241, 1251, 1291 and 1311.
  • Particular isotopic variants of a compound according to the invention especially those in which one or more radioactive isotopes have been incorporated, may be beneficial, for example, for the examination of the mechanism of action or of the active compound distribution in the body.
  • isotopes for example of deuterium
  • isotopes can lead to particular therapeutic benefits as a consequence of greater metabolic stability of the compound, for example an extension of the half-life in the body or a reduction in the active dose required.
  • modifications of the compounds according to the invention may therefore in some cases also constitute a preferred embodiment of the present invention.
  • Isotopic variants of the compounds according to the invention can be prepared by processes known to those skilled in the art, for example by the methods described below and the methods described in the working examples, by using corresponding isotopic modifications of the particular reagents and/or starting compounds therein.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium, iodine-125 or carbon-14. All isotopic variations of the compounds of the invention, whether radioactive or not, are intended to be encompassed within the scope of the invention.
  • hydrogen atoms of the compounds described herein may be replaced with deuterium atoms.
  • compounds of Formula I are prepared as prodrugs.
  • Prodrugs are generally drug precursors that, following administration to a subject and subsequent absorption, are converted to an active, or a more active species via some process, such as conversion by a metabolic pathway.
  • Examples of prodrugs include Ci -6 alkyl esters of carboxylic acid groups and esters of boronic acids, which, upon administration to a subject, are capable of providing active compounds. Esters of boronic acids and esters are illustrated by Formula II:
  • Yi and Y 2 are each independently selected from hydrogen, optionally substituted Ci. 6 alkyl, C3-iocycloalkyl, Ci-eheterocycle, aryl and heteroaryl, or Yi and Y 2 are joined together so that the group:
  • Y 1 and Y 2 forms an optionally substituted C 2-6 alkyl, optionally substituted heterocycle, optionally substituted aryl or optionally substituted heteroaryl.
  • the optional substituents include, for example, hydroxyl, halogen and As will be appreciated by one of skill in the art, the squiggly lines shown above, describe the point at which the moiety shown is attached to the parent molecule. Illustrating the boronic acid esters are:
  • Yi and Y 2 can also form a 6-membered trioxatriborinane or a 4-membered dioxadiboretane.
  • pharmaceutically acceptable carrier refers to a carrier or an adjuvant that may be administered to a patient, together with a compound of this invention, or a pharmaceutically acceptable salt thereof, 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.
  • composition as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • composition in relation to pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • compositions of the present invention encompass any composition made by admixing a compound of the present invention, or a pharmaceutically acceptable salt, or solvate or solvate of the salt thereof, and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the present invention includes within its scope prodrugs of the compounds of this invention.
  • prodrugs will be functional derivatives of the compounds of this invention which are readily convertible in vivo into the required compound.
  • the terms "administration of or "administering a” compound shall encompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985. Metabolites of these compounds include active species produced upon introduction of compounds of this invention into the biological milieu.
  • the amount administered depends on the compound formulation, route of administration, etc. and is generally empirically determined in routine trials, and variations will necessarily occur depending on the target, the host, and the route of administration, etc.
  • the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1, 3, 10 or 30 to about 30, 100, 300 or 1000 mg, according to the particular application.
  • the total daily dosage may be divided and administered in portions during the day if desired.
  • This invention is directed to novel Boronic acid derivatives of Formula I, and pharmaceutically acceptable salts and esters thereof, useful in the prevention (e.g., delaying the onset of or reducing the risk of developing) and treatment (e.g., controlling, alleviating, or slowing the progression of) of Age-related Macular Degeneration (AMD) and related diseases of the eye.
  • AMD Age-related Macular Degeneration
  • These diseases include dry-AMD, Wet-AMD, geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, diabetic macula edema (DME), other retinopathies such as choroidal neovascularisation (CNV), choroidal neovascular membrane (CNVM), cystoid macular edema (CME), epi- retinal membrane (ERM) and macular hole, hypertrophic changes of the retinal pigment epithelium (RPE), atrophic changes of the retinal pigment epithelium, retinal detachment, choroidal vein occlusion, retinal vein occlusion, corneal angiogenesis following, for example, keratitis, cornea transplantation or keratoplasty, corneal angiogenesis due to hypoxia (e.g., induced by extensive contact lens wearing), pterygium conjunctivae, subretinai edema, intraretinal e
  • the invention disclosed herein is further directed to methods of prevention, slowing the progress of, and treatment of dry-AMD, Wet-AMD, and geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, diabetic macula edema (DME), other retinopathies such as choroidal neovasculari sation (CNV), choroidal neovascular membrane (CNVM), cystoid macular edema (CME), epi -retinal membrane (ERM) and macular hole, hypertrophic changes of the retinal pigment epithelium (RPE), atrophic changes of the retinal pigment epithelium, retinal detachment, choroidal vein occlusion, retinal vein occlusion, corneal angiogenesis following, for example, keratitis, cornea transplantation or keratoplasty, corneal angiogenesis due to hypoxia (e.g., induced by extensive contact lens wearing), ptery
  • the compounds of the invention are inhibitors of HTRA1.
  • the compounds of the invention are useful in the prevention and treatment of a wide range diseases mediated (in whole or in part) by HTRA1.
  • the compounds of the invention are also useful for inhibiting HtrAl protease activity in an eye and elsewhere.
  • the compounds of the present invention are particularly suitable for the treatment and/or prevention of ocular disorders, such as age-related macular degeneration (AMD) like wet-AMD or dry-AMD, geographic atrophy, diabetic retinopathy, stargardt disease choroidal neovascularisation (CNV), and diabetic macula edema (DME).
  • AMD age-related macular degeneration
  • CNV stargardt disease choroidal neovascularisation
  • DME diabetic macula edema
  • the compounds and compositions described herein can, for example, be administered orally, parenterally (e.g., subcutaneously, intracutaneously, intravenously, intramuscularly, intraarticularly, intraarterially, intrasynovially, intrasternally, intrathecally, intralesionally and by intracranial injection or infusion techniques), by inhalation spray, topically, rectally, nasally, buccally, vaginally, via an implanted reservoir, by injection, subdermally, intraperitoneally, transmucosally, or in an ophthalmic preparation, with a dosage ranging from about 0.01 mg/kg to about 1000 mg/kg, (e.g., from about 0.01 to about 100 mg/kg, from about 0.1 to about 100 mg/kg, from about 1 to about 100 mg/kg, from about 1 to about 10 mg/kg) every 4 to 120 hours, or according to the requirements of the particular drug.
  • parenterally e.g., subcutaneously, intracutaneously, intravenously, intramus
  • compositions are administered by oral administration or by injection.
  • 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.
  • Dosage forms include from about 0.001 milligrams to about 2,000 milligrams (including, from about 0.001 milligrams to about 1,000 milligrams, from about 0.001 milligrams to about 500 milligrams, from about 0.01 milligrams to about 250 milligrams, from about 0.01 milligrams to about 100 milligrams, from about 0.05-milligrams to about 50 milligrams, and from about 0.1 milligrams to about 25 milligrams) of a compound of Formula I (and/or a compound of any of the other formulae described herein) or a salt (e.g., a pharmaceutically acceptable salt) thereof as defined anywhere herein.
  • the dosage forms can further include a pharmaceutically acceptable carrier and/or an additional therapeutic agent.
  • ophthalmic preparation because AMD and related diseases (including dry-AMD, Wet-AMD, geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, and degeneration of retinal or photoreceptor cells) primarily afflict the back of the eye, local administration such as topical administration, trans-scleral drug delivery and intravitreal administration may be preferable over systemic administration. Intravitreal administration can be further divided into intravitreal injection and intravitreal implants. Of these, intravitreal injection appears to be the most widely used. Products utilizing intravitreal injection include Macugen, Lucentis, Ozurdex and Ileuvien.
  • the preferred dosage range for local administration to the back of the eye ranges from 0.001 mg to 100 mg (including from about 0.01 milligrams to about 500 milligrams, from about 0.05 milligrams to about 250 milligrams, from about 0.05 milligrams to about 100 milligrams, from about 0.1 milligrams to about 100 milligrams, from about 0.1 milligrams to about 50 milligrams, and from about 0.1 milligrams to about 10 milligrams).
  • Useful references on the subject of ophthalimic drug delivery include: Kompella U.B., et. al., Recent Advances in Ophthalmic Drug Delivery, Ther. Deliv. 2010 1(3): 435-456; Gaudana R.
  • the preferred route for administering the compounds of the invention is topically at the eye or by an ocular drug delivery system.
  • Intraocular injections are another way to administer the compounds of the present invention that is suitable for such purposes.
  • Delivery to areas within the eye can be accomplished by injection, employing a cannula or another invasive device designed to introduce precisely metered amounts of a desired formulation to a particular compartment or tissue within the eye (e.g., posterior chamber or retina).
  • An intraocular injection may be into the vitreous (intravitreal), under the conjunctiva (subconjunctival), behind the eye (retrobulbar), into the sclera, or under the Capsule of Tenon (sub-Tenon), and may be in a depot form.
  • Other intraocular routes of administration and injection sites and forms are also contemplated and are within the scope of the invention.
  • the compounds according to the invention may be formulated in a manner known to those skilled in the art so as to give adequate delivery to the back of the eye, which may be by regular dosing, such as with eye drops, or by using a delivery system to give a controlled release, such as slow release, of the compounds according to the invention.
  • Preferred ocular formulations for the compounds of the present invention include aqueous solutions, suspensions or gels of these compounds in the form of drops of liquid, liquid washes, sprays, ointments or gels, in a mixture with excipients suitable for the manufacture and use of such application forms.
  • the compounds of the present invention may be applied to the eye via liposomes or other ocular delivery systems that are known in the art.
  • Appropriate dosage levels may be determined by any suitable method known to one skilled in the art of treating eye diseases.
  • the active substance is administered at a frequency of 1 to 4 times per day for topical administration, or less often if a drug delivery system is used.
  • an ocular formulation intended for topical application contains the active ingredient in a concentration range of about 0.001% to 10%.
  • actual dosage levels and time course of administration of the active ingredients in the pharmaceutical compositions of the invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition and mode of administration, without being toxic to the patient.
  • the compounds of the invention may be co-administered with one or more additional agents.
  • the additional agents include, but are not limited to Acuvail (ketorolac tromethamine), AK-Con-A (naphazoline), Akten (lidocaine hydrochloride), Alamast (pemirolast potassium), Alphagan (brimonidine), Bepreve (bepotastine besilate), Besivance (besifloxacin), Betaxon, Cosopt, Cystaran (cysteamine hydrochloride), Durezol (difluprednate), Eylea (aflibercept), Jetrea (ocriplasmin), Lotemax, Lucentis (ranibizumab), Lumigan (bimatoprost), Macugen (pegaptanib), Ocuflox (ofloxacin), OcuHist, Omidria (phenylephrine and ketorolac injection), Ozurdex (dexamethasone), Quix
  • the compounds of the invention may be co-administered with one or more inhibitors of VEGF- mediated angiogenesis, such as, for example, ACTB-1003, aflibercept, apatinib, axitinib, bevacizumab, bevasiranib, BMS-690514, brivanib, cediranib, CT-322, dovitinib, E7080, foretinib, KH-902, linifanib, MGCD-265, motesanib, OTS-102, pazopanib, pegaptanib, ranibizumab, regorafenib, ruboxystaurin, sorafenib, SU-14813, sunitinib, telatinib, TG- 100801, tivozanib, TSU-68, vandetanib, vargatef, vatalanib and XL-184, or with inhibitors of other signaling pathways, such as,
  • the additional agents may be administered separately (e.g., sequentially; on different overlapping schedules), as part of a multiple dose regimen, from the compounds of this invention (e.g., one or more compounds of Formula (I) and/or a compound of any of the other formulae, including any subgenera or specific compounds thereof).
  • these agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition.
  • these agents can be given as a separate dose that is administered at about the same time as that of one or more compounds of Formula (I) (and/or a compound of any of the other formulae, including any subgenera or specific compounds thereof) are administered (e.g., simultaneously with the administration of one or more compounds of Formula (I) (and/or a compound of any of the other formulae, including any subgenera or specific compounds thereof)).
  • compositions of this invention include 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 can 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.
  • compositions of this invention may contain any conventional nontoxic pharmaceutically-acceptable carriers, adjuvants or vehicles.
  • 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.
  • compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions.
  • carriers which are commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried corn starch.
  • Serial dilutions (1/3) from 1000 ⁇ down to 0.051 ⁇ of test compounds were prepared in dimethyl sulfoxide (DMSO). Then 2 ⁇ _, of DMSO from each dilution were added to 100 ⁇ _, of 4 nM full-length human His-HtrAl in assay buffer (50 mM Tris, pH 7.5, 200 mM NaCl and 0.25% CHAPS) in white non-binding 96-well plates. The assay solutions were mixed for 5 seconds on a shaker plate and incubated for 10 minutes at room temperature.
  • assay buffer 50 mM Tris, pH 7.5, 200 mM NaCl and 0.25% CHAPS
  • SNP's include rsl 1200638, rsl0490924, rs3750848, rs3793917 and rs932275.
  • the risk allele rsl 1200638 was found to be associated with increased HTRAl mRNA and protein expression, and HtrAl is present in drusen in patients with AMD (see Dewan et al, 2006, Science 314:989-992; Yang et al, 2006, Science 314:992- 993).
  • Synthesis [0119]
  • the starting materials used for the synthesis are either synthesized or obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, Fluka, Acros Organics, Alfa Aesar, VWR Scientific, and the like. General methods for the preparation of compounds can be modified by the use of appropriate reagents and conditions for the introduction of the various moieties found in the structures as provided herein.
  • a boronate ester (prepared using standard procedures described in the literature, including those as described within Boronic Acids: Preparation and Applications in Organic Synthesis, Medicine and Materials; Dennis Hall, Ed.; John Wiley & Sons) is reacted with dichloromethyllithium as described by Matteson in Chemical Reviews, 1989, 89, 1535-1551.
  • the corresponding a-chloro boronate is converted to an a-amino boronate by treatment with an amine or protected amine (such as LiHMDS).
  • the prepared a-amino boronate can be attached to the proline residue using standard amide coupling conditions described in the literature (e.g. Chemical Society Reviews, 2009, 38, 606-631).
  • the proline acid can be coupled to the a-amino boronate using HATU in the presence of EtN(/ ' Pr) 2 and CH 2 C1 2 .
  • the proline acid can be first converted to an N-hydrosuccinimide ester (using for example NHS, EDCI in CH 2 C1 2 ) and then reacted with the a-amino boronate in the presence of a suitable base (e.g. Et 3 N).
  • the proline acid may be protected at the nitrogen (e.g. Boc, CBz) or may be further functionalized with an a-amino acid or derivative.
  • Method C Amide coupling of proline analogs with a-amino acids
  • a substituted proline analog (or salt thereof) can be joined together with an appropriate carboxylic acid to afford the coupled product under standard amide coupling conditions (e.g. HATU, EtN(zPr) 2 , CH 2 C1 2 ).
  • standard amide coupling conditions e.g. HATU, EtN(zPr) 2 , CH 2 C1 2 .
  • Typical amide coupling conditions have been described in the literature, including the review article by Eric Valeur and Mark Bradley in Chemical Society Reviews 2009, 38, 606-631.
  • the alcohol moiety from a 4-hydroxyproline analog is converted into a suitable leaving group (e.g. mesylate) under standard conditions and then reacted in the presence of a suitable nucleophile (e.g. amine, thiol) in the presence of a base (e.g. Et 3 N or NaH) to afford a 4-substituted proline derivative.
  • a suitable nucleophile e.g. amine, thiol
  • a base e.g. Et 3 N or NaH
  • the proline may contain a 2-ester moiety or may be further functionalized with an a-amino boronate.
  • An appropriate 4-amino proline analog is reacted with an acylating reagent (such as an acyl chloride, acyl anhydride or sulfonyl chloride) in the presence of a suitable base (e.g. Et 3 ) and solvent (e.g. CH 2 CI 2 ).
  • acylating reagent such as an acyl chloride, acyl anhydride or sulfonyl chloride
  • a suitable base e.g. Et 3
  • solvent e.g. CH 2 CI 2
  • the proline may be protected at the proline nitrogen (e.g. Boc, Cbz) or may be further functionalized with an a-amino acid or derivative.
  • the substituent close to the a-amino boronate can be further functionalized through conversion to an amine, which can then be reacted with a range of acylating rea ents, including isocyanates, acyl chlorides and sulfonyl chlorides.
  • Boronate esters can be converted to boronic acids using a number of procedures described in the literature, including those described within Boronic Acids: Preparation and Applications in Organic Synthesis, Medicine and Materials; Dennis Hall, Ed.; John Wiley & Sons.
  • the boronate ester can be reacted with a sacrificial boronic acid (e.g. phenyl boronic acid, isobutyl boronic acid) in an appropriate solvent (e.g. methanol, ethanol, hexanes or octane) with an acid catalyst (e.g. hydrochloric acid, acetic acid).
  • a sacrificial boronic acid e.g. phenyl boronic acid, isobutyl boronic acid
  • an appropriate solvent e.g. methanol, ethanol, hexanes or octane
  • an acid catalyst e.g. hydrochloric acid, acetic acid
  • Step 1 Preparation of (3a,S',4 ) S',6 ) S',7aR)-2-isopropyl-3a,5,5-trimethylhexahydro-4,6- methanob enzo [d ⁇ [ 1 , 3 ,2] di oxab orol e
  • Step 2 Preparation of (3a,S',4 ) S',6 ) S',7aR)-2-((S)-l-chloro-2-methylpropyl)-3a,5,5- trimethylhexahydro-4,6-methanobenzo[ ⁇ i][l,3,2]dioxaborole [0130]
  • anhydrous THF 100 mL
  • CH 2 C1 2 3.0 mL, 47.2 mmol, 1.5 equiv.
  • the solution was cooled to between -110 °C and -100 °C in an Et 2 0/liquid N 2 Dewar.
  • the Et 2 0 is added to the Dewar first, followed by portion wise addition of liq. N 2 until the Et 2 0 becomes semi-solid.
  • the temperature of the bath is monitored with a thermometer.
  • a solution of 2.5 M «-BuLi in hexanes (15.2 mL, 37.8 mmol, 1.2 equiv) was added via syringe over a period of 15 minutes, down the side of flask and maintaining an internal reaction temperature below -90 °C.
  • Additional aliquots of liq. N 2 were added to the Dewar to maintain the bath temperature between -110 and -100 °C.
  • Step 3 Preparation of (R)-2-methyl-l-((3a,S',4 ) S',6 ) S',7aR)-3a,5,5-trimethylhexahydro- 4,6-methanobenzo[ ⁇ i] [ 1 ,3 ,2]dioxaborol-2-yl)propan- 1 -amine hydrochloride
  • the resulting yellow solution was concentrated under reduced pressure and the resulting oil suspended in hexanes (150 mL) and filtered through a pad of celite (4 x 4 cm) on a sintered plastic funnel. The filter cake was further washed with hexanes (2 x 20 mL) and the resulting yellow filtrate was collected into a 500 mL round-bottom flask. To the flask containing the filtrate was added a magnetic stir bar, septa and nitrogen inlet and the solution was cooled to -78 °C in a dry ice/acetone Dewar.
  • Step 1 Preparation of (3a,S',4 ) S',6 ) S',7aR)-2-(4-bromobutyl)-3a,5,5-trimethylhexahydro- 4,6-methanobenzo[ ⁇ i] [ 1 ,3 ,2]dioxaborole
  • Step 2 Preparation of (3a,S',4 ) S',6 ) S',7aR)-2-(( ) S)-5-bromo-l-chloropentyl)-3a,5,5- trimethylhexahydro-4,6-methanobenzo[ ⁇ i][l,3,2]dioxaborole
  • Step 3 Preparation of (R)-5-bromo-l-((3a,S',4 ) S',6 ) S',7aR)-3a,5,5-trimethylhexahydro- 4,6-methanobenzo[ ⁇ i][l,3,2]dioxaborol-2-yl)pentan-l-amine hydrochloride
  • the resulting yellow solution was concentrated under reduced pressure and the resulting oil suspended in hexanes (150 mL) and filtered through a pad of celite (4 x 4 cm) on a sintered funnel. The filter cake was further washed with hexanes (2 x 20 mL) and the resulting yellow filtrate was collected into a 500 mL round-bottom flask. To the flask containing the filtrate was added a magnetic stir bar, septa and nitrogen inlet and the solution was cooled to -78 °C in a dry ice/acetone Dewar.
  • Step 1 Preparation of (3a,S',4 ) S',6 ) S',7aR)-2-(3-bromopropyl)-3a,5,5- trimethylhexahydro-4,6-methanobenzo[ ⁇ i][l,3,2]dioxaborole
  • Step 2 Preparation of (3aS,4S,6S,7aR)-2-((S)-4-bromo-l-chlorobutyl)-3a,5,5- trimethylhexahydro-4,6-methanobenzo[ ⁇ i][l,3,2]dioxaborole
  • Step 3 Preparation of (R)-4-bromo-l-((3a,S',4 ) S',6 ) S',7aR)-3a,5,5-trimethylhexahydro- 4,6-methanobenzo[ ⁇ i] [ 1 ,3 ,2]dioxaborol-2-yl)butan- 1 -amine hydrochloride
  • the resulting yellow solution was concentrated under reduced pressure and the resulting oil suspended in hexanes (120 mL) and filtered through a pad of celite (4 x 4 cm) on a sintered funnel. The filter cake was further washed with hexanes (2 x 20 mL) and the resulting yellow filtrate was collected into a 500 mL round-bottom flask. To the flask containing the filtrate was added a magnetic stir bar, septa and nitrogen inlet and the solution was cooled to -78 °C in a dry ice/acetone Dewar.
  • Step 1 Preparation of methyl (R)-2-(2-naphthamido)-3-cyclohexylpropanoate
  • reaction was quenched with water (25 mL) and poured into a 250 mL separately funnel containing 1 M aqueous HCl solution (100 mL) and the aqueous layer was extracted with CH 2 C1 2 (2 x 75 mL). The combined organic layers were washed with brine (50 mL), dried over MgS0 4 , filtered and concentrated under reduced pressure. The reaction mixture was purified by column chromatography on silica gel, eluting with 80:20 Hexanes:EtOAc to afford the indicated product as a white foam (2.36 g, 62%).
  • Step 2 Preparation of (R)-2-(2-naphthamido)-3-cyclohexylpropanoic acid [0142] Into a 100 mL round-bottom flask equipped with a magnetic stir bar was added methyl (R)-2-(2-naphthamido)-3-cyclohexylpropanoate (2.35 g, 6.92 mmol, 1.0 equiv), THF (10 mL) and MeOH (10 mL). The solution was treated with 1.0 M aqueous LiOH solution (10.4 mL, 10. 4 mmol, 1.5 equiv) and stirred at room temperature for 3 h. TLC analysis reveals complete conversion of starting material.
  • the reaction mixture was concentrated under reduced pressure and the resulting solids were taken up in 5 mL of methanol and acidified to pH ⁇ 2 with 1.0 M aqueous HCI solution (approx 15 mL).
  • the resulting white suspension was stirred at room temperature for 4 h and then filtered through a Buchner funnel containing Whatman # 1 filter paper under vacuum. The filter cake was dried under vacuum to afford a white free flowing solid (2.07 g, 92% yield).
  • Step 1 Preparation of (R)-3-cyclohexyl-2-(((R)-2,2,2-trifluoro-l-(naphthalen-2- yl)ethyl)amino)propanoic acid
  • Step 1 Preparation of tert-butyl (2 ⁇ 4R)-2-(((R)-2-methyl-l-((3a ⁇ 4 ⁇ 6 ⁇ ,7aR)-3a,5,5- trimethylhexahydro-4,6-methanobenzo[ii][l,3,2]dioxaborol-2-yl)propyl)carbamoyl)-4- phenylpyrrolidine- 1 -carboxylate
  • Step 2 Preparation of (2 ⁇ ,4R)-N-((R)-2-methyl-l-((3a ⁇ ,4 ⁇ ,6 ⁇ ,7aR)-3a,5,5- trimethylhexahydro-4,6-methanobenzo[ ⁇ i][l,3,2]dioxaborol-2-yl)propyl)-4- phenylpyrrolidine-2-carboxamide hydrochloride
  • Step 3 Preparation of (2,S',4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N- ((R)-2-methyl-l-((3a,S',45',65',7aR)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[ ⁇ i][l,3,2]dioxaborol-2-yl)propyl)-4-phenylpyrrolidine-2-carboxamide
  • the reaction mixture was stirred at room temperature overnight.
  • the reaction mixture was diluted with EtOAc (100 mL) and poured into a 250 mL separatory funnel.
  • the organic layer was washed with water (50 mL), 1 M aqueous HC1 (50 mL), saturated aqueous NaHC0 3 (50 mL) and brine (50 mL).
  • the combined organic layers were dried over MgS0 4 , filtered and concentrated under reduced pressure. Purification by column chromatography on silica gel, eluting with 100:0 to 30:70 Hexanes:EtOAc as a gradient. The title product was obtained as a solid (160 mg, 61%).
  • Step 4 Preparation of ((R)-l -((2S,4R)-l-((R)-2-(2-naphthamido)-3- cyclohexylpropanoyl)-4-phenylpyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid
  • Example 8 ((R)-l-((l ⁇ ,3aR,6a5)-2-((R)-2-(2-naphthamido)-3- cyclohexylpropanoyl)octahydrocyclopenta[c]pyrrole-l-carboxamido)-2- methylpropyl)boronic acid
  • Step 1 Preparation of tert-butyl (l,S',3aR,6a ) S)-2-((R)-2-(2-naphthamido)-3- cyclohexylpropanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylate
  • Step 2 Preparation of (15,3aR,6aS)-2-((R)-2-(2-naphthamido)-3- cyclohexylpropanoyl)octahydrocyclopenta[c]pyrrole-l -carboxylic acid
  • Step 3 Preparation of (l,S',3aR,6a ) S)-2-((R)-2-(2-naphthamido)-3- cyclohexylpropanoyl)-N-((R)-2-methyl-l-((3a,S',4 ) S',6 ) S',7aR)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[ ⁇ i][l,3,2]dioxaborol-2-yl)propyl)octahydrocyclopenta[c]pyrrole-l- carboxamide
  • Step 4 Preparation of ((R)-l-((l ⁇ ,3aR,6a5)-2-((R)-2-(2-naphthamido)-3- cyclohexylpropanoyl)octahydrocyclopenta[c]pyrrole-l-carboxamido)-2- methylpropyl)boronic acid
  • the biphasic mixture was stirred vigorously at room temperature for 18 h overnight. Stirring was stopped and the bottom methanolic layer of the biphasic solution was removed, and the top hexane layer was further extracted with methanol (3 x 2 mL). The combined methanol layers were washed with hexanes (3 x 2 mL) and concentrated under reduced pressure to afford the desired product (50 mg, 1 1%).
  • Step 1 Preparation of (2,S',4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (fert-butylthio)-N-((R)-2-me
  • Step 2 Preparation of ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3- cyclohexylpropanoyl)-4-(tert-butylthio)pyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid
  • the biphasic mixture was stirred vigorously at room temperature for 18 h. Stirring was stopped and the bottom methanolic layer of the biphasic solution was removed, and the top hexane layer was further extracted with methanol (3 x 1 mL). The combined methanol layers were washed with octane (3 x 1 mL) and concentrated under reduced pressure to afford the desired product as a white solid (22 mg, 99%).
  • Example 14 ((R)-l -((2 ⁇ ,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (piperidin-l-yl)pyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid
  • Step 1 Preparation of l-(tert-butyl) 2-methyl (2,S',4R)-4-(piperidin-l-yl)pyrrolidine- 1,2-dicarboxylate
  • Step 2 Preparation of methyl (2,S',4R)-4-(piperidin-l-yl)pyrrolidine-2-carboxylate hydrochloride
  • Step 3 Preparation of methyl (2£,4R)-l-((R)-2-(2-naphthamido)-3- cyclohexylpropanoyl)-4-(piperidin-l-yl)pyrrolidine-2-carboxylate
  • Step 4 Preparation of 2,5-dioxopyrrolidin-l-yl (2£,4R)-l-((R)-2-(2-naphthamido)-3- cyclohexylpropanoyl)-4-(piperidin-l-yl)pyrrolidine-2-carboxylate
  • reaction mixture was poured into a 250 mL separately funnel containing water (100 mL) and extracted with EtOAc (100 mL). The organic layer was further washed with water (2 x 50 mL) and the combined aqueous layers were further extracted with EtOAc (50 mL). The combined organic layers were dried over MgS0 4 , filtered and concentrated under reduced pressure. This material was used without further purification (504 mg).
  • Step 5 Preparation of (2,S',4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N- ((R)-2-methyl-l-((3a,S',45',65',7aR)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[ ⁇ i][l,3,2]dioxaborol-2-yl)propyl)-4-(piperidin-l-yl)pyrrolidine-2-carboxamide
  • Step 6 Preparation of ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3- cyclohexylpropanoyl)-4-(piperidin-l-yl)pyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid
  • the solids were suspended in methanol (0.5 mL) and octane (0.5 mL) and treated with 4 M HC1 in dioxane (38 ⁇ L, 0.15 mmol, 2.5 equiv).
  • the biphasic reaction mixture was vigorously stirred at room temperature for 18 h. Stirring was stopped and the mixture quenched with saturated aqueous NaHC0 3 solution (200 ⁇ L).
  • the bottom methanolic layer of the biphasic solution was removed, and the top hexane layer was further extracted with methanol (3 x 1 mL).
  • the combined methanol layers were washed with octane (3 x 1 mL) and concentrated under reduced pressure to afford the desired product as a white solid (34 mg, 92%).
  • Example 17 ((R)- 1 -((2S,4S)- 1 -((R)-2-(2-naphthamido)-3 -cyclohexylpropanoyl)-4- chloropyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid
  • Step 1 Preparation of 1 -(tert-butyl) 2-methyl ( ⁇ -chloropyrrolidine-l,!- dicarboxylate
  • the reaction mixture was stirred at 0 °C for 20 minutes, then heated to 40 °C for 30 minutes and then cooled to room temperature and stirred for an additional 15 minutes.
  • the reaction mixture was diluted with heptanes (200 mL) and concentrated under reduced pressure to a total volume of 100 mL. Another 200 mL of heptanes were added, and the reaction contents concentrated under reduced pressure to 200 mL volume at which point a precipitate formed.
  • the reaction mixture was stirred overnight.
  • the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification by column chromatography through silica gel, eluting with 100:0 to 60:40 Hexanes:EtOAc as a gradient.
  • the desired product was obtained as a white solid (2.62 g, 99%).
  • Step 2 Preparation of (2S,4S)- l-(tert-butoxycarbonyl)-4-chloropyrrolidine-2- carboxylic acid
  • Step 3 Preparation of fert-butyl (2 ⁇ ,45)-4-chloro-2-(((R)-2-methyl-l- ((3a,S',4 ) S',6 ) S',7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[ ⁇ i][l,3,2]dioxaborol-2- yl)propyl)carbamoyl)pyrrolidine- 1 -carboxylate
  • Step 4 Preparation of (2 ⁇ ,45)-4-chloro-N-((R)-2-methyl-l-((3a ⁇ ,4 ⁇ ,6 ⁇ ,7aR)-3a,5,5- trimethylhexahydro-4,6-methanobenzo[ ⁇ i][l,3,2]dioxaborol-2-yl)propyl)pyrrolidine-2- carboxamide
  • reaction mixture was stirred at room temperature for 2 h, at which time additional 4 M HC1 in dioxane (2 mL) was added. The reaction was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure and used directly in the next step without further purification (283 mg).
  • Step 5 Preparation of (2,S',4 ) S)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- chloro-N-((R)-2-methyl-l-((3a,S',45',65',7aR)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[ ⁇ i][l,3,2]dioxaborol-2-yl)propyl)pyrrolidine-2-carboxamide
  • Step 6 Preparation of ((R)-l -((2S,4S)- l-((R)-2-(2-naphthamido)-3- cyclohexylpropanoyl)-4-chloropyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid
  • Example 18 ((R)- 1 -((2S,4R)- 1 -((R)-2-(2-naphthamido)-3 -cyclohexylpropanoyl)-4- (phenethylthio)pyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid
  • Step 1 Preparation of tert-butyl (2 ⁇ ,4R)-4-hydroxy-2-(((R)-2-methyl-l- ((3a,S',4 ) S',6 ) S',7aR)-3a,5,54rimethylhexahydro-4,6-methanobenzo[ii][l,3,2]dioxaborol-2- yl)propyl)carbamoyl)pyrrolidine- 1 -carboxylate
  • Step 2 Preparation of fert-butyl (2 ⁇ ,45)-4-chloro-2-(((R)-2-methyl-l- ((3a,S',4 ) S',6 ) S',7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[ ⁇ i][l,3,2]dioxaborol-2- yl)propyl)carbamoyl)pyrrolidine- 1 -carboxylate
  • reaction mixture was cooled to 0 °C in an ice bath and carbon tetrachloride (838 ⁇ ⁇ , 8.7 mmol, 8.7 equiv) was added.
  • the reaction mixture was heated to 40 °C for 2 h and then cooled to room temperature.
  • the mixture was poured into a 125 mL separately funnel containing water (75 mL) and extracted with CH 2 CI 2 (2 x 50 mL).
  • the combined organic layers were dried over MgS0 4 , filtered and concentrated under reduced pressure. Purification by column chromatography through silica gel, eluting with 100:0 to 30:70 Hexanes:EtOAc as a gradient afforded the title compound (382 mg, 79%).
  • Step 3 Preparation of tert-butyl (2 ⁇ ,4R)-2-(((R)-2-methyl-l-((3a ⁇ ,4 ⁇ ,6 ⁇ ,7aR)-3a,5,5- trimethylhexahydro-4,6-methanobenzo[ ⁇ i][l,3,2]dioxaborol-2-yl)propyl)carbamoyl)-4- (phenethylthio)pyrrolidine- 1 -carboxylate
  • Step 4 Preparation of (2 ⁇ ,4R)-N-((R)-2-methyl-l-((3a ⁇ ,4 ⁇ ,6 ⁇ ,7aR)-3a,5,5- trimethylhexahydro-4,6-methanobenzo[ ⁇ i][l,3,2]dioxaborol-2-yl)propyl)-4- (phenethylthio)pyrrolidine-2-carboxamide hydrochloride
  • Step 5 Preparation of (2,S',4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N- ((R)-2-methyl-l-((3a,S',45',65',7aR)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[ ⁇ i][l,3,2]dioxaborol-2-yl)propyl)-4-(phenethylthio)pyrrolidine-2-carboxamide
  • Step 6 Preparation of ((R)-l -((2S,4R)-l-((R)-2-(2-naphthamido)-3- cyclohexylpropanoyl)-4-(phenethylthio)pyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid
  • Example 19 ((R)- 1 -((2S,4S)- 1 -((R)-2-(2-naphthamido)-3 -cyclohexylpropanoyl)-4-(3 - phenylpropanamido)pyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid
  • Step 1 Preparation of tert-butyl (2 ⁇ ,45)-4-azido-2-(((R)-2-methyl-l- ((3a,S',4 ) S',6 ) S',7aR)-3a,5,54rimethylhexahydro-4,6-methanobenzo[ii][l,3,2]dioxaborol-2- yl)propyl)carbamoyl)pyrrolidine- 1 -carboxylate
  • Step 2 Preparation of tert-butyl (2 ⁇ ,45)-4-amino-2-(((R)-2-methyl-l- ((3a,S',4 ) S',6 ) S',7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[ ⁇ i][l,3,2]dioxaborol-2- yl)propyl)carbamoyl)pyrrolidine- 1 -carboxylate
  • Step 3 Preparation of fert-butyl (2 ⁇ ,45)-2-(((R)-2-methyl-l-((3a ⁇ ,4 ⁇ ,6 ⁇ ,7aR)-3a,5,5- trimethylhexahydro-4,6-methanobenzo[ ⁇ i][l,3,2]dioxaborol-2-yl)propyl)carbamoyl)-4-(3- phenylpropanamido)pyrrolidine-l -carboxylate
  • Step 4 Preparation of (2 ⁇ ,45)-N-((R)-2-methyl-l-((3a ⁇ ,4 ⁇ ,6 ⁇ ,7aR)-3a,5,5- trimethylhexahydro-4,6-methanobenzo[ ⁇ i][l,3,2]dioxaborol-2-yl)propyl)-4-(3- phenylpropanamido)pyrrolidine-2-carboxamide hydrochloride
  • Step 5 Preparation of (2,S',4 ) S)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N- ((R)-2-methyl-l-((3a,S',45',65',7aR)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[ ⁇ i][l,3,2]dioxaborol-2-yl)propyl)-4-(3-phenylpropanamido)pyrrolidine-2- carboxamide

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Abstract

This invention is directed to novel Boronic acid derivatives of Formula I, and pharmaceutically acceptable salts, solvate, solvate of the salt and prodrugs thereof, useful in the prevention (e.g., delaying the onset of or reducing the risk of developing) and treatment (e.g., controlling, alleviating, or slowing the progression of) of Age-related Macular Degeneration (AMD) and related diseases of the eye. These diseases include dry-AMD, Wet-AMD, geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, and degeneration of retinal or photoreceptor ceils. The invention disclosed herein is further directed to methods of prevention, slowing the progress of, and treatment of dry -AMD, Wet- AMD, and geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, and degeneration of retinal or photoreceptor cells, comprising: administration of a therapeutically effective amount of compound of the invention. The compounds of the invention are inhibitors of HTRA1. Thus, the compounds of the invention are useful in the prevention and treatment of a wide range diseases mediated (in whole or in part) by HTRA1. The compounds of the invention are also useful for inhibiting HTRA1 protease activity in an eye or locus of an arthritis or related condition.

Description

BORONIC ACID DERIVATIVES AND USES THEREOF
FIELD OF THE INVENTION
[0001] This invention is directed to novel boronic acid derivatives of Formula I, and pharmaceutically acceptable salts, solvate, solvate of the salt and prodrugs thereof, useful in the prevention (e.g., delaying the onset of or reducing the risk of developing) and treatment (e.g., controlling, alleviating, or slowing the progression of) of Age-related Macular Degeneration (AMD) and related diseases of the eye. These diseases include dry- AMD, Wet-AMD, geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, and degeneration of retinal or photoreceptor cells. The invention disclosed herein is further directed to methods of prevention, slowing the progress of, and treatment of dry-AMD, Wet-AMD, and geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, and degeneration of retinal or photoreceptor cells, comprising: administration of a therapeutically effective amount of a compound of the invention. The compounds of the invention are inhibitors of HTRA1. Thus, the compounds of the invention are useful in the prevention and treatment of a wide range diseases mediated (in whole or in part) by HTRA1. The compounds of the invention are also useful for inhibiting HtrAl protease activity in an eye or locus of an arthritis or related condition.
