WO2010039789A1 - Spiro-imidazolone derivatives as glucagon receptor antagonists - Google Patents

Spiro-imidazolone derivatives as glucagon receptor antagonists Download PDF

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WO2010039789A1
WO2010039789A1 PCT/US2009/058963 US2009058963W WO2010039789A1 WO 2010039789 A1 WO2010039789 A1 WO 2010039789A1 US 2009058963 W US2009058963 W US 2009058963W WO 2010039789 A1 WO2010039789 A1 WO 2010039789A1
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formula
alkyl
compound
independently selected
substituted
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PCT/US2009/058963
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French (fr)
Inventor
Andrew Stamford
Michael W. Miller
Duane Eugene Demong
William J. Greenlee
Joseph A. Kozlowski
Brian J. Lavey
Michael K.C. Wong
Wensheng Yu
Xing DAI
De-Yi Yang
Guowei Zhou
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Schering Corporation
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Priority to EP09741076.5A priority Critical patent/EP2350020B1/en
Priority to US13/121,725 priority patent/US8361959B2/en
Priority to JP2011530161A priority patent/JP2012504630A/en
Priority to AU2009298617A priority patent/AU2009298617A1/en
Priority to CA2738663A priority patent/CA2738663A1/en
Publication of WO2010039789A1 publication Critical patent/WO2010039789A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems

Definitions

  • the present invention relates to certain novel compounds as glucagon receptor antagonists, compositions comprising these compounds, and methods for their use in treating, preventing, or delaying the onset of type 2 diabetes and related conditions BACKGROUND OF THE INVENTION
  • Diabetes refers to a disease state or process derived from multiple causative factors and is characterized by elevated levels of plasma glucose (hyperglycemia) in the fasting state or after administration of glucose during a glucose tolerance test
  • Persistent or uncontrolled hyperglycemia is associated with a wide range of pathologies Diabetes melhtus, is associated with elevated fasting blood glucose levels and increased and premature cardiovascular disease and premature mortality It is also related directly and indirectly to various metabolic conditions, including alterations of lipid, lipoprotein, apohpoprotein metabolism and other metabolic and hemodynamic diseases As such, the diabetic patient is at increased risk of macrovascular and microvascular complications Such complications can lead to diseases and conditions such as coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy Accordingly, therapeutic control and correction of glucose homeostasis is regarded as important in the clinical management and treatment of diabetes melhtus.
  • type 1 diabetes or insulin-dependent diabetes melhtus
  • IDDM insulin-dependent diabetes melhtus
  • NIDDM noninsulin dependent diabetes melhtus
  • patients often produce plasma insulin levels comparable to those of nondiabetic subjects, however, the cells of patients suffering from type 2 diabetes develop a resistance to the effect of insulin, even in normal or elevated plasma levels, on glucose and lipid metabolism, especially in the main insulin- sensitive tissues (muscle, liver and adipose tissue) Insulin resistance is not associated with a diminished number of cellular insulin receptors but rather with a post-insulin receptor binding defect that is not well understood This cellular resistance to insulin results in insufficient insulin activation of cellular glucose uptake, oxidation, and storage in muscle, and inadequate insulin repression of lipolysis in adipose tissue, and of glucose production and secretion in the liver A net effect of decreased sensitivity
  • the glitazones are another class of compounds that have proven useful for the treatment of type 2 diabetes These agents increase insulin sensitivity in muscle, liver and adipose tissue in several animal models of type 2 diabetes, resulting in partial or complete correction of the elevated plasma levels of glucose without occurrence of hypoglycemia
  • the ghtazones that are currently marketed are agonists of the peroxisome prohferator activated receptor (PPAR), primarily the PPAR-gamma subtype PPAR-gamma agonism is generally believed to be responsible for the improved insulin sensitization that is observed with the ghtazones
  • Newer PPAR agonists that are being tested for treatment of Type Il diabetes are agonists of the alpha, gamma or delta subtype, or a combination thereof, and in many cases are chemically different from the ghtazones ( ⁇ e , they are not thiazolidinediones
  • DPP-IV dipeptidyl peptidase-IV
  • PPP- 1 B protein tyrosine phosphatase-1 B
  • glucagon hormone receptor Glucagon and insulin are the two primary hormones regulating plasma glucose levels
  • Insulin released in response to a meal, increases the uptake of glucose into insulin-sensitive tissues such as skeletal muscle and fat Glucagon, which is secreted by alpha cells in pancreatic islets in response to decreased postprandial glucose levels or during fasting, signals the production and release of glucose from the liver Glucagon binds to specific receptors in liver cells that trigger glycogenosis and an increase in gluconeogenesis through cAMP-mediated events
  • These responses generate increases in plasma glucose levels (e g , hepatic glucose production), which help to regulate glucose homeostasis
  • Type 2 diabetic patients typically have fasting hyperglycemia that is associated with elevated rates of hepatic glucose production This is due to increased gluconeogenesis coupled with hepatic insulin resistance
  • Such patients typically have a relative deficiency in their fasting and postprandial insulin
  • the compounds of the invention have the general structure shown in Formula (A)
  • the invention also relates to compositions, including pharmaceutically acceptable compositions, comprising the compounds of the invention (alone and in combination with one or more additional therapeutic agents), and to methods of using such compounds and compositions as glucagon receptor antagonists and for the treatment or prevention of type 2 diabetes and conditions related thereto.
  • compositions including pharmaceutically acceptable compositions, comprising the compounds of the invention (alone and in combination with one or more additional therapeutic agents), and to methods of using such compounds and compositions as glucagon receptor antagonists and for the treatment or prevention of type 2 diabetes and conditions related thereto.
  • the compounds of the invention have the general structure shown in Formula (A):
  • L 1 is selected from the group consisting of a bond, -N(R 4 )-, -N(R 4 )-(C(R 5A ) 2 )-(C(R 5 ) 2 ) q -, -(C(R 5A ) 2 )-(C(R 5 ) 2 ) r -(C(R 5A ) 2 )-N(R 4 )-, -O-, -O-(C(R SA ) 2 )-(C(R 5 ) 2 ) q -, -(C(R 5A ) 2 )-(C(R ⁇ ) 2 ) r -(C(R 5A ) 2 )-O-, and -(C(R 5A ) 2 )-(C(R 5 ) 2 ) S -, each q is independently an integer from 0 to 5, each r is independently an integer from 0 to 3; s is an integer from 0 to 5; L 2
  • ring A represents a spirocycloalkyl ring or a spirocycloalkenyl ring, wherein said ring A is substituted on one or more available ring carbon atoms with from 0 to 5 independently selected R 2 groups, or, alternatively, ring A represents a spiroheterocycloalkyl ring or a spiroheterocycloalkenyl ring, wherein said ring A is substituted on one or more available ring carbon atoms with from 0 to 5 independently selected R 2 groups, and wherein said ring A is optionally further substituted on one or more available ring nitrogen atoms (when present) with from 0 to 3 R 2A groups, ring B is a phenyl ring, wherein said phenyl ring is (in addition to the -L 1 - and -C(O)N(R 3 )-Z moieties shown) optionally further substituted with one or more substituents R a , wherein each
  • R 1 is independently selected from the group consisting of aryl and heteroaryl, wherein said aryl and said heteroaryl of R 1 are unsubstituted or substituted with one or more groups independently selected from
  • alkyl or heteroalkyl each substituted with from O to 5 groups independently selected from -OH, oxo, halo, heteroalkyl, deuteroalkyl, alkoxy, -O-haloalkyl, -CO 2 R 6 , and phenyl substituted with from O to 5 groups independently selected from -OH, halo, aryl, substituted aryl, alkyl, alkoxy, heteroalkyl, haloalkyl, -O-haloalkyl, haloheteroalkyl, -CO 2 R 6 , CN, -S(O)R 7 , -S(O) 2 R 7 , -SF 5 , -OSF 5 , -C(O)NR 8 R 9 , and -NO 2 ,
  • O to 5 groups independently selected from -OH, halo, aryl, substituted aryl, alkyl, alkoxy, heteroalkyl, haloalkyl, -O-haloalkyl, haloheteroalkyl, -CO 2 R 6 , CN, -S(O)R 7 , -S(O) 2 R 7 , -C(O)NR 8 R 9 , -NR 10 -C(0)R ⁇ , -SO 2 -NR 8 R 9 , -SF 5 , -OSF 5 , and -NO 2 , and (f) -S ⁇ (alkyl) 3 or, alternatively, two R 2 groups attached to the same atom of ring A are taken together to form a moiety selected from the group consisting of carbonyl, oxime, substituted oxime (said oxime substituents being independently selected from the group consisting of alkyl, haloalkyl, hydroxyl-substituted
  • R 3 is selected from H and lower alkyl
  • Z is a moiety selected from -(C(R 11 ) 2 )-(C(R 12 R 13 )) m -C(O)OH, -(C(R 11 ) 2 )-(C(R 14 ) 2 ) n -C(0)OH, from -(C(R 11 ) 2 )-(C(R 12 R 13 )) m -C(0)Oalkyl,
  • n is an integer from O to 5
  • p is an integer from O to 5
  • each R 4 is independently selected from H, -OH, lower alkyl, haloalkyl, alkoxy, heteroalkyl, cyano-substituted lower alkyl, hydroxy-substituted lower alkyl cycloalkyl, -O-cycloalkyl, -O-alkyl-cycloalkyl, and heterocycloalkyl, -O-heterocycloalkyl, and -O-alkyl-heterocycloalkyl, each R 5A is independently selected from H, alkyl, -alkyl-Si(CH 3 )3, haloalkyl, heteroalkyl, cyano-substituted alkyl, hydroxy-substituted alkyl.
  • each R 6 is independently selected from H, -OH, alkyl, -alkyl-S ⁇ (CH 3 ) 3 , haloalkyl, alkoxy, heteroalkyl, cyano-substituted alkyl, hydroxy-substituted alkyl, cycloalkyl, -alkyl-cycloalkyl
  • ring A represents a 3-8-membered spirocycloalkyl or spirocycloalkenyl ring
  • ring A represents a 3-8-membered spirocycloalkyl or spirocycloalkenyl ring, which ring is substituted with from 1 to 5 independently selected R 2 groups, which R 2 groups may be attached to the same or different ring carbon atom(s)
  • ring A represents a 3-8-membered spirocycloalkyl or spirocycloalkenyl ring, which ring is substituted with from 1 to 3 independently selected R 2 groups, which R 2 groups may be attached to the same or different ring carbon atom(s)
  • ring A represents a 3-8-membered spirocycloalkyl or spirocycloalkenyl ring, which ring is substituted with from 1 to 2 independently selected R 2 groups, which R 2 groups may be attached to the same or different ring carbon atom(s)
  • ring A represents a 3-8-membered spirocycloalkyl or spirocycloalkenyl ring, which ring is substituted with 1 R 2 group In one embodiment, in Formula (A), ring A represents a 4-6-membered spirocycloalkyl or spirocycloalkenyl ring
  • ring A represents a 4-6-membered spirocycloalkyl or spirocycloalkenyl ring, which ring is substituted with from 1 to 5 independently selected R 2 groups, which R 2 groups may be attached to the same or different ring carbon atom(s)
  • ring A represents a 4-6-membered spirocycloalkyl or spirocycloalkenyl ring, which ring is substituted with from 1 to 3 independently selected R 2 groups, which R 2 groups may be attached to the same or different ring carbon atom(s)
  • ring A represents a 4-6-membered spirocycloalkyl or spirocycloalkenyl ring, which ring is substituted with from 1 to 2 independently selected R 2 groups, which R 2 groups may be attached to the same or different ring carbon atom(s)
  • ring A represents a 4-6-membered spirocycloalkyl or spirocycloalkenyl ring, which ring is substituted with 1 R 2 group
  • Non-limiting examples of ring A when ring A represents a spirocycloalkyl ring, which may be unsubstituted or substituted as described herein, include sprirocyclobutyl, spirocyclopentyl, spirocyclohexyl, spirocycloheptyl, spirocyclooctyl, spironorbornanyl, and spiroadamantanyl
  • Non-limiting examples of ring A when ring A represents a spirocycloalkenyl ring, which may be unsubstituted or substituted as described herein, include partially or fully unsaturated versions of the spirocycloalkyl moieties described above
  • Non- hmiting examples include spirocyclopentenyl, spirocyclohexenyl, spirocycloheptenyl, and spirocyclooctenyl
  • ring A represents a 3-8-membered spiroheterocycloalkyl ring containing up to 3 ring heteroatoms, 1-3 of which are selected from O, S, S(O), S(O) 2 , and N or N-oxide
  • ring A represents a 3-8-membered spiroheterocycloalkenyl ring containing up to 3 ring heteroatoms, 1-3 of which are selected from O, S, S(O), S(O) 2 , and N or N-oxide
  • ring A represents a 3-8-membered spiroheterocycloalkyl ring containing up to 3 ring heteroatoms, 0-1 of which are O, S, S(O), and S(O) 2 , and 1 -2 of which are N or N-oxide, which ring A is substituted on one or more available ring carbon atom(s) with from 1 to 5 independently selected R 2 groups and which ring A is optionally further substituted on one or more available ring nitrogen atoms with from O to 2 independently selected R 2A groups
  • ring A represents a 3-8-membered spiroheterocycloalkenyl ring containing up to 3 ring heteroatoms, 0-1 of which are O, S, S(O), and S(O) 2 , and 1 -2 of which are N or N-oxide, which ring A is substituted on one or more available ring carbon atom(s) with from 1 to 5 independently selected R 2 groups, and which ring A is optionally further substituted on one or more available ring nitrogen atoms with 0 to 2 independently selected R 2 * groups
  • ring A represents a 4-8-membered spiroheterocycloalkyl ring containing up to 3 ring heteroatoms 0-1 of which are O, S, S(O), and S(0) 2 , and 1 -2 of which are N or N-oxide, which ring A is substituted on one or more available ring carbon atom(s) with from 1 to 5 independently selected R 2
  • ring A represents a 4-8-membered spiroheterocycloalkenyl ring containing up to 3 ring heteroatoms, 0-1 of which are O, S, S(O), and S(O) 2 , and 1 -2 of which are N or N-oxide, which ring A is substituted on one or more available ring carbon atom(s) with from 1 to 5 independently selected R 2 groups, and which ring A is optionally further substituted on one or more available ring nitrogen atoms with O to 2 independently selected R 2 * groups
  • ring A represents a spiropiperidinyl ring
  • ring A represents a spiropiperidinyl ring, which ring A is substituted on one or more available ring carbon atom(s) with from 1 to 5 independently selected R 2 groups, and which ring A is optionally further substituted on the spiropiperidinyl nitrogen with R 2 *
  • ring A represents a spiropiperidinyl ring, which ring A is substituted on one or more available ring carbon atom(s) with from 1 to 3 independently selected R 2 groups
  • ring A represents a spiropiperidinyl ring, which ring A is substituted on one or more available ring carbon atom(s) with from 1 to 2 independently selected R 2 groups
  • ring A represents a spiropiperidinyl ring, which ring A is substituted on one or more available ring carbon atom(s) with an R 2 group
  • ring A when ring A represents a spiroheterocycloalkyl ring which may be unsubstituted or substituted as described herein, include spiropyrrolidinyl, spirodioxolanyl, spiroimidazolidinyl, spiropyrazolidinyl, spiropipe ⁇ dinyl, spirodioxanyl, spiromorpholinyl, spirotetrahydropyranyl, spirodithianyl, spirothiomorpholinyl, spriro piperazinyl, and spirotrithianyl
  • ring A when ring A represents a spiroheterocycloalkyenyl ring which may be unsubstituted or substituted as described herein, include unsaturated versions of the following moieties spiropyrrolidinyl, spirodioxolanyl, spiroimidazolidinyl, spiropyrazolidinyl, spiropiperidinyl, spirodioxanyl, spiromorpholinyl, spirodithianyl, spirothiomorpholinyl, spriro piperazinyl, and spirotrithianyl
  • the compounds of the invention have the general structure shown in Formula (A-1)
  • the compounds of the invention have the general structure shown in Formula (A-1 a)
  • the compounds of the invention have the general structure shown in Formula (A-1 b)
  • (A-1 b) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers of said compounds, wherein ring B, L 1 , L 2 , R 1 , R 2 , R 3 , and Z are selected independently of each other and as defined in Formula (A)
  • the compounds of the invention have the general structure shown in Formula (A-2a)
  • the compounds of the invention have the general structure shown in Formula (A-2b)
  • the compounds of the invention have the general structure shown in Formula (A-2c)
  • (A-2c) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers of said compounds, wherein ring B, L 1 , L 2 , R 1 , R 2 , R 3 , and Z are selected independently of each other and as defined in Formula (A)
  • the compounds of the invention have the general structure shown in Formula (A-2d)
  • ring B is a phenyl ring wherein the -L 1 - and the -C(O)N(R 3 )Z moieties shown in the formula are bound to said phenyl ring in a 1 ,4-relat ⁇ onsh ⁇ p, and wherein said phenyl ring is (in addition to the -L 1 - and -C(O)N(R 3 )-Z moieties shown) optional
  • ring B is a 5-membered heteroaromatic ring containing from 1 to 3 ring heteroatoms independently selected from N, O, and S, wherein the -L 1 - and the -C(O)N(R 3 )-Z moieties shown in the formula are bound to said 5-membered ring in a 1 ,3-relat ⁇ onsh ⁇ p, and wherein said 5-membered heteroaromatic ring is (in addition to the -L 1 - and -C(O)N(R 3 )-Z moieties shown) optionally further substituted with one or more substituents R a , wherein each R a (when present) is independently selected from the group consisting of halo, alkyl, and haloalky
  • ring B is a 6-membered heteroaromatic ring containing from 1 to 3 ring nitrogen atoms, wherein the -L 1 - and the -C(O)N(R 3 )-Z moieties shown in the formula are bound to said 6-membered ring in a 1 ,4-relat ⁇ onsh ⁇ p, and wherein said 6- membered heteroaromatic ring is (in addition to -L 1 - and -C(O)N(R 3 )Z moieties shown) optionally further substituted with one or more substituents R a , wherein each R a (when present) is independently selected from the group consisting of halo, alkyl, and haloalkyl,
  • ring B is phenyl
  • ring B is phenyl which, in addition to the moieties -L 1 - and - C(O)N(R 3 )-Z shown in the formula, is further substituted with one or more independently selected R a groups
  • ring B is a phenyl which, in addition to the moieties -L 1 - and -
  • C(O)N(R 3 )-Z shown in the formula is further substituted with from 1 to 2 substituents, each independently selected from halo, alkyl, and haloalkyl
  • ring B is a 5-membered heteroaromatic ring having from 1 to 3 ring heteroatoms independently selected from N, O, and S, wherein said ring B is not further substituted
  • ring B is a 6-membered heteroaromatic ring having from 1 to 3 ring nitrogen atoms, wherein said ring B is not further substituted
  • ring B is a 5-membered heteroaromatic ring having from 1 to 3 ring heteroatoms independently selected from N, O, and S, wherein said ring B is further substituted with one or more substituents Said further substituents in such embodiments may be bound to one or more available ring carbon atoms and/or ring nitrogen atoms
  • ring B is a 6-membered heteroaromatic ring having from 1 to 3 ring nitrogen atoms wherein said ring B is further substituted with one or more substituents Said further substituents in such embodiments may be bound to one or more available ring carbon atoms and/or ring nitrogen atoms.
  • Formula (A) in each of Formula (A), Formula (A-1 ), Formula (A-1 a),
  • ring B is a 5- membered heteroaromatic ring having from 1 to 3 ring heteroatoms independently selected from N, O, and S, wherein said 5- membered heteroaromatic ring is further substituted with from 1 to 2 substituents, each substituent being independently selected from halo, alkyl, and haloalkyl
  • ring B contains two said substituents
  • ring B contains one said substitutent
  • ring B is a 5-membered heteroaromatic ring, non-limiting examples of such rings include, but are not limited to furan, thiophene, pyrrole, imidazole, pyrazole, 1 ,2,3-triazole, 1 ,2,4-triazole, thiazole, thiadiazole, oxazole, oxadiazole, and isoxazole, each of which may be optionally further substituted as described herein.
  • Non-limiting examples of ring B (shown connected to moieties L 1 and -C(O)-N(R 3 )-Z) include
  • each ring B shown is optionally further substituted on an available ring carbon atom or ring nitrogen atom with one or more groups R a , wherein each R a , when attached to a ring carbon atom, is independently selected from halo, alkyl, and haloalkyl, and wherein each R a , when attached to a ring nitrogen atom, is independently selected from alkyl, and haloalkyl
  • groups substituted on an available ring nitrogen atom include
  • ring B is a 6-membered heteroaromatic ring having from 1 to 3 ring nitrogen atoms, wherein said ring B is further substituted with from 1 to 3 substituents, each substituent being independently selected from halo, alkyl, and haloalkyl
  • ring B contains three said substituents
  • ring B contains two said substituents
  • ring B contains one said substitutent
  • ring B is a 6-membered heteroaromatic ring, non-limiting examples of such rings include pyridine, py ⁇ midine, pyrazine, py ⁇ dazine, and triazine, each of which may be optionally further substituted as described herein
  • Non-limiting examples of ring B (shown connected to moieties
  • any of such moieties may be optionally further substituted with one or more groups R a , wherein each R a is independently selected from halo, alkyl, and haloalkyl
  • L 1 is selected from the group consisting of a bond, -N(R 4 )-, -N(R 4 )-(C(R 5A ) 2 )-, -O-, -O-(C(R SA ) Z )-, and -(C(R 5A ) 2 )-(C(R 5 ) 2 ) S -, wherein s is an integer from 0 to 3
  • L 1 is selected from the group consisting of a bond and -(C(R 5A ) 2 )-(C(R 5 )2) S -, wherein s is an integer from 0 to 1 , and wherein each R 5 and each R 5A is independently selected from the group consisting of H, lower alkyl, -lower alkyl-S ⁇ (CH 3 ) 3 , lower haloalkyl, and lower alkyl substituted with one or more groups independently selected from hydroxyl and cyano
  • s is 0 In one such embodiment, s is 1
  • L 1 is selected from the group consisting of lower branched alkyl and -lower alkyl-S ⁇ (CH 3 ) 3
  • L 1 is a bond
  • L 1 is -N(R 4 )-(C(R 5A ) 2 )-, wherein each R 5A is independently selected from H, lower alkyl, lower haloalkyl, and lower alkyl substituted with one or more hydroxyl and R 4 is selected from H and lower alkyl
  • L 1 is -O-(C(R 5A ) 2 )-, wherein each R 5A is independently selected from H, lower alkyl, lower haloalkyl, and lower alkyl substituted with one or more hydroxyl
  • L 1 is selected from the group consisting of a bond,-NH-(CH 2 ) 2 -, -O-(CH 2 ) 2 -, -O- , -NH-,- N(CH 3 )-, -CH 2 -,-CH(CH 3 )-, and -CH 2 CH 2 -.
  • L 1 is selected from the group consisting of -CH 2 -,-CH(CH 3 )-, and -CH 2 CH 2 -.
  • L 1 is selected from the group consisting of' -CH(cycloalkylalkyl)- and -CH(heterocycloalkylalkyl)-.
  • Formula (A) in each of Formula (A), Formula (A-1 ), Formula (A-1a),
  • L 1 is -C(R 5A ) 2 -, wherein each R 5A is independently selected from the group consisting of H, lower alkyl, -lower alkyl-S ⁇ (CH 3 ) 3 , haloalkyl, heteroalkyl, cya no-substituted lower alkyl, hydroxy-substituted lower alkyl, cycloalkyl, cycloalkylalkyl-, heterocycloalkyl, and heterocycloalkylalkyk
  • L 1 is -CH(R 5A )-, wherein R 5A is selected from the group consisting of H, lower alkyl, -lower alkyl-S ⁇ (CH 3 ) 3 , haloalkyl, heteroalkyl, cyano-substituted lower alkyl, hydroxy- substituted lower alkyl, cycloalkyl, cycloalkylalkyl-, heterocycloalkyl, and heterocycloalkylalkyl-
  • L 1 is selected from the group consisting of: -(CH 2 ) ⁇ 3 -.
  • L 1 is selected from the group consisting of , and
  • L 1 is selected from the group consisting of and In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1a),
  • L 1 is selected from the group consisting of:
  • L 1 is selected from the group consisting of
  • L 1 is selected from the group consisting of
  • L 1 is selected from the group consisting of
  • L 1 is selected from the group consisting of
  • L 1 is selected from the group consisting of , and
  • L 1 is selected from the group consisting of , and
  • L 2 is selected from the group consisting of a bond, -N(R 4 )-, -N(R 4 )-(C(R 5A ) 2 )-, -(C(R 5 ) 2 ) U -(C(R 5A ) 2 )-N(R 4 )-, wherein u is 0 to 2, -O- -O-(C(R 5A ) 2 )-, and -(C(R S ) 2 ) V -, wherein v is 1 -3, and each R 5 and each R SA is independently selected from the group consisting of H, lower alkyl, lower haloalkyl, and lower alkyl substituted with one or more groups independently selected from hydroxyl and cyano, and wherein each R 4 is independently selected from the group consisting
  • L 2 is selected from the group consisting of a -(C(R 5 ) 2 ) u -(C(R 5A ) 2 )-N(R 4 )-, wherein u is 0 to 2, -O-, and each R 4 , each R s , and each R 6A is independently selected from the group consisting of H and lower alkyl
  • L 2 is selected from a bond and -(C(R 5 ) 2 ) V -, wherein v is 1-2, and each R 5 is independently selected from the group consisting of H, -OH, lower alkyl, loweralkoxy, lower haloalkyl, and lower alkyl substituted with one or more groups independently selected from hydroxyl and cyano
  • v is 1 and each R 5 is independently selected from H and lower alkyl
  • v is 1 and each R 5 is independently selected from H, lower alkyl, and OH
  • L 2 is a bond
  • L 2 is selected from the group consisting of -CH 2 -,-CH(CH 3 )-, -CH 2 CH 2 -, -CH(OH)-, -CH(CH 3 )-CH 2 -, -CH 2 -CH(CH 3 )-, -CH(OH)-CH 2 -, and -CH 2 -CH(OH)-
  • L 2 is selected from the group consisting of
  • L 2 is selected from the group consisting of
  • L 2 is selected from the group consisting of
  • L 2 is selected from the group consisting of
  • any two R 5A groups bound to the same carbon atom may be taken together to form a carbonyl group, an oxime group, or a substituted oxime group
  • each R 5A group is selected independently
  • any two R 5 groups bound to the same carbon atom may be taken together to form a carbonyl group, an oxime group, or a substituted oxime group
  • any two R 5 groups bound to the same carbon atom may be taken together to form a carbonyl group, an oxime group, or a substituted oxime group
  • such oxime groups when
  • R 15 is selected from the group consisting of H, alkyl, haloalkyl, hydroxyl-substituted alkyl, and cycloalkyl.
  • R 1 is selected from the group consisting of: aryl and heteroaryl, wherein each of said aryl and said heteroaryl are unsubstituted or substituted with from 1 to 3 groups each independently selected from:
  • R 1 is selected from the group consisting of: phenyl or naphthyl, wherein said phenyl and said naphthyl are unsubstituted or substituted with from 1 to 3 groups each independently selected from
  • R 1 is selected from the group consisting of phenyl, wherein said phenyl is unsubstituted or substituted with one or more groups each independently selected from halo, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, alkoxy, -O-haloalkyl, and cycloalkyl
  • R 1 is selected from the group consisting of heteroaryl, wherein said heteroaryl is unsubstituted or substituted with one or more groups each independently selected from halo, alkyl, haloalkyl, alkoxy, -O-haloalkyl, and cycloalkyl
  • each R z is independently selected from the group consisting of phenyl substituted with from 0 to 5 groups independently selected from -OH, halo, alkyl, haloalkyl, hydroxyalkyl, alkyl substituted with from 1 to 2 -CO 2 R 6 groups, alkoxy, -O-haloalkyl, hydroxyalkoxy, alkoxy substituted with from 1 to 2 -CO2R 6 groups, -CO 2 R 6 , CN, -SO 2 R 7 , -C(O)NR 8 R 9 , and -NO 2
  • ring A represents a spirocycloalkyl ring or a spirocycloalkenyl ring, wherein said ring A is substituted on one or more available ring carbon atoms with from 1 to 5 independently selected R 2 groups
  • ring A represents a spirocycloalkyl ring, wherein said ring A is substituted on one or more available ring carbon atoms with from 1 to 5 independently selected R 2 groups
  • each R 2 is independently selected from the group consisting of phenyl substituted with from O to 5 groups independently selected from -OH, halo, alkyl, haloalkyl, alkoxy, -O-haloalkyl, hydroxyalkoxy, -CO 2 R 6 , CN, -SO 2 R 7 , -C(O)NR 8 R 9 , and -NO 2 .
  • each R 2 is independently selected from the group consisting of' unsubstituted phenyl
  • each R 2 is independently selected from the group consisting of: phenyl substituted with from 1 to 5 groups independently selected from halo. In one embodiment, in each of Formula (A), Formula (A-1), Formula (A-1 a),
  • each R 2 is independently selected from the group consisting of alkyl substituted with from O to 5 groups independently selected from -OH, oxo, halo, heteroalkyl, alkoxy, -O-haloalkyl, -CO 2 R 6 , and phenyl substituted with from O to 5 groups independently selected from -OH, halo, aryl, substituted aryl, alkyl, alkoxy, heteroalkyl, haloalkyl, haloheteroalkyl, -CO 2 R 6 , CN, -S(O)R 7 , -S(O) 2 R 7 , -C(O)NR 8 R 9 , and -NO 2 .
  • each R 2 is selected from the group consisting of t-butyl and -S ⁇ (CH 3 ) 3
  • each R 2 is t-butyl
  • each R 2 is deuteroalkyl In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1a), Formula (A-1b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), each R 2 is deuteroalkyl In one embodiment, in each of Formula (A), Formula (A-1), Formula (A-1 a),
  • each R 2 is -C(CD 3 ) 3
  • each R 2 is cycloalkyl or substituted cycloalkyl.
  • Non-limiting examples of R 2 when R 2 is cycloalkyl include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl
  • Non-limiting illustrations of points of attachment of such substituents include:
  • each R 2 is heterocycloalkyl or substituted heterocycloalkyl.
  • R 2 when R 2 is heterocycloalkyl include pipe ⁇ dyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1 ,4-dioxanyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, oxetanes, and the like.
  • R 2 when R 2 is heterocycloalkyl include pipe ⁇ dyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1 ,4-dioxanyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, oxetanes, and the like.
  • each R 2 is -S ⁇ (alkyl) 3 .
  • each R 2 is -S ⁇ (Ch 3 ) 3
  • R 3 is H.
  • R 3 is selected from methyl, ethyl, n-propyl, and isopropyl.
  • each R 8 is independently selected from H and alkyl.
  • each R 9 is independently selected from H and alkyl
  • R 8 and R 9 are taken together with the nitrogen to which they are attached to form a 5-, 6-, or 7-membered heteroaromatic ring, which ring contains (including said nitrogen to which R 8 and R 9 are attached) from 1 to 2 ring heteroatoms.
  • R 8 and R 9 are taken together with the nitrogen to which they are attached to form a 5-, 6-, or 7-membered saturated heterocyclic ring, which ring contains (including said nitrogen to which R 8 and R 9 are attached) from 1 to 2 ring heteroatoms
  • R 8 and R 9 are taken together with the nitrogen to which they are attached to form a 5-, 6-, or 7-membered partially or fully unsaturated heterocyclic ring, which ring contains (including said nitrogen to which R 8 and R 9 are attached) form 1 to 2 ring heteroatoms
  • R 8 and R 9 are taken together with the nitrogen to which they are attached to form a 5-, or 6-membered saturated, or partially or fully unsaturated, heterocyclic ring, which ring contains (including said nitrogen to which R 8 and R 9 are attached) form 1 to 2 ring heteroatoms
  • R 8 and R 9 are taken together with the nitrogen to which they are attached to form a 5-, or 6-membered saturated, or partially or fully unsaturated, heterocyclic ring, which ring contains (including said nitrogen to which R 8 and R 9 are attached) form 1 to 2 ring heteroatoms
  • Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), R 8 and R 9 are taken together with the nitrogen to which they are attached to form a 5-, 6-, or 7-membered ring moiety, non-limiting examples of such moieties include pyrrolidine, imidazoline, piperazine, morpholine, thiomorpholine, oxazolidme, and thiazolidine
  • Z is -(CH 2 )- (CH(CH 3 ))-C(O)OH
  • Z is -(CH 2 )-(CH 2 )- (CHa)-C(O)OH
  • Z is -(CH 2 )-C(CH 3 ) 2 - C(O)OH
  • Z is -(CH 2 )- C(CH 3 )(OH)-C(O)OH
  • Formula (A) in each of Formula (A), Formula (A-1 ), Formula (A-1 a),
  • Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), Z is -CH 2 -CH 2 - C(O)OH
  • Z is -CH 2 -CH(OH)- C(O)OH
  • Z is -CH(CH 3 )-CH 2 - C(O)OH
  • Z is -C(CH 3 ) 2 -CH 2 - C(O)OH
  • Z is -(C(R 11 ) 2 )-(C(R 14 ) 2 ) n -C(O)OH
  • Z is -CH 2 -CH(F)- C(O)OH
  • Formula (A), Formula (A-1 ), Formula (A-1 a), Formula (A-1b), Formula (A-2a), Formula (A-2b), Formula (A-2c), Z is -CH 2 -CF 2 - C(O)OH
  • Z is -CH(CH 3 )-CF 2 - C(O)OH.
  • Z is -CH 2 -CH 2 -CF 2 - C(O)OH.
  • L 1 is selected from the group consisting of a bond, -N(R 4 )-, -N(R 4 )-(C(R 5A ) 2 )-, -O-, -O-(C(R 5A ) 2 )-, and -(C(R 5A ) 2 )-(C(R S ) 2 ) S -, s is 0-3,
  • L 2 is selected from the group consisting of bond, -N(R 4 )-, -N(R 4 )-(C(R 5A ) 2 )-, -(C(R 5 ) 2 ) U -(C(R SA ) 2 )-N(R 4 )-, -(C(R 5A ) 2 )-N(R 4 )-, -O-, -O-(C(R 5A ) 2 )-, -(C(R 5A ) 2 )-O- and -(C(R 5 ) 2 )v-, wherein v is 1 -3,
  • R 3 is selected from the group consisting of H and lower alkyl
  • Z is a moiety selected from -(C(R 11 ) 2 )-(C(R 12 R 13 )) m -C(O)OH, -(C(R") 2 )-(C(R 14 ) 2 )n-C(O)OH, and m is an integer from 0 to 5, n is an integer from 0 to 5, p is an integer from 0 to 5, each R 4 is independently selected from H, lower alkyl, cycloalkyl, heterocycloalkyl, heteroalkyl, and haloalkyl, each R 5A is independently selected from H, lower alkyl, -lower alkyl-S ⁇ (CH 3 ) 3 , -lower alkyl-S ⁇ (CH 3 ) 3 , lower haloalkyl, and hydroxy-substituted lower alkyl, each R 5 is independently selected from H, -OH, lower alkyl, -lower alkyl-S ⁇ (CH 3 ) 3 , -low
  • ring A represents a spirocycloalkyl ring or a spirocycloalkenyl ring, wherein said ring A is substituted on one or more available ring carbon atoms with from 0 to 5 independently selected R 2 groups,
  • R 1 is selected from the group consisting of aryl and heteroaryl, wherein each of said aryl and said heteroaryl are unsubstituted or substituted with from 1 to 3 groups each independently selected from
  • each R 2 (when present) is independently selected from the group consisting of -Si(CH 3 J 3 and alkyl, wherein said alkyl substituted with from O to 5 groups independently selected from -OH, oxo, halo, heteroalkyl, alkoxy, -O-haloalkyl, -CO 2 R 6 , and phenyl substituted with from O to 5 groups independently selected from -OH, halo, aryl, substituted aryl, alkyl, alkoxy, -O-haloalkyl, heteroalkyl, haloalkyl, haloalkyl, halo
  • ring A represents a spirocycloalkyl ring or a spirocycloalkenyl ring, wherein said ring A is substituted on one or more available ring carbon atoms with from 0 to 5 independently selected R 2 groups;
  • R 1 is selected from the group consisting of. phenyl, wherein said phenyl and is unsubstituted or substituted with from 1 to 3 groups each independently selected from
  • the compounds of the invention have the general structure shown in Formula (1-1 )
  • the compounds of the invention have the general structure shown in Formula (II)
  • L 1 is selected from the group consisting of a bond and -(C(R SA ) 2 )-(C(R 5 ) 2 ) S -,
  • s 0-1 ,
  • L 2 is selected from the group consisting of a bond, -(C(R 5 ) 2 ) U -(C(R 6A ) 2 )-N(R 4 )-, and -(C(R 5 ) 2 )v,
  • R 1 is selected from the group consisting of phenyl, wherein said phenyl is unsubstituted or substituted with one or more groups each independently selected from halo, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, alkoxy,
  • each R 2 is independently selected from the group consisting of -S ⁇ (CH 3 ) 3 and alkyl, wherein said alkyl is substituted with from 0 to 5 groups independently selected from -OH, halo, alkyl, haloalkyl, hydroxyalkyl, alkyl substituted with from 1 to 2 -CO 2 R 6 groups, alkoxy, -O-haloalkyl, hydroxyalkoxy, alkoxy substituted with from 1 to 2 -CO 2 R 6 groups, -CO 2 R 6 , CN, -SO 2 R 7 , -C(O)NR 6 R 9 , and -NO 2 ,
  • R 3 is selected from the group consisting of H and lower alkyl
  • Z is a moiety selected from the group consisting of -(CH 2 )-(CH(CH 3 ))-C(O)OH, -(CH 2 )-(CH 2 )-(CH 2 )-C(O)OH, -(CH 2 )-C(CH 3 ) 2 -C(O)OH, -(CH 2 )-C(CH 3 )(OH)-C(O)OH, -CH 2 CH 2 -C(O)OH, -CH 2 -CH(OH)-C(O)OH, -CH(CH 3 )-CH 2 -C(O)OH,
  • each R 5A is independently selected from H, lower alkyl, -lower alkyl-S ⁇ (CH 3 ) 3 , lower haloalkyl, and lower alkyl substituted with from 1 to 2 hydroxyl, each R 5 is independently selected from H, -OH, lower alkyl,
  • each R 6 is independently selected from H, alkyl, and haloalkyl
  • each R 7 is independently selected from H, alkyl, heteroalkyl, and haloalkyl
  • each R 8 is independently selected from H and alkyl; and each R 9 is independently selected from H and alkyl.