BACKGROUND OF THE INVENTION
[0002] Age-related macular degeneration (AMD) is the leading cause of severe loss of vision in people over the age of 60. Age is the major risk factor for the onset of AMD: the likelihood of developing AMD triples after age 55. Many factors, however, contribute to the likelihood that an individual will develop AMD.
[0003] As summarized in WO2001/006262: "Environmental" conditions may modulate the rate at which an individual develops AMD or the severity of the disease. Light exposure has been proposed as a possible risk factor, since AMD most severely affects the macula, where light exposure is high. (See Young, R. W. (1988), Surv. Ophthalmol. 32(4), 252-69; Taylor, H. R. et al. (1990), Trans. Amer. Ophthalmol Soc. 88, 163-73; Schalch W. (1992), Exs, 62, 280-98). The amount of time spent outdoors is associated with increased risk of choroidal neovascularization in men, and wearing hats and/or sunglasses is associated with a decreased incidence of soft drusen (Cruickshanks, K. et al. (1993), Arch. Ophthalmol., I l l, 514-518). Accidental exposure to microwave irradiation has also been shown to be associated with the development of numerous drusen (Lim, J. et al. (1993), Retina. 13, 230- 3). Cataract removal and light iris pigmentation has also been reported as a risk factor in some studies (Sandberg, M. et al. (1994), Invest. Ophthalmol. Vis. Sci.. 35(6), 2734-40). This suggests that: 1) eyes prone to cataracts may be more likely to develop AMD; 2) the surgical stress of cataract removal may result in increased risk of AMD, due to inflammation or other surgically-induced factors; or 3) cataracts prevent excessive light exposure from falling on the macula, and are in some way prophylactic for AMD. While it is possible that dark iris pigmentation may protect the macula from light damage, it is difficult to distinguish between iris pigmentation alone and other, cosegregating genetic factors which may be actual risk factors.
[0004] Smoking, gender (women are at greater risk), obesity, and repeated exposure to UV radiation also increase the risk of AMD.
[0005] More recently, a number of HTRAl single nucleotide polymorphs (SNP) have been found to be associated with an increased risk of AMD. See, for example, WO2008/013893A2, WO2008/067040A2 and WO2008/094370A2. These S P's include rsl 1200638, rsl0490924, rs3750848, rs3793917 and rs932275. In particular, the risk allele rsl 1200638, was found to be associated with increased HTRAl mRNA and protein expression, and HtrAl is present in drusen in patients with AMD. (See Dewan et al, 2006, Science 314:989-992; Yang et al, 2006, Science 314:992-993). These disclosures provide evidence in support of our belief that HtrAl is an important factor in AMD and the progression thereof.
[0006] In broad terms, there are two forms of AMD: dry AMD and wet AMD. The dry form is the more common, and accounts for 85-90% of the patients with AMD, and does not typically result in blindness. In dry AMD, (also called non-neovascular AMD or non-exudative AMD) drusen appear in the macula of the eye, the cells in the macula die, and vision becomes blurry. Dry AMD can progress in three stages: 1) early, 2) intermediate, and 3) advanced dry AMD. Dry AMD can also progress into wet AMD during any of these stages.
[0007] Wet AMD (also called neovascular or exudative AMD), is associated with pathologic posterior segment neovascularization. The posterior segment neovascularization (PSNV) found in exudative AMD is characterized as pathologic choroidal neovascularization. Leakage from abnormal blood vessels forming in this process damages the macula and impairs vision, eventually leading to blindness.
[0008] The end stage of AMD is characterized by a complete degeneration of the neurosensory retina and of the underlying retinal pigment epithelium in the macular area. Advanced stages of AMD can be subdivided into geographic atrophy (GA) and exudative AMD. Geographic atrophy is characterized by progressive atrophy of the retinal pigment epithelium (RPE). While GA is typically considered less severe than the exudative AMD because its onset is less sudden, to date no treatment has been effective at halting or slowing its progression.
[0009] Currently, treatment of dry AMD includes the administration of antioxidant vitamins and/or zinc. For example, one study at the National Eye Institute assessed a composition comprising Vitamin C, Beta Carotene, zinc oxide and cupric oxide.
[0010] Treatment of AMD is also wanting. Available drug therapies include: Bevacizumab (Avastin), Ranibizumab (Lucentis), Pegaptanib (Macugen), and Aflibercept (Eylea). In each instance, the medication is injected into the eye. Injections may be repeated every four weeks to maintain the beneficial effect of the medication. Those with a positive result, may partially recover vision as the blood vessels shrink and the fluid under the retina is absorbed, allowing retinal cells to regain some function.
[0011] Grau, S. et. al, J. Biol. Chem., vol 281, (10), 6124-6129, March 10, 2006, entitled The Role of HtrAl in Arthritic Disease, discloses the boronic acid derivative (l-{3- cyclohexyl-2-[naphthylene-2-carbonyl)-amino]-propionyl}-pyrrolidine-2-carboxylic acid[5- (3-cyclohexyl-ureido)-l-dihydroxyboranyl-pentyl]amide as an inhibitor of HtrAl . The compound was tested in arthritis assays. WO2012/078540, published December 6, 2012, also discloses this compound (identified therein as NVP-LB976) as an inhibitor of HtrAl, and claims the use of a composition "... comprising nanoparticles and peripheral blood cells, wherein the nanoparticles comprise an HTRAl/htral and/or a CIS/cish activator" in the prevention or treatment of a number of diseases, including age-related macular degeneration.
[0012] Today, no pharmacologic therapy is approved for the treatment of macular edema associated with AMD. The current standard of care is laser photocoagulation, which is used to stabilize or resolve macular edema and retard the progression to later stage disease. Laser photocoagulation may reduce retinal ischemia by destroying healthy tissue and thereby decreasing metabolic demand; it also may modulate the expression and production of various cytokine and trophic factors. There are no current treatments for preventing loss of vision after dry AMD enters an advanced stage. There are also no definitive methods for preventing progression of dry AMD to an advanced stage, other than by avoiding and/or reducing risk factors and using dietary supplements, which cannot guarantee or be relied on to stop AMD progression. Thus, there is a need for therapeutics that can treat dry AMD and prevent progression of dry to wet AMD.
SUMMARY OF THE INVENTION
This invention is directed to novel boronic acid derivatives of Formula I,
Figure imgf000006_0001
I
and pharmaceutically acceptable salts, solvates and solvates of the salts and prodrugs thereof, useful in the prevention (e.g., delaying the onset of or reducing the risk of developing) and treatment (e.g., controlling, alleviating, or slowing the progression of) of Age-related Macular Degeneration (AMD) and related diseases of the eye. These diseases include dry- AMD, Wet-AMD, geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, and degeneration of retinal or photoreceptor cells. The invention disclosed herein is further directed to methods of prevention, slowing the progress of, and treatment of dry-AMD, Wet-AMD, and geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, and degeneration of retinal or photoreceptor cells, comprising: administration of a therapeutically effective amount of a compound of the invention. The compounds of the invention are inhibitors of HTRAl . Thus, the compounds of the invention are useful in the prevention and treatment of a wide range diseases mediated (in whole or in part) by HTRAl . The compounds of the invention are also useful for inhibiting HtrAl protease activity in an eye or locus of an arthritis or related condition,
[0014] In a first embodiment, the boronic acid derivative is a compound of Formula I
Figure imgf000007_0001
I
or a pharmaceutically acceptable salt, solvate, solvate of the salt or prodrug thereof wherein:
each n is independently selected from 0, 1, or 2;
X is selected from -C(O)-, -S02- and -CHCH3, wherein 1, 2 or 3 of the CH3 hydrogens may optionally be replaced with a halogen;
R1 is selected from the group consisting of:
(a) phenyl or naphthyl,
(b) 5- or 6-membered monocyclic heteroaryl ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(c) 8-, 9-, or 10-membered fused bicyclic heteroaryl ring, said ring having 1, 2, 3 or 4, heteroatoms independently selected from N, S and O,
(d) 5- or 6-membered monocyclic heterocycloalkyl ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O, (e) 8-, 9-, or 10-membered fused bicyclic heterocycloalkyl ring, said ring having 1, 2, 3 or 4, heteroatoms independently selected from N, S and O,
wherein R1 choices (a), (b), (c), (d) and (e) are optionally mono- or di- substituted with substituents independently selected from halogen, -CH3, -CF3, -
Figure imgf000008_0001
R2 is selected from the group consisting of:
(a) -(CH2)n-C3-8cycloalkyl,
(b) -(CH2)n-phenyl,
(c) -(CH2)n-heteroaryl, wherein the heteroaryl is a 5- or 6-membered monocyclic ring, having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
wherein R2 choices (a), (b) and (c) are optionally mono- or di- substituted with substituents independently selected from halogen, -CH3, -CF3, -OCH3 and -OCF3;
R3a and R3b are each independently selected from the group consisting of:
(a) hydrogen,
(b) hydroxyl,
(c) halogen,
(d) -S(0)n-Ci-6alkyl, optionally substituted with phenyl,
(e) -N(H)-C(=0)-Ci-6alkyl, optionally substituted with phenyl, or heteroaryl, wherein the heteroaryl is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(f) -N(H)-C(=0)-N(H)-Ci-6alkyl, optionally substituted with phenyl, or heteroaryl, wherein the heteroaryl is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(g) -N(H)-S02-aryl,
(h) -N(H)-S02-heteroaiyl, wherein the heteroaryl is a 5- or 6- membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(i) -N(H)-Ci-6alkyl, (j) -N(Ci-6alkyl)(Ci.6alkyl), optionally substituted with phenyl, or heteroaryl, wherein the heteroaryl is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(k) -N(Ci.6alkyl)(Ci-6alkenyl),
(1) -N(Ci-6alkyl)(Ci-6alkynyl),
(m) -N(H)-C3-6cycloalkyl,
(n) -N(H)-heterocycle, wherein the heterocycle is a 5- or 6- membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(o) -S02-N(H)-aryl,
(p) -S02-N(H)-heteroaryl,
(q) 5- or 6-membered saturated monocyclic heterocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(r) -phenyl, and
(s) -O-phenyl,
wherein the alkyl of R3a and R3b choices (d), (e), (f), (i), (j), (k) and (1) and the cycloalkyl of R3a and R3b choice (m), are optionally mono- or di-substituted with substituents independently selected from halogen, hydroxyl, -CH3, -CF3, -OCH3 and -OCF3, wherein the aryl of R3a and R3b choices (d), (e), (f), (g), Q), (o), (r) and (s), and the heteroaryl of R3a and R3b choices (e), (f), (h), (j) and (p), and the heterocycle of R3a and R3b choice (n) and (q) are optionally mono- or di-substituted with substituents independently selected from halogen, hydroxyl, -CH3, -CF3, -OCH3 and -OCF3, or
R3a and R3b taken together with the atom to which they are attached form a carbonyl, with the proviso that at least one of R3a and R3b is other than hydrogen;
R4a and R4b are each independently hydrogen or
Figure imgf000009_0001
or
R3a and R4a or R3a and R4b or R3b and R4a or R3b and R4b are j oined together to form a bond or joined together so that together with the atoms to which they are attached there is formed a ring selected from phenyl, Cs-ecycloalkyl, optionally mono- or di-substituted with substituents independently selected from hydroxyl, - CH3, -CF3, -OCH3 and -OCF3; R5 is selected from the group consisting of:
(a) -Ci-6alkyl, and
(b) -Ci-6alkyl-R6;
R6 is selected from the group consisting of:
(a) - H2, optionally substituted with Ci-3alkyl, -SO2-CF3, phenyl or Ci-3alkyl-phenyl,
(b) - H-S02-Ci-3alkyl, - H-S02-phenyl, - H-S02-Ci-3alkyl- phenyl, - H-S02-heterocycle or - H-S02-Ci-3alkyl-heterocycle, wherein the heterocycle is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(c) -S(0)n-aryl,
(d) -phenyl,
(e) 5- or 6-membered monocyclic heteroaryl ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O, optionally substituted with Ci-3alkyl, phenyl or Ci-3alkyl-phenyl,
(f) 5- or 6-membered monocyclic heterocycloalkyl ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O, optionally substituted with Ci-3alkyl, phenyl or Ci-3alkyl-phenyl,
Figure imgf000010_0001
3alkyl-phenyl, - H-C(=0)-heterocycle or - H-C(=0)-Ci-3alkyl-heterocycle, wherein the heterocycle is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(h) -N(H)-C(=0)- H2, optionally substituted with Ci-3alkyl, phenyl, naphthyl, Ci-3alkyl-phenyl, Ci-3alkyl-naphthyl, heterocycle, C3-6 -cycloalkyl or Ci. 3alkyl-heterocycle, wherein the heterocycle is a 5- or 6-membered monocyclic ring, said ring havin 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
Figure imgf000010_0002
(j) -N(H)-C(= H)- H, optionally substituted with -Ci-4alkyl, - C(=0)-0-Ci-4alkyl, or -C(=0)-Ci-4alkyl, and (k) - H-SO2- H2 optionally substituted with
Figure imgf000011_0001
phenyl, naphthyl,
Figure imgf000011_0002
Ci-3alkyl-naphthyl, heterocycle, C3-6 -cycloalkyl or Ci. 3alkyl-heterocycle, wherein the heterocycle is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O, wherein the alkyl of R6 choices (a), (b), (e), (f), (g), (h), (i), (k) and (1), and the aryl of R6 choices (a), (b), (c), (d), (e), (f), (g), (h), (k) and (1), and the heteroaryl of R6 choice (e) and the heterocycle of R6 choices (b), ,(g),(h) and (1), and the heterocycloalkyl of R6 choice (f) are each optionally mono or di-substituted with substituents independently selected from halogen, hydroxyl, -CH3, -CF3, -OCH3 and
[0015] In a second embodiment, for a compound of the first embodiment, X is selected from -C(O)- and -CHCF3.
[0016] In a third embodiment, for a compound of the second embodiment, X is -
C(O)-
[0017] In a fourth embodiment, for a compound of any of the first through third embodiments, R1 is selected from the group consisting of:
(a) phenyl or naphthyl,
(b) 5- or 6-membered monocyclic heteroaryl ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O, and
(c) 8-, 9-, or 10-membered fused bicyclic heteroaryl ring, said ring having 1, 2, 3 or 4, heteroatoms independently selected from N, S and O,
wherein R1 choices (a), (b) and (c) are optionally mono- or di-substituted with substituents independently selected from halogen, -CH3, -CF3, -OCH3 and -OCF3.
[0018] In a fifth embodiment, for a compound of the fourth embodiment, R1 is naphthyl.
[0019] In a sixth embodiment, for a compound of any of the first through fifth embodiments, R2 is
Figure imgf000011_0003
wherein the C seyeloalkyl is optionally mono- or di-substituted with substituents independently selected from halogen, -CH3, -CF3, -OC¾ and -OCF3.
[0020] In a seventh embodiment, for a compound of the sixth embodiment, R2 is
~(CH2)~cyclohexyl . [0021] In an eighth embodiment, for a compound of any of the first through seventh embodiments, R,a is hydrogen, and R b is selected from the group consisting of:
(a) phenyl,
(b) -O-phenyl,
(c) hydroxyl,
(d) chloro,
(e) -S-C(CH3)3,
(f) -S-(CH2)2-phenyl,
(g) piperidinyl,
(h) morpholinyl,
(i) pyrrolidinyl,
G) -N(CH3)-CH2-phenyl,
(k) -N(CH3)-CH2-ethynyl,
(1) -N(CH3)-(CH2)2-OH,
(m) - H-C(=0)-(CH2)2-phenyl,
(n) - H-C(=0)-CH2-pyridinyl,
(o) - H-C(=0)-(CH2)3-phenyl-OCH3,
(p) - H-C(=0)- H-(CH2)3-phenyl, and
(q) - H-S(0)2-pyrazolyl-CH3, or
R3a and R3b taken together with the atom to which they are attached form a carbonyl, or
R3b and R4a or R3b and R4b are joined together so that together with the atoms to which they are attached there is formed a ring selected from phenyl, C5- 6cycloalkyl, optionally mono- or di- substituted with substituents independently selected from hydroxyl, -CH3, -CF3, -OCH3 and -OCF3.
[0022] In a ninth embodiment, for a compound of the eighth embodiment,
R3a is hydrogen, and
R3b is selected from the group consisting of:
(a) phenyl,
(b) -S-C(CH3)3,
(c) piperidinyl, (d) morpholinyl,
(e) pyrrolidinyl, and
(f) - H-S(0)2-pyrazolyl-CH3.
[0023] In a tenth embodiment, for a compound of the ninth embodiment,
is hydrogen, and
R3b is selected from the group consisting of:
(a) piperidinyl,
(b) morpholinyl, and
(c) -NH-C(=0)-CH2-pyridinyl.
[0024] In an eleventh embodiment, for a compound of any of the first through tenth embodiments,
R4a and R4b are each hydrogen, or
R3b and R4a or R3b and R4b are joined together so that together with the atoms to which they are attached there is formed a ring selected from phenyl, C,. 6Cycloalkyl, optionally mono- or di- substituted with substituents independently selected from hydroxyl, -CH3, -CF3, -OCH3 and -OCF3.
[0025] In a twelfth embodiment, for a compound of any of the first through eleventh embodiments, R4a and R',a are each hydrogen.
[0026] In a thirteenth embodiment, for a compound of any of the first through twelfth embodiments,
t is selected from 3, 4 and 5;
R5 is selected from the group consisting of:
(a) -CH2(CH3)2,
(b) -CH2-phenyl,
(c) -(CH2)4-S-phenyl,
(d) -(CH2)t-R6
(e) -(CH2)t-NH-S02-phenyl,
(f) -(CH2)t-NH-S02-CF3,
(g) -(CH2)t- H-S02-CH3,
(h) -(CH2),-NH-S02-piperidinyl,
(i) -(CH2)r-triazolyl-phenyl, (j) -(CH2)t-NH-C(=0)-CH3,
(k) -(CH2)t- H-C(=0)-phenyl,
(1) -(CH2)t-NH-C(=0)-CH2-phenyl,
(m) -(CH2)t-NH-C(= H)-NH-C(=0)-0-C(CH3)3,
(n) -(CH2),- H-C(=0)- H-cyclohexyl,
(o) -(CH2)t- H-C(=0)- H-phenyl, optionally substituted with halo or methoxy,
(p) -(CH2)t-NH-C(=0)-NH-CH2-phenyl,
(q) -(CH2)t- H-C(=0)- H-(CH2)2-phenyl,
(r) -(CH2)t-NH-C(=0)- H-(CH2)3-phenyl,
(s) -(CH2)t-NH-C(=0)- H-phenyl,
(t) -(CH2)t-NH-C(=0)-NH-CH2CH3,
(u) -(CH2)t- H-C(=0)- H-naphthyl, and
(v) -(CH2)t- H-C(=0)-NH-pyridinyl; and
R6 is
Figure imgf000014_0001
[0027] In a fourteenth embodiment, for a compound of the thirteenth embodiment, R5 is selected from the group consisting of:
(a) -CH2(CH3)2,
(b) -CH2-phenyl,
(c) -(CH2)4-NH-S02-phenyl,
(d) -(CH2)4- H-C(=0)-CH3,
(e) -(CH2)3- H-C(=0)-phenyl,
(f) -(CH2)4-NH-C(=0)-phenyl,
(g) -(CH2)4-NH-C(=0)-CH2-phenyl,
(h) -(CH2)3- H-C(=0)- H-cyclohexyl,
(i) -(CH2)4- H-C(=0)- H-cyclohexyl,
G) -(CH2)5-NH-C(=0)-NH-cyclohexyl, (k) -(CH2)4-NH-C(=0)-NH-phenyl, optionally substituted with halo or methoxy,
(1) -(CH2)3- H-C(=0)-NH-CH2-phenyl,
(m) -(CH2)4- H-C(=0)- H-CH2-phenyl,
(n) -(CH2)3- H-C(=0)-NH-phenyl,
(0) -(CH2)3- H-C(=0)-NH-CH2CH3,
(p) -(CH2)4- H-C(=0)-NH-CH2CH3, and
(q) -(CH2)4- H-C(=0)- H-pyridinyl.
[0028] In a fifteenth embodiment, for a compound of the fourteenth embodiment, R5 is selected from the group consisting of:
(a) -CH2(CH3)2,
(b) -(CH2)3- H-C(=0)- H-cyclohexyl,
(c) -(CH2)4- H-C(=0)- H-cyclohexyl,
(d) -(CH2)5- H-C(=0)- H-cyclohexyl,
(e) -(CH2)4- H-C(=0)- H-phenyl, optionally substituted with halo or methoxy,
(f) -(CH2)3- H-C(=0)- H-CH2-phenyl,
(g) -(CH2)4-NH-C(=0)-NH-CH2-phenyl,
(h) -(CH2)4- H-C(=0)-NH-CH2CH3, and
(1) -(CH2)4- H-C(=0)- H-pyridinyl.
[0029] In a sixteenth embodiment, the compound of the first embodiment is a compound of Formula la:
Figure imgf000015_0001
or a pharmaceutically acceptable salt, solvate, solvate of the salt or prodrug thereof, wherein:
X is selected from -C(O)- and -CHCF3-;
R a is hydrogen;
R3b is selected from the group consisting of:
(a) phenyl,
(b) -O-phenyl,
(c) hydroxyl,
(d) chloro,
(e) -S-C(CH3)3,
(f) -S-(CH2)2-phenyl,
(g) piperidinyl,
(h) morpholinyl,
(i) pyrrolidinyl,
G) -N(CH3)-CH2-phenyl,
(k) -N(CH3)-CH2-ethynyl,
(1) -N(CH3)-(CH2)2-OH,
(m) -NH-C(=0)-(CH2)2-phenyl,
(n) - H-C(=0)-CH2-pyridinyl,
(o) - H-C(=0)-(CH2)3-phenyl-OCH3,
(p) - H-C(=0)- H-(CH2)3-phenyl, and
(q) - H-S(0)2-pyrazolyl-CH3, or
R a and R3b taken together with the atom to which they are attached form a carbonyl,
R4 is hydrogen or Ci-ealkyl, or
R3b and R4 are joined to form a bond or joined so that together with the atoms to which they are attached there is formed a ring selected from phenyl and cyclopentyl;
R5 is selected from the group consisting of:
(a) -CH2(CH3)2,
(b) -CH2-phenyl, (c) -(CH2)4-S-phenyl,
(d) -(CH2)4-R6,
(e) -(CH2)3- H-S02-phenyl,
(f) -(CH2)4- H-S02-phenyl,
(g) -(CH2)4- H-S02-CF3,
(h) -(CH2)4-NH-S02-CH3,
(i) -(CH2)4-NH-S02-piperidinyl,
(j) -(CH2)4-triazolyl-phenyl,
(k) -(CH2)4-NH-C(=0)-CH3,
(1) -(CH2)3-NH-C(=0)-phenyl,
(m) -(CH2)4-NH-C(=0)-phenyl,
(n) -(CH2)4- H-C(=0)-CH2-phenyl,
(o) -(CH2)4- H-C(= H)- H-C(=0)-0-C(CH3)3,
(p) -(CH2)3- H-C(=0)- H-cyclohexyl,
(q) -(CH2)4-NH-C(=0)- H-cyclohexyl,
(r) -(CH2)5-NH-C(=0)-NH-cyclohexyl,
(s) -(CH2)4- H-C(=0)- H-phenyl, optionally substituted with halooxy,
(t) -(CH2)3-NH-C(=0)-NH-CH2-phenyl,
(u) -(CH2)3-NH-C(=0)-NH-(CH3)2-phenyl,
(v) -(CH2)3- H-C(=0)- H-(CH2)3-phenyl,
(w) -(CH2)4-NH-C(=0)-NH-CH2-phenyl,
(x) -(CH2)4- H-C(=0)- H-(CH2)2-phenyl,
(y) -(CH2)4-NH-C(=0)-NH-(CH2)3-phenyl,
(z) -(CH2)3- H-C(=0)- H-phenyl,
(aa) -(CH2)3- H-C(=0)- H-CH2CH3,
(bb) -(CH2)4- H-C(=0)-NH-CH2CH3,
(cc) -(CH2)3-NH-C(=0)- H-naphthyl,
(dd) -(CH2)4-NH-C(=0)-NH-naphthyl, and
(ee) -(CH2)4-NH-C(=0)-NH-pyridinyl;
and R6 is
Figure imgf000018_0001
[0030] In a seventeenth embodiment, the compound of the sixteenth embodiment pound of Formula ib:
Figure imgf000018_0002
lb
or a pharmaceutically acceptable salt, solvate, solvate of the salt or prodrug thereof, wherein:
R,bis selected from the group consisting of:
(a) piperidinyl,
(b) morpholinyl, and
(c) -NH-C(=0)-CH2-pyridinyl;
R5 is selected from the group consisting of:
(a) -CH2(CH3)2,
(b) -(CH2)3- H-C(=0)- H-cyclohexyl,
(c) -(CH2)4- H-C(=0)- H-cyclohexyl,
(d) -(CH2)5- H-C(=0)- H-cyclohexyl,
(e) -(CH2)4- H-C(=0)- H-phenyl, optionally substituted with halo or methoxy,
(f) -(CH2)3- H-C(=0)- H-CH2-phenyl,
(g) -(CH2)4- H-C(=0)-NH-CH2-phenyl,
(h) -(CH2)4- H-C(=0)-NH-CH2CH3, and
(i) -(CH2)4- H-C(=0)- H-pyridinyl. [0031] In an eighteenth embodiment, the compound of the first embodiment is selected from the group consisting of:
(1) ((R)-l -((2^,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- phenylpyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid,
(2) ((lR)-l-(2-((R)-2-(2-naphthamido)-3- cyclohexylpropanoyl)isoindoline-l-carboxamido)-2-methylpropyl)boronic acid,
(3) ((R)-l-((2S,4S)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- phenylpyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid,
(4) ((lR)-l-((4S)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- phenoxypyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid,
(5) ((R)- 1 -((2S,4S)- 1 -((R)-2-(2-naphthamido)-3 -cy clohexylpropanoyl)-4- hydroxypyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid,
(6) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- hydroxypyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid,
(7) ((R)-l-((S)-l -((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- oxopyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid,
(8) ((R)- 1 -(( 1 S,3 aR, 6aS)-2-((R)-2-(2-naphthamido)-3 - cyclohexylpropanoyl)octahydrocyclopenta[c]pyrrole-l-carboxamido)-2- methylpropyl)boronic acid,
(9) ((R)-l -((2^,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (tert-butylthio)pyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid,
(10) ((R)-l-((2S,4R)-l -((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- mo holinopyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid,
(1 1) ((R)-l-((2S,4R)-l -((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (benzyl(methyl)amino)pyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid,
(12) ((R)-l-((2S,4R)-l -((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (methyl(prop-2-yn-l-yl)amino)pyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid,
(13) ((R)-l-((2S,4R)-l -((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- ((2-hydroxyethyl)(methyl)amino)pyrrolidine-2-carboxamido)-2- methylpropyl)boronic acid, (14) ((R)-l -((2^,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (piperidin-l-yl)pyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid,
(15) ((R)- 1 -((3 'R, 5 ' S)- 1 ' -((R)-2-(2-naphthamido)-3 -cyclohexylpropanoyl)- [1,3 ' -bipyrrolidine]-5 ' -carboxamido)-2-methylpropyl)boronic acid,
( 16) ((R)- 1 -((2S,4S)- 1 -((R)-2-(2-naphthamido)-3 -cyclohexylpropanoyl)-4- (piperidin-l-yl)pyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid,
( 17) ((R)- 1 -((2S,4S)- 1 -((R)-2-(2-naphthamido)-3 -cy clohexylpropanoyl)-4- chloropyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid,
(18) ((R)-l -((2^,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (phenethylthio)pyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid,
( 19) ((R)- 1 -((2S,4S)- 1 -((R)-2-(2-naphthamido)-3 -cy clohexylpropanoyl)-4- (3-phenylpropanamido)pyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid,
(20) ((R)- 1 -((2S,4S)- 1 -((R)-2-(2-naphthamido)-3 -cyclohexylpropanoyl)-4- ((l-methyl-lH-pyrazole)-4-sulfonamido)pyrrolidine-2-carboxamido)-2- methylpropyl)boronic acid,
(21) ((R)-l -((2^,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (2-(pyridin-3-yl)acetamido)pyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid,
(22) ((R)-l-((2S,4R)-l -((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (2-(pyridin-2-yl)acetamido)pyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid,
(23) ((R)-l-((2S,4R)-l -((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (4-(4-methoxyphenyl)butanamido)pyrrolidine-2-carboxamido)-2- methylpropyl)boronic acid,
(24) ((R)-l-((2S,4R)-l -((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (3-(3-phenylpropyl)ureido)pyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid,
(25) ((R)-l-((2S,4R)-l -((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (2-(pyridin-4-yl)acetamido)pyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid,
(26) ((R)-l-((2S,4R)-l -((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (3-phenylpropanamido)pyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid,
(27) ((R)-l-((2S,4R)-l -((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- ((l-methyl-lH-pyrazole)-4-sulfonamido)pyrrolidine-2-carboxamido)-2- methylpropyl)boronic acid, (28) ((R)-l -((2^,4R)-l-((R)-3-cyclohexyl-2-(((R)-2,2,2-trifluoro-l- (naphthalen-2-yl)ethyl)amino)propanoyl)-4-phenylpyrrolidine-2-carboxamido)-2- methylpropyl)boronic acid,
(29) ((R)-l -((2^,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (piperidin-l-yl)pyrrolidine-2-carboxamido)-5-(3-cyclohexylureido)pentyl)boronic acid hydrochloride,
(30) ((R)-l-((2S,4R)-l -((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (piperidin-l-yl)pyrrolidine-2-carboxamido)-5-(3-ethylureido)pentyl)boronic acid,
(31) ((R)-l-((2S,4R)-l -((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (piperidin-l-yl)pyrrolidine-2-carboxamido)-5-(3-phenylureido)pentyl)boronic acid,
(32) ((R)-l-((2S,4R)-l -((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (piperidin-l-yl)pyrrolidine-2-carboxamido)-5-(3-benzylureido)pentyl)boronic acid,
(33) ((R)-l-((2S,4R)-l -((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (piperidin-l-yl)pyrrolidine-2-carboxamido)-5- ((trifluoromethyl)sulfonamido)pentyl)boronic acid,
(34) ((R)-l-((2S,4R)-l -((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (piperidin-l-yl)pyrrolidine-2-carboxamido)-5-acetamidopentyl)boronic acid,
(35) ((R)-l-((2S,4R)-l -((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (piperidin-l-yl)pyrrolidine-2-carboxamido)-5-benzamidopentyl)boronic acid,
(36) ((R)-l-((2S,4R)-l -((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (piperidin-l-yl)pyrrolidine-2-carboxamido)-5-(methylsulfonamido)pentyl)boronic acid,
(37) ((R)-l-((2S,4R)-l -((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (piperidin-l-yl)pyrrolidine-2-carboxamido)-5-(phenylsulfonamido)pentyl)boronic acid,
(38) ((R)-l-((2S,4R)-l -((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (piperidin-l-yl)pyrrolidine-2-carboxamido)-5-(3-phenethylureido)pentyl)boronic acid,
(39) ((R)-l-((2S,4R)-l -((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (piperidin-l-yl)pyrrolidine-2-carboxamido)-5-(3-(3- phenylpropyl)ureido)pentyl)boronic acid, (40) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (piperidin-l-yl)pyrrolidine-2-carboxamido)-5-(3-(naphthalen-l- yl)ureido)pentyl)boronic acid,
(41) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (piperidin- 1 -yl)pyrrolidin-2-yl)-9-imino- 13, 13 -dimethyl- 1,11 -dioxo- 12-oxa-2,8, 10- tri azatetradecan-3 -y l)b oroni c aci d,
(42) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (piperidin-l-yl)pyrrolidine-2-carboxamido)-5-(2-phenylacetamido)pentyl)boronic acid,
(43) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (piperidin-l-yl)pyrrolidine-2-carboxamido)-5-(piperidine-l- sulfonamido)pentyl)boronic acid,
(44) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (piperidin-l-yl)pyrrolidine-2-carboxamido)-5-(3-(pyridin-4-yl)ureido)pentyl)boronic acid,
(45) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (piperidin-l-yl)pyrrolidine-2-carboxamido)-5-(3-(2- chlorophenyl)ureido)pentyl)boronic acid,
(46) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (piperidin-l-yl)pyrrolidine-2-carboxamido)-5-(3-(3- chlorophenyl)ureido)pentyl)boronic acid,
(47) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (piperidin-l-yl)pyrrolidine-2-carboxamido)-5-(3-(4- chlorophenyl)ureido)pentyl)boronic acid,
(48) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (piperidin-l-yl)pyrrolidine-2-carboxamido)-5-(3-(2- methoxyphenyl)ureido)pentyl)boronic acid,
(49) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (piperidin-l-yl)pyrrolidine-2-carboxamido)-5-(3-(3- methoxyphenyl)ureido)pentyl)boronic acid, (50) ((R)-l-((2S,4R)-l -((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (piperidin-l-yl)pyrrolidine-2-carboxamido)-5-(3-(4- methoxyphenyl)ureido)pentyl)boronic acid,
(51) ((R)-l -((2^,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (piperidin-l-yl)pyrrolidine-2-carboxamido)-5-(2-thia-6-azaspiro[3.3]heptan-6- yl)pentyl)boronic acid hydrochloride,
(52) ((R)-l-((2S,4R)-l -((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (piperidin-l-yl)pyrrolidine-2-carboxamido)-5-(phenylthio)pentyl)boronic acid hydrochloride,
(53) ((R)-l -((2^,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (piperidin- 1 -yl)pyrrolidine-2-carboxamido)-5-(4-phenyl- \H- 1 ,2,3 -triazol- 1 - yl)pentyl)boronic acid,
(54) ((R)-l-((2S,4R)-l -((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (piperidin-l-yl)pyrrolidine-2-carboxamido)-4-(3-cyclohexylureido)butyl)boronic acid,
(55) ((R)-l-((2S,4R)-l -((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (piperidin-l-yl)pyrrolidine-2-carboxamido)-4-(3-ethylureido)butyl)boronic acid,
(56) ((R)-l-((2S,4R)-l -((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (piperidin-l-yl)pyrrolidine-2-carboxamido)-4-(3-phenylureido)butyl)boronic acid,
(57) ((R)-l-((2S,4R)-l -((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (piperidin-l-yl)pyrrolidine-2-carboxamido)-4-(3-benzylureido)butyl)boronic acid,
(58) ((R)-l-((2S,4R)-l -((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (piperidin-l-yl)pyrrolidine-2-carboxamido)-4-benzamidobutyl)boronic acid,
(59) ((R)-l-((2S,4R)-l -((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (piperidin-l-yl)pyrrolidine-2-carboxamido)-4-(phenylsulfonamido)butyl)boronic acid,
(60) ((R)-l-((2S,4R)-l -((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (piperidin-l-yl)pyrrolidine-2-carboxamido)-4-(3-phenethylureido)butyl)boronic acid,
(61) ((R)-l-((2S,4R)-l -((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (piperidin-l-yl)pyrrolidine-2-carboxamido)-4-(3-(3- pheny lpropy l)urei do)buty l)b oroni c aci d, (62) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (piperidin-l-yl)pyrrolidine-2-carboxamido)-4-(3-(naphthalen-l- yl)ureido)butyl)boronic acid,
(63) ((R)-l-((2^,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (piperidin-l-yl)pyrrolidine-2-carboxamido)-6-(3-cyclohexylureido)hexyl)boronic acid formate, and
(64) ((lR)-l-(l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-phenyl- 2,5-dihydro-lH-pyrrole-2-carboxamido)-2-methylpropyl)boronic acid,
or a pharaceutically acceptable salt, solvate, solvate of the salt or prodrug thereof.
[0032] In a nineteenth embodiment, a pharmaceutical composition is provided comprising any one of the compounds of the first through eighteenth embodiments, or a pharmaceutically acceptable salt, solvate, solvate of the salt or prodrug thereof, and a pharmaceutically acceptable carrier.
[0033] In a twentieth embodiment, a method of preventing, or treating a disease of the eye selected from dry-AMD, Wet-AMD, and geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, and degeneration of retinal or photoreceptor cells is provided, comprising: administration of a therapeutically effective amount of any one of the compounds of the first through eighteenth embodiments or a pharmaceutically acceptable salt, solvate, solvate of the salt or prodrug thereof.
[0034] In a twenty-first embodiment, for the method of the twentieth embodiment, the method of prevention is selected from delaying the onset of disease and reducing the risk of developing a disease of the eye, wherein the disease of the eye is selected from dry-AMD, Wet-AMD, and geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, and degeneration of retinal or photoreceptor cells.
[0035] In a twenty-second embodiment, for the method of the twentieth embodiment, the method of treating a disease of the eye is selected from controlling, alleviating, and slowing the progression of, wherein the disease is selected from dry-AMD, Wet-AMD, and geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, and degeneration of retinal or photoreceptor cells. [0036] In a twenty-third embodiment, for the method of any one of the twentieth through the twenty-second embodiments, the disease is geographic atrophy.
[0037] In a twenty-fourth embodiment, a method of inhibiting HtrAl protease activity in an eye is provided, comprising administration of a therapeutically effective amount of any one of the compounds of the first through eighteenth embodiments or a pharmaceutically acceptable salt, solvate, solvate of the salt or prodrug thereof.
[0038] In a twenty-fifth embodiment, a method of preventing, or treating a disease of the eye selected from dry-AMD, Wet-AMD, and geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, and degeneration of retinal or photoreceptor cells is provided, comprising: administration of a therapeutically effective amount of a compound of Formula I:
Figure imgf000025_0001
I
or a pharmaceutically acceptable salt, solvate, solvate of the salt or prodrug thereof wherein:
each n is independently selected from 0, 1, or 2;
X is selected from -C(O)-, -S02- and -CHCH3, wherein 1, 2 or 3 of the CH3 hydrogens may optionally be replaced with a halogen;
R1 is selected from the group consisting of:
(a) phenyl or naphthyl,
(b) 5- or 6-membered monocyclic heteroaryl ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(c) 8-, 9-, or 10-membered fused bicyclic heteroaryl ring, said ring having 1, 2, 3 or 4, heteroatoms independently selected from N, S and O, (d) 5- or 6-membered monocyclic heterocycloalkyl ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(e) 8-, 9-, or 10-membered fused bicyclic heterocycloalkyl ring, said ring having 1, 2, 3 or 4, heteroatoms independently selected from N, S and O,
wherein R1 choices (a), (b), (c), (d) and (e) are optionally mono- or di- substituted with substituents independently selected from halogen, -CH3, -CF3, -
Figure imgf000026_0001
R2 is selected from the group consisting of:
(a) -(CH2)n-C3-8cycloalkyl,
(b) -(CH2)n-phenyl,
(c) -(CH2)n-heteroaryl, wherein the heteroaryl is a 5- or 6-membered monocyclic ring, having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
wherein R2 choices (a), (b) and (c) are optionally mono- or di- substituted with substituents independently selected from halogen, -CH3, -CF3, -OCH3 and -OCF3;
R3a and R3b are each independently selected from the group consisting of:
(a) hydrogen,
(b) hydroxyl,
(c) halogen,
(d) -S(0)n-Ci-6alkyl, optionally substituted with phenyl,
(e) -N(H)-C(=0)-Ci-6alkyl, optionally substituted with phenyl, or heteroaryl, wherein the heteroaryl is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(f) -N(H)-C(=0)-N(H)-Ci-6alkyl, optionally substituted with phenyl, or heteroaryl, wherein the heteroaryl is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(g) -N(H)-S02-aryl,
(h) -N(H)-S02-heteroaiyl, wherein the heteroaryl is a 5- or 6- membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(i) -N(H)-Ci-6alkyl, (j) -N(Ci-6alkyl)(Ci.6alkyl), optionally substituted with phenyl, or heteroaryl, wherein the heteroaryl is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(k) -N(Ci.6alkyl)(Ci-6alkenyl),
(1) -N(Ci-6alkyl)(Ci-6alkynyl),
(m) -N(H)-C3-6cycloalkyl,
(n) -N(H)-heterocycle, wherein the heterocycle is a 5- or 6- membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(o) -S02-N(H)-aryl,
(p) -S02-N(H)-heteroaryl,
(q) 5- or 6-membered saturated monocyclic heterocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(r) -phenyl, and
(s) -O-phenyl,
wherein the alkyl of R3a and R3b choices (d), (e), (f), (i), (j), (k) and (1) and the cycloalkyl of R3a and R3b choice (m), are optionally mono- or di-substituted with substituents independently selected from halogen, hydroxyl, -CH3, -CF3, -OCH3 and -OCF3, wherein the aryl of R3a and R3b choices (d), (e), (f), (g), Q), (o), (r) and (s), and the heteroaryl of R3a and R3b choices (e), (f), (h), (j) and (p), and the heterocycle of R3a and R3b choice (n) and (q) are optionally mono- or di-substituted with substituents independently selected from halogen, hydroxyl, -CH3, -CF3, -OCH3 and -OCF3, or
R3a and R3b taken together with the atom to which they are attached form a carbonyl, or
R4a and R4b are each independently hydrogen or
Figure imgf000027_0001
or
R3a and R4a or R3a and R4b or R3b and R4a or R3b and R4b are j oined together to form a bond or joined together so that together with the atoms to which they are attached there is formed a ring selected from phenyl, Cs-ecycloalkyl, optionally mono- or di-substituted with substituents independently selected from hydroxyl, - CH3, -CF3, -OCH3 and -OCF3; R5 is selected from the group consisting of:
(a) -Ci-6alkyl, and
(b) -Ci-6alkyl-R6;
R6 is selected from the group consisting of:
(a) - H2, optionally substituted with Ci-3alkyl, -SO2-CF3, phenyl or Ci-3alkyl-phenyl,
(b) - H-S02-Ci-3alkyl, - H-S02-phenyl, - H-S02-Ci-3alkyl- phenyl, - H-S02-heterocycle or - H-S02-Ci-3alkyl-heterocycle, wherein the heterocycle is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(c) -S(0)n-aryl,
(d) -phenyl,
(e) 5- or 6-membered monocyclic heteroaryl ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O, optionally substituted with Ci-3alkyl, phenyl or Ci-3alkyl-phenyl,
(f) 5- or 6-membered monocyclic heterocycloalkyl ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O, optionally substituted with C1-3 alkyl, phenyl or C1-3 alkyl-phenyl,
Figure imgf000028_0001
3alkyl-phenyl, - H-C(=0)-heterocycle or - H-C(=0)-Ci-3alkyl-heterocycle, wherein the heterocycle is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(h) -N(H)-C(=0)- H2, optionally substituted with Ci-3alkyl, phenyl, naphthyl, Ci-3alkyl-phenyl, Ci-3alkyl-naphthyl, heterocycle, C3-6 -cycloalkyl or Ci. 3alkyl-heterocycle, wherein the heterocycle is a 5- or 6-membered monocyclic ring, said ring havin 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
Figure imgf000028_0002
0) -N(H)-C(= H)- H, optionally substituted with -Ci-4alkyl, - C(=0)-0-Ci-4alkyl, or -C(=0)-Ci-4alkyl, and (k) - H-SO2- H2 optionally substituted with Ci-3alkyl, phenyl, naphthyl,
Figure imgf000029_0001
Ci-3alkyl-naphthyl, heterocycle, C3-6 -cycloalkyl or Ci. 3alkyl-heterocycle, wherein the heterocycle is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O, wherein the alkyl of R6 choices (a), (b), (e), (f), (g), (h), (i), (k) and (1), and the aryl of R6 choices (a), (b), (c), (d), (e), (f), (g), (h), (k) and (1), and the heteroaryl of R6 choice (e) and the heterocycle of R6 choices (b), (g), (h) and (1), and the heterocycloalkyl of R6 choice (f) are each optionally mono or di-substituted with substituents independently selected from halogen, hydroxyl, -CH3, -CF3, -OCH3 and
[0039] Any of the features of an embodiment is applicable to all embodiments identified herein. Moreover, any of the features of an embodiment is independently combinable, partly or wholly with other embodiments described herein in any way, e.g., one, two, or three or more embodiments may be combinable in whole or in part. Further, any of the features of an embodiment may be made optional to other embodiments. Any embodiment of a method can comprise another embodiment of a compound, and any embodiment of a compound can be configured to perform a method of another embodiment.
INCORPORATION BY REFERENCE
[0040] All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.
DETAILED DESCRIPTION OF THE INVENTION
In one aspect, the invention is directed to compounds of Formula I
Figure imgf000030_0001
I
or a pharmaceutically acceptable salt, solvate, solvate of the salt or prodrug thereof wherein: each n is independently selected from 0, 1, or 2;
X is selected from -C(O)-, -S02- and -CHCH3, wherein 1, 2 or 3 of the CH3 hydrogens may optionally be replaced with a halogen;
R1 is selected from the group consisting of:
(a) phenyl or naphthyl,
(b) 5- or 6-membered monocyclic heteroaryl ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(c) 8-, 9-, or 10-membered fused bicyclic heteroaryl ring, said ring having 1, 2, 3 or 4, heteroatoms independently selected from N, S and O,
(d) 5- or 6-membered monocyclic heterocyloalkyl ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(e) 8-, 9-, or 10-membered fused bicyclic heterocycloalkyl ring, said ring having 1, 2, 3 or 4, heteroatoms independently selected from N, S and O,
wherein R1 choices (a), (b), (c), (d) and (e) are optionally mono- or di- substituted with substituents independently selected from halogen, -CH3, -CF3, -OCH3 and -OCF3;
R2 is selected from the group consisting of:
(a) -(CH2)n-C3-8cycloalkyl,
(b) -(CH2)n-phenyl,
(c) -(CH2)n-heteroaryl, wherein the heteroaryl is a 5- or 6-membered monocyclic ring, having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
wherein R2 choices (a), (b) and (c) are optionally mono- or di-substituted with substituents independently selected from halogen, -CH3, -CF3, -OCH3 and -OCF3; R a and R are each independently selected from the group consisting of:
(a) hydrogen,
(b) hydroxyl,
(c) halogen,
(d) -S(0)n-Ci-6alkyl, optionally substituted with phenyl,
(e) -N(H)-C(=0)-Ci-6alkyl, optionally substituted with phenyl, or heteroaryl, wherein the heteroaryl is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(f) -N(H)-C(=0)-N(H)-Ci-6alkyl, optionally substituted with phenyl, or heteroaryl, wherein the heteroaryl is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(g) -N(H)-S02-aryl,
(h) -N(H)-S02-heteroaryl, wherein the heteroaryl is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(i) -N(H)-Ci-6alkyl,
(j) -N(Ci-6alkyl)(Ci-6alkyl), optionally substituted with phenyl, or heteroaryl, wherein the heteroaryl is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(k) -N(Ci.6alkyl)(Ci-6alkenyl),
(1) -N(Ci-6alkyl)(Ci-6alkynyl),
(m) -N(H)-C3-6cycloalkyl,
(n) -N(H)-heterocycle, wherein the heterocycle is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(o) -S02-N(H)-aryl,
(p) -S02-N(H)-heteroaiyl,
(q) 5- or 6-membered saturated monocyclic heterocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(r) -phenyl, and
(s) -O-phenyl,
wherein the alkyl of R3a and R3b choices (d), (e), (f), (i), (j), (k) and (1) and the cycloalkyl of R3a and R3b choice (m), are optionally mono- or di- substituted with substituents independently selected from halogen, hydroxyl, -CH3, -CF3, -OCH3 and -OCF3, wherein the aryl of R3a and R3b choices (d), (e), (f), (g), (j), (o), (r) and (s), and the heteroaryl of R3a and R3b choices (e), (f), (h), (j) and (p), and the heterocycle of R3a and R3b choice (n) and (q) are optionally mono- or di-substituted with substituents independently selected from halogen, hydroxyl, -CH3, -CF3, -OCH3 and -OCF3, or
R3a and R3b taken together with the atom to which they are attached form a carbonyl, with the proviso that at least one of R3a and R3b is other than hydrogen;
R4a and R4b are each independently hydrogen or
Figure imgf000032_0001
or
R3a and R4a or R3a and R4b or R3b and R4a or R3b and R4b are joined together to form a bond or joined together so that together with the atoms to which they are attached there is formed a ring selected from phenyl, Cs-ecycloalkyl, optionally mono- or di-substituted with substituents independently selected from hydroxyl, -CH3, -CF3, -OCH3 and -OCF3;
R5 is selected from the group consisting of:
(a) -Ci-6alkyl, and
(b) -Ci-6alkyl-R6;
R6 is selected from the group consisting of:
(a) - H2, optionally substituted with Ci-3alkyl, -S02-CF3, phenyl or Ci-3alkyl- phenyl,
(b) - H-S02-Ci-3alkyl, - H-S02-phenyl, - H-S02-Ci-3alkyl-phenyl, - H-S02- heterocycle or - H-S02-Ci-3alkyl-heterocycle, wherein the heterocycle is a 5- or 6- membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(c) -S(0)n-aryl,
(d) -phenyl,
(e) 5- or 6-membered monocyclic heteroaryl ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O, optionally substituted with Ci-3alkyl, phenyl or Ci-3alkyl-phenyl,
(f) 5- or 6-membered monocyclic hetercycloalkyl ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O, optionally substituted with Ci. 3alkyl, phenyl or Ci-3alkyl-phenyl,
Figure imgf000033_0001
H-C(=0)-heterocycle or -NH-C(=0)-Ci-3alkyl-heterocycle, wherein the heterocycle is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(h) -N(H)-C(=0)- H2, optionally substituted with Ci-3alkyl, phenyl, naphthyl, Ci. 3alkyl-phenyl, Ci-3alkyl-naphthyl, heterocycle, C3-6 -cycloalkyl or Ci-3alkyl-heterocycle, wherein the heterocycle is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms inde endently selected from N, S and O,
Figure imgf000033_0002
(j) -N(H)-C(= H)- H, optionally substituted with -Ci-4alkyl, -C(=0)-0-Ci-4alkyl, or -C(=0)-Ci-4alkyl, and
(k) - H-S02- H2 optionally substituted with Ci-3alkyl, phenyl, naphthyl, Ci-3alkyl- phenyl, Ci-3alkyl-naphthyl, heterocycle, C3-6 -cycloalkyl or Ci-3alkyl-heterocycle, wherein the heterocycle is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
wherein the alkyl of R6 choices (a), (b), (e), (f), (g), (h), (i), (k) and (1), and the aryl of R6 choices (a), (b), (c), (d), (e), (f), (g), (h), (k) and (1), and the heteroaryl of R6 choice (e) and the heterocycle of R6 choices (b), (g), (h) and (1), and the heterocycloalkyl of R6 choice (f) are each optionally mono or di- substituted with substituents independently selected from halogen, hydroxyl, -CH3, -CF3, -OCH3 and -OCF3.
[0042] Within this aspect there is a genus wherein
X is selected from -C(O)- and -CHCF3.
[0043] Within this genus there is a sub-genus wherein
X is -C(O)- .
[0044] Within this aspect there is a genus wherein
R1 is selected from the group consisting of:
(a) phenyl or naphthyl, (b) 5- or 6-membered monocyclic heteroaryl ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O, and
(c) 8-, 9-, or 10-membered fused bicyclic heteroaryl ring, said ring having 1, 2, 3 or 4, heteroatoms independently selected from N, S and O,
wherein R1 choices (a), (b) and (c) are optionally mono- or di-substituted with substituents independently selected from halogen, -CH3, -CF3, -OCH3 and -OCF3.
[0045] Within this genus there is a sub-genus wherein
R1 is naphthyl.
[0046] Within this aspect there is a genus wherein
R2 is -(CH2)n-C3-8cycloalkyl,
wherein the C3-8cycloalkyl is optionally mono- or di-substituted with substituents independently selected from halogen, -CH3, -CF3, -OCH3 and -OCF3.
[0047] Within this genus there is a sub-genus wherein
R2 is -(CH2)-cyclohexyl.
[0048] Within this aspect there is a genus wherein
R3a is hydrogen, and
R3b is selected from the group consisting of:
(a) phenyl,
(b) -O-phenyl,
(c) hydroxyl,
(d) chloro,
(e) -S-C(CH3)3,
(f) -S-(CH2)2-phenyl,
(g) piperidinyl,
(h) morpholinyl,
(i) pyrrolidinyl,
G) -N(CH3)-CH2-phenyl,
(k) -N(CH3)-CH2-ethynyl,
(1) -N(CH3)-(CH2)2-OH,
(m) - H-C(=0)-(CH2)2-phenyl,
(n) - H-C(=0)-CH2-pyridinyl, (o) -NH-C(=0)-(CH2)3-phenyl-OCH3,
(p) -NH-C(=0)-NH-(CH2)3-phenyl, and
(q) - H-S(0)2-pyrazolyl-CH3, or
R3a and R3b taken together with the atom to which they are attached form a carbonyl, or
R3 and R4a or R3b and R4b are joined together so that together with the atoms to which they are attached there is formed a ring selected from phenyl, Cs-ecycloalkyl, optionally mono- or di-substituted with substituents independently selected from hydroxyl, - CH3, -CF3, -OCH3 and -OCF3.
[0049] Within this genus there is a sub-genus wherein
R3a is hydrogen, and
R,b is selected from the group consisting of:
(a) phenyl,
(b) -S-C(CH3)3,
(c) piperidinyl,
(d) morpholinyl,
(e) pyrrolidinyl, and
(f) - H-S(0)2-pyrazolyl-CH3.
[0050] Within this sub-genus there is a class wherein
R3 is hydrogen, and
R,b is selected from the group consisting of:
(a) piperidinyl,
(b) morpholinyl, and
(c) -NH-C(=0)-CH2-pyridinyl.
[0051] Within this aspect there is a genus wherein
R4a and R4b are each hydrogen, or
R3b and R4a or R3b and R4b are joined together so that together with the atoms to which they are attached there is formed a ring selected from phenyl, Cs-ecycloalkyl, optionally mono- or di-substituted with substituents independently selected from hydroxyl, - CH3, -CF3, -OCH3 and -OCF3.
[0052] Within this genus there is a sub-genus wherein R a and R are each hydrogen.
[0053] Within this aspect there is a genus wherein
t is selected from 3, 4 or 5; and
R5 is selected from the group consisting of:
(a) -CH2(CH3)2,
(b) -CH2-phenyl,
(c) -(CH2)t-S-phenyl,
(d) -(CH2)t-R6
(e) -(CH2)t- H-S02-phenyl,
(f) -(CH2)t- H-S02-CF3,
(g) -(CH2)t- H-S02-CH3,
(h) -(CH2)t- H-S02-piperidinyl,
(i) -(CH2)t-triazolyl-phenyl,
(j) -(CH2)t- H-C(=0)-CH3,
(k) -(CH2)t- H-C(=0)-phenyl,
(1) -(CH2)t- H-C(=0)-CH2-phenyl,
(m -(CH2)t-NH-C(=NH)-NH-C(=0)-0-C(CH3)3,
(n) -(CH2)t- H-C(=0)-NH-cyclohexyl,
(o) -(CH2)t-NH-C(=0)-NH-phenyl, optionally substituted with halo or methoxy,
(p) -(CH2)t- H-C(=0)-NH-CH2-phenyl,
(q) -(CH2)t- H-C(=0)- H-(CH2)2-phenyl,
(r) -(CH2)t-NH-C(=0)- H-(CH2)3-phenyl,
(s) -(CH2)t- H-C(=0)- H-phenyl,
(t) -(CH2)t- H-C(=0)-NH-CH2CH3,
(u) -(CH2)t-NH-C(=0)-NH-naphthyl, and
(v) -(CH2)t- H-C(=0)- H-pyridinyl; and
R6 is
Figure imgf000036_0001
[0054] Within this genus there is a sub-genus wherein R5 is selected from the group consisting of:
(a) -CH2(CH3)2,
(b) -CH2-phenyl,
(c) -(CH2)4- H-S02-phenyl,
(d) -(CH2)4- H-C(=0)-CH3,
(e) -(CH2)3- H-C(=0)-phenyl,
(f) -(CH2)4- H-C(=0)-phenyl,
(g) -(CH2)4- H-C(=0)-CH2-phenyl,
(h) -(CH2)3- H-C(=0)- H-cyclohexyl,
(i) -(CH2)4- H-C(=0)- H-cyclohexyl,
Q )-(CH2)5- H-C(=0)- H-cyclohexyl,
(k) -(CH2)- H-C(=0)- H-phenyl, optionally substituted with halo or methoxy, (1) -(CH2)3- H-C(=0)- H-CH2-phenyl,
(m) -(CH2)4- H-C(=0)-NH-CH2-phenyl,
(n) -(CH2)3- H-C(=0)- H-phenyl,
(0) -(CH2)3- H-C(=0)- H-CH2CH3,
(p) -(CH2)4- H-C(=0)- H-CH2CH3, and
(q) -(CH2)4- H-C(=0)- H-pyridinyl.
[0055] Within this sub-genus there is a class wherein
R5 is selected from the group consisting of:
(a) -CH2(CH3)2,
(b) -(CH2)3- H-C(=0)- H-cyclohexyl,
(c) -(CH2)4- H-C(=0)- H-cyclohexyl,
(d) -(CH2)5- H-C(=0)- H-cyclohexyl,
(e) -(CH2)- H-C(=0)- H-phenyl, optionally substituted with halo or methoxy,
(f) -(CH2)3- H-C(=0)-NH-CH2-phenyl,
(g) -(CH2)4- H-C(=0)- H-CH2-phenyl,
(h) -(CH2)4- H-C(=0)- H-CH2CH3, and
(1) -(CH2)4- H-C(=0)- H-pyridinyl.
[0056] Within this aspect there is a genus of Formula la wherein
or a pharmaceutically acceptable salt, solvate, solvate of the salt or prodrug thereof, wherein X is selected from -C(O)- and -CHCF3-;
R,a is hydrogen;
R3b is selected from the group consisting of:
(a) phenyl,
(b) -O-phenyl,
(c) hydroxyl,
(d) chloro,
(e) -S-C(CH3)3,
(f) -S-(CH2)2-phenyl,
(g) piperidinyl,
(h) morpholinyl,
(i) pyrrolidinyl,
(j) -N(CH3)-CH2-phenyl,
(k) -N(CH3)-CH2-ethynyl,
(1) -N(CH3)-(CH2)2-OH,
(m) -NH-C(=0)-(CH2)2-phenyl,
(n) - H-C(=0)-CH2-pyridinyl,
(o) - H-C(=0)-(CH2)3-phenyl-OCH3,
(p) - H-C(=0)-NH-(CH2)3-phenyl, and
(q) -NH-S(0)2-pyrazolyl-CH3, or
R a and R3b taken together with the atom to which they are attached form a carbonyl, R4 is hydrogen or C^alkyl, or
R3b and R4 are joined together to form a bond or joined so that together with the atomsh they are attached there is formed a ring selected from phenyl and cyclopentyl;
R5 is selected from the group consisting of:
(a) -CH2(CH3)2,
(b) -CH2-phenyl,
(c) -(CH2)4-S-phenyl,
(d) -(CH2)4-R6
(e) -(CH2)3- H-S02-phenyl,
(g) -(CH2)4- H-S02-phenyl,
(h) -(CH2)4- H-S02-CF3,
(i) -(CH2)4- H-S02-CH3,
0) -(CH2)4-NH-S02-piperidinyl,
(k) -(CH2)4-triazolyl-phenyl,
(1) -(CH2)4- H-C(=0)-CH3,
(m) -(CH2)3- H-C(=0)-phenyl,
(n) -(CH2)4- H-C(=0)-phenyl,
(o) -(CH2)4- H-C(=0)-CH2-phenyl,
(p) -(CH2)4-NH-C(=NH)-NH-C(=0)-0-C(CH3)3,
(q) -(CH2)3- H-C(=0)- H-cyclohexyl,
(r) -(CH2)4- H-C(=0)- H-cyclohexyl,
(s) -(CH2)5- H-C(=0)- H-cyclohexyl,
(t) -(CH2)- H-C(=0)- H-phenyl, optionally substituted with halo or methoxy,
(u) -(CH2)3- H-C(=0)-NH-CH2-phenyl,
(v) -(CH2)3-NH-C(=0)-NH-(CH3)2-phenyl,
(w) -(CH2)3- H-C(=0)- H-(CH2)3-phenyl,
(x) -(CH2)4- H-C(=0)-NH-CH2-phenyl,
(y) -(CH2)4- H-C(=0)- H-(CH2)2-phenyl,
(z) -(CH2)4- H-C(=0)- H-(CH2)3-phenyl,
(aa) -(CH2)3- H-C(=0)- H-phenyl,
(bb) -(CH2)3-NH-C(=0)-NH-CH2CH3,
Figure imgf000040_0001
(dd) -(CH2)3- H-C(=0)- H-naphthyl,
(ee) -(CH2)4- H-C(=0)- H-naphthyl, and
(ff) -(CH2)4- H-C(=0)- H-pyridinyl;
R6 is
Figure imgf000040_0002
[0057] Within this genus there is a sub-genus of Formula lb wherein
Figure imgf000040_0003
lb
rmaceutically acceptable salt, solvate, solvate of the salt or prodrug thereof, wherein R3bis selected from the group consisting of:
(a) piperidinyl,
(b) morpholinyl, and
(c) -NH-C(=0)-CH2-pyridinyl;
R5 is selected from the group consisting of:
(a) -CH2(CH3)2,
(b) -(CH2)3- H-C(=0)- H-cyclohexyl,
(c) -(CH2)4- H-C(=0)- H-cyclohexyl,
(d) -(CH2)5- H-C(=0)- H-cyclohexyl,
(e) -(CH2)4- H-C(=0)- H-phenyl, optionally substituted with halo or methoxy,
(f) -(CH2)3- H-C(=0)- H-CH2-phenyl,
(g) -(CH2)4- H-C(=0)-NH-CH2-phenyl,
Figure imgf000041_0001
(i) -(CH2)4- H-C(=0)- H-pyridinyl.
[0058] Illustrating this aspect are Examples 1- 64.
or a pharmaceutically acceptable salt, solvate, solvate of the salt or prodrug thereof.
[0059] In a second aspect the invention is directed to a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt, solvate, solvate of the salt or prodrug thereof, and a pharmaceutically acceptable carrier.
[0060] In a third aspect the invention is directed to a method of preventing, or treating a disease of the eye selected from dry-AMD, Wet-AMD, and geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, diabetic macula edema (DME), other retinopathies such as choroidal neovascularisation (CNV), choroidal neovascular membrane (CNVM), cystoid macular edema (CME), epi-retmal membrane (ERM) and macular hole, hypertrophic changes of the retina! pigment epithelium (RPE), atrophic changes of the retinal pigment epithelium, retinal detachment, choroidal vein occlusion, retinal vein occlusion, corneal angiogenesis following, for example, keratitis, cornea transplantation or keratoplasty, corneal angiogenesis due to hypoxia (e.g., induced by extensive contact lens wearing), pterygium conjunctivae, subretinal edema, intraretinai edema, stargardt disease and degeneration of retinal or photoreceptor cells, comprising: administration of a therapeutically effective amount of compound of Formula I or a pharmaceutically acceptable salt, solvate, solvate of the salt or prodrug thereof.
[0061] Within this third aspect there is a genus directed to a method of preventing a disease of the eye, wherein the method of prevention is selected from delaying the onset of disease and reducing the risk of developing a disease of the eye, wherein the disease of the eye is selected from dry-AMD, Wet-AMD, and geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, diabetic macula edema (DME), other retinopathies such as choroidal neovascularisation (CNV), choroidal neovascular membrane (CNVM), cystoid macular edema (CME), epi-retinal membrane (ERM) and macular hole, hypertrophic changes of the retinal pigment epithelium (RPE), atrophic changes of the retinal pigment epithelium, retinal detachment, choroidal vein occlusion, retinal vein occlusion, corneal angiogenesis following, for example, keratitis, cornea tra splantation or keratoplasty, corneal angiogenesis due to hypoxia (e.g., induced by extensive contact lens wearing), pterygium conjunctivae, subretinal edema, intraretinal edema, stargardt disease and degeneration of retinal or photoreceptor cells.
[0062] Within this third aspect there is a genus directed to a method treating a disease of the eye wherein the method is selected from controlling, alleviating, and slowing the progression of, wherein the disease is selected from dry-AMD, Wet-AMD, and geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, diabetic macula edema (DME), other retinopathies such as choroidal neovasculari sation (CNV), choroidal neovascular membrane (CNVM), cystoid macular edema (CME), epi -retinal membrane (ERM) and macular hole, hypertrophic changes of the retinal pigment epithelium (RPE), atrophic changes of the retinal pigment epithelium, retinal detachment, choroidal vein occlusion, retinal vein occlusion, corneal angiogenesis following, for example, keratitis, cornea transplantation or keratoplasty, corneal angiogenesis due to hypoxia (e.g., induced by extensive contact lens wearing), pterygium conjunctivae, subretinal edema, intraretinal edema, stargardt disease and degeneration of retinal or photoreceptor cells.
[0063] Within this genus there is a sub-genus wherein the disease is age-related macular degeneration (AMD) like wet-AMD or dry-AMD, geographic atrophy, diabetic retinopathy, stargardt disease, choroidal neovascularisation (CNV), and diabetic macula edema (DME).
[0064] Within this genus there is a sub-genus wherein the disease is geographic atrophy.
[0065] In a fourth aspect the invention is directed to a method of inhibiting Htr Al protease activity in an eye comprising administration of a therapeutically effective amount of compound of Formula I or a pharmaceutically acceptable salt, solvate, solvate of the salt or prodrug thereof.
[0066] In a fifth aspect the invention is directed to a method of preventing, or treating a disease of the eye selected from dry-AMD, Wet-AMD, and geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, diabetic macula edema (DME), other retinopathies such as choroidal neovascularisation (CNV), choroidal neovascular membrane (CNVM), cystoid macular edema (CME), epi-retinal membrane (ERM) and macular hole, hypertrophic changes of the retinal pigment epithelium (RPE), atrophic changes of the retina! pigment epithelium, retinal detachment, choroidal vein occlusion, retinal vein occlusion, corneal angiogenesis following, for example, keratitis, cornea transplantation or keratoplasty, corneal angiogenesis due to hypoxia (e.g., induced by extensive contact lens wearing), pterygium conjunctivae, subretinal edema, intraretinai edema, stargardt disease and degeneration of retinal or photoreceptor cells, comprising: administration of a therapeuticall effective amount of a compound of Formula I
Figure imgf000043_0001
I
or a pharmaceutically acceptable salt, solvate, solvate of the salt or prodrug thereof wherein: each n is independently selected from 0, 1, or 2;
X is selected from -C(O)-, -S02- and -CHCH3, wherein 1, 2 or 3 of the CH3 hydrogens may optionally be replaced with a halogen;
R1 is selected from the group consisting of:
(a) phenyl or naphthyl,
(b) 5- or 6-membered monocyclic heteroaryl ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(c) 8-, 9-, or 10-membered fused bicyclic heteroaryl ring, said ring having 1, 2, 3 or 4, heteroatoms independently selected from N, S and O,
(d) 5- or 6-membered monocyclic heterocycloalkyl ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(e) 8-, 9-, or 10-membered fused bicyclic heterocycloalkyl ring, said ring having 1 , 2, 3 or 4, heteroatoms independently selected from N, S and O,
wherein R1 choices (a), (b), (c), (d) and (e) are optionally mono- or di- substituted with substituents independently selected from halogen, -CH3, -CF3, -OCH3 and -OCF3;
R2 is selected from the group consisting of: (a) -(CH2)n-C3-8cycloalkyl,
(b) -(CH2)n-phenyl,
(c) -(CH2)n-heteroaryl, wherein the heteroaryl is a 5- or 6-membered monocyclic ring, having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
wherein R2 choices (a), (b) and (c) are optionally mono- or di-substituted with substituents independently selected from halogen, -CH3, -CF3, -OCH3 and -OCF3;
R3a and R3b are each independently selected from the group consisting of:
(a) hydrogen,
(b) hydroxyl,
(c) halogen,
(d) -S(0)n-Ci-6alkyl, optionally substituted with phenyl,
(e) -N(H)-C(=0)-Ci-6alkyl, optionally substituted with phenyl, or heteroaryl, wherein the heteroaryl is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(f) -N(H)-C(=0)-N(H)-Ci-6alkyl, optionally substituted with phenyl, or heteroaryl, wherein the heteroaryl is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(g) -N(H)-S02-aryl,
(h) -N(H)-S02-heteroaiyl, wherein the heteroaryl is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(i) -N(H)-Ci-6alkyl,
(j) -N(Ci-6alkyl)(Ci-6alkyl), optionally substituted with phenyl, or heteroaryl, wherein the heteroaryl is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(k) -N(Ci.6alkyl)(Ci-6alkenyl),
(1) -N(Ci-6alkyl)(Ci-6alkynyl),
(m) -N(H)-C3-6cycloalkyl,
(n) -N(H)-heterocycle, wherein the heterocycle is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(o) -S02-N(H)-aryl,
(p) -S02-N(H)-heteroaiyl, (q) 5- or 6-membered saturated monocyclic heterocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(r) -phenyl, and
(s) -O-phenyl,
wherein the alkyl of R3a and R3b choices (d), (e), (f), (i), (j), (k) and (1) and the cycloalkyl of R3a and R3b choice (m), are optionally mono- or di-substituted with substituents independently selected from halogen, hydroxyl, -CH3, -CF3, -OCH3 and -OCF3, wherein the aryl of R3a and R3b choices (d), (e), (f), (g), (j), (o), (r) and (s), and the heteroaryl of R3a and R3b choices (e), (f), (h), (j) and (p), and the heterocycle of R3a and R3b choice (n) and (q) are optionally mono- or di-substituted with substituents independently selected from halogen, hydroxyl, -CH3, -CF3, -OCH3 and -OCF3, or
R3a and R3b taken together with the atom to which they are attached form a carbonyl, or
R4a and R4b are each independently hydrogen or
Figure imgf000045_0001
or
R3a and R4a or R3a and R4b or R3b and R4a or R3b and R4b are joined together to form a bond or joined together so that together with the atoms to which they are attached there is formed a ring selected from phenyl, Cs-ecycloalkyl, optionally mono- or di-substituted with substituents independently selected from hydroxyl, -CH3, -CF3, -OCH3 and -OCF3;
R5 is selected from the group consisting of:
(a) -Ci-6alkyl, and
(b) -Ci-6alkyl-R6;
R6 is selected from the group consisting of:
(a) -NH2, optionally substituted with Ci-3alkyl, -S02-CF3, phenyl or Ci-3alkyl- phenyl,
(b) - H-S02-Ci-3alkyl, - H-S02-phenyl, - H-S02-Ci-3alkyl-phenyl, - H-S02- heterocycle or - H-S02-Ci-3alkyl-heterocycle, wherein the heterocycle is a 5- or 6- membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(c) -S(0)n-aryl,
(d) -phenyl, (e) 5- or 6-membered monocyclic heteroaryl ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O, optionally substituted with Ci-3alkyl, phenyl or Ci-3alkyl-phenyl,
(f) 5- or 6-membered monocyclic heterocycloalkyl ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O, optionally substituted with Ci.
3alkyl, phenyl or Ci-3alkyl-phenyl,
Figure imgf000046_0001
H-C(=0)-heterocycle or -NH-C(=0)-Ci-3alkyl-heterocycle, wherein the heterocycle is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(h) -N(H)-C(=0)- H2, optionally substituted with Ci-3alkyl, phenyl, naphthyl, Ci. 3alkyl-phenyl, Ci-3alkyl-naphthyl, heterocycle, C3-6 -cycloalkyl or Ci-3alkyl-heterocycle, wherein the heterocycle is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms inde endently selected from N, S and O,
Figure imgf000046_0002
(j) -N(H)-C(= H)- H, optionally substituted with -Ci-4alkyl, -C(=0)-0-Ci-4alkyl, or -C(=0)-Ci-4alkyl, and
(k) - H-S02- H2 optionally substituted with Ci-3alkyl, phenyl, naphthyl, Ci-3alkyl- phenyl, Ci-3alkyl-naphthyl, heterocycle, C3-6 -cycloalkyl or Ci-3alkyl-heterocycle, wherein the heterocycle is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
wherein the alkyl of R6 choices (a), (b), (e), (f), (g), (h), (i), (k) and (1), and the aryl of R6 choices (a), (b), (c), (d), (e), (f), (g), (h), (k) and (1), and the heteroaryl of R6 choice (e) and the heterocycle of R6 choices (b), (g),(h) and (1), and the heterocycloalkyl of R6 choice (f) are each optionally mono or di- substituted with substituents independently selected from halogen, hydroxyl, -CH3, -CF3, -OCH3 and -OCF3.
Definitions [0067] The term "patient" includes mammals such as mice, rats, cows, sheep, pigs, rabbits, goats, horses, monkeys, dogs, cats, and humans.
[0068] The term "halo" or "halogen" refers to any radical of fluorine, chlorine, bromine or iodine.
[0069] The term "alkyl" refers to a saturated hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, Ci-6alkyl indicates that the group may have from 1 to 6 (inclusive) carbon atoms in it. In some embodiments, an alkyl is a
Figure imgf000047_0001
which represents a straight-chain or branched saturated hydrocarbon radical having 1 to 6 carbon atoms. Examples include methyl, ethyl, ^-propyl, isopropyl, «-butyl, isobutyl, sec-butyl, tert-butyl. Any atom can be optionally substituted, e.g., by one or more substituents. Examples of alkyl groups include without limitation methyl, ethyl, ^-propyl, isopropyl, «-butyl, sec-butyl and tert-butyl.
[0070] The term "haloalkyl" refers to an alkyl group, in which at least one hydrogen atom is replaced by halo. In some embodiments, more than one hydrogen atom (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) are replaced by halo. In these embodiments, the hydrogen atoms can each be replaced by the same halogen (e.g., fluoro) or the hydrogen atoms can be replaced by a combination of different halogens (e.g., fluoro and chloro). "Haloalkyl" also includes alkyl moieties in which all hydrogens have been replaced by halo (sometimes referred to herein as perhaloalkyl, e.g., perfluoroalkyl, such as trifluoromethyl). Any atom can be optionally substituted, e.g., by one or more substituents. In some embodiments, a haloalkyl is a Ci-6haloalkyl. In some embodiments, a fluoroalkyl is a Ci. 6fluoroalkyl.
[0071] As referred to herein, the term "alkoxy" refers to a group of formula -O- (alkyl). Alkoxy can be, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso- butoxy, sec-butoxy, pentoxy, 2-pentoxy, 3-pentoxy, or hexyloxy. Likewise, the term "thioalkoxy" refers to a group of formula -S-(alkyl). The terms "haloalkoxy" and "thiohaloalkoxy" refer to -O-(haloalkyl) and -S-(haloalkyl), respectively. The term "sulfhydryl" refers to -SH.
[0072] The term "aralkyl" refers to an alkyl moiety in which an alkyl hydrogen atom is replaced by an aryl group. One of the carbons of the alkyl moiety serves as the point of attachment of the aralkyl group to another moiety. Any ring or chain atom can be optionally substituted e.g., by one or more substituents. Non-limiting examples of "aralkyl" include benzyl, 2-phenylethyl, and 3-phenylpropyl groups.
[0073] The term "alkenyl" refers to a straight or branched hydrocarbon chain containing the indicated number of carbon atoms and having one or more carbon-carbon double bonds. Any atom can be optionally substituted, e.g., by one or more substituents. Alkenyl groups can include, e.g., vinyl, allyl, 1-butenyl, and 2-hexenyl. In some embodiments, an alkenyl is a C2-6alkenyl.
[0074] The term "heterocycle" or "heterocyclic" includes heterocycloalkyls and heteroaryls.