  • the compounds of the invention have the general structure shown in Formula (ll-a):
  • the compounds of the invention have the general structure shown in Formula (ll-b)'
  • L 1 is selected from the group consisting of: a bond, straight or branched lower alkyl, and -(CH(-lower alkyl-S ⁇ (CH 3 ) 3 )-;
  • L 2 is selected from the group consisting of' a bond and straight or branched lower alkyl
  • R 1 is selected from the group consisting of' phenyl, wherein said phenyl is unsubstituted or substituted with from 1 to 3 groups each independently selected from, halo, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, alkoxy, and -O-haloalkyl
  • each R 2 is independently selected from the group consisting of H, straight or branched lower alkyl, and -Si(CH 3 ) 3 ,
  • R 3 is selected from the group consisting of H and lower alkyl
  • Z is a moiety selected from the group consisting of: -(CH 2 )-(CH(CH 3 ))-C(O)OH, -(CH 2 )-(CH 2 )-(CH 2 )-C(O)OH, -(CH 2 )-C(CH 3 ) 2 -C(O)OH, -(CHa)-C(CH 3 )(OH)-C(O)OH, -CH 2 -CH 2 -C(O)OH, -CH 2 -CH(OH)-C(O)OH, -CH(CH 3 )-CH 2 -C(O)OH, -C(CH 3 ) 2 -CH 2 -C(O)OH, -(C(R 11 ) 2 )-(C(R 14 ) 2 )n-C(O)OH, -CH 2 -CH(F)-C(O)OH, -CH 2 -
  • L 1 is selected from the group consisting of: a bond
  • L 1 is
  • L 1 is In one such embodiment, L 1 is . In
  • L 1 is I . In one such embodiment, L 1 is
  • L 1 is In one embodiment, in each of Formula (II), Formula (ll-a), and Formula (ll-b):
  • L 1 is selected from the group consisting of:
  • L 2 is selected from the group consisting of a bond and straight or branched lower alkyl;
  • R 1 is selected from the group consisting of. phenyl, wherein said phenyl is unsubstituted or substituted with from 1 to 3 groups each independently selected from'
  • each R 2 is independently selected from the group consisting of H, straight or branched lower alkyl, and -S ⁇ (CHs)3,
  • R 3 is selected from the group consisting of H and lower alkyl, and Z is selected from the group consisting of -CH 2 CH 2 -C(O)OH and , wherein p is 1 and R 11 is H
  • L 1 is selected from the group consisting of , and , and L 2 is a bond
  • R 1 is selected from the group consisting of phenyl, wherein said phenyl is unsubstituted or substituted with from 1 to 3 groups each independently selected from halo, each R 2 is independently selected from the group consisting of iso-propyl, tert- butyl and tert-pentyl, R 3 is H, and
  • Z is selected from the group consisting of -CH 2 CH 2 -C(O)OH and , wherein p is 1 and R 11 is H
  • the compounds of the invention have the general structure shown in the tables below, and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers of said compounds
  • a compound or compounds of the invention is/are in isolated or purified form
  • a patient is a human or non-human mammal
  • a patient is a human
  • a patient is a non-human mammal, including, but not limited to, a monkey, baboon, mouse, rat, horse, dog, cat or rabbit
  • a patient is a companion animal, including but not limited to a dog, cat,
  • an obese patient refers to a patient being overweight and having a body mass index (BMI) of 25 or greater In one embodiment, an obese patient has a BMI of 25 or greater In another embodiment, an obese patient has a BMI from 25 to 30 In another embodiment, an obese patient has a BMI greater than 30 In still another embodiment, an obese patient has a BMI greater than 40
  • ITT paired glucose tolerance
  • IGF paired fasting glucose
  • an effective amount refers to an amount of Compound of Formula (I) and/or an additional therapeutic agent, or a composition thereof that is effective in producing the desired therapeutic, ameliorative, inhibitory or preventative effect when administered to a patient suffering from a Condition
  • an effective amount can refer to each individual agent or to the combination as a whole, wherein the amounts of all agents administered are together effective, but wherein the component agent of the combination may not be present individually in an effective amount
  • Halogen means fluorine, chlorine, bromine, or iodine Preferred are fluorine, chlorine and bromine
  • Alkyl means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain
  • Lower alkyl means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched
  • Alkyl may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being as described herein or independently selected from the group consisting of halo, alkyl, haloalkyl, spirocycloalkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, -NH
  • haloalkyl refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms have been independently replaced with -F, -Cl, -Br or -I
  • Non-limiting illustrative examples of haloalkyl groups include -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CHF 2 , -CH 2 CF 3 , -CCI 3 , -CHCI 2 , -CH 2 CI, and -CH 2 CHCI 3
  • deuteroalkyl refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms have been independently replaced with deuterium.
  • Heteroalkyl means an alkyl moiety as defined above, having one or more carbon atoms, for example one, two or three carbon atoms, replaced with one or more heteroatoms, which may be the same or different, where the point of attachment to the remainder of the molecule is through a carbon atom of the heteroalkyl radical Suitable such heteroatoms include O, S, S(O), S(O) 2 , and -NH-, -N(alkyl)-.
  • Non- limiting examples include ethers, thioethers, amines, 2-am ⁇ noethyl, 2- dimethylammoethyl, and the like.
  • alkenyl means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain
  • Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain.
  • Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain
  • “Lower alkenyl” means about 2 to about 6 carbon atoms in the chain which may be straight or branched.
  • alkenyl may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl. aryl, cycloalkyl, cyano, alkoxy and — S(alkyl).
  • suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.
  • Alkylene means a difunctional group obtained by removal of a hydrogen atom from an alkyl group that is defined above.
  • Non-limiting examples of alkylene include methylene, ethylene and propylene. Further non-limiting examples of alkylene groups include -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH(CH 3 )CH 2 CH 2 - and - CH 2 CH(CH 3 )CH 2 - In one embodiment, an alkylene group has from 1 to about 6 carbon atoms In another embodiment, an alkylene group is branched In another embodiment, an alkylene group is linear More generally, the suffix "ene" on alkyl, aryl, hetercycloalkyl, etc indicates a divalent moiety, e g , -CH 2 CH 2 - is ethylene, and ispara-phenylene
  • ⁇ lkynyl means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain
  • Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain, and more preferably about 2 to about 4 carbon atoms in the chain
  • Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain
  • “Lower alkynyl” means about 2 to about 6 carbon atoms in the chain which may be straight or branched
  • suitable alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-methylbutynyl
  • Alkynyl may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl,
  • ⁇ eteroalkynyl means an alkynyl moiety as defined above, having one or more carbon atoms, for example one, two or three carbon atoms, replaced with one or more heteroatoms, which may be the same or different, where the point of attachment to the remainder of the molecule is through a carbon atom of the heteroalkynyl radical
  • Alkenylene means a difunctional group obtained by removal of a hydrogen from an alkenyl group that is defined above
  • the aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein
  • suitable aryl groups include phenyl and naphthyl
  • Heteroaryl means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination Preferred heteroaryls contain about 5 to about 6
  • heteroaryl can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein.
  • ring system substituents which may be the same or different, and are as defined herein.
  • the prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom.
  • a nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide
  • Heteroaryl may also include a heteroaryl as defined above fused to an aryl as defined above.
  • Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyrido ⁇ e (including N-substituted py ⁇ dones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, t ⁇ azolyl, 1 ,2,4- thiadiazolyl, pyrazinyl, py ⁇ dazinyl, quinoxalinyl, phthalazinyl, oxindolyl, ⁇ m ⁇ dazo[1 ,2- ajpyndinyl, ⁇ m ⁇ dazo[2,1-b]th ⁇ azolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolin
  • heteroaryl also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like.
  • the bond to the parent moiety may be through an available carbon or nitrogen atom.
  • Cycloalkyl means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms.
  • the cycloalkyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein.
  • suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • Non-limiting examples of suitable multicyclic cycloalkyls include 1 -decal ⁇ nyl, 2-decal ⁇ nyl, norbornyl, adamantyl and the like Further non-limiting examples of cycloalkyl include the following:
  • Cycloalkenyl means a non-aromatic mono or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms which contains at least one carbon-carbon double bond. Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms.
  • the cycloalkenyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above.
  • suitable monocyclic cycloalk ⁇ nyls include cyclopentenyl, cyclohexenyl, cyclohepta-1 ,3-dienyl, and the like.
  • Non-limiting example of a suitable multicyclic cycloalkenyl is norbomylenyl.
  • Heterocycloalkyl (or “heterocyclyl”) means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination There are no adjacent oxygen and/or sulfur atoms present in the ring system Preferred heterocyclyls contain about 5 to about 6 ring atoms
  • the prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom
  • Any -NH in a heterocyclyl ring may exist protected such as, for example, as an -N(Boc), -N(CBz), - N(Tos) group and the like, such protections are also considered part of this invention
  • the heterocyclyl can be optional
  • Heterocycloalkenyl (or “heterocyclenyl”) means a non-aromatic monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur atom, alone or in combination, and which contains at least one carbon-carbon double bond or carbon- nitrogen double bond There are no adjacent oxygen and/or sulfur atoms present in the ring system Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms
  • the prefix aza, oxa or thia before the heterocyclenyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom
  • the heterocyclenyl can be optionally substituted by one or more ring system substituents, wherein "ring system substituent” is as defined herein
  • hetero-atom containing ring systems of this invention there are no hydroxyl groups on carbon atoms adjacent to a N, O or S, as well as there are no N or S groups on carbon adjacent to another heteroatom
  • N, O or S there are no hydroxyl groups on carbon atoms adjacent to a N, O or S
  • N is equivalent to a compound of the invention.
  • hetero-containing functional groups described herein e.g., heterocycloalkyl, heterocycloalkenyl, heteroalkyl, heteroaryl, and arylheterocycloalkyl (e.g , benzo-fused heterocycloalkyl)
  • the bond to the parent moiety can be through an available carbon or heteroatom (e g., nitrogen atom)
  • Arylcycloalkyl (or “arylfused cycloalkyl”) means a group derived from a fused aryl and cycloalkyl as defined herein.
  • Preferred arylcycloalkyls are those wherein aryl is phenyl (which may be referred to as “benzofused") and cycloalkyl consists of about 5 to about 6 ring atoms.
  • arylcycloalkyl can be optionally substituted as described herein
  • suitable arylcycloalkyls include indanyl (a benzofused cycloalkyl) and 1 ,2,3,4-tetrahydronaphthyl and the like
  • the bond to the parent moiety is through a non-aromatic carbon atom.
  • Arylheterocycloalkyl (or “arylfused heterocycloalkyl”) means a group derived from a fused aryl and heterocycloalkyl as defined herein.
  • Preferred arylheterocycloalkyls are those wherein aryl is phenyl (which may be referred to as “benzofused") and heterocycloalkyl consists of about 5 to about 6 ring atoms
  • the arylheterocycloalkyl can be optionally substituted, and/or contain the oxide or oxo, as described herein
  • suitable arylfused heterocycloalkyls include.
  • cycloalkylfused cycloalkenyl "cycloalkylfused heterocycloalkyl”, “cycloalkylfused heterocycloalkenyl”, “cycloalkylfused heteroaryl, "cycloalkenylfused aryl”, “cycloalkenylfused cycloalkyl”, “cycloalkenylfused heterocycloalkyl”, “cycloalkenylfused heterocycloalkenyl”, “cycloalkenylfused heteroaryl”, “heterocycloalkylfused aryl”, “heterocycloalkylfused cycloalkyl”, “heterocycloalkylfused cycloalkenyl”, “heterocycloalkylfused heterocycloalkyl”, “heterocycloalkylfused heterocycloalkenyl”, “heterocycloalkylfused heteroaryl”,
  • Aralkyl or “arylalkyl” means an aryl-alkyl- group in which the aryl and alkyl are as previously described Preferred aralkyls comprise a lower alkyl group
  • suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl
  • the bond to the parent moiety is through the alkyl.
  • the term (and similar terms) may be written as "arylalkyl-" to indicate the point of attachment to the parent moiety
  • heteroarylalkyl means a heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, etc. as described herein bound to a parent moiety through an alkyl group
  • Preferred groups contain a lower alkyl group.
  • Such alkyl groups may be straight or branched, unsubstituted and/or substituted as described herein.
  • arylfused arylalkyl- means an arylfused aryl group, arylfused cycloalkyl group, etc. linked to a parent moiety through an alkyl group.
  • Preferred groups contain a lower alkyl group. Such alkyl groups may be straight or branched, unsubstituted and/or substituted as described herein.
  • Alkylaryl means an alkyl-aryl- group in which the alkyl and aryl are as previously described. Preferred alkylaryls comprise a lower alkyl group
  • Non-limiting example of a suitable alkylaryl group is tolyl. The bond to the parent moiety is through the aryl.
  • Cycloalkylether means a non-aromatic ring of 3 to 7 members comprising an oxygen atom and 2 to 7 carbon atoms Ring carbon atoms can be substituted, provided that substituents adjacent to the ring oxygen do not include halo or substituents joined to the ring through an oxygen, nitrogen or sulfur atom.
  • Cycloalkylalkyl means a cycloalkyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
  • suitable cycloalkylalkyls include cyclohexylmethyl, adamantylmethyl, adamantylpropyl, and the like
  • Cycloalkenylalkyl means a cycloalkenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core
  • suitable cycloalkenylalkyls include cyclopentenylmethyl, cyclohexenylmethyl and the like.
  • Heteroarylalkyl means a heteroaryl moiety as defined above linked via an alkyl moiety (defined above) to a parent core
  • suitable heteroaryls include 2-py ⁇ d ⁇ nylmethyl, quinolinylmethyl and the like
  • Heterocyclylalkyl (or “heterocycloalkylalkyl”) means a heterocyclyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
  • suitable heterocyclylalkyls include pipendinylmethyl, piperazinylmethyl and the like
  • Heterocyclenylalkyl means a heterocyclenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
  • Alkynylalkyl means an alkynyl-alkyl- group in which the alkynyl and alkyl are as previously described. Preferred alkynylalkyls contain a lower alkynyl and a lower alkyl group. The bond to the parent moiety is through the alkyl
  • suitable alkynylalkyl groups include propargylmethyl.
  • Heteroaralkyl means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl, and qu ⁇ nol ⁇ n-3- ylmethyl. The bond to the parent moiety is through the alkyl
  • Hydroxyalkyl means a HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyalkyls contain lower alkyl Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.
  • Cyanoalkyl means a NC-alkyl- group in which alkyl is as previously defined.
  • Preferred cyanoalkyls contain lower alkyl.
  • suitable cyanoalkyl groups include cyanomethyl and 2-cyanoethyl.
  • Acyl means an H-C(O)-, alkyl-C(O)- or cycloalkyl-C(O)-, group in which the various groups are as previously described.
  • the bond to the parent moiety is through the carbonyl
  • Preferred acyls contain a lower alkyl.
  • suitable acyl groups include formyl, acetyl and propanoyl.
  • Aroyl means an aryl-C(O)- group in which the aryl group is as previously described. The bond to the parent moiety is through the carbonyl.
  • suitable groups include benzoyl and 1- naphthoyl.
  • Heteroaroyl means an heteroaryl-C(O)- group in which the heteroaryl group is as previously described
  • the bond to the parent moiety is through the carbonyl.
  • suitable groups include py ⁇ doyl.
  • Alkoxy means an alkyl-O- group in which the alkyl group is as previously described.
  • suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
  • the bond to the parent moiety is through the ether oxygen.
  • Alkyoxyalkyl means a group derived from an alkoxy and alkyl as defined herein The bond to the parent moiety is through the alkyl
  • 'Aryloxy' means an aryl-O- group in which the aryl group is as previously described
  • suitable aryloxy groups include phenoxy and naphthoxy
  • the bond to the parent moiety is through the ether oxygen
  • Aralkyloxy means an aralkyl-O- group (an arylaklyl-O- group) in which the aralkyl group is as previously described
  • suitable aralkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy
  • the bond to the parent moiety is through the ether oxygen
  • Arylalkenyl means a group derived from an aryl and alkenyl as defined herein Preferred arylalkenyls are those wherein aryl is phenyl and the alkenyl consists of about 3 to about 6 atoms
  • the arylalkenyl can be optionally substituted by one or more substituents
  • the bond to the parent moiety is through a non-aromatic carbon atom
  • Arylalkynyl means a group derived from a aryl and alkenyl as defined herein
  • arylalkynyls are those wherein aryl is phenyl and the alkynyl consists of about 3 to about 6 atoms
  • the arylalkynyl can be optionally substituted by one or more substituents
  • the bond to the parent moiety is through a non-aromatic carbon atom
  • Alkylthio means an alkyl-S- group in which the alkyl group is as previously described
  • suitable alkylthio groups include methylthio and ethylthio
  • the bond to the parent moiety is through the sulfur
  • Arylthio means an aryl-S- group in which the aryl group is as previously described Non-limiting examples of suitable arylthio groups include phenylthio and naphthylthio The bond to the parent moiety is through the sulfur
  • ⁇ ralkylthio means an aralkyl-S- group in which the aralkyl group is as previously described
  • a suitable aralkylthio group is benzylthio
  • the bond to the parent moiety is through the sulfur
  • Alkoxycarbonyl means an alkyl-O-CO- group
  • suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl
  • the bond to the parent moiety is through the carbonyl
  • Aryloxycarbonyl means an aryl-O-C(O)- group.
  • suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The bond to the parent moiety is through the carbonyl.
  • Alkoxycarbonyl means an aralkyl-O-C(O)- group.
  • a suitable aralkoxycarbonyl group is benzyloxycarbonyl.
  • the bond to the parent moiety is through the carbonyl
  • Alkylsulfonyl means an alkyl-S(O 2 )- group Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfonyl.
  • Arylsulfonyl means an aryl-S(O2)- group The bond to the parent moiety is through the sulfonyl
  • Spirocycloalkyl means a monocyclic or multicyclic cycloalkyl group attached to a parent moiety by replacement of two available hydrogen atoms attached to the same carbon atom.
  • the spirocycloalkyl may optionally be substituted as described herein.
  • suitable monocyclic spirocycloalkyl groups include spirocyclopropyl, spirorcyclobutyl, spirocycloheptyl, spirocyclohexyl, and spirocyclooctyl.
  • suitable multicyclic spirocycloalkyl groups include spirocyclopropyl, spirorcyclobutyl, spirocycloheptyl, spirocyclohexyl, and spirocyclooctyl.
  • Spirocycloalkenyl means a spirocycloalkyl group which contains at least one carbon-carbon double bond
  • Preferred spirocycloalkenyl rings contain about 5 to about 7 ring atoms
  • the spirocycloalkenyl can be optionally substituted as described herein
  • suitable monocyclic cycloalkenyls include spirocyclopentenyl, spirocyclohexenyl, sp ⁇ rocyclohepta-1 ,3-d ⁇ enyl, and the like
  • Non-limiting examples of suitable monocyclic cycloalkenyls include spirocyclopentenyl, spirocyclohexenyl, sp ⁇ rocyclohepta-1 ,3-d ⁇ enyl, and the like
  • Non-limiting examples of suitable monocyclic cycloalkenyls include spirocyclopentenyl, spirocyclohexenyl, sp ⁇
  • Sp ⁇ oheterocycloalkyl means a monocyclic or multicyclic heterocycloalkyl group (include oxides thereof) attached to the parent moiety by replacement of two available hydrogen atoms attached to the same carbon atom
  • the spiroheterocycloalkyl may be optionally substituted as described herein
  • Suitable multicyclic spiroheterocycloalkyl include
  • Spiroheterocycloalkenyl (or “spiroheterocyclenyl) means a spiroheterocycloalkyl group which contains at least one carbon-carbon double bond.
  • Non-lirniting examples of suitable multicyclic spiroheterocycloalkenyl include:
  • substituted means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • stable compound' or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • substitution on a cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylfused cycloalkylalkyl- moiety or the like includes substitution on any ring portion and/or on the alkyl portion of the group.
  • variables can be the same or different.
  • compound(s) of the invention refers, collectively or independently, to any of the compounds embraced by the general formulas described herein, e.g., Formula (A), Formula (I), Formula (H-A), Formula (H-B), Formula (II-B1 ), Formula (II-B2), Formula (II-B3), Formula (II-B4), Formula (II-B5), Formula (H-C), Formula (II-C1), Formula (II-C2), Formula (II-C3), Formula (II-C4), Formula (H-C5), Formula (H-D), Formula (II-D1), Formula (II-D2), Formula (III), Formula (IV), Formula (IV), Formula (V), and Formula (Vl), and the example compounds thereof.
  • Ring system substituent means a substituent attached to an aromatic or non-aromatic ring system which, for example, replaces an available hydrogen on the ring system Ring system substituents may be the same or different, each being as described herein or independently selected from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulf
  • composition 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
  • the line — -,as a bond generally indicates a mixture of, or either of, the possible isomers, e g , containing (R)- and (S)- stereochemistry
  • H H In the structure H is equivalent to Similarly, and by way of additional non-limiting example, when -Lr is , the is implied Thus, is equivalent to
  • each wavy line in the following structure indicates a point of attachment to the rest of the compound
  • each wavy line in the following structure indicates a point of attachment to the rest of the compound
  • Lines drawn into the ring systems such as, for example indicate that the indicated line (bond) may b-e attached to any of the substitutable ring carbon atoms
  • Oxo is defined as a oxygen atom that is double bonded to a ring carbon in a cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, or other ring described herein, e g ,
  • purified refers to the physical state of said compound after being isolated from a synthetic process (e g from a reaction mixture), or natural source or combination thereof
  • purified refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan (e g , chromatography, recrystallization and the like) , in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan
  • any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences
  • protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T W Greene er a/, Protective Groups in Organic Synthesis (1999), Wiley, New York
  • composition 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
  • Prodrugs and solvates of the compounds of the invention are also contemplated herein
  • a discussion of prodrugs is provided in T Higuchi and V Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A C S Symposium Series and in Bioreversible Carriers in Drug Design, (1987) Edward B Roche, ed , American Pharmaceutical Association and Pergamon Press
  • prodrug means a compound (e g, a drug precursor) that is transformed in vivo to yield a compound of the invention or a pharmaceutically acceptable salt, hydrate or solvate of the compound The transformation may occur by various mechanisms (e g , by metabolic or chemical processes), such as, for example, through hydrolysis in blood
  • T Higuchi and W Stella "Pro-drugs as Novel Delivery Systems," VoI
  • a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (C 1 -C 6 )alkyl, (C 2 - C 12 )alkanoyloxymethyl, 1 -(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1 - methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1 -(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)am ⁇ nomethyl having from 3 to 9 carbon atoms, 1 -
  • a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (CrC 6 )alkanoyloxymethyl, 1-((C 1 -C 6 )alkanoyloxy)ethyl, 1-methyl-1-((C 1 -C 6 )alkanoyloxy)ethyl, (C 1 -C 6 )alkoxycarbonyloxymethyl, N-(C 1 -C 6 )alkoxycarbonylam ⁇ nomethyl, succinoyl, (CrC 6 )alkanoyl, ⁇ -am ⁇ no(C 1 -C 4 )alkanyl, arylacyl and ⁇ -am ⁇ noacyl, or ⁇ -aminoacyl- ⁇ - aminoacyl, where each ⁇ -am ⁇ noacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH
  • a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR'-carbonyl where R and R' are each independently (C 1 -C 1 o)alkyl, (C 3 -C 7 ) cycloalkyl, benzyl, or R-carbonyl is a natural ⁇ -am ⁇ noacyl or an unnatural ⁇ -am ⁇ noacyl, — C(OH)C(O)OY 1 wherein Y 1 is H, (CrCjs)alkyl or benzyl, -C(OY 2 )Y 3 wherein Y 2 is (C 1 -C 4 ) alkyl and Y 3 is (d- C 6 )alkyl, carboxy (CrC 6 )alkyl, am ⁇ no(C 1 -C 4 )alkyl or mono
  • One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms
  • “Solvate” means a physical association of a compound of this invention with one or more solvent molecules This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding
  • the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid
  • suitable solvates include ethanolates, methanolates, and the like
  • “Hydrate” is a solvate wherein the solvent molecule is H 2 O
  • One or more compounds of the invention may optionally be converted to a solvate
  • Preparation of solvates is generally known Thus, for example, M Caira ef a/, J Pharmaceutical Sci 93(3), 601-611 (2004)
  • Effective amount or “therapeutically effective amount” is meant to describe an amount of compound or a composition of the present invention effective in inhibiting the above-noted diseases and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect
  • salts can form salts which are also within the scope of this invention
  • Reference to a compound of the invention herein is understood to include reference to salts thereof, unless otherwise indicated
  • the term "salt(s)" denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases
  • a compound of the invention contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid
  • zwitterions inner salts
  • Pharmaceutically acceptable ( ⁇ e , non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful Salts of the compounds of the invention may be formed, for example, by reacting a compound of the invention with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipit
  • Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like
  • acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P Stahl et al, Camille G (eds ) Handbook of Pharmaceutical Salts Properties, Selection and Use (2002) Zurich Wiley- VCH, S Berge et al,
  • Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as argimne, lysine and the like
  • Basic nitrogen-containing groups may be quatemized with agents such as lower alkyl halides (e g methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e g dimethyl, diethyl, and dibutyl sulfates), long chain halides (e g decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e g benzyl and phenethyl bromides), and others
  • esters of the present compounds include the following groups (1 ) carboxylic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl n- propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl) aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted with, for example, halogen, C 1 4 alkyl, or C 1 - 4 alkoxy or amino), (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl), (3) amino acid esters (for example, L-valyl or L-isoleucyl), (4)
  • the compounds of the invention may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomers forms It is intended that all stereoisomers forms of the compounds of the invention as well as mixtures thereof, including racemic mixtures, form part of the present invention
  • the present invention embraces all geometric and positional isomers
  • Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e g , chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereo
  • an appropriate optically active compound e g , chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
  • All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4- py ⁇ dyl and 3-pyr ⁇ dyl) (For example, if a compound of the invention incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention )
  • the compounds of the invention have the general structure shown in Formula (ll-b):
  • Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers.
  • the chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations.
  • the use of the terms "salt”, “solvate”, “ester”, “prodrug” and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.
  • the present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, 36 S, 18 F, and 36 CI, respectively
  • Certain isotopically-labelled compounds of the invention e g , those labeled with 3 H and 14 C
  • Tritiated ( ⁇ e , 3 H) and carbon-14 ( ⁇ e , 14 C) isotopes are particularly preferred for their ease of preparation and detectability Further, substitution with heavier isotopes such as deuterium ( ⁇ e , 2 H) may afford certain
  • flash chromatography is carried out on an Isco, Analogix, or Biotage automated chromatography system using a commercially available cartridge as the column Columns may be purchased from Isco, Analogix, Biotage, Vanan, or Supelco and are usually filled with silica gel as the stationary phase Microwave chemistry is performed in sealed glass tubes in a Biotage microwave oven
  • the amino intermediates such as vi can be oxidized to the spiro-imidazolone intermediates vii (e.g. Dean, A.W., Porter, R.A , WO 2007014762).
  • the ester in vii can be hydrolyzed to provide the acid viii.
  • the acid can be coupled to amines using standard protocols to provide the amides such as x.
  • One skilled in the art would recognize that there are numerous coupling conditions for formation of amides.
  • acids viii will produce amino-tetrazole terminated compounds such as xc using standard amide bond coupling procedures that are known to those skilled in the art.
  • diastereomers can be purified by crystallization or chiral HPLC methods that are known to those skilled in the art
  • the pure diasteroemers xvi and xvii can be treated with HCI to provide the enantiomerically enriched amine HCI salt xviii and xix, respectively
  • the N-BOC glycine xxii can be processed heterocycles such as xxvi using previously described procedures
  • the heterocycles can be treated with m-CPBA to provide the hydroxy intermediates xxvii
  • the hydroxy intermediates xxvii can be converted into the corresponding inflate intermediates xxviii
  • the inflate intermediates xxviii can be converted into the arylated analogs xxix using standard palladium catalyzed chemistry that is known by those skilled in the art Further transformation of the arylated intermediates xxix into the desired compounds has previously been described
  • the Boc-glycine xxii can be converted into spiro-amides of the type xxv These can be treated with m-CPBA which provide oxidized heterocycles such as xxxii Heterocycles such as xxxii can be treated with Br 2 PPri 3 to provide bromide analogs of the type xxxiii These intermediates can be reacted with various organometallic reagents to furnish arylated intermediates such as xxix. As shown previously, these intermediates can be processed into the desired compounds xxxi using standard procedures
  • Racemic 2-(fert-butoxycarbonylamino)-2-(3,5-dichlorophenyl)acetic acid (1.64 g, 5.1 mmol), (R)-methyl 4-(1-aminoethyl)benzoate HCI (1.0 g, 4.65 mmol), PyBOP (2.66 g, 5.1 mmol), and JPr 2 NEt (2.4 mL) were taken up in CH 3 CN (35 mL), and the solution was stirred at room temperature for 18 hours. The solution was concentrated, and the residue was partitioned between EtOAc and sat. NaHC03( aq .).
  • Example 1 2 The product from Step 6 (300 mg, 0 52 mmol) was reacted according to the procedure outlined in Step 7 of Scheme A to afford 87 mg (32 %) of Example 1.2 as a white solid LC/MS ret time (4 9 mm), (MH) + 516
  • the benzoic acid in Scheme C was prepared according to the procedure outlined in Scheme A (Steps 1 - 5) using the amino acid, ketone, and amine
  • the benzoic acid (65 mg, 0 13 mmol), PyBOP (83 mg, 0 16 mmol), IPr 2 NEt (0 1 ml_), and aminotetrazole hydrate (20 mg) were taken up in CH 3 CN (10 mL)
  • the solution was heated to 80 °C until everything had dissolved
  • the solution was stirred at room temperature (18 hours)
  • the formed solid was collected and washed with Et 2 O which provided 24 mg (33 %) of Example 1.3 as a white solid LC/MS ret time (6 0 mm), (MH) + 554
  • the benzoic acid in Scheme E was prepared according to the procedure outlined in Scheme A (Steps 1 - 5) using the requisite amino acid, ketone, and amine.
  • the benzoic acid 200 mg, 0.42 mmol
  • DCM 35 mL
  • Oxalyl chloride 0.1 mL
  • DMF 3-4 drops
  • the acid chloride from Step 1 was partitioned between DCM and sat. NaHCU 3 ( aq.j.
  • the ⁇ -alanine tert-butyl ester HCI salt (115 mg, 0.63 mmol) was added, and the mixture was stirred at room temperature for 2 hours.
  • the layers were separated, and the aqueous layer was extracted with DCM.
  • the combined organic layers were dried (MgSCU), filtered, and concentrated.
  • the residue was purified via gradient flash chromatography (Analogix, 0-35 % EtOAc in hexanes, SiO 2 ) which afforded 194 mg (77 %) of the fert-butyl ester as a colorless foam.
  • Example 1.6 as a white foam (111 mg, 61 %).
  • the Boc-protected peptide (1 6 g, 2 76 mmol) and TFA (3 ml) were taken up in DCM (10 ml), and the solution was stirred at 25 °C for 18 h The solution was concentrated The residue was partitioned between DCM and 1 N NaOH( aq > The aqueous layer was extracted with with DCM The combined organic layers were dried (MgSO ⁇ , filtered, and concentrated The amino-peptide (1 3 g, Quant ) was used without further purification
  • the ketone (866 mg, 3 7 mmol), Ti(OEt) 4 (0.94 mL, 4.5 mmol), and the (R) sulfinamide (493 mg, 4 mmol) were taken up in THF (40 mL). The resulting solution was heated at 70 °C for 16 h The solution of the imine was used without further purification.
  • the benzoic acid was prepared according to Scheme I (Steps 1 -5) using the appropriate amino acid, amine, and ketone
  • the benzoic acid (90 mg, 0 18 mmol), IPr 2 NEt (0 12 mL, 0 72 mmol), PyBOP (122 mg, 0 23 mmol), and taurine (34 rng, 0 27 mmol) were taken up in DMF (4 mL), and the resulting solution was heated at 80 °C for 2 5 h
  • the reaction was concentrated
  • the residue was purified via reversed- phase chromatography (water/CH 3 CN gradient) which provided 85 mg (77%) of Example 1.72 as a colorless foam
  • the benzoic acid was prepared according to Scheme I (Steps 1 -5) using the appropriate amino acid, amine, and ketone
  • the benzoic acid 200 mg, 04 mmol
  • 1Pr 2 NEt 158 mg
  • HOBt 83 mg
  • EDCI 117 mg
  • taurine 76 mg
  • the reaction was quenched with 1 M HCI( aq )
  • the resulting solid was collected and purified via reversed-phase chromatography (water/CHaCN gradient) which provided 33 mg (14 %) of Example 1.73 as a colorless foam
  • the benzoic acid was prepared according t Scheme I 1 -5) using the appropriate amino acid, amine, and ketone
  • the benzoic acid (320 mg, 0.71 mmol) and pyridine (0.2 mL) were taken up in DCM (15 mL) at 0 °C. Cyanuric fluoride (0.13 ml) was added, and the resulting solution was stirred at 0 °C for 2 h.
  • the solution was diluted with DCM and washed with sat. NaHCC ⁇ aq.)
  • the aqueous layer was extracted with DCM.
  • the combined organic layers were dried (MgSO4, filtered and concentrated.
  • the acid fluoride was used without further purification.
  • Example 1 76 The acid fluoride (0 7 mmol) from the previous step and amino-tetrazole hydrate (70 mg) were taken up in pyridine and stirred at 25 °C for 18 h The solution was concentrated The residue was purified via reversed-phase chromatography (water/CH 3 CN gradient) provided 47 mg (12 %) of Example 1 ,76 as a colorless solid
  • the methyl ester was prepared according to Scheme I (Step 1 -4) using the appropriate amino acid, amine, and ketone
  • the methyl ester (350 mg, 0 6 mmol) was taken up in DMF (5 ml_) Sodium hydride (40 mg, 60% wt dispersion in oil) was added The solution was stirred at 25 °C for 1 hr Methyl iodide (150 mg) was added, and the solution was stirred at 25 °C for 3 h More NaH and MeI were added, and the resulting solution was stirred at 25 °C for 18 h
  • the solution was partitioned between Et 2 O and water The aqueous layer was extracted with Et 2 O The combined organic layers were washed with brine and dried (MgSCU) Filtration and concentration gave an orange oil
  • the residue was purified via gradient flash chromatography (0-25 % EtOAc in hexanes, S1O2) which provided 220 mg (61 %) of the methyl ether
  • Step 2 The methyl ester HCI salt (3 5 g, 13 mmol) was taken up in MeOH (45 ml) A methanol solution containing NH 3 (7 N, 80 mL) was added, and the resulting solution was stirred at 25 °C for 50 h The solution was concentrated The residue was partitioned between DCM and water The aqueous layer was extracted with DCM The combined organic layers were dried (MgSO ⁇ , filtered, and concentrated This provided 2 7 g (95 %) of the ammo-amide as a colorless solid
  • the spiro-amide (589 mg, 1 1 mmol) was taken up in DCM (20 ml), and NBS (235 mg, 1 32 mmol) was added. After stirring at 25 °C for 1 h, t ⁇ ethylamine (445 mg, 44 mmol) was added, and the solution was stirred at 25 °C for 2 h The solution was concentrated. The residue was purified via gradient flash chromatography (0-20% EtOAc in hexanes, SiO 2 ) which provided 386 mg (66%) of the bromo thiophene as a white solid
  • Triphenylphosphine (220 mg, 0 84 mmol) was taken up in DCM (1 mL), and bromine (40 ⁇ L) was added at 0 °C After stirring at 0 °C for 15 minutes, the nitrone (250 mg, 0 56 mmol) and triethylamine (0 17 mmol) was added at 0 °C The solution was warmed to 25 °C and stirred at that temperature for 1 h The solution was diluted with DCM and washed with brine The aqueous layer was extracted with DCM The combined organic layers were dried (MgSO 4 ), filtered, and concentrated The residue was purified via gradient flash chromatography (0-40% EtOAc in hexanes, SiO 2 ) to provide the desired product contaminated with triphenylphosphine oxide The material was purified via gradient flash chromatography (0-30% EtOAc in hexanes, SiO 2 ) which provided 60 mg (21 %) of the bromide as an oil
  • Example 4.1 was prepared according to the procedures outlined in Scheme T using Steps 2 and 8.
  • Example 4.2 was prepared according to the procedures outlined in Scheme T using Steps 2 and 8.
  • Example 4.11 was prepared according to the procedures outlined in Scheme T using Steps 2 and 8.
  • Example 4.12 was prepared according to the procedures outlined in Scheme T using the Steps 2 and 8.
  • the starting material (prepared according to Scheme I - Steps 1-5) was taken up in 1 N NaOH (aq ) /d ⁇ oxane/MeOH [1/1/1 , 10 mL], and the solution was heated at 60 °C for 14 hours. The solution was cooled to the room temperature The solution was concentrated. The residue was partitioned between DCM and 1 M HCI ⁇ aq >. The mixture was stirred at room temperature for 0.5 h. The layers were separated, and the aqueous layer was extracted with DCM The combined organic layers were dried (Na 2 SO,t), filtered, and concentrated which afforded the acid as a white solid.
  • the bromide was prepared according to the Scheme I (Steps 1 -5) using the requisite amino acid, amine, and ketone.
  • Triphenylphosphine (69 mg, 0 263 mmol, 1 4 eq) was dissolved in CH 2 CI 2 (0 3 mL) and was cooled to 0°C Bromine (0 013 mL, 024 mmol, 1 3 eq) was added and the resulting mixture was stirred for 10 minutes at 0°C
  • the nitrone from Step 1 70 mg, 0 20 mmol, 1 eq
  • triethylamine (0 035 mL, 0 25 mmol, 1 3 eq) at 0°C
  • the ice bath was removed and the reaction was stirred for 2 hours at room temperature
  • the reaction was partitioned between CH 2 CI 2 and brine
  • the organic layer was separated and saved
  • the aqueous layer was extracted with CH 2 CI 2
  • the organic layers were combined and evaporated to afford a residue which was purified via silica gel chromatography (gradient elution, 0% to 100% Et
  • Step 1
  • Methyl 4-(cyanomethyl)benzoate (1 8 g, 10 mmol, 1 eq) was dissolved in THF (100 mL) and cooled to 0°C Sodium hydride (60% w/w in mineral oil, 820 mg, 20 mmol, 2 eq) was added portionwise and the mixture was stirred for 10 minutes Methyl iodide (1 3 mL, 20 mmol, 2 eq) was added dropwise and the reaction was stirred at 0°C until the starting material was consumed by TLC (2 hours) The reaction mixture was quenched with water and was partitioned between EtOAc and brine The aqueous layer was discarded, and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated to afford a crude residue which was chromatographed on silica gel (gradient elution, 0% to 50% EtOAc in hexanes, SiO 2 ) to afford the desired product as
  • Step i
  • Example 1.557 Intermediate AAI-3 (33 mg, 0.052 mmol, 1 eq) was dissolved in CH2CI2 (6 ml_). Trifluoroacetic acid (3 mL) was added and the reaction was stirred for 3h at room temperature. The volatiles were removed in vacuo to afford a crude residue which was purified via reversed-phase, C-18 column chromatography (gradient elution, 10% to 80% MeCN in water with 0.1% HCOOH) to afford Example 1.557 (20 mg) as a white solid.
  • Example 1.552 (110 mg) as a white solid.
  • Example 1.375 was prepared in a manner similar to that described in Steps 1 -2 of Scheme AAL with the exception that (S)-methyl 3-am ⁇ no-2-hydroxypropanoate hydrochloride was substituted for (fi)-methyl 3-am ⁇ no-2-hydroxypropanoate hydrochloride
  • the sulfinimine (90 0 g, 305 mmol, 1 00 eq) was dissolved in CH 2 CI 2 (1000 mL), and the solution was cooled to -40°C.
  • the previously prepared isopentylmagnesium bromide solution was added dropwise over a one hour period via a dropping funnel to the sulfinimine solution
  • the reaction was stirred at -40°C for 4h.
  • the reaction was stirred for an additional 16h, during which time the cold bath was allowed to expire Saturated ammonium chloride ⁇ «,) was added to the reaction and the resulting murky suspension was stirred for 30 mm
  • An attempt to filter the reaction through Celite® resulted in a clogged filter pad.
  • the crude reaction including the clogged Celite® pad was transferred to an Erlenmeyer flask EtOAc (2000 mL) and 20% sodium citrate ( 3q > (2000 mL) were added to the crude mixture and the solution was stirred for 2h.
  • EtOAc Erlenmeyer flask
  • 3q > 2000 mL
  • the biphasic solution was filtered, and the Celite® left behind in the filter was washed with EtOAc and water
  • the combined biphasic filtrate was separated.
  • the aqueous layer was extracted with EtOAc
  • the organic layers were combined, washed with brine twice, dried over anhydrous MgSO 4 , filtered, and evaporated to afford a viscous green oil.
  • the enriched material was recrystalized from hot hexanes to afford the major diastereomer (intermediate AAN-1 , 9.71 g, 99.8.0.1 dr, ChiralPak AD, 95 5 hexanes.isopropanol, 1 mL/min, 254 nm) as white crystals Additional crops of crystals can be obtained from the mixed fractions.
  • Example 1.539 was prepared from Intermediate AAO-3 in a manner similar to that described in Steps 1-2 of Scheme J.
  • Intermediate AAP-1 was prepared from the requisite starting materials in a manner similar to that described in Steps 1-3 of Scheme I.
  • Intermediate AAP-2 was prepared from Intermediate AAP-1 in a manner similar to that described in Steps 1-4 of Scheme AAA.
  • Example 2.118 was prepared from Intermediate AAP-2 in a manner similar to that described in Step 9 of Scheme AAE.
  • Example 1.556 was prepared using a method similar to that described in Step 1 of Scheme AAE followed by Steps 2-5 of Scheme I then Steps 1-2 of Scheme J
  • Example 1.532 was prepared from the benzoic acid in a manner similar to that described in Step 9 of Scheme AAE.