[0075] The term "heterocycloalkyl" as used herein except where noted, represents a stable 3-, 4-, 5-, 6- or 7-membered monocyclic- or stable 6-, 7-, 8-, 9-, 10-, 11-, or 12- membered fused bicyclic heterocyclic ring system which comprises at least one non-aromatic (i.e. saturated or partially unsaturated) ring which consists of carbon atoms and from one to four, preferably up to three, heteroatoms selected from the group consisting of N, O and S, wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and wherein the nitrogen heteroatom may optionally be quaternized. In some embodiments, a heterocycloalkyl is a C2-ioheterocycloalkyl. In other embodiments, a heterocycloalkyl is a C2-6heterocycloalkyl. In some embodiments, a heterocycloalkyl is monocyclic preferably having a total number of 4 to 7, more preferably 4 to 6 ring atoms, including 3 to 6, preferably 3 to 5 carbon atoms and up to 2 heteroatoms and/or hetero-groups independently selected from the group consisting of N, O, S, SO and S02, which ring system can be bonded via a ring carbon atom or, if possible, via a ring nitrogen atom. In some embodiments, a heterocycloalkyl is bicyclic. In the case of a "heterocycloalkyl" which is a bicyclic group, the second ring may also be a non-aromatic ring which consists of carbon atoms and from one to four, preferably up to three, heteroatoms selected from the group consisting of N, O and S, as defined above, or the second ring may be a benzene ring, or a "cycloalkyl", or a "cycloalkenyl", as defined immediately below. Examples of such heterocyclic groups include, but are not limited to, aziridine, azetidine, chroman, dihydrofuran, dihydropyran, dioxane, dioxolane, hexahydroazepine, imidazolidine, imidazoline, indoline, isochroman, isoindoline, isothiazoline, isothiazolidine, isoxazoline, isoxazolidine, morpholine, oxazoline, oxazolidine, oxetane, piperazine, piperidine, pyran, pyrazolidine, pyrazoline, pyrrolidine, pyrroline, tetrahydrofuran, tetrahydropyran, thiamorpholine, thiazoline, thiazolidine, thiomorpholine, thietane, thiolane, sulfolane, 1,3-dioxolane, 1,3-oxazolidine, 1,3- thiazolidine, tetrahydrothiopyran, 1,3-dioxane, 1,4-dioxane, 1,1-dioxidothiomorpholine, perhydroazepine, perhydro-l,4-diazepine, perhydro-l,4-oxazepine, 7- azabicyclo[2.2.1]heptane, 3-azabicyclo[3.2.0]heptane, 7-azabicyclo[4.1.0]heptane, 2,5- diazabicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane and N-oxides thereof. Particular preference is given to 5- or 6-membered monocyclic heterocycloalkyl radicals having up to 2 heteroatoms selected from the group consisting of N, O and S, such as illustratively and preferably tetrahydrofuran, 1,3-dioxolane, pyrrolidine, tetrahydropyran, 1,4-dioxane, piperidine, piperazine, morpholine, and thiomorpholine.
[0076] The term "cycloalkyl" refers to a fully saturated monocyclic, bicyclic, tricyclic, or other polycyclic hydrocarbon groups. Any atom can be optionally substituted, e.g., by one or more substituents. A ring carbon serves as the point of attachment of a cycloalkyl group to another moiety. Cycloalkyl moieties can include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and norbornyl (bicyclo[2.2.1]heptyl). In some embodiments, a cycloalkyl is a C3.i0cycloalkyl. In other embodiments, a cycloalkyl is a C3-6cycloalkyl. In some embodiments, a cycloalkyl is monocyclic. In some embodiments, a cycloalkyl is bicyclic.
[0077] The term "cycloalkenyl" refers to partially unsaturated monocyclic, bicyclic, tricyclic, or other polycyclic hydrocarbon groups. A ring carbon (e.g., saturated or unsaturated) is the point of attachment of the cycloalkenyl substituent. Any atom can be optionally substituted e.g., by one or more substituents. Cycloalkenyl moieties can include, e.g., cyclopentenyl, cyclohexenyl, cyclohexadienyl, or norbornenyl. In some embodiments, a cycloalkenyl is a C4-iocycloalkenyl. In other embodiments, a cycloalkenyl is a C4. 6Cycloalkenyl. In some embodiments, a cycloalkenyl is monocyclic. In some embodiments, a cycloalkenyl is bicyclic.
[0078] The term "cycloalkylene", as used herein, refers to a divalent monocyclic cycloalkyl group having the indicated number of ring atoms.
[0079] The term "heterocycloalkylene", as used herein, refers to a divalent monocyclic heterocycloalkyl group having the indicated number of ring atoms. [0080] The term "aryl" as used herein, is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, or biphenyl.
[0081] The term "heteroaryl", as used herein except where noted, represents a stable 5-, 6- or 7-membered monocyclic- or stable 9 or 10-membered fused bicyclic ring system which comprises at least one aromatic ring, -which consists of carbon atoms and from one to four, preferably up to three, heteroatoms selected from the group consisting of N, O and S wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. In the case of a "heteroaryl" which is a bicyclic group, the second ring need not be aromatic and need not comprise a heteroatom. Accordingly, "heteroaryl" includes, for example, a stable 5-, 6- or 7-membered monocyclic aromatic ring consisting of carbon atoms and from one to four, preferably up to three , heteroatoms, as defined immediately above, fused to a benzene ring, or fused to a "heterocycloalkyl", a "cycloalkyl", or a "cycloalkenyl", as defined above. Examples of such heteroaryl groups include, but are not limited to, benzimidazole, benzisothiazole, benzisoxazole, benzofuran, isobenzofuran, benzothiazole, benzothiophene, benzotriazole, benzoxazole, carboline, cinnoline, furan, furazan, imidazole, indazole, indole, indolizine, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, phthalazine, pteridine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazine, triazole, triazole, benzimidazole, benzothiadiazole, isoindole, phthalazine, imidazopyridine, pyrazolopyridine, pyrrolopyrimidine and N-oxides thereof. Preference is given to 6-membered heteroaryl radicals having up to 2 nitrogen atoms, such as pyridyl, pyrimidyl, pyridazinyl and pyrazinyl, and to 5-membered heteroaryl radicals having up to 2 heteroatoms selected from the group consisting of N, O and S, such as illustratively and preferably thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isothiazolyl, and isoxazolyl.
[0082] The term "acyl", as used herein, refers to those groups derived from an organic acid by removal of the hydroxy portion of the acid. Accordingly, acyl is meant to include, for example, acetyl, propionyl, butyryl, decanoyl, pivaloyl, benzoyl and the like. Compound Forms And Salts [0083] The compounds of this invention may contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, enantiomerically enriched mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. The compounds of this invention include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof. 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.
[0084] The compounds of this invention include the compounds themselves, as well as their salts, solvate, solvate of the salt and their prodrugs, if applicable. Salts for the purposes of the present invention are preferably pharmaceutically acceptable salts of the compounds according to the invention (for example, see S. M. Berge et al, "Pharmaceutical Salts", J. Pharm. Sci. 1977, 66, 1-19). Salts which are not themselves suitable for pharmaceutical uses but can be used, for example, for isolation or purification of the compounds according to the invention are also included. A salt, for example, can be formed between an anion and a positively charged substituent (e.g., amino) on a compound described herein. Suitable anions include chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, and acetate. Likewise, a salt can also be formed between a cation and a negatively charged substituent (e.g., carboxylate) on a compound described herein. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion.
[0085] As used herein, "pharmaceutically acceptable salts" refer to derivatives wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfonic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2- acetoxybenzoic, fumaric, benzenesulfonic, toluenesulfonic, naphthalenedisulfonic, methanesulfonic, ethanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
[0086] When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, naphthalenedisulfonic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, ^-toluenesulfonic acid, and the like. In one aspect of the invention the salts are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids.
[0087] When the compound of the present invention is acidic, salts may be prepared from pharmaceutically acceptable non-toxic bases, including inorganic and organic acids. Such salts that may be prepared include lithium salt, sodium salt, potassium salt, magnesium salt, calcium salt, dicyclohexylamine salt, N-methyl-D-glucamine salt, tris(hydroxymethyl)methylamine salt, arginine salt, lysine salt, and the like.
[0088] Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418; Journal of Pharmaceutical Science, 66, 2 (1977); and "Pharmaceutical Salts: Properties, Selection, and Use. A Handbook"; Wermuth, C. G. and Stahl, P. H. (eds.) Verlag Helvetica Chimica Acta, Zurich, 2002 [ISBN 3-906390-26-8] each of which is incorporated herein by reference in their entireties.
[0089] Solvates in the context of the invention are designated as those forms of the compounds according to the invention which form a complex in the solid or liquid state by stoichiometric coordination with solvent molecules. Hydrates are a specific form of solvates, in which the coordination takes place with water. Hydrates are preferred solvates in the context of the present invention.
[0090] The compounds of this invention may, either by nature of asymmetric centers or by restricted rotation, be present in the form of isomers (enantiomers, diastereomers). Any isomer may be present in which the asymmetric center is in the (R)-, (S)-, or (R,S)-configuration.
[0091] It will also be appreciated that when two or more asymmetric centers are present in the compounds of the invention, several diastereomers and enantiomers of the exemplified structures will often be possible, and that pure diastereomers and pure enantiomers represent preferred embodiments. It is intended that pure stereoisomers, pure diastereomers, pure enantiomers, and mixtures thereof, are within the scope of the invention.
[0092] All isomers, whether separated, pure, partially pure, or in racemic mixture, of the compounds of this invention are encompassed within the scope of this invention. The purification of said isomers and the separation of said isomeric mixtures may be accomplished by standard techniques known in the art. For example, diastereomeric mixtures can be separated into the individual isomers by chromatographic processes or crystallization, and racemates can be separated into the respective enantiomers either by chromatographic processes on chiral phases or by resolution.
[0093] In addition, all possible tautomeric forms of the compounds described above are included according to the present invention.
[0094] The present invention also encompasses all suitable isotopic variants of the compounds according to the invention. An isotopic variant of a compound according to the invention is understood to mean a compound in which at least one atom within the compound according to the invention has been exchanged for another atom of the same atomic number, but with a different atomic mass than the atomic mass which usually or predominantly occurs in nature. Examples of isotopes which can be incorporated into a compound according to the invention are those of hydrogen, carbon, nitrogen, oxygen, fluorine, chlorine, bromine and iodine, such as 2H (deuterium), 3H (tritium), 13C, 14C, 15N, 170, 180, 18F, 36C1, 82Br, 1231, 1241, 1251, 1291 and 1311. Particular isotopic variants of a compound according to the invention, especially those in which one or more radioactive isotopes have been incorporated, may be beneficial, for example, for the examination of the mechanism of action or of the active compound distribution in the body. Due to comparatively easy preparability and detectability, especially compounds labelled with 3H, 14C and/or 18F isotopes are suitable for this purpose. In addition, the incorporation of isotopes, for example of deuterium, can lead to particular therapeutic benefits as a consequence of greater metabolic stability of the compound, for example an extension of the half-life in the body or a reduction in the active dose required. Such modifications of the compounds according to the invention may therefore in some cases also constitute a preferred embodiment of the present invention. Isotopic variants of the compounds according to the invention can be prepared by processes known to those skilled in the art, for example by the methods described below and the methods described in the working examples, by using corresponding isotopic modifications of the particular reagents and/or starting compounds therein.
[0095] The compounds may be radiolabeled with radioactive isotopes, such as for example tritium, iodine-125 or carbon-14. All isotopic variations of the compounds of the invention, whether radioactive or not, are intended to be encompassed within the scope of the invention.
[0096] In some embodiments, hydrogen atoms of the compounds described herein may be replaced with deuterium atoms.
[0097] In some embodiments, compounds of Formula I are prepared as prodrugs. Prodrugs are generally drug precursors that, following administration to a subject and subsequent absorption, are converted to an active, or a more active species via some process, such as conversion by a metabolic pathway. Examples of prodrugs include Ci-6 alkyl esters of carboxylic acid groups and esters of boronic acids, which, upon administration to a subject, are capable of providing active compounds. Esters of boronic acids and esters are illustrated by Formula II:
Figure imgf000054_0001
wherein:
Yi and Y2 are each independently selected from hydrogen, optionally substituted Ci. 6alkyl, C3-iocycloalkyl, Ci-eheterocycle, aryl and heteroaryl, or Yi and Y2 are joined together so that the group:
!-Yi-Y2- where Y1 and Y2 forms an optionally substituted C2-6alkyl, optionally substituted heterocycle, optionally substituted aryl or optionally substituted heteroaryl. The optional substituents include, for example, hydroxyl, halogen and
Figure imgf000055_0001
As will be appreciated by one of skill in the art, the squiggly lines shown above, describe the point at which the moiety shown is attached to the parent molecule. Illustrating the boronic acid esters are:
Figure imgf000055_0002
Yi and Y2 can also form a 6-membered trioxatriborinane or a 4-membered dioxadiboretane.
Figure imgf000055_0003
Pharmaceutical Compositions
[0098] The term "pharmaceutically acceptable carrier" refers to a carrier or an adjuvant that may be administered to a patient, together with a compound of this invention, or a pharmaceutically acceptable salt thereof, 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.
[0099] The term "composition" as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Such term in relation to pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention, or a pharmaceutically acceptable salt, or solvate or solvate of the salt thereof, and a pharmaceutically acceptable carrier. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
[0100] The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds of this invention which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the terms "administration of or "administering a" compound shall encompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985. Metabolites of these compounds include active species produced upon introduction of compounds of this invention into the biological milieu.
[0101] The amount administered depends on the compound formulation, route of administration, etc. and is generally empirically determined in routine trials, and variations will necessarily occur depending on the target, the host, and the route of administration, etc. Generally, the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1, 3, 10 or 30 to about 30, 100, 300 or 1000 mg, according to the particular application. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.
[0102] This invention is directed to novel Boronic acid derivatives of Formula I, and pharmaceutically acceptable salts and esters thereof, useful in the prevention (e.g., delaying the onset of or reducing the risk of developing) and treatment (e.g., controlling, alleviating, or slowing the progression of) of Age-related Macular Degeneration (AMD) and related diseases of the eye. These diseases include dry-AMD, Wet-AMD, geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, diabetic macula edema (DME), other retinopathies such as choroidal neovascularisation (CNV), choroidal neovascular membrane (CNVM), cystoid macular edema (CME), epi- retinal membrane (ERM) and macular hole, hypertrophic changes of the retinal pigment epithelium (RPE), atrophic changes of the retinal pigment epithelium, retinal detachment, choroidal vein occlusion, retinal vein occlusion, corneal angiogenesis following, for example, keratitis, cornea transplantation or keratoplasty, corneal angiogenesis due to hypoxia (e.g., induced by extensive contact lens wearing), pterygium conjunctivae, subretinai edema, intraretinal edema, stargardt disease and degeneration of retinal or photoreceptor ceils. The invention disclosed herein is further directed to methods of prevention, slowing the progress of, and treatment of dry-AMD, Wet-AMD, and geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, diabetic macula edema (DME), other retinopathies such as choroidal neovasculari sation (CNV), choroidal neovascular membrane (CNVM), cystoid macular edema (CME), epi -retinal membrane (ERM) and macular hole, hypertrophic changes of the retinal pigment epithelium (RPE), atrophic changes of the retinal pigment epithelium, retinal detachment, choroidal vein occlusion, retinal vein occlusion, corneal angiogenesis following, for example, keratitis, cornea transplantation or keratoplasty, corneal angiogenesis due to hypoxia (e.g., induced by extensive contact lens wearing), pterygium conjunctivae, subretinal edema, intraretinal edema, stargardt disease and degeneration of retinal or photoreceptor cells, comprising: administration of a therapeutically effective amount of compound of the invention. The compounds of the invention are inhibitors of HTRA1. Thus, the compounds of the invention are useful in the prevention and treatment of a wide range diseases mediated (in whole or in part) by HTRA1. The compounds of the invention are also useful for inhibiting HtrAl protease activity in an eye and elsewhere. By virtue of their activity profile, the compounds of the present invention are particularly suitable for the treatment and/or prevention of ocular disorders, such as age-related macular degeneration (AMD) like wet-AMD or dry-AMD, geographic atrophy, diabetic retinopathy, stargardt disease choroidal neovascularisation (CNV), and diabetic macula edema (DME).
Administration
[0103] The compounds and compositions described herein can, for example, be administered orally, parenterally (e.g., subcutaneously, intracutaneously, intravenously, intramuscularly, intraarticularly, intraarterially, intrasynovially, intrasternally, intrathecally, intralesionally and by intracranial injection or infusion techniques), by inhalation spray, topically, rectally, nasally, buccally, vaginally, via an implanted reservoir, by injection, subdermally, intraperitoneally, transmucosally, or in an ophthalmic preparation, with a dosage ranging from about 0.01 mg/kg to about 1000 mg/kg, (e.g., from about 0.01 to about 100 mg/kg, from about 0.1 to about 100 mg/kg, from about 1 to about 100 mg/kg, from about 1 to about 10 mg/kg) every 4 to 120 hours, or according to the requirements of the particular drug. The interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described by Freireich et al, Cancer Chemother. Rep. 50, 219 (1966). Body surface area may be approximately determined from height and weight of the patient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 537 (1970). In certain embodiments, the compositions are administered by oral administration or by injection. 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.
[0104] Lower or higher doses than those recited above may be required. Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the patient's disposition to the disease, and the judgment of the treating physician.
[0105] Dosage forms include from about 0.001 milligrams to about 2,000 milligrams (including, from about 0.001 milligrams to about 1,000 milligrams, from about 0.001 milligrams to about 500 milligrams, from about 0.01 milligrams to about 250 milligrams, from about 0.01 milligrams to about 100 milligrams, from about 0.05-milligrams to about 50 milligrams, and from about 0.1 milligrams to about 25 milligrams) of a compound of Formula I (and/or a compound of any of the other formulae described herein) or a salt (e.g., a pharmaceutically acceptable salt) thereof as defined anywhere herein. The dosage forms can further include a pharmaceutically acceptable carrier and/or an additional therapeutic agent.
[0106] With regard to ophthalmic preparation, because AMD and related diseases (including dry-AMD, Wet-AMD, geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, and degeneration of retinal or photoreceptor cells) primarily afflict the back of the eye, local administration such as topical administration, trans-scleral drug delivery and intravitreal administration may be preferable over systemic administration. Intravitreal administration can be further divided into intravitreal injection and intravitreal implants. Of these, intravitreal injection appears to be the most widely used. Products utilizing intravitreal injection include Macugen, Lucentis, Ozurdex and Ileuvien. The preferred dosage range for local administration to the back of the eye ranges from 0.001 mg to 100 mg (including from about 0.01 milligrams to about 500 milligrams, from about 0.05 milligrams to about 250 milligrams, from about 0.05 milligrams to about 100 milligrams, from about 0.1 milligrams to about 100 milligrams, from about 0.1 milligrams to about 50 milligrams, and from about 0.1 milligrams to about 10 milligrams). Useful references on the subject of ophthalimic drug delivery include: Kompella U.B., et. al., Recent Advances in Ophthalmic Drug Delivery, Ther. Deliv. 2010 1(3): 435-456; Gaudana R. et.al., Ocular Drug Delivery, AAPS Journal, Vol. 12, No. 3 : 348-360 (2010); and Haghjou N., et. al., Sustained Release Intraocular Drug Delivery Devices for Treatment of Uveitis, J. Ophthalimc Vis. Res. 2011; 6 (4): 317-329, all of which are incorporated by reference.
[0107] For the treatment and/or prevention of ocular disorders, as described above, the preferred route for administering the compounds of the invention is topically at the eye or by an ocular drug delivery system. Intraocular injections are another way to administer the compounds of the present invention that is suitable for such purposes.
[0108] Delivery to areas within the eye can be accomplished by injection, employing a cannula or another invasive device designed to introduce precisely metered amounts of a desired formulation to a particular compartment or tissue within the eye (e.g., posterior chamber or retina). An intraocular injection may be into the vitreous (intravitreal), under the conjunctiva (subconjunctival), behind the eye (retrobulbar), into the sclera, or under the Capsule of Tenon (sub-Tenon), and may be in a depot form. Other intraocular routes of administration and injection sites and forms are also contemplated and are within the scope of the invention.
[0109] The compounds according to the invention may be formulated in a manner known to those skilled in the art so as to give adequate delivery to the back of the eye, which may be by regular dosing, such as with eye drops, or by using a delivery system to give a controlled release, such as slow release, of the compounds according to the invention.
[0110] Preferred ocular formulations for the compounds of the present invention include aqueous solutions, suspensions or gels of these compounds in the form of drops of liquid, liquid washes, sprays, ointments or gels, in a mixture with excipients suitable for the manufacture and use of such application forms. Alternatively, the compounds of the present invention may be applied to the eye via liposomes or other ocular delivery systems that are known in the art.
[0111] Appropriate dosage levels may be determined by any suitable method known to one skilled in the art of treating eye diseases. Preferably, the active substance is administered at a frequency of 1 to 4 times per day for topical administration, or less often if a drug delivery system is used. Typically, an ocular formulation intended for topical application contains the active ingredient in a concentration range of about 0.001% to 10%. [0112] Nevertheless, actual dosage levels and time course of administration of the active ingredients in the pharmaceutical compositions of the invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition and mode of administration, without being toxic to the patient. It may therefore be necessary where appropriate to deviate from the stated amounts, in particular as a function of age, gender, body weight, diet and general health status of the patient, route of administration, individual response to the active ingredient, nature of the preparation, and time or interval over which administration takes place. Thus, it may be satisfactory in some cases to manage with less than the aforementioned minimum amount, whereas in other cases the stated upper limit must be exceeded. It may in the event of administration of larger amounts be advisable to divide these into multiple individual doses spread over the day.
[0113] In one aspect the compounds of the invention may be co-administered with one or more additional agents. The additional agents include, but are not limited to Acuvail (ketorolac tromethamine), AK-Con-A (naphazoline), Akten (lidocaine hydrochloride), Alamast (pemirolast potassium), Alphagan (brimonidine), Bepreve (bepotastine besilate), Besivance (besifloxacin), Betaxon, Cosopt, Cystaran (cysteamine hydrochloride), Durezol (difluprednate), Eylea (aflibercept), Jetrea (ocriplasmin), Lotemax, Lucentis (ranibizumab), Lumigan (bimatoprost), Macugen (pegaptanib), Ocuflox (ofloxacin), OcuHist, Omidria (phenylephrine and ketorolac injection), Ozurdex (dexamethasone), Quixin (levofloxacin), Rescula (unoprostone isopropyl ophthalmic solution) 0.15%, Restasis (cyclosporine ophthalmic emulsion), Salagen Tablets, Travatan (travoprost ophthalmic solution), Valcyte (valganciclovir HC1), Vistide (cidofovir), Visudyne (verteporfin), Vitrasert Implant, Vitravene Injection, Zioptan (tafluprost ophthalmic solution), Zirgan (ganciclovir ophthalmic gel), and Zymaxid (gatifloxacin ophthalmic solution). Furthermore the compounds of the invention may be co-administered with one or more inhibitors of VEGF- mediated angiogenesis, such as, for example, ACTB-1003, aflibercept, apatinib, axitinib, bevacizumab, bevasiranib, BMS-690514, brivanib, cediranib, CT-322, dovitinib, E7080, foretinib, KH-902, linifanib, MGCD-265, motesanib, OTS-102, pazopanib, pegaptanib, ranibizumab, regorafenib, ruboxystaurin, sorafenib, SU-14813, sunitinib, telatinib, TG- 100801, tivozanib, TSU-68, vandetanib, vargatef, vatalanib and XL-184, or with inhibitors of other signaling pathways, such as, for example, ACU-4429, disulfiram, E- 10030, fenretinide, mecamylamine, PF-04523655, sirolimus, sonepcizumab, tandospirone and volociximab.
[0114] In certain embodiments, the additional agents may be administered separately (e.g., sequentially; on different overlapping schedules), as part of a multiple dose regimen, from the compounds of this invention (e.g., one or more compounds of Formula (I) and/or a compound of any of the other formulae, including any subgenera or specific compounds thereof). In other embodiments, these agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition. In still another embodiment, these agents can be given as a separate dose that is administered at about the same time as that of one or more compounds of Formula (I) (and/or a compound of any of the other formulae, including any subgenera or specific compounds thereof) are administered (e.g., simultaneously with the administration of one or more compounds of Formula (I) (and/or a compound of any of the other formulae, including any subgenera or specific compounds thereof)). When the compositions of this invention include 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 can 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.
[0115] The compositions of this invention may contain any conventional nontoxic 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.
[0116] The compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions and/or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oily phase and then combined with emulsifying and/or suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added. Biological Function
[0117] The utility of the invention can be demonstrated by one or more of the following methods or other methods known in the art:
Full Length HtrAl Assay
Serial dilutions (1/3) from 1000 μΜ down to 0.051 μΜ of test compounds were prepared in dimethyl sulfoxide (DMSO). Then 2 μΙ_, of DMSO from each dilution were added to 100 μΙ_, of 4 nM full-length human His-HtrAl in assay buffer (50 mM Tris, pH 7.5, 200 mM NaCl and 0.25% CHAPS) in white non-binding 96-well plates. The assay solutions were mixed for 5 seconds on a shaker plate and incubated for 10 minutes at room temperature. Mca-H20PT (Mca-Ile-Arg-Arg-Val-Ser-Tyr-Ser-Phe-Lys(Dnp)-Lys-OH trifluoroacetate salt) (5 μΜ) in 100 μΙ_, of assay buffer was added to the assay solutions. The reaction mixture was shaken for 5 seconds on a shaker plate and cleavage of Mca-H20PT was monitored by spectrofluorometry for 10 minutes (Εχλ = 330 nm; Ειηλ = 420 nm). Percent inhibition was calculated by fitting values to a standard mathematical model for determining the dose response curve.
[0118] It has been reported (Jones, A., et. al., PNAS 2011, 108(35): 14578- 14583) that over expression of HtrAl in retinal pigment epithelial cells induces an AMD-like phenotype in mice (polypoidal choroidal vasculopathy). This transgenic mouse reveals degradation of the elastic lamina of Bruch's membrane. In humans, a number of HTRAl single nucleotide polymorphs (SNP) have been found to be associated with an increased risk of AMD. See, for example, WO2008/013893A2, WO2008/067040A2 and WO2008/094370A2. These SNP's include rsl 1200638, rsl0490924, rs3750848, rs3793917 and rs932275. In particular, the risk allele rsl 1200638, was found to be associated with increased HTRAl mRNA and protein expression, and HtrAl is present in drusen in patients with AMD (see Dewan et al, 2006, Science 314:989-992; Yang et al, 2006, Science 314:992- 993). These disclosures provide evidence in support of our belief that HtrAl is an important factor in AMD and the progression thereof. Thus, we believe that an inhibitor of HtrAl will ameliorate an AMD phenotype.
Synthesis [0119] The starting materials used for the synthesis are either synthesized or obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, Fluka, Acros Organics, Alfa Aesar, VWR Scientific, and the like. General methods for the preparation of compounds can be modified by the use of appropriate reagents and conditions for the introduction of the various moieties found in the structures as provided herein.
[0120] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.
Abbreviations
BuLi butyllithium
Boc tert-butyl carbonate
C Celcius
CBz carboxybenzyl
DME dimethoxy ethane
DMF dimethylformamide
DMSO dimethylsulfoxide
EDCI l-ethyl-3-(3-dimethylaminopropyl)carbodiimide
EtOAc ethyl acetate
Et ethyl equiv equivalents h hours HATU l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate
HOBt hydroxybenzotriazole
g grams
L liter
LCMS liquid chromatography - mass spectrometry
LiHMDS lithium bis(trimethylsilyl)amide
liq. liquid
M molar
Me methyl
MeCN acetonitrile
mg milligrams
mL milliliter
mmol millimoles
mol moles
MS mass spectrometry
NHS N-hydroxysuccinimide
Pr propyl
sat. saturated
THF tetrahydrofuran
TLC thin layer chromatography (normally silica gel based)
TFA trifluoroacetic acid
Tf20 triflic anhydride
iL microliter General Synthetic Scheme
[0121] In some embodiments, compounds described herein are prepared as outlined in the following general synthetic schemes.
Method A: Synthesis of a-amino boronates
[0122] A boronate ester (prepared using standard procedures described in the literature, including those as described within Boronic Acids: Preparation and Applications in Organic Synthesis, Medicine and Materials; Dennis Hall, Ed.; John Wiley & Sons) is reacted with dichloromethyllithium as described by Matteson in Chemical Reviews, 1989, 89, 1535-1551. The corresponding a-chloro boronate is converted to an a-amino boronate by treatment with an amine or protected amine (such as LiHMDS).
n-BuLi/CH2CI2
O-PG 1 ) LiHMDS
THF, -100 °C CI O-PG H2
THF p-PG,
5-B'
O- G, then ZnCI2 R5^ b-PG, 2) acid treatment R5^ O-PG,
-100 °C to 23 °C, 18 h (e.g. HCI)
or salt therof
Method B: Amide coupling with a-amino boronates
[0123] The prepared a-amino boronate can be attached to the proline residue using standard amide coupling conditions described in the literature (e.g. Chemical Society Reviews, 2009, 38, 606-631). For example, the proline acid can be coupled to the a-amino boronate using HATU in the presence of EtN(/'Pr)2 and CH2C12. Alternatively, the proline acid can be first converted to an N-hydrosuccinimide ester (using for example NHS, EDCI in CH2C12) and then reacted with the a-amino boronate in the presence of a suitable base (e.g. Et3N). The proline acid may be protected at the nitrogen (e.g. Boc, CBz) or may be further functionalized with an a-amino acid or derivative.
Figure imgf000066_0001
Method C: Amide coupling of proline analogs with a-amino acids [0124] A substituted proline analog (or salt thereof) can be joined together with an appropriate carboxylic acid to afford the coupled product under standard amide coupling conditions (e.g. HATU, EtN(zPr)2, CH2C12). Typical amide coupling conditions have been described in the literature, including the review article by Eric Valeur and Mark Bradley in Chemical Society Reviews 2009, 38, 606-631.
Figure imgf000067_0001
Method D: Nucleophilic displacement to afford substituted proline analogs
[0125] The alcohol moiety from a 4-hydroxyproline analog is converted into a suitable leaving group (e.g. mesylate) under standard conditions and then reacted in the presence of a suitable nucleophile (e.g. amine, thiol) in the presence of a base (e.g. Et3N or NaH) to afford a 4-substituted proline derivative. The proline may contain a 2-ester moiety or may be further functionalized with an a-amino boronate.
Figure imgf000067_0002
Figure imgf000067_0003
Method E: Synthesis of 4-amide and 4-sulfonamide proline analogs
[0126] An appropriate 4-amino proline analog is reacted with an acylating reagent (such as an acyl chloride, acyl anhydride or sulfonyl chloride) in the presence of a suitable base (e.g. Et3 ) and solvent (e.g. CH2CI2). The proline may be protected at the proline nitrogen (e.g. Boc, Cbz) or may be further functionalized with an a-amino acid or derivative.
Figure imgf000068_0001
Method F: Further functionalization of R5 analogs
[0127] In certain examples, the substituent close to the a-amino boronate can be further functionalized through conversion to an amine, which can then be reacted with a range of acylating rea ents, including isocyanates, acyl chlorides and sulfonyl chlorides.
Figure imgf000068_0002
Method G: Deprotection of boronate esters to boronic acids
[0128] Boronate esters can be converted to boronic acids using a number of procedures described in the literature, including those described within Boronic Acids: Preparation and Applications in Organic Synthesis, Medicine and Materials; Dennis Hall, Ed.; John Wiley & Sons. For example, the boronate ester can be reacted with a sacrificial boronic acid (e.g. phenyl boronic acid, isobutyl boronic acid) in an appropriate solvent (e.g. methanol, ethanol, hexanes or octane) with an acid catalyst (e.g. hydrochloric acid, acetic acid).
Figure imgf000069_0001
Preparation Of Intermediates
Intermediate A: (R)-2-methyl-l-((3a,S',4)S',6)S',7aR)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[<i] [ 1 ,3 ,2]dioxaborol-2-yl)propan- 1 -amine hydrochloride
Figure imgf000069_0002
Intermediate A
Step 1: Preparation of (3a,S',4)S',6)S',7aR)-2-isopropyl-3a,5,5-trimethylhexahydro-4,6- methanob enzo [d\ [ 1 , 3 ,2] di oxab orol e
[0129] Into a 250 mL round-bottom flask equipped with a magnetic stir bar and under nitrogen was weighed isopropyl boronic acid (12.5 g, 142 mmol, 1.1 equiv). The solid was taken up in diethyl ether (100 mL), affording a yellow suspension. To this suspension was added over 4 equal portions (l-S'^^SR^^^^^-trimethylbicyclo . l . lJheptane^^-diol (22.0 g, 129 mmol, 1.0 equiv) [NOTE: Slight exotherm observed]. The resulting yellow suspension became a light white opaque solution. The reaction mixture was stirred for 16 h. The mixture was concentrated under reduced pressure and the crude yellow oil poured onto a pad of silica gel (10 cm wide x 6 cm high) on a sintered glass funnel and the product eluted with 2% EtOAc in hexanes (500 mL). The clear filtrate was concentration under reduced pressure to afford a clear oil (23.7 g, 83%).
Step 2: Preparation of (3a,S',4)S',6)S',7aR)-2-((S)-l-chloro-2-methylpropyl)-3a,5,5- trimethylhexahydro-4,6-methanobenzo[<i][l,3,2]dioxaborole [0130] Into a flame-dried 250 mL round-bottom flask equipped with a magnetic stir bar and under nitrogen was added anhydrous THF (100 mL) and CH2C12 (3.0 mL, 47.2 mmol, 1.5 equiv). The solution was cooled to between -110 °C and -100 °C in an Et20/liquid N2 Dewar. The Et20 is added to the Dewar first, followed by portion wise addition of liq. N2 until the Et20 becomes semi-solid. The temperature of the bath is monitored with a thermometer. Once the THF/CH2C12 solution had cooled to between -110 °C and -100 °C, a solution of 2.5 M «-BuLi in hexanes (15.2 mL, 37.8 mmol, 1.2 equiv) was added via syringe over a period of 15 minutes, down the side of flask and maintaining an internal reaction temperature below -90 °C. Additional aliquots of liq. N2 were added to the Dewar to maintain the bath temperature between -110 and -100 °C. A solution of (3a,S',4)S',6)S',7aR)-2-isopropyl-3a,5,5-trimethylhexahydro-4,6- methanobenzo[<i][l,3,2]dioxaborole (7.0 g, 31.6 mmol, 1.0 equiv) in anhydrous THF (50 mL) was added to the «-BuLi/CH2Cl2 reaction mixture via cannula over a period of 15 minutes. After addition was complete, a solution of ZnCl2 (28.4 mL, 28.4 mmol, 0.9 equiv, 1.0 M in Et20) was added over 15 minutes via syringe and the reaction mixture was allowed to warm to room temperature overnight.
[0131] The resulting mixture was concentrated under reduced pressure to afford a light yellow oil. The crude reaction mixture was poured into a 500 mL separately funnel containing a sat. aqueous H4CI solution (200 mL) and extracted with hexanes (3 x 100 mL). The combined organic layers were washed with brine (75 mL), dried over MgS04, filtered and concentrated under reduced pressure to afford an oil. The resulting oil was loaded onto a pad of silica gel (7 cm wide x 4 cm high) on a sintered glass funnel and eluted with 5% EtOAc in hexanes (400 mL). The clear, colorless filtrate was concentrated under reduced pressure to afford a colorless oil (6.9 g, 81%)
Step 3: Preparation of (R)-2-methyl-l-((3a,S',4)S',6)S',7aR)-3a,5,5-trimethylhexahydro- 4,6-methanobenzo[<i] [ 1 ,3 ,2]dioxaborol-2-yl)propan- 1 -amine hydrochloride
[0132] Into a flame-dried 250 mL round-bottom flask equipped with a magnetic stir bar and under nitrogen was added anhydrous THF (50 mL). The solution was cooled to - 78°C in a dry ice/acetone Dewar and a solution of 1.0 M LiHMDS in THF (31 mL, 31 mmol, 1.2 equiv) was added. The yellow solution was maintained at -78 °C while a solution of (3a,S',4)S',6)S',7aR)-2-((S)-l-chloro-2-methylpropyl)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[<i][l,3,2]dioxaborole (6.9 g, 25.5 mmol, 1.0 equiv) in THF (50 mL) was added via cannula over 10 minutes. The reaction mixture was stirred at -78 °C for 2 h and allowed to warm to room temperature overnight. The resulting yellow solution was concentrated under reduced pressure and the resulting oil suspended in hexanes (150 mL) and filtered through a pad of celite (4 x 4 cm) on a sintered plastic funnel. The filter cake was further washed with hexanes (2 x 20 mL) and the resulting yellow filtrate was collected into a 500 mL round-bottom flask. To the flask containing the filtrate was added a magnetic stir bar, septa and nitrogen inlet and the solution was cooled to -78 °C in a dry ice/acetone Dewar. A solution of 4 M HC1 in dioxane (20 mL, 80 mol, 3.1 equiv) was added and the off- white suspension was stirred at -78 °C for 2 h and allowed to warm to room temperature over 4 h. The suspension was filtered through a Hirsch funnel containing Whatman #1 filter paper under vacuum, and the white solid was washed with hexanes (2 x 10 mL). The resulting off- white solid was dried under vacuum affording the desired product (6.5 g, 89%).
Intermediate B: (R)-5-bromo-l-((3a,S',4)S',6)S',7aR)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[<i] [ 1 ,3 ,2]dioxaborol-2-yl)pentan- 1 -amine hydrochloride
Figure imgf000071_0001
Step 1: Preparation of (3a,S',4)S',6)S',7aR)-2-(4-bromobutyl)-3a,5,5-trimethylhexahydro- 4,6-methanobenzo[<i] [ 1 ,3 ,2]dioxaborole
[0133] Into a 40 mL vial equipped with a magnetic stir bar and under nitrogen was added catechol borane (8.79 g, 72 mmol, 1.0 equiv) and 4-bromo-l-butene (10 g, 72 mmol, 1.0 equiv). The solution turned slightly cloudy and was heated to 110 °C for 18 h overnight. The contents of the vial were cooled to room temperature and transferred into a 250 mL round-bottom flask using THF (60 mL). To the flask was added IS,2S,3R,5S)- 2,6,6-trimethylbicyclo[3.1.1]heptane-2,3-diol (12.5 g, 72 mmol, 1.0 equiv) and the mixture stirred at room temperature for 18 h. The solution was concentrated under reduced pressure and loaded onto a silica gel column (240 g) and eluted with 100:0 to 90: 10 Hexanes:EtOAc as a gradient. The product fractions were concentrated under reduced pressure to afford a clear oil (15.8 g, 70%).
Step 2: Preparation of (3a,S',4)S',6)S',7aR)-2-(()S)-5-bromo-l-chloropentyl)-3a,5,5- trimethylhexahydro-4,6-methanobenzo[<i][l,3,2]dioxaborole
[0134] Into a flame-dried 250 mL round-bottom flask equipped with a magnetic stir bar and under nitrogen was added anhydrous THF (90 mL) and CH2CI2 (2.4 mL, 37.5 mmol, 1.5 equiv). The solution was cooled to between -110 °C and -100 °C in an Et20/liquid N2 Dewar. The Et20 is added to the Dewar first, followed by portion wise addition of liq. N2 until the Et20 becomes semi-solid. The temperature of the bath is monitored with a thermometer. Once the THF/CH2C12 solution had cooled to between -110 °C and -100 °C, a solution of 2.5 M «-BuLi in hexanes (12 mL, 30 mmol, 1.2 equiv) was added via syringe over a period of 15 minutes, down the side of flask and maintaining an internal reaction temperature below -90 °C. Additional aliquots of liq. N2 were added to the Dewar to maintain the bath temperature between -110 and -100 °C. A solution of (3a,S',4)S',6)S',7aR)-2-(4-bromobutyl)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[<i][l,3,2]dioxaborole (7.88 g, 25 mmol, 1.0 equiv) in anhydrous THF (20 mL) was added to the «-BuLi/CH2Cl2 reaction mixture via cannula over a period of 15 minutes. After addition was complete, a solution of ZnCl2 (24 mL, 24 mmol, 1.0 equiv, 1.0 M in Et20) was added over 15 minutes via syringe and the reaction mixture was allowed to warm to room temperature overnight.
[0135] The resulting mixture was concentrated under reduced pressure. The crude reaction mixture was poured into a 500 mL separately funnel containing a sat. aqueous H4CI solution (200 mL) and extracted with hexanes (3 x 100 mL). The combined organic layers were washed with brine (75 mL), dried over MgS04, filtered and concentrated under reduced pressure to afford an oil. The resulting oil was loaded onto a pad of silica gel (7 cm wide x 4 cm high) on a sintered glass funnel and eluted with 5% EtOAc in hexanes (400 mL). The clear, colorless filtrate was concentrated under reduced pressure to afford a colorless oil (7.4 g, 81%)
Step 3: Preparation of (R)-5-bromo-l-((3a,S',4)S',6)S',7aR)-3a,5,5-trimethylhexahydro- 4,6-methanobenzo[<i][l,3,2]dioxaborol-2-yl)pentan-l-amine hydrochloride
[0136] Into a flame-dried 250 mL round-bottom flask equipped with a magnetic stir bar and under nitrogen was added anhydrous THF (50 mL). The solution was cooled to - 78°C in a dry ice/acetone Dewar and a solution of 1.0 M LiHMDS in THF (24.4 mL, 24.4 mmol, 1.2 equiv) was added. The yellow solution was maintained at -78 °C while a solution of (3a,S',4)S',6)S',7aR)-2-(()S)-5-bromo-l-chloropentyl)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[<i][l,3,2]dioxaborole (7.4 g, 20.3 mmol, 1.0 equiv) in THF (50 mL) was added via cannula over 10 minutes. The reaction mixture was stirred at -78 °C for 2 h and allowed to warm to room temperature overnight. The resulting yellow solution was concentrated under reduced pressure and the resulting oil suspended in hexanes (150 mL) and filtered through a pad of celite (4 x 4 cm) on a sintered funnel. The filter cake was further washed with hexanes (2 x 20 mL) and the resulting yellow filtrate was collected into a 500 mL round-bottom flask. To the flask containing the filtrate was added a magnetic stir bar, septa and nitrogen inlet and the solution was cooled to -78 °C in a dry ice/acetone Dewar. A solution of 4 M HCl in dioxane (15.2 mL, 61 mmol, 3 equiv) was added and the off-white suspension was stirred at -78 °C for 2 h and allowed to warm to room temperature over 4 h. The suspension was filtered through a Hirsch funnel containing Whatman #1 filter paper under vacuum, and the white solid was washed with hexanes (2 x 10 mL). The resulting off-white solid was dried under vacuum affording the desired product (4.6 g, 61%).
Intermediate C: (R)-4-bromo-l-((3a,S',4)S',6)S',7aR)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[<i] [ 1 ,3 ,2]dioxaborol-2-yl)butan- 1 -amine hydrochloride
Figure imgf000074_0001
Figure imgf000074_0002
Intermediate C
Step 1: Preparation of (3a,S',4)S',6)S',7aR)-2-(3-bromopropyl)-3a,5,5- trimethylhexahydro-4,6-methanobenzo[<i][l,3,2]dioxaborole
[0137] Into a round-bottom flask equipped with a magnetic stir bar and under nitrogen was added catechol borane (6.2 mL, 58 mmol, 1.0 equiv) and allyl bromide (5 mL, 58 mmol, 1.0 equiv). The solution was heated to 1 10 °C for 8 h. The contents of the vial were cooled to room temperature and transferred with THF (100 mL). To the flask was added (l^,2^,3R,55)-2,6,6-trimethylbicyclo[3.1.1]heptane-2,3-diol (9.8 g, 58 mmol, 1.0 equiv) and the mixture stirred at room temperature for 18 h. The solution was concentrated under reduced pressure, loaded onto a silica gel column (220 g) and eluted with 100:0 to 90: 10 Hexanes:EtOAc as a gradient. The product fractions were concentrated under reduced pressure to afford a clear oil (9.93 g, 57%).
Step 2: Preparation of (3aS,4S,6S,7aR)-2-((S)-4-bromo-l-chlorobutyl)-3a,5,5- trimethylhexahydro-4,6-methanobenzo[<i][l,3,2]dioxaborole
[0138] Into a flame-dried 250 mL round-bottom flask equipped with a magnetic stir bar and under nitrogen was added anhydrous THF (100 mL) and CH2CI2 (1.6 mL, 24.7 mmol, 1.5 equiv). The solution was cooled to between -110 °C and -100 °C in an Et20/liquid N2 Dewar. The Et20 is added to the Dewar first, followed by portion wise addition of liq. N2 until the Et20 becomes semi-solid. The temperature of the bath is monitored with a thermometer. Once the THF/CH2C12 solution had cooled to between -110 °C and -100 °C, a solution of 1.6 M «-BuLi in hexanes (12.4 mL, 30 mmol, 1.2 equiv) was added via syringe over a period of 15 minutes, down the side of flask and maintaining an internal reaction temperature below -90 °C. Additional aliquots of liq. N2 were added to the Dewar to maintain the bath temperature between -110 and -100 °C. A solution of (3a,S',4)S',6)S',7aR)-2-(3-bromopropyl)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[<i][l,3,2]dioxaborole (4.9 g, 16.5 mmol, 1.0 equiv) in anhydrous THF (10 mL) was added to the «-BuLi/CH2Cl2 reaction mixture via cannula over a period of 5 minutes. After addition was complete, a solution of ZnCl2 (16.5 mL, 16.5 mmol, 1.0 equiv, 1.0 M in Et20) was added over 5 minutes via syringe and the reaction mixture was allowed to warm to room temperature overnight.
[0139] The resulting mixture was concentrated under reduced pressure. The crude reaction mixture was poured into a 500 mL separatory funnel containing a sat. aqueous H4CI solution (200 mL) and extracted with diethyl ether (3 x 100 mL). The combined organic layers were washed with brine (75 mL), dried over MgS04, filtered and concentrated under reduced pressure to afford an oil. The resulting oil was loaded onto a pad of silica gel (7 cm wide x 4 cm high) on a sintered glass funnel and eluted with 5% EtOAc in hexanes (400 mL). The clear, colorless filtrate was concentrated under reduced pressure to afford a colorless oil (5.28 g, 93%)
Step 3: Preparation of (R)-4-bromo-l-((3a,S',4)S',6)S',7aR)-3a,5,5-trimethylhexahydro- 4,6-methanobenzo[<i] [ 1 ,3 ,2]dioxaborol-2-yl)butan- 1 -amine hydrochloride
[0140] Into a flame-dried 250 mL round-bottom flask equipped with a magnetic stir bar and under nitrogen was added anhydrous THF (55 mL). The solution was cooled to - 78 °C in a dry ice/acetone Dewar and a solution of 1.0 M LiHMDS in THF (34 mL, 33.2 mmol, 1.1 equiv) was added. The yellow solution was maintained at -78 °C while a solution of (3a,S',4)S',6)S',7aR)-2-(()S)-5-bromo-l-chlorobutyl)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[<i][l,3,2]dioxaborole (10.56 g, 30.2 mmol, 1.0 equiv) in THF (20 mL) was added via cannula over 10 minutes. The reaction mixture was stirred at -78 °C for 2 h and allowed to warm to room temperature overnight. The resulting yellow solution was concentrated under reduced pressure and the resulting oil suspended in hexanes (120 mL) and filtered through a pad of celite (4 x 4 cm) on a sintered funnel. The filter cake was further washed with hexanes (2 x 20 mL) and the resulting yellow filtrate was collected into a 500 mL round-bottom flask. To the flask containing the filtrate was added a magnetic stir bar, septa and nitrogen inlet and the solution was cooled to -78 °C in a dry ice/acetone Dewar. A solution of 4 M HCl in dioxane (23 mL, 90 mmol, 3.5 equiv) was added and the off-white suspension was stirred at -78 °C for 2 h and allowed to warm to room temperature over 4 h. The suspension was filtered through a Hirsch funnel containing Whatman #1 filter paper under vacuum, and the white solid was washed with hexanes (2 x 10 mL). The resulting off-white solid was dried under vacuum affording the desired product (7.66 g, 69%). -2-(2-naphthamido)-3-cyclohexylpropanoic acid
Figure imgf000076_0001
Intermediate D
Step 1: Preparation of methyl (R)-2-(2-naphthamido)-3-cyclohexylpropanoate
[0141] Into a 100 mL round-bottom flask equipped with a magnetic stir bar and under a nitrogen atmosphere was added methyl (R)-2-amino-3-cyclohexylpropanoate hydrochloride (2.50 g, 11.3 mmol, 1.0 equiv) and CH2CI2 (30 mL). The suspension was treated with 2-naphthoyl chloride (2.36 g, 12.4 mmol, 1.1 equiv) followed by EtN(/'Pr)2 (4.1 mL, 23.7 mmol, 2.1 equiv). The slight yellow solution was stirred at room temperature for 3 h. TLC analysis reveals complete conversion of starting material. The reaction was quenched with water (25 mL) and poured into a 250 mL separately funnel containing 1 M aqueous HCl solution (100 mL) and the aqueous layer was extracted with CH2C12 (2 x 75 mL). The combined organic layers were washed with brine (50 mL), dried over MgS04, filtered and concentrated under reduced pressure. The reaction mixture was purified by column chromatography on silica gel, eluting with 80:20 Hexanes:EtOAc to afford the indicated product as a white foam (2.36 g, 62%).
Step 2: Preparation of (R)-2-(2-naphthamido)-3-cyclohexylpropanoic acid [0142] Into a 100 mL round-bottom flask equipped with a magnetic stir bar was added methyl (R)-2-(2-naphthamido)-3-cyclohexylpropanoate (2.35 g, 6.92 mmol, 1.0 equiv), THF (10 mL) and MeOH (10 mL). The solution was treated with 1.0 M aqueous LiOH solution (10.4 mL, 10. 4 mmol, 1.5 equiv) and stirred at room temperature for 3 h. TLC analysis reveals complete conversion of starting material. The reaction mixture was concentrated under reduced pressure and the resulting solids were taken up in 5 mL of methanol and acidified to pH < 2 with 1.0 M aqueous HCI solution (approx 15 mL). The resulting white suspension was stirred at room temperature for 4 h and then filtered through a Buchner funnel containing Whatman # 1 filter paper under vacuum. The filter cake was dried under vacuum to afford a white free flowing solid (2.07 g, 92% yield).
Intermediate E: (R)-3-cyclohexyl-2-(((R)-2,2,2-trifluoro-l-(naphthalen-2- yl)ethyl)amino)propanoic acid
Figure imgf000077_0001
Intermediate E
Step 1: Preparation of (R)-3-cyclohexyl-2-(((R)-2,2,2-trifluoro-l-(naphthalen-2- yl)ethyl)amino)propanoic acid
[0143] A suspension of (R)-methyl 2-amino-3-cyclohexylpropanoate hydrochloride (546 mg, 2.46 mmol, 1.1 equiv), 2-napthyltrifluoromethyl ketone (502 mg, 2.24 mmol, 1.0 equiv) and K2C03 (150 mg, 4.70 mmol, 2.1 equiv) in MeOH (5 mL) was heated to 50 °C and stirred for 18 hours. The suspension was cooled to room temperature and filtered through a plug of celite. The plug of celite was washed with MeOH (20 mL) and the filtrate was concentrated to provide (R,Z)-3-cyclohexyl-2-((2,2,2-trifluoro-l-(naphthalen- 2-yl)ethylidene)amino)propanoic acid (844 mg, 100%) which was used directly without purification.
[0144] A fine suspension of (R,Z)-3-cyclohexyl-2-((2,2,2-trifluoro-l-(naphthalen- 2-yl)ethylidene)amino)propanoic acid (844 mg, 2.24 mmol, 1.0 equiv) in CH3CN (5 mL) and MeOH (1 mL) was added to a pre-formed cold (-40 °C) suspension of ZnCl2 (610 mg, 4.48 mmol, 2.0 equiv)/NaBH4 (340 mg, 8.96 mmol, 4 equiv) in DME (4.5 mL) (The suspension of ZnCl2/NaBH4 was formed by stirring ZnCl2 and NaBH4 in DME at room temperature for 18 h). The suspension was stirred at -40 °C for 3 hours. Acetone (5 mL) was added and the suspension was warmed to room temperature and then poured into a 250 mL separatory funnel containing ice, water (50 mL) and EtOAc (50 mL). The aqueous layer was separated and then extracted with EtOAc (4 x 50 mL). The combined organics were washed with brine (1 x 50 mL), dried over MgS04, filtered and concentrated under reduced pressure. Purification by column chromatography on silica gel, eluting with 100:0 to 95 :5 CH2Cl2:MeOH as a gradient afforded the title product as a solid (454 mg, 53%).
PREPARATION OF EXAMPLES
Example 1: ((R)-l-((2^,4R)-l -((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- phenylpyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid
Figure imgf000078_0001
Step 1: Preparation of tert-butyl (2^4R)-2-(((R)-2-methyl-l-((3a^4^6^,7aR)-3a,5,5- trimethylhexahydro-4,6-methanobenzo[ii][l,3,2]dioxaborol-2-yl)propyl)carbamoyl)-4- phenylpyrrolidine- 1 -carboxylate
[0145] Into a 25 mL round-bottom flask, equipped with a magnetic stir bar and under nitrogen was added (2S,4R)-l -(tert-butoxycarbonyl)-4-phenylpyrrolidine-2-carboxylic acid (125 mg, 0.43 mmol, 1.0 equiv), (R)-2-methyl-l-((3a^,4^,6^,7aR)-3a,5,5- trimethylhexahydro-4,6-methanobenzo[<i][l,3,2]dioxaborol-2-yl)propan-l-amine
(Intermediate A, 136 mg, 0.47 mmol, 1.1 equiv), HATU (196 mg, 0.52 mmol, 1.2 equiv). The solids were suspended in CH2CI2 (5 mL) and treated with EtN(/'Pr)2 (224 μΐ^, 1.29 mmol, 3.0 equiv) and stirred at room temperature for 30 minutes. LCMS analysis reveals conversion to product. The reaction was poured into a 250 mL separatory funnel containing CH2C12 (100 mL) and washed with water (50 mL), 1 M aqueous HC1 (50 mL) and water (50 mL). The combined aqueous layers were further extracted with CH2C12 (50 mL). The combined organics were dried over MgS04, filtered and concentrated under reduced pressure. Purification by column chromatography on silica gel, eluting with 100:0 to 50:50 Hexanes:EtOAc as a gradient afforded the title product (223 mg, 99%).
Step 2: Preparation of (2^,4R)-N-((R)-2-methyl-l-((3a^,4^,6^,7aR)-3a,5,5- trimethylhexahydro-4,6-methanobenzo[<i][l,3,2]dioxaborol-2-yl)propyl)-4- phenylpyrrolidine-2-carboxamide hydrochloride
[0146] A solution of tert-butyl (2^,4R)-2-(((R)-2-methyl-l-((3a^,4^,6^,7aR)- 3a,5,5-trimethylhexahydro-4,6-methanobenzo[<i][l,3,2]dioxaborol-2-yl)propyl)carbamoyl)- 4-phenylpyrrolidine-l -carboxylate (194 mg, 0.37 mmol, 1.0 equiv) in hexanes (10 mL) was treated with 4 M HC1 in dioxane (500 [iL, 2.0 mmol, 5.4 equiv). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated to dryness, affording a white solid which was used directly without purification (165 mg).
Step 3: Preparation of (2,S',4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N- ((R)-2-methyl-l-((3a,S',45',65',7aR)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[<i][l,3,2]dioxaborol-2-yl)propyl)-4-phenylpyrrolidine-2-carboxamide
[0147] A solution of (2^,4R)-N-((R)-2-methyl-l-((3a^,4^,6^,7aR)-3a,5,5- trimethylhexahydro-4,6-methanobenzo[<i][l,3,2]dioxaborol-2-yl)propyl)-4- phenylpyrrolidine-2-carboxamide hydrochloride (165 mg, 0.36 mmol, 1.0 equiv) and (R)-2- (2-naphthamido)-3-cyclohexylpropanoic acid (Intermediate D, 1 17 mg, 0.36 mmol, 1.0 equiv) in CH2CI2 (6 mL) was treated with HATU (152 mg, 0.40 mmol, 1.1 equiv) and EtN(/'Pr)2 (188 μΐ^, 1.08 mmol, 3.0 equiv). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (100 mL) and poured into a 250 mL separatory funnel. The organic layer was washed with water (50 mL), 1 M aqueous HC1 (50 mL), saturated aqueous NaHC03 (50 mL) and brine (50 mL). The combined organic layers were dried over MgS04, filtered and concentrated under reduced pressure. Purification by column chromatography on silica gel, eluting with 100:0 to 30:70 Hexanes:EtOAc as a gradient. The title product was obtained as a solid (160 mg, 61%).
Step 4: Preparation of ((R)-l -((2S,4R)-l-((R)-2-(2-naphthamido)-3- cyclohexylpropanoyl)-4-phenylpyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid
[0148] Into a 25 mL round-bottom flask, equipped with a magnetic stir bar and under nitrogen was added (2,S',4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N- ((R)-2-methyl-l-((3a,S',45',65',7aR)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[<i][l,3,2]dioxaborol-2-yl)propyl)-4-phenylpyrrolidine-2-carboxamide (152 mg, 0.21 mmol, 1.0 equiv), isobutyl boronic acid (32 mg, 0.32 mmol, 1.5 equiv) in methanol (2 mL) and hexanes (2 mL). The reaction mixture was treated with 4 M HC1 in dioxane (80 μί, 0.32 mmol, 1.5 equiv) and the biphasic suspension was stirred at room temperature for 18 h. LCMS analysis reveals approximately 80% conversion of starting material to desired product. The bottom methanol layer was removed and washed with octane (3 mL). The top hexanes layer was further extracted with methanol (3 mL), and the combined methanol layers were combined and concentrated under reduced pressure. Purification by reverse-phase column chromatography using a C18 column, eluting with 90: 10 to 0: 100 H20:MeCN + 0.1%) formic acid as a gradient. Fractions containing the desired product were concentrated under reduced pressure to afford the title compound (63 mg, 50%>).
[0149] The following compounds were prepared in a similar manner as Example 1, from commercially available proline derivatives.
Figure imgf000080_0001
Figure imgf000081_0001
carb oxami do)-2-methy Ipropy l)b oroni c aci d
Figure imgf000082_0001
carb oxami do)-2-methy lpropy l)b oroni c aci d
Figure imgf000083_0001
Example 8: ((R)-l-((l^,3aR,6a5)-2-((R)-2-(2-naphthamido)-3- cyclohexylpropanoyl)octahydrocyclopenta[c]pyrrole-l-carboxamido)-2- methylpropyl)boronic acid
Figure imgf000084_0001
Step 1: Preparation of tert-butyl (l,S',3aR,6a)S)-2-((R)-2-(2-naphthamido)-3- cyclohexylpropanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylate
[0150] Into a 25 mL round-bottom flask, equipped with a magnetic stir bar and under nitrogen was added tert-butyl (l^aR^a^-octahydrocyclopentaf^pyrrole-l- carboxylate formate salt (250 mg, 0.82 mmol, 1.0 equiv), (R)-2-(2-naphthamido)-3- cyclohexylpropanoic acid (Intermediate D, 135 mg, 0.82 mmol, 1.0 equiv), EDCI (230 mg, 1.2 mmol, 1.5 equiv) and HOBt (140 mg, 1.4 mmol, 1.7 equiv). The solids were suspended in CH2CI2 (10 mL), cooled to 0 °C in an ice bath and then treated with N-methyl morpholine (250 μΐ^, 2.5 mmol, 3.0 equiv). The reaction mixture was allowed to warm to room temperature with stirring overnight. The reaction mixture was poured into a 125 mL separatory funnel containing 1.0 M aqueous HCl solution (50 mL) and extracted with CH2C12 (3 x 25 mL). The combined organics were washed with brine (25 mL), dried over MgS04, filtered and concentrated under reduced pressure. The crude reaction mixture was purified by column chromatography through silica gel, eluting with 100:0 to 0: 100 Hexanes:EtOAc as a gradient to afford the ester product.
Step 2: Preparation of (15,3aR,6aS)-2-((R)-2-(2-naphthamido)-3- cyclohexylpropanoyl)octahydrocyclopenta[c]pyrrole-l -carboxylic acid
[0151] The ester from the step 1 was placed into a 25 mL round-bottom flask together with a magnetic stir bar and treated with CH2CI2 (5 mL) followed by trifluoroacetic acid (5 mL). The solution was stirred at room temperature overnight and the reaction mixture concentrated under reduced pressure. The carboxylic acid product was used directly without further purification.
Step 3: Preparation of (l,S',3aR,6a)S)-2-((R)-2-(2-naphthamido)-3- cyclohexylpropanoyl)-N-((R)-2-methyl-l-((3a,S',4)S',6)S',7aR)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[<i][l,3,2]dioxaborol-2-yl)propyl)octahydrocyclopenta[c]pyrrole-l- carboxamide
[0152] To a 25 mL round-bottom flask, equipped with a magnetic stir bar and under nitrogen was added tert-butyl (lS,3aR,6aS)-2-((R)-2-(2-naphthamido)-3- cyclohexylpropanoyl)octahydrocyclopenta[c]pyrrole-l-carboxylate (0.8 mmol, 1.0 equiv) and (R)-2-methyl-l-((3a,S',45',65',7aR)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[<i][l,3,2]dioxaborol-2-yl)propan-l-amine hydrochloride (259 mg, 0.9 mmol, 1.1 equiv). The solids were suspended in CH2CI2 (5 mL) and treated with HATU (350 mg, 1.0 mmol, 1.2 equiv) followed by EtN(/Pr)2 (302 μΕ, 1.6 mmol, 2 equiv). The solution was stirred at room temperature for 4 h. LCMS analysis reveals complete conversion to product. The reaction mixture was quenched with 1 M aqueous HC1 (5 mL) and extracted with CH2C12 (3 x 5 mL) using a chlorinated phase-separator cartridge. The combined organic layers were concentrated under reduced pressure and used directly in the next step without further purification.
Step 4: Preparation of ((R)-l-((l^,3aR,6a5)-2-((R)-2-(2-naphthamido)-3- cyclohexylpropanoyl)octahydrocyclopenta[c]pyrrole-l-carboxamido)-2- methylpropyl)boronic acid
[0153] Into an 8 mL sample vial was combined (lS,3aR,6aS)-2-((R)-2-(2- naphthamido)-3-cyclohexylpropanoyl)-N-((R)-2-methyl-l-((3a,S',4)S',6)S',7aR)-3a,5,5- trimethylhexahydro-4,6-methanobenzo[<i][l,3,2]dioxaborol-2- yl)propyl)octahydrocyclopenta[c]pyrrole-l-carboxamide (0.8 mmol, 1.0 equiv), 2- methylpropylboronic acid (404 mg, 4 mmol, 5 equiv), methanol (5 mL), hexanes (5 mL) and 1 M aqueous HCl (3.2 mL, 3.2 mmol, 4 equiv). The biphasic mixture was stirred vigorously at room temperature for 18 h overnight. Stirring was stopped and the bottom methanolic layer of the biphasic solution was removed, and the top hexane layer was further extracted with methanol (3 x 2 mL). The combined methanol layers were washed with hexanes (3 x 2 mL) and concentrated under reduced pressure to afford the desired product (50 mg, 1 1%).
Figure imgf000086_0001
Example 9: ((R)-l -((2^,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(tert- butylthio)pyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid
Figure imgf000087_0001
Intermediate from Example 5
Figure imgf000087_0002
Step 1: Preparation of (2,S',4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (fert-butylthio)-N-((R)-2-me
methanobenzo[<i][l,3,2]dioxaborol-2-yl)propyl)pyrrolidine-2-carboxamide
[0154] Into a 25 mL round-bottom flask, equipped with a magnetic stir bar and under nitrogen was added (2,S',4)S)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- hydroxy-N-((R)-2-methyl-l-((3a,S',45',65',7aR)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[<i][l,3,2]dioxaborol-2-yl)propyl)pyrrolidine-2-carboxamide (336 mg, 0.5 mmol, 1.0 equiv), EtN(/Pr)2 (130 μί, 0.75 mmol, 1.5 equiv) and CH2C12 (5 mL). The solution was cooled to 0 °C in an ice bath and treated with drop wise addition of triflic anhydride (109 μΐ^, 0.65 mmol, 1.3 equiv). The solution was stirred at 0 °C for 20 minutes and then allowed to warm to room temperature over 1 h. The reaction mixture was quenched with water (20 mL) and extracted with CH2C12 (3 x 10 mL) using a 75 mL separatory funnel. The combined organic layers were washed with brine (10 mL), dried over MgS04, filtered and concentrated under reduced pressure. The crude reaction mixture as taken up in ethanol (10 mL) and split into two portions. One portion (5 mL, approx 0.25 mmol) was treated with sodium thio tert-butoxide (56 mg, 0.5 mmol, 2.0 equiv) and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and purified by reverse-phase column chromatography through a CI 8 column, eluting with 90: 10 to 0: 100 H20:MeCN + 0.1% formic acid as a gradient. Fractions containing the desired product were concentrated under reduced pressure to afford the title compound (27 mg, 14%).
Step 2: Preparation of ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3- cyclohexylpropanoyl)-4-(tert-butylthio)pyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid
[0155] A mixture of (2^,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)- 4-(tert-butylthio)-N-((R)-2-methyl-l-((3a)S',4^,6^,7aR)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[<i][l,3,2]dioxaborol-2-yl)propyl)pyrrolidine-2-carboxamide (27 mg, 0.036 mmol, 1.0 equiv) and isopropyl boronic acid (5.5 mg, 0.054 mmol, 1.5 equiv) in methanol (0.3 mL) and octane (0.3 mL) was treated with 4 M HC1 in dioxane (14 [iL, 0.054 mmol, 1.5 equiv). The biphasic mixture was stirred vigorously at room temperature for 18 h. Stirring was stopped and the bottom methanolic layer of the biphasic solution was removed, and the top hexane layer was further extracted with methanol (3 x 1 mL). The combined methanol layers were washed with octane (3 x 1 mL) and concentrated under reduced pressure to afford the desired product as a white solid (22 mg, 99%).
[0156] The following compounds were prepared in a similar manner as example 9, using amine nucleophiles in place of sodium thio tert-butoxide (example 10 = morpholine, example 11 = N-methylbenzylamine, example 12 = N-methyl propargylamine, example 13 = N-methylethanol amine). For examples 10-13, a solution of NaHC03 was added for the workup in step 2 to facilitate isolation of the free amine.
Figure imgf000088_0001
Figure imgf000089_0001
cyclohexylpropanoyl)-4-(methyl(prop-2-yn- 1 -
Figure imgf000090_0001
carb oxami do)-2-methy lpropy l)b oroni c aci d
Example 14: ((R)-l -((2^,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (piperidin-l-yl)pyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid
Figure imgf000091_0001
n erme a e
Figure imgf000091_0002
Step 1: Preparation of l-(tert-butyl) 2-methyl (2,S',4R)-4-(piperidin-l-yl)pyrrolidine- 1,2-dicarboxylate
[0157] Into a 250 mL round-bottom flask equipped with a magnetic stir bar and under nitrogen was weighed l-(tert-butyl) 2-methyl (2,S',4)S)-4-hydroxypyrrolidine-l,2- dicarboxylate (1.5 g, 6.1 mmol, 1.0 equiv). The solid was dissolved in CH2CI2 (50 mL) and cooled to -78 °C in a dry ice/acetone Dewar. The cold solution was treated with EtN(/'Pr)2 (2.7 mL, 15.3 mmol, 2.5 equiv) and then triflic anhydride (1.4 mL, 8.5 mmol, 1.5 equiv) was added drop wise over 30 minutes. After stirring at -78 °C for 1 h, the mixture was warmed to -20 °C and piperidine (1.8 mL, 18.3 mmol, 3.0 equiv) was added drop-wise over 15 minutes. The reaction mixture was allowed to warm to room temperature with stirring overnight. LCMS analysis reveals product formation. The reaction mixture was poured into a 250 mL separatory funnel containing water (75 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over MgS04, filtered and concentrated. Purification by column chromatography through silica gel, eluting with 100:0 to 90: 10 EtOAc:MeOH as a gradient afforded the desired product (1.90 g, 99%).
Step 2: Preparation of methyl (2,S',4R)-4-(piperidin-l-yl)pyrrolidine-2-carboxylate hydrochloride
[0158] Into a 100 mL round-bottom flask, equipped with a magnetic stir bar and under nitrogen was charged l-(tert-butyl) 2-methyl (2,S',4R)-4-(piperidin-l-yl)pyrrolidine- 1,2-dicarboxylate (545 mg, 1.75 mmol, 1.0 equiv) and CH2C12 (15 mL). The solution was treated with 4 M HCl in dioxane (2.2 mL, 8.7 mmol, 5 equiv) and the reaction was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure and used directly in the next step without further purification.
Step 3: Preparation of methyl (2£,4R)-l-((R)-2-(2-naphthamido)-3- cyclohexylpropanoyl)-4-(piperidin-l-yl)pyrrolidine-2-carboxylate
[0159] The following reagents were added to a 50 mL round-bottom flask: methyl (2iS,,4R)-4-(piperidin-l-yl)pyrrolidine-2-carboxylate hydrochloride (495 mg, 1.75 mmol, 1.0 equiv), (R)-2-(2-naphthamido)-3-cyclohexylpropanoic acid (Intermediate D, 569 mg, 1.75 mmol, 1.0 equiv) and HATU (731 mg, 1.93 mmol, 1.1 equiv). To the flask was added a magnetic stir bar and the solids were suspended in CH2C12 (20 mL). The mixture was treated with EtN(/'Pr)2 (1.52 mL, 8.75 mmol, 5 equiv) and stirred at room temperature for 18 h under a nitrogen atmosphere. LCMS analysis reveals product formation. The reaction mixture was poured into a 125 mL separatory funnel containing water (50 mL) and extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with brine (50 mL), dried over MgS04, filtered and concentrated under reduced pressure. Purification by column chromatography through silica gel, eluting with 100:0 to 90: 10 EtOAc:MeOH as a gradient afforded the desired product (682 mg, 75%).
Step 4: Preparation of 2,5-dioxopyrrolidin-l-yl (2£,4R)-l-((R)-2-(2-naphthamido)-3- cyclohexylpropanoyl)-4-(piperidin-l-yl)pyrrolidine-2-carboxylate
[0160] A solution of methyl (2£4R)-l-((R)-2-(2-naphthamido)-3- cyclohexylpropanoyl)-4-(piperidin-l-yl)pyrrolidine-2-carboxylate (682 mg, 1.3 mmol, 1.0 equiv) in methanol (10 mL) was treated with 1 M aqueous Li OH (2 mL). The solution was stirred at room temperature for 4 h. The reaction mixture was acidified with 1 M aqueous HC1 and concentrated under reduced pressure. The resulting solid was diluted in water (10 mL) and extracted with CH2C12 (3 x 10 mL). The combined organic layers were dried over MgS04, filtered and concentrated to afford a white solid.
[0161] Into a 100 mL round-bottom flask equipped with a magnetic stir bar and under nitrogen was added the carboxylic acid product from the step above (413 mg, 0.82 mmol, 1.0 equiv), N-hydroxysuccinimide (141 mg, 1.23 mmol, 1.5 equiv) and EDCI (189 mg, 0.98 mmol, 1.2 equiv). The solids were suspended in CH2C12 (10 mL) and stirred at room temperature for 3 h. At this time, another 0.25 equiv of N-hydroxysuccinimide (24 mg) and EDCI (40 mg) were added and the mixture stirred at room temperature overnight. The reaction mixture was poured into a 250 mL separately funnel containing water (100 mL) and extracted with EtOAc (100 mL). The organic layer was further washed with water (2 x 50 mL) and the combined aqueous layers were further extracted with EtOAc (50 mL). The combined organic layers were dried over MgS04, filtered and concentrated under reduced pressure. This material was used without further purification (504 mg).
Step 5: Preparation of (2,S',4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N- ((R)-2-methyl-l-((3a,S',45',65',7aR)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[<i][l,3,2]dioxaborol-2-yl)propyl)-4-(piperidin-l-yl)pyrrolidine-2-carboxamide
[0162] A solution of 2,5-dioxopyrrolidin-l-yl (2^,4R)-l-((R)-2-(2-naphthamido)- 3-cyclohexylpropanoyl)-4-(piperidin-l-yl)pyrrolidine-2-carboxylate (200 mg, 0.33 mmol, 1.0 equiv) and (R)-2-methyl-l-((3a,S',4)S',6)S',7aR)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[<i][l,3,2]dioxaborol-2-yl)propan-l-amine hydrochloride (Intermediate A, 105 mg, 0.36 mmol, 1.1 equiv) in CH2C12 (3 mL) was treated with EtN(/'Pr)2 (174 μΕ, 1.0 mmol, 3 equiv) and stirred at room temperature for 1 h. The reaction was poured into a 125 mL separately funnel containing water (50 mL) and extracted with EtOAc (2 x 75 mL). The combined organic layers were washed with brine (25 mL), dried over MgS04, filtered and concentrated under reduced pressure. Purification by reverse-phase column chromatography through a CI 8 column, eluting with 90: 10 to 0: 100 H20:MeCN + 0.1% formic acid as a gradient. Fractions containing the desired product were concentrated under reduced pressure to afford the title compound (163 mg, 67%). Step 6: Preparation of ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3- cyclohexylpropanoyl)-4-(piperidin-l-yl)pyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid
[0163] Into a 25 mL round-bottom flask equipped with a magnetic stir bar was weighed (2^,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-((R)-2-methyl-l- ((3a,S',4)S',6)S',7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[<i][l,3,2]dioxaborol-2- yl)propyl)-4-(piperidin-l-yl)pyrrolidine-2-carboxamide (45 mg, 0.06 mmol, 1.0 equiv) and isobutyl boronic acid (9.4 mg, 0.09 mmol, 1.5 equiv). The solids were suspended in methanol (0.5 mL) and octane (0.5 mL) and treated with 4 M HC1 in dioxane (38 μL, 0.15 mmol, 2.5 equiv). The biphasic reaction mixture was vigorously stirred at room temperature for 18 h. Stirring was stopped and the mixture quenched with saturated aqueous NaHC03 solution (200 μL). The bottom methanolic layer of the biphasic solution was removed, and the top hexane layer was further extracted with methanol (3 x 1 mL). The combined methanol layers were washed with octane (3 x 1 mL) and concentrated under reduced pressure to afford the desired product as a white solid (34 mg, 92%).
[0164] The following compounds were prepared in a similar manner as example 14, by replacing the piperidine in step 1 with pyrrolidine (example 15), or by utilizing the diastereomeric alcohol in step 1 (l-(tert-butyl) 2-m ethyl (2,S',4R)-4-hydroxypyrrolidine-l,2- dicarboxylate, Example 16).
Figure imgf000094_0001
Figure imgf000095_0001
carb oxami do)-2-methy lpropy l)b oroni c aci d
Example 17: ((R)- 1 -((2S,4S)- 1 -((R)-2-(2-naphthamido)-3 -cyclohexylpropanoyl)-4- chloropyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid
Figure imgf000096_0001
Figure imgf000096_0002
Step 1: Preparation of 1 -(tert-butyl) 2-methyl ( ^^^-chloropyrrolidine-l,!- dicarboxylate
[0165] Into a 100 mL round-bottom flask equipped with magnetic stir bar and under nitrogen was added l-(tert-butyl) 2-methyl (2,S',4R)-4-hydroxypyrrolidine-l,2- dicarboxylate (2.45 g, 10 mmol, 1.0 equiv), triphenylphosphine (4.57 g, 17.5 mmol, 1.75 equiv) and CH2CI2 (20 mL). The contents of the flask were cooled to 0 °C in an ice bath and carbon tetrachloride (8.38 mL, 86.5 mmol, 8.7 equiv) was added. The reaction mixture was stirred at 0 °C for 20 minutes, then heated to 40 °C for 30 minutes and then cooled to room temperature and stirred for an additional 15 minutes. The reaction mixture was diluted with heptanes (200 mL) and concentrated under reduced pressure to a total volume of 100 mL. Another 200 mL of heptanes were added, and the reaction contents concentrated under reduced pressure to 200 mL volume at which point a precipitate formed. The reaction mixture was stirred overnight. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification by column chromatography through silica gel, eluting with 100:0 to 60:40 Hexanes:EtOAc as a gradient. The desired product was obtained as a white solid (2.62 g, 99%).
Step 2: Preparation of (2S,4S)- l-(tert-butoxycarbonyl)-4-chloropyrrolidine-2- carboxylic acid
[0166] A solution of l-(ferf-butyl) 2-methyl (2^,45)-4-chloropyrrolidine-l,2- dicarboxylate (264 mg, 1.0 mmol, 1.0 equiv) in methanol (10 mL) was added 1.0 M aqueous LiOH (2 mL, 2.0 mmol, 2.0 equiv). The solution was stirred at room temperature overnight. The reaction mixture was poured into a 125 mL separatory funnel containing 0.2 M NaOH (50 mL) and washed with EtOAc (2 x 20 mL). The aqueous layer was acidified with 1 M aqueous HC1 solution (20 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over MgS04, filtered and concentrated under reduced pressure to afford a white crystalline solid (213 mg, 86%).
Step 3: Preparation of fert-butyl (2^,45)-4-chloro-2-(((R)-2-methyl-l- ((3a,S',4)S',6)S',7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[<i][l,3,2]dioxaborol-2- yl)propyl)carbamoyl)pyrrolidine- 1 -carboxylate
[0167] A suspension of (2S,4S)- l-(tert-butoxycarbonyl)-4-chloropyrrolidine-2- carboxylic acid (213 mg, 0.86 mmol, 1.0 equiv), (R)-2-methyl-l-((3aS,4S,6S,7aR)-3a,5,5- trimethylhexahydro-4,6-methanobenzo[<i][l,3,2]dioxaborol-2-yl)propan-l-amine
hydrochloride (Intermediate A, 247 mg, 0.86 mmol, 1.0 equiv) and HATU (343 mg, 0.9 mmol, 1.05 equiv) in CH2C12 (10 mL) was treated with EtN(/Pr)2 (450 L, 2.6 mmol, 3 equiv). The reaction mixture was stirred at room temperature for 1 h, at which stage LCMS analysis reveals product formation. The reaction was poured into a 125 mL separatory funnel containing water (50 mL) and extracted with CH2C12 (50 mL). The organic layer was dried over MgS04, filtered and concentrated under reduced pressure. Purification by column chromatography through silica gel, eluting with 100:0 to 0: 100 Hexanes:EtOAc as a gradient afforded the title compound (311 mg, 75%).