  • the grignard reagent was made as follows Magnesium turnings (2 4 g, 100 mmol) were suspended in dry Et 2 O (150 ml) under N 2 A few iodine crystals were added to the mixture The 1-bromo-3,3-d ⁇ emthyl butane (16 5 g, 100 mmol) in Et 2 O (50 ml) was added in portions over ⁇ 45 minutes to maintain gentle reflux After the addition of all of the 1 -bromo-3,3-d ⁇ emthyl butane, the reaction was refluxed for 2 hr The gringnard solution was used as is in the next step
  • the grignard reagent (100 mmol in 200 ml of Et 2 O) was added to a solution of the imine (9 9 g, 33 5 mmol) at -78°C The solution was slowly warmed to RT After stirring at RT for 2 h, the reaction was quenched with sat NH 4 CI( a q > at 0 °C Ethyl acetate was added, and the mixture was stirred at RT for 1 h The layers were separated, and the aqueous layer was extracted with EtOAc The combined organic layers were washed with brine and dried (MgS ⁇ 4) The mixture was filtered and concentrated The residue was purified via gradient flash chromatography (0-40% EtOAc in hexanes, SiO 2 ) The major fraction was recrystallized from heptane/IPA which yielded 2 8 g of the desired product. The mother liquor was recrystallized once again to provide an additional 1.3 g (32 % total).
  • Step i Magnesium turnings (2.21 g, 90.9 mmol) were stirred with a magnetic stir bar overnight in a 500 ml round-bottom flask Anhydrous ethyl ether 9173 ml) was added. 1-Bromo-5-methylhexane (15.0 g, 909 mmol) was added dropwise over 40 minutes. The solution was stirred at RT for 3 5 hours The grignard solution was added to (S)- isopropyl 4-((fert-butylsulf ⁇ nyl ⁇ m ⁇ no)methyl)benzoate (134 g, 45.4 mmol) in 100 mL anhydrous DCM at -48 °C.
  • the acid chloride (4.20 g, 28.8 mmol), PdCI 2 (PPh 3 )2 (960 mg, 5 mol%), and zinc reagent (55 ml, 27 45 mmol, 0.5 M in THF) were taken up in 60 mL THF at RT.
  • step 3 4, 5-tr ⁇ methylcyclohexanol obtained in step 1 was dissolved in dichloromethane.
  • Dess-Martin reagent 3.1 g, 7.34 mmol
  • T ⁇ fluoroacetic acid anhydride 0. 56 mL, 7 34 mmol
  • Sodium hydroxide (1 N, 30 mL) and diethyl ether (100 mL) were added.
  • the reaction mixture was stirred at RT for one hour.
  • BA-4 (387 mg, 0.65 mmol) was dissolved in dioxane (4 ml.) and methanol (2 mL) Aq 1.0 M lithium hydroxide was added (1.3 mL). The reaction mixture was stirred at RT overnight. After 20 h, additional aq 1 0 M LiOH was added (1 0 mL) About 7 h later, the reaction mixture was concentrated to near dryness. EtOAc (80 mL) and 1 0 M aq NaHSO 4 (10 mL) were added. The layers were separated. The aqueous layer was extracted with EtOAc The combined organic layer was gravity filtered and concentrated to dryness giving compound BA-5 as a white foam (0 33 g)
  • BA-5 14 5 mg, 0.026 mmol, 1 0 eq
  • beta alanine tert butyl ester hydrochloride 5 4 mg, 0.03 mmol
  • HOBT 3.6 mg, 0.026 mmol
  • CH 2 CI 2 03 mL
  • DIPEA 15 ⁇ L, 0.087 mmol
  • EDC 6 mg, 0.031 mmol
  • the vial was capped and the reaction mixture was left stirring at RT over the weekend
  • the reaction mixture was diluted with CH 2 CI 2 and washed with aq NH 4 CI, water, and brine
  • the resulting organic solution was gravity filtered and concentrated to dryness.
  • the crude product was purified via flash sgc using a 15% to 30% EtOAc/Hex gradient as the mobile phase. The major peak was collected as product to give 12 mg of BA-6 as a clear oil.
  • Compound BF-1 may be prepared using procedures similar to those described in Scheme I (Steps 1-4)
  • Compound BG-1 may be prepared using procedures similar to those described in Scheme I (Steps 1-4)

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Abstract

The present invention relates to compounds of the general formula: (I) wherein ring A, ring B, R1, R3, Z, L1, and L2 are selected independently of each other and are as defined herein, to compositions comprising the compounds, and to methods of using the compounds as glucagon receptor antagonists and for the treatment or prevention of type 2 diabetes and conditions related thereto.

Description

SPIRO-IMIDAZOLONE DERIVATIVES AS GLUCAGON RECEPTOR ANTAGONISTS
CROSS-REFERENCE TO RELATED APPLICATION
This application claims priority to provisional application U S Serial No 61/102,565, filed October 3 2008, incorporated by reference FIELD OF THE INVENTION
The present invention relates to certain novel compounds as glucagon receptor antagonists, compositions comprising these compounds, and methods for their use in treating, preventing, or delaying the onset of type 2 diabetes and related conditions BACKGROUND OF THE INVENTION
Diabetes refers to a disease state or process derived from multiple causative factors and is characterized by elevated levels of plasma glucose (hyperglycemia) in the fasting state or after administration of glucose during a glucose tolerance test Persistent or uncontrolled hyperglycemia is associated with a wide range of pathologies Diabetes melhtus, is associated with elevated fasting blood glucose levels and increased and premature cardiovascular disease and premature mortality It is also related directly and indirectly to various metabolic conditions, including alterations of lipid, lipoprotein, apohpoprotein metabolism and other metabolic and hemodynamic diseases As such, the diabetic patient is at increased risk of macrovascular and microvascular complications Such complications can lead to diseases and conditions such as coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy Accordingly, therapeutic control and correction of glucose homeostasis is regarded as important in the clinical management and treatment of diabetes melhtus. There are two generally recognized forms of diabetes In type 1 diabetes, or insulin-dependent diabetes melhtus (IDDM), the diabetic patient's pancreas is incapable of producing adequate amounts of insulin, the hormone which regulates glucose uptake and utilization by cells In type 2 diabetes, or noninsulin dependent diabetes melhtus (NIDDM), patients often produce plasma insulin levels comparable to those of nondiabetic subjects, however, the cells of patients suffering from type 2 diabetes develop a resistance to the effect of insulin, even in normal or elevated plasma levels, on glucose and lipid metabolism, especially in the main insulin- sensitive tissues (muscle, liver and adipose tissue) Insulin resistance is not associated with a diminished number of cellular insulin receptors but rather with a post-insulin receptor binding defect that is not well understood This cellular resistance to insulin results in insufficient insulin activation of cellular glucose uptake, oxidation, and storage in muscle, and inadequate insulin repression of lipolysis in adipose tissue, and of glucose production and secretion in the liver A net effect of decreased sensitivity to insulin is high levels of insulin circulating in the blood without appropriate reduction in plasma glucose (hyperglycemia) Hypeπnsulinemia is a risk factor for developing hypertension and may also contribute to vascular disease
The available treatments for type 2 diabetes, some of which have not changed substantially in many years, are used alone and in combination Many of these treatments have recognized limitations, however For example, while physical exercise and reductions in dietary intake of fat, high glycemic carbohydrates, and calories can dramatically improve the diabetic condition, compliance with this treatment is very poor because of well-entrenched sedentary lifestyles and excess food consumption, especially of foods containing high amounts of saturated fat Increasing the plasma level of insulin by administration of sulfonylureas (e g tolbutamide and glipizide) or meglitmide, which stimulate the pancreatic beta-cells to secrete more insulin, and/or by injection of insulin when sulfonylureas or meglitmide become ineffective, can result in insulin concentrations high enough to stimulate insulin-resistance in tissues However, dangerously low levels of plasma glucose can result from administration of insulin or insulin secretagogues (sulfonylureas or meglitmide), and an increased level of insulin resistance due to the even higher plasma insulin levels can occur The biguanides are a separate class of agents that can increase insulin sensitivity and bring about some degree of correction of hyperglycemia These agents, however, can induce lactic acidosis, nausea and diarrhea
The glitazones (ι e 5-benzylthιazolιdιne-2,4-dιones) are another class of compounds that have proven useful for the treatment of type 2 diabetes These agents increase insulin sensitivity in muscle, liver and adipose tissue in several animal models of type 2 diabetes, resulting in partial or complete correction of the elevated plasma levels of glucose without occurrence of hypoglycemia The ghtazones that are currently marketed are agonists of the peroxisome prohferator activated receptor (PPAR), primarily the PPAR-gamma subtype PPAR-gamma agonism is generally believed to be responsible for the improved insulin sensitization that is observed with the ghtazones Newer PPAR agonists that are being tested for treatment of Type Il diabetes are agonists of the alpha, gamma or delta subtype, or a combination thereof, and in many cases are chemically different from the ghtazones (ι e , they are not thiazolidinediones) Serious side effects (e g liver toxicity) have been noted in some patients treated with glitazone drugs, such as troghtazone
Compounds that are inhibitors of the dipeptidyl peptidase-IV (DPP-IV) enzyme are also under investigation as drugs that may be useful in the treatment of diabetes, and particularly type 2 diabetes Additional methods of treating hyperglycemia and diabetes are currently under investigation New biochemical approaches include treatment with alpha- glucosidase inhibitors (e g acarbose) and protein tyrosine phosphatase-1 B (PTP- 1 B) inhibitors
Other approaches to treating hyperglycemia, diabetes, and indications attendant thereto have focused on the glucagon hormone receptor Glucagon and insulin are the two primary hormones regulating plasma glucose levels Insulin, released in response to a meal, increases the uptake of glucose into insulin-sensitive tissues such as skeletal muscle and fat Glucagon, which is secreted by alpha cells in pancreatic islets in response to decreased postprandial glucose levels or during fasting, signals the production and release of glucose from the liver Glucagon binds to specific receptors in liver cells that trigger glycogenosis and an increase in gluconeogenesis through cAMP-mediated events These responses generate increases in plasma glucose levels (e g , hepatic glucose production), which help to regulate glucose homeostasis Type 2 diabetic patients typically have fasting hyperglycemia that is associated with elevated rates of hepatic glucose production This is due to increased gluconeogenesis coupled with hepatic insulin resistance Such patients typically have a relative deficiency in their fasting and postprandial insulin-to-glucagon ratio that contributes to their hyperglycemic state Several studies have demonstrated that hepatic glucose production correlates with fasting plasma glucose levels, suggesting that chronic hepatic glucagon receptor antagonism should improve this condition In addition, defects in rapid postprandial insulin secretion as well as ineffective suppression of glucagon secretion, lead to increased glucagon levels that elevate hepatic glucose production and contribute to hyperglycemia Suppression of elevated postprandial glucagon levels in type 2 diabetics with somatostatin has been shown to lower blood glucose concentrations This indicates that acute postprandial glucagon receptor antagonism would also be beneficial Based on these and other data, glucagon receptor antagonism holds promise as a potential treatment of type 2 diabetes by reducing hyperglycemia There is thus a need in the art for small- molecule glucagon receptor antagonists with good safety profiles and efficacy that are useful for the treatment of hyperglycemia, diabetes, and related metabolic diseases and indications The present invention addresses that need
SUMMARY OF THE INVENTION
In one embodiment, the compounds of the invention have the general structure shown in Formula (A)
Figure imgf000005_0001
(A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers of said compounds, wherein ring A, ring B, L1, L2, R1, R3, and Z are selected independently of each other and are as defined below
The invention also relates to compositions, including pharmaceutically acceptable compositions, comprising the compounds of the invention (alone and in combination with one or more additional therapeutic agents), and to methods of using such compounds and compositions as glucagon receptor antagonists and for the treatment or prevention of type 2 diabetes and conditions related thereto. DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the compounds of the invention have the general structure shown in Formula (A):
Figure imgf000006_0001
(A) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers of said compounds, wherein ring A, ring B, L1, L2, R1, R3, and Z are selected independently of each other and wherein:
L1 is selected from the group consisting of a bond, -N(R4)-, -N(R4)-(C(R5A)2)-(C(R5)2)q-, -(C(R5A)2)-(C(R5)2)r-(C(R5A)2)-N(R4)-, -O-, -O-(C(RSA)2)-(C(R5)2)q-, -(C(R5A)2)-(C(Rδ)2)r-(C(R5A)2)-O-, and -(C(R5A)2)-(C(R5)2)S-, each q is independently an integer from 0 to 5, each r is independently an integer from 0 to 3; s is an integer from 0 to 5; L2 is selected from the group consisting of a bond, -N(R4)-, -N(R4)-(C(R5A)2)-(C(R5)2),-, -(C(R5)2)U-(C(R5A)2)-N(R4)-, -O-, -O-(C(RSA)2)-(C(R5)2)r, -(C(R5)2)U-(C(R5A)2)-O-, -S-, -S-(C(R5A)2)-(C(R5)2),-,
-(C(R5)2)U-(C(R5A)2)-S-, -S(O)-, -S(O)-(C(RSA)2)-(C(R5)2),-, -(C(R5)2)U-(C(R5A)2)-S(O)-, -S(O)2-, -S(O)2-(C(RSA)2)-(C(R5)2)r, -(C(R5)2)U-(C(R5A)2)-S(O)2-, -(C(R5J2V, each t is independently an integer from 0 to 3; each u is independently an integer from 0 to 3, v is an integer from 1 to 5,
ring A represents a spirocycloalkyl ring or a spirocycloalkenyl ring, wherein said ring A is substituted on one or more available ring carbon atoms with from 0 to 5 independently selected R2 groups, or, alternatively, ring A represents a spiroheterocycloalkyl ring or a spiroheterocycloalkenyl ring, wherein said ring A is substituted on one or more available ring carbon atoms with from 0 to 5 independently selected R2 groups, and wherein said ring A is optionally further substituted on one or more available ring nitrogen atoms (when present) with from 0 to 3 R2A groups, ring B is a phenyl ring, wherein said phenyl ring is (in addition to the -L1- and -C(O)N(R3)-Z moieties shown) optionally further substituted with one or more substituents Ra, wherein each Ra (when present) is independently selected from the group consisting of halo, -OH, -SF5, -OSF5, alkyl, haloalkyl, heteroalkyl, hydroxyalkyl, alkoxy, and -O-haloalkyl, or ring B is a 5-membered heteroaromatic ring containing from 1 to 3 ring heteroatoms independently selected from N, O, and S, wherein said 5-membered heteroaromatic ring is (in addition to the -L1- and -C(O)N(R3)-Z moieties shown) optionally further substituted with one or more substituents Ra, wherein each Ra (when present) is independently selected from the group consisting of halo, -OH, -SF5, -OSF5, alkyl, haloalkyl, heteroalkyl, hydroxyalkyl, alkoxy, and -O-haloalkyl, or ring B is a 6-membered heteroaromatic ring containing from 1 to 3 ring nitrogen atoms, wherein said 6-membered heteroaromatic ring is (in addition to -L1- and -C(O)N(R3)Z moieties shown) optionally further substituted with one or more substituents Ra, wherein each Ra (when present) is independently selected from the group consisting of halo, -OH, -SF5, -OSF5, alkyl, haloalkyl, hydroxyalkyl, alkoxy, and - O-haloalkyl,
R1 is independently selected from the group consisting of aryl and heteroaryl, wherein said aryl and said heteroaryl of R1 are unsubstituted or substituted with one or more groups independently selected from
(1) halo, -OH, -CO2R6, -C(O)R6, -SR7, -S(O)R7, -SO2R7, -SF5, -OSF5, CN, NO2, -C(O)NR8R9, -NR8R9, -NR10-C(O)-NR8R9,
-NR10-CO2R6, -NR10-C(O)R6, -NR10-SO2R6, -SO2-NR8R9, -C(O)NR8R9, and -OC(O)NR8R9, (2) alkyl, alkoxy, heteroalkyl, -O-heteroalkyl, alkenyl, heteroalkenyl, alkynyl, and heteroalkynyl, wherein each of said alkyl, alkoxy, heteroalkyl, -O-heteroalkyl, alkenyl, heteroalkenyl, alkynyl, and heteroalkynyl, are unsubstituted or optionally independently substituted with one or more groups each independently selected from halo, OH, -CO2R6, -C(O)R8, -SR7, -S(O)R7, -SO2R7, CN, NO2, -C(O)NR8R9, -NR8R9, -O-haloalkyl, - NR10-C(O)-NR8R9, -NR10-C02Rβ, -NR10-C(0)R6,
-NR10-SO2Rβ, -SO2-NR8R9, -C(O)NR8R9, and -OC(O)NR8R9, and
(3) aryl, -O-aryl, -C(O)-aryl, -S-aryl, -S(O)-aryl, -S(O)2-aryl, -N(R4)-aryl, -C(O)-N(R4)-aryl, -N(R4)-C(0)-aryl heteroaryl, -O-heteroaryl,
-C(0)-heteroaryl, -S-heteroaryl, -S(O)-heteroaryl, -S(O)2-heteroaryl, -N(R4)-heteroaryl, -C(O)-N(R4)-heteroaryl, -N(R4)-C(O)-heteroaryl, cycloalkyl, -O- cycloalkyl, -C(O)- cycloalkyl, -S-cycloalkyl, -S(O)-cycloalkyl, -S(O)2-cycloalkyl, -N(R4)- cycloalkyl, -C(O)-N(R4)-cycloalkyl, -N(R4)-C(O)-cycloalkyl, heterocycloalkyl, -O- heterocycloalkyl, -C(O)- heterocycloalkyl, -S-heterocycloalkyl, -S(O)-heterocycloalkyl, -S(O)2-heterocycloalkyl, -N(R4)-heterocycloalkyl, -C(O)-N(R4)-heterocycloalkyl, -N(R4)-C(O)-heterocycloalkyl, cycloalkenyl, -O- cycloalkenyl, -C(O)- cycloalkenyl, -S-cycloalkenyl, -S(O)-cycloalkenyl, -S(O)2-cycloalkenyl, -N(R4)-cycloalkenyl,
-C(O)-N(R4)-cycloalkenyl, -N(R4)-C(O)-cycloalkenyl, heterocydoalkenyl, -O- heterocydoalkenyl, -C(O)-heterocycloalkenyl, -S-heterocycloalkenyl, -S(0)-heterocycloalkenyl, -S(O)2-heterocycloalkenyl, -N(R4)-heterocycloalkenyl, -C(O)-N(R4)-heterocycloalkenyl, and -N(R4)-C(O)-heterocycloalkenyl, each of which is unsubstituted or optionally independently substituted with from 1 to 2 groups each independently selected from (1 ) and (2) above, each R2 (when present) is independently selected from the group consisting of:
(a) phenyl substituted with from 0 to 5 groups independently selected from -OH, halo, alkyl, haloalkyl, hydroxyalkyl, alkyl substituted with from 1 to 2 -CO2R6 groups, alkoxy, -O-haloalkyl, hydroxyalkoxy, alkoxy substituted with from 1 to 2 -CO2R6 groups, -C(O)R6, -CO2R6, CN, -SO2R7, -SF5, -OSF6, -C(O)NR8R9, and -NO2,
(b) alkyl or heteroalkyl, each substituted with from O to 5 groups independently selected from -OH, oxo, halo, heteroalkyl, deuteroalkyl, alkoxy, -O-haloalkyl, -CO2R6, and phenyl substituted with from O to 5 groups independently selected from -OH, halo, aryl, substituted aryl, alkyl, alkoxy, heteroalkyl, haloalkyl, -O-haloalkyl, haloheteroalkyl, -CO2R6, CN, -S(O)R7, -S(O)2R7, -SF5, -OSF5, -C(O)NR8R9, and -NO2,
(C) -NR10-C(O)-NR8R8, -NR10-CO2R6, -NR10-C(0)R6, -NR8R9, -NR10SO2R6, -SO2-NR8R9, -C(O)NR8R9, and -OC(O)-NR8R9;
(d) cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, each substituted with from O to 5 groups independently selected from -OH, oxo, halo, heteroalkyl, alkoxy, -O-haloalkyl, -CO2R6, and phenyl substituted with from O to 5 groups independently selected from -OH, halo, aryl, substituted aryl, alkyl, alkoxy, heteroalkyl, haloalkyl, -O-haloalkyl, haloheteroalkyl, -CO2R6, CN, -S(O)R7, -S(O)2R7, -SF5, -OSF5, -C(O)NR8R9, -NR10-C(O)R6, -SO2-NR8R9, and -NO2,
(e) heteroaryl substituted from O to 5 groups independently selected from -OH, oxo, halo, heteroalkyl, alkoxy, -O-haloalkyl, -CO2R6, and phenyl substituted with from
O to 5 groups independently selected from -OH, halo, aryl, substituted aryl, alkyl, alkoxy, heteroalkyl, haloalkyl, -O-haloalkyl, haloheteroalkyl, -CO2R6, CN, -S(O)R7, -S(O)2R7, -C(O)NR8R9, -NR10-C(0)Rβ, -SO2-NR8R9, -SF5, -OSF5, and -NO2, and (f) -Sι(alkyl)3 or, alternatively, two R2 groups attached to the same atom of ring A are taken together to form a moiety selected from the group consisting of carbonyl, oxime, substituted oxime (said oxime substituents being independently selected from the group consisting of alkyl, haloalkyl, hydroxyl-substituted alkyl, and cycloalkyl), spirocycloalkyl, spiroheterocycloalkyl, spirocycloalkenyl, and spiroheterocycloalkenyl, or, alternatively, two R2 groups attached to adjacent ring atoms of ring A are taken together to form a 5-6-membered aromatic or heteroaromatic ring; each R2A (when present) is independently selected from the group consisting of -C(O)NR8R9, -CO2R6, -C(O)Rβ,-SO2R7, alkyl, heteroalkyl, haloalkyl, hydroxyl- substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl-, heteroaryl,
R3 is selected from H and lower alkyl,
Z is a moiety selected from -(C(R11)2)-(C(R12R13))m-C(O)OH, -(C(R11)2)-(C(R14)2)n-C(0)OH, from -(C(R11)2)-(C(R12R13))m-C(0)Oalkyl,
-(C(R11)2)-(C(R14)2)n-C(O)Oalkyl,
Figure imgf000010_0001
-(C(R11)2)-(C(R12R13))m-Q, and -(C(R11)2)-(C(R14)2)n-Q, wherein Q is a moiety selected from the group consisting of
Figure imgf000010_0002
m is an integer from O to 5, n is an integer from O to 5, p is an integer from O to 5,
each R4 is independently selected from H, -OH, lower alkyl, haloalkyl, alkoxy, heteroalkyl, cyano-substituted lower alkyl, hydroxy-substituted lower alkyl cycloalkyl, -O-cycloalkyl, -O-alkyl-cycloalkyl, and heterocycloalkyl, -O-heterocycloalkyl, and -O-alkyl-heterocycloalkyl, each R5A is independently selected from H, alkyl, -alkyl-Si(CH3)3, haloalkyl, heteroalkyl, cyano-substituted alkyl, hydroxy-substituted alkyl. cycloalkyl, -alkyl-cycloalkyl, and heterocycloalkyl, -alkyl-heterocycloalkyl, or, alternatively, two R5A groups are taken together with the carbon atom to which they are attached to form a carbonyl group, a spirocycloalkyl group, a spiroheterocycloalkyl group, an oxime group, or a substituted oxime group (said oxime substituents being independently selected from alkyl, haloalkyl, hydroxyl-substituted alkyl, and cycloalkyl); each R6 is independently selected from H, -OH, alkyl, -alkyl-Sι(CH3)3, haloalkyl, alkoxy, heteroalkyl, cyano-substituted alkyl, hydroxy-substituted alkyl, cycloalkyl, -alkyl-cycloalkyl, -O-cycloalkyl, -O-alkyl-cycloalkyl, and heterocycloalkyl, -alkyl-heterocycloalkyl, -O-heterocycloalkyl, and -O-alkyl-heterocycloalkyl, or, alternatively, two R5 groups bound to the same carbon atom are taken together with the carbon atom to which they are attached to form a carbonyl group, a spirocycloalkyl group, a spiroheterocycloalkyl group, an oxime group, or a substituted oxime group (said oxime substituents being independently selected from alkyl, haloalkyl, hydroxyl-substituted alkyl, and cycloalkyl); each R6 is independently selected from H1 alkyl, haloalkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, and heteroalkynyl, each R7 is independently selected from H, alkyl, heteroalkyl, and haloalkyl; each R8 is independently selected from H and alkyl; each R9 is independently selected from H and alkyl, or alternatively R8 and R9 are taken together with the nitrogen to which they are attached to form a 5-, 6-, or 7-membered saturated heterocyclic ring, or a 5-, 6-, or 7- membered unsaturated heterocyclic ring, which ring contains (including said nitrogen) from 1 to 2 ring heteroatoms each independently selected from N, N-oxide, O, S, S(O), or S(O)2, or alternatively R8 and R9 are taken together with the nitrogen to which they are attached to form a 5-membered heteroaromatic ring containing (including the nitrogen to which R8 and R9 are attached) from 1 to 3 ring nitrogens; each R10 is independently selected from H and alkyl; each R11 is independently selected from H and lower alkyl; each R12 is independently selected from H, lower alkyl, -OH, hydroxy- substituted lower alkyl, each R13 is independently selected from H, unsubstituted lower alkyl, lower alkyl substituted with one or more groups each independently selected from hydroxyl and alkoxy, or R12 and R13 are taken together to form an oxo, and each R14 is independently selected from H and fluoro
In one embodiment, in Formula (A), ring A represents a 3-8-membered spirocycloalkyl or spirocycloalkenyl ring In one embodiment, in Formula (A), ring A represents a 3-8-membered spirocycloalkyl or spirocycloalkenyl ring, which ring is substituted with from 1 to 5 independently selected R2 groups, which R2 groups may be attached to the same or different ring carbon atom(s)
In one embodiment, in Formula (A), ring A represents a 3-8-membered spirocycloalkyl or spirocycloalkenyl ring, which ring is substituted with from 1 to 3 independently selected R2 groups, which R2 groups may be attached to the same or different ring carbon atom(s)
In one embodiment, in Formula (A), ring A represents a 3-8-membered spirocycloalkyl or spirocycloalkenyl ring, which ring is substituted with from 1 to 2 independently selected R2 groups, which R2 groups may be attached to the same or different ring carbon atom(s)
In one embodiment, in Formula (A), ring A represents a 3-8-membered spirocycloalkyl or spirocycloalkenyl ring, which ring is substituted with 1 R2 group In one embodiment, in Formula (A), ring A represents a 4-6-membered spirocycloalkyl or spirocycloalkenyl ring
In one embodiment, in Formula (A), ring A represents a 4-6-membered spirocycloalkyl or spirocycloalkenyl ring, which ring is substituted with from 1 to 5 independently selected R2 groups, which R2 groups may be attached to the same or different ring carbon atom(s)
In one embodiment, in Formula (A), ring A represents a 4-6-membered spirocycloalkyl or spirocycloalkenyl ring, which ring is substituted with from 1 to 3 independently selected R2 groups, which R2 groups may be attached to the same or different ring carbon atom(s)
In one embodiment, in Formula (A), ring A represents a 4-6-membered spirocycloalkyl or spirocycloalkenyl ring, which ring is substituted with from 1 to 2 independently selected R2 groups, which R2 groups may be attached to the same or different ring carbon atom(s)
In one embodiment, in Formula (A), ring A represents a 4-6-membered spirocycloalkyl or spirocycloalkenyl ring, which ring is substituted with 1 R2 group
Non-limiting examples of ring A when ring A represents a spirocycloalkyl ring, which may be unsubstituted or substituted as described herein, include sprirocyclobutyl, spirocyclopentyl, spirocyclohexyl, spirocycloheptyl, spirocyclooctyl, spironorbornanyl, and spiroadamantanyl
Non-limiting examples of ring A when ring A represents a spirocycloalkenyl ring, which may be unsubstituted or substituted as described herein, include partially or fully unsaturated versions of the spirocycloalkyl moieties described above Non- hmiting examples include spirocyclopentenyl, spirocyclohexenyl, spirocycloheptenyl, and spirocyclooctenyl
In one embodiment, in Formula (A), ring A represents a 3-8-membered spiroheterocycloalkyl ring containing up to 3 ring heteroatoms, 1-3 of which are selected from O, S, S(O), S(O)2, and N or N-oxide
In one embodiment, in Formula (A), ring A represents a 3-8-membered spiroheterocycloalkenyl ring containing up to 3 ring heteroatoms, 1-3 of which are selected from O, S, S(O), S(O)2, and N or N-oxide
In one embodiment, in Formula (A), ring A represents a 3-8-membered spiroheterocycloalkyl ring containing up to 3 ring heteroatoms, 0-1 of which are O, S, S(O), and S(O)2, and 1 -2 of which are N or N-oxide, which ring A is substituted on one or more available ring carbon atom(s) with from 1 to 5 independently selected R2 groups and which ring A is optionally further substituted on one or more available ring nitrogen atoms with from O to 2 independently selected R2A groups
In one embodiment, in Formula (A), ring A represents a 3-8-membered spiroheterocycloalkenyl ring containing up to 3 ring heteroatoms, 0-1 of which are O, S, S(O), and S(O)2, and 1 -2 of which are N or N-oxide, which ring A is substituted on one or more available ring carbon atom(s) with from 1 to 5 independently selected R2 groups, and which ring A is optionally further substituted on one or more available ring nitrogen atoms with 0 to 2 independently selected R2* groups In one embodiment, in Formula (A), ring A represents a 4-8-membered spiroheterocycloalkyl ring containing up to 3 ring heteroatoms 0-1 of which are O, S, S(O), and S(0)2, and 1 -2 of which are N or N-oxide, which ring A is substituted on one or more available ring carbon atom(s) with from 1 to 5 independently selected R2 groups, and which ring A is optionally further substituted on one or more available ring nitrogen atoms with O to 2 independently selected R2* groups
In one embodiment, in Formula (A), ring A represents a 4-8-membered spiroheterocycloalkenyl ring containing up to 3 ring heteroatoms, 0-1 of which are O, S, S(O), and S(O)2, and 1 -2 of which are N or N-oxide, which ring A is substituted on one or more available ring carbon atom(s) with from 1 to 5 independently selected R2 groups, and which ring A is optionally further substituted on one or more available ring nitrogen atoms with O to 2 independently selected R2* groups
In one embodiment, in Formula (A), ring A represents a spiropiperidinyl ring In one embodiment, in Formula (A), ring A represents a spiropiperidinyl ring, which ring A is substituted on one or more available ring carbon atom(s) with from 1 to 5 independently selected R2 groups, and which ring A is optionally further substituted on the spiropiperidinyl nitrogen with R2*
In one embodiment, in Formula (A), ring A represents a spiropiperidinyl ring, which ring A is substituted on one or more available ring carbon atom(s) with from 1 to 3 independently selected R2 groups In one embodiment, in Formula (A), ring A represents a spiropiperidinyl ring, which ring A is substituted on one or more available ring carbon atom(s) with from 1 to 2 independently selected R2 groups
In one embodiment, in Formula (A), ring A represents a spiropiperidinyl ring, which ring A is substituted on one or more available ring carbon atom(s) with an R2 group
Additional non-limiting examples of ring A when ring A represents a spiroheterocycloalkyl ring, which may be unsubstituted or substituted as described herein, include spiropyrrolidinyl, spirodioxolanyl, spiroimidazolidinyl, spiropyrazolidinyl, spiropipeπdinyl, spirodioxanyl, spiromorpholinyl, spirotetrahydropyranyl, spirodithianyl, spirothiomorpholinyl, spriro piperazinyl, and spirotrithianyl
Additional non-limiting examples of ring A when ring A represents a spiroheterocycloalkyenyl ring, which may be unsubstituted or substituted as described herein, include unsaturated versions of the following moieties spiropyrrolidinyl, spirodioxolanyl, spiroimidazolidinyl, spiropyrazolidinyl, spiropiperidinyl, spirodioxanyl, spiromorpholinyl, spirodithianyl, spirothiomorpholinyl, spriro piperazinyl, and spirotrithianyl
In one embodiment, the compounds of the invention have the general structure shown in Formula (A-1)
Figure imgf000015_0001
(A-I) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers of said compounds, wherein ring B, L1, L2, R1, each R2, R3, and Z are selected independently of each other and as defined in Formula (A)
In one embodiment, the compounds of the invention have the general structure shown in Formula (A-1 a)
Figure imgf000016_0001
(A-Ia) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers of said compounds, wherein ring B, L1, L2, R1, each R2, R3, and Z are selected independently of each other and as defined in Formula (A)
In one embodiment, the compounds of the invention have the general structure shown in Formula (A-1 b)
Figure imgf000016_0002
(A-1 b) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers of said compounds, wherein ring B, L1, L2, R1, R2, R3, and Z are selected independently of each other and as defined in Formula (A)
In one embodiment, the compounds of the invention have the general structure shown in Formula (A-2a)
Figure imgf000017_0001
(A 2a) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers of said compounds, wherein ring B, L1, L2, R1, each R2, R3, and Z are selected independently of each other and as defined in Formula (A)
In one embodiment, the compounds of the invention have the general structure shown in Formula (A-2b)
Figure imgf000017_0002
(A-2b) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers of said compounds, wherein ring B, L1, L2, R1, each R2, R3, and Z are selected independently of each other and as defined in Formula (A)
In one embodiment, the compounds of the invention have the general structure shown in Formula (A-2c)
Figure imgf000018_0001
(A-2c) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers of said compounds, wherein ring B, L1, L2, R1, R2, R3, and Z are selected independently of each other and as defined in Formula (A)
In one embodiment, the compounds of the invention have the general structure shown in Formula (A-2d)
Figure imgf000018_0002
(A-2d) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers of said compounds, wherein ring B, L1, L2, R1, R2, R3, and Z are selected independently of each other and as defined in Formula (A) In one embodiment, in each of Formula (A), Formula (A-1), Formula (A-1 a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), and Formula (A-2d), ring B is a phenyl ring wherein the -L1- and the -C(O)N(R3)Z moieties shown in the formula are bound to said phenyl ring in a 1 ,4-relatιonshιp, and wherein said phenyl ring is (in addition to the -L1- and -C(O)N(R3)-Z moieties shown) optionally further substituted with one or more substituents Ra, wherein each Ra (when present) is independently selected from the group consisting of halo, alkyl, and haloalkyl,
In one embodiment, in each of Formula (A), Formula (A-1), Formula (A-1 a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), and Formula (A-2d), ring B is a 5-membered heteroaromatic ring containing from 1 to 3 ring heteroatoms independently selected from N, O, and S, wherein the -L1- and the -C(O)N(R3)-Z moieties shown in the formula are bound to said 5-membered ring in a 1 ,3-relatιonshιp, and wherein said 5-membered heteroaromatic ring is (in addition to the -L1- and -C(O)N(R3)-Z moieties shown) optionally further substituted with one or more substituents Ra, wherein each Ra (when present) is independently selected from the group consisting of halo, alkyl, and haloalkyl,
In one embodiment, in each of Formula (A), Formula (A-1), Formula (A-1 a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), and Formula (A-2d), ring B is a 6-membered heteroaromatic ring containing from 1 to 3 ring nitrogen atoms, wherein the -L1- and the -C(O)N(R3)-Z moieties shown in the formula are bound to said 6-membered ring in a 1 ,4-relatιonshιp, and wherein said 6- membered heteroaromatic ring is (in addition to -L1- and -C(O)N(R3)Z moieties shown) optionally further substituted with one or more substituents Ra, wherein each Ra (when present) is independently selected from the group consisting of halo, alkyl, and haloalkyl,
In one embodiment, in each of Formula (A), Formula (A-1), Formula (A-1 a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), and Formula (A-2d), ring B is phenyl
In one embodiment, in each of Formula (A), Formula (A-1), Formula (A-1 a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), and Formula (A-2d), ring B is phenyl which, in addition to the moieties -L1- and - C(O)N(R3)-Z shown in the formula, is further substituted with one or more independently selected Ra groups
In one embodiment, in each of Formula (A), Formula (A-1), Formula (A-1a),
Formula (A-1b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), and Formula (A-2d), ring B is a phenyl which, in addition to the moieties -L1- and -
C(O)N(R3)-Z shown in the formula, is further substituted with from 1 to 2 substituents, each independently selected from halo, alkyl, and haloalkyl
In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1 a),
Formula (A-1b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), and Formula (A-2d), ring B is a 5-membered heteroaromatic ring having from 1 to 3 ring heteroatoms independently selected from N, O, and S, wherein said ring B is not further substituted
In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1 a),
Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), and Formula (A-2d), ring B is a 6-membered heteroaromatic ring having from 1 to 3 ring nitrogen atoms, wherein said ring B is not further substituted
In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1 a),
Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), and Formula (A-2d), ring B is a 5-membered heteroaromatic ring having from 1 to 3 ring heteroatoms independently selected from N, O, and S, wherein said ring B is further substituted with one or more substituents Said further substituents in such embodiments may be bound to one or more available ring carbon atoms and/or ring nitrogen atoms
In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1 a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), and Formula (A-2d), ring B is a 6-membered heteroaromatic ring having from 1 to 3 ring nitrogen atoms wherein said ring B is further substituted with one or more substituents Said further substituents in such embodiments may be bound to one or more available ring carbon atoms and/or ring nitrogen atoms In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1 a),
Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), and Formula (A-2d), ring B is a 5- membered heteroaromatic ring having from 1 to 3 ring heteroatoms independently selected from N, O, and S, wherein said 5- membered heteroaromatic ring is further substituted with from 1 to 2 substituents, each substituent being independently selected from halo, alkyl, and haloalkyl In one such embodiment, ring B contains two said substituents In another such embodiment, ring B contains one said substitutent In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1 a),
Formula (A-1b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), and Formula (A-2d), ring B is a 5-membered heteroaromatic ring, non-limiting examples of such rings include, but are not limited to furan, thiophene, pyrrole, imidazole, pyrazole, 1 ,2,3-triazole, 1 ,2,4-triazole, thiazole, thiadiazole, oxazole, oxadiazole, and isoxazole, each of which may be optionally further substituted as described herein. Non-limiting examples of ring B (shown connected to moieties L1 and -C(O)-N(R3)-Z) include
Figure imgf000021_0001
Figure imgf000021_0002
, and
Figure imgf000021_0003
, wherein each ring B shown is optionally further substituted on an available ring carbon atom or ring nitrogen atom with one or more groups Ra, wherein each Ra, when attached to a ring carbon atom, is independently selected from halo, alkyl, and haloalkyl, and wherein each Ra, when attached to a ring nitrogen atom, is independently selected from alkyl, and haloalkyl Non-limiting examples of such groups substituted on an available ring nitrogen atom include
Figure imgf000022_0001
In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), and Formula (A-2d), ring B is a 6-membered heteroaromatic ring having from 1 to 3 ring nitrogen atoms, wherein said ring B is further substituted with from 1 to 3 substituents, each substituent being independently selected from halo, alkyl, and haloalkyl In one such embodiment, ring B contains three said substituents In one such embodiment, ring B contains two said substituents In another such embodiment, ring B contains one said substitutent
When, in each of Formula (A), Formula (A-1 ), Formula (A-1a), Formula (A- 1b), Formula (A-2a), Formula (A-2b), Formula (A-2c), ring B is a 6-membered heteroaromatic ring, non-limiting examples of such rings include pyridine, pyπmidine, pyrazine, pyπdazine, and triazine, each of which may be optionally further substituted as described herein Non-limiting examples of ring B (shown connected to moieties
Figure imgf000022_0002
Figure imgf000022_0003
wherein any of such moieties may be optionally further substituted with one or more groups Ra, wherein each Ra is independently selected from halo, alkyl, and haloalkyl
In the various embodiments of the compounds of the invention described herein, functional groups for L1 and L2 are to be read from left to right unless otherwise stated In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), and Formula (A-2d), L1 is selected from the group consisting of a bond, -N(R4)-, -N(R4)-(C(R5A)2)-, -O-, -O-(C(RSA)Z)-, and -(C(R5A)2)-(C(R5)2)S-, wherein s is an integer from 0 to 3
In one embodiment, in each of Formula (A), Formula (A-1), Formula (A-1a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), and Formula (A-2d), L1 is selected from the group consisting of a bond and -(C(R5A)2)-(C(R5)2)S-, wherein s is an integer from 0 to 1 , and wherein each R5 and each R5A is independently selected from the group consisting of H, lower alkyl, -lower alkyl-Sι(CH3)3, lower haloalkyl, and lower alkyl substituted with one or more groups independently selected from hydroxyl and cyano In one such embodiment, s is 0 In one such embodiment, s is 1
In one embodiment, in each of Formula (A), Formula (A-1), Formula (A-1 a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), and Formula (A-2d), L1 is selected from the group consisting of lower branched alkyl and -lower alkyl-Sι(CH3)3
In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1 a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), and Formula (A-2d), L1 is a bond
In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1 a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), and Formula (A-2d), L1 is -N(R4)-(C(R5A)2)-, wherein each R5A is independently selected from H, lower alkyl, lower haloalkyl, and lower alkyl substituted with one or more hydroxyl and R4 is selected from H and lower alkyl
In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1 a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), L1 is -O-(C(R5A)2)-, wherein each R5A is independently selected from H, lower alkyl, lower haloalkyl, and lower alkyl substituted with one or more hydroxyl
In one embodiment, in each of Formula (A), Formula (A-1), Formula (A-1 a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), L1 is selected from the group consisting of a bond,-NH-(CH2)2-, -O-(CH2)2-, -O- , -NH-,- N(CH3)-, -CH2-,-CH(CH3)-, and -CH2CH2-.