Step 4: Preparation of (2^,45)-4-chloro-N-((R)-2-methyl-l-((3a^,4^,6^,7aR)-3a,5,5- trimethylhexahydro-4,6-methanobenzo[<i][l,3,2]dioxaborol-2-yl)propyl)pyrrolidine-2- carboxamide [0168] A solution of tert-butyl (25,4.5)-4-οΜθΓθ-2-(((Λ)-2^βΛγ1-1- ((3a,S',4)S',6)S',7aR)-3a,5,54rimethylhexahydro-4,6-methanobenzo[ii][l,3,2]dioxaborol-^ yl)propyl)carbamoyl)pyrrolidine-l-carboxylate (311 mg, 0.65 mmol, 1.0 equiv) in hexanes (5 mL) and CH2C12 (5 mL) was treated with 4 M HC1 in dioxane (1 mL). The reaction mixture was stirred at room temperature for 2 h, at which time additional 4 M HC1 in dioxane (2 mL) was added. The reaction was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure and used directly in the next step without further purification (283 mg).
Step 5: Preparation of (2,S',4)S)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- chloro-N-((R)-2-methyl-l-((3a,S',45',65',7aR)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[<i][l,3,2]dioxaborol-2-yl)propyl)pyrrolidine-2-carboxamide
[0169] A 25 mL round-bottom flask was equipped with a magnetic stir bar and placed under an atmosphere of nitrogen. To the flask were added (2S,4S)-4-c \oro-N-((R)-2- methyl- 1 -((3 aS,4S,6S, 7aR)-3 a, 5 , 5 -trimethylhexahy dro-4, 6- methanobenzo[<i][l,3,2]dioxaborol-2-yl)propyl)pyrrolidine-2-carboxamide (283 mg, 0.68 mmol, 1.0 equiv), (R)-2-(2-naphthamido)-3-cyclohexylpropanoic acid (Intermediate D, 240 mg, 0.75 mmol, 1.1 equiv) and HATU (285 mg, 0.75 mmol, 1.1 equiv). The solids were suspended in CH2C12 (10 mL) and treated with EtN(/'Pr)2 (355 μΐ^, 2.0 mmol, 3 equiv). The reaction was stirred for 18 h at room temperature. The reaction mixture was poured into a 125 mL separatory funnel containing water (50 mL) and extracted with CH2C12 (3 x 10 mL). The combined organic layers were washed with brine (20 mL), dried over MgS04, filtered and concentrated under reduced pressure. Purification by reverse-phase column chromatography through a C18 column, eluting with 90: 10 to 0: 100 H20:MeCN + 0.1% formic acid as a gradient. Fractions containing the desired product were concentrated under reduced pressure to afford the title compound (73 mg, 15%).
Step 6: Preparation of ((R)-l -((2S,4S)- l-((R)-2-(2-naphthamido)-3- cyclohexylpropanoyl)-4-chloropyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid
[0170] Into a 25 mL round-bottom flask equipped with a magnetic stir bar was weighed (2S,4S)- l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-chloro-N-((R)-2- methyl- 1 -((3 aS, 4S,6S, 7aR)-3 a, 5 , 5 -trimethylhexahy dro-4, 6- methanobenzo[<i][l,3,2]dioxaborol-2-yl)propyl)pyrrolidine-2-carboxamide (73 mg, 0.11 mmol, 1.0 equiv) and isobutyl boronic acid (53 mg, 0.53 mmol, 5 equiv). The solids were suspended in methanol (1 mL) and octane (1 mL) and treated with 4 M HC1 in dioxane (132 μL, 0.53 mmol, 5 equiv). The biphasic reaction mixture was vigorously stirred at room temperature for 1 h. Stirring was stopped and the bottom methanolic layer of the biphasic solution was removed, and the top hexane layer was further extracted with methanol (3 x 1 mL). The combined methanol layers were washed with octane (3 x 1 mL) and concentrated under reduced pressure. Purification by reverse-phase column chromatography through a C18 column, eluting with 90: 10 to 0: 100 H20:MeCN + 0.1% formic acid as a gradient afforded the desired product (33 mg, 54%).
Figure imgf000099_0001
Example 18: ((R)- 1 -((2S,4R)- 1 -((R)-2-(2-naphthamido)-3 -cyclohexylpropanoyl)-4- (phenethylthio)pyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid
Intermediate A
Figure imgf000100_0001
Figure imgf000100_0002
Figure imgf000100_0003
Step 1: Preparation of tert-butyl (2^,4R)-4-hydroxy-2-(((R)-2-methyl-l- ((3a,S',4)S',6)S',7aR)-3a,5,54rimethylhexahydro-4,6-methanobenzo[ii][l,3,2]dioxaborol-2- yl)propyl)carbamoyl)pyrrolidine- 1 -carboxylate
[0171] Into a 250 mL round-bottom flask equipped with a magnetic stir bar and under nitrogen was added (R)-2-methyl-l-((3a,S',4)S',6)S',7aR)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[<i][l,3,2]dioxaborol-2-yl)propan-l-amine (Intermediate A, 2.0 g, 7.0 mmol, 1.0 equiv), (2,S',4R)-l-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (1.77 g, 7.7 mmol, 1.1 equiv) and HATU (2.78 g, 7.3 mmol, 1.05 equiv). The solids were suspended in CH2CI2 (60 mL) and treated with EtN(/'Pr)2 (3.63 mL, 21 mmol, 3 equiv). The reaction mixture was stirred at room temperature for 1 h and then poured into a 250 mL separatory funnel containing water (75 mL) and extracted with CH2C12 (2 x 50 mL). The combined organic layers were dried over MgS04, filtered and concentrated under reduced pressure. Purification by column chromatography through silica gel, eluting with 100:0 to 90: 10 EtOAc:MeOH as a gradient afforded the desired compound (3.05 g, 94%).
Step 2: Preparation of fert-butyl (2^,45)-4-chloro-2-(((R)-2-methyl-l- ((3a,S',4)S',6)S',7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[<i][l,3,2]dioxaborol-2- yl)propyl)carbamoyl)pyrrolidine- 1 -carboxylate
[0172] Into a 25 mL round-bottom flask equipped with a magnetic stir bar and under nitrogen was added fert-butyl (25,,4R)-4-hydroxy-2-(((R)-2-methyl-l-((3a,S',45',65',7aR)- 3a,5,5-trimethylhexahydro-4,6-methanobenzo[<i][l,3,2]dioxaborol-2- yl)propyl)carbamoyl)pyrrolidine-l -carboxylate (464 mg, 1.0 mmol, 1.0 equiv), triphenylphosphine (456 mg, 1.75 mmol, 1.75 equiv) and CH2CI2 (5 mL). The reaction mixture was cooled to 0 °C in an ice bath and carbon tetrachloride (838 μΐ^, 8.7 mmol, 8.7 equiv) was added. The reaction mixture was heated to 40 °C for 2 h and then cooled to room temperature. The mixture was poured into a 125 mL separately funnel containing water (75 mL) and extracted with CH2CI2 (2 x 50 mL). The combined organic layers were dried over MgS04, filtered and concentrated under reduced pressure. Purification by column chromatography through silica gel, eluting with 100:0 to 30:70 Hexanes:EtOAc as a gradient afforded the title compound (382 mg, 79%).
Step 3: Preparation of tert-butyl (2^,4R)-2-(((R)-2-methyl-l-((3a^,4^,6^,7aR)-3a,5,5- trimethylhexahydro-4,6-methanobenzo[<i][l,3,2]dioxaborol-2-yl)propyl)carbamoyl)-4- (phenethylthio)pyrrolidine- 1 -carboxylate
[0173] Into a 100 mL round-bottom flask equipped with a magnetic stir bar and under nitrogen was charged sodium hydride (60% in mineral oil, 1 1 mg, 0.27 mmol, 1.3 equiv) and DMF (1 mL). The suspension was treated with benzene ethanethiol (42 [iL, 0.32 mmol, 1.5 equiv) and stirred at room temperature for 15 minutes, becoming a yellow suspension. A solution of tert-butyl (25,,45)-4-chloro-2-(((R)-2-methyl-l-((3a,S',45',65',7aR)- 3a,5,5-trimethylhexahydro-4,6-methanobenzo[<i][l,3,2]dioxaborol-2- yl)propyl)carbamoyl)pyrrolidine-l -carboxylate (100 mg, 0.21 mmol, 1.0 equiv) in DMF (1 mL) was added and the reaction mixture was stirred at room temperature for 2 h. LCMS analysis reveals about 50% conversion to desired product. Another addition of benzene ethanethiol (42 [iL, 0.32 mmol, 1.5 equiv) and sodium hydride (60% in mineral oil, 1 1 mg, 0.27 mmg, 1.3 equiv) were placed into the reaction vial and the mixture stirred at room temperature for an additional 1 h. The reaction mixture was quenched with saturated aqueous H4C1 solution (15 mL) and poured into a 125 mL separatory funnel containing water (50 mL). The mixture was extracted with EtOAc (3 x 20 mL) and the combined organic layers were washed with brine (50 mL), dried over MgS04, filtered and concentrated under reduced pressure. Purification by column chromatography through silica gel, eluting with 100:0 to 50:50 Hexanes:EtOAc as a gradient afforded the title compound (57 mg, 46%).
Step 4: Preparation of (2^,4R)-N-((R)-2-methyl-l-((3a^,4^,6^,7aR)-3a,5,5- trimethylhexahydro-4,6-methanobenzo[<i][l,3,2]dioxaborol-2-yl)propyl)-4- (phenethylthio)pyrrolidine-2-carboxamide hydrochloride
[0174] A solution of tert-butyl (2^,4R)-2-(((R)-2-methyl-l-((3a^,4^,6^,7aR)- 3a,5,5-trimethylhexahydro-4,6-methanobenzo[<i][l,3,2]dioxaborol-2-yl)propyl)carbamoyl)- 4-(phenethylthio)pyrrolidine-l-carboxylate (57 mg, 0.10 mmol) in CH2C12 (2 mL) was treated with 4 M HC1 in dioxane (0.5 mL). The reaction mixture was stirred at room temperature for 6 h and then concentrated under reduced pressure to afford an off-white solid (48 mg, 92%).
Step 5: Preparation of (2,S',4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N- ((R)-2-methyl-l-((3a,S',45',65',7aR)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[<i][l,3,2]dioxaborol-2-yl)propyl)-4-(phenethylthio)pyrrolidine-2-carboxamide
[0175] Into a 25 mL round-bottom flask equipped with a magnetic stir bar and under an atmosphere of nitrogen was added (2,S',4R)-N-((R)-2-methyl-l-((3a)S',4)S',6)S',7aR)- 3a,5,5-trimethylhexahydro-4,6-methanobenzo[<i][l,3,2]dioxaborol-2-yl)propyl)-4- (phenethylthio)pyrrolidine-2-carboxamide hydrochloride (48 mg, 0.09 mmol, 1.0 equiv), (R)- 2-(2-naphthamido)-3-cyclohexylpropanoic acid (Intermediate D, 36 mg, 0.1 1 mmol, 1.2 equiv), HATU (38 mg, 0.10 mmol, 1.1 equiv) and CH2C12 (1 mL). The mixture was treated with EtN(/'Pr)2 (64 μΐ^, 0.37 mmol, 4.0 equiv) and the mixture was stirred at room temperature for 18 h. LCMS analysis reveals about 30% conversion to product, and so another portion of HATU (38 mg, 0.10 mmol, 1.1 equiv) was added to the reaction and the mixture stirred at room temperature for 4 h. The reaction was diluted with water (10 mL) and extracted with CH2C12 (2 x 10 mL). The combined organic layers were dried over MgS04, filtered and concentrated under reduced pressure. Purification by reverse-phase column chromatography through a C 18 column, eluting with 90: 10 to 0: 100 H20:MeCN + 0.1% formic acid as a gradient afforded the desired product (24 mg, 33%).
Step 6: Preparation of ((R)-l -((2S,4R)-l-((R)-2-(2-naphthamido)-3- cyclohexylpropanoyl)-4-(phenethylthio)pyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid
[0176] Into a 25 mL round-bottom flask equipped with a magnetic stir bar was weighed (2^,4R)-l -((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-((R)-2-methyl-l- ((3a,S',4)S',6)S',7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[<i][l,3,2]dioxaborol-2- yl)propyl)-4-(phenethylthio)pyrrolidine-2-carboxamide (24 mg, 0.03 mmol, 1.0 equiv) and isobutyl boronic acid (15 mg, 0.15 mmol, 5 equiv). The solids were suspended in methanol (1 mL) and octane (1 mL) and treated with 4 M HC1 in dioxane (45 [iL, 0.15 mmol, 6 equiv). The biphasic reaction mixture was vigorously stirred at room temperature for 18 h. Stirring was stopped and the bottom methanolic layer of the biphasic solution was removed, and the top hexane layer was further extracted with methanol (3 x 1 mL). The combined methanol layers were washed with octane (3 x 1 mL) and concentrated under reduced pressure. Purification by reverse-phase column chromatography through a C 18 column, eluting with 90: 10 to 0: 100 H20:MeCN + 0.1% formic acid as a gradient afforded the desired product (14 mg, 71%).
Figure imgf000103_0001
Example 19: ((R)- 1 -((2S,4S)- 1 -((R)-2-(2-naphthamido)-3 -cyclohexylpropanoyl)-4-(3 - phenylpropanamido)pyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid
Figure imgf000104_0001
Step 1: Preparation of tert-butyl (2^,45)-4-azido-2-(((R)-2-methyl-l- ((3a,S',4)S',6)S',7aR)-3a,5,54rimethylhexahydro-4,6-methanobenzo[ii][l,3,2]dioxaborol-2- yl)propyl)carbamoyl)pyrrolidine- 1 -carboxylate
[0177] Into a 100 mL round-bottom flask equipped with a magnetic stir bar and under nitrogen was added (2,S',4)S)-4-azido-l-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (513 mg, 2.0 mmol, 1.0 equiv), (R)-2-methyl-l-((3a^4^6^,7aR)-3a,5,5- trimethylhexahydro-4,6-methanobenzo[<i][l,3,2]dioxaborol-2-yl)propan-l-amine
(Intermediate A, 633 mg, 2.2 mmol, 1.1 equiv), HATU (778 mg, 2.1 mmol, 1.05 equiv) and CH2CI2 (20 mL). The reagents were treated with EtN(/'Pr)2 (1.0 mL, 6.0 mmol, 3 equiv) and stirred at room temperature for 1 h. The reaction mixture was diluted with water (50 mL) and poured into a 125 mL separatory funnel. The aqueous mixture was extracted with CH2C12 (2 x 30 mL). The combined organic layers were dried over MgS04, filtered and concentrated under reduced pressure. Purification by column chromatography through silica gel, eluting with 100:0 to 0: 100 Hexanes:EtOAc as a gradient afforded the desired product (941 mg, 96%).
Step 2: Preparation of tert-butyl (2^,45)-4-amino-2-(((R)-2-methyl-l- ((3a,S',4)S',6)S',7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[<i][l,3,2]dioxaborol-2- yl)propyl)carbamoyl)pyrrolidine- 1 -carboxylate
[0178] Into a 25 mL round-bottom flask was combined tert-butyl (2,S',4)S)-4- azido-2-(((R)-2-methyl-l-((3a,S',45',65',7aR)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[<i][l,3,2]dioxaborol-2-yl)propyl)carbamoyl)pyrrolidine-l-carboxylate (105 mg, 0.21 mmol, 1.0 equiv) and methanol (3 mL). The contents of the flask were purged under a steady stream of nitrogen for 5 minutes. To the flask was added 5 wt% palladium on carbon (50% wet, 86 mg) and nitrogen was bubbled for another 5 minutes. The nitrogen inlet was replaced with a balloon of hydrogen and the reaction was stirred at room temperature under a hydrogen atmosphere for 40 minutes. The reaction mixture was filtered through a pad of celite, washing with CH2C12 and the combined clear filtrate was concentrated under reduced pressure to afford the title compound (102 mg).
Step 3: Preparation of fert-butyl (2^,45)-2-(((R)-2-methyl-l-((3a^,4^,6^,7aR)-3a,5,5- trimethylhexahydro-4,6-methanobenzo[<i][l,3,2]dioxaborol-2-yl)propyl)carbamoyl)-4-(3- phenylpropanamido)pyrrolidine-l -carboxylate
[0179] A solution of fert-butyl (2^,45)-4-amino-2-(((R)-2-methyl-l- ((3a,S',4)S',6)S',7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[<i][l,3,2]dioxaborol-2- yl)propyl)carbamoyl)pyrrolidine-l-carboxylate (100 mg, 0.22 mmol, 1.0 equiv) in CH2C12 (3 mL) and EtN(/'Pr)2 (1 15 μΐ^, 0.66 mmol, 3 equiv) was treated with 3-phenylpropanoyl chloride (42 μΐ^, 0.29 mmol, 1.3 equiv). The reaction mixture was stirred at room temperature for 1 h and then quenched with water (20 mL). The mixture was extracted with CH2C12 (2 x 10 mL) and the combined organic layers were dried over MgS04, filtered and concentrated under reduced pressure. Purification by column chromatography through silica gel, eluting with 100:0 to 0: 100 Hexanes:EtOAc as a gradient afforded the title compound (84 mg, 64%).
Step 4: Preparation of (2^,45)-N-((R)-2-methyl-l-((3a^,4^,6^,7aR)-3a,5,5- trimethylhexahydro-4,6-methanobenzo[<i][l,3,2]dioxaborol-2-yl)propyl)-4-(3- phenylpropanamido)pyrrolidine-2-carboxamide hydrochloride
[0180] A solution of tert-butyl (2^,45)-2-(((R)-2-methyl-l-((3a^,4^,6^,7aR)- 3a,5,5-trimethylhexahydro-4,6-methanobenzo[<i][l,3,2]dioxaborol-2-yl)propyl)carbamoyl)- 4-(3-phenylpropanamido)pyrrolidine-l-carboxylate (84 mg, 0.14 mmol, 1.0 equiv) in CH2CI2 (3 mL) was treated with 4 M HC1 in dioxane (0.3 mL). The reaction mixture was stirred at room temperature for 18 h. LCMS analysis reveals complete conversion to product. The reaction mixture was concentrated under reduced pressure and used directly in the next step without further purification (71 mg).
Step 5: Preparation of (2,S',4)S)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N- ((R)-2-methyl-l-((3a,S',45',65',7aR)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[<i][l,3,2]dioxaborol-2-yl)propyl)-4-(3-phenylpropanamido)pyrrolidine-2- carboxamide
[0181] Into a 25 mL round-bottom flask equipped with a magnetic stir bar and under nitrogen was added (2^,45)-N-((R)-2-methyl-l-((3a^,4^,6^,7aR)-3a,5,5- trimethylhexahydro-4,6-methanobenzo[<i][l,3,2]dioxaborol-2-yl)propyl)-4-(3- phenylpropanamido)pyrrolidine-2-carboxamide hydrochloride (71 mg, 0.13 mmol, 1.0 equiv), (R)-2-(2-naphthamido)-3-cyclohexylpropanoic acid (Intermediate D, 52 mg, 0.16 mmol, 1.2 equiv) and HATU (56 mg, 0.15 mmol, 1.1 equiv). The solids were suspended in CH2CI2 (2 mL) and treated with EtN(/'Pr)2 (70 μΐ^, 0.4 mmol, 3 equiv). The reaction mixture was stirred at room temperature for 18 h overnight. The mixture as quenched with water (25 mL) and extracted with CH2C12 (3 x 10 mL). The combined organic layers were dried over MgS04, filtered and concentrated under reduced pressure. Purification by reverse-phase column chromatography through a C 18 column, eluting with 90: 10 to 0: 100 LLOMeCN + 0.1% formic acid as a gradient afforded the desired product (81 mg, 76%).
Step 6: Preparation of ((R)-l -((2S,4S)- l-((R)-2-(2-naphthamido)-3- cyclohexylpropanoyl)-4-(3-phenylpropanamido)pyrrolidine-2-carboxamido)-2- methylpropyl)boronic acid [0182] Into a 25 mL round-bottom flask equipped with a magnetic stir bar was weighed (2S,4S)- 1 -((R)-2-(2-naphthamido)-3 -cy clohexylpropanoyl)-N-((R)-2-methyl- 1 - ((3a,S',4)S',6)S',7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[<i][l,3,2]dioxaborol-2- yl)propyl)-4-(3-phenylpropanamido)pyrrolidine-2-carboxamide (81 mg, 0.1 mmol, 1.0 equiv) and isobutyl boronic acid (51 mg, 0.5 mmol, 5 equiv). The solids were suspended in methanol (1 mL) and octane (1 mL) and treated with 4 M HC1 in dioxane (150 μL, 0.6 mmol, 6 equiv). The biphasic reaction mixture was vigorously stirred at room temperature for 2 h and then quenched with saturated aqueous NaHC03 solution (200 [iL). The reaction was concentrated under reduced pressure. Purification by reverse-phase column chromatography through a CI 8 column, eluting with 90: 10 to 0: 100 H20:MeCN + 0.1% formic acid as a gradient. The product containing fractions were concentrated under reduced pressure and treated with saturated aqueous NaHC03 solution (10 mL). The mixture was portioned between water (10 mL) and EtOAc (10 mL) and the organic layer removed. The aqueous layer was further extracted with EtOAc (10 mL) and the combined organic layers dried over MgS04, filtered and concentrated under reduced pressure to afford the title product (29 mg, 17%).
[0183] The following compounds were prepared in a similar manner as example 19, by replacing the 3-phenylpropanoyl chloride in step 3 with 1 -methyl- lH-pyrazole-4- sulfonyl chloride (Example 20).
Figure imgf000108_0001
methylpropyl)boronic acid
Example 21 : ((R)- 1 -((2S,4R)- 1 -((R)-2-(2-naphthamido)-3 -cyclohexylpropanoyl)-4-(2- (pyridin-3-yl)acetamido)pyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid
Figure imgf000109_0001
Figure imgf000109_0002
Step 1: Preparation of fert-butyl (2^,4R)-4-azido-2-(((R)-2-methyl-l- ((3a,S',4)S',6)S',7aR)-3a,5,54rimethylhexahydro-4,6-methanobenzo[ii][l,3,2]dioxaborol-2- yl)propyl)carbamoyl)pyrrolidine- 1 -carboxylate
[0184] Into a 250 mL round-bottom flask equipped with a magnetic stir bar and under an atmosphere of nitrogen was added (2,S',4R)-4-azido-l-(tert- butoxycarbonyl)pyrrolidine-2-carboxylic acid (936 mg, 3.65 mmol, 1.05 equiv), (R)-2- methyl- 1 -((3 aS,4S,6S, 7aR)-3 a, 5 , 5 -trimethylhexahy dro-4, 6- methanobenzo[<i][l,3,2]dioxaborol-2-yl)propan-l-amine (Intermediate A, 1.00 g, 3.48 mmol, 1.0 equiv) and CH2CI2 (40 mL). The mixture was treated with EtN(/'Pr)2 (1.9 mL, 11.0 mmol, 3 equiv) followed by HATU (1.4 g, 3.65 mmol, 1.05 equiv). The reaction mixture was stirred at room temperature for 2 h, and then poured into 100 mL of water in a 250 mL separatory funnel. The mixture was extracted with CH2C12 (2 x 40 mL). The combined organic layers were dried over MgS04, filtered and concentrated under reduced pressure. Purification by column chromatography through silica gel, eluting with 100:0 to 0: 100 Hexanes:EtOAc as a gradient. The title compound was obtained (1.0 g, 59%).
Step 2: Preparation of (2^,4R)-4-azido-N-((R)-2-methyl-l-((3a^,4^,6^,7aR)-3a,5,5- trimethylhexahydro-4,6-methanobenzo[<i][l,3,2]dioxaborol-2-yl)propyl)pyrrolidine-2- carboxamide hydrochloride
[0185] A mixture of tert-butyl (2^,4R)-4-azido-2-(((R)-2-methyl-l- ((3a,S',4)S',6)S',7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[<i][l,3,2]dioxaborol-2- yl)propyl)carbamoyl)pyrrolidine-l-carboxylate (1.87 g, 3.82 mmol, 1.0 equiv) in CH2C12 (40 mL) was treated with 4 M HC1 in dioxane (4 mL). The reaction mixture was stirred at room temperature for 18 h overnight, and then concentrated under reduced pressure to afford an off-white solid (1.67 g) which was used directly without further purification.
Step 3: Preparation of fert-butyl ((R)-l-((2^,4R)-4-azido-2-(((R)-2-methyl-l- ((3a,S',4)S',6)S',7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[<i][l,3,2]dioxaborol-2- yl)propyl)carbamoyl)pyrrolidin- 1 -yl)-3 -cyclohexyl- 1 -oxopropan-2-yl)carbamate
[0186] A 100 mL round-bottom flask equipped with a magnetic stir bar and under nitrogen was charged with (25,,4R)-4-azido-N-((R)-2-methyl-l-((3a,S',45',65',7aR)-3a,5,5- trimethylhexahydro-4,6-methanobenzo[<i][l,3,2]dioxaborol-2-yl)propyl)pyrrolidine-2- carboxamide hydrochloride (1.66 g, 3.9 mmol, 1.0 equiv), (R)-2-((tert- butoxycarbonyl)amino)-3-cyclohexylpropanoic acid (1.27 g, 4.68 mmol, 1.2 equiv), HATU (1.63 g, 4.29 mmol, 1.1 equiv) and CH2C12 (40 mL). The mixture was treated with EtN(/'Pr)2 (2.03 mL, 4.29 mmol, 1.1 equiv) and stirred at room temperature for 20 minutes. LCMS analysis reveals complete formation of product. The reaction mixture was poured into a 250 mL separatory funnel containing water (100 mL) and extracted with CH2C12 (3 x 40 mL). The combined organic layers were washed with brine (25 mL), dried over MgS04, filtered and concentrated under reduced pressure. Purification by column chromatography through silica gel, eluting with 100:0 to 0: 100 Hexanes:EtOAc as a gradient afforded the desired product (2.06 g, 82%)
Step 4: Preparation of (2,S',4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- azido-N-((R)-2-methyl-l-((3a,S',45',65',7aR)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[<i][l,3,2]dioxaborol-2-yl)propyl)pyrrolidine-2-carboxamide
[0187] A solution of fert-butyl ((R)-l-((2^,4R)-4-azido-2-(((R)-2-methyl-l- ((3a,S',4)S',6)S',7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[<i][l,3,2]dioxaborol-2- yl)propyl)carbamoyl)pyrrolidin-l-yl)-3-cyclohexyl-l-oxopropan-2-yl)carbamate (2.06 g, 3.2 mmol, 1.0 equiv) in CH2CI2 (40 mL) was treated with 4 M HC1 in dioxane (5 mL). The reaction mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure. The amine hydrochloride was placed into a 100 mL round-bottom flask containing 2-naphthoic acid (736 mg, 4.28 mmol, 1.25 equiv) and HATU (1.43 g, 3.78 mmol, 1.1 equiv). The solids were suspended in CH2CI2 (40 mL) and treated with EtN(/'Pr)2 (2.08 mL, 12 mmol, 3.5 equiv). The reaction mixture was stirred at room temperature for 40 minutes and then diluted with water (100 mL). The mixture was poured into a 250 mL separately funnel and extracted with CH2CI2 (2 x 40 mL). The combined organic layers were dried over MgS04, filtered and concentrated under reduced pressure. Purification by column chromatography through silica gel, eluting with 100:0 to 0: 100 Hexanes:EtOAc as a gradient afforded the desired product (1.70 g, 72%).
Step 5: Preparation of (2,S',4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- amino-N-((R)-2-methyl-l-((3a,S',45',65',7aR)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[<i][l,3,2]dioxaborol-2-yl)propyl)pyrrolidine-2-carboxamide
[0188] A solution of (2^,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)- 4-azido-N-((R)-2-methyl-l-((3a,S',45',65',7aR)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[<i][l,3,2]dioxaborol-2-yl)propyl)pyrrolidine-2-carboxamide (1.45 g, 2.08 mmol, 1.0 equiv) in methanol (40 mL) was degassed with a steady flow of nitrogen for 5 minutes. After this time, the flask was charged with 5 wt% palladium on carbon (881 mg). The flask was further purged with a steady flow of nitrogen and then the nitrogen line was replaced with a balloon of hydrogen. The contents of the flask were stirred under an atmosphere of hydrogen for 3 h. The mixture was filtered through a pad of celite on a sintered plastic funnel, washing with CH2CI2. The clear filtrate was concentrated under reduced pressure and used directly without further purification (1.24 g, 93%).
Step 6: Preparation of (2,S',4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N- ((R)-2-methyl- 1 -((3 aS,4S,6S, 7aR)-3 a, 5 , 5 -trimethylhexahy dro-4, 6- methanobenzo[ii][l,3,2]dioxaborol-2-yl)propyl)-4-(2-(pyridin-3-yl)acetamido)pyrrolidine-2- carboxamide
[0189] Into a round-bottom flask equipped with a magnetic stir bar and under a nitrogen atmosphere was weighed (2,S',4R)-l-((R)-2-(2-naphthamido)-3- cyclohexylpropanoyl)-4-amino-N-((R)-2-methyl-l-((3a,S',4)S',6)S',7aR)-3a,5,5- trimethylhexahydro-4,6-methanobenzo[<i][l,3,2]dioxaborol-2-yl)propyl)pyrrolidine-2- carboxamide (67 mg, 0.1 mmol, 1.0 equiv), 2-(pyridin-3-yl)acetic acid (18 mg, 0.13 mmol, 1.3 equiv), HATU (46 mg, 0.12 mmol, 1.2 equiv) and CH2CI2 (2 mL). The reagents were treated with EtN(/'Pr)2 (70 [iL, 0.4 mmol, 4 equiv) and stirred at room temperature for 20 minutes. The reaction was quenched with water (10 mL) and extracted with CH2C12 (3 x 5 mL). The combined organic layers were dried over MgS04, filtered and concentrated under reduced pressure. Purification by column chromatography through silica gel, eluting with 100:0 to 0: 100 Hexanes:EtOAc as a gradient afforded the title compound (60 mg, 76%).
Step 7: Preparation of ((R)-l-((2^,4R)-l-((R)-2-(2-naphthamido)-3- cyclohexylpropanoyl)-4-(2-(pyridin-3-yl)acetamido)pyrrolidine-2-carboxamido)-2- methylpropyl)boronic acid
[0190] Into a 25 mL round-bottom flask equipped with a magnetic stir bar was weighed (2^,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-((R)-2-methyl-l- ((3a,S',4)S',6)S',7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[<i][l,3,2]dioxaborol-2- yl)propyl)-4-(2-(pyridin-3-yl)acetamido)pyrrolidine-2-carboxamide (60 mg, 0.076 mmol, 1.0 equiv) and isobutyl boronic acid (30 mg, 0.3 mmol, 4 equiv). The solids were suspended in methanol (1 mL) and octane (1 mL) and treated with 4 M HC1 in dioxane (95 μΐ^, 0.38 mmol, 5 equiv). The biphasic reaction mixture was vigorously stirred at room temperature for 2 h and concentrated under reduced pressure. Purification by reverse-phase column chromatography through a C18 column, eluting with 90: 10 to 0: 100 H20:MeCN + 0.1% formic acid as a gradient. The product containing fractions were concentrated under reduced pressure and treated with saturated aqueous NaHCC solution (10 mL). The mixture was portioned between water (10 mL) and EtOAc (10 mL) and the organic layer removed. The aqueous layer was further extracted with EtOAc (10 mL) and the combined organic layers dried over MgS04, filtered and concentrated under reduced pressure to afford the title product (44 mg, 88%).
[0191] The following compounds were prepared in a similar manner as described for example 21, substituting 2-(pyridin-3-yl)acetic acid in step 6 with the appropriate carboxylic acid (example 22 = 2-pyridin-2-yl)acetic acid, example 23 = 4-(4- methoxyphenyl)butanoic acid, example 25 = 2-(pyridin-4-yl)acetic acid, example 26 = 3- phenylpropanoic acid). In the case of example 24, the carboxylic acid was replaced with phenyl propyl isocyanate and the HATU reagent was omitted. In the case of example 27, the carboxylic acid was replaced with l-methyl-lH-pyrazole-4-sulfonyl chloride and the HATU reagent omitted.
Figure imgf000113_0001
Figure imgf000114_0001
phenylpropyl)ureido)pyrrolidine-2-carboxamido)-2-
Figure imgf000115_0001
cyclohexylpropanoyl)-4-((l-methyl-lH-pyrazole)-4- sulfonamido)pyrrolidine-2-carboxamido)-2- methylpropyl)boronic acid
Example 28: ((R)-l-((2^,4R)-l -((R)-3-cyclohexyl-2-(((R)-2,2,2-trifluoro-l-(naphthalen-2- yl)ethyl)amino)propanoyl)-4-phenylpyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid
Figure imgf000116_0001
Step 1: Preparation (2^,4R)-l-((R)-3-cyclohexyl-2-(((R)-2,2,2-trifluoro-l- (naphthalen-2-yl)ethyl)amino)propanoyl)-N-((R)-2-m
trimethylhexahydro-4,6-methanobenzo[d][l,3,2]dioxaborol-2-yl)propyl)-4- phenylpyrrolidine-2-carboxamide
[0192] A solution of (2^4R)-N-((R)-2-methyl-l-((3a^4^6^,7aR)-3a,5,5- trimethylhexahydro-4,6-methanobenzo[<i][l,3,2]dioxaborol-2-yl)propyl)-4- phenylpyrrolidine-2-carboxamide hydrochloride (from Example 1, step 2: 73 mg, 0.16 mmol, 1.2 equiv) and (R)-3-cyclohexyl-2-(((R)-2,2,2-trifluoro-l-(naphthalen-2- yl)ethyl)amino)propanoic acid (Intermediate E, 50 mg, 0.13 mmol, 1.0 equiv) in DMF (0.7 mL) was treated with HATU (50 mg, 0.13 mmol, 1.0 equiv) and EtN(/Pr)2 (69 μί, 0.40 mmol, 3.0 equiv). The reaction mixture was stirred at room temperature overnight. To the reaction mixture was added 1 M aqueous HCI (3 mL) and Et20 (10 mL). The aqueous layer was separated and extracted with Et20 (3 x 50 mL). The combined organics were washed with brine (1 x 50 mL), dried over MgS04, filtered and concentrated under reduced pressure. Purification by column chromatography on silica gel, eluting with 100:0 to 50:50 Hexanes:EtOAc as a gradient. The title product was obtained as a solid (25 mg, 24%).
Step 2: Preparation of ((R)-l -((2^,4R)-l-((R)-3-cyclohexyl-2-(((R)-2,2,2-trifluoro-l- (naphthalen-2-yl)ethyl)amino)propanoyl)-4-phenylpyrrolidine-2-carboxamido)-2- methylpropyl)boronic acid
[0193] Into a 4 mL vial, equipped with a magnetic stir bar and under nitrogen was added (2^,4R)-l-((R)-3-cyclohexyl-2-(((R)-2,2,2-trifluoro-l-(naphthalen-2- yl)ethyl)amino)propanoyl)-N-((R)-2-methyl-l-((3a,S',4)S',6)S',7aR)-3a,5,5-trimethylhexahydro- 4,6-methanobenzo[d][l,3,2]dioxaborol-2-yl)propyl)-4-phenylpyrrolidine-2-carboxamide (25 mg, 0.03 mmol, 1.0 equiv), isobutyl boronic acid (16 mg, 0.16 mmol, 5.3 equiv) in methanol (1 mL) and hexanes (1 mL). The reaction mixture was treated with 1 M aqueous HC1 (127 μΐ^, 0.13 mmol, 4.3 equiv) and the biphasic suspension was stirred vigorously at room temperature for 18 h. The bottom methanol layer was removed. The top hexanes layer was further extracted with methanol (3 x 1 mL), and the combined methanol layers were washed with hexanes (2 x 2 mL) and concentrated under reduced pressure. The title compound was obtained as a solid (15 mg, 73%).
Figure imgf000117_0001
Example 29: ((R)- 1 -((2S,4R)- 1 -((R)-2-(2-naphthamido)-3 -cyclohexylpropanoyl)-4- (piperidin-l-yl)pyrrolidine-2-carboxamido)-5-(3-cyclohexylureido)pentyl)boronic acid hydrochloride
Figure imgf000118_0001
Step 1: Preparation of (2,S',4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N- ((R)-5-bromo-l-((3a,S',4)S',6)S',7aR)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[<i][l,3,2]dioxaborol-2-yl)pentyl)-4-(piperidin-l-yl)pyrrolidine-2-carboxamide
[0194] Into a 25 mL round-bottom flask equipped with a magnetic stir bar and under nitrogen was added 2,5-dioxopyrrolidin-l-yl (2S,4R)- 1 -((R)-2-(2-naphthamido)-3 - cyclohexylpropanoyl)-4-(piperidin-l-yl)pyrrolidine-2-carboxylate (From Example 14, step 4: 301 mg, 0.5 mmol, 1.0 equiv), (R)-5-bromo-l-((3a,S',4)S',6)S',7aR)-3a,5,5-trimethylhexahydro- 4,6-methanobenzo[<i][l,3,2]dioxaborol-2-yl)pentan-l-amine hydrochloride (Intermediate B, 202 mg, 0.53 mmol, 1.05 equiv) in CH2CI2 (5 mL). The suspension was treated with EtN(/'Pr)2 (217 [iL, 1.25 mmol, 2.5 equiv) and stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc (60 mL) and poured into a 125 mL separately funnel. The organic layer was washed with water (3 x 30 mL). The aqueous layers were further extracted with EtOAc (20 mL) and the combined organic layers were dried over MgS04, filtered and concentrated under reduced pressure. The material was used directly in the next step without further purification (400 mg).
Step 2: Preparation of (2,S',4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N- ((R)-5-amino-l-((3a,S',4)S',6)S',7aR)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[<i][l,3,2]dioxaborol-2-yl)pentyl)-4-(piperidin-l-yl)pyrrolidine-2-carboxamide
[0195] A solution of (2^,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)- N-((R)-5-bromo-l-((3a^,4^,6^,7aR)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[<i][l,3,2]dioxaborol-2-yl)pentyl)-4-(piperidin-l-yl)pyrrolidine-2-carboxamide (400 mg, 0.48 mmol, 1.0 equiv) in DMF (6 mL) was treated with sodium azide (62 mg, 0.96 mmol, 2.0 equiv) and potassium iodide (80 mg, 0.48 mmol, 1.0 equiv). The reaction mixture was heated to 50 °C for 18 h overnight. The reaction mixture was cooled to room temperature and poured into a 125 mL separately funnel containing a 1 : 1 mixture of EtOAc:Hexanes (75 mL). The combined organics were washed with brine (3 x 50 mL), dried over MgS04, filtered and concentrated under reduced pressure. Purification by column chromatography through silica gel, eluting with 100:0 to 0: 100 Hexanes:EtOAc+10% methanol as a gradient afforded the title compound (205 mg, 54%).
[0196] A solution of the azide above (150 mg, 0.19 mmol, 1.0 equiv) in methanol (5 mL) was purged with a steady flow of nitrogen for 15 minutes. The flask was charged with 5 wt% palladium on carbon (80 mg) and purged with nitrogen for 10 minutes. After this time, the nitrogen inlet was replaced with a balloon of hydrogen and the contents of the flask stirred under a hydrogen atmosphere for 2 h. The mixture was filtered through a pad of celite on a sintered funnel, washing with CH2C12 and the clear filtrate was concentrated under reduced pressure (122 mg).
Step 3: Preparation of (2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-iV- ((R)-5-(3-cyclohexylureido)-l-((3a,S',4)S',6)S',7aR)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[<i][l,3,2]dioxaborol-2-yl)pentyl)-4-(piperidin-l-yl)pyrrolidine-2-carboxamide
[0197] Into a 25 mL vial equipped with a magnetic stir bar and under nitrogen was added (2S,4R)-1 -((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-((R)-5-amino-l- ((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[i/][l,3,2]dioxaborol-2- yl)pentyl)-4-(piperidin-l-yl)pyrrolidine-2-carboxamide (122 mg, 0.16 mmol, 1.0 equiv), cyclohexyl isocyanate (22 [iL, 0.18 mmol, 1.1 equiv) and CH2CI2 (3 mL). The reaction was treated with EtN(/'Pr)2 (69 [iL, 0.40 mmol, 2.5 equiv) and stirred at room temperature for 1 h. The reaction mixture was diluted with CH2C12 (20 mL) and washed with water (5 mL). The organic layer was dried over MgS04, filtered and concentrated under reduced pressure. Purification by column chromatography through silica gel, eluting with 100:0 to 0: 100 Hexanes:EtOAc+10% methanol as a gradient afforded the title compound (69 mg, 50%).
Step 4: Preparation of ((R)-l-((2^,4R)-l-((R)-2-(2-naphthamido)-3- cyclohexylpropanoyl)-4-(piperidin-l-yl)pyrrolidine-2-carboxamido)-5-(3- cyclohexylureido)pentyl)boronic acid hydrochloride
[0198] A solution of (2^,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)- N-((R)-5-(3-cyclohexylureido)-l-((3a,S',45',65',7aR)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[<i][l,3,2]dioxaborol-2-yl)pentyl)-4-(piperidin-l-yl)pyrrolidine-2-carboxamide (69 mg, 0.077 mmol, 1.0 equiv) in methanol (1 mL) and octane (1 mL) was treated with isobutyl boronic acid (24 mg, 0.23 mmol, 3 equiv) and 4 M HC1 in dioxane (97 μΐ^, 0.38 mmol, 5 equiv). The biphasic mixture was stirred vigorously at room temperature for 18 h overnight. The mixture was concentrated under reduced pressure. Purification by reverse- phase column chromatography through a CI 8 column, eluting with 90: 10 to 0: 100 H20:MeCN + 0.1% formic acid as a gradient. The product containing fractions were concentrated under reduced pressure and treated with saturated aqueous NaHC03 solution (10 mL). The mixture was portioned between water (10 mL) and EtOAc (10 mL) and the organic layer removed. The aqueous layer was further extracted with EtOAc (10 mL) and the combined organic layers dried over MgS04, filtered and concentrated under reduced pressure. The product was dissolved in CH2C12 (10 mL) and treated with 4 M HC1 in dioxane (100 μΕ) and concentrated under reduced pressure to afford the hydrochloride salt (33 mg, 26%).
[0199] The following compounds were prepared in a similar manner as described for example 29, where cyclohexyl isocyanate in step 3 was replaced with another electrophile (example 30 = ethyl isocyanate, example 31 = phenyl isocyanate, example 32 = benzyl isocyanate, example 33 = trifluoromethanesulfonyl anhydride, example 34 = acetyl chloride, example 35 = benzoyl chloride, example 36 = methanesulfonyl chloride, example 37 = phenyl sulfonyl chloride, example 38 = (2-isocyanatoethyl)benzene, example 39 = (3- isocyanatopropyl)benzene, example 40 = 1-isocyanatonaphthalene, example 41 = 1,3-di-boc- 2-(trifluoromethylsulfonyl)guanidine), example 42 = 2-phenylacetyl chloride, example 43 = piperidine-1 -sulfonyl chloride, example 44 = 4-pyridyl isocyanate, example 45 = 2- chlorophenyl isocyanate, example 46 = 3-chlorophenyl isocyanate, example 47 = 4- chlorophenyl isocyanate, example 48 = 2-methoxyphenyl isocyanate, example 49 = 3- methoxyphenyl isocyanate, example 50 = 4-methoxyphenyl isocyanate). For isolation of the free amine, treatment with HCl in dioxane in CH2CI2 at the very end of step 4 was omitted (examples 30-50).
Figure imgf000121_0001
Figure imgf000122_0001
((R)- 1 -((2S,4R)- 1 -((R)-2-(2-naphthamido)-3 -
Figure imgf000123_0001
Figure imgf000124_0001
acid
Figure imgf000125_0001
yl)ureido)pentyl)boronic acid
Figure imgf000126_0001
((R)- 1 -((2S, O4R)- 1 -((R H)-2-(2-naphthamido)-3 -
Figure imgf000127_0001
chlorophenyl)ureido)pentyl)boronic acid
Figure imgf000128_0001
Figure imgf000129_0001
methoxy pheny l)urei do)penty l)b oroni c aci d Example 51 : ((R)- 1 -((2S,4R)- 1 -((R)-2-(2-naphthamido)-3 -cyclohexylpropanoyl)-4- (piperidin-l-yl)pyrrolidine-2-carboxamido)-5-(2-thia-6-azaspiro[3.3]heptan-6- yl)pentyl)boronic acid hydrochloride
Figure imgf000130_0001
Step 1: Preparation of (2,S',4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N- ((R)-5-(2-thia-6-azaspiro[3.3]heptan-6-yl)-l-((3a,S',4)S',6)S',7aR)-3a,5,5-trimethylhexahydro- 4,6-methanobenzo[<i][l,3,2]dioxaborol-2-yl)pentyl)-4-(piperidin-l-yl)pyrrolidine-2- carboxamide
[0200] A solution of (2^,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)- N-((R)-5-amino-l-((3a,S',45',65',7aR)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[ii][l,3,2]dioxaborol-2-yl)pentyl)-4-(piperidin-l-yl)pyrrolidine-2-carboxamide (from Example 29, step 1 : 100 mg, 0.12 mmol, 1.0 equiv) in acetonitrile (1 mL) was treated with 2-thia-6-azaspiro[3.3]heptanes (30 mg, 0.18 mmol, 1.5 equiv), potassium carbonate (83 mg, 0.60 mmol, 5 equiv) and potassium iodide (20 mg, 0.12 mmol, 1.0 equiv). The suspension was heated to 50 °C for 18 h. The reaction mixture was cooled to room temperature, diluted with water (25 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (10 mL), dried over MgS04, filtered and concentrated under reduced pressure. Purification by column chromatography through silica gel, eluting with 100:0 to 0: 100 Hexanes:EtOAc + 10% MeOH as a gradient. The product fractions were concentrated under reduced pressure and dried under vacuum to afford the title compound (24 mg, 23%).
Step 2: Preparation of ((R)-l-((2^,4R)-l-((R)-2-(2-naphthamido)-3- cyclohexylpropanoyl)-4-(piperidin-l-yl)pyrrolidine-2-carboxamido)-5-(2-thia-6- azaspiro[3.3]heptan-6-yl)pentyl)boronic acid hydrochloride
[0201] A solution of (2^,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)- N-((R)-5-(2-thia-6-azaspiro[3.3]heptan-6-yl)-l-((3a,S',4)S',6)S',7aR)-3a,5,5-trimethylhexahydro- 4,6-methanobenzo[<i][l,3,2]dioxaborol-2-yl)pentyl)-4-(piperidin-l-yl)pyrrolidine-2- carboxamide (24 mg, 0.028 mmol, 1.0 equiv) in methanol (1 mL) was treated with isobutyl boronic acid (10 mg, 0.083 mmol, 3 equiv) and 4 M HC1 in dioxane (25 [iL, 0.083 mmol, 3 equiv). The mixture was stirred vigorously at room temperature for 18 h overnight. The mixture was diluted with octane (1 mL) and the bottom methanolic layer of the biphasic solution was removed, and the top octane layer was further extracted with methanol (3 x 1 mL). The combined methanol layers were washed with octane (3 x 1 mL) and concentrated under reduced pressure to afford the desired product as an HC1 salt (20 mg, 99%).
[0202] The following compounds were prepared in a similar manner as described for example 51, where 2-thia-6-azaspiro[3.3]heptanes in step 1 was replaced with thiophenol and acetonitrile was exchanged with DMF.
Figure imgf000132_0001
hydrochloride Example 53: ((R)- 1 -((2S,4R)- 1 -((R)-2-(2-naphthamido)-3 -cyclohexylpropanoyl)-4- (piperidin- 1 -yl)pyrrolidine-2-carboxamido)-5-(4-phenyl- \H- 1 ,2,3 -triazol- 1 -yl)pentyl)boronic acid
Figure imgf000133_0001
Step 1: Preparation of (2,S',4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N- ((R)-5-(4-phenyl-lH-l ,2,34riazol-l-yl)-l-((3a^,4^,6^,7aR)-3a,5,5 rimethylhexahydro-4,6- methanobenzo[ii][l,3,2]dioxaborol-2-yl)pentyl)-4-(piperidin-l-yl)pyrrolidine-2-carboxamide
[0203] A solution of (2^,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)- N-((R)-5-azido-l -((3a^,4^,6^,7aR)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[ii][l,3,2]dioxaborol-2-yl)pentyl)-4-(piperidin-l-yl)pyrrolidine-2-carboxamide (from example 29, step 2, 100 mg, 0.13 mmol, 1.0 equiv) in t-BuOH (0.5 mL) and water (0.5 mL) was added ethynylbenzene (14 μΐ^, 0.17 mmol, 1.3 equiv), CuS04"5H20 (3 mg, 0.013 mmol, 0.1 equiv) and sodium ascorbate (5 mg, 0.025 mmol, 0.2 equiv). The mixture was heated to 50 °C for 3 h and then cooled to room temperature. The mixture was quenched with saturated aqueous H4C1 solution (5 mL) and extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with brine (10 mL), dried over MgS04, filtered and concentrated under reduced pressure to afford the title compound (1 10 mg, 94%). Step 2: Preparation of ((R)-l -((2S,4R)-l-((R)-2-(2-naphthamido)-3- cyclohexylpropanoyl)-4-(piperidin- 1 -yl)pyrrolidine-2-carboxamido)-5-(4-phenyl- 1H- 1,2,3- triazol-l-yl)pentyl)boronic acid
[0204] Into a 25 mL round-bottom flask equipped with a magnetic stir bar was weighed (2^,4R)-l -((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-((R)-5-(4-phenyl-lH- 1 ,2,3 -triazol- 1 -yl)- 1 -((3 aS,4S,6S,7aR)-3 a, 5, 5-trimethylhexahydro-4,6- methanobenzo[<i][l,3,2]dioxaborol-2-yl)pentyl)-4-(piperidin-l-yl)pyrrolidine-2-carboxamide (1 10 mg, 0.12 mmol, 1.0 equiv) and isobutyl boronic acid (63 mg, 0.61 mmol, 5 equiv). The solids were suspended in methanol (1 mL) and treated with 4 M HC1 in dioxane (150 μΐ., 0.61 mmol, 5 equiv). The reaction mixture was vigorously stirred at room temperature for 18 h. Purification by reverse-phase column chromatography through a CI 8 column, eluting with 90: 10 to 0: 100 H20:MeCN + 0.1% formic acid as a gradient. The product containing fractions were concentrated under reduced pressure and treated with saturated aqueous NaHC03 solution (10 mL). The mixture was portioned between water (10 mL) and EtOAc (10 mL) and the organic layer removed. The aqueous layer was further extracted with EtOAc (10 mL) and the combined organic layers dried over MgS04, filtered and concentrated under reduced pressure to afford the title product (13 mg, 14%).
Figure imgf000134_0001
Example 54: ((R)- 1 -((2S,4R)- 1 -((R)-2-(2-naphthamido)-3 -cyclohexylpropanoyl)-4- (piperidin-l-yl)pyrrolidine-2-carboxamido)-4-(3-cyclohexylureido)butyl)boronic acid
Figure imgf000135_0001
Step 1: Preparation of (2,S',4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N- ((R)-4-bromo-l-((3a,S',45',65',7aR)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[ii][l,3,2]dioxaborol-2-yl)butyl)-4-(piperidin-l-yl)pyrrolidine-2-carboxamide
[0205] Into a 50 mL round-bottom flask equipped with a magnetic stir bar and under nitrogen was added 2,5-dioxopyrrolidin-l-yl (2S,4R)- 1 -((R)-2-(2-naphthamido)-3 - cyclohexylpropanoyl)-4-(piperidin-l-yl)pyrrolidine-2-carboxylate (From Example 14, step 4: 1.20 g, 2.0 mmol, 1.0 equiv), (R)-4-bromo-l-((3a,S',45',65',7aR)-3a,5,5-trimethylhexahydro- 4,6-methanobenzo[<i][l,3,2]dioxaborol-2-yl)butan-l-amine (Intermediate C, 725 mg, 2.2 mmol, 1.1 equiv) in CH2CI2 (10 mL). The suspension was treated with EtN(/'Pr)2 (885 μΐ^, 5.0 mmol, 2.5 equiv) and stirred at room temperature for 1 h. The reaction mixture was diluted with CH2C12 (60 mL) and poured into a 125 mL separately funnel. The organic layer was washed with water (3 x 30 mL). The combined organic layers were dried over MgS04, filtered and concentrated under reduced pressure. Purification by column chromatography through silica gel, eluting with 100:0 to 0: 100 Hexanes:EtOAc + 10% methanol as a gradient afforded the desired product (843 mg, 52%).
Step 2: Preparation of (2,S',4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N- ((R)-4-amino-l-((3a,S',4)S',6)S',7aR)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[<i][l,3,2]dioxaborol-2-yl)butyl)-4-(piperidin-l-yl)pyrrolidine-2-carboxamide
[0206] A solution of (2^,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)- N-((R)-4-bromo-l-((3a^,4^,6^,7aR)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[<i][l,3,2]dioxaborol-2-yl)butyl)-4-(piperidin-l-yl)pyrrolidine-2-carboxamide (843 mg, 1.0 mmol, 1.0 equiv) in DMF (10 mL) was treated with sodium azide (134 mg, 2.0 mmol, 2.0 equiv) and potassium iodide (171 mg, 1.0 mmol, 1.0 equiv). The mixture was heated to 50 °C for 3 h. The reaction was cooled to room temperature and poured into a 125 mL separatory funnel containing water (50 mL). The mixture was extracted with EtOAc (2 x 30 mL) and the combined organics were further washed with brine (25 mL), dried over MgS04, filtered and concentrated under reduced pressure. Purification by column chromatography through silica gel, eluting with 100:0 to 0: 100 Hexanes:EtOAc + 10% methanol as a gradient afforded the title compound (631 mg).
[0207] A 100 mL round-bottom flask was equipped with a magnetic stir bar and charged with the azide above (631 mg, 0.79 mmol, 1.0 equiv) and methanol (10 mL). The solution was degassed with a steady flow of nitrogen for 15 minutes. After this time, 5 wt% palladium on carbon (63 mg) was charged into the flask and nitrogen purging was continued for an additional 10 minutes. The nitrogen line was replaced with a balloon of hydrogen and the contents of the flask were stirred under a hydrogen atmosphere for 3 h. LCMS reveals complete conversion of starting material. The balloon was removed and the reaction mixture was filtered through a pad of celite on a sintered funnel, washing with CH2C12 (2 x 5 mL). The clear filtrate was concentrated under reduced pressure to afford the title compound (598 mg, 40% over 2 steps).
Step 3: Preparation of (2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-iV- ((R)-4-(3-cyclohexylureido)-l-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[<i][l,3,2]dioxaborol-2-yl)butyl)-4-(piperidin-l-yl)pyrrolidine-2-carboxamide [0208] A solution of (2^,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)- N-((R)-4-amino- 1 -((3 aS,4S,6S, 7aR)-3 a, 5 , 5 -trimethylhexahy dro-4, 6- methanobenzo[<i][l,3,2]dioxaborol-2-yl)butyl)-4-(piperidin-l-yl)pyrrolidine-2-carboxamide (100 mg, 0.133 mmol, 1.0 equiv) in CH2C12 (1 mL) was treated with cyclohexyl isocyanate (19 μΐ^, 0.146 mmol, 1.1 equiv) and EtN(/'Pr)2 (58 μΐ^, 0.33 mmol, 2.5 equiv). The mixture was stirred at room temperature for 18 h. The mixture was diluted with CH2C12 (10 mL) and washed with water (10 mL) and saturated aqueous NaHC03 (10 mL). The organic layer was dried over MgS04, filtered and concentrated under reduced pressure. Purification by column chromatography through silica gel, eluting with 100:0 to 0: 100 Hexanes:EtOAc + 10% methanol as a gradient afforded the desired product (66 mg, 56%).
Step 4: Preparation of ((R)-l-((2^,4R)-l-((R)-2-(2-naphthamido)-3- cyclohexylpropanoyl)-4-(piperidin-l-yl)pyrrolidine-2-carboxamido)-4-(3- cy clohexy lurei do)buty l)b oroni c aci d
[0209] Into a 25 mL round-bottom flask equipped with a magnetic stir bar was weighed (2^,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-((R)-4-(3- cyclohexylureido)-l-((3a,S',4)S',6)S',7aR)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[<i][l,3,2]dioxaborol-2-yl)butyl)-4-(piperidin-l-yl)pyrrolidine-2-carboxamide (66 mg, 0.07 mmol, 1.0 equiv) and isobutyl boronic acid (68 mg, 0.35 mmol, 5 equiv). The solids were suspended in methanol (1 mL) and treated with 4 M HC1 in dioxane (88 [iL, 0.35 mmol, 5 equiv). The mixture was vigorously stirred at room temperature for 18 h and concentrated under reduced pressure. Purification by reverse-phase column chromatography through a CI 8 column, eluting with 90: 10 to 0: 100 H20:MeCN + 0.1% formic acid as a gradient. The product containing fractions were concentrated under reduced pressure and treated with saturated aqueous NaHC03 solution (10 mL). The mixture was portioned between water (10 mL) and EtOAc (10 mL) and the organic layer removed. The aqueous layer was further extracted with EtOAc (10 mL) and the combined organic layers dried over MgS04, filtered and concentrated under reduced pressure to afford the title product (9 mg, 17%).
[0210] The following compounds were prepared in a similar manner as described for example 54, where cyclohexyl isocyanate in step 3 was replaced with another electrophile (example 55 = ethyl isocyanate, example 56 = phenyl isocyanate, example 57 = benzyl isocyanate, example 58 = benzoyl chloride, example 59 = phenyl sulfonyl chloride, example 60 = (2-isocyanatoethyl)benzene, example 61 = (3-isocyanatopropyl)benzene, example 62 = 1 -isocyanatonaphthalene.
Figure imgf000138_0001
Figure imgf000139_0001
cyclohexylpropanoyl)-4-(piperidin- 1 -yl)pyrrolidine-2-
Figure imgf000140_0001
acid
Figure imgf000141_0001
yl)ureido)butyl)boronic acid
Example 63: ((R)- 1 -((2S,4R)- 1 -((R)-2-(2-naphthamido)-3 -cyclohexylpropanoyl)-4- (piperidin-l-yl)pyrrolidine-2-carboxamido)-6-(3-cyclohexylureido)hexyl)boronic acid formate
Figure imgf000142_0001
Step 1: Preparation of (3a,S',4)S',6)S',7aR)-2-(5-bromopentyl)-3a,5,5- trimethylhexahydro-4,6-methanobenzo[<i][l,3,2]dioxaborole
[0211] Into a 40 mL vial equipped with a magnetic stir bar and under nitrogen was combined 5-bromo-l-pentene (10 g, 66 mmol, 1.0 equiv) and catecholborane (8.1 g, 66 mmol, 1.0 equiv). The neat mixture was heated to 1 10 °C for 16 h. In a separate 250 mL round bottom flask equipped with a magnetic stir bar was added (\S,2S,3R,5S)-2,6,6- trimethylbicyclo[3.1.1]heptane-2,3-diol (11.4 g, 66 mmol, 1.0 equiv) and THF (60 mL). After the solids had dissolved, the prepared borate was added via syringe over 20 minutes. The mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography through silica gel, eluting with 100:0 to 90: 10 Hexanes:EtOAc as a gradient. The desired product was obtained as a clear oil (6.6 g, 77%).
Step 2: Preparation of (3a,S',4)S',6)S',7aR)-2-(5-azidopentyl)-3a,5,5-trimethylhexahydro- 4,6-methanobenzo[<i] [ 1 ,3 ,2]dioxaborole
[0212] Into a 50 mL round-bottom flask equipped with a magnetic stir bar was combined (3a,S',4)S',6)S',7aR)-2-(5-bromopentyl)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[<i][l,3,2]dioxaborole (1.97 g, 6.0 mmol, 1.0 equiv), sodium azide (3.89 g, 60 mmol, 10 equiv) and tetrabutyl ammonium bromide (966 mg, 3.0 mmol, 0.5 equiv). The solids were dissolved in EtOAc (12 mL) and water (3 mL) and the biphasic solution was stirred vigorously at 80 °C for 8 h. The solution was cooled to room temperature and extracted with EtOAc (2 x 6 mL). The combined organic layers were washed with water (2 x 15 mL), dried over MgS04, filtered and concentrated under reduced pressure to afford an oil (1.6 g, 92%).
Step 3: Preparation of (3a,S',4)S',6)S',7aR)-2-(()S)-6-azido-l-chlorohexyl)-3a,5,5- trimethylhexahydro-4,6-methanobenzo[<i][l,3,2]dioxaborole
[0213] Into a flame-dried 100 mL round-bottom flask equipped with a magnetic stir bar and under nitrogen was added anhydrous THF (11 mL) and CH2CI2 (1 mL, 16.5 mmol, 3 equiv). The solution was cooled to between -110 °C and -100 °C in an Et20/liquid N2 Dewar. The Et20 is added to the Dewar first, followed by portion wise addition of liq. N2 until the Et20 becomes semi-solid. The temperature of the bath is monitored with a thermometer. Once the THF/CH2CI2 solution had cooled to between -110 °C and -100 °C, a solution of 2.5 M «-BuLi in hexanes (2.85 mL, 7.1 mmol, 1.3 equiv) was added via syringe over a period of 15 minutes, down the side of flask and maintaining an internal reaction temperature below -90 °C. Additional aliquots of liq. N2 were added to the Dewar to maintain the bath temperature between -110 and -100 °C. A solution of (3a,S',4)S',6)S',7aR)-2- (5-azidopentyl)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[<i][l,3,2]dioxaborole (1.6 g, 5.5 mmol, 1.0 equiv) in anhydrous THF (5 mL) was added to the «-BuLi/CH2Cl2 reaction mixture via cannula over a period of 5 minutes. After addition was complete, a solution of ZnCl2 (11 mL, 11 mmol, 2.0 equiv, 1.0 M in Et20) was added over 5 minutes via syringe and the reaction mixture was allowed to warm to room temperature overnight.
[0214] The resulting mixture was concentrated under reduced pressure. The crude reaction mixture was poured into a 250 mL separatory funnel containing a sat. aqueous H4CI solution (100 mL) and extracted with diethyl ether (3 x 50 mL). The combined organic layers were washed with brine (25 mL), dried over MgS04, filtered and concentrated under reduced pressure to afford an oil. The resulting oil was purified by column chromatography through silica gel, eluting with 40% diethyl ether in hexanes. The clear, colorless filtrate was concentrated under reduced pressure to afford a colorless oil (570 mg, 30%).
Step 4: Preparation of (R)-6-azido-l-((3a,S',4)S',6)S',7aR)-3a,5,5-trimethylhexahydro- 4,6-methanobenzo[<i] [ 1 ,3 ,2]dioxaborol-2-yl)hexan- 1 -amine hydrochloride
[0215] Into a flame-dried 100 mL round-bottom flask equipped with a magnetic stir bar and under nitrogen was added anhydrous THF (10 mL). The solution was cooled to - 78°C in a dry ice/acetone Dewar and a solution of 1.0 M LiHMDS in THF (2.0 mL, 2.0 mmol, 1.2 equiv) was added. The yellow solution was maintained at -78 °C while a solution of (3a,S',4)S',6)S',7aR)-2-(()S)-6-azido-l-chlorohexyl)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[<i][l,3,2]dioxaborole (570 mg, 1.68 mmol, 1.0 equiv) in THF (5 mL) was added via cannula over 10 minutes. The reaction mixture was stirred at -78 °C for 2 h and allowed to warm to room temperature overnight. The resulting yellow solution was concentrated under reduced pressure and the resulting oil suspended in hexanes (50 mL) and filtered through a pad of celite (4 x 4 cm) on a sintered funnel. The filter cake was further washed with hexanes (2 x 5 mL) and the resulting yellow filtrate was collected into a 250 mL round-bottom flask. To the flask containing the filtrate was added a magnetic stir bar, septa and nitrogen inlet and the solution was cooled to -78 °C in a dry ice/acetone Dewar. A solution of 4 M HC1 in dioxane (1.26 mL, 5 mmol, 3 equiv) was added and the off-white suspension was stirred at -78 °C for 2 h and allowed to warm to room temperature over 4 h. The suspension was filtered through a Hirsch funnel containing Whatman #1 filter paper under vacuum, and the white solid was washed with hexanes (2 x 5 mL). The resulting off- white solid was dried under vacuum affording the desired product (560 mg, 94%).
Step 5: Preparation of (2,S',4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N- ((R)-6-azido-l-((3a,S',4)S',6)S',7aR)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[<i][l,3,2]dioxaborol-2-yl)hexyl)-4-(piperidin-l-yl)pyrrolidine-2-carboxamide
[0216] Into a 50 mL round-bottom flask equipped with a magnetic stir bar and under nitrogen was added 2,5-dioxopyrrolidin-l-yl (2S,4R)- 1 -((R)-2-(2-naphthamido)-3 - cyclohexylpropanoyl)-4-(piperidin-l-yl)pyrrolidine-2-carboxylate (From Example 14, step 4: 620 mg, 1.6 mmol, 1.0 equiv) and (R)-6-azido-l-((3aS,4S,6S,7aR)-3a,5,5- trimethylhexahydro-4,6-methanobenzo[<i][ 1 ,3,2]dioxaborol-2-yl)hexan- 1 -amine
hydrochloride (560 mg, 1.6 mmol, 1.0 equiv) in CH2C12 (2 mL). The suspension was treated with EtN(/'Pr)2 (371 μΕ, 2.1 mmol, 1.3 equiv) and stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography through silica gel, eluting with 100:0 to 90: 10 CH2C12 Methanol as a gradient afforded the desired product (360 mg, 28%).
Step 6: Preparation of (2,S',4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N- ((R)-6-azido-l-((3a,S',4)S',6)S',7aR)-3a,5,5-trimethylhexahydro-4,6- methanobenzo[<i][l,3,2]dioxaborol-2-yl)hexyl)-4-(piperidin-l-yl)pyrrolidine-2-carboxamide
[0217] Into a 100 mL round-bottom flask equipped with a magnetic stir bar was added (2S,4R)- 1 -((R)-2-(2-naphthamido)-3 -cyclohexylpropanoyl)-N-((R)-6-azido- 1 -
((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[i/][l,3,2]dioxaborol-2- yl)hexyl)-4-(piperidin-l-yl)pyrrolidine-2-carboxamide (360 mg, 0.44 mmol, 1.0 equiv) and methanol (10 mL). The solution was degassed under a steady stream of nitrogen for 15 minutes. At this stage, palladium on carbon was added (100 mg) and nitrogen purging of the suspension was continued for 5 minutes. The nitrogen inlet was replaced with a balloon of hydrogen and the contents of the flask were stirred under a hydrogen atmosphere for 2 h. The reaction mixture was filtered through a pad of celite on a sintered funnel, washing with CH2C12 (2 x 5 mL). The clear filtrate was concentrated under reduced pressure to afford the title compound (290 mg, 85%). Step 7: Preparation of (2,S',4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N- ((R)-6-(3 -cyclohexylureido)- 1 -((3 aS,4S,6S,7aR)-3 a, 5, 5-trimethylhexahydro-4,6- methanobenzo[ii][l,3,2]dioxaborol-2-yl)hexyl)-4-(piperidin-l-yl)pyrrolidine-2-carboxamide
[0218] Into a 4 mL vial was added (2^,4R)-l-((R)-2-(2-naphthamido)-3- cyclohexylpropanoyl)-N-((R)-6-azido-l-((3a,S',4)S',6)S',7aR)-3a,5,5 rimethylhexahydro-4,6- methanobenzo[ii][l,3,2]dioxaborol-2-yl)hexyl)-4-(piperidin-l-yl)pyrrolidine-2-carboxamide (145 mg, 0.19 mmol, 1.0 equiv), cyclohexyl isocyanate (26 mg, 0.21 mmol, 1.1 equiv) and CH2CI2 (1 mL). The mixture was treated with EtN(/'Pr)2 (67 μΐ^, 0.38 mmol, 2 equiv). The reaction mixture was stirred at room temperature for 18 h. The solution was concentrated under reduced pressure and purified by column chromatography through silica gel, eluting with 100:0 to 90: 10 CH2Cl2:Methanol as a gradient to afford the desired compound (100 mg, 58%).
Step 8: Preparation of ((R)-l-((2^,4R)-l-((R)-2-(2-naphthamido)-3- cyclohexylpropanoyl)-4-(piperidin-l-yl)pyrrolidine-2-carboxamido)-6-(3- cyclohexylureido)hexyl)boronic acid formate
[0219] Into a 4 mL vial equipped with a magnetic stir bar was added (2^,4 ?)-!- ((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-((R)-6-(3-cyclohexylureido)-l- ((3a,S',4)S',6)S',7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[<i][l,3,2]dioxaborol-2- yl)hexyl)-4-(piperidin-l-yl)pyrrolidine-2-carboxamide (100 mg, 0.11 mmol, 1.0 equiv), 2- methyl propyl boronic acid (50 mg, 0.55 mmol, 5 equiv), methanol (1 mL) and hexanes (1 mL). The biphasic mixture was treated with 1 M aqueous HCl solution (440 μΐ^, 0.44 mmol, 4 equiv) and stirred vigorously at room temperature for 18 h. Stirring was stopped and the bottom methanol layer was separated. The top hexanes layer was extracted with methanol (2 x 1 mL) and the combined methanol layers were concentrated under reduced pressure. Purification by reverse-phase column chromatography through a C18 column, eluting with 90: 10 to 0: 100 H20:MeCN + 0.1% formic acid as a gradient afforded the desired compound as a formate salt (6 mg, 7%).
Figure imgf000147_0001
cyclohexylureido)hexyl)boronic acid formate
Example 64: ((lR)-l-(l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-phi dihydro- lH-pyrrole-2-carboxamido)-2-methylpropyl)boronic acid
Figure imgf000148_0001
Step 1: Preparation of l-(tert-butyl) 2-methyl 4-(((trifluoromethyl)sulfonyl)oxy)-2,5- dihydro- lH-pyrrole- 1 ,2-dicarboxylate
[0220] Into a 250 mL round bottom flask equipped with a magnetic stir bar and under nitrogen was added l-(tert-butyl) 2-methyl (S)-4-oxopyrrolidine-l,2-dicarboxylate (2.43 g, 10 mmol, 1.0 equiv) and THF (100 mL). The solution was cooled to -78 °C in a dry ice/acetone bath and a solution of LiHMDS (11 mL, 11 mmol, 1.1 equiv, 1.0 M in THF) was added over 5 minutes via syringe. The solution was stirred at -78 °C for 15 minutes and then treated with a solution of N-phenyl triflimide (3.93 g, 11 mmol, 1.1 equiv) in THF (20 mL) added via syringe over 5 minutes. The reaction mixture was stirred at -78 °C for 1 h and then allowed to warm to room temperature with stirring for 18 h overnight. The reaction mixture was concentrated under reduced pressure and redissolved in EtOAc (100 mL). The mixture was poured into a 250 mL separatory funnel and washed with 1 M aqueous HCl (2 x 50 mL), water (50 mL), brine (50 mL), dried over MgS04, filtered and concentrated under reduced pressure. Purification by column chromatography through silica gel, eluting with 100:0 to 70:30 Hexanes:EtOAc as a gradient afforded the title compound (1.47 g, 39%).
Step 2: Preparation of l-(tert-butoxycarbonyl)-4-phenyl-2,5-dihydro-lH-pyrrole-2- carboxylic acid
[0221] A suspension of l-(tert-butyl) 2-methyl 4-
(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-lH-pyrrole-l,2-dicarboxylate (398 mg, 0.93 mmol, 1.0 equiv), phenylboronic acid (226 mg, 1.86 mmol, 2.0 equiv) and solid NaHC03 (409 mg, 4.65 mmol, 5 equiv) in DME/water (1 : 1, 5 mL) was degassed with a steady stream of nitrogen for 10 minutes. At this time, PdCl2bis(diphenylphosphinoferrocene) (76 mg, 0.09 mmol, 0.1 equiv) was added and the mixture heated to 70 °C under a nitrogen atmosphere for 1 h. LCMS reveals product formation. The reaction mixture was cooled to room temperature and partitioned between water (10 mL) and EtOAc (10 mL). The EtOAc layer was removed, dried over MgS04, filtered and concentrated under reduced pressure. Purification by column chromatography through silica gel, eluting with 100:0 to 40:60 Hexanes:EtOAc as a gradient afforded the desired product (201 mg, 66%).
[0222] The methyl ester obtained above (201 mg) was dissolved in methanol (5 mL) and treated with 1 M aqueous Li OH solution (2 mL) at room temperature for 18 h overnight. The reaction mixture was acidified to pH « 2 with 1 M aqueous HCl solution and concentrated under reduced pressure. The residue was taken up in water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over MgS04, filtered and concentrated under reduced pressure. The title compound was obtained as a solid (158 mg, 59% over 2 steps).
Step 3: Preparation of fert-butyl 2-(((R)-2-methyl-l-((3aS,4l?,6l?,7aR)-3a,5,5- trimethylhexahydro-4,6-methanobenzo[<i][l,3,2]dioxaborol-2-yl)propyl)carbamoyl)-4- phenyl-2,5 -dihydro- lH-pyrrole- 1 -carboxylate
[0223] Into a 25 mL round-bottom flask equipped with a magnetic stir bar and under nitrogen was added l-(tert-butoxycarbonyl)-4-phenyl-2,5-dihydro-lH-pyrrole-2- carboxylic acid (158 mg, 0.55 mmol, 1.0 equiv), (R)-2-methyl-l-((3aS,4S,6S,7aR)-3a,5,5- trimethylhexahydro-4,6-methanobenzo[<i][l,3,2]dioxaborol-2-yl)propan-l-amine
hydrochloride (Intermediate A: 173 mg, 0.60 mmol, 1.1 equiv), HATU (220 mg, 0.58 mmol, 1.05 equiv) and CH2CI2 (5 mL). The reaction was treated with EtN(/'Pr)2 (287 μΐ^, 1.65 mmol, 3 equiv) and stirred at room temperature for 1.5 h. The mixture was partitioned between water (10 mL) and CH2C12 (10 mL) and the organic layer removed. The aqueous layer was further extracted with CH2C12 (10 mL) and the combined organic layers were dried over MgS04, filtered and concentrated under reduced pressure. Purification by column chromatography through silica gel, eluting with 100:0 to 70:30 Hexanes:EtOAc as a gradient afford the title compound (232 mg, 81%).
Step 4: Preparation of N-((R)-2-methyl-l-((3a^,4^,6^,7aR)-3a,5,5- trimethylhexahydro-4,6-methanobenzo[<i][l,3,2]dioxaborol-2-yl)propyl)-4-phenyl-2,5- dihydro- lH-pyrrole-2-carboxamide hydrochloride
[0224] A solution of fert-butyl 2-(((R)-2-methyl-l-((3a^,4^,6^,7aR)-3a,5,5- trimethylhexahydro-4,6-methanobenzo[<i][l,3,2]dioxaborol-2-yl)propyl)carbamoyl)-4- phenyl-2,5-dihydro-lH-pyrrole-l-carboxylate (232 mg, 0.44 mmol, 1.0 equiv) in CH2C12 (10 mL) was treated with 4 M HC1 in dioxane (1 mL). The reaction mixture was stirred at room temperature for 18 h overnight. The reaction was concentrated under reduced pressure and the residue used directly in the next step without further purification (216 mg).
Step 5: Preparation of l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-((R)-2- methyl- 1 -((3 aS,4S,6S, 7aR)-3 a, 5 , 5 -trimethylhexahy dro-4, 6- methanobenzo[<i][l,3,2]dioxaborol-2-yl)propyl)-4-phenyl-2,5-dihydro-lH-pyrrole-2- carboxamide
[0225] Into a 25 mL round-bottom flask equipped with a magnetic stir bar and under nitrogen was added N-((R)-2-methyl-l-((3a,S',4)S',6)S',7aR)-3a,5,5-trimethylhexahydro- 4,6-methanobenzo[<i][l,3,2]dioxaborol-2-yl)propyl)-4-phenyl-2,5-dihydro-lH-pyrrole-2- carboxamide hydrochloride (184 mg, 0.40 mmol, 1.0 equiv), (R)-2-(2-naphthamido)-3- cyclohexylpropanoic acid (Intermediate D: 133 mg, 0.40 mmol, 1.0 equiv), HATU (168 mg, 0.44 mmol, 1.1 equiv) and CH2C12 (2 mL). The mixture was treated with EtN(/Pr)2 (208 \iL, 1.2 mmol, 3 equiv) and the mixture was stirred at room temperature for 1 h. The mixture was diluted with water (10 mL) and extracted with CH2C12 (2 x 10 mL). The combined organics were dried over MgS04, filtered and concentrated under reduced pressure. Purification by reverse-phase column chromatography through a C 18 column, eluting with 90: 10 to 0: 100 H20:MeCN + 0.1% formic acid as a gradient. The fractions containing the desired product were combined and treated with saturated aqueous NaHC03 solution (200 μί) and concentrated to remove acetonitrile. The aqueous layer was extracted with EtOAc (3 x 10 mL) and the combined organic layers dried over MgS04, filtered and concentrated to afford the title compound (77 mg, 26%).