In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1a), Formula (A-1b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), L1 is selected from the group consisting of -CH2-,-CH(CH3)-, and -CH2CH2-.
In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1 a), Formula (A-1b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), L1 is selected from the group consisting of' -CH(cycloalkylalkyl)- and -CH(heterocycloalkylalkyl)-. In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1a),
Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), L1 is -C(R5A)2-, wherein each R5A is independently selected from the group consisting of H, lower alkyl, -lower alkyl-Sι(CH3)3, haloalkyl, heteroalkyl, cya no-substituted lower alkyl, hydroxy-substituted lower alkyl, cycloalkyl, cycloalkylalkyl-, heterocycloalkyl, and heterocycloalkylalkyk
In one embodiment, in each of Formula (A), Formula (A-1), Formula (A-1 a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), L1 is -CH(R5A)-, wherein R5A is selected from the group consisting of H, lower alkyl, -lower alkyl-Sι(CH3)3, haloalkyl, heteroalkyl, cyano-substituted lower alkyl, hydroxy- substituted lower alkyl, cycloalkyl, cycloalkylalkyl-, heterocycloalkyl, and heterocycloalkylalkyl-
In one embodiment, in each of Formula (A), Formula (A-1), Formula (A-1 a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), L1 is selected from the group consisting of:
Figure imgf000024_0001
-(CH2)^3-.
In one embodiment, in each of Formula (A), Formula (A-1), Formula (A-1 a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d),
Figure imgf000025_0001
In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1 a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d),
L1 is selected from the group consisting of
Figure imgf000025_0002
, and
Figure imgf000025_0003
In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d),
L1 is selected from the group consisting of
Figure imgf000025_0004
and
Figure imgf000025_0005
In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1a),
Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), L1 is selected from the group consisting of:
Figure imgf000026_0001
In one embodiment, in each of Formula (A), Formula (A-1), Formula (A-1a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), L1 is selected from the group consisting of
In one embodiment, in each of Formula (A), Formula (A-1), Formula (A-1 a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), L1 is selected from the group consisting of
Figure imgf000026_0003
In one embodiment, in each of Formula (A), Formula (A-1), Formula (A-1 a),
Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), L1 is selected from the group consisting of
Figure imgf000026_0004
In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1 a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d),
L1 is selected from the group consisting of
Figure imgf000026_0005
Figure imgf000027_0001
one embodi Ament, in each of Formula (A), Formula (A-1 ), Formula (A-1a), Formula (A-1b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d),
L1 is selected from the group consisting of
Figure imgf000027_0006
Figure imgf000027_0002
, and
Figure imgf000027_0003
In one embodiment, in each of Formula (A), Formula (A-1), Formula (A-1 a), Formula (A 1b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d),
L1 is selected from the group consisting of
Figure imgf000027_0005
, and
Figure imgf000027_0004
In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1 a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), L2 is selected from the group consisting of a bond, -N(R4)-, -N(R4)-(C(R5A)2)-, -(C(R5)2)U-(C(R5A)2)-N(R4)-, wherein u is 0 to 2, -O- -O-(C(R5A)2)-, and -(C(RS)2)V-, wherein v is 1 -3, and each R5 and each RSA is independently selected from the group consisting of H, lower alkyl, lower haloalkyl, and lower alkyl substituted with one or more groups independently selected from hydroxyl and cyano, and wherein each R4 is independently selected from the group consisting of H, lower alkyl, lower haloalkyl, and lower alkyl substituted with one or more groups independently selected from hydroxyl and cyano
In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1a), Formula (A-1b), Formula (A-2a), Formula (A-2b), Formula (A-2c), L2 is selected from the group consisting of a -(C(R5)2)u-(C(R5A)2)-N(R4)-, wherein u is 0 to 2, -O-, and each R4, each Rs, and each R6A is independently selected from the group consisting of H and lower alkyl
In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1 a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), L2 is selected from a bond and -(C(R5)2)V-, wherein v is 1-2, and each R5 is independently selected from the group consisting of H, -OH, lower alkyl, loweralkoxy, lower haloalkyl, and lower alkyl substituted with one or more groups independently selected from hydroxyl and cyano In one such embodiment, v is 1 and each R5 is independently selected from H and lower alkyl In another such embodiment, v is 1 and each R5 is independently selected from H, lower alkyl, and OH
In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), L2 is a bond
In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1 a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), L2 is selected from the group consisting of -CH2-,-CH(CH3)-, -CH2CH2-, -CH(OH)-, -CH(CH3)-CH2-, -CH2-CH(CH3)-, -CH(OH)-CH2-, and -CH2-CH(OH)-
In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1 a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), L2 is selected from the group consisting of
Figure imgf000028_0001
In one embodiment, in each of Formula (A), Formula (A-1), Formula (A-1a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), L2 is selected from the group consisting of
Figure imgf000029_0001
In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1 a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d),
L2 is selected from the group consisting of
Figure imgf000029_0003
In one embodiment, in each of Formula (A), Formula (A-1), Formula (A-1 a), Formula (A-1b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), L2 is selected from the group consisting of
Figure imgf000029_0002
In embodiments wherein either L1 or L2 (or both) contains a group -(C(R5Λ)2)-, any two R5A groups bound to the same carbon atom may be taken together to form a carbonyl group, an oxime group, or a substituted oxime group As indicated herein each R5A group is selected independently Similarly, in embodiments wherein either L1 or L2 (or both) contains a group -(C(R5J2)-, any two R5 groups bound to the same carbon atom may be taken together to form a carbonyl group, an oxime group, or a substituted oxime group For illustrative purposes only, such oxime groups, when
present, may be pictured as
Figure imgf000029_0004
, wherein each wavy line presents a point of attachment to the rest of the molecule and wherein R15 is selected from the group consisting of H, alkyl, haloalkyl, hydroxyl-substituted alkyl, and cycloalkyl.
In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1 a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), R1 is selected from the group consisting of: aryl and heteroaryl, wherein each of said aryl and said heteroaryl are unsubstituted or substituted with from 1 to 3 groups each independently selected from:
(1) halo, -SOaR7, -SF5, -OSF5, CN,
(2) alkyl, alkoxy, heteroalkyl, -O-heteroalkyl, wherein each of said alkyl, alkoxy, heteroalkyl, and -O-heteroalkyl, is unsubstituted or optionally independently substituted with from 1 to 3 groups each independently selected from: halo, OH, -CO2R8, -C(O)R6, -SR7, -S(O)R7, -SO2R7, CN, NO2, -C(O)NR8R9, -NR8R9, -O-haloalkyl, - NR10-C(O)-NRβR9, -NR10-C02Rβ, -NR10-C(O)Rβ, -NR10-SO2Rβ, -SO2-NR8R9, -C(O)NR8R8, and
-OC(O)NR8R9, and
(3) aryl, -O-aryl, -S-aryl, -S(O)-aryl, -S(O)2-aryl, heteroaryl, cycloalkyl, cycloalkenyl, and heterocycloalkenyl, each of which is unsubstituted or optionally independently substituted with from 1 to 2 groups each independently selected from (1) and (2) above.
In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1 a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), R1 is selected from the group consisting of: phenyl or naphthyl, wherein said phenyl and said naphthyl are unsubstituted or substituted with from 1 to 3 groups each independently selected from
(1) halo, -SO2R7, -SF5, -OSF5, CN, (2) alkoxy, haloalkyl, -O-haloalkyl, heteroalkyl, -O-heteroalkyl,
(3) aryl, -O-aryl, -S-aryl, -S(O)-aryl, -S(O)2-aryl, heteroaryl, cycloalkyl, cycloalkenyl, and heterocycloalkenyl, each of which is unsubstituted or optionally independently substituted with from 1 to 2 groups each independently selected from (1) and (2) above
In one embodiment, in each of Formula (A), Formula (A-1), Formula (A-1a), Formula (A-1b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), R1 is selected from the group consisting of phenyl, wherein said phenyl is unsubstituted or substituted with one or more groups each independently selected from halo, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, alkoxy, -O-haloalkyl, and cycloalkyl
In one embodiment, in each of Formula (A), Formula (A-1), Formula (A-1 a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), R1 is selected from the group consisting of heteroaryl, wherein said heteroaryl is unsubstituted or substituted with one or more groups each independently selected from halo, alkyl, haloalkyl, alkoxy, -O-haloalkyl, and cycloalkyl
In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), each Rz is independently selected from the group consisting of phenyl substituted with from 0 to 5 groups independently selected from -OH, halo, alkyl, haloalkyl, hydroxyalkyl, alkyl substituted with from 1 to 2 -CO2R6 groups, alkoxy, -O-haloalkyl, hydroxyalkoxy, alkoxy substituted with from 1 to 2 -CO2R6 groups, -CO2R6, CN, -SO2R7, -C(O)NR8R9, and -NO2
In one embodiment, in each of Formula (A), Formula (A-1), Formula (A-1a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), ring A represents a spirocycloalkyl ring or a spirocycloalkenyl ring, wherein said ring A is substituted on one or more available ring carbon atoms with from 1 to 5 independently selected R2 groups
In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1 a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), ring A represents a spirocycloalkyl ring, wherein said ring A is substituted on one or more available ring carbon atoms with from 1 to 5 independently selected R2 groups
In one embodiment, in each of Formula (A), Formula (A-1), Formula (A-1 a), Formula (A-1b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), each R2 is independently selected from the group consisting of phenyl substituted with from O to 5 groups independently selected from -OH, halo, alkyl, haloalkyl, alkoxy, -O-haloalkyl, hydroxyalkoxy, -CO2R6, CN, -SO2R7, -C(O)NR8R9, and -NO2.
In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1 a), Formula (A-1b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), each R2 is independently selected from the group consisting of' unsubstituted phenyl
In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1 a), Formula (A-1b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), each R2 is independently selected from the group consisting of: phenyl substituted with from 1 to 5 groups independently selected from halo. In one embodiment, in each of Formula (A), Formula (A-1), Formula (A-1 a),
Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), each R2 is independently selected from the group consisting of alkyl substituted with from O to 5 groups independently selected from -OH, oxo, halo, heteroalkyl, alkoxy, -O-haloalkyl, -CO2R6, and phenyl substituted with from O to 5 groups independently selected from -OH, halo, aryl, substituted aryl, alkyl, alkoxy, heteroalkyl, haloalkyl, haloheteroalkyl, -CO2R6, CN, -S(O)R7, -S(O)2R7, -C(O)NR8R9, and -NO2.
In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), each R2 is selected from the group consisting of t-butyl and -Sι(CH3)3
In one embodiment, in each of Formula (A), Formula (A-1), Formula (A-1 a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), each R2 is t-butyl
In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1a), Formula (A-1b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), each R2 is deuteroalkyl In one embodiment, in each of Formula (A), Formula (A-1), Formula (A-1 a),
Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), each R2 is -C(CD3)3
In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1 a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), each R2 is cycloalkyl or substituted cycloalkyl. Non-limiting examples of R2 when R2 is cycloalkyl include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl Non-limiting examples of said substituents when R2 when R2 is substituted cycloalkyl -OH, halo, aryl, substituted aryl, alkyl, alkoxy, heteroalkyl, haloalkyl, haloheteroalkyl, -CO2R6, CN, -S(O)R7, -S(O)2R7, -C(O)NR8R9, and -NO2. Non-limiting illustrations of points of attachment of such substituents include:
Figure imgf000033_0001
and
Figure imgf000033_0002
, where the wavy line represents the point of attachment of R2 to ring A.
In one embodiment, in each of Formula (A), Formula (A-1), Formula (A-1 a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), each R2 is heterocycloalkyl or substituted heterocycloalkyl. Non-limiting examples of R2 when R2 is heterocycloalkyl include pipeπdyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1 ,4-dioxanyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, oxetanes, and the like. Non-limiting illustrations of points of attachment of such substituents when R2 is substituted heterocycloalkyl
(such as an oxetane or substituted oxetane) include:
Figure imgf000034_0001
and
In one embodiment, in each of Formula (A), Formula (A-1), Formula (A-1a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), each R2 is -Sι(alkyl)3.
In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1 a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), each R2 is -Sι(Ch3)3
In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1a), Formula (A-1b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), R3 is H.
In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1 a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), and Formula (A-2d), R3 is selected from methyl, ethyl, n-propyl, and isopropyl.
In one embodiment, in each of Formula (A), Formula (A-1), Formula (A-1 a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), each R8 is independently selected from H and alkyl.
In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), each R9 is independently selected from H and alkyl
In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), R8 and R9 are taken together with the nitrogen to which they are attached to form a 5-, 6-, or 7-membered heteroaromatic ring, which ring contains (including said nitrogen to which R8 and R9 are attached) from 1 to 2 ring heteroatoms.
In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1 a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), R8 and R9 are taken together with the nitrogen to which they are attached to form a 5-, 6-, or 7-membered saturated heterocyclic ring, which ring contains (including said nitrogen to which R8 and R9 are attached) from 1 to 2 ring heteroatoms
In one embodiment, in each of Formula (A), Formula (A-1), Formula (A-1a), Formula (A-1b), Formula (A-2a), Formula (A-2b), Formula (A-2c), R8 and R9 are taken together with the nitrogen to which they are attached to form a 5-, 6-, or 7-membered partially or fully unsaturated heterocyclic ring, which ring contains (including said nitrogen to which R8 and R9 are attached) form 1 to 2 ring heteroatoms
In one embodiment, in each of Formula (A), Formula (A-1), Formula (A-1 a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), R8 and R9 are taken together with the nitrogen to which they are attached to form a 5-, or 6-membered saturated, or partially or fully unsaturated, heterocyclic ring, which ring contains (including said nitrogen to which R8 and R9 are attached) form 1 to 2 ring heteroatoms In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1 a),
Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), R8 and R9 are taken together with the nitrogen to which they are attached to form a 5-, 6-, or 7-membered ring moiety, non-limiting examples of such moieties include pyrrolidine, imidazoline, piperazine, morpholine, thiomorpholine, oxazolidme, and thiazolidine
In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1 a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), Z is -(C(R11)2)-(C(R12)(R13))m-C(O)OH Pharmaceutically acceptable salts of such acids are also contemplated as being within the scope of the invention Thus, in another embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1 a), Formula (A-1b), Formula (A-2a), Formula (A-2b), Formula (A-2c), Z is -(C(R11)2)-(C(R12)(R13))m-C(O)O Na+ Additional non-limiting salts contemplated as alternatives to the sodium salt are known to those of ordinary skill in the art and/or are as described herein
In one embodiment, in each of Formula (A), Formula (A-1), Formula (A-1 a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), Z is -(CH2)- (CH(CH3))-C(O)OH In one embodiment, in each of Formula (A), Formula (A-1), Formula (A-1a), Formula (A-1b), Formula (A-2a), Formula (A-2b), Formula (A-2c), Z is -(CH2)-(CH2)- (CHa)-C(O)OH
In one embodiment, in each of Formula (A), Formula (A-1), Formula (A-1 a), Formula (A-1b), Formula (A-2a), Formula (A-2b), Formula (A-2c), Z is -(CH2)-C(CH3)2- C(O)OH
In one embodiment, in each of Formula (A), Formula (A-1), Formula (A-1 a), Formula (A-1b), Formula (A-2a), Formula (A-2b), Formula (A-2c), Z is -(CH2)- C(CH3)(OH)-C(O)OH In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1 a),
Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), Z is -CH2-CH2- C(O)OH
In one embodiment, in each of Formula (A), Formula (A-1), Formula (A-1 a), Formula (A-1b), Formula (A-2a), Formula (A-2b), Formula (A-2c), Z is -CH2-CH(OH)- C(O)OH
In one embodiment, in each of Formula (A), Formula (A-1), Formula (A-1 a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), Z is -CH(CH3)-CH2- C(O)OH
In one embodiment, in each of Formula (A), Formula (A-1), Formula (A-1 a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), Z is -C(CH3)2-CH2- C(O)OH
In one embodiment, in each of Formula (A), Formula (A-1), Formula (A-1 a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), Z is -(C(R11)2)-(C(R14)2)n-C(O)OH
In one embodiment, in each of Formula (A), Formula (A-1), Formula (A-1 a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), Z is -CH2-CH(F)- C(O)OH
In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1 a), Formula (A-1b), Formula (A-2a), Formula (A-2b), Formula (A-2c), Z is -CH2-CF2- C(O)OH In one embodiment, in each of Formula (A), Formula (A-1), Formula (A-1a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), Z is -CH(CH3)-CF2- C(O)OH.
In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1 a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), Z is -CH2-CH2-CF2- C(O)OH.
In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1 a), Formula (A-1b), Formula (A-2a), Formula (A-2b), Formula (A-2c),
Figure imgf000037_0001
In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1 a),
Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c),
Figure imgf000037_0002
In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1 a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c),
Figure imgf000037_0003
In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1 a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), when Z is a moiety selected from -(C(R11)2)-(C(R12R13))m-C(O)OH, or -(C(R11)2)-(C(R14)2)n-C(O)OH, the - C(O)OH group may be replaced by a moiety -Q, wherein Q is selected from the group consisting of:
"
Figure imgf000038_0001
Such moieties
Q are readily available to those skilled in the art and may be made, for example, by methods according to Stensbol et al., J. Med. Chem , 2002, 45, 19-31 , or according to Moreira Lima et al., Current Med. Chem , 2005, 12, 23-49.
In one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1 a), Formula (A-1b), Formula (A-2a), Formula (A-2b), Formula (A-2c), the compounds of the invention have the general structure shown in Formula (I):
Figure imgf000038_0002
(I) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers of said compounds, wherein ring A, L1, L2, R1, R3, and Z are selected independently of each other and wherein ring A and R1 are as defined in Formula (A);
L1 is selected from the group consisting of a bond, -N(R4)-, -N(R4)-(C(R5A)2)-, -O-, -O-(C(R5A)2)-, and -(C(R5A)2)-(C(RS)2)S-, s is 0-3,
L2 is selected from the group consisting of bond, -N(R4)-, -N(R4)-(C(R5A)2)-, -(C(R5)2)U-(C(RSA)2)-N(R4)-, -(C(R5A)2)-N(R4)-, -O-, -O-(C(R5A)2)-, -(C(R5A)2)-O- and -(C(R5)2)v-, wherein v is 1 -3,
R3 is selected from the group consisting of H and lower alkyl,
Z is a moiety selected from -(C(R11)2)-(C(R12R13))m-C(O)OH, -(C(R")2)-(C(R14)2)n-C(O)OH, and
Figure imgf000039_0001
m is an integer from 0 to 5, n is an integer from 0 to 5, p is an integer from 0 to 5, each R4 is independently selected from H, lower alkyl, cycloalkyl, heterocycloalkyl, heteroalkyl, and haloalkyl, each R5A is independently selected from H, lower alkyl, -lower alkyl-Sι(CH3)3, -lower alkyl-Sι(CH3)3, lower haloalkyl, and hydroxy-substituted lower alkyl, each R5 is independently selected from H, -OH, lower alkyl, -lower alkyl-Sι(CH3)3, -lower alkyl-Sι(CH3)3, lower haloalkyl, and hydroxy-substituted lower alkyl, each R6 is independently selected from H, alkyl, and haloalkyl, each R7 is independently selected from H, alkyl, heteroalkyl, and haloalkyl, each R8 is independently selected from H and alkyl, each R9 is independently selected from H and alkyl, each R11 is independently selected from H and lower alkyl, each R12 is independently selected from H, lower alkyl, -OH hydroxy- substituted lower alkyl, each R13 is independently selected from H, unsubstituted lower alkyl, lower alkyl substituted with one or more groups each independently selected from hydroxyl and alkoxy, or R12 and R13 are taken together to form an oxo, and each R14 is independently selected from H and fluoro
In one embodiment, in Formula (I) ring A represents a spirocycloalkyl ring or a spirocycloalkenyl ring, wherein said ring A is substituted on one or more available ring carbon atoms with from 0 to 5 independently selected R2 groups,
R1 is selected from the group consisting of aryl and heteroaryl, wherein each of said aryl and said heteroaryl are unsubstituted or substituted with from 1 to 3 groups each independently selected from
(1) halo, -SO2R7, -SF5, -OSF6, CN,
(2) alkyl, alkoxy, heteroalkyl, -O-heteroalkyl, wherein each of said alkyl, alkoxy, heteroalkyl, and -O-heteroalkyl, is unsubstituted or optionally independently substituted with from 1 to 3 groups each independently selected from halo, OH, -CO2R6, -C(O)R6, -SR7, -S(O)R7, -SO2R7, CN, NO2, -C(O)NR8R9, -NR8R9, -O-haloalkyl, - NR10-C(O)-NR8R9, -NR10-CO2R6, -NR10-C(O)R6, -NR10-SO2R6, -SO2-NR8R9, -C(O)NR8R9, and
-OC(O)NR8R9, and
(3) aryl, -O-aryl, -S-aryl, -S(O)-aryl, -S(O)2-aryl, heteroaryl, cycloalkyl, cycloalkenyl, and heterocycloalkenyl, each of which is unsubstituted or optionally independently substituted with from 1 to 2 groups each independently selected from (1) and (2) above, and each R2 (when present) is independently selected from the group consisting of -Si(CH3J3 and alkyl, wherein said alkyl substituted with from O to 5 groups independently selected from -OH, oxo, halo, heteroalkyl, alkoxy, -O-haloalkyl, -CO2R6, and phenyl substituted with from O to 5 groups independently selected from -OH, halo, aryl, substituted aryl, alkyl, alkoxy, -O-haloalkyl, heteroalkyl, haloalkyl, haloheteroalkyl, -CO2R6, CN, -S(O)R7, -S(O)2R7, -SF5, -OSF5, -C(O)NR8R9, and -NO2
In one embodiment, in Formula (I). ring A represents a spirocycloalkyl ring or a spirocycloalkenyl ring, wherein said ring A is substituted on one or more available ring carbon atoms with from 0 to 5 independently selected R2 groups; R1 is selected from the group consisting of. phenyl, wherein said phenyl and is unsubstituted or substituted with from 1 to 3 groups each independently selected from
(1) halo, -SO2R7, -SF5, -OSF5, CN,
(2) alkyl, alkoxy, haloalkyl, -O-haloalkyl, heteroalkyl, -O-heteroalkyl,
(3) aryl, -O-aryl, -S-aryl, -S(O)-aryl, -S(O)2-aryl, heteroaryl, cycloalkyl, cycloalkenyl, and heterocycloalkenyl, each of which said aryl, -O-aryl, -S-aryl, -S(O)-aryl, -S(O)2-aryl, heteroaryl, cycloalkyl, cycloalkenyl, and heterocycloalkenyl, is unsubstituted or optionally independently substituted with from 1 to 2 groups each independently selected from (1) and (2) above, and each R2 (when present) is independently selected from the group consisting of -Si(CH3)3 and alkyl, wherein said alkyl is substituted with from 0 to 5 groups independently selected from -OH, oxo, halo, heteroalkyl, alkoxy, -O-haloalkyl, -CO2R8, and phenyl substituted with from 0 to 5 groups independently selected from -OH, halo, aryl, substituted aryl, alkyl, alkoxy, heteroalkyl, haloalkyl, haloheteroalkyl, -CO2R6, CN, -S(O)R7, -S(O)2R7, -C(O)NR8R9, and -NO2.
In one embodiment, the compounds of the invention have the general structure shown in Formula (1-1 )
Figure imgf000042_0001
(H) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers of said compounds, wherein L1, L2, R1, each R2, R3, and Z are selected independently of each other and as defined in Formula (I)
In one embodiment, the compounds of the invention have the general structure shown in Formula (II)
Figure imgf000042_0002
(H) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers of said compounds, wherein L1, L2, R1, each R2, R3, and Z are selected independently of each other and wherein
L1 is selected from the group consisting of a bond and -(C(RSA)2)-(C(R5)2)S-,
s is 0-1 ,
L2 is selected from the group consisting of a bond, -(C(R5)2)U-(C(R6A)2)-N(R4)-, and -(C(R5)2)v,
U IS 0 tO 2, v is 1 -2,
R1 is selected from the group consisting of phenyl, wherein said phenyl is unsubstituted or substituted with one or more groups each independently selected from halo, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, alkoxy,
-O-haloalkyl, and cycloalkyl, each R2 is independently selected from the group consisting of -Sι(CH3)3 and alkyl, wherein said alkyl is substituted with from 0 to 5 groups independently selected from -OH, halo, alkyl, haloalkyl, hydroxyalkyl, alkyl substituted with from 1 to 2 -CO2R6 groups, alkoxy, -O-haloalkyl, hydroxyalkoxy, alkoxy substituted with from 1 to 2 -CO2R6 groups, -CO2R6, CN, -SO2R7, -C(O)NR6R9, and -NO2,
R3 is selected from the group consisting of H and lower alkyl, Z is a moiety selected from the group consisting of -(CH2)-(CH(CH3))-C(O)OH, -(CH2)-(CH2)-(CH2)-C(O)OH, -(CH2)-C(CH3)2-C(O)OH, -(CH2)-C(CH3)(OH)-C(O)OH, -CH2 CH2-C(O)OH, -CH2-CH(OH)-C(O)OH, -CH(CH3)-CH2-C(O)OH,
-C(CH3J2-CH2-C(O)OH, -CH2-CH(F)-C(O)OH, -CH2-CF2-C(O)OH, -CH(CH3)-
CF2-C(O)OH, -CH2-CH2-CF2-C(O)OH, and
Figure imgf000043_0001
, wherein p is an integer from O to 1 , and R11 (when present) is selected from the group consisting of H and lower alkyl, each R5A is independently selected from H, lower alkyl, -lower alkyl-Sι(CH3)3, lower haloalkyl, and lower alkyl substituted with from 1 to 2 hydroxyl, each R5 is independently selected from H, -OH, lower alkyl,
-lower alkyl-Sι(CH3)3, lower haloalkyl, and lower alkyl substituted with from 1 to 2 hydroxyl, each R6 is independently selected from H, alkyl, and haloalkyl, each R7 is independently selected from H, alkyl, heteroalkyl, and haloalkyl,
each R8 is independently selected from H and alkyl; and each R9 is independently selected from H and alkyl.
In one embodiment, the compounds of the invention have the general structure shown in Formula (ll-a):
Figure imgf000044_0001
(II-a) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers of said compounds, wherein L1, L2, R1, each R2, R3, and Z are selected independently of each other and as defined in Formula (II).
In one embodiment, the compounds of the invention have the general structure shown in Formula (ll-b)'
Figure imgf000045_0001
(π-b) and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers of said compounds, wherein L1, L2, R1, R2, R3, and Z are selected independently of each other and as defined in Formula (II). In one embodiment, in each of Formula (II), Formula (ll-a), and Formula (ll-b)
L1 is selected from the group consisting of: a bond, straight or branched lower alkyl, and -(CH(-lower alkyl-Sι(CH3)3)-;
L2 is selected from the group consisting of' a bond and straight or branched lower alkyl, R1 is selected from the group consisting of' phenyl, wherein said phenyl is unsubstituted or substituted with from 1 to 3 groups each independently selected from, halo, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, alkoxy, and -O-haloalkyl; each R2 is independently selected from the group consisting of H, straight or branched lower alkyl, and -Si(CH3)3,
R3 is selected from the group consisting of H and lower alkyl, Z is a moiety selected from the group consisting of: -(CH2)-(CH(CH3))-C(O)OH, -(CH2)-(CH2)-(CH2)-C(O)OH, -(CH2)-C(CH3)2-C(O)OH, -(CHa)-C(CH3)(OH)-C(O)OH, -CH2-CH2-C(O)OH, -CH2-CH(OH)-C(O)OH, -CH(CH3)-CH2-C(O)OH, -C(CH3)2 -CH2-C(O)OH, -(C(R11)2)-(C(R14)2)n-C(O)OH, -CH2-CH(F)-C(O)OH, -CH2-CF2- C(O)OH, -CH(CH3)-CF2-C(O)OH, -CH2-CH2-CF2-C(O)OH, -(CH2)-(CH(CH3))-C(O)OCH3, -(CH2)-(CH2)-(CH2)-C(O)OCH3, -(CH2)-C(CH3)2-C(O)OCHs, -(CH2)-C(CH3)(OH)-C(O)OCH3, -CH2-CH2-C(O)OCH3, -CH2-CH(OH)-C(O)OCH3, -CH(CHa)-CH2-C(O)OCH3, -C(CH3J2-CH2-C(O)OCH3, -(C(R11)2)-(C(R14)2)n-C(O)OCH3, -CH2-CH(F)-C(O)OCH3, -CH2-CF2-C(O)OCH3, -CH(CHs)-CF2-C(O)OCH3, -CH2-CH2-CF2-C(O)OCH3, and
Figure imgf000046_0001
, wherein p is an integer from 0 to 1 , and R (when present) is selected from the group consisting of H and lower alkyl; each R5 is independently selected from H, -OH, lower alkyl, -lower alkyl-Sι(CH3)3, lower haloalkyl, and lower alkyl substituted with from 1 to 2 hydroxyl; each R6 is independently selected from H, alkyl, and haloalkyl; each R7 is independently selected from H, alkyl, heteroalkyl, and haloalkyl; each R8 is independently selected from H and alkyl; and each R9 is independently selected from H and alkyl
In one embodiment, in each of Formula (II), Formula (ll-a), and Formula (ll-b),
L1 is selected from the group consisting of: a bond,
Figure imgf000046_0002
, and -(CH2)1-3-. In one such embodiment, L1 is
Figure imgf000046_0003
selected from the group consisting o iff:: a annHd
Figure imgf000047_0001
In one such
Figure imgf000047_0007
embodiment, L1 is
Figure imgf000047_0008
In one such embodiment, L1 is
Figure imgf000047_0002
. In
one such embodiment, L1 is
Figure imgf000047_0004
I . In one such embodiment, L1
Figure imgf000047_0003
is
In one such embodiment, L1 is
Figure imgf000047_0005
In one embodiment, in each of Formula (II), Formula (ll-a), and Formula (ll-b):
L1 is selected from the group consisting of:
Figure imgf000047_0009
Figure imgf000047_0006
L2 is selected from the group consisting of a bond and straight or branched lower alkyl; R1 is selected from the group consisting of. phenyl, wherein said phenyl is unsubstituted or substituted with from 1 to 3 groups each independently selected from'
halo, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, alkoxy, and
-O-haloalkyl, each R2 is independently selected from the group consisting of H, straight or branched lower alkyl, and -Sι(CHs)3,
R3 is selected from the group consisting of H and lower alkyl, and Z is selected from the group consisting of -CH2 CH2-C(O)OH and
Figure imgf000048_0001
, wherein p is 1 and R11 is H
In one embodiment, in each of Formula (II), Formula (ll-a), and Formula (ll-b)
L1 is selected from the group consisting of
Figure imgf000048_0002
Figure imgf000048_0003
Figure imgf000048_0004
, and
Figure imgf000048_0005
, and L2 is a bond,
R1 is selected from the group consisting of phenyl, wherein said phenyl is unsubstituted or substituted with from 1 to 3 groups each independently selected from halo, each R2 is independently selected from the group consisting of iso-propyl, tert- butyl and tert-pentyl, R3 is H, and
Z is selected from the group consisting of -CH2 CH2-C(O)OH and
Figure imgf000049_0001
, wherein p is 1 and R11 is H
In one embodiment, the compounds of the invention have the general structure shown in the tables below, and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers of said compounds
In the various embodiments described herein, variables of each of the general formulas not explicitly defined in the context of the respective formula are as defined in Formula (A)
In one embodiment, a compound or compounds of the invention is/are in isolated or purified form
The terms used herein have their ordinary meaning and the meaning of such terms is independent at each occurrence thereof That notwithstanding and except where stated otherwise, the following definitions apply throughout the specification and claims Chemical names, common names and chemical structures may be used interchangeably to describe that same structure These definitions apply regardless of whether a term is used by itself or in combination with other terms, unless otherwise indicated Hence the definition of "alkyl" applies to "alkyl" as well as the "alkyl" portion of "hydroxyalkyl", "haloalkyl", arylalkyl-, alkylaryl-, "alkoxy" etc "Mammal" means humans and other mammalian animals A "patient" is a human or non-human mammal In one embodiment, a patient is a human In another embodiment, a patient is a non-human mammal, including, but not limited to, a monkey, baboon, mouse, rat, horse, dog, cat or rabbit In another embodiment, a patient is a companion animal, including but not limited to a dog, cat, rabbit, horse or ferret In one embodiment, a patient is a dog In another embodiment, a patient is a cat
The term "obesity" as used herein, refers to a patient being overweight and having a body mass index (BMI) of 25 or greater In one embodiment, an obese patient has a BMI of 25 or greater In another embodiment, an obese patient has a BMI from 25 to 30 In another embodiment, an obese patient has a BMI greater than 30 In still another embodiment, an obese patient has a BMI greater than 40
The term "impaired glucose tolerance" (IGT) as used herein, is defined as a two-hour glucose level of 140 to 199 mg per dL (7 8 to 1 1 0 mmol) as measured using the 75-g oral glucose tolerance test A patient is said to be under the condition of impaired glucose tolerance when he/she has an intermediately raised glucose level after 2 hours, wherein the level is less than would qualify for type 2 diabetes mellitus
The term "impaired fasting glucose" (IFG) as used herein, is defined as a fasting plasma glucose level of 100 to 125 mg/dL, normal fasting glucose values are below 100 mg per dL
The term "effective amount" as used herein, refers to an amount of Compound of Formula (I) and/or an additional therapeutic agent, or a composition thereof that is effective in producing the desired therapeutic, ameliorative, inhibitory or preventative effect when administered to a patient suffering from a Condition In the combination therapies of the present invention, an effective amount can refer to each individual agent or to the combination as a whole, wherein the amounts of all agents administered are together effective, but wherein the component agent of the combination may not be present individually in an effective amount
"Halogen" means fluorine, chlorine, bromine, or iodine Preferred are fluorine, chlorine and bromine
"Alkyl" means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain "Lower alkyl" means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched "Alkyl" may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being as described herein or independently selected from the group consisting of halo, alkyl, haloalkyl, spirocycloalkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, -NH(alkyl), -NH(cycloalkyl), -N(alkyl)2> -O-C(O)-alkyl, -O-C(O)-aryl, -O-C(O)-cycloalkyl, carboxy and -C(O)O-alkyl Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl Additional non-limiting examples of branched lower alkyl include -loweralkyl-isopropyl, (e.g , -CH2CH2CH(CH3);.), -loweralkyl-t-butyl (e g., -CH2CH2C(CHa)3).
The term "haloalkyl" as used herein, refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms have been independently replaced with -F, -Cl, -Br or -I Non-limiting illustrative examples of haloalkyl groups include -CH2F, -CHF2, -CF3, -CH2CHF2, -CH2CF3, -CCI3, -CHCI2, -CH2CI, and -CH2CHCI3
The term "deuterioalkyl" (or "deuteroalkyl") as used herein, refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms have been independently replaced with deuterium.
"Heteroalkyl" means an alkyl moiety as defined above, having one or more carbon atoms, for example one, two or three carbon atoms, replaced with one or more heteroatoms, which may be the same or different, where the point of attachment to the remainder of the molecule is through a carbon atom of the heteroalkyl radical Suitable such heteroatoms include O, S, S(O), S(O)2, and -NH-, -N(alkyl)-. Non- limiting examples include ethers, thioethers, amines, 2-amιnoethyl, 2- dimethylammoethyl, and the like.
"Alkenyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain "Lower alkenyl" means about 2 to about 6 carbon atoms in the chain which may be straight or branched. "Alkenyl" may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl. aryl, cycloalkyl, cyano, alkoxy and — S(alkyl). Non-limiting examples of suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl. "Alkylene" means a difunctional group obtained by removal of a hydrogen atom from an alkyl group that is defined above. Non-limiting examples of alkylene include methylene, ethylene and propylene. Further non-limiting examples of alkylene groups include -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH(CH3)CH2CH2- and - CH2CH(CH3)CH2- In one embodiment, an alkylene group has from 1 to about 6 carbon atoms In another embodiment, an alkylene group is branched In another embodiment, an alkylene group is linear More generally, the suffix "ene" on alkyl, aryl, hetercycloalkyl, etc indicates a divalent moiety, e g , -CH2CH2- is ethylene, and
Figure imgf000052_0001
ispara-phenylene
Αlkynyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain, and more preferably about 2 to about 4 carbon atoms in the chain Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain "Lower alkynyl" means about 2 to about 6 carbon atoms in the chain which may be straight or branched Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-methylbutynyl "Alkynyl" may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, aryl and cycloalkyl
Ηeteroalkynyl" means an alkynyl moiety as defined above, having one or more carbon atoms, for example one, two or three carbon atoms, replaced with one or more heteroatoms, which may be the same or different, where the point of attachment to the remainder of the molecule is through a carbon atom of the heteroalkynyl radical
"Alkenylene" means a difunctional group obtained by removal of a hydrogen from an alkenyl group that is defined above Non-limiting examples of alkenylene include -CH=CH-, -C(CH3)=CH-, and -CH=CHCH2- 'Aryl means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms The aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein Non-limiting examples of suitable aryl groups include phenyl and naphthyl "Heteroaryl" means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination Preferred heteroaryls contain about 5 to about 6 ring atoms. The "heteroaryl" can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide "Heteroaryl" may also include a heteroaryl as defined above fused to an aryl as defined above. Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridoπe (including N-substituted pyπdones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, tπazolyl, 1 ,2,4- thiadiazolyl, pyrazinyl, pyπdazinyl, quinoxalinyl, phthalazinyl, oxindolyl, ιmιdazo[1 ,2- ajpyndinyl, ιmιdazo[2,1-b]thιazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyπdyl, isoquinolinyl, benzoazamdolyl, 1 ,2,4-trιazinyl, benzothiazolyl and the like. The term "heteroaryl" also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like. The bond to the parent moiety may be through an available carbon or nitrogen atom.
"Cycloalkyl" means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms. The cycloalkyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable multicyclic cycloalkyls include 1 -decalιnyl, 2-decalιnyl, norbornyl, adamantyl and the like Further non-limiting examples of cycloalkyl include the following:
Figure imgf000054_0001
"Cycloalkenyl" means a non-aromatic mono or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms which contains at least one carbon-carbon double bond. Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. The cycloalkenyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above. Non-limiting examples of suitable monocyclic cycloalkβnyls include cyclopentenyl, cyclohexenyl, cyclohepta-1 ,3-dienyl, and the like. Non-limiting example of a suitable multicyclic cycloalkenyl is norbomylenyl.