Step 6: Preparation of ((lR)-l-(l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- phenyl-2,5-dihydro-lH-pyrrole-2-carboxamido)-2-methylpropyl)boronic acid
[0226] Into a 25 mL round-bottom flask equipped with a magnetic stir bar was weighed l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-((R)-2-methyl-l- ((3a,S',4)S',6)S',7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[<i][l,3,2]dioxaborol-2- yl)propyl)-4-phenyl-2,5-dihydro-lH-pyrrole-2-carboxamide (77 mg, 0.1 1 mmol, 1.0 equiv) and isobutyl boronic acid (33 mg, 0.32 mmol, 3 equiv). The solids were suspended in methanol (1 mL) and octane (1 mL) and treated with 4 M HC1 in dioxane (105 μΐ^, 0.42 mmol, 4 equiv). The biphasic reaction mixture was vigorously stirred at room temperature for 18 h overnight. The reaction was concentrated under reduced pressure. Purification by reverse-phase column chromatography through a CI 8 column, eluting with 90: 10 to 0: 100 H20:MeCN + 0.1% formic acid as a gradient. The product containing fractions were concentrated under reduced pressure and treated with saturated aqueous NaHC03 solution (10 mL). The mixture was portioned between water (10 mL) and EtOAc (10 mL) and the organic layer removed. The aqueous layer was further extracted with EtOAc (10 mL) and the combined organic layers dried over MgS04, filtered and concentrated under reduced pressure to afford the title product (16 mg, 26%). This compound was the second eluting isomer from the reverse-phase column.
Figure imgf000152_0001
pyrrole-2-carboxamido)-2-methylpropyl)boronic acid
Example 65: Full Length HtrAl Enzyme Assay
[0227] Serial dilutions (1/3) from 1000 μΜ down to 0.051 μΜ of test compounds were prepared in dimethyl sulfoxide (DMSO). Then 2 μΙ_, of DMSO from each dilution were added to 100 iL of 4 nM full-length human His-HtrAl in assay buffer (50 mM Tris, pH 7.5, 200 mM NaCl and 0.25% CHAPS) in white non-binding 96-well plates. The assay solutions were mixed for 5 seconds on a shaker plate and incubated for 10 minutes at room temperature. Mca-H20PT (Mca-Ile-Arg-Arg-Val-Ser-Tyr-Ser-Phe-Lys(Dnp)-Lys-OH trifluoroacetate salt) (5 μΜ) in 100 μΙ_, of assay buffer was added to the assay solutions. The reaction mixture was shaken for 5 seconds on a shaker plate and cleavage of Mca-H20PT was monitored by spectrofluorometry for 10 minutes (Εχλ = 330 nm; Ειηλ = 420 nm). Percent inhibition was calculated by fitting values to a standard mathematical model for dose response curves. Example HtrAl IC50 Example HtrAl IC50
(μΜ) (μΜ)
1 0.004 28 0.014
8 0.016 29 0.028
9 0.005 51 0.66
14 0.007 53 0.049
17 0.060 54 0.057
18 0.002 63 0.049
19 0.011 64 0.010
21 0.005

Claims

WHAT IS CLAIMED IS:
1. A compound of Formula I
Figure imgf000154_0001
I
or a pharmaceutically acceptable salt, solvate, solvate of the salt or prodrug thereof wherein: each n is independently selected from 0, 1, or 2;
X is selected from -C(O)-, -S02- and -CHCH3, wherein 1, 2 or 3 of the CH3 hydrogens may optionally be replaced with a halogen;
R1 is selected from the group consisting of:
(a) phenyl or naphthyl,
(b) 5- or 6-membered monocyclic heteroaryl ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(c) 8-, 9-, or 10-membered fused bicyclic heteroaryl ring, said ring having 1, 2, 3 or 4, heteroatoms independently selected from N, S and O,
(d) 5- or 6-membered monocyclic heterocycloalkyl ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(e) 8-, 9-, or 10-membered fused bicyclic heterocycloalkyl ring, said ring having 1, 2, 3 or 4, heteroatoms independently selected from N, S and O,
wherein R1 choices (a), (b), (c), (d) and (e) are optionally mono- or di- substituted with substituents independently selected from halogen, -CH3, -CF3, -OCH3 and -OCF3;
R2 is selected from the group consisting of:
(a) -(CH2)n-C3-8cycloalkyl,
(b) -(CH2)n-phenyl, (c) -(CH2)n-heteroaryl, wherein the heteroaryl is a 5- or 6-membered monocyclic ring, having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
wherein R2 choices (a), (b) and (c) are optionally mono- or di-substituted with substituents independently selected from halogen, -CH3, -CF3, -OCH3 and -OCF3;
R3a and R3b are each independently selected from the group consisting of:
(a) hydrogen,
(b) hydroxyl,
(c) halogen,
(d) -S(0)n-Ci-6alkyl, optionally substituted with phenyl,
(e) -N(H)-C(=0)-Ci-6alkyl, optionally substituted with phenyl, or heteroaryl, wherein the heteroaryl is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(f) -N(H)-C(=0)-N(H)-Ci-6alkyl, optionally substituted with phenyl, or heteroaryl, wherein the heteroaryl is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(g) -N(H)-S02-aryl,
(h) -N(H)-S02-heteroaiyl, wherein the heteroaryl is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(i) -N(H)-Ci-6alkyl,
(j) -N(Ci-6alkyl)(Ci-6alkyl), optionally substituted with phenyl, or heteroaryl, wherein the heteroaryl is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(k) -N(Ci.6alkyl)(Ci-6alkenyl),
(1) -N(Ci-6alkyl)(Ci-6alkynyl),
(m) -N(H)-C3-6cycloalkyl,
(n) -N(H)-heterocycle, wherein the heterocycle is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(o) -S02-N(H)-aryl, (p) -S02-N(H)-heteroaiyl,
(q) 5- or 6-membered saturated monocyclic heterocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(r) -phenyl, and
(s) -O-phenyl,
wherein the alkyl of R3a and R3b choices (d), (e), (f), (i), (j), (k) and (1) and the cycloalkyl of R3a and R3b choice (m), are optionally mono- or di-substituted with substituents independently selected from halogen, hydroxyl, -CH3, -CF3, -OCH3 and -OCF3, wherein the aryl of R3a and R3b choices (d), (e), (f), (g), (j), (o), (r) and (s), and the heteroaryl of R3a and R3b choices (e), (f), (h), (j) and (p), and the heterocycle of R3a and R3b choice (n) and (q) are optionally mono- or di-substituted with substituents independently selected from halogen, hydroxyl, -CH3, -CF3, -OCH3 and -OCF3, or
R3a and R3b taken together with the atom to which they are attached form a carbonyl, with the proviso that at least one of R3a and R3b is other than hydrogen;
R4a and R4b are each independently hydrogen or
Figure imgf000156_0001
or
R3a and R4a or R3a and R4b or R3b and R4a or R3b and R4b are joined together to form a bond or joined together so that together with the atoms to which they are attached there is formed a ring selected from phenyl, Cs-ecycloalkyl, optionally mono- or di-substituted with substituents independently selected from hydroxyl, -CH3, -CF3, -OCH3 and -OCF3;
R5 is selected from the group consisting of:
(a) -Ci-6alkyl, and
(b) -Ci-6alkyl-R6;
R6 is selected from the group consisting of:
(a) - H2, optionally substituted with Ci-3alkyl, -S02-CF3, phenyl or Ci. 3alkyl-phenyl,
(b) - H-S02-Ci-3alkyl, - H-S02-phenyl, - H-S02-Ci-3alkyl-phenyl, - H-S02-heterocycle or - H-S02-Ci-3alkyl-heterocycle, wherein the heterocycle is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(c) -S(0)n-aryl,
(d) -phenyl, (e) 5- or 6-membered monocyclic heteroaryl ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O, optionally substituted with Ci. 3alkyl, phenyl or Ci-3alkyl-phenyl,
(f) 5- or 6-membered monocyclic heterocycloalkyl ring, said ring having 1, 2,
3 or 4 heteroatoms independently selected from N, S and O, optionally substituted with Ci-3alkyl, phenyl or Ci-3alkyl-phenyl,
Figure imgf000157_0001
phenyl, -NH-C(=0)-heterocycle or -NH-C(=0)-Ci-3alkyl-heterocycle, wherein the heterocycle is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(h) -N(H)-C(=0)- H2, optionally substituted with Ci-3alkyl, phenyl, naphthyl, Ci-3alkyl-phenyl, Ci-3alkyl-naphthyl, heterocycle, C3-6 -cycloalkyl or Ci. 3alkyl-heterocycle, wherein the heterocycle is a 5- or 6-membered monocyclic ring, said rin having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(j) -N(H)-C(= H)- H, optionally substituted with -Ci-4alkyl, -C(=0)-0- Ci-4alkyl, or -C(=0)-Ci-4alkyl, and
(k) - H-S02- H2 optionally substituted with Ci-3alkyl, phenyl, naphthyl, Ci. 3alkyl-phenyl, Ci-3alkyl-naphthyl, heterocycle, C3-6 -cycloalkyl or Ci-3alkyl- heterocycle, wherein the heterocycle is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O, wherein the alkyl of R6 choices (a), (b), (e), (f), (g), (h), (i), (k) and (1), and the aryl of R6 choices (a), (b), (c), (d), (e), (f), (g), (h), (k) and (1), and the heteroaryl of R6 choice (e) and the heterocycle of R6 choices (b), ,(g),(h) and (1), and the heterocycloalkyl of R6 choice (f) are each optionally mono or di- substituted with substituents independently selected from halogen, hydroxyl, -CH3, -CF3, -OCH3 and -OCF3.
2. A compound according to Claim 1, wherein:
X is selected from -C(O)- and -CHCF3.
3. A compound according to Claim 2, wherein:
X is -C(O)- .
4. A compound according to any of Claims 1 to 3, wherein R1 is selected from the group consisting of:
(a) phenyl or naphthyl,
(b) 5- or 6-membered monocyclic heteroaryl ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O, and
(c) 8-, 9-, or 10-membered fused bicyclic heteroaryl ring, said ring having 1, 2, 3 or 4, heteroatoms independently selected from N, S and O,
wherein R1 choices (a), (b) and (c) are optionally mono- or di-substituted with substituents independently selected from halogen, -CH3, -CF3, -OCH3 and -OCF3.
5. A compound according to Claim 4, wherein:
R1 is naphthyl.
6. A compound according to any of Claims 1 to 5, wherein:
R2 is -(CH2)n-C3-8cycloalkyl,
wherein the C3-8cycloalkyl is optionally mono- or di-substituted with substituents independently selected from halogen, -CH3, -CF3, -OCH3 and -OCF3.
7. A compound according to Claim 6 wherein:
R2 is -(CH2)-cyclohexyl.
8. A compound according to any of Claims 1 to 7 wherein:
R3a is hydrogen, and
R3b is selected from the group consisting of:
(a) phenyl,
(b) -O-phenyl,
(c) hydroxyl,
(d) chloro, (e) -S-C(CH3)3,
(f) -S-(CH2)2-phenyl,
(g) piperidinyl,
(h) morpholinyl,
(i) pyrrolidinyl,
G) -N(CH3)-CH2-phenyl,
(k) -N(CH3)-CH2-ethynyl,
(1) -N(CH3)-(CH2)2-OH,
(m) - H-C(=0)-(CH2)2-phenyl,
(n) - H-C(=0)-CH2-pyridinyl,
(o) - H-C(=0)-(CH2)3-phenyl-OCH3,
(p) - H-C(=0)- H-(CH2)3-phenyl, and
(q) - H-S(0)2-pyrazolyl-CH3, or
R3a and R3b taken together with the atom to which they are attached form a carbonyl, or
R3b and R4a or R3b and R4b are joined together so that together with the atoms to which they are attached there is formed a ring selected from phenyl, Cs-ecycloalkyl, optionally mono- or di-substituted with substituents independently selected from hydroxyl, - CH3, -CF3, -OCH3 and -OCF3.
9. A compound according to Claim 8 wherein:
R3a is hydrogen, and
R3b is selected from the group consisting of:
(a) phenyl,
(b) -S-C(CH3)3,
(c) piperidinyl,
(d) morpholinyl,
(e) pyrrolidinyl, and
(f) - H-S(0)2-pyrazolyl-CH3.
10. A compound according to Claim 9, wherein: R is hydrogen, and
R3b is selected from the group consisting of:
(a) piperidinyl,
(b) morpholinyl, and
(c) -NH-C(=0)-CH2-pyridinyl.
11. A compound according to any of Claims 1 to 10, wherein:
R4a and R4b are each hydrogen, or
R3b and R4a or R3b and R4b are joined together so that together with the atoms to which they are attached there is formed a ring selected from phenyl, Cs-ecycloalkyl, optionally mono- or di-substituted with substituents independently selected from hydroxyl, - CH3, -CF3, -OCH3 and -OCF3.
12. A compound according to any of Claims 1 to 11, wherein:
R4a and R4b are each hydrogen.
13. A compound according to any of Claims 1 to 12, wherein:
t is selected from 3, 4 and 5;
R5 is selected from the group consisting of:
(a) -CH2(CH3)2,
(b) -CH2-phenyl,
(c) -(CH2)4-S-phenyl,
(d) -(CH2)t-R6
(e) -(CH2)t- H-S02-phenyl,
(f) -(CH2)t- H-S02-CF3,
(g) -(CH2)t- H-S02-CH3,
(h) -(CH2)t- H-S02-piperidinyl,
(i) -(CH2)t-triazolyl-phenyl,
G) -(CH2)t- H-C(=0)-CH3,
(k) -(CH2)t- H-C(=0)-phenyl,
(1) -(CH2)t- H-C(=0)-CH2-phenyl, (m) -(CH2)t- H-C(= H)- H-C(=0)-0-C(CH3)3,
(n) -(CH2)t- H-C(=0)- H-cyclohexyl,
(o) -(CH2)t- H-C(=0)- H-phenyl, optionally substituted with halo or methoxy,
(p) -(CH2)t- H-C(=0)- H-CH2-phenyl,
(q) -(CH2)t- H-C(=0)- H-(CH2)2-phenyl,
(r) -(CH2)t- H-C(=0)- H-(CH2)3-phenyl,
(s) -(CH2)t- H-C(=0)- H-phenyl,
(t) -(CH2)t- H-C(=0)- H-CH2CH3,
(u) -(CH2)t- H-C(=0)- H-naphthyl, and
(v) -(CH2)t- H-C(=0)-NH-pyridinyl; and
R6 is
Figure imgf000161_0001
14. A compound according to Claim 13, wherein:
R5 is selected from the group consisting of:
(a) -CH2(CH3)2,
(b) -CH2-phenyl,
(c) -(CH2)4- H-S02-phenyl,
(d) -(CH2)4- H-C(=0)-CH3,
(e) -(CH2)3- H-C(=0)-phenyl,
(f) -(CH2)4- H-C(=0)-phenyl,
(g) -(CH2)4- H-C(=0)-CH2-phenyl,
(h) -(CH2)3- H-C(=0)- H-cyclohexyl,
(i) -(CH2)4- H-C(=0)- H-cyclohexyl,
G) -(CH2)5- H-C(=0)- H-cyclohexyl,
(k) -(CH2)4- H-C(=0)- H-phenyl, optionally substituted with halo or methoxy,
(1) -(CH2)3- H-C(=0)-NH-CH2-phenyl, (m) -(CH2)4- H-C(=0)- H-CH2-phenyl,
(n) -(CH2)3- H-C(=0)- H-phenyl,
(0) -(CH2)3- H-C(=0)-NH-CH2CH3,
(p) -(CH2)4- H-C(=0)-NH-CH2CH3, and
(q) -(CH2)4- H-C(=0)- H-pyridinyl.
15. A compound according to Claim 14, wherein:
R5 is selected from the group consisting of:
(a) -CH2(CH3)2,
(b) -(CH2)3- H-C(=0)- H-cyclohexyl,
(c) -(CH2)4- H-C(=0)- H-cyclohexyl,
(d) -(CH2)5- H-C(=0)- H-cyclohexyl,
(e) -(CH2)4- H-C(=0)- H-phenyl, optionally substituted with halo or methoxy,
(f) -(CH2)3- H-C(=0)- H-CH2-phenyl,
(g) -(CH2)4- H-C(=0)-NH-CH2-phenyl,
(h) -(CH2)4- H-C(=0)-NH-CH2CH3, and
(1) -(CH2)4- H-C(=0)- H-pyridinyl.
16. A compound according to Claim 1 of Formula la
Figure imgf000162_0001
la
or a pharmaceutically acceptable salt, solvate, solvate of the salt or prodrug thereof, wherein:
X is selected from -C(O)- and -CHCF3-; R ais hydrogen;
R3b is selected from the group consisting of:
(a) phenyl,
(b) -O-phenyl,
(c) hydroxyl,
(d) chloro,
(e) -S-C(CH3)3,
(f) -S-(CH2)2-phenyl,
(g) piperidinyl,
(h) morpholinyl,
(i) pyrrolidinyl,
G) -N(CH3)-CH2-phenyl,
(k) -N(CH3)-CH2-ethynyl,
(1) -N(CH3)-(CH2)2-OH,
(m) - H-C(=0)-(CH2)2-phenyl,
(n) - H-C(=0)-CH2-pyridinyl,
(o) - H-C(=0)-(CH2)3-phenyl-OCH3,
(p) - H-C(=0)- H-(CH2)3-phenyl, and
(q) - H-S(0)2-pyrazolyl-CH3, or
R3a and R3b taken together with the atom to which they are attached form a carbonyl, R4 is hydrogen or
Figure imgf000163_0001
or
R3b and R4 are joined to form a bond or joined so that together with the atoms to which they are attached there is formed a ring selected from phenyl and cyclopentyl;
R5 is selected from the group consisting of:
(a) -CH2(CH3)2,
(b) -CH2-phenyl,
(c) -(CH2)4-S-phenyl,
(d) -(CH2)4-R6,
(e) -(CH2)3- H-S02-phenyl,
(f) -(CH2)4- H-S02-phenyl,
(g) -(CH2)4- H-S02-CF3, (h) -(CH2)4- H-S02-CH3,
(i) -(CH2)4- H-S02-piperidinyl,
(j) -(CH2)4-triazolyl-phenyl,
(k) -(CH2)4- H-C(=0)-CH3,
(1) -(CH2)3- H-C(=0)-phenyl,
(m) -(CH2)4- H-C(=0)-phenyl,
(n) -(CH2)4- H-C(=0)-CH2-phenyl,
(o) -(CH2)4- H-C(= H)- H-C(=0)-0-C(CH3)3,
(p) -(CH2)3- H-C(=0)- H-cyclohexyl,
(q) -(CH2)4- H-C(=0)- H-cyclohexyl,
(r) -(CH2)5- H-C(=0)- H-cyclohexyl,
(s) -(CH2)4- H-C(=0)- H-phenyl, optionally substituted with halo or methoxy,
(t) -(CH2)3- H-C(=0)-NH-CH2-phenyl,
(u) -(CH2)3- H-C(=0)- H-(CH3)2-phenyl,
(v) -(CH2)3- H-C(=0)- H-(CH2)3-phenyl,
(w) -(CH2)4- H-C(=0)-NH-CH2-phenyl,
(x) -(CH2)4- H-C(=0)- H-(CH2)2-phenyl,
(y) -(CH2)4- H-C(=0)- H-(CH2)3-phenyl,
(z) -(CH2)3- H-C(=0)- H-phenyl,
(aa) -(CH2)3- H-C(=0)- H-CH2CH3,
(bb) -(CH2)4- H-C(=0)-NH-CH2CH3,
(cc) -(CH2)3- H-C(=0)- H-naphthyl,
(dd) -(CH2)4- H-C(=0)- H-naphthyl, and
(ee) -(CH2)4- H-C(=0)-NH-pyridinyl;
and R6 is
Figure imgf000164_0001
A compound according to Claim 16, of Formula lb
Figure imgf000165_0001
lb
or a pharmaceutically acceptable salt, solvate, solvate of the salt or prodrug thereof, wherein:
R3b is selected from the group consisting of:
(a) piperidinyl,
(b) morpholinyl, and
(c) -NH-C(=0)-CH2-pyridinyl;
R5 is selected from the group consisting of:
(a) -CH2(CH3)2,
(b) -(CH2)3- H-C(=0)- H-cyclohexyl,
(c) -(CH2)4- H-C(=0)- H-cyclohexyl,
(d) -(CH2)5- H-C(=0)- H-cyclohexyl,
(e) -(CH2)4- H-C(=0)- H-phenyl, optionally substituted with halo or methoxy,
(f) -(CH2)3- H-C(=0)- H-CH2-phenyl,
(g) -(CH2)4- H-C(=0)-NH-CH2-phenyl,
(h) -(CH2)4- H-C(=0)-NH-CH2CH3, and
(i) -(CH2)4- H-C(=0)- H-pyridinyl.
18. A compound according to Claim 1 selected from the group consisting of:
( 1 ) ((R)- 1 -((2S,4R)- 1 -((R)-2-(2-naphthamido)-3 -cy clohexylpropanoyl)-4- phenylpyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid,
(2) (( 1R)- 1 -(2-((R)-2-(2-naphthamido)-3 -cyclohexylpropanoyl)isoindoline- 1 - carboxamido)-2-methylpropyl)boronic acid, (3) ((R)-l-((2S,4S)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- phenylpyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid,
(4) (( 1 R)- 1 - ((4 S) - 1 -((R)-2-(2-naphthamido)-3 -cy clohexylpropanoyl)-4- phenoxypyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid,
(5) ((R)- 1 -((2S,4S)- 1 -((R)-2-(2-naphthamido)-3 -cyclohexylpropanoyl)-4- hydroxypyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid,
(6) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- hydroxypyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid,
(7) ((R)-l-((S)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-oxopyrrolidine- 2-carboxamido)-2-methylpropyl)boronic acid,
(8) ((R)-l-((l^,3aR,6a5)-2-((R)-2-(2-naphthamido)-3- cyclohexylpropanoyl)octahydrocyclopenta[c]pyrrole-l-carboxamido)-2- methylpropyl)boronic acid,
(9) ((R)- 1 -((2S,4R)- 1 -((R)-2-(2-naphthamido)-3 -cyclohexylpropanoyl)-4-(tert- butylthio)pyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid,
(10) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- mo holinopyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid,
(1 1) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (benzyl(methyl)amino)pyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid,
(12) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4- (methyl(prop-2-yn-l-yl)amino)pyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid,
(13) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-((2- hydroxyethyl)(methyl)amino)pyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid,
( 14) ((R)- 1 -((2^,4R)- 1 -((R)-2-(2-naphthamido)-3 -cy clohexylpropanoyl)-4-(piperidin- 1 -yl)pyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid,
(15) ((R)- 1 -((3 'R, 5 ' S)- 1 ' -((R)-2-(2-naphthamido)-3 -cyclohexylpropanoyl)-[ 1 ,3 ' - bipyrrolidine]-5 ' -carboxamido)-2-methylpropyl)boronic acid,
( 16) ((R)- 1 -((2S,4S)- 1 -((R)-2-(2-naphthamido)-3 -cy clohexylpropanoyl)-4-(piperidin- 1 -yl)pyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid,
( 17) ((R)- 1 -((2S,4S)- 1 -((R)-2-(2-naphthamido)-3 -cy clohexylpropanoyl)-4- chloropyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid, ( 18) ((R)- 1 -((2S,4R)- 1 -((R)-2-(2-naphthamido)-3 -cyclohexylpropanoyl)-4- (phenethylthio)pyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid,
( 19) ((R)- 1 -((2S,4S)- 1 -((R)-2-(2-naphthamido)-3 -cy clohexylpropanoyl)-4-(3 - phenylpropanamido)pyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid,
(20) ((R)- 1 -((2S,4S)- 1 -((R)-2-(2-naphthamido)-3 -cyclohexylpropanoyl)-4-(( 1 - methyl-lH-pyrazole)-4-sulfonamido)pyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid,
(21 ) ((R)- 1 -((2S,4R)- 1 -((R)-2-(2-naphthamido)-3 -cyclohexylpropanoyl)-4-(2- (pyridin-3-yl)acetamido)pyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid,
(22) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(2- (pyridin-2-yl)acetamido)pyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid,
(23) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(4-(4- methoxyphenyl)butanamido)pyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid,
(24) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(3-(3- phenylpropyl)ureido)pyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid,
(25) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(2- (pyridin-4-yl)acetamido)pyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid,
(26) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(3- phenylpropanamido)pyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid,
(27) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-((l- methyl-lH-pyrazole)-4-sulfonamido)pyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid,
(28) ((R)- 1 -((2S,4R)- 1 -((R)-3 -cyclohexyl-2-(((R)-2,2,2-trifluoro- 1 -(naphthalen-2- yl)ethyl)amino)propanoyl)-4-phenylpyrrolidine-2-carboxamido)-2-methylpropyl)boronic acid,
(29) ((R)- 1 -((2^,4R)- 1 -((R)-2-(2-naphthamido)-3 -cyclohexylpropanoyl)-4-(piperidin- l-yl)pyrrolidine-2-carboxamido)-5-(3-cyclohexylureido)pentyl)boronic acid hydrochloride,
(30) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(piperidin- l-yl)pyrrolidine-2-carboxamido)-5-(3-ethylureido)pentyl)boronic acid,
(31) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(piperidin- l-yl)pyrrolidine-2-carboxamido)-5-(3-phenylureido)pentyl)boronic acid, (32) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(piperidin- l-yl)pyrrolidine-2-carboxamido)-5-(3-benzylureido)pentyl)boronic acid,
(33) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(piperidin- l-yl)pyirolidine-2-carboxamido)-5-((trifluoromethyl)sulfonamido)pentyl)boronic acid,
(34) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(piperidin- l-yl)pyrrolidine-2-carboxamido)-5-acetamidopentyl)boronic acid,
(35) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(piperidin- l-yl)pyrrolidine-2-carboxamido)-5-benzamidopentyl)boronic acid,
(36) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(piperidin- l-yl)pyrrolidine-2-carboxamido)-5-(methylsulfonamido)pentyl)boronic acid,
(37) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(piperidin- l-yl)pyrrolidine-2-carboxamido)-5-(phenylsulfonamido)pentyl)boronic acid,
(38) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(piperidin- l-yl)pyrrolidine-2-carboxamido)-5-(3-phenethylureido)pentyl)boronic acid,
(39) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(piperidin- l-yl)pyrrolidine-2-carboxamido)-5-(3-(3-phenylpropyl)ureido)pentyl)boronic acid,
(40) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(piperidin- l-yl)pyrrolidine-2-carboxamido)-5-(3-(naphthalen-l-yl)ureido)pentyl)boronic acid,
(41) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(piperidin- 1 -yl)pyrrolidin-2-yl)-9-imino- 13,13 -dimethyl- 1,11 -dioxo- 12-oxa-2,8, 10-triazatetradecan-3 - yl)boronic acid,
(42) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(piperidin- l-yl)pyrrolidine-2-carboxamido)-5-(2-phenylacetamido)pentyl)boronic acid,
(43) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(piperidin- l-yl)pyrrolidine-2-carboxamido)-5-(piperidine-l-sulfonamido)pentyl)boronic acid,
(44) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(piperidin- l-yl)pyrrolidine-2-carboxamido)-5-(3-(pyridin-4-yl)ureido)pentyl)boronic acid,
(45) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(piperidin- l-yl)pyrrolidine-2-carboxamido)-5-(3-(2-chlorophenyl)ureido)pentyl)boronic acid,
(46) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(piperidin- l-yl)pyrrolidine-2-carboxamido)-5-(3-(3-chlorophenyl)ureido)pentyl)boronic acid, (47) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(piperidin- l-yl)pyrrolidine-2-carboxamido)-5-(3-(4-chlorophenyl)ureido)pentyl)boronic acid,
(48) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(piperidin- l-yl)pyrrolidine-2-carboxamido)-5-(3-(2-methoxyphenyl)ureido)pentyl)boronic acid,
(49) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(piperidin- l-yl)pyrrolidine-2-carboxamido)-5-(3-(3-methoxyphenyl)ureido)pentyl)boronic acid,
(50) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(piperidin- l-yl)pyrrolidine-2-carboxamido)-5-(3-(4-methoxyphenyl)ureido)pentyl)boronic acid,
(51) ((R)-l-((25',4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(piperidin- l-yl)pyrrolidine-2-carboxamido)-5-(2-thia-6-azaspiro[3.3]heptan-6-yl)pentyl)boronic acid hydrochloride,
(52) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(piperidin- l-yl)pyrrolidine-2-carboxamido)-5-(phenylthio)pentyl)boronic acid hydrochloride,
(53) ((R)-l-((25',4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(piperidin- l-yl)pyrrolidine-2-carboxamido)-5-(4-phenyl-lH-l,2,3-triazol-l-yl)pentyl)boronic acid,
(54) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(piperidin- l-yl)pyrrolidine-2-carboxamido)-4-(3-cyclohexylureido)butyl)boronic acid,
(55) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(piperidin- l-yl)pyrrolidine-2-carboxamido)-4-(3-ethylureido)butyl)boronic acid,
(56) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(piperidin- l-yl)pyrrolidine-2-carboxamido)-4-(3-phenylureido)butyl)boronic acid,
(57) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(piperidin- l-yl)pyrrolidine-2-carboxamido)-4-(3-benzylureido)butyl)boronic acid,
(58) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(piperidin- 1 -yl)pyrrolidine-2-carboxamido)-4-benzamidobutyl)boronic acid,
(59) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(piperidin- l-yl)pyrrolidine-2-carboxamido)-4-(phenylsulfonamido)butyl)boronic acid,
(60) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(piperidin- l-yl)pyrrolidine-2-carboxamido)-4-(3-phenethylureido)butyl)boronic acid,
(61) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(piperidin- l-yl)pyrrolidine-2-carboxamido)-4-(3-(3-phenylpropyl)ureido)butyl)boronic acid, (62) ((R)-l-((2S,4R)-l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(piperidin- l-yl)pyrrolidine-2-carboxamido)-4-(3-(naphthalen-l-yl)ureido)butyl)boronic acid,
(63) ((R)- 1 -((2S,4R)- 1 -((R)-2-(2-naphthamido)-3 -cyclohexylpropanoyl)-4-(piperidin- l-yl)pyrrolidine-2-carboxamido)-6-(3-cyclohexylureido)hexyl)boronic acid formate, and
(64) ((lR)-l-(l-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-phenyl-2,5- dihydro- lH-pyrrole-2-carboxamido)-2-methylpropyl)boronic acid,
or a pharaceutically acceptable salt, solvate, solvate of the salt or prodrug thereof.
19. A pharmaceutical composition comprising a compound according to any one of Claims 1-18, or a pharmaceutically acceptable salt, solvate, solvate of the salt or prodrug thereof, and a pharmaceutically acceptable carrier.
20. A method of preventing, or treating a disease of the eye selected from dry- AMD, Wet-AMD, and geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, and degeneration of retinal or photoreceptor cells, comprising: administration of a therapeutically effective amount of compound according to Claim 1-18 or a pharmaceutically acceptable salt, solvate, solvate of the salt or prodrug thereof.
21. The method of preventing a disease of the eye, according to Claim 20 wherein the method of prevention is selected from delaying the onset of disease and reducing the risk of developing a disease of the eye, wherein the disease of the eye is selected from dry-AMD, Wet-AMD, and geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, and degeneration of retinal or photoreceptor cells.
22. The method treating a disease of the eye according to Claim 20 wherein the method is selected from controlling, alleviating, and slowing the progression of, wherein the disease is selected from dry-AMD, Wet-AMD, and geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, and degeneration of retinal or photoreceptor cells.
23. The method according to any of Claims 20 to 22 wherein the disease is geographic atrophy.
24. A method of inhibiting HtrAl protease activity in an eye comprising administration of a therapeutically effective amount of compound according to Claims 1-18 or a pharmaceutically acceptable salt, solvate, solvate of the salt or prodrug thereof.
25. A method of preventing, or treating a disease of the eye selected from dry- AMD, Wet-AMD, and geographic atrophy, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, and degeneration of retinal or photoreceptor cells, comprising: administration of a therapeutically effective amount of a compound of Formula I:
Figure imgf000171_0001
I
or a pharmaceutically acceptable salt, solvate, solvate of the salt or prodrug thereof wherein: each n is independently selected from 0, 1, or 2;
X is selected from -C(O)-, -S02- and -CHCH3, wherein 1, 2 or 3 of the CH3 hydrogens may optionally be replaced with a halogen;
R1 is selected from the group consisting of:
(a) phenyl or naphthyl,
(b) 5- or 6-membered monocyclic heteroaryl ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(c) 8-, 9-, or 10-membered fused bicyclic heteroaryl ring, said ring having 1, 2, 3 or 4, heteroatoms independently selected from N, S and O, (d) 5- or 6-membered monocyclic heterocycloalkyl ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(e) 8-, 9-, or 10-membered fused bicyclic heterocycloalkyl ring, said ring having 1, 2, 3 or 4, heteroatoms independently selected from N, S and O,
wherein R1 choices (a), (b), (c), (d) and (e) are optionally mono- or di- substituted with substituents independently selected from halogen, -CH3, -CF3, -OCH3 and -OCF3;
R2 is selected from the group consisting of:
(a) -(CH2)n-C3-8cycloalkyl,
(b) -(CH2)n-phenyl,
(c) -(CH2)n-heteroaryl, wherein the heteroaryl is a 5- or 6-membered monocyclic ring, having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
wherein R2 choices (a), (b) and (c) are optionally mono- or di-substituted with substituents independently selected from halogen, -CH3, -CF3, -OCH3 and -OCF3;
R3a and R3b are each independently selected from the group consisting of:
(a) hydrogen,
(b) hydroxyl,
(c) halogen,
(d) -S(0)n-Ci-6alkyl, optionally substituted with phenyl,
(e) -N(H)-C(=0)-Ci-6alkyl, optionally substituted with phenyl, or heteroaryl, wherein the heteroaryl is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(f) -N(H)-C(=0)-N(H)-Ci-6alkyl, optionally substituted with phenyl, or heteroaryl, wherein the heteroaryl is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(g) -N(H)-S02-aryl,
(h) -N(H)-S02-heteroaiyl, wherein the heteroaryl is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(i) -N(H)-Ci-6alkyl, (j) -N(Ci-6alkyl)(Ci.6alkyl), optionally substituted with phenyl, or heteroaryl, wherein the heteroaryl is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(k) -N(Ci.6alkyl)(Ci-6alkenyl),
(1) -N(Ci-6alkyl)(Ci-6alkynyl),
(m) -N(H)-C3-6cycloalkyl,
(n) -N(H)-heterocycle, wherein the heterocycle is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(o) -S02-N(H)-aryl,
(p) -S02-N(H)-heteroaryl,
(q) 5- or 6-membered saturated monocyclic heterocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(r) -phenyl, and
(s) -O-phenyl,
wherein the alkyl of R3a and R3b choices (d), (e), (f), (i), (j), (k) and (1) and the cycloalkyl of R3a and R3b choice (m), are optionally mono- or di-substituted with substituents independently selected from halogen, hydroxyl, -CH3, -CF3, -OCH3 and -OCF3, wherein the aryl of R3a and R3b choices (d), (e), (f), (g), (j), (o), (r) and (s), and the heteroaryl of R3a and R3b choices (e), (f), (h), (j) and (p), and the heterocycle of R3a and R3b choice (n) and (q) are optionally mono- or di-substituted with substituents independently selected from halogen, hydroxyl, -CH3, -CF3, -OCH3 and -OCF3, or
R3a and R3b taken together with the atom to which they are attached form a carbonyl, or
R4a and R4b are each independently hydrogen or
Figure imgf000173_0001
or
R3a and R4a or R3a and R4b or R3b and R4a or R3b and R4b are joined together to form a bond or joined together so that together with the atoms to which they are attached there is formed a ring selected from phenyl, Cs-ecycloalkyl, optionally mono- or di-substituted with substituents independently selected from hydroxyl, -CH3, -CF3, -OCH3 and -OCF3;
R5 is selected from the group consisting of:
(a) -Ci-6alkyl, and (b) -Ci-6alkyl-R6;
R6 is selected from the group consisting of:
(a) - H2, optionally substituted with Ci-3alkyl, -SO2-CF3, phenyl or Ci. 3alkyl-phenyl,
(b) - H-S02-Ci-3alkyl, - H-S02-phenyl, - H-S02-Ci-3alkyl-phenyl, - H-S02-heterocycle or - H-S02-Ci-3alkyl-heterocycle, wherein the heterocycle is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(c) -S(0)n-aryl,
(d) -phenyl,
(e) 5- or 6-membered monocyclic heteroaryl ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O, optionally substituted with Ci. 3alkyl, phenyl or Ci-3alkyl-phenyl,
(f) 5- or 6-membered monocyclic heterocycloalkyl ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O, optionally substituted with Ci-3 alkyl, phenyl or C1-3 alkyl-phenyl,
Figure imgf000174_0001
phenyl, -NH-C(=0)-heterocycle or -NH-C(=0)-Ci-3alkyl-heterocycle, wherein the heterocycle is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
(h) -N(H)-C(=0)- H2, optionally substituted with Ci-3alkyl, phenyl, naphthyl, Ci-3alkyl-phenyl, Ci-3alkyl-naphthyl, heterocycle, C3-6 -cycloalkyl or Ci. 3alkyl-heterocycle, wherein the heterocycle is a 5- or 6-membered monocyclic ring, said rin having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O,
Figure imgf000174_0002
(j) -N(H)-C(= H)- H, optionally substituted with -Ci-4alkyl, -C(=0)-0- Ci-4alkyl, or -C(=0)-Ci-4alkyl, and
(k) - H-S02- H2 optionally substituted with Ci-3alkyl, phenyl, naphthyl, Ci. 3alkyl-phenyl, Ci-3alkyl-naphthyl, heterocycle, C3-6 -cycloalkyl or Ci-3alkyl- heterocycle, wherein the heterocycle is a 5- or 6-membered monocyclic ring, said ring having 1, 2, 3 or 4 heteroatoms independently selected from N, S and O, wherein the alkyl of R6 choices (a), (b), (e), (f), (g), (h), (i), (k) and (1), and the aryl of R6 choices (a), (b), (c), (d), (e), (f), (g), (h), (k) and (1), and the heteroaryl of R6 choice (e) and the heterocycle of R6 choices (b), (g), (h) and (1), and the heterocycloalkyl of R6 choice (f) are each optionally mono or di- substituted with substituents independently selected from halogen, hydroxyl, -CH3, -CF3, -OCH3 and -OCF3.
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