"Heterocycloalkyl" (or "heterocyclyl") means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination There are no adjacent oxygen and/or sulfur atoms present in the ring system Preferred heterocyclyls contain about 5 to about 6 ring atoms The prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom Any -NH in a heterocyclyl ring may exist protected such as, for example, as an -N(Boc), -N(CBz), - N(Tos) group and the like, such protections are also considered part of this invention The heterocyclyl can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dιoxιde Thus, the term "oxide," when it appears in a definition of a variable in a general structure described herein, refers to the corresponding N-oxide, S-oxide, or S,S-dιoxιde Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1 ,4-dιoxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, and the like "Heterocyclyl" also includes rings wherein =0 replaces two available hydrogens on the same carbon atom (ι e , heterocyclyl includes rings having a carbonyl group in the ring) Such =O groups may be referred to herein as "oxo " Example of such moiety is pyrrolidinone (or pyrrolidone)
Figure imgf000055_0001
"Heterocycloalkenyl" (or "heterocyclenyl") means a non-aromatic monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur atom, alone or in combination, and which contains at least one carbon-carbon double bond or carbon- nitrogen double bond There are no adjacent oxygen and/or sulfur atoms present in the ring system Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms The prefix aza, oxa or thia before the heterocyclenyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom The heterocyclenyl can be optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined herein The nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dιoxιde Non-limiting examples of suitable heterocyclenyl groups include 1 ,2,3,4- tetrahydropyπdinyl, 1 ,2-dιhydropyrιdιnyl, 1 ,4-dιhydropyrιdιnyl, 1 ,2,3,6- tetrahydropyridinyl, 1 ,4,5,6-tetrahydropyrιmιdιnyl, 2-pyrrolιnyl, 3-pyrrolιnyl, 2- imidazohnyl, 2-pyrazolιnyl, dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dιhydro-2H-pyranyl, dihydrofuranyl, fluorodihydrofuranyl, 7- oxabιcyclo[2 2 1]heptenyl, dihydrothiophenyl, dihydrothiopyranyl, and the like "Heterocyclenyl" also includes rings wherein =O replaces two available hydrogens on the same carbon atom (ι e , heterocyclyl includes rings having a carbonyl group in the ring) Example of such moiety is pyrrolidenone (or pyrrolone)
Figure imgf000056_0001
It should be noted that in hetero-atom containing ring systems of this invention, there are no hydroxyl groups on carbon atoms adjacent to a N, O or S, as well as there are no N or S groups on carbon adjacent to another heteroatom Thus, for example, in the ring
Figure imgf000056_0002
there is no -OH attached directly to carbons marked 2 and 5 It should also be noted that tautomeric forms such as, for example, the moieties
Figure imgf000057_0001
and
Figure imgf000057_0002
are considered equivalent in certain embodiments of this invention
Thus, for example, when a compound of the invention contains a
Figure imgf000057_0003
group,
Figure imgf000057_0004
N is equivalent to
Figure imgf000057_0005
. It should be understood that for hetero-containing functional groups described herein, e.g., heterocycloalkyl, heterocycloalkenyl, heteroalkyl, heteroaryl, and arylheterocycloalkyl (e.g , benzo-fused heterocycloalkyl), the bond to the parent moiety can be through an available carbon or heteroatom (e g., nitrogen atom)
"Arylcycloalkyl" (or "arylfused cycloalkyl") means a group derived from a fused aryl and cycloalkyl as defined herein. Preferred arylcycloalkyls are those wherein aryl is phenyl (which may be referred to as "benzofused") and cycloalkyl consists of about 5 to about 6 ring atoms. The arylcycloalkyl can be optionally substituted as described herein Non-limiting examples of suitable arylcycloalkyls include indanyl (a benzofused cycloalkyl) and 1 ,2,3,4-tetrahydronaphthyl and the like The bond to the parent moiety is through a non-aromatic carbon atom.
"Arylheterocycloalkyl" (or "arylfused heterocycloalkyl") means a group derived from a fused aryl and heterocycloalkyl as defined herein. Preferred arylheterocycloalkyls are those wherein aryl is phenyl (which may be referred to as "benzofused") and heterocycloalkyl consists of about 5 to about 6 ring atoms The arylheterocycloalkyl can be optionally substituted, and/or contain the oxide or oxo, as described herein Non-limiting examples of suitable arylfused heterocycloalkyls include.
Figure imgf000058_0001
The bond to the parent moiety is through a non-aromatic carbon atom. It is also understood that the terms "arylfused aryl", "arylfused cycloalkyl", "arylfused cycloalkenyl", "arylfused heterocycloalkyl", arylfused heterocycloalkenyl", "arylfused heteroaryl", "cycloalkylfused aryl", "cycloalkylfused cycloalkyl",
"cycloalkylfused cycloalkenyl", "cycloalkylfused heterocycloalkyl", "cycloalkylfused heterocycloalkenyl", "cycloalkylfused heteroaryl, "cycloalkenylfused aryl", "cycloalkenylfused cycloalkyl", "cycloalkenylfused cycloalkenyl", "cycloalkenylfused heterocycloalkyl", "cycloalkenylfused heterocycloalkenyl", "cycloalkenylfused heteroaryl", "heterocycloalkylfused aryl", "heterocycloalkylfused cycloalkyl", "heterocycloalkylfused cycloalkenyl", "heterocycloalkylfused heterocycloalkyl", "heterocycloalkylfused heterocycloalkenyl", "heterocycloalkylfused heteroaryl", "heterocycloalkenylfused aryl", "heterocycloalkenylfused cycloalkyl", "heterocycloalkenylfused cycloalkenyl", "heterocycloalkenylfused heterocycloalkyl", "heterocycloalkenylfused heterocycloalkenyl", "heterocycloalkenylfused heteroaryl", "heteroarylfused aryl", "heteroarylfused cycloalkyl", "heteroarylfused cycloalkenyl", "heteroarylfused heterocycloalkyl", "heteroarylfused heterocycloalkenyl", and "heteroarylfused heteroaryl" are similarly represented by the combination of the groups aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, and heteroaryl, as previously described. Any such groups may be unsubstituted or substituted with one or more ring system substituents at any available position as described herein
"Aralkyl" or "arylalkyl" means an aryl-alkyl- group in which the aryl and alkyl are as previously described Preferred aralkyls comprise a lower alkyl group Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl The bond to the parent moiety is through the alkyl. The term (and similar terms) may be written as "arylalkyl-" to indicate the point of attachment to the parent moiety
Similarly, "heteroarylalkyl", "cycloalkylalkyl", "cycloalkenylalkyl", "heterocycloalkylalkyl", "heterocycloalkenylalkyl", etc., mean a heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, etc. as described herein bound to a parent moiety through an alkyl group Preferred groups contain a lower alkyl group. Such alkyl groups may be straight or branched, unsubstituted and/or substituted as described herein.
Similarly, "arylfused arylalkyl-", arylfused cycloalkylalkyl-, etc., means an arylfused aryl group, arylfused cycloalkyl group, etc. linked to a parent moiety through an alkyl group. Preferred groups contain a lower alkyl group. Such alkyl groups may be straight or branched, unsubstituted and/or substituted as described herein. "Alkylaryl" means an alkyl-aryl- group in which the alkyl and aryl are as previously described. Preferred alkylaryls comprise a lower alkyl group Non-limiting example of a suitable alkylaryl group is tolyl. The bond to the parent moiety is through the aryl.
"Cycloalkylether" means a non-aromatic ring of 3 to 7 members comprising an oxygen atom and 2 to 7 carbon atoms Ring carbon atoms can be substituted, provided that substituents adjacent to the ring oxygen do not include halo or substituents joined to the ring through an oxygen, nitrogen or sulfur atom.
"Cycloalkylalkyl" means a cycloalkyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable cycloalkylalkyls include cyclohexylmethyl, adamantylmethyl, adamantylpropyl, and the like
"Cycloalkenylalkyl" means a cycloalkenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core Non-limiting examples of suitable cycloalkenylalkyls include cyclopentenylmethyl, cyclohexenylmethyl and the like.
"Heteroarylalkyl" means a heteroaryl moiety as defined above linked via an alkyl moiety (defined above) to a parent core Non-limiting examples of suitable heteroaryls include 2-pyπdιnylmethyl, quinolinylmethyl and the like
"Heterocyclylalkyl" (or "heterocycloalkylalkyl") means a heterocyclyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable heterocyclylalkyls include pipendinylmethyl, piperazinylmethyl and the like
"Heterocyclenylalkyl" means a heterocyclenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. "Alkynylalkyl" means an alkynyl-alkyl- group in which the alkynyl and alkyl are as previously described. Preferred alkynylalkyls contain a lower alkynyl and a lower alkyl group. The bond to the parent moiety is through the alkyl Non-limiting examples of suitable alkynylalkyl groups include propargylmethyl.
"Heteroaralkyl" means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl, and quιnolιn-3- ylmethyl. The bond to the parent moiety is through the alkyl
"Hydroxyalkyl" means a HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyalkyls contain lower alkyl Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.
"Cyanoalkyl" means a NC-alkyl- group in which alkyl is as previously defined.
Preferred cyanoalkyls contain lower alkyl. Non-limiting examples of suitable cyanoalkyl groups include cyanomethyl and 2-cyanoethyl. "Acyl" means an H-C(O)-, alkyl-C(O)- or cycloalkyl-C(O)-, group in which the various groups are as previously described. The bond to the parent moiety is through the carbonyl Preferred acyls contain a lower alkyl. Non-limiting examples of suitable acyl groups include formyl, acetyl and propanoyl.
"Aroyl" means an aryl-C(O)- group in which the aryl group is as previously described. The bond to the parent moiety is through the carbonyl. Non-limiting examples of suitable groups include benzoyl and 1- naphthoyl.
"Heteroaroyl" means an heteroaryl-C(O)- group in which the heteroaryl group is as previously described The bond to the parent moiety is through the carbonyl. Non- limiting examples of suitable groups include pyπdoyl. "Alkoxy" means an alkyl-O- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond to the parent moiety is through the ether oxygen.
"Alkyoxyalkyl" means a group derived from an alkoxy and alkyl as defined herein The bond to the parent moiety is through the alkyl
'Aryloxy' means an aryl-O- group in which the aryl group is as previously described Non-limiting examples of suitable aryloxy groups include phenoxy and naphthoxy The bond to the parent moiety is through the ether oxygen
"Aralkyloxy" (or "arylalkyloxy") means an aralkyl-O- group (an arylaklyl-O- group) in which the aralkyl group is as previously described Non-limiting examples of suitable aralkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy The bond to the parent moiety is through the ether oxygen "Arylalkenyl" means a group derived from an aryl and alkenyl as defined herein Preferred arylalkenyls are those wherein aryl is phenyl and the alkenyl consists of about 3 to about 6 atoms The arylalkenyl can be optionally substituted by one or more substituents The bond to the parent moiety is through a non-aromatic carbon atom "Arylalkynyl" means a group derived from a aryl and alkenyl as defined herein
Preferred arylalkynyls are those wherein aryl is phenyl and the alkynyl consists of about 3 to about 6 atoms The arylalkynyl can be optionally substituted by one or more substituents The bond to the parent moiety is through a non-aromatic carbon atom "Alkylthio" means an alkyl-S- group in which the alkyl group is as previously described Non-limiting examples of suitable alkylthio groups include methylthio and ethylthio The bond to the parent moiety is through the sulfur
"Arylthio" means an aryl-S- group in which the aryl group is as previously described Non-limiting examples of suitable arylthio groups include phenylthio and naphthylthio The bond to the parent moiety is through the sulfur
Αralkylthio" means an aralkyl-S- group in which the aralkyl group is as previously described Non-limiting example of a suitable aralkylthio group is benzylthio The bond to the parent moiety is through the sulfur
"Alkoxycarbonyl" means an alkyl-O-CO- group Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl The bond to the parent moiety is through the carbonyl "Aryloxycarbonyl" means an aryl-O-C(O)- group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The bond to the parent moiety is through the carbonyl.
"Aralkoxycarbonyl" means an aralkyl-O-C(O)- group. Non-limiting example of a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond to the parent moiety is through the carbonyl
"Alkylsulfonyl" means an alkyl-S(O2)- group Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfonyl. "Arylsulfonyl" means an aryl-S(O2)- group The bond to the parent moiety is through the sulfonyl
"Spirocycloalkyl" means a monocyclic or multicyclic cycloalkyl group attached to a parent moiety by replacement of two available hydrogen atoms attached to the same carbon atom. The spirocycloalkyl may optionally be substituted as described herein. Non-limiting examples of suitable monocyclic spirocycloalkyl groups include spirocyclopropyl, spirorcyclobutyl, spirocycloheptyl, spirocyclohexyl, and spirocyclooctyl. Non-limiting examples of suitable multicyclic spirocycloalkyl groups
Figure imgf000062_0001
like. "Spirocycloalkenyl" means a spirocycloalkyl group which contains at least one carbon-carbon double bond Preferred spirocycloalkenyl rings contain about 5 to about 7 ring atoms The spirocycloalkenyl can be optionally substituted as described herein Non-limiting examples of suitable monocyclic cycloalkenyls include spirocyclopentenyl, spirocyclohexenyl, spιrocyclohepta-1 ,3-dιenyl, and the like Non-
Figure imgf000063_0001
"Spπoheterocycloalkyl" means a monocyclic or multicyclic heterocycloalkyl group (include oxides thereof) attached to the parent moiety by replacement of two available hydrogen atoms attached to the same carbon atom The spiroheterocycloalkyl may be optionally substituted as described herein Non-limiting
examples of suitable multicyclic spiroheterocycloalkyl include
Figure imgf000063_0002
Figure imgf000063_0003
Figure imgf000064_0001
"Spiroheterocycloalkenyl" (or "spiroheterocyclenyl") means a spiroheterocycloalkyl group which contains at least one carbon-carbon double bond.
Non-lirniting examples of suitable multicyclic spiroheterocycloalkenyl include:
Figure imgf000064_0002
Figure imgf000064_0003
The term "substituted" means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By "stable compound' or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The term "optionally substituted" means optional substitution with the specified groups, radicals or moieties. Substitution on a cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylfused cycloalkylalkyl- moiety or the like includes substitution on any ring portion and/or on the alkyl portion of the group.
When a variable appears more than once in a group, e.g., R8 in -N(R8)2, or a variable appears more than once in a structure presented herein such as Formula (I), the variables can be the same or different.
The term, "compound(s) of the invention," as used herein, refers, collectively or independently, to any of the compounds embraced by the general formulas described herein, e.g., Formula (A), Formula (I), Formula (H-A), Formula (H-B), Formula (II-B1 ), Formula (II-B2), Formula (II-B3), Formula (II-B4), Formula (II-B5), Formula (H-C), Formula (II-C1), Formula (II-C2), Formula (II-C3), Formula (II-C4), Formula (H-C5), Formula (H-D), Formula (II-D1), Formula (II-D2), Formula (III), Formula (IV), Formula (IV), Formula (V), and Formula (Vl), and the example compounds thereof.
With reference to the number of moieties (e.g , substituents, groups or rings) in a compound, unless otherwise defined, the phrases "one or more" and "at least one" mean that there can be as many moieties as chemically permitted, and the determination of the maximum number of such moieties is well within the knowledge of those skilled in the art. With respect to the compositions and methods comprising the use of "at least one compound of the invention, e g., of Formula (I)," one to three compounds of the invention, e.g., of Formula (I) can be administered at the same time, preferably one.
Compounds of the invention may contain one or more rings having one or more ring system substituents. "Ring system substituent" means a substituent attached to an aromatic or non-aromatic ring system which, for example, replaces an available hydrogen on the ring system Ring system substituents may be the same or different, each being as described herein or independently selected from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocyclyl, -O-C(O)-alkyl, -O-C(O)-aryl, -O-C(O)-cycloalkyl, -C(=N-CN)- NH2, -C(=NH)-NH2, -C(=NH)-NH(alkyl), Y1Y2N-, Y^N-alkyl-, Y1Y2NC(O)-, Y1Y2NSO2- and -SO2NY1Y2, wherein Yi and Y2 can be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl "Ring system substituent" may also mean a single moiety which simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) on a ring system Examples of such moieties are rings such as heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl rings Additional non-limiting examples include methylene dioxy, ethylenedioxy, -C(CH3J2- and the like which form moieties such as, for example
Figure imgf000066_0001
As used herein, the term "composition" 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 The line — -,as a bond generally indicates a mixture of, or either of, the possible isomers, e g , containing (R)- and (S)- stereochemistry For example means containing both and |
Figure imgf000066_0004
H
Figure imgf000066_0005
Figure imgf000066_0006
H In the structure
Figure imgf000066_0002
H is equivalent to
Figure imgf000066_0003
Similarly, and by way of additional non-limiting example, when -Lr is
Figure imgf000066_0007
, the is implied Thus, is equivalent to
Figure imgf000066_0008
Figure imgf000066_0009
Figure imgf000066_0010
The wavy line
Figure imgf000066_0011
, as used herein, indicates a point of attachment to the rest of the compound For example, each wavy line in the following structure
Figure imgf000067_0001
2 indicates a point of attachment to the core structure, as described herein
Lines drawn into the ring systems, such as, for example
Figure imgf000067_0005
indicate that the indicated line (bond) may b-e attached to any of the substitutable ring carbon atoms
"Oxo" is defined as a oxygen atom that is double bonded to a ring carbon in a cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, or other ring described herein, e g ,
Figure imgf000067_0002
In this specification, where there are multiple oxygen and/or sulfur atoms in a ring system, there cannot be any adjacent oxygen and/or sulfur present in said ring system It is noted that the carbon atoms for compounds of the invention may be replaced with 1 to 3 silicon atoms so long as all valency requirements are satisfied.
As well known in the art, a bond drawn from a particular atom wherein no moiety is depicted at the terminal end of the bond indicates a methyl group bound through that bond to the atom, unless stated otherwise For example
represents
Figure imgf000067_0004
Figure imgf000067_0003
The term "purified", "in purified form" or "in isolated and purified form" for a compound refers to the physical state of said compound after being isolated from a synthetic process (e g from a reaction mixture), or natural source or combination thereof Thus, the term "purified", "in purified form" or "in isolated and purified form" for a compound refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan (e g , chromatography, recrystallization and the like) , in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan
It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences When a functional group in a compound is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T W Greene er a/, Protective Groups in Organic Synthesis (1999), Wiley, New York
As used herein, the term "composition" 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 Prodrugs and solvates of the compounds of the invention are also contemplated herein A discussion of prodrugs is provided in T Higuchi and V Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A C S Symposium Series and in Bioreversible Carriers in Drug Design, (1987) Edward B Roche, ed , American Pharmaceutical Association and Pergamon Press The term "prodrug" means a compound (e g, a drug precursor) that is transformed in vivo to yield a compound of the invention or a pharmaceutically acceptable salt, hydrate or solvate of the compound The transformation may occur by various mechanisms (e g , by metabolic or chemical processes), such as, for example, through hydrolysis in blood A discussion of the use of prodrugs is provided by T Higuchi and W Stella, "Pro-drugs as Novel Delivery Systems," VoI 14 of the A C S Symposium Series, and in Bioreversible Carriers in Drug Design, ed Edward B Roche, American Pharmaceutical Association and Pergamon Press, 1987
For example, if a compound of the invention or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (C1-C6)alkyl, (C2- C12)alkanoyloxymethyl, 1 -(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1 - methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1 -(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)amιnomethyl having from 3 to 9 carbon atoms, 1 -(N-(alkoxycarbonyl)amιno)ethyl having from 4 to 10 carbon atoms, 3-phthalιdyl, 4- crotonolactonyl, gamma-butyrolacton-4-yl, dι-N,N-(C1-C2)alkylamιno(C2-C3)alkyl (such as β-dimethylaminoethyl), carbamoyl-(CrC2)alkyl, N,N-dι (CrC2)alkylcarbamoyl-(C1- C2)alkyl and pipeπdino-, pyrrolidino- or morpholιno(C2-C3)alkyl, and the like
Similarly, if a compound of the invention contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (CrC6)alkanoyloxymethyl, 1-((C1-C6)alkanoyloxy)ethyl, 1-methyl-1-((C1-C6)alkanoyloxy)ethyl, (C1-C6)alkoxycarbonyloxymethyl, N-(C1-C6)alkoxycarbonylamιnomethyl, succinoyl, (CrC6)alkanoyl, α-amιno(C1-C4)alkanyl, arylacyl and α-amιnoacyl, or α-aminoacyl-α- aminoacyl, where each α-amιnoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)2, -P(O)(O(C1-C6)alkyl)2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate), and the like
If a compound of the invention incorporates an amine functional group, a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR'-carbonyl where R and R' are each independently (C1-C1o)alkyl, (C3-C7) cycloalkyl, benzyl, or R-carbonyl is a natural α-amιnoacyl or an unnatural α-amιnoacyl, — C(OH)C(O)OY1 wherein Y1 is H, (CrCjs)alkyl or benzyl, -C(OY2)Y3 wherein Y2 is (C1-C4) alkyl and Y3 is (d- C6)alkyl, carboxy (CrC6)alkyl, amιno(C1-C4)alkyl or mono-N — or dι-N,N-(C1-
C6)alkylamιnoalkyl, -C(Y4) Y5 wherein Y4 is H or methyl and Y5 is mono-N— or dι- N,N-(CrC6)alkylamιno morpholino, pιpeπdιn-1 -yl or pyrrolιdιn-1 -yl, and the like
Compounds of the invention wherein Z is an ester moiety, such as those selected from -(C(R11)2)-(C(R12R13))m-C(O)Oalkyl, and -(C(R11)2)-(C(R14)2)n-C(O)Oalkyl, are also expected to form prodrugs
One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms "Solvate" means a physical association of a compound of this invention with one or more solvent molecules This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid "Solvate" encompasses both solution-phase and isolatable solvates Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like "Hydrate" is a solvate wherein the solvent molecule is H2O One or more compounds of the invention may optionally be converted to a solvate Preparation of solvates is generally known Thus, for example, M Caira ef a/, J Pharmaceutical Sci 93(3), 601-611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water Similar preparations of solvates, hemisolvate, hydrates and the like are described by E C van Tonder et al, AAPS PharmSciTech , 5(11, article 12 (2004), and A L Bingham et al, Chem Commun , 603-604 (2001 ) A typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods Analytical techniques such as, for example I R spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate)
"Effective amount" or "therapeutically effective amount" is meant to describe an amount of compound or a composition of the present invention effective in inhibiting the above-noted diseases and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect
The compounds of the invention can form salts which are also within the scope of this invention Reference to a compound of the invention herein is understood to include reference to salts thereof, unless otherwise indicated The term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases In addition, when a compound of the invention contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term salt(s)" as used herein Pharmaceutically acceptable (ι e , non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful Salts of the compounds of the invention may be formed, for example, by reacting a compound of the invention with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization
Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P Stahl et al, Camille G (eds ) Handbook of Pharmaceutical Salts Properties, Selection and Use (2002) Zurich Wiley- VCH, S Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19, P Gould, International J of Pharmaceutics (1986) 33 201-217, Anderson ef a/, The Practice of Medicinal Chemistry (1996), Academic Press, New York, and in The Orange Book (Food & Drug Administration Washington, D C on their website) These disclosures are incorporated herein by reference thereto
Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as argimne, lysine and the like Basic nitrogen-containing groups may be quatemized with agents such as lower alkyl halides (e g methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e g dimethyl, diethyl, and dibutyl sulfates), long chain halides (e g decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e g benzyl and phenethyl bromides), and others
All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention
Pharmaceutically acceptable esters of the present compounds include the following groups (1 ) carboxylic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl n- propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl) aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted with, for example, halogen, C1 4alkyl, or C1-4alkoxy or amino), (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl), (3) amino acid esters (for example, L-valyl or L-isoleucyl), (4) phosphonate esters and (5) mono-, dι- or triphosphate esters The phosphate esters may be further esteπfied by, for example, a C1 20 alcohol or reactive derivative thereof, or by a 2,3-di (C624)acyl glycerol
Compounds of the invention, and salts, solvates, esters and prodrugs thereof, may exist in their tautomeric form (for example as an amide or imino ether) All such tautomeric forms are contemplated herein as part of the present invention
The compounds of the invention may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomers forms It is intended that all stereoisomers forms of the compounds of the invention as well as mixtures thereof, including racemic mixtures, form part of the present invention In addition the present invention embraces all geometric and positional isomers For example, if a compound of the invention incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e g , chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e g , hydrolyzing) the individual diastereomers to the corresponding pure enantiomers Also, some of the compounds of the invention may be atropisomers (e g , substituted biaryls) and are considered as part of this invention Enantiomers can also be separated by use of chiral HPLC column
It is also possible that the compounds of the invention may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention
All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4- pyπdyl and 3-pyrιdyl) (For example, if a compound of the invention incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention )
By way of further non-limiting example, compounds of the invention having the general structure shown in Formula (ll-b)
In one embodiment, the compounds of the invention have the general structure shown in Formula (ll-b):
Figure imgf000074_0001
ll-b) encompass compounds of the formula
Figure imgf000074_0002
Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms "salt", "solvate", "ester", "prodrug" and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.
The present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 180, 170, 31P, 32P, 36S, 18F, and 36CI, respectively Certain isotopically-labelled compounds of the invention (e g , those labeled with 3H and 14C) are useful in compound and/or substrate tissue distribution assays Tritiated (ι e , 3H) and carbon-14 (ι e , 14C) isotopes are particularly preferred for their ease of preparation and detectability Further, substitution with heavier isotopes such as deuterium (ι e , 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e g , increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances lsotopically labelled compounds of the invention can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples hereinbelow, by substituting an appropriate isotopically labelled reagent for a non- isotopically labelled reagent Such compounds are within the scope of the compounds of the invention Non-limiting examples of deuterated compounds are described herein, including examples 1 369, 1 371 , 1 371 , 1 372, and 1 312, and elsewhere
Polymorphic forms of the compounds of the invention, and of the salts, solvates, esters and prodrugs of the compounds of the invention, are intended to be included in the present invention EXPERIMENTALS
Abbreviations Used in the Experimentals May Include the Following:
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
General Experimental Information:
Unless otherwise noted, all reactions are magnetically stirred
Unless otherwise noted, when ethyl acetate, hexanes, dichloromethane, 2-propanol, and methanol are used in the experiments described below, they are Fisher Optima grade solvents
Unless otherwise noted, when diethyl ether is used in the experiments described below, it is Fisher ACS certified material and is stabilized with BHT Unless otherwise noted, "concentrated to dryness" means evaporating the solvent from a solution or mixture using a rotary evaporator
Unless otherwise noted, flash chromatography is carried out on an Isco, Analogix, or Biotage automated chromatography system using a commercially available cartridge as the column Columns may be purchased from Isco, Analogix, Biotage, Vanan, or Supelco and are usually filled with silica gel as the stationary phase Microwave chemistry is performed in sealed glass tubes in a Biotage microwave oven
General Synthetic Schemes
The general approach to these types of spiro-heterocycles is depicted in Scheme I The Boc-amino acid 1 can be coupled to an appropriately substituted amine ii using standard conditions to provide amides iii The BOCgroup in iii can be removed under acid conditions which provide ammo-amides Iv Ammo-amides ιv can be reacted with ketones v to provide spiro-amino amides such as vi (e g microwave mediated - Feliu, L , Font, D , Soley, R , Tailhades, J , Martinez, J , Amblard, M ARKIVOC 2007, 65, thermal conditions - Gomes, P , Araujo, M J , Rodngues, M , Vale, N., Azevedo, Z., Hey, J , Chanbel, P., Morais, J., Moreira, R. Tetrahedron 2004, 60, 5551 and Cheng, S., Wu, H., Hu. X Syn Comm. 2007, 37, 297), TsOH mediated cychzation as described herein. The amino intermediates such as vi can be oxidized to the spiro-imidazolone intermediates vii (e.g. Dean, A.W., Porter, R.A , WO 2007014762). The ester in vii can be hydrolyzed to provide the acid viii. The acid can be coupled to amines using standard protocols to provide the amides such as x. One skilled in the art would recognize that there are numerous coupling conditions for formation of amides.
Scheme I
Figure imgf000078_0001
When the HN(R3JZ is an amine containing an additional protected acid moiety (e g. R3 = H, Z = -CHaCHaCOatert-Butyl xa or R3 = H, Z = -CH2CH2CO2Me xb, respectively), the moiety can be deprotected using standards conditions to provide the acid analogs xi
Scheme Il
Figure imgf000079_0001
When HN(R3JZ is 5-amιno tetrazole, acids viii will produce amino-tetrazole terminated compounds such as xc using standard amide bond coupling procedures that are known to those skilled in the art.
Scheme III
Figure imgf000079_0002
Also known to those skilled in the art, are the formation of tetrazole terminated compounds of the formula xd The coupling of acids viii with cyano-substituted amines produces cyano-amides of the type xii. The cyano group in xii will react with various reagents, including sodium azide in the presence of an alkyl amine hydrochloride, to provide compounds xd.
Scheme IV
PyBofyi Pr2NEt
Figure imgf000080_0001
Alternatively, those skilled in the art can utilize the reaction depicted in Scheme V for the formation of tetrazole analogs xd The coupling reaction of acids viii with amino tetrazoles provides compounds xd using standard amide bond coupling procedures that are known to those skilled in the art
Scheme V
Figure imgf000080_0002
A general approach to enantiomerically enriched amines xvii and xiv is illustrated in Scheme Vl This approach is familiar to one skilled in the art, and numerous examples exist in the literature (for example see Cogan, D A , Liu, G , Ellman, J A Tetrahedron ! 999, 55, 8883-8904) The condensation of the sulfinamide xiii with aldehydes xiv provides the imines xv Organometallic reagents (such as grignards RSAMgBr) add to imines xv to provide diastereomeric mixtures of the sulfinamides xvi and xvii. These diastereomers can be purified by crystallization or chiral HPLC methods that are known to those skilled in the art The pure diasteroemers xvi and xvii can be treated with HCI to provide the enantiomerically enriched amine HCI salt xviii and xix, respectively
Scheme Vl
<■>
Figure imgf000081_0001
A related approach to these types of enantiomericaly enriched amine HCI salts is illustrated in Scheme VII The condensation of the sulfinamide xiu with the ketones such as xx provide imines xxi The imines can be reduced (see Tanuwidjaja, J Peltier, H M , Ellman, J A J Org Chem 2007, 72, 626) with various reducing reagents to provide sulfinamides such as xvi and xvii As previously, these can be treated with HCI to provide the enantiomerically enriched amine HCI salts xviii and
XlX
Scheme VII
Figure imgf000082_0002
Figure imgf000082_0001
The N-BOC glycine xxii can be processed heterocycles such as xxvi using previously described procedures The heterocycles can be treated with m-CPBA to provide the hydroxy intermediates xxvii The hydroxy intermediates xxvii can be converted into the corresponding inflate intermediates xxviii The inflate intermediates xxviii can be converted into the arylated analogs xxix using standard palladium catalyzed chemistry that is known by those skilled in the art Further transformation of the arylated intermediates xxix into the desired compounds has previously been described
Scheme VIII
Figure imgf000083_0001
The Boc-glycine xxii can be converted into spiro-amides of the type xxv These can be treated with m-CPBA which provide oxidized heterocycles such as xxxii Heterocycles such as xxxii can be treated with Br2PPri3 to provide bromide analogs of the type xxxiii These intermediates can be reacted with various organometallic reagents to furnish arylated intermediates such as xxix. As shown previously, these intermediates can be processed into the desired compounds xxxi using standard procedures
Scheme VIX
Figure imgf000084_0001
Procedures/Examples
Scheme A
Figure imgf000085_0001
Racemic 2-(fert-butoxycarbonylamino)-2-(3,5-dichlorophenyl)acetic acid (1.64 g, 5.1 mmol), (R)-methyl 4-(1-aminoethyl)benzoate HCI (1.0 g, 4.65 mmol), PyBOP (2.66 g, 5.1 mmol), and JPr2NEt (2.4 mL) were taken up in CH3CN (35 mL), and the solution was stirred at room temperature for 18 hours. The solution was concentrated, and the residue was partitioned between EtOAc and sat. NaHC03(aq.). The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4 The mixture was filtered and concentrated which provided a yellow oil The residue was purified by gradient flash chromatography (Analogix, 0 to 60 % EtOAc in hexanes, SiO2) gave 2 2 grams (100 %) of the amide as a white solid
Figure imgf000086_0001
The product from Step 1 (22 g, 4 5 mmol) was taken up in DCM (35 mL), and TFA (10 mL) was added at room temperature The solution was stirred at room temperature for 18 hours The solution was concentrated, and the residue was partitioned between DCM and 1 N NaOH(aq) The aqueous layer was extracted with DCM The combined organic layers were dried (MgSθ4), filtered and concentrated which furnished 1 6 g (94 %) of the amine as a colorless oil
Figure imgf000086_0002
The product from Step 2 (890 mg, 2 3 mmol) 4-tert-butyl-cyclohexanone (719 mg, 4 6 mmol) 4 A mol sieves (900 mg), and Et3N (0 65 mL) were taken up in MeOH (12 mL) The mixture was heated in a microwave (130 °C, 2 h) The mixture was filtered, and the solution was concentrated The residue was purified via gradient flash chromatography (Analogix® 0 - 35 % EtOAc in hexanes S1O2) which furnished 570 mg (48 %) of the spiro-amme as a colorless oil Step 4
Figure imgf000087_0001
The product from Step 3 (570 mg, 1.1 mmol) was taken up in DCM (35 ml_), and W-bromosuccinimide (196 mg, 2.2 mmol) were added to the solution at room temperature. After the solution was stirred at room temperature for 5 hours, the solution was partitioned between 10 % NaHSC^aq ) The aqueous layer was extracted with DCM. The combined organic layers were dried (MgSCu), filtered, and concentrated which gave a yellow oil The residue was purified via gradient flash chromatography (Analogix, 0-15% EtOAc in hexanes, SiO2) which furnished 500 mg (88%) of the imidazolone as a colorless oil.
Figure imgf000087_0002
The product from Step 4 (500 mg, 0 97 mmol) was taken up in 1 N NaOH(aq /dioxane/MeOH (1/1/1 , 90 ml total), and the solution was heated at 65 °C for 5 hours. The solution was cooled and stirred at room temperature for 16 hours The solution was concentrated The residue was partitioned between DCM and 1 M HCI (aq ). The mixture was stirred at room temperature for 0.5 h. The layers were separated, and the aqueous layer was extracted with DCM The combined organic layers were dried (MgSO^, filtered, and concentrated which afforded 485 mg (Quant ) of the acid as a white solid.
Step 6
Figure imgf000088_0001
The product from Step 5 (200 mg, 0.40 mmol), PyBOP (311 mg, 0.60 mmol), IPr2NEt (0 2 mL), and β-alanine, tert-butyl ester HCI salt (109 mg, 0.60 mmol) were taken up in CH3CN (20 mL), and the solution was stirred at room temperature for 18 hours. The solution was concentrated, and the residue was partitioned between EtOAc and sat. NaHCO3(aq). The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and dried (MgSO^. Filtration and concentration provided a yellow oil. The residue was purified via thin-layer preparative chromatography (2/1 hexanes/EtOAc, SiO2) which provided 170 mg (67 %) of the fert-butyl ester as a colorless oil
Figure imgf000088_0002
Example 1 1
The product from Step 6 (170 mg, 0.27 mmol) and TFA (2 mL) were taken up in DCM (15 mL), and the solution was stirred at room temperature for 18 hours The solution was concentrated and dried under high vacuum which provided 132 mg (85%) of Example 1.1 as an off-white solid LC/MS ret time (6 4 mm); (MH)+ 572 HRMS calc'd for C30H35Cl2N3NaO2 (M+Na)+ 594 1902, found 594.1926
Scheme B
Figure imgf000089_0001
(S)-Boc-Λomopheπyl alanine (3.0 g, 10.7 mmol), PyBOP (6.1 g, 11. 8 mmol), JPr2NEt (5.6 mL), and methyl 4-(amιnomethyl)benzoate HCI (2.4 g, 11.8 mmol) were reacted according to the procedure outlined in Step 1 of Scheme A to afford 4.5 g (98 %) of the amide a colorless foam.
Step 2
Figure imgf000090_0001
The product from Step 1 (4.53 g, 10.6 mmol) and 20 mL of TFA were reacted according to the procedure outlined in Step 2 of Scheme A to afford 3.25 g (93 %) of the amine as a white solid.
Figure imgf000090_0002
The product from Step 2 (2.5 g, 7 7 mmol), 4-tert-butyl cyclohexanone (2.4 g,
15.3 mmol), 4A mol sieves (2 5 g), and EXsN (2.1 mL) were reacted according to the procedure outlined in Step 3 of Scheme A to afford 3 3 grams (94 %) of the spiro- amme as a white solid.
Figure imgf000090_0003
The product from Step 3 (500 mg, 1 2 mmol) was taken up in dioxane (15 mL), and the solution was cooled to 0 °C tert-Butyl hypochlorite (02 mL) was added, and the solution was warmed to room temperature. After the solution had stirred at room temperature for 30 minutes, potassium tert-butoxide (300 mg) was added. The resulting mixture was stirred at room temperature for 2 hours. The mixture was partitioned between EtOAc and sat. NH4CI (aq >. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with 10% NaaSaOβ (aq ). The combined organic layers were dried (MgSO4), filtered, and concentrated. The residue was purified via gradient flash chromatography (Analogix, 0-15 % EtOAc in hexanes, S1O2) which afforded 310 mg (56 %) of the imidazolone as a colorless oil.
Figure imgf000091_0001
The product from Step 4 (310 mg, 0.67 mmol) was reacted according to the procedure outlined in Step 5 of Scheme A to afford 300 mg (Quant.) of the acid as a yellow solid.
Figure imgf000091_0002
The product from Step 5 (300 mg, 0 67 mmol) was reacted according to the procedure outlined in Step 6 of Scheme A to afford 300 mg (78 %) of the fert-butyl ester as a colorless oil
Figure imgf000091_0003
Example 1 2 The product from Step 6 (300 mg, 0 52 mmol) was reacted according to the procedure outlined in Step 7 of Scheme A to afford 87 mg (32 %) of Example 1.2 as a white solid LC/MS ret time (4 9 mm), (MH)+ 516
Scheme C
Steps 1-5
Figure imgf000092_0001
Scheme A
Figure imgf000092_0002
The benzoic acid in Scheme C was prepared according to the procedure outlined in Scheme A (Steps 1 - 5) using the amino acid, ketone, and amine The benzoic acid (65 mg, 0 13 mmol), PyBOP (83 mg, 0 16 mmol), IPr2NEt (0 1 ml_), and aminotetrazole hydrate (20 mg) were taken up in CH3CN (10 mL) The solution was heated to 80 °C until everything had dissolved The solution was stirred at room temperature (18 hours) The formed solid was collected and washed with Et2O which provided 24 mg (33 %) of Example 1.3 as a white solid LC/MS ret time (6 0 mm), (MH)+ 554 HRMS calc'd for C27H29CI2N3NaO2 (M+Na)+ 576 1658, found 576 1642
Scheme D
Figure imgf000093_0001
The benzoic acid (Product of Step 5, Scheme A, 150 mg, 0.30 mmol) was suspended in DCM (20 mL). Oxaiyl chloride (113 mg) was added followed by two drops of DMF, and the solution was stirred at room temperature for 20 minutes. More oxaiyl chloride (113 mg) was added, and after an additional 30 minutes at room temperature, the solution was concentrated The acid chloride was used directly in the next step.
Figure imgf000093_0002
.4 The acid chloride from Step 1 and Et3N (100 mg) were taken up in DCM (20 mL), and aminotetrazole hydrate (30 mg) was added to the solution After stirring at room temperature for 2 hours, the solution was washed with sat NaHCOe <aq ) The aqueous layer was extracted with DCM The combined organic layers were dried (MgSO^, filtered, and concentrated The residue was purified via preparative thin- layer chromatography (16 % MeOH in DCM, SiO2) which gave 81 mg (48 %) of Example 1.4 as a white solid LC/MS ret time (62 mm), (MH)+ 568
Scheme E
°<x
Figure imgf000094_0001
Figure imgf000094_0002
The benzoic acid in Scheme E was prepared according to the procedure outlined in Scheme A (Steps 1 - 5) using the requisite amino acid, ketone, and amine. The benzoic acid (200 mg, 0.42 mmol) was suspended in DCM (35 mL). Oxalyl chloride (0.1 mL) followed by 3-4 drops of DMF was added. The solution was stirred at room temperature for 2.5 hours. The solution was concentrated. The crude acid chloride was used without further purification.
Figure imgf000095_0001
The acid chloride from Step 1 , was partitioned between DCM and sat. NaHCU3 (aq.j. The β-alanine tert-butyl ester HCI salt (115 mg, 0.63 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were dried (MgSCU), filtered, and concentrated. The residue was purified via gradient flash chromatography (Analogix, 0-35 % EtOAc in hexanes, SiO2) which afforded 194 mg (77 %) of the fert-butyl ester as a colorless foam.
Figure imgf000095_0002
The fert-butyl ester (194 mg, 0.32 mmol) was reacted according to the procedure outlined in Step 7 of Scheme A which afforded 124 mg (71 %) of Example 1.5. LC/MS ret. time (5.8 min); (MH)+ 544.
Scheme F
Figure imgf000095_0003
4-(2-Amιnoethyl)benzoιc acid HCI (20 g, 99 mmol) and 4 M HCI in dioxane (20 ml_) were taken up in MeOH (200 mL) and heated at 85 °C for 24 hours The solution was cooled to room temperature at which time a solid precipitated The solid was collected The mother liquor was concentrated to afford a solid that was washed with Et2θ The two crops were combined to afford 20 g (94 %) of the methyl ester HCI salt as a white solid
Scheme G
Figure imgf000096_0004
M5
4-(2-Amtnoethoxy)benzoιc acid HCI salt (1 5 g, 6 9 mmol) was taken up in MeOH (75 mL) and 4 M HCI in dioxane (15 mL) The solution was heated at 70 °C for 18 hours The solution was concentrated which provided a yellow solid This material was used without further purification
Scheme H
Figure imgf000096_0001
Figure imgf000096_0002
Ex
Step i
Figure imgf000096_0003
ne
A solution of D,L-ιsoseπne (1g, 9 52 mmol), MeOH (20 mL) and 4N HCI in dioxane (20 mL) in a round bottomed flask with a reflux condenser attached was heated 3h in an 80°C oil bath The reaction mixture was then cooled and evaporated to afford the desired methyl ester hydrochloride salt as an oil which was used without further purification
Step 2
in 5 A
Figure imgf000097_0001
A solution of the methyl ester prepared in Step 1 (62 mg, 040 mmol, 1 eq), the benzoic acid prepared in Scheme A, steps 1-5 (200 mg, 040 mmol, 1 eq), PyBOP (208 mg, 0 40 mmol, 1 eq) and IPr2NEt (028 mL, 1 60 mmol, 4 eq) in DMF (3 mL) was stirred 16h at room temperature The reaction was then partitioned between EtOAc and brine diluted with aqueous HCI After discarding the aqueous layer, the organic layer was washed successively with brine, saturated NaHCθ3 (aq), and again with brine The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to afford a crude residue which was purified via silica gel chromatography (gradient elution 10% to 100% EtOAc in hexanes, S1O2) to afford the desired product (188 mg, 78%) as a 1 1 mixture of diastereomers
Step 3
Figure imgf000097_0002
Example 1 6
A solution of the coupling product from Step 2 (188 mg, 0 31 mmol, 1 eq) in MeOH (1 5 mL) and THF (3 mL) was treated with 2M LiOH (aq) (1 5 mL, 3 mmol, 10 eq) and stirred at room temperature Upon completion of the reaction (2h), the reaction was acidified with 4N HCI in dioxane and evaporated The white solid was suspended in water with 0.1 % formic acid and stirred for 16h at room temperature. The suspension was transferred to a polypropylene tube, centrifuged, and the liquid decanted The solid was then re-suspended in water with 0.1 % formic acid, centrifuged, and decanted again Dissolution of the wet solid in THF was followed by transfer to a round bottomed flask and concentration in vacuo to afford Example 1.6 as a white foam (111 mg, 61 %).
Scheme 1
Figure imgf000098_0001
Step 1
Figure imgf000098_0002
The amine (1.1 grams, 35 mmol), the N-BOC amino acid (1.1 g, 3.5 mmol), PyBOP (2.2 g, 4,2 mmol), and /-Pr2NEt (1.8 g, 14 mmol) were taken up in CH3CN (20 ml), and the resulting solution was stirred at 25 °C for 18 h. The solution was concentrated, and the residue was partitioned between EtOAc and 1 N NaOH(aq) The aqueous layer was extracted with EtOAc The combined organic layers were washed with brine and dried (MgSθ4) The solution was filtered and concentrated The residue was purified via gradient flash chromagragphy (Analogix, 0-30 % EtOAc in hexanes, S1O2) which provided 1 6 g (79%) of the BOC protected peptide as an oil
Step 2
Figure imgf000099_0001
The Boc-protected peptide (1 6 g, 2 76 mmol) and TFA (3 ml) were taken up in DCM (10 ml), and the solution was stirred at 25 °C for 18 h The solution was concentrated The residue was partitioned between DCM and 1 N NaOH(aq > The aqueous layer was extracted with with DCM The combined organic layers were dried (MgSO^, filtered, and concentrated The amino-peptide (1 3 g, Quant ) was used without further purification
Step 3
Figure imgf000099_0002
The amino-peptide (039 g, 0 67 mmol), 4-tert-butyl-cyclohexanone (021 g, 1 3 mmol), Et3N (0 14 g, 1 3 mmol), and powdered 4A mol sieves (0 5 g) were taken up in IPA (10 ml) The mixture was heated in a microwave (13O °C, 5 h) The mixture was filtered and concentrated The residue was purified via gradient flash chromatography (Analogix, 0-20% EtOAc in hexanes, SiO2) to afford 0 43 g (50 %) of the spiro-amide as a colorless oil
Step 4
Figure imgf000100_0001
The spiro-amine (0.43 g, 0.7 mmol) was taken up in DCM (20 ml), and t- BuOCI (100 mg, 0.84 mmol) was added dropwise. After 2 hours, Et3N (0.283 g, 2.8 mmol) was added, and the resulting solution was stirred at 25 °C for 1 h. The solution was diluted with DCM and washed with NaHSO3(aq.>. The aqueous layer was extracted with DCM. The combined organic layers were dried (MgSO-O, filtered, and concentrated. The residue was purified via gradient flash chromatography (Analogix, 0-50% DCM in hexanes, SiO2) which provided 0.28 g (65%) of the imidazolone-ester as a colorless oil.
Step 5
Figure imgf000100_0002
The ester (0.28 g, 0.46 mmol) was taken up in MeOH/dioxane/1 N NaOH(aq )
(10/5/1 mL), and the resulting solution was stirred at 25 °C for 18 h. The solution was concentrated, and the residue was partitioned between DCM and 1 M HCI(aq.). The aqueous layer was extracted with DCM. The combined organic layers were dried (MgSOJ, filtered, and concentrated. This provided 0.25 g (96 %) of the acid as a colorless foam.
Step 6
Figure imgf000101_0001
The acid (0 25 g, 0 44 mmol), PyBOP (O 27 g, O 53 mmol), IPr2NEt (O 17 g, 1 3 mmol), and the ammo-methyl tetrazole HBr salt (O 12 g, O 66 mmol) were taken up in DMF (5 mL), and the resulting solution was heated at 70 °C for 18 h The solution was concentrated, and the residue was purified via reversed-phase chromatography (Biotage, water/CH3CN gradient) which provided 0 22 g (77%) of Ex 1.45 as a colorless solid
Scheme J
Figure imgf000101_0002
Figure imgf000102_0001
The amino acid, amine, and ketone were used according to Steps 1-5 \n Scheme I to afford the benzoic acid The benzoic acid (240 mg, 0 50 mmol), β- alanine fert-butyl ester HCI (110 mg, 0 60 mmol), PyBOP (313 mg, 0 6 mmol), and IPr2NEt (260 mg, 2 mmol) were taken up in CH3CN (5 ml_), and the resulting solution was stirred at 25 oC for 18 h The solution was concentrated The residue was partitioned between EtOAc and 1 N NaOH(aq > The aqueous layer was extracted with EtOAc The combined organic layers were washed with brine and dried (MgSO^ Filtration and concentration gave a yellow oil The residue was purified via thin-layer preparative chromatgraphy (1/1 hexanes/EtOAc, SiO2) which gave 180 mg (60 %) of the fert-butyl ester as a colorless oil Step 2
Figure imgf000102_0002
The fert-butyl ester (180 mg, 0 30 mmol) was taken up in TFA (2 5 mL) and DCM (15 ml) The solution was stirred at 25 °C for 18 h The solution was concentrated The residue was co-evaporated with DCM 3 times (25 mL) which provided 170 mg (Quant ) of Example 1.46 as a colorless foam Scheme K
Figure imgf000103_0001
Step i
Figure imgf000103_0002
Cyclobutyl carbonyl chloride (0.6 mL, 5.2 mmol) and PdCI2(PPh3)3 (176 mg, 0.25 mmol) were taken up in THF (35 mL) The aryl zinc reagent (10 mL of a 0.5 M solution in THF, 5 mmol) was added to the reaction at 25 °C. The resulting dark solution was stirred at 25 °C (5 hr). The yellow solution was partitioned between Et2O and sat. NH4CI (aq ). The aqueous layer was extracted with Et2O The combined organic layers were washed with brine and dried (MgSO4). Filtration and concentration provided a yellow oil The residue was purified via gradient flash chromatography (0-5 % EtOAc in hexanes, S1O2, Analogix) which provided 866 mg (74 %) of the ketone as a yellow oil.
Step 2
Figure imgf000103_0003
The ketone (866 mg, 3 7 mmol), Ti(OEt)4 (0.94 mL, 4.5 mmol), and the (R) sulfinamide (493 mg, 4 mmol) were taken up in THF (40 mL). The resulting solution was heated at 70 °C for 16 h The solution of the imine was used without further purification.
Step 3
Figure imgf000104_0001
The imine from the previous step (3.7 mmol) was taken up in THF (20 ml), and the resulting solution was cooled to -78 °C. Sodium borohydride (420 mg, 11 1 mmol) was added at -78 °C, and the resulting solution was allowed to warm to 25 °C over 18 h. The residue was partitioned between EtOAc and sat. NH4CI (aq.). The aqueous layer was extracted with EtOAc The combined organic layers were washed with brine and dried (MgSO4). Fitlration and concentration provided a yellow oil. The residue was purified via gradient flash chromatography (0-40% EtOAc in hexanes, S1O2, Analgogix) which provided 580 mg (46 %) of the sulfinimide as a mixture of diastereomers (3/1).
Step 4
Figure imgf000104_0002
The sulfinamide (580 mg, 1 7 mmol) was taken up in EtOH (30 ml) at 25 °C Dioxane (4 0 M HCI, 15 mL) was added, and the solution was stirred at 25 °C for 18 h The solution was concentrated and dried which provided the amine HCI salt as a white solid. The material was used without further purification. All final compounds prepared from this amine are a 3/1 mix of enantiomers.
Scheme LD
Figure imgf000105_0001
The benzoic acid was prepared according to Scheme I (Steps 1 -5) using the appropriate amino acid, amine, and ketone The benzoic acid (90 mg, 0 18 mmol), IPr2NEt (0 12 mL, 0 72 mmol), PyBOP (122 mg, 0 23 mmol), and taurine (34 rng, 0 27 mmol) were taken up in DMF (4 mL), and the resulting solution was heated at 80 °C for 2 5 h The reaction was concentrated The residue was purified via reversed- phase chromatography (water/CH3CN gradient) which provided 85 mg (77%) of Example 1.72 as a colorless foam
Scheme M
Figure imgf000106_0001
The benzoic acid was prepared according to Scheme I (Steps 1 -5) using the appropriate amino acid, amine, and ketone The benzoic acid (200 mg, 04 mmol), 1Pr2NEt (158 mg), HOBt (83 mg), EDCI (117 mg), and taurine (76 mg) were taken up in DMF (3 ml_), and the resulting solution was stirred at 25 °C for 3 days The reaction was quenched with 1 M HCI(aq) The resulting solid was collected and purified via reversed-phase chromatography (water/CHaCN gradient) which provided 33 mg (14 %) of Example 1.73 as a colorless foam
Scheme N
Steps 1-5 Scheme I
Figure imgf000107_0001
76
Siep i
Figure imgf000107_0002
The benzoic acid was prepared according t Scheme I 1 -5) using the appropriate amino acid, amine, and ketone The benzoic acid (320 mg, 0.71 mmol) and pyridine (0.2 mL) were taken up in DCM (15 mL) at 0 °C. Cyanuric fluoride (0.13 ml) was added, and the resulting solution was stirred at 0 °C for 2 h. The solution was diluted with DCM and washed with sat. NaHCC^aq.) The aqueous layer was extracted with DCM. The combined organic layers were dried (MgSO4, filtered and concentrated. The acid fluoride was used without further purification.
Step 2
Figure imgf000107_0003
Example 1 76 The acid fluoride (0 7 mmol) from the previous step and amino-tetrazole hydrate (70 mg) were taken up in pyridine and stirred at 25 °C for 18 h The solution was concentrated The residue was purified via reversed-phase chromatography (water/CH3CN gradient) provided 47 mg (12 %) of Example 1 ,76 as a colorless solid
Scheme O
Figure imgf000108_0001
The methyl ester was prepared according to Scheme I (Step 1 -4) using the appropriate amino acid, amine, and ketone The methyl ester (350 mg, 0 6 mmol) was taken up in DMF (5 ml_) Sodium hydride (40 mg, 60% wt dispersion in oil) was added The solution was stirred at 25 °C for 1 hr Methyl iodide (150 mg) was added, and the solution was stirred at 25 °C for 3 h More NaH and MeI were added, and the resulting solution was stirred at 25 °C for 18 h The solution was partitioned between Et2O and water The aqueous layer was extracted with Et2O The combined organic layers were washed with brine and dried (MgSCU) Filtration and concentration gave an orange oil The residue was purified via gradient flash chromatography (0-25 % EtOAc in hexanes, S1O2) which provided 220 mg (61 %) of the methyl ether as a colorless oil The methyl ester from the previous step was converted into Example 1.77 according to Scheme J (Steps 1 and 2) Scheme P
Figure imgf000109_0001
Example 1.78
The methyl ester (Scheme O) was converted into Example 1.78 according to Scheme I (Steps 5 and 6).
Scheme Q
Figure imgf000109_0002
Step 1
Figure imgf000110_0001
Thionyl chloride (1 5 mL) was added dropwise to MeOH (35 mL) at 0 °C After stirring at 0 °C for 45 minutes, the phenyl glycine (3 g, 13 7 mmol) was added, and the resulting solution was heated at 45 °C for 16 h The solution was concentrated The residue was triturated with Et2θ The solid was collected and dried which furnished 3 5 g (94 %) of the methyl ester HCI salt
Step 2
Figure imgf000110_0002
The methyl ester HCI salt (3 5 g, 13 mmol) was taken up in MeOH (45 ml) A methanol solution containing NH3 (7 N, 80 mL) was added, and the resulting solution was stirred at 25 °C for 50 h The solution was concentrated The residue was partitioned between DCM and water The aqueous layer was extracted with DCM The combined organic layers were dried (MgSO^, filtered, and concentrated This provided 2 7 g (95 %) of the ammo-amide as a colorless solid
Step 3
Figure imgf000110_0003
The ammo-amide (1 1 g, 5 0 mol), ketone (1 5 g), 4 A mol sieves (3 g), and Et3N (1 5 g) were taken up in MeOH (20 ml), and the resulting mixture was heated at 70 °C for 18 h The solution was filtered and concentrated The residue was purified via gradient flash chromatography (0-50% EtOAc in hexanes, SiO2) which provided 500 mg (28%) of the spiro-amide a and 660 mg (37%) the spiro-amine b as a colorless oil
Step 4
Figure imgf000111_0001
The spiro-amine b (660 mg, 1 86 mmol) was taken up in DCM (35 mL), and NBS (400 mg) was added The solution was stirred at 25 °C for 18 h The solution was diluted with DCM and washed with 10% NaHSO3(aq) The aqueous layer was extracted with DCM The combined organic layers were washed with 10% NaHCOe (aq), dried (MgSO4), filtered, and concentrated The residue was purified via gradient flash chromatography (0-50% EtOAc in hexanes, S1O2) which provided 95 mg (14 %) of the imidazolone as a colorless solid Step 5
Figure imgf000111_0002
The imidazolone (95 mg, 0 27 mmol), K2CO3 (48 mg), and the benzyl bromide (310 mg) were taken up in acetone (20 mL), and the resulting solution was heated at 65 °C for 18 h The solution was filtered and concentrated The residue was purified via thin-layer preparative chromatography (14% Et2O in hexanes, SiO2) which provided 40 mg (30 %) of the methyl ester as a colorless oil
Figure imgf000112_0001
The methyl ester was converted into Example 1.79 according to the procedures outlined in Scheme I (Step 5) and Scheme J (Steps 1 and 2).
Scheme R
Figure imgf000112_0002
Step i
Figure imgf000113_0001
from Scheme Q
The spiro-amide a from Scheme Q (1 g, 2 8 mmol) was taken up in DCM (25 mL) tert-Butyl hypochlorite (370 mg) was added dropwise at 25 °C After 1 h at 25 °C, triethylamine (1.1 g) was added, and the resulting solution was stirred at 25 °C for 2 h The solution was diluted with DCM and washed with NaHSO3(aq.). The aqueous layer was extracted with DCM The combined organic layers were dried (MgSθ4), filtered, and concentrated. This provided 1 g (Quant.) of the imidazolone as a colorless oil.
Step 2
Figure imgf000113_0002
The imidazolone (1 g, 2.85 mmol), K2CO3 (786 mg), and the bromide (1.46 g) were reacted according to the procedure outlined in Step 5 of Scheme Q which provided 720 mg (48 %) of the ketone as a colorless oil
Step 3
Figure imgf000113_0003
The ketone (360 mg, 068 mmol) was taken up in MeOH (20 mL), and sodium borohydride (40 mg) was added After stirring at 25 °C for 2 hr, the solution was concentrated The residue was partitioned between EtOAc and water The aqueous layer was extracted with EtOAc The combined organic layers were washed with brine and dried (MgSO4) Filtration and concentration provided 345 mg (95 %) of the alcohol as a yellow oil
Step 4
Figure imgf000114_0001
The alcohol (345 mg, 0 65 mmol) was taken up in THF (8 mL), and sodium hydride (30 mg, 60 wt % dispersion in oil) was added After 15 minutes, methyl iodide (100 mg) was added After stirring at 25 °C for 1 h, the solution was concentrated The residue was partitioned between EtOAc and brine The aqueous layer was extracted with EtOAc The combined organic layers were dried (MgSO4), filtered, and concentrated The residue was purified via gradient flash chromatography (0-30% EtOAc in hexanes, SiO2) which provided 180 mg (50%) of the methyl ether as a colorless oil The methyl ether was converted into Example 1.82 according to the procedures outlined in Scheme J (Steps 1 and 2)
Scheme S
Steps 1 and 2 Scheme J
Figure imgf000115_0001
Step i
Figure imgf000115_0002
The ketone from Scheme R (Step 2) (140 mg, 0.26 mmol) was taken up in Et2O (8 ml) at 0 °C. Methyl magnesium iodide (0.15 mL of a 3 M solution in Et2O) was added at 0 °C. After one hour at 0 °C, the solution was partitioned between Et2O and sat. NH4CI(aq. ) The aqueous layer was extracted with Et2O The combined Et2O layers were washed with brine and dried (MgSO4). Filtration and concentration provided a yellow oil. The residue was purified via gradient flash chromatography (0- 30% EtOAc in hexanes, Analogix) which provided 40 mg (28 %) of the alcohol as a colorless oil.
The alcohol was converted into Example 1 ,83 according to the procedures outlined in Scheme J (Steps 1 and 2). Scheme T
Figure imgf000116_0001
Step i
Figure imgf000116_0002
The amine 5.07 g (25 mmol) and CbzC1 19.3 g (113 mmol) were partitioned in water (100 mL). A sodium hydroxide solution (2 N, 15 mL) was added at 25 °C. Additional aqueous sodium hydroxide solution was added at later time points (10 mm - 5 mL and 30 mm 10 mL of 2 N NaOH). The mixture was stirred at 25 °C for 18 h. Diethyl ether was added (30 mL), and the mixture was stirred The layers were separated. The aqueous layer was cooled to 0 °C, and acidified via careful addition of cone. HCI until pH = 3 0 The formed white solid was collected and washed with water. The white solid was dried under vacuum to provide 7 1 g (94%) of the Cbz protected acid
Step 2
Figure imgf000117_0001
The acid (410 mg, 1.37 mmol), PyBOP (784 mg, 1 5 mmol), IPr2NEt (0 7 mL,
4.1 mmol), and β-alanine methyl ester HCI salt (191 mg, 1.37 mmol) were taken up in DCM (13 mL), and the resulting solution stirred at 25 °C for 18 h. The solution was washed with sat. NaHCθ3(aq ) The aqueous layer was extracted with DCM. The combined organic layers were dried (MgSO4), filtered and concentrated. The residue was purified via gradient flash chromatography (0-80 % EtOAc in hexanes, S1O2) which provided 260 mg (49%) of the amide as a white solid
Step 3
Figure imgf000117_0002
The Cbz protected amine (260 mg, 0 7 mmol) and 10% Pd/C (220 mg) were stirred in MeOH (7 mL) under H2 (1 atm) for 18 h The mixture was filtered through Celite®. The solution was concentrated which provided 170 mg (Quant ) of the amine as a colorless foam. Step 4
Figure imgf000118_0001
The amine (170 mg, 0 7 mmol), N-BOC phenyl glycine (234 mg, O 7 mmol), PyBOP (400 mg, O 77 mmol), and IPr2NEt (O 4 mL) were taken up in DMF (20 mL), and the resulting solution was stirred at 25 °C for 18h The solution was partitioned between 1 N NaOH (aq > and EtOAc The aqueous layer was extracted with EtOAc The combined organic layers were dried (MgSO^, filtered, and concentrated The residue was purified via gradient flash chromatography (50-100 % EtOAc in hexanes, SiO2) which provided 114 mg (29 %) of the BOC protected peptide as a foam
Step 5
Figure imgf000118_0002
The BOC protected amine (114 mg, 0 2 mmol) and TFA (1 mL) were taken up in DCM (1 mL), and the solution was stirred at 25 °C for 3 h The solution was concentrated The residue was partitioned between DCM and 1 N NaOH (aq ) The aqueous layer was extracted with DCM The combined organic layers were dried (MgSO4), filtered, and concentrated The amine was used without further purification
Step 6
Figure imgf000119_0001
The amine (0 2 mmol), ketone (79 mg, 0 5 mmol), EtβN (O 1 mL), 4A mol sieves (125 mg), and MeOH (2 mL) were processed according to Step 3 of Scheme I The crude material was purified via gradient flash chromatography (30-70% EtOAc in hexanes, S1O2) which provided 88 mg (73%) of the spiro-amide
Step 7
Figure imgf000119_0002
The spiro-amide (88 mg, 0 146 mmol), tBuOCI (40 μl_), and Et3N (100 μL) were used according to Step 4 of Scheme I to provide the imidazolone The material was purified via gradient flash chromatography (30-50% EtOAc in hexanes, S1O2) which provide 80 mg (90 %) of the methyl ester as a colorless oil
Step s
Figure imgf000120_0001
The methyl ester (80 mg, 0 13 mmol) was taken up in 1 N NaOH(aq /MeOH/dioxane (1/1/1 , 4 5 ml) The solution was stirred at 25 °C for 18 h The reaction was concentrated The residue was acidified with 1 N HCI <aq > The solution was extracted with EtOAc The combined organic layers were dried (MgSO4), filtered, and concentrated The residue was purified via gradient flash chromatography (10-30% MeOH in DCM, SiOa) which provided 75 mg (Quant ) of Example 1.98 as a colorless solid after freeze drying
Scheme U
Figure imgf000120_0002
Step i
Figure imgf000120_0003
The acid (330 mg, 3 mmol), amine HCI salt (280 mg, 2 mmol), PyBOP (1 25 g, 2 4 mmol), and 1Pr2NEt (1 ml.) were taken up in DCM (20 mL) The solution was stirred for 18 h The solution was partitioned between 0 5 N NaOH (aq) and DCM The aqueous layer was extracted with DCM The combined organic layers were dried (MgSO<i), filtered, and concentrated The residue was purified via gradient flash chromatography (EtOAc in hexanes, S1O2) which provided 517 mg (Quant ) of the cyano-amide as a foam
Step 2
Figure imgf000121_0001
The cyano-amide (517 mg, 2 mmol) and 10% Pd/C (200 mg) were taken up in EtOH/water/HOAc (10 mL/3 mL/0 3 mL), and the resulting solution was charged with 50 psi H2 After 0 5 h, the solution was filtered (Celite®) and concentrated The residue was basified with 0 5 N NaOH to pH = 11 The solution was extracted with DCM The DCM layers were dried (MgSO4), filtered, and concentrated which provided 394 mg ( 79%) of the amine as a colorless oil
Figure imgf000121_0002
The amine, N-BOC phenyl glycine, and ketone were processed into Example
1.106 according to the procedures outlined in Scheme M (Steps 6,7 and 8)
Scheme V
Figure imgf000122_0001
Step 2
Figure imgf000122_0002
The Boc-amide (1.25 g, 3 O mmol; prepared according to Scheme I - Step 1 using the appropriate amine and acid) and NCS (1 25 g) were taken up in
CHCI3/HOAC (1/1 , 50 ml_). The solution was heated at reflux for 6 h. The solution was concentrated The residue was purified via gradient flash chromatography (10- 50% EtOAc in hexanes, S1O2) which provided 1.1 g (81 %) of the chloro thiophene as a colorless oil
Figure imgf000122_0003
The BOC protected chloro thiophene was processed according to the procedures outlined in Scheme M (Steps 5-8) to provide Example 1.110.
Scheme W
1,114
Figure imgf000123_0001
The benzoic acid in Scheme W was processed according to the procedures outlined in Scheme U to provide Example 1.114.
Scheme X
Figure imgf000123_0002
Step i
Figure imgf000124_0001
The N-BOC phenyl glycine (1.56 g, 5 8 mmol), amine (1.41 g, 5 8 mmol), PyBOP (3 64 g, 7 mmol), and IPr2NEt (2.3 mL) were reacted according to the procedure outlined in Scheme I (Step 1 ) to provide 2 78 g (100 %) of the amide as a colorless foam.
Step 2
Figure imgf000124_0002
The methyl ester (2.78 g, 6.1 mmol) was dissolved in THF (30 mL), MeOH (10 mL), and 2 M LiOH (12.2 mL). The solution was stirred at 25 °C for 2 h and at 80 °C for 1 h The solution was concentrated The residue was taken up in water and neutralized with 2 N HCI (pH = 3). The mixture was extracted with DCM. The combined organic layers were dried (MgSOJ, filtered, and concentrated which provided 2 52 g (94%) of the acid as a colorless foam.
Step 3
Figure imgf000124_0003
The acid (2.5 g, 5.7 mmol), amine HCI salt (800 mg, 5 7 mmol), PyBOP (3.56 g, 6.84 mmol), and IPr2NEt (3 mL) were processed according to Scheme T (Step 2) to provide the 2.7 g (91 %) of the Boc-amine as a colorless foam. 1 117
The BOC amine was processed according to Scheme T (Steps 5-8) to provide Example 1.117
Scheme Y
Figure imgf000126_0001
Step i
Figure imgf000126_0002
The N-BOC acid and the amine HCI salt were processed according to the procedure outlined in Scheme I (Step 1 ) to provide the BOC protected amide.
Step 2
Figure imgf000127_0001
The Boc-amide (1 62 g, 3 87 mmol) and NBS (688 mg, 3 87 mmol) were taken up in CHCI3/HOAC (1/1 , 50 ml_) The solution was heated at 80 °C for 1 h The solution was concentrated The residue was partitioned between EtOAc and sat NaHCOe (aq) The aqueous layer was extracted with EtOAc The combined organic layers were dried (MgSOJ, filtered, and concentrated The residue was purified via gradient flash chromatography (0-30% EtOAc in hexanes, SiO2) provided 424 mg (22 %) of the bromo thiophene as an oil
Step 3
The Boc-amine was processed into the amine using the conditions outlined in Scheme T Step 5
Step 4
Figure imgf000127_0003
The amine was processed into the spiro-amide using conditions outlined in Scheme T Step 6.
Step 5
Figure imgf000128_0001
The spiro-amide (589 mg, 1 1 mmol) was taken up in DCM (20 ml), and NBS (235 mg, 1 32 mmol) was added. After stirring at 25 °C for 1 h, tπethylamine (445 mg, 44 mmol) was added, and the solution was stirred at 25 °C for 2 h The solution was concentrated. The residue was purified via gradient flash chromatography (0-20% EtOAc in hexanes, SiO2) which provided 386 mg (66%) of the bromo thiophene as a white solid
Step 6
Figure imgf000128_0002
The bromo thiophene (55 mg, 0 1 mmol), cyclopropyl boronic acid (12 mg, 0 13 mmol), Pd(OAc)2 (1 mg), PCy3 (3 mg), and K3PO4 H2O (83 mg, 0.36 mmol) were taken up in toluene/water (2 ml_/0 1 mL), and the mixture was heated in a sealed tube at 100 °C for 3 h. The mixture was diluted with EtOAc, filtered, and concentrated. The residue was purified via gradient flash chromatography (0-20% EtOAc in hexanes, SiO2) which provided 40 mg (79%) of the cyclopropyl thiophene as a white solid
Figure imgf000129_0001
The product from the previous step was processed according to Scheme J (Steps 1 and 2) to furnish Example 1.120
Scheme Z
Figure imgf000129_0002
Step i
Figure imgf000130_0001
The acid (106 mg, 0 22 mol, prepared according to Scheme I Steps 1-5 using the appropriate ammo acid, amine, and ketone) was taken up in DCM (8 mL), and thionyl chloride (0 5 mL, 0 72 mmol) was added The solution was heated at 55 °C for 3 h The solution was concentrated with 3 volumes of DCM The residue was dried under high vacuum for 18 h which provided the acid chloride as a foam This material was used without further purification
Step 2
Figure imgf000130_0002
1 140
The acid chloride from the previous step was processed into Example 1.140 using the conditions described in Scheme D Step 2
Scheme AA
Figure imgf000131_0001
Step i
Figure imgf000131_0002
The acid (220 mg, 0.47 mmol, prepared according to Scheme I (Steps 1 -5) using the appropriate ammo acid, amine, and ketone), EDCI (150 mg, 0 78 mmol), 4A mol. sieves (100 mg), and HOBt (106 mg, 0 78 mmol) were taken up in pyridine (6 mL) The mixture was stirred at 50 °C for 3 h and then at 25 °C for 18 h The solution was concentrated The residue was purified via gradient flash chromatography (0-10% MeOH in DCM, S1O2). Additional purification using preparative thin-layer chromatography (10/2/0.3 DCM/MeOH/HOAc, SiO2) provided 55 mg (21 %) of Example 1.145 as an off-white solid
Scheme AB
Figure imgf000132_0001
Example 1 149
The amino acid, amine, and ketone were converted into the acid using procedures outlined in Scheme I (Steps 1 -5). The acid was subsequently converted into Example 1.149 using Steps 2 and 8 of Scheme T.
Scheme AC
Figure imgf000133_0001
Step 1
Figure imgf000133_0002
The mixture of tetrazole isomers (O 16 mmol, prepared according to Scheme I using the appropriate amino acid, amine, and ketone) was purified via reversed-phase preparative HPLC (0-95% CH3CN in water/95% CH3CN for 20 minutes) to provide 29 mg (31 %) of Example 1.154 (Isomer A, faster eluting) and 31 mg (33 %) of Isomer B
Scheme AD
Figure imgf000134_0001
Step t
Figure imgf000134_0002
The amine (572 mg, 2 mmol; prepared according to Scheme T Steps 1-3), N- lycine (350 mg, 2 mmol), PyBOP (1.2 g, 2 4 mmol), and IPr2NEt (1 mL) were taken up in DMF (10 mL), and the resulting solution was stirred at 25 °C for 18 h The solution was partitioned between EtOAc and sat NaHCOe (aq) The aqueous layer was extracted with EtOAc The combined organic layers were washed with brine and dried (MgSOJ The mixture was filtered and concentrated The residue was purified via gradient flash chromatography (0-30% MeOH in DCM, S1O2) provided the desired product contaminated with the PyBOP by-product The residue was treated with 20 mL of EtOAc The formed precipitate was collected and dried under high vac This provided 730 mg (90 %) of the Boc-protected amide Step 2
Figure imgf000135_0001
The Boc-amine (370 mg, 0 9 mmol) and TFA (4 mL) were taken up in DCM (4 mL) The solution was stirred at 25 °C for 18 h The solution was concentrated, and the residue was partitioned between DCM and 1 N NaOH The aqueous layer was extracted with DCM The combined organic layers were dried (MgSO4), filtered, and concentrated The amine was used without further purification
Step 3
Figure imgf000135_0002
The amine from the previous step (0 9 mmol), ketone (3 mmol), Et3N (3 mmol), and 4A mol sieves (1 g) were taken up in MeOH (8 ml), and the mixture was subjected to microwave conditions (Biotage - 130 °C for 4 h) The mixture was filtered and concentrated The residue was purified via gradient flash chromatography (0-100% EtOAc in hexanes, SiO2) to provide 281 mg (73 %) of the spiro-amide as a pale yellow solid
Step 4
Figure imgf000136_0001
The spiro-amide (280 mg, 0 65 mmol) was taken up in DCM (4 mL) at 0 °C , and m-CPBA (440 mg, 1 96 mmol, 77%) was added at O °C After stirring at O °C for 3 h, the reaction was quenched with 3 ml of 10% Na2S2O3 solution The mixture was partitioned between sat NaHCC>3 and DCM The aqueous layer was extracted with DCM The combined organic layers were dried (MgSO,*), filtered, and concentrated The residue was purified via flash chromatography (EtOAc, SiO2) which provided 250 mg (87 %) of the nitrone as an oil
Step 5
Figure imgf000136_0002
Triphenylphosphine (220 mg, 0 84 mmol) was taken up in DCM (1 mL), and bromine (40 μL) was added at 0 °C After stirring at 0 °C for 15 minutes, the nitrone (250 mg, 0 56 mmol) and triethylamine (0 17 mmol) was added at 0 °C The solution was warmed to 25 °C and stirred at that temperature for 1 h The solution was diluted with DCM and washed with brine The aqueous layer was extracted with DCM The combined organic layers were dried (MgSO4), filtered, and concentrated The residue was purified via gradient flash chromatography (0-40% EtOAc in hexanes, SiO2) to provide the desired product contaminated with triphenylphosphine oxide The material was purified via gradient flash chromatography (0-30% EtOAc in hexanes, SiO2) which provided 60 mg (21 %) of the bromide as an oil
Step 6
Figure imgf000137_0001
The bromide (60 mg, O 12 mmol), Pd(PPh3)2CI2 (4 mg), Na2CO3 (O 5 ml_ of a 2 M solution), and the boronic acid (40 mg, 0 24 mmol) were taken up in DME (1 mL) and heated at 85 °C for 4 h in a sealed tube The reaction was partitioned between 1 M HCI and EtOAc The aqueous layer was extracted with EtOAc The combined organic layers were washed with brine and dried (Na2SO4) The mixture was filtered and concentrated The residue was purified via gradient flash chromatography (0- 30% EtOAc in hexanes, SiO2) provided 50 mg (77 %) of the arylated imidazolone as a colorless oil
Step 7
2 1
Figure imgf000137_0002
The methyl ester was processed into Example 2.1 using the condtions outlined in Scheme T (Step 8)
Scheme AE
Figure imgf000138_0001
Step i
Figure imgf000138_0002
The amine (1 g, 3 5 mmol, prepared according to Scheme I (Steps 1 and 2), 4A mol sieves (1 g), Et3N (3 ml), and the ketone (3 3 g, 21 mmol) were taken up in MeOH (15 ml) The mixture was placed into a sealed tube and heated at 100 °C for 7 h The mixture was filtered and concentrated The residue was purified via gradient flash chromatography (2-10% MeOH in DCM, S1O2) which provided the spiro-amide (2 5 g) contaminated with - 15 % of the ketone This material was used without further purification
Figure imgf000138_0003
The spiro-amide was processed into Example 1.156 using the condtions outlined in Scheme I (Steps 4,5, and 6)
Scheme AF
Figure imgf000139_0001
The ammo acid, amine, and ketone were converted into the methyl ester using procedures outlined in Scheme AE. The methyl ester was subsequently converted into Example 1.164 using Steps 2 and 8 of Scheme T
Scheme AG
Figure imgf000140_0001
The Boc-protected amino acid, amine, ketone, and boronic acid were converted into the methyl ester following procedures outlined in Scheme AD (Steps 1- 5) The methyl ester was converted into Example 2.6 using Steps 5 and 6 of Scheme I
Scheme AH
Figure imgf000141_0001
The Boc-protected ammo acid, amine, ketone, and boronic acid were converted into the methyl ester following procedures outlined in Scheme AD (Steps 1 - 5). The methyl ester was converted into Example 2.12 using Steps 2 and 8 of Scheme T.
Scheme Al
Figure imgf000142_0001
Step i
Figure imgf000142_0002
The bromide (198 mg, 031 mmol, prepared according to Scheme I using the appropriate ammo acid, ketone, and amine), CH3SO2Na (115 mg, 0 95 mmol), CuI (185 mg, 0 95 mmol), and L-proline Na salt (87 mg, 0 63 mmol) were taken up in DMF (5 ml_), and the resulting mixture was heated at 135 °C for 6 5 h The solution was concentrated The residue was purified via gradient flash chromatography (0-50% EtOAc in hexanes, S1O2) which provided 160 mg (81%) of the aryl sulfone as an off- white solid
Scheme 1
Figure imgf000143_0001
The aryl sulfone was processed into Example 3.1 using condition outlined in Scheme I (Steps 5 and 6)
Scheme AJ
Figure imgf000143_0002
The sulfone was prepared according the procedures outlined in Scheme Al The ester was processed using conditions outlined in Scheme T to provide Example 3.3
Scheme AK
Figure imgf000144_0001
Example 4.1 was prepared according to the procedures outlined in Scheme T using Steps 2 and 8.
Scheme AL
Figure imgf000145_0001
Example 4.2 was prepared according to the procedures outlined in Scheme T using Steps 2 and 8.
Scheme AM
Figure imgf000146_0001
41-1
Example 4.11 was prepared according to the procedures outlined in Scheme T using Steps 2 and 8.
Scheme AN
Figure imgf000147_0001
Example 4.12 was prepared according to the procedures outlined in Scheme T using the Steps 2 and 8.
Scheme AO
Figure imgf000148_0001
Step i
MeOH/draxane
Figure imgf000148_0002
The starting material (prepared according to Scheme I - Steps 1-5) was taken up in 1 N NaOH(aq )/dιoxane/MeOH [1/1/1 , 10 mL], and the solution was heated at 60 °C for 14 hours. The solution was cooled to the room temperature The solution was concentrated. The residue was partitioned between DCM and 1 M HCI <aq >. The mixture was stirred at room temperature for 0.5 h. The layers were separated, and the aqueous layer was extracted with DCM The combined organic layers were dried (Na2SO,t), filtered, and concentrated which afforded the acid as a white solid.
The acid was processed using conditions described in Scheme J (Steps 1 and 2) to provide Example 1 ,210
Scheme AP
Figure imgf000149_0001
Step 1
Figure imgf000149_0002
The methyl ester (prepared according to Scheme J - Steps 1 -5 using the appropriate ammo acid, ketone, and amine was taken up in 1 N NaOH(aq) /dioxane/MeOH [1/1/1 , 10 mL], and the solution was heated at 60 °C for 14 hours. The solution was cooled to room temperature. The solution was concentrated The residue was partitioned between DCM and 1 M HCI (aq ) The mixture was stirred at room temperature for 0.5 h. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were dried (NaaSCM, filtered, and concentrated which afforded the acids A and B as a mixture (A : B = 3 : 1 ) This mixture was carried on to the coupling step directly
The mixture of A and B were processed into Example 1.224 and 1.225 using the conditions described in Scheme I Step 6.
Scheme AQ
Figure imgf000150_0001
The corresponding N-BOC phenyl glycine, amine, and ketone were processed to the benzoic acid intermediate using procedures outlined in Scheme A (Steps 1-5). The benozoic acid was processed into Example 1 32 using similar conditions outlined in Scheme A (Steps 6 and 7) using fe/t-butyl 4-amιnobutanoate HCI salt as depicted in Scheme AQ
Scheme AR
Figure imgf000151_0001
The N-BOC phenyl glycine, amine, and ketone were processed according to Scheme I (Steps 1-5) to provide the benzoic acid intermediate. The benzoic acid was coupled to 2-(2H-tetrazol-5-yl)ethanamine using conditions similar to those in Scheme I (Step 6) which provided Example 1.231.
Figure imgf000151_0002
Figure imgf000152_0001
To a 20 imL v/al was added bromide (100 mg, 0 19 mmol, prepared according to the procedures outlined in Scheme I), Pd(PPh3)4 (22 mg, 0 10 equiv ), the boronic acid (456 mg, 1 5 equiv ) and 0 5 mL of aq NaHCOs solution, followed by 5 mL of toluene/EtOH (1/1) The vιa\ was capped, sealed, and heated at 110 °C overnight The mixture was cooled to RT, diluted with ether, filtered through Celite®, and concentrated The residue was purified via gradient flash chromatography (ISCO, 0 - 50 % EtOAc in hexanes, S1O2) to furnish the desired compound (103 mg, 91% yield)
The methyl ester was processed into Example 2.84 using conditions outlined in Scheme J (Steps 1 and 2)
Scheme IB
Figure imgf000152_0002
The methyl ester (Scheme IA) was processed into Example 2.86 using conditions outlined in Scheme I (Steps 5 and 6)
Scheme IC
Figure imgf000153_0001
Step i
Figure imgf000153_0002
The bromide was prepared according to the Scheme I (Steps 1 -5) using the requisite amino acid, amine, and ketone.
To a 20 mL vιa\ was added bromide (100 mg, 0.15 mmol), Pd(PPh3J4 (18 mg, 0.10 equiv.), boronic acid (45 mg, 1.5 equiv.) and 0.5 mL of aq NaHCC>3 solution, followed by 5 mL of toluene/EtOH (1/1 ) The vial was capped, sealed, and heated at 110 °C overnight. The mixture was cooled to RT and diluted with ether and filtered through Celite® and concentrated. The residue was purified via gradient flash chromatography (ISCO, 0 - 50 % EtOAc in hexanes, S1O2) which furnished the desired compound (100 mg, 92% yield)
The fert-butyl ester was processed into Example 2.90 using conditions outlined in Scheme J (Step 2)
Scheme ID
Figure imgf000154_0001
Step i
Figure imgf000154_0002
LDA was generated in situ from π-BuLι (6 85 mL, 17 1 mmol, 2 5 M in hexanes, S1O2) and diisopropylamine (2 40 mL, 17 1 mmol) in THF (10 mL) Benzyl cyanide (3 0 g, 20 0 mmol) was added to a solution of LDA at -78 °C Then the solution was warmed to 0 °C and stirred for 10 mm To this solution was added 4-bromo 1 ,1 ,1- tnfluorobutane (1 92 mL, 18 0 mmol) followed by HMPA (2 5 mL, 14 0 mmol) in 5 mm The reaction was allowed to warm to room temperature gradually overnight Then the reaction was partitioned between EtOAc and 1 N HCI The aqueous layer was discarded and the organic layer washed with 1 N HCI and brine then dried (Na2SO4) Filtration and concentration provided a yellow oil The residue was purified via gradient flash chromatography (ISCO, 0 - 40 % EtOAc in hexanes, SiO2) which provided the cyano-ester 1 92 g (41 % yield)
Step 2
Figure imgf000154_0003
A mixture of cyano-ester (1 92 g), Pd(OH)2/C (300 mg 10 mol%) in 50 mL
MeOH and 5 mL con HCI was stirred under 50 atm H2 overnight (20 h) The reaction was purged with nitrogen, filtered through Celite®, and concentrated This provided the crude product 1 93 g (99% yield), which was used without further purification Scheme IE
Figure imgf000155_0001
Step i
Figure imgf000155_0002
A pre-made solution (at O °C) of PPh3 (477 mg) and Br2 (264 mg) in DCM (4 mL) was added to a solution of nitrone (628 mg) in DCM (4 mL) at 0 °C After 10 mins, Et3N (0 24 mL) was added, and the reaction stirred for another 10 mm at 0 °C The ice water bath was removed and the reaction was stirred at room temperature for 3 h Brine (10 ml) was added and the mixture was stirred for 20 mm The organic layer was separated, the aqueous layer was washed with DCM twice The combined organic layers were dried over NaaSO4 filtered, and concentrated The residue was chromatographed through a short column of S1O2 (EtOAc/hexane 1/3) to give the desired product as a white solid 504 mg (77% yield)
Step 2
Figure imgf000156_0001
To a 20 mL wal was added chloride (100 mg, 0 20 mmol), Pd(PPh3)2CI2 (14 mg, 0 10 equiv ), boronic acid (56 mg, 1 5 equiv ) and 0 5 mL of aq NaaCOβ solution, followed by 5 mL of dioxane The wal was capped and heated at 110 °C overnight The mixture was cooled to RT, diluted with ether, filtered through Celite®, and concentrated The residue was purified via gradient flash chromatography (ISCO, 0 - 50 % EtOAc in hexanes, S1O2) to furnish the desired compound (87 mg, 72% yield) The product from above was processed into Example 2.95 according to the procedures outlined in Scheme I (Steps 5 and 6)
SCHEME AAA
Figure imgf000157_0001
Step i
Figure imgf000157_0002
Methyl 4-(aminomethyl)benzoate hydrochloride, N-Boc-glycιne, and 4-tert- butylcyclohexanone were used according to Steps 1-3 in Scheme I to afford the desired Intermediate AAA-1. Intermediate AAA-1 (200 mg, 0 558 mmol, 1 eq) was dissolved in CH2CI2 (2.4 mL), cooled to OX, and treated with m-CPBA (77% w/w with water, 280 mg, 1 25 mmol, 2 24 eq) in three portions over 2.5 hours Upon completion of the reaction by TLC, 10% sodium thιosulfate(aq) (0 66 mL) and saturated NaHCOe (aq > were added The resulting biphasic mixture was stirred until both layers were clear The layers were separated and both were saved The aqueous layer was extracted twice with CH2Ct The combined organic layers were washed with saturated NaHCO3(aq ), and brine, were dried over anhydrous sodium sulfate, filtered, and evaporated to afford the desired nitrone (181 mg, 87%) which was used in the next step without further purification
Step 2
Figure imgf000158_0001
Triphenylphosphine (69 mg, 0 263 mmol, 1 4 eq) was dissolved in CH2CI2 (0 3 mL) and was cooled to 0°C Bromine (0 013 mL, 024 mmol, 1 3 eq) was added and the resulting mixture was stirred for 10 minutes at 0°C The nitrone from Step 1 (70 mg, 0 20 mmol, 1 eq) was added, followed by triethylamine (0 035 mL, 0 25 mmol, 1 3 eq) at 0°C After stirring the resulting mixture for 10 minutes at O°C, the ice bath was removed and the reaction was stirred for 2 hours at room temperature The reaction was partitioned between CH2CI2 and brine The organic layer was separated and saved The aqueous layer was extracted with CH2CI2 The organic layers were combined and evaporated to afford a residue which was purified via silica gel chromatography (gradient elution, 0% to 100% EtOAc in hexanes, SiO2) to afford the desired product as a clear film (57 mg, 70%)
Step 3
Figure imgf000158_0002
A solution of the bromoimidazolone prepared in Step 2 (57 mg, 0 13 mmol, 1 eq), bιs(trιphenylphosphιno)palladιum(ll)chlorιde (4 mg, 0 006 mmol, 0 05 eq), 2M Na2CO3(aq > (0 5 mL), and 4-fluorophenylboronιc acid (20 mg, 0 14 mmol, 1 1 eq) in DME (1 mL) in a Biotage microwave viai was subjected to microwave heating (100°C, 5 mm, very high absorption) The reaction mixture was then partitioned between water and EtOAc The organic layer was removed and saved and the aqueous layer was extracted with EtOAc The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to afford a residue which was purified via silica gel chromatography (gradient elution, 0% to 100% EtOAc in hexanes, S1O2) to afford the desired product (45 mg, 76%) Step 4
Figure imgf000159_0001
A solution of the coupling product from Step 3 (45 mg, 0 10 mmol, 1 eq) in THF (2 mL) and MeOH (1 mL) was treated with 1 M NaOH(aq ) (1 mL, 1 00 mmol, 10 eq) The resulting solution was stirred overnight at room temperature The reaction mixture was then partitioned between CH2Cb and 1 M HCI(aq ) The organic layer was removed and saved and the aqueous layer was extracted with CH2CI2 The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated to afford the desired product, which was used in the next step without further purification
Figure imgf000159_0002
The benzoic acid prepared in Step 4 was converted to the desired Example 1.564 using the method outlined in Steps 1 and 2 of Scheme J Scheme AAB
Figure imgf000160_0001
Step 1 :
Figure imgf000160_0002
A solution of A/,N-dιisopropylethylamine (2 4 ml_, 17.1 mmol, 1 eq) in THF (10 mL) was cooled to -78°C. A solution of n-butyllithium in hexanes (2 5M, 6.85 mL, 17.1 eq) was added dropwise with stirring. The solution was warmed to 0°C for 10 mm, then cooled again to -78X. At -78°C, a solution of methyl 4-(cyanomethyl)benzoate (3g, 20 mmol, 1 eq) in THF (8 mL) was added dropwise to the LDA solution (a dark red slurry formed) After stirring the resulting slurry for 10 minutes at -78°C, 1-bromo-3,3- dimethylbutane (2.46 mL, 17 9 mmol, 1.05 eq) was added rapidly The reaction was stirred for 30 minutes at -78°C then was warmed to room temperature After 1h, hexamethylphosphoramide (2.5 mL, 14 mmol) was added, and the reaction was stirred at room temperature for 16h The reaction mixture was partitioned between EtOAc and 1 N HCI The aqueous layer was discarded, and the organic layer was washed with 1 N HCI and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to afford a crude residue which was chromatographed on silica gel (gradient elution, 0% to 30% EtOAc in hexanes, S1O2) to afford the desired product as a white crystalline solid (2.49g, 54%)
Step 2
Figure imgf000161_0001
A solution of the product from Step 1 (2.49 g, 9.60 mmol, 1 eq) and cone. HCI (5 mL, 60 mmol, 6 eq) in MeOH (100 mL) was added to a Parr hydrogenation bottle containing 20% Pd(OH)2 on carbon (50% w/w water, 660 mg, 0.94 mmol, 0.098 eq). The resulting heterogeneous mixture was purged with nitrogen, then pressurized with hydrogen (60 psi). The bottle was shaken for 16 hours at room temperature, refilling the hydrogen to 60 psi. as necessary. After releasing the hydrogen pressure and purging the vessel with nitrogen, the reaction mixture was filtered through Celite®, and the Celite® pad was washed with MeOH. The resulting filtrates were combined and evaporated to afford the desired amine hydrochloride salt (2.87g) which was used in the next step without further purification. Table AAB
Using the conditions described in Scheme AB and the requisite alkyl halide, the following intermediate was prepared:
Figure imgf000161_0002
Scheme AAC
Figure imgf000162_0001
Methyl 4-(cyanomethyl)benzoate (1 8 g, 10 mmol, 1 eq) was dissolved in THF (100 mL) and cooled to 0°C Sodium hydride (60% w/w in mineral oil, 820 mg, 20 mmol, 2 eq) was added portionwise and the mixture was stirred for 10 minutes Methyl iodide (1 3 mL, 20 mmol, 2 eq) was added dropwise and the reaction was stirred at 0°C until the starting material was consumed by TLC (2 hours) The reaction mixture was quenched with water and was partitioned between EtOAc and brine The aqueous layer was discarded, and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated to afford a crude residue which was chromatographed on silica gel (gradient elution, 0% to 50% EtOAc in hexanes, SiO2) to afford the desired product as a white crystalline solid (1 88g, 74%)
Step 2
Figure imgf000162_0002
A solution of the product from Step 1 (1 88 g, 740 mmol, 1 eq) and 10% Palladium on carbon (50% w/w water, 660 mg, 0 310 mmol, 0 4 eq) in MeOH (100 mL) was purged with nitrogen, then with hydrogen A balloon of hydrogen was affixed to the flask, and the reaction was stirred overnight Concentrated aqueous HCI (-12M, 5 mL, 60 mmol, 8 eq) was added to the reaction and stirring was continued under a balloon of hydrogen for 24h The incomplete reaction was purged with nitrogen and transferred to a Parr hydrogenation bottle containing 20% Pd(OH)2 on carbon (50% w/w water, 660 mg, 0 94 mmol, 0 13 eq) The resulting heterogeneous mixture was purged with nitrogen, then pressurized with hydrogen (50 psi) The bottle was shaken for 72 hours at room temperature, refilling the hydrogen to 50 psi as necessary After releasing the hydrogen pressure and purging the vessel with nitrogen, the reaction mixture was filtered through Celite®, and the Celite® pad was washed with MeOH The resulting filtrates were combined and evaporated to afford the desired amine hydrochloride salt (2 08g, quant ) which was used in the next step without further purification
Scheme AAD
Figure imgf000163_0001
M204
Ethyl 4-(2-oxopropyl)benzoate (2 25 g, 10 9 mmol, 1 eq) and ammonium acetate (8 40 g, 109 mmol, 9 97 eq) were dissolved in MeOH (45 mL) While stirring at room temperature, sodium borohydride (684 mg, 18 1 mmol, 1 65 eq) was added The resulting reaction mixture was stirred overnight at room temperature The reaction was concentrated and partitioned between CH2CI2 and 1 M NaOH (aq ) The organic layer was removed and saved and the aqueous layer was extracted with CH2Cb The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated to afford a residue which was purified via silica gel chromatography (gradient elution, 0% to 100% EtOAc in hexanes, S1O2) to afford ethyl 4-(2-hydroxypropyl)benzoate (1 18 g, 52%) The same silica gel column was then subjected to a second set of chromatography conditions (gradient elution, 0% to 80% MeOH in EtOAc) to afford racemic ethyl 4-(2-amιnopropyl) benzoate (610 mg, 27%)
Figure imgf000164_0001
Step i
Figure imgf000165_0001
A solution of N-BOC-glycine (6 13 g, 35 O mmol, 1 10 eq), HOBt (2 68 g, 17 5 mmol, 0 55 eq), and 1Pr2NEt (18 3 mL, 105 mmol, 3 29 eq) in MeCN (100 mL) at 0°C was treated with EDCI (6 71 g, 35 0 mmol, 1 10 eq) followed by the amine hydrochloride salt (10 00 g, 31 9 mmol, 1 00 eq) The resulting mixture was stirred at 0°C for 15 minutes The reaction was allowed to warm to room temperature and was stirred 16h The reaction was partitioned between EtOAc and a mixture of 1 N HCI(aq > and brine The aqueous layer was discarded and the organic layer was washed successively with saturated NaHCO^ > and brine, was dried over anhydrous sodium sulfate, filtered and evaporated to afford the desired product (14 1 g, quant ) which was used in the next step without further purification
Step 2
Figure imgf000165_0002
The product from Step 1 (14 1 g, 32 4 mmol, 1 eq) was dissolved in CH2CI2 (200 mL) and treated with TFA (20 mL) After 2 hours, TLC showed the reaction to be incomplete An additional amount of TFA (2OmL) was added and the reaction was stirred for 2 hours more, at which point, the voltiles were removed in vacuo to afford an oily residue The crude residue was partitioned between CH2CI2 and 1 M NaOH(aq ). The organic layer was saved and the aqueous layer was extracted with CH2CI2. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated to afford the desired product (10 51 g, 97%), which was used in the next step without further purification
Step 3
Figure imgf000166_0001
A solution of the product from Step 2 (2 63 g, 7 86 mmol, 1 00 eq), 4-tert- butylcyclohexanone (3.63 g, 23.5 mmol, 2.99 eq), and tπethylamine (5.90 mL, 42 3 mmol, 5.38 eq) in MeOH (45 mL) in a round bottomed flask was charged with powdered, 4 angstrom molecular sieves (3 6g, dried under vacuum, 72 hours at 130°C). A reflux condenser and nitrogen line were attached and the mixture was refluxed 24h. The reaction was cooled to room temperature and filtered through Celite® The Celite® pad was washed with MeOH The filtrates were combined and concentrated to afford a residue which was purified via silica gel chromatography (gradient elution, 0% to 100% EtOAc in hexanes, S1O2) to afford the desired product (1 78 g, 48%) as a viscous oil Step 4
Figure imgf000166_0002
A solution of the product from Step 3 (1 00 g, 2 12 mmol, 1 00 eq) in CH2CI2 (30 mL) at room temperature was treated with tert-butyl hypochlorite (0.29 mL, 2 55 mmol, 1 20 eq) After stirring for 45 minutes, triethylamine (1 2 mL, 8 50 mmol, 400 eq) was added dropwise, and the resulting solution was stirred for 45 minutes more The reaction was quenched by adding 10% sodium bisulfite (aq) while stirring The organic layer was removed and saved, and the aqueous layer was extracted with CH2Cb The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated to afford a crude residue which was purified via silica gel chromatography (gradient elution, 0% to 30% EtOAc in hexanes, S1O2) to afford the desired product (730 mg, 73%) as a white foam Step 5
Figure imgf000167_0001
The product from Step 4 (730 mg, 1 6 mmol, 1 0 eq) was dissolved in CH2CI2 (10 mL), and treated with m-CPBA (77% w/w with water, 1 05 g, 4 67 mmol, 3 00 eq) and stirred at room temperature overnight Th reaction was quenched with 10% sodium thιosulfate(aq > and saturated NaHCO3 <aq > The resulting biphasic mixture was stirred until both layers were clear The layers were separated and both were saved The aqueous layer was extracted with CH2CI2 The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated to afford a crude product which was purified via silica gel chromatography (gradient elution, 0% to 100% EtOAc in hexanes, SiO2) to afford the desired product (560 mg, 74%) as a white foam Step 6
Figure imgf000168_0001
The product from Step 5 (560 mg, 1 16 mmol, 1 00 eq) and 1Pr2NEt (0 50 mL, 2 89 mmol, 25 eq) were dissolved in CH2Cb (30 mL) and cooled to -1O°C Tπfluoromethanesulfonic anhydride (0 233 mL, 1 39 mmol, 1 20 eq) was added dropwise and the mixture was stirred for 30 minutes at -10°C An additional amount of tπfluoromethaπesulfonic anhydride (0 2 mL) was added and the reaction was stirred for an additional 30 minutes An additional amount of 1Pr2NEt (1 0 mL, 5 78 mmol, 5 eq) was added and the reaction was stirred for 5 minutes The reaction mixture was partitioned between CH2CI2 and brine The layers were separated and both were saved The aqueous layer was extracted with CH2CI2 The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated to afford a crude product which was purified via silica gel chromatography (gradient elution, 0% to 20% EtOAc in hexanes, SiO2) to afford the desired product (478 mg, 67%)
Step 7
Figure imgf000168_0002
The product from Step 6 (120 mg, 0 194 mmol, 1 00 eq), 4-ιsopropoxyphenylboronιc acid (52 mg, 0 29 mmol, 1 5 eq), and bιs(trιphenylphosphιno)palladιum(ll)chlorιde (7 mg, 0 01 mmol, 0 05 eq) were combined with 2M Na2Cθ3(aq) (07 mL) and DME (1 mL) in a Biotage microwave vial The reaction underwent microwave heating (45 minutes, 100°C, very high absorption) The organic layer of the reaction was removed and saved The aqueous layer was extracted with EtOAc The organic layers were combined and evaporated to afford a crude product which was purified via silica gel chromatography (gradient elution, 0% to 100% EtOAc in hexanes, S1O2) to afford the desired product (71 mg, 60%)
Step 8
Figure imgf000169_0001
A solution of the product from Step 7 (71 mg, 0 12 mmol, 1 eq) in THF (3 mL) and MeOH (3 mL) was treated with 1 M NaOH(aq ) (1 5 mL, 1 50 mmol, 13 eq) The resulting solution was stirred overnight at room temperature The reaction mixture was then partitioned between EtOAc and 1 M HCI(aq ) The aqueous layer was discarded, and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated to afford the desired product (70 mg, quant ), which was used in the next step without further purification
2 117
Figure imgf000170_0001
The product from Step 8 (70 mg, 0 12 mmol, 1 0 eq), (2H-tetrazol-5-yl)methanamme hydrobromide (34 mg, 0 19 mmol, 1 5 eq), IPr2NEt (0 065 mL, 0 37 mmol, 3 0 eq), and PyBOP (78 mg, 0 15 mmol, 1 2 eq) were combined in DMF (1 mL) and were stirred at room temperature for 3 hours The solvent was removed in vacuo to afford a crude residue which was dissolved in DMSO and purified via reversed-phase C18 chromatography (gradient elution, 10% MeCN in water with 0 1% HCOOH to 100% MeCN with 0 1% HCOOH) to afford Example 2.117.
Scheme AAF
Figure imgf000170_0002
Step i
Figure imgf000171_0001
The product from Scheme AAE, Step 6 (200 mg, 0 324 mmol, 1 eq), 4- ethoxyphenylboronic acid (81 mg, 049 mmol, 1 5 eq), and bιs(trιphenylphσsphιno)palladιum(ll)chlorιde (10 mg, 0 02 mmol, 0 05 eq) were combined with 2M Na2CO3 (aq > (1 5 mL) and DME (3 ml.) in a scintillation vιa\ The reaction was heated in a heating block at 70°C for 3h The reaction was cooled and was partitioned between EtOAc and water The organic layer was removed and saved, and the aqueous layer was extracted with EtOAc The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filitered, and evaporated to afford a crude product which was purified via silica gel chromatography (gradient elution, 0% to 100% EtOAc in hexanes, S1O2) to afford the desired product (77 mg, 40%)
The product from Step 1 was converted to Example 2.137 using the conditions outlined in Steps 8-9 of Scheme AAE
Scheme AAG
Figure imgf000172_0001
The requisite amine, ketone, and N-BOC glycine were converted into the bromide using the Scheme AAA (Steps 1 and 2) The bromide was reacted according to the conditions outlined in Scheme AD Step 6 to provide the arylated intermediate This intermediate was processed according to the Scheme I (Steps 5 and 6) which provided Example 2.97.
Scheme AAH
Figure imgf000172_0002
(/^-Methyl 4-(1 -amιnoethyl)benzoate hydrochloride and 2-(feιt-butoxycarbonylamιno)- 2-(3,5-dιchlorophenyl)acetιc acid were converted to Intermediate AAH-1 via a method similar to that outlined in Steps 1-2 in Scheme I
Step i :
Intermediate AAH-1 (400 mg, 1 05 mmol, 1 eq), (±)-2-fert-butyldihydro-2H-pyran- 4(3H)-one (328 mg, 2 1 mmol, 2 eq), Et3N (0 29 mL, 2 1 mmol, 2 eq), and powdered 4A molecular sieves (400 mg) were taken up in methanol (10 mL) The mixture was heated in a microwave (130°C, high absorption) for 2h The mixture was cooled to room temperature, filtered, and concentrated The residue was purified via silica gel chromatography (gradient elution, 0-50% EtOAc in hexanes, S1O2) to afford the two diastereomeric mixtures Intermediate AAH-2 (68 mg) and Intermediate AAH-3 (290 mg) which were used in the next step without further purification
Scheme AAI
Figure imgf000173_0001
Intermediate AAH-2 was converted to Intermediate AAI-1 via a method similar to that described in Step 4 of Scheme I Intermediate AAI-1 was converted to Intermediate AAI-2 via a method similar to that described in Step 4 of Scheme AAA.
Intermediate AAI-2 was converted to Intermediate AAI-3 via a method similar to that described in Step 1 of Scheme AAA.
Scheme AAI, Step 1
-3 Example 1.557
Figure imgf000174_0001
Intermediate AAI-3 (33 mg, 0.052 mmol, 1 eq) was dissolved in CH2CI2 (6 ml_). Trifluoroacetic acid (3 mL) was added and the reaction was stirred for 3h at room temperature. The volatiles were removed in vacuo to afford a crude residue which was purified via reversed-phase, C-18 column chromatography (gradient elution, 10% to 80% MeCN in water with 0.1% HCOOH) to afford Example 1.557 (20 mg) as a white solid.
Table AAI
Using the requisite starting material, and the method outlined in Scheme AAI, the following examples were prepared:
Figure imgf000174_0002
Scheme AAJ
Figure imgf000175_0001
The amine hydrochloride salt and 2-(fert-butoxycarbonylamino)-2-(4- fluorophenyl)acetic acid were used according to Steps 1-2 in Scheme I to afford the desired Intermediate AAJ-1.
Step i
Figure imgf000176_0001
Intermediate AAJ-2
Intermediate AAJ-1 (800 mg, 1 87 mmol, 1 eq) was combined with 4- phenylcyclohexanone (650 mg, 3 73 mmol, 2 eq), 3 angstrom molecular sieves (8-12 mesh beads, dried under vacuum at 130°C, 1 6 g), and para-toluenesulfonic acid monohydrate (36 mg, 0 19 mmol, 0 1 eq) in isopropanol (10 ml_) under a nitrogen atmosphere A reflux condenser was attached, and the reaction was heated at reflux (105°C oil bath) for 16h The reaction was then cooled to room temperature, filtered through Celite® and the resulting filter cake washed with isopropanol The filtrates were combined and evaporated to afford a crude residue with was partitioned between EtOAc and saturated NaHCOa^q > The aqueous layer was discarded and the organic layer was washed with brine, dried over anhydrous sodium sulfate filtered and evaporated to afford a crude product which was purified via silica gel chromatography (gradient elution, 0% to 40% EtOAc in hexanes, SiOa) to afford the desired product (Intermediate AAJ-2, 1 05 g, 96%) as an inseparable mixture of diastereomers
Preparation of Intermediate AAJ-3
Figure imgf000176_0002
Intermediate AAJ-3 was prepared from Intermediate AAJ-2 in a manner similar to that described in Scheme I, Step 4
Preparation of Example 1.373
Steps 8-9 Scheme AAE
Figure imgf000177_0001
Using a method similar to that outlined in Steps 8-9 of Scheme AAE, Intermediate AAJ-3 was converted to Example 1.373
Scheme AAK
Figure imgf000177_0002
The benzoic acid prepared from the requisite starting materials via a method similar to that outlined in either Steps 1-5 of Scheme A or Steps 1-5 of Scheme I (195 mg, 0 40 mmol), (2H-tetrazol-5-yl)methanamιne hydrochloride (81 mg, 060 mmol), HOBt H2O (89 mg, 0 66 mmol), and EDCI (127 mg, 0 66 mmol) were combined in pyridine (3 mL) and were stirred at 5O°C for 4 hours. The reaction was cooled to room temperature and concentrated to afford a dark residue, which was dissolved in DMSO and chromatographed Wa reversed-phase C-18 column chromatography (gradient elution, 10% to 100% MeCN in water with 0.1% HCOOH) to afford Example 1.552 (110 mg) as a white solid.
Scheme AAL
Figure imgf000178_0001
Step i
/H
Figure imgf000178_0002
The benzoic acid prepared in Steps 1-5 of Scheme A (106 mg, 0.21 mmol, 1 eq), (R)- methyl 3-amino-2-hydroxypropanoate hydrochloride (33 mg, 0.21 mmol, 1 eq), PyBOP (111 mg, 0.21 mmol, 1 eq), and IPr2NEt (0.11 mL, 0.64 mmol, 3 eq) were combined in MeCN (2 mL) at room temperature. After stirring overnight at room temperature, the reaction mixture was partitioned between EtOAc and 1 M HCI(aq /brine. The aqueous layer was discarded and the organic layer was washed with saturated NaHCC>3 (aq ) and brine, was dried over anhydrous Na2SO^ was filtered, and was evaporated to afford a crude material. Silica gel chromatography (gradient elution, 0% to 100% EtOAc in hexanes, S1O2) afforded the desired product (137 mg, quant ) as a clear, colorless film
Step 2
Figure imgf000179_0001
A solution of the product from Step 1 (137 mg, 0.23 mmol, 1 eq) in MeOH (2 ml_) and THF (4 mL) was treated with 1 M NaOH (aq ) (1.14 ml_, 1 14 mmol, 5 eq) The resulting mixture was stirred for 2h at room temperature. After adding 1 M HCI («, ) (1 mL) to the reaction mixture, the reaction was concentrated. The crude residue was dissolved in DMSO and purified via reversed-phase C18 chromatography (gradient elution, 10% MeCN in water with 0 1 % HCOOH to 100% MeCN with 0.1% HCOOH) to afford Example 1.374 (93 mg, 67%) as a white solid.
Scheme AAM
Figure imgf000179_0002
Example 1.375 was prepared in a manner similar to that described in Steps 1 -2 of Scheme AAL with the exception that (S)-methyl 3-amιno-2-hydroxypropanoate hydrochloride was substituted for (fi)-methyl 3-amιno-2-hydroxypropanoate hydrochloride
Scheme AAN
Figure imgf000180_0001
Step i
Figure imgf000180_0002
Magnesium turnings (14 6 g, 600 mmol, 1 eq) were added to EtaO (400 mL) under a nitrogen atmosphere in a round bottomed flask with a reflux condenser attached. A crystal of iodine was added to the mixture, followed by 1-bromo-3-methylbutane (20 mL). The mixture was gently warmed to 30°C, at which point the reaction initiated and a vigorous refluxing ensued. Additional ahquots of 1 -bromo-3-methylbutane were added at a rate such that the refluxing was maintained. After completion of the addition of 1 -bromo-3-methylbutane (total amount- 72 mL, 601 1 mmol, 1 eq), the mixture was refluxed for 2h The reaction was then cooled to room temperature, affording the requisite isopentylmagnesium bromide solution.
The sulfinimine (90 0 g, 305 mmol, 1 00 eq) was dissolved in CH2CI2 (1000 mL), and the solution was cooled to -40°C. The previously prepared isopentylmagnesium bromide solution was added dropwise over a one hour period via a dropping funnel to the sulfinimine solution The reaction was stirred at -40°C for 4h. The reaction was stirred for an additional 16h, during which time the cold bath was allowed to expire Saturated ammonium chloride <«,) was added to the reaction and the resulting murky suspension was stirred for 30 mm An attempt to filter the reaction through Celite® resulted in a clogged filter pad. The crude reaction, including the clogged Celite® pad was transferred to an Erlenmeyer flask EtOAc (2000 mL) and 20% sodium citrate (3q > (2000 mL) were added to the crude mixture and the solution was stirred for 2h. The biphasic solution was filtered, and the Celite® left behind in the filter was washed with EtOAc and water The combined biphasic filtrate was separated. The aqueous layer was extracted with EtOAc The organic layers were combined, washed with brine twice, dried over anhydrous MgSO4, filtered, and evaporated to afford a viscous green oil. Silica chromatography (performed in two batches, each on a 600 g silica gel column, gradient elution, 0% to 100% EtOAc in hexanes, SiOz) afforded the desired addition product as a 5.6:1 mixture of diastereomers The latter fractions of the product peak were collected separately, as they were enriched in the major diastereomer. The enriched material was recrystalized from hot hexanes to afford the major diastereomer (intermediate AAN-1 , 9.71 g, 99.8.0.1 dr, ChiralPak AD, 95 5 hexanes.isopropanol, 1 mL/min, 254 nm) as white crystals Additional crops of crystals can be obtained from the mixed fractions.
Step 2
Intermediate AAN-1
Figure imgf000181_0001
A solution of Intermediate AAN-1 (22.2 g) in MeOH (100 mL) at room temperature was treated with 4N HCI in dioxane (28 mL). The resulting solution was stirred for 45 mm at room temperature. The reaction was concentrated and treated with Et2O (500 mL) to afford a white solid, which was collected via filtration, washed with Et2O and dried under vacuum to afford Intermediate Amine HCI salt M15a as a white solid (14.7 g)
Figure imgf000182_0001
Intermediate AAO-3
Intermediate AAO-2
Figure imgf000182_0002
Example 1 539
Intermediate AAO-1 was prepared in two steps from the requisite starting materials in a manner similar to that described in Step 1 of Scheme AAE followed by Step 2 of Scheme I.
Intermediate AAO-2 was prepared from Intermediate AAO-1 in a manner similar to that described in Step 1 of Scheme AAJ.
Intermediate AAO-3 was prepared from Intermediate AAO-2 in a manner similar to that described in Steps 4-5 of Scheme I.
Example 1.539 was prepared from Intermediate AAO-3 in a manner similar to that described in Steps 1-2 of Scheme J.
Scheme AAP
Figure imgf000183_0001
Intermediate AAP-1 was prepared from the requisite starting materials in a manner similar to that described in Steps 1-3 of Scheme I. Intermediate AAP-2 was prepared from Intermediate AAP-1 in a manner similar to that described in Steps 1-4 of Scheme AAA.
Example 2.118 was prepared from Intermediate AAP-2 in a manner similar to that described in Step 9 of Scheme AAE.
Scheme AAQ
Figure imgf000184_0001
Step i
Figure imgf000184_0002
The benzoic acid {200 mg, 0 430 mmol, 1 eq) (prepared according to Scheme AAQ) was dissolved in methylene chloride (3 mL) and pyridine (0 14 mL) The resulting solution was cooled to 0°C and cyanunc fluoride (0 075 mL, 0 861 mmol, 2 eq) was added After stirring the reaction at 0°C for 30 mm, saturated NaHCOe (aq ) was added and the mixture was stirred 5 mm at 0°C The organic layer was removed, dried over anhydrous Na2SO4, filtered, and evaporated to afford the desired acid fluoride (215 mg, quant ) which was used in the next step without further purification
Figure imgf000185_0001
A solution of the acid fluoride prepared in Step 1 (201 mg, 043 mmol, 1 eq) and (2H- tetrazol-5-yl)methanamιne (49 mg, 0.50 mmol, 1 15 eq) were added to pyridine (2 mL) and methylene chloride (2 mL) at room temperature. The resulting suspension was stirred at room temperature for 72h The reaction was concentrated, dissolved in DMSO, and chromatographed via reversed-phase C-18 column chromatography (gradient elution, 10% to 100% MeCN in water with 0.1 % HCOOH) to afford Example 1.551 (62 mg, 26%) as an off-white foam
Scheme AAR
Figure imgf000185_0002
Using the appropriate starting materials, Example 1.556 was prepared using a method similar to that described in Step 1 of Scheme AAE followed by Steps 2-5 of Scheme I then Steps 1-2 of Scheme J
Scheme AAS
Figure imgf000186_0001
Step i
Figure imgf000186_0002
The benzoic acid (Prepared from the requisite starting materials via a method similar to that described in Steps 1-5 of Scheme 1, 166 mg, 0 33 mmol, 1 eq), aminoacetonitrile (19 mg, 0 33 mmol, 1 eq), IPr2NEt (0 12 mL, 0 66 mmol, 2 eq), and PyBOP (171 mg, 0 33 mmol, 1 eq) were combined in MeCN (5 mL) and were stirred overnight at room temperature The reaction was partitioned between EtOAc and 1 N HCI(aq /brine The aqueous layer was discarded and the organic layer was washed with saturated NaHCO3 (aq) and brine was dried over anhydrous Na2SO4, was filtered, and was evaporated to afford a crude yellow foam Silica gel chromatography (gradient elution, 10% to 100% EtOAc in hexanes, SiO2) afforded the desired amide (175 mg, 98%) as a glass
Step 2
Figure imgf000187_0001
1 561
The benzamide prepared in Step 1 (160 mg, 0 30 mmol, 1 eq), sodium azide (59 mg, 0 90 mmol, 3 eq), and triethylamine hydrochloride (123 mg, 0 90 mmol, 3 eq) were combined in toluene and were heated at reflux for 16h Additional amounts of sodium azide (59 mg, 0 90 mmol, 3 eq) and triethylamine hydrochloride (123 mg, 0 90 mmol, 3 eq) were added and the reaction heated at reflux for an additional 6h The solvent was removed in vacuo to afford a crude residue which was dissolved in methanol, and chromatographed via reversed-phase C-18 column chromatography (gradient elution, 10% to 100% MeCN in water with 0 1% HCOOH) to afford a mixture of starting material and product This mixture was then subjected to silica gel chromatography (gradient elution, 0% to 100% EtOAc in hexanes, SiO2 then gradient elution 20% to 50% MeOH in EtOAc) to afford Example 1.561 (126 mg) as a foam
Scheme AAT
Figure imgf000188_0001
The benzoic acid intermediate in Scheme AAT was prepared from the requisite starting materials using a method similar to that described in Step 1 of Scheme AAE followed by Steps 2-5 of Scheme I.
Example 1.532 was prepared from the benzoic acid in a manner similar to that described in Step 9 of Scheme AAE.
Scheme AAU
diate AAU-2
Figure imgf000188_0002
Figure imgf000189_0001
Magnesium turnings (3.85 g, 158 mmol, 1 eq) were added to Et2θ (100 mL) under a nitrogen atmosphere in a round bottomed flask with a reflux condenser attached. A crystal of iodine was added to the mixture, followed by (2-bromoethyl) trimethyl silane (5 mL). The mixture was gently warmed to 32°C, at which point the reaction initiated and a vigorous refluxing ensued. Additional ahquots of (2- bromoethyl) trimethyl silanewere added at a rate such that the refluxing was maintained After completion of the addition of (2-bromoethyl) trimethyl sιlane(total amount 25 mL, 158.7 mmol, 1 eq), the mixture was refluxed for 1 h. The reaction was then cooled to room temperature, affording the requisite (2- (trιmethylsιlyl)ethyl)magnesιum bromide solution.
The sulfinimine (23 8 g, 80.7 mmol, 1 00 eq) was dissolved in CH2CI2 (300 mL), and the solution was cooled to -40°C The previously prepared (2-
(tπmethylsιlyl)ethyl)magnesιum bromide solution was added dropwise over a one hour period via a dropping funnel to the sulfinimine solution The reaction was stirred at - 40°C for 3h. The reaction was stirred for an additional 16h, during which time the cold bath was allowed to expire A 20% sodium citrate (aq > solution (300 mL) was added to quench the reaction, and the resulting mixture was stirred for 30 mm. The biphasic solution was separated The aqueous layer was extracted with CH2CI2. The organic layers were combined, washed with brine, dried over anhydrous Na2SCv, filtered, and evaporated to afford a viscous oil which was subjected to silica gel chromatography (gradient elution, 0% to 60% EtOAc in hexanes, SiO2) to afford the desired addition product as a 1.1 mixture of diastereomers (7 59 g) The diastereomeric mixture of addition products was dissolved in 50 mL of hot heptane and was then allowed to slowly cool to room temperature The solution was allowed to stand at room temperature for 4 days, during which time clusters of white needles formed, which were collected via filtration, washed with heptane and dried to afford pure Intermediate AAU-1 (2 72 g, 8.5% yield).
Step 2
Figure imgf000190_0001
A solution of Intermediate AAU-1 (2 7 g) in MeOH (40 mL) at room temperature was treated with 4N HCI in dioxane (4 mL) The resulting solution was stirred for 2 h at room temperature The reaction was concentrated and treated with Et2θ to afford a white solid, which was collected via filtration, washed with Et∑O and dried under vacuum to afford amine HCI salt M205 as a white solid (1 4 g)
Scheme L
Figure imgf000190_0002
Ste i
Figure imgf000190_0003
The aldehyde (20 g, 133 mmol), isopropyl iodide (68 g, 399 mmol), and K2CO3 (37 g, 266 mmol) were taken up in THF/DMF (2/1 , 300 ml), and the mixture was heated at 70 °C for 64 h The solution was partitioned between EtOAc and water The aqueous layer was extracted with EtOAc. The combined organic layers were washed wtih brine and dried (MgSO^ The solution was filtered and concentrated which yielded 20 3 g (79 %) of the ester as an oil that solidified upon standing
Step 2
Figure imgf000191_0001
The aldehyde (21 2 g, 110 mmol), (S)-2-methylpropane-2-sulfιnamιde (13 4 g, 110 mmol), and Cs2CO3 (36 g 110 mmol) were taken up in DCM (400 ml), and the mixture was stirred at 42 °C for 30 h The solution was filtered and concentrated This yielded 32 2 g (99 %) of the imine as an oil that solidified upon standing Step 3
Figure imgf000191_0002
The grignard reagent was made as follows Magnesium turnings (2 4 g, 100 mmol) were suspended in dry Et2O (150 ml) under N2 A few iodine crystals were added to the mixture The 1-bromo-3,3-dιemthyl butane (16 5 g, 100 mmol) in Et2O (50 ml) was added in portions over ~ 45 minutes to maintain gentle reflux After the addition of all of the 1 -bromo-3,3-dιemthyl butane, the reaction was refluxed for 2 hr The gringnard solution was used as is in the next step
The grignard reagent (100 mmol in 200 ml of Et2O) was added to a solution of the imine (9 9 g, 33 5 mmol) at -78°C The solution was slowly warmed to RT After stirring at RT for 2 h, the reaction was quenched with sat NH4CI(aq > at 0 °C Ethyl acetate was added, and the mixture was stirred at RT for 1 h The layers were separated, and the aqueous layer was extracted with EtOAc The combined organic layers were washed with brine and dried (MgSθ4) The mixture was filtered and concentrated The residue was purified via gradient flash chromatography (0-40% EtOAc in hexanes, SiO2) The major fraction was recrystallized from heptane/IPA which yielded 2 8 g of the desired product. The mother liquor was recrystallized once again to provide an additional 1.3 g (32 % total).
Step 4
Figure imgf000192_0001
The sulfinamide (3 18 g, 8.3 mmol) was taken up in MeOH (30 ml), and 4 M HCI in dioxane (4.1 ml) was added at RT. The solution was stirred at RT for 1.5 h. The solution was concentrated, and ether was added which resulted in the formation of a white solid The solid was collected and rinsed with ether. The solid was dried which provided 2.2 g (84 %) of the amine HCI salt M6.
Figure imgf000192_0002
Step i Magnesium turnings (2.21 g, 90.9 mmol) were stirred with a magnetic stir bar overnight in a 500 ml round-bottom flask Anhydrous ethyl ether 9173 ml) was added. 1-Bromo-5-methylhexane (15.0 g, 909 mmol) was added dropwise over 40 minutes. The solution was stirred at RT for 3 5 hours The grignard solution was added to (S)- isopropyl 4-((fert-butylsulfιnylιmιno)methyl)benzoate (134 g, 45.4 mmol) in 100 mL anhydrous DCM at -48 °C. The solution was allowed to gradually warm to RT and was stirred at RT for 18 h. Saturated NH4CI (150 ml) and EtOAc (200 mL) were added. The aqueous layer was separated and extracted with EtOAc (100 mL). The organic layers were washed with brine (200 mL), dried over anhydrous NaaSθ4, filtered, and concentrated The product was purified by SiO2 chromatagraphy (200 g, Hexane/EtOAc, 25% to 33%) to give a mixture of R isomer and S isomer of isopropyl 4-(1 -((S)-1 ,1-dιmethylethylsulfιnamιdo)-6-methylheptyl)benzoate (14.8 g, 82 4%, R.S = 2 1) This mixture of two isomers (6 g) was resolved by Chiralpak AD coloum (4% isopropyl alcohol in hexane) to give isopropyl 4-((fl)-1 -((S)-1 ,1- dιmethylethylsulfιnamιdo)-6-methylheptyl)benzoate (2 61 g)
Step 2
Figure imgf000193_0001
4-((f?)-1-((S)-1 ,1 -dιmethylethylsulfιnamido)-6-methylheptyl)benzoate (2.60 g, 6.81 mmol) was dissolved in MeOH (10 mL) HCI (4N in dioxane, 4 3 mL, 17 0 mmol) was added The reaction mixture was stirred at RT overnight. The solvent was removed via use of a rotary evaporator. The residue was stirred with ethyl ether (100 mL) for 10 minutes. The solid was collected by filtration. The solid was washed with ethyl ether 910 mL) twice which furnished upon drying (R)-ιsopropyl 4-(1-amino-6- methylheptyl) benzoate hydrochloride M72 (1.50 g 75.6%).
Figure imgf000193_0002
(fl)-lsopropyl 4-(1 -amιno-5-methylhexyl)benzoate hydrochloride M71 was prepared in a similar manner as (fi)-ιsopropyl 4-(1-amιno-6-methylheptyl)benzoate hydrochloride using the appropriate grignard reagent (Scheme LA)
Scheme MA
Figure imgf000194_0001
Step i
Figure imgf000194_0002
An oven-dπed 250 mL flask was cooled under nitrogen and charged with (S)- fert-butanesulfmamide (493 g, 407 mmol), tetrahydrofuran (100 mL), and methyl 4- formylbenzoate (6 68 g, 40 7 mmol) Tιtanιum(IV) methoxide (15 4 g, 89 5 mmol, 2 2 equiv ) was added at 0 °C, and the solution was allowed to stir at room temperature for 18 h A mixture of sodium bicarbonate (40 0 g, 471 mmol) in methanol (250 mL) was added to the reaction After stirring for 20 mm, the solids were removed by filtration though Celite®, and the resulting organic solution was concentrated by rotary evaporation The residue was partitioned between DCM and sat NaHCO3(aq) The aqueous layer was extracted with DCM, and the combined organic layers were dried over Na2SO4 The mixture was filtered and concentrated which provided a white solid The residue was purified via gradient flash chromatography (ISCO, 0 - 40 % EtOAc in hexanes, S1O2) to give the desired product as a white solid Rf = 0.20 in 20% ethyl acetate in hexane (7 20 g, 66%% yield)
Step 2
Figure imgf000195_0001
An oven-dried 125 ml. flask was cooled under nitrogen, and it was charged with (S)-methyl 4-((fert-butylsulfιnylιmιno)methyl)benzoate (2.67 g, 10.0 mmol) and dichloromethane (60 mL) The colorless solution was cooled to -48 °C ( CH3CN/CO2) Pentylmagnesium bromide (6 0 mL, 12 mmol, 2.0M in EfeO) was added dropwise The mixture was stirred at -48 °C for 6 h, then allowed to warm to room temperature. Afer stirring at room temperature for 18 h, the reaction mixture was quenched with 25 mL of saturated ammonium chloride aqueous solution, and the aqueous layer was extracted with EtOAc (30 mL X 3) The combined organic layers were dried over Na2SO4. The mixture was filtered and concentrated which provided a white solid The residue was purified via gradient flash chromatography (ISCO, 0 - 40 % EtOAc in hexanes, SiO2) to give the desired product as a white solid (1.20 g, 36% yield, with dr ratio > 7/1) Recrystallization from hexanes gave the pure isomer (820 mg, 24% yield).
Step 3
Figure imgf000195_0002
The sulfinamide derivative (820 mg) in 2 5 mL MeOH and 1 21 mL of 4M HCl 1 ,4-dιoxane solution were strried at RT for 1 h The solution was concentrated, and diethyl ether was added to precipitate the amine hydrochloride salt M73 (620 mg, 95% yield, [α]D 20 = -20 3 (c = 1.22, MeOH)).
Scheme MB
Figure imgf000196_0001
Step i
Figure imgf000196_0003
The acid (5.0 g, 39 1 mmol) and SOCI2 (4 24 mL) were added to a flame-dried 50 mL round flask. The resulting mixture was heated at 100 °C for 1.5 h. The resulting brown mixture was carefully distilled under vacuum to give the desired product as colorless oil (4 20 g, 74% yield)
Step 2
Figure imgf000196_0002
The acid chloride (4.20 g, 28.8 mmol), PdCI2(PPh3)2 (960 mg, 5 mol%), and zinc reagent (55 ml, 27 45 mmol, 0.5 M in THF) were taken up in 60 mL THF at RT. The resulted mixture was stirred at RT for 4 h The reaction was quenched by addition of a 1 N HCI solution The mixture was then extracted with diethyl ether, and the organic layer was washed with brine, dried with Na2SO4 and evaporated under reduced pressure The residue was purified via gradient flash chromatography (ISCO, 0 - 20 % EtOAc in hexanes, S1O2) to give the desired product as a colorless oil (5 0 g, 67% yield)
Step 3
Figure imgf000197_0001
An oven-dried 250 mL flask was cooled under nitrogen and charged with (R)- tert-butanesulfinamide (2 33 g, 19 2 mmol, 1 00 equiv ), tetrahydrofuran (40 mL), and Ti(OEt)4 (8 76g, 38 4 mmol, 2 0 equiv) and ketone (5 O g, 19 2 mmol, 1 0 equiv) The mixture was heated to 70 °C for 18 hours and then cooled to rt While rapidly stirring, the reaction was quenched by adding an equal volume of brine The mixture was diluted with EtOAc and stirred vigorously for 20 mm The resulting mixture was filtered through a pad of Celite®, and the pad of Celite® was washed with EtOAc The filtrate was transferred to a separatory funnel and washed with brine The brine was then extracted with a small amount of EtOAc The combined organic layers were dried over Na2SO4 and concentrated The material was purified by silica gel chromatography (0- 40% EtOAc in hexanes) to give the desired product (433g, 62% yield)
Step 4
Figure imgf000197_0002
Sodium borohydnde (907 mg, 23 9 mmol) was added to a solution of the imine (4 33g, 11 9 mmol) in 50 mL THF at - 78 °C The resulting mixture was allowed warm to RT, and the resulting solution was stirred at RT for 18 h The reaction was quenched by addition of water (carefully) The mixture was then extracted with diethyl ether, and the organic layer washed with brine, dried with Na2SO4 and evaporated under reduced pressure The residue was purified via gradient flash chromatography (ISCO, 0 - 20 % EtOAc in hexanes, SiO2) which furnished the desired product as a mixture of two diasteromers The two diasteromers were separated by preparative HPLC (Chiral OD, 5% iPr/Hexanes, 30 mL/min) to give the (R,R) isomer (2 88 g, 67% yield) and the (R,S) isomer (583 mg, 14% yield)
Step 5
Figure imgf000198_0001
The sulfonamide derivative (2.88 g, 7.89 mmol) in 7 mL MeOH and 3 95 mL of
4N HCI 1 ,4-dιoxane solution were stirred at RT for 1 h The solution was concentrated, and diethyl ether was added to precipitate the amine hydrochloride salt M18. The mixture was filtered to give the desired product 2 O g (85% yield) [α]o25 = -19 5 (c = 072, MeOH) as a white solid.
(The (S) isomer was deprotected in a similar fashion)
Figure imgf000198_0002
The sulfinamide derivative (583 mg) in 1 5 mL MeOH and 080 mL of 4M HCI
1 ,4-dιoxane solution were stirred at RT for 1 h The solution was concentrated, and diethyl ether was added to precipitate the amine hydrochloride The mixture was filtered to provide the desired product 420 mg (89% yield). [α]D 25 = +21.0 (c = 070,
MeOH)
Scheme KA
Figure imgf000199_0001
Step i
Figure imgf000199_0002
3, 4, 5-trιmethylphenol (1 0 g, 7.34 mmol) was suspended in a mixture of hexane 915 mL) and buffer (pH = 7.4, 15 ml_) tetra-n-Butylammonium sulfate (426 mg, 0 736 mmol) and ruthenιum(lll) chloride monohydrate (167 mg, 0 734 mmol) was added. The reaction mixture was shaken under a hydrogen atmosphere at 60 psi for two days. The reaction mixture was filtered through a short pad of Celite®. The organic layer was separated. The aqueous layer was extracted with EtOAc (30 mLx3). The organic layers were combined, washed by brine (50 mL), dried over anhydrous Na2SO,!, filtered, and concentrated by rotary evaporator The crude 3, 4, 5-trimethylcyclohexanol was used without further purification.
Step 2
Figure imgf000199_0003
3, 4, 5-trιmethylcyclohexanol obtained in step 1 was dissolved in dichloromethane. Dess-Martin reagent (3.1 g, 7.34 mmol) was added in one portion Tπfluoroacetic acid anhydride (0 56 mL, 7 34 mmol) was added, and the solution was stirred at RT for 18h. Sodium hydroxide (1 N, 30 mL) and diethyl ether (100 mL) were added. The reaction mixture was stirred at RT for one hour. The organic layer was washed with NaOH (1 N, 30 ml), brine 930 ml), dried over anhydrous Na2SO4, filtered, and concentrated The product was purified by S1O2 chromatography (Hexane/EtOAc 5.1) to give 3, 4, 5-trιmethylcyclohexanone (758 mg, 73 6% from 3, 4, 5- tπmethylphenol) Scheme BA
Figure imgf000200_0001
Compound BA-4 was prepared using procedures similar to those described in Scheme I (Steps 1-4).
BA-4 (387 mg, 0.65 mmol) was dissolved in dioxane (4 ml.) and methanol (2 mL) Aq 1.0 M lithium hydroxide was added (1.3 mL). The reaction mixture was stirred at RT overnight. After 20 h, additional aq 1 0 M LiOH was added (1 0 mL) About 7 h later, the reaction mixture was concentrated to near dryness. EtOAc (80 mL) and 1 0 M aq NaHSO4 (10 mL) were added. The layers were separated. The aqueous layer was extracted with EtOAc The combined organic layer was gravity filtered and concentrated to dryness giving compound BA-5 as a white foam (0 33 g)
BA-5 (14 5 mg, 0.026 mmol, 1 0 eq), beta alanine tert butyl ester hydrochloride (5 4 mg, 0.03 mmol), and HOBT (3.6 mg, 0.026 mmol), were added to a 1 dram vial equipped with a stir bar CH2CI2 (03 mL) and DIPEA (15 μL, 0.087 mmol), were added followed by EDC (6 mg, 0.031 mmol). The vial was capped and the reaction mixture was left stirring at RT over the weekend The reaction mixture was diluted with CH2CI2 and washed with aq NH4CI, water, and brine The resulting organic solution was gravity filtered and concentrated to dryness. The crude product was purified via flash sgc using a 15% to 30% EtOAc/Hex gradient as the mobile phase. The major peak was collected as product to give 12 mg of BA-6 as a clear oil.
Compound BA-6 was dissolved in a solution consisting of CH2CI2 (8mL) and TFA (2 mL). The reaction mixture was stirred at RT for 7 h, then concentrated to dryness on the rotovap. CH2CI2 and hexanes were added and the solution was concentrated to dryness The crude product was purified i/rareversed-phase chromatography on a 13 g lsco C-18 cartridge using a 80% to 100% CH3CN/H2O gradient as the mobile phase Each component of the mobile phase contained formic acid (0 1% by volume) The major peak was collected as product to give 8 mg of Example 1.302.
Scheme BB
Figure imgf000201_0001
Compound BB-1 was prepared using procedures similar to those described in Scheme BA-(Steps 1 -5)
Compound BB-1 (228 mg, 041 mmol, 1.0 eq) and (1 -H-tetrazol-5-yl methyl) amine hydrobromide (89 mg, 0.49 mmol, purchased from ChemBridge) were dissolved in DMF (4 mL) DIPEA (1 6 mL) was added, followed by PyBOP (260 mg, 0 5 mmol) The reaction mixture was placed under N2 The flask was placed in an oil bath and warmed to 70 °C The reaction mixture was stirred at 70 °C for 2 h and at 50 C for 1 h The heat was turned off and the reaction mixture was left stirring overnight at RT under N2 The reaction mixture was partially concentrated on the rotovap, then purified v/areversed-phase chromatography using a 50 g Vanan C-18 cartridge The column was eluted using a 50% to 100% CH3CN/H2O gradient as the mobile phase Each component of the mobile phase contained formic acid (0 1% by volume) The major peak was collected as product to give Example 1.305 (0 23 g) as a clear oil
Scheme BC
Figure imgf000202_0001
Compound BC-1 was prepared using procedures similar to those described in Scheme I, (Steps 1-4) using the appropriate phenyl glycine, amine, and ketone
Compound BC-1 (0 55 g, 0 90 mmol, 1 0 eq), pinacolatodiboron (0 69 g, 2 7 mmol, 3 0 eq), Pd(dppf)CI2 (7 3 mg, 0 01 mmol, 0 1 eq), and potassium acetate (0 18 g, 1 8 mmol, 2 0 eq) were added to a 100 mL round bottomed flask equipped with a stir bar The flask was equipped with a septum and connected to a vacuum manifold via a syringe needle and tubing The air in the flask was removed and replaced with N2 by cycling between vacuum and nitrogen several times Dioxane (10 mL, anhydrous) was added via syringe The reaction mixture was heated at 90 °C for 3 h under N2 then left stirring overnight at rt Sodium perborate (1 38 g, 10 eq) and water (3 mL) were added The reaction mixture was stirred at RT overnight The resulting reaction mixture was poured into 200 mL of EtOAc, then washed with 1% aq HCI solution and water The organic layer was concentrated to dryness on the rotovap The crude product was purified via flash silica gel chromatography using a 5%-80%
EtOAc/hexanes gradient on a 24 g lsco SiO2 cartridge to give 036 g of compound BC-2
Compound BC-2 (020 g, 0 366 mmol, 1 0 eq) was added to a 50 mL round bottomed flask equipped with a stir bar DMF (3 mL), cesium carbonate (0 18 g, 1 5 eq), and 1- bromo-3, 3-dιmethylbutane (91 mg, 1 5 eq) were added The reaction mixture was stirred overnight at rt After about 16 h, the reaction mixture was heated for 5 h at 70 °C The reaction mixture was poured into 100 mL of EtOAc The resulting mixture was washed with water (2 x 20 mL) and concentrated to dryness The crude product was purified via flash sgc using an lsco 24 g SiO2 cartridge and a 5%-60% EtOAC/hexanes gradient as the mobile phase giving 0 17 g of BC-3.
Compound BC-3 was converted to BC-4 and to Example 1.317 using procedures similar to those described in Schemes BA and BB
Scheme BD
Figure imgf000204_0001
Compound BD-1 was prepared using procedures similar to those described in Scheme BA BD-1 was converted to Example 1.321 using procedures similar to those described in Scheme BA
Scheme BF
Figure imgf000204_0002
Compound BF-1 may be prepared using procedures similar to those described in Scheme I (Steps 1-4)
Compound BF-1 (0 1 g, 0 19 mmol, 1 0 eq), BF-2 (48 mg, 2 eq), and Pd(dppf)CI2 (16 mg, 0 1 eq) were added to a rb flask equipped with a stir bar The flask was capped with a septum and connected to a vacuum manifold via a syringe and tubing The flask was cycled between vacuum and nitrogen several times to blanket the reaction mixture with nitrogen Acetonitrile (1 4 mL) and 1 M aq K2CO3 (1 4 mL) were added via syringe The reaction was heated to 80 °C in an oil bath and left stirring at 80 °C overnight under N2 The reaction mixture was removed from the oil bath and diluted with EtOAc and brine The layers were separated The organic layer was concentrated to dryness The crude product was purified via flash sgc using a 0 5% to 6% MeOH/CH2Cl2 gradient as the mobile phase to give 70 mg of BF-3 Compound BF-3 may be converted to Example 1.339 using procedures similar to those described in Scheme BA (Steps 5-7)
Scheme BG
Figure imgf000205_0001
Compound BG-1 may be prepared using procedures similar to those described in Scheme I (Steps 1-4)
Compound BG-2 (73 mg, 2 eq) Pd(dppf)Cl2 (16 mg, 0 1eq) and tripotassium phosphate (0 2 g, 5 eq) were added to a 5 mL microwave vial equipped with a stir bar The vial was capped and connected to a vacuum manifold via a syringe and tubing The flask was cycled between vacuum and nitrogen several times to blanket the reaction mixture with nitrogen Compound BG-1 (0 11 g, 0 19 mmol, 1 0 eq) was dissolved in 2 mL of anhydrous dioxane The resulting solution was added via syringe, and the reaction mixture was heated overnight in an oil bath at 110 °C under N2 The reaction mixture was poured into 100 mL of EtOAc and washed with water (2 x 20 mL) the resulting organic solution was concentrated to dryness The crude product was purified via sgc on a 12 g lsco S1O2 carridge using a 5%-20% EtOAc/Hexanes gradient as the mobile phase to give 48 mg of BG-3 Compound BG-3 was converted to Example 1.326 using procedures similar to those described in Schemes BA and BB
Scheme BH
Figure imgf000205_0002
Compound BH-1 may be prepared using procedures similar to those described in Scheme I. (Steps 1-4) Compound BF-1 (0 1g, 0 19 mmol, 1 0 eq), Zn(CN)2 (27 mg, 0 05 eq), zinc (1 5 mg, 0 12 eq) and Pd(dppf)CI2 (8 mg, 0 1eq) were added to a rb flask equipped with a stir bar The flask was capped with a septum and connected to a vacuum manifold via a syringe and tubing The flask was cycled between vacuum and nitrogen several times to blanket the reaction mixture with nitrogen N,N-Dιmethyl acetamide (1 0 mL) was added via syringe and the reaction mixture was stirred overnight at 120 °C under N2 TLC showed SM remained The reaction mixture was heated overnight at 140 °C under N2 The reaction mixture was allowed to cool to RT and diluted with EtOAc The resulting solution was washed with water and concentrated to dryness The crude product was purified via sgc using a 5%-70% EtOAc/hexanes gradient as the mobile phase The major peak was isolated as product to give 48 mg of BH-2
Compound BH-2 may be converted to compound Example 1.358 using procedures similar to those described in Scheme BA (Steps 5-7)
Figure imgf000206_0001
Compound BI-1 may be prepared using procedures similar to those described in Scheme I (Steps 1 -4)
Compound BI-1 (0 1 g, 0 19 mmol, 1 0 eq), CuI (6 mg, 0 1 eq), L-proline (6 mg, 0 18 eq) and K2CO3 (80 mg, 2 0 eq) were added to a rb flask equipped with a stir bar The flask was capped with a septum and connected to a vacuum manifold via a syringe and tubing The flask was cycled between vacuum and nitrogen several times to blanket the reaction mixture with nitrogen A solution of pipendine (37 mg, 1 5 eq) in 2 ml. of DMSO was added via syringe The reaction mixture was stirred overnight at 140 °C under N2 The reaction mixture was allowed to cool to RT and was diluted with EtOAc The resulting solution was washed with water and concentrated to dryness on the rotovap The crude product was purified via flash chromatography using a 0 5%-6% CH3OHZCH2CI2 gradient as the mobile phase to give 39 mg of impure BI-2 The fractions containing BI-2 were purified a second time via flash sgc using a 5%-80% EtOAc/Hexanes gradient as the mobile phase with 0 5% formic acid (by volume) in the EtOAc component of the mobile phase to give 32 mg of BI-2
Compound BI-2 was converted to Example 1.361 using procedures similar to those described in Scheme BA (Steps 5-7)
Scheme BM
Figure imgf000207_0001
Compound BM-1 may be prepared using procedures similar to those described in Scheme I (Steps 1-4) Compound BM-1 (0 1g, 0 19 mmol, 1 0 eq), CuCI (2 mg, 0 1 eq), phenol (45 mg, 25 eq), 2,2,6,6 tetraethylheptane-3,5-dione (5 mg, 0 1 eq), and Cs2CO3 (0 12 g, 2 0 eq) were added to a 5 mL microwave vial equipped with a stir bar The vial was capped and connected to a vacuum manifold via a syringe and tubing The flask was cycled between vacuum and nitrogen several times to blanket the reaction mixture with nitrogen N-methyl pyrolidinone was added via syringe and the reaction mixture was heated overnight in an oil bath at 140 °C The reaction mixture allowed to cool and was diluted with 100 mL of EtOAc The resulting solution was washed with saturated aq NH4CI and water (20 mL), then concentrated to dryness The crude product was purified via sgc on a 12 gram lsco S1O2 cartridge using a 5%-100% EtOAc/hexanes gradient in which 0 5% formic acid (by volume) had been added to the EtOAc, giving compound BM-2 mixed with some of the des-bromo analog of BM-1 The product was used in the next step without further purification
Compound BM-2 may be converted to Example 1.335 using chemistry similar to that described in Scheme BA (Steps 5-7)
Scheme BN
Figure imgf000208_0001
Compound BN-1 may be prepared using procedures similar to those described in Scheme I (Steps 1-4)
Compound BN-1 (0 1 g, 0 19 mmol, 1 0 eq), cyclopropyl boronic acid (21 mg, 1 3 eq), and Pd(dppf)CI2 (16 mg, 0 1 eq), K3PO4 (0 1 g, 2 5 eq) were added to a 5 mL microwave vial equipped with a stir bar The flask was capped and connected to a vacuum manifold via a syringe and tubing The vial was cycled between vacuum and nitrogen several times to blanket the reaction mixture with nitrogen Dioxane (2 mL) was added via syringe The reaction was heated at 135 °C overnight with stirring The reaction mixture was allowed to cool to RT and diluted with EtOAc and water The layers were separated The organic layer was concentrated to dryness The crude product was purified via sgc using a 5%-80% EtOAc / hexanes gradient as the mobile phase to give 79 mg of BN-2 Compound BN-2 may be converted to Example 1.340 using chemistry similar to that described in Scheme BA (Steps 5-7)
Figure imgf000209_0001
Compound BO-1 may be prepared using procedures similar to those described in Scheme BC (Step 1 to compound BC-2)
Compound BO-1 (84 mg, 0 18 mmol) was added to a 50 mL rb flask equipped with a stir bar Acetonitrile (1 mL) was added with stirring, followed by N-iodosuccinamide (45 mg, 1 1 eq) The reaction mixture was stirred at RT ON The reaction mixture was concentrated to dryness The crude product was purified via flash sgc using an lsco 12 g SiO2 cartridge and a 5%-60% EtOAc/hexanes gradient as the mobile phase to give 50 mg of BO-2
Compound BO-2 (50 mg, 0 085 mmol, 1 0 eq), CuI (2 mg, 0 011 mmol, 0 12 eq ), and Pd(PPh3J2CI2 (2 mg, 0 003 mmol, 0 03 eq ) were added to a 5 mL microwave vial equipped with a stir bar The vial was capped and connected to a vacuum manifold via a syringe and tubing The vial was cycled between vacuum and nitrogen several times to blanket the reaction mixture with nitrogen A solution of TMS acetylene (12 mg, 1 5 eq) and dnsopropylamine (50 μL) dissolved in DMF (1 mL) was added via syringe The reaction mixture was placed in an oil bath and stirred at 80 °C under N2 overnight The reaction mixture was poured into 50 mL of EtOAc and 30 mL of water The layers were separated The organic layer was washed with 2 x 20 mL of water, then concentrated to dryness The crude product was purified via prep TLC on SiO2 plates using a 1.1 EtOAc: Hexanes solution as the mobile phase to give 21 mg of BO- 3.
Compound BO-3 was converted to Example 1.331 using procedures similar to those described in Scheme BA (Steps 5-7)
Figure imgf000210_0001
Compound BP-1 was prepared using procedures similar to those described in Scheme BA (Steps 1 -5).
Compound BP-1 (120 mg, 0.24 mmol, 1 0 eq) and PyBOP (137 mg, 0 26 mmol, 1.1 eq) were added to a 40 mL vial equipped with a stir bar DMF and N-methyl morpholine were added The vial was capped and the reaction mixture was stirred at RT for 3 h. Tetradeuterated beta-alanme (2, 2, 3, 3-D4) was added (CAS number 116173-67-2, purchased from CDN Isotopes) The reaction mixture was left stirring at rt for 26 h. The reaction mixture was diluted with EtOAc (120 mL) and 0 5 M citric acid (20 mL) The layers were separated. The organic layer was washed with water and brine, dried with MgSO4, and filtered. The resulting solution was concentrated to a clear oil. The crude product was purified via sgc using a 12 g lsco SiO2 cartridge and an EtOAc/Hex gradient (15%-70%) as the mobile phase The EtOAc contained 0 5% (by volume) formic acid. The major peak was collected as product. The product was purified further via reversed-phase HPLC on a C-18 column using a 60%-99% CH3CN/H2O gradient as the mobile phase. Formic acid (0 1 % by volume) was added to each component of the mobile phase Example 1.312 (0.07 g) was obtained as a clear oil
BQ
Boc
Figure imgf000211_0001
Compound BQ-1 (1.0 g, 3.74 mmol, 1.0 eq), compound BQ-2 (0.90 g, 1.0 eq), HOBT (0.51 g, 1.0 eq), N-methyl morpholine (1.13 g, 3.0 eq), DMF (15 mL), and EDCI (1.08 g, 1.5 eq). were added to a 250 mL rb flask and stirred at RT ON. The reaction mixture was diluted with 300 mL of EtOAc and washed with water (2 x 100 mL). The organic layer was concentrated to dryness to give BQ-3 (1.78 g).
Compound BQ-3 (0.93 g, 2.0 mmol, 1.0 eq), cesium carbonate (0.73 g, 1.1 eq) and DMF (10 mL) were added to a 250 mL rb flask. Benzyl bromide (0.38 g, 1.1 eq), dissolved in 1 mL of DMF was added slowly to the reaction mixture with stirring. The reaction mixture was stirred ON at rt, then concentrated to near dryness on the rotovap. The residue was diluted with 200 mL of EtOAc then washed with water (2 x 200 rtiL) The resulting organic solution was concentrated to dryness. The crude product was purified via sgc using a 40 gram lsco SiC>2 cartridge and a 10%-100% EtOAc/Hexanes gradient as the mobile phase to give 0.84 g of compound BQ-4. Compound BQ-4 was converted to compound BQ-6 using procedures that are similar to those described in Scheme A-(Step 3) and Scheme l-(Step 4).
Compound BQ-6 (0.53 g, 0.94 mmol, 1.0 eq) was dissolved in 20 mL of CH2Cb in a 250 mL flask equipped with a stir bar. The flask was cooled in an ice-water bath, tert- Butyl hypochlorite (0.12 g, 1.2 eq) was added dropwise. The reaction mixture was stirred at 0 °C for 1 h The bath was removed and the reaction mixture was warmed to rt. The reaction mixture was stirred at RT for 3 h Triethylamine (0 47 g, 5.0 eq) was added and the reaction mixture was stirred overnight at rt. The reaction mixture was concentrated to dryness. The crude product was purified via sgc using a 23 g S1O2 cartridge and a 5%-80% EtOAc/hexanes gradient as the mobile phase. Two fractions were isolated as impure compound BQ-7a and BQ-7b (0.25 g) The fraction containing BQ-7a was repurified via reversed-phase HPLC on a semi-preparative C- 18 column using a 70%-100% CH3CN/H2O gradient over 20 mm as the mobile phase. Formic acid (0 1% by volume) was added to each component of the mobile phase. Compounds BQ-7a (156 mg) and BQ-7b (47 mg) were isolated as product
Compound BQ-7a was converted to Example 1.366 using procedures similar to those described in Scheme BB. Compound BQ-7b was converted to Example 1.359 using procedures similar to those described in Scheme BB.
Scheme BR
Figure imgf000213_0001
Compound BR-1 was prepared according to the procedures described in Scheme I Compound BR-1 (0 54 g, 0.91 mmol, 1 0 eq), compound BR-2 (4-tert-butyl cyclohexanone [2H9]- purchased from Isosciences, LLC- (270 mg, 1 65 mmol, 1.8 eq)), and para-toluene sulfonic acid monohydrate (18 mg, 0.09 mmol, 0 10 eq) were added to a 20 mL microwave vial equipped with a stir bar. Molecular sieves (3 A, 2 03 g) were added, followed by 2-propanol N2 was blown over the reaction mixture and the vial was capped. The vial was placed in an oil bath and heated to 102 °C. The reaction was stirred at 102 °C for 15 h, then allowed to cool to rt. The reaction mixture was diluted with CH2Ct and gravity filtered The filtrate was concentrated to a brown oil The oil was chromatographed on a 50 g Supelco S1O2 cartridge using a 5% to 25% EtOAc/hexanes gradient as the mobile phase. The second large peak off the column was collected as product to give 0.29 g of BR-3.
Compound BR-3 was converted to Example 1.371 using procedures similar to those described in Scheme BA and Scheme BB.
Figure imgf000214_0001
Compound BS-1 was prepared according to the procedures described in Tagat, J. R et al WO2006/098961 A2 "Compounds for Inhibiting KSP Kinesin Activity."
Compound BS-4 was prepared according to the procedures described in Scheme I
A 3-necked 500 mL flask equipped with a stir bar and septa was charged with high purity (Aldrich, 99.9995%) metallic zinc (1O g, 153 mmol, 3.5 eq) and 80 mL of dimethoxyethane. The flask was equipped with septa and the reaction mixture was placed under a nitrogen blanket. The reaction mixture was sonicated and heated using a Fisher Scientific 150 watt FS60 sonicating bath. Acetyl chloride (0 34 g, 5 1 mmol) was added via syringe, followed by compound BS-1 (8 0 g, 43 9 mmol, 1.0 eq) and diiodomethane (42 3 g, 158 mmol, 3 6 eq), which were also added via syringe. The reaction mixture was sonicated and heated at 60 °C for 5 h under N2. The sonication and heating were stopped and the reaction mixture was allowed to stand at RT under N2 overnight. The reaction mixture was quenched with saturated aq NH4CI solution and poured into 1 L of EtOAc. The layers were separated. The organic layer was washed with saturated aq NH4CI and dried over sodium sulfate. The resulting mixture was filtered and the filtrate was concentrated to dryness, giving 10 16 g of impure BS-2 The crude product was used in the next step without further purification (See also Repic, O et al Tetrahedron Letters 1982, 23, 2729-2732 for a leading reference on the use of sonication in the Simmons-Smith reaction )
In a 250 ml_ round bottomed flask, compound BS-2 (10 16 g) was dissolved in 20 ml_ of THF Aqueous 4 N HCI was added (20 ml_) and the resulting solution was stirred at RT overnight The resulting reaction mixture was partially concentrated on the rotovap then added to 1 L of EtOAc The organic layer was washed with 2 x 100 mL of water and dried over sodium sulfate The solution was gravity filtered and concentrated to dryness The crude K201 was purified via flash sgc on a 120 g lsco S1O2 cartridge using a 0%-40% EtOAc/hexanes gradient as the mobile phase to give 4 34 g of K201 (65% yield over the two steps) Compound K201 was converted to Example 1.376 using procedures similar to those described in Scheme BA and Scheme BB
Scheme CA
Preparation of Example 1.931
Figure imgf000216_0001
Step 1
In a 125-mL round-bottom flask, amino acid A1 (1.0 g, 3.1 mmol), amine hydrochloride salt M50 (652 mg, 2.8 mmol), EDOHCI (817 mg, 4.3 mmol) and HOBT«H2O (423 mg, 3.1 mmol), and DIPEA (1.5 mL, 1.1 g, 8.5 mmol) were combined and collectively dissolved in DMF (5.7 mL). The resulting solution was stirred overnight at rt, then diluted with EtOAc (80 mL) and water (40 mL). The organic layer was separated and washed sequentially with water (3 x 20 mL) and brine (20 ml_), then dried over anhydrous MgSCU, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (Isco Combiflash Rf®, 40 g RediSep silica gel cartridge, 0-30% EtOAc/hexanes over 16 column volumes @ 40 mUmin) The desired product CA-1 was obtained as a pale yellow oil (1.22 g, 86%).
Step 2
In a 500-mL round-bottom flask, Compound CA-1 (1.22 g, 246 mmol) was dissolved in a mixture of dioxane (11 mL) and methanol (5 5 mL) and the solution was treated with 1 Naq. NaOH. The reaction mixture was heated with stirring at 60 °C for
2 h and then was then allowed to cool to rt The solvent was removed by rotary evaporation under reduced pressure. The residue was redissolved in water (50 mL) and then acidified to pH 2 using 2 Naq HCI. EtOAc (10O mL) was added. The aq. layer was separated and extracted with EtOAc (3 x 30 mL) The combined organic phases were washed with brine (-50 mL), dried over anhydrous MgSO4, filtered, and concentrated by rotary evaporation under reduced pressure to afford Compound CA-
2 as a white foam (1 16 g, 97%), which was used without further purification
Step 3 In a 250-mL round-bottom flask, the carboxylic acid CA-2 (1 16 g, 2 41 mmol), ϋefa-alanine methyl ester hydrochloride (505 mg, 3.61 mmol), EDOHCI (693 mg,
3 61 mmol), HOBT«H2O (360 mg), and DIPEA (1 3 mL, 934 mg, 723 mmol) were mixed and collectively dissolved in DMF (8 mL). The resulting solution was stirred overnight at rt. The reaction mixture was diluted with EtOAc (60 mL). Water (30 mL) was added. The organic layer was separated, washed with water (3 x 10 mL) and brine (10 mL), dried over anhydrous MgSO4, filtered, and concentrated by rotary evaporation under reduced pressure to afford a crude product CA-3 (off-white solid, 1.34 g, 98% yield), which was used without further purification Step 4
In a 250-mL round-bottom flask, a solution of Compound CA-3 (1.34 g, 2.37 mmol) in dichloromethane (4 7 mL) was treated with HCI (24 mL, 2 M in diethyl ether; 48 mmol) and the reaction was allowed to proceed overnight at rt. The solvent was removed by rotary evaporation under reduced pressure to give a crude product, Compound CA-4, as a light yellow solid (1 27 g, in excess of theoretical yield) Compound CA-4 was used without further purification
Step 5
In a Biotage® 20-mL microwave tube, Compound CA-4 (118 mg, 0 235 mmol), 4-f-pentylcyclohexanone (Compound K3, 316 mg, 1 88 mmol), triethylamine (0 2 mL, 142 mg, 1 4 mmol) and 4 A molecular sieves (100 mg, 04-0 8 mm beads) were admixed and suspended in dry methanol (0 94 mL) The tube was sealed and the reaction was allowed to proceed at 130 °C (microwave heating) for 6 h The reaction mixture was filtered through a Celite®* pad, which was then washed with dichloromethane (~10 mL) The filtrate was concentrated under reduced pressure and the residue was purified by flash silica gel chromatography (Isco Combiflash Rf8, 12 g RediSep silica gel cartridge, 0-30% EtOAc/hexanes over 28 column volumes @ 30 mL/min) The desired product CA-5 was obtained as a pale yellow oil (122 mg, 84% yield)
Step 6
In a 125-mL round-bottom flask, Compound CA-5 (122 mg, 0 197 mmol) was dissolved in dichloromethane (2 mL) and treated with f-butyl hypochlorite (0 03 mL, 27 mg, 0 24 mmol) The reaction mixture was stirred at RT for 1 h Triethylamine (0 11 mL, 80 mg, 0 80 mmol) was added and the reaction was allowed to proceed at RT for 1 h The reaction mixture was then diluted with dichloromethane (30 mL) and washed sequentially with 1 N aq NaHSOe ( 5 mL), water (5 mL), and brine (5 mL) The organic layer was dried over anhydrous MgSO4, filtered, and concentrated by rotary evaporation under reduced pressure The resulting residue was purified by flash silica gel chromatography (Isco Combiflash Rf®, 12 g RediSep silica gel cartridge, 0- 30% EtOAc/hexanes over 28 column volumes @ 30 mL/min) to give desired product CA-6 as a yellow oil (89 mg, 74% yield)
Step 7
In a 125-mL round-bottom flask, substrate CA-6 (89 mg, 0 145 mmol) was dissolved in dioxane (0 64 mL) and methanol (032 mL) and the resulting solution was treated with 1 Naq. NaOH (0.160 ml_). The reaction mixture was stirred at 60 °C for 2 h, then allowed to cool to rt, and was concentrated under reduced pressure. The resulting residue was redissolved in water (15 mL) and the solution was acidified to pH 2 using 2 N aq HCI. EtOAc (30 mL) was added. The aq. layer was separated and extracted with further amounts of EtOAc (3 x 15 mL) The combined organic layers were washed with brine (-25 mL), dried over anhydrous MgSO4, filtered, and concentrated by rotary evaporation under reduced pressure. The resulting residue was purified by flash silica gel chromatography (Isco Combiflash Rf*; 12 g RediSep silica gel cartridge, 0-100% EtOAc/hexanes over 28 column volumes @ 30 mL/min) to give Example 1.902 as a yellow oil (76 mg, 86% yield).
Scheme CB
Preparation of Example 1.931
Figure imgf000220_0001
Step 1
In a 250-mL round-bottom flask, an admixture of Compound A6 (4.37 g, 13 7 mmol), Compound M50 (2 86 g, 12.4 mmol), and PyBOP (7.12 g, 13.7 mmol) was dissolved in dry acetonitrile (54 ml_). The solution was stirred at RT for 3 days. The solvent was removed by rotary evaporation under reduced pressure. The residue was purified directly by flash silica gel chromatography (Isco Combiflash Rf*; 80 g RediSep silica gel cartridge, 0-30% EtOAc/hexanes over 20 column volumes @ 80 mL/min) to afford Compound CB-1 as a yellow solid (5.81 g, 94% yield).
Step 2 Compound CB-1 was converted to Compound CB-2 following the procedure in Scheme CA, Step 2.
Step 3
In a 1-L round-bottom flask, an admixture of Compound CB-2 (5 36 g, 11 2 mmol), £>efa-alanιne methyl ester hydrochloride (2 34 g, 16.7 mmol), DIPEA (7.7 mL, 5.8 g, 45 mmol), and PyBOP (6.38 g, 12 3 mmol) was dissolved in dry acetonitrile (55 mL) The solution was stirred overnight at rt The solvent was removed by rotary evaporation under reduced pressure. The residue was purified directly by flash silica gel chromatography (Isco Combiflash Rf®, 80 g RediSep silica gel cartridge, 0-30% EtOAc /hexanes over 20 column volumes @ 80 mL/min) to afford Compound CB-3 as an off-white solid (6.05 g, 96% yield)
Step 4
In a 100-mL round-bottom flask, TFA (3.0 mL, 4.6 g, 41 mmol) was added to a stirred solution of Compound CB-3 (2 3 g, 4 1 mmol) in dichloromethane (16 mL). The reaction mixture was stirred overnight at rt. The solvent and other volatile components were removed by rotary evaporation under reduced pressure The residue was redissolved in dichloromethane (150 mL) and the solution was washed with 1 Naq. NaOH (-50 mL). The organic layer was set aside while the aqueous layer was extracted with dichloromethane (3 x 25 mL) The combined organic phases were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to afford Compound CB-4 as an off-white solid (1.77 g, 94% yield).
Steps 5 and 6 Compound CB-4 was converted to Compound CB-6 by sequential application of procedures given in steps 5 and 6 of Scheme CA, and substituting Compound K6 for Compound K3 in step 5. Step 7
Compound CB-6 was converted to Example 1.931 following the procedure of Scheme CA, step 7
Scheme CC Preparation of Example 1.951
Figure imgf000222_0001
Example 1 951
Steps 1-6 Compound A6 was converted to Example 1.951 by sequential application of procedures given in steps 1-6 of Scheme CB, substituting Compound K11 for Compound K6 in step 5
Scheme CD Preparation of Compound K95
Figure imgf000222_0002
Step 1
In a 500-mL Parr® hydrogenation vessel, Compound CD-1 (8 74 g, 38 mmol) was dissolved in hexane (20 mL) and aqueous pH 7 4 buffer (20 mL, Fisher Scientific SB110-1 , potassium phosphate monobasic — sodium hydroxide buffer, 0 05 M) RhCb*xHaO (1 0 g, 3 8 mmol, Alfa Aesar) and tetrabutylammonium sulfate solution (44 mL, 50 wt% in H2O, 4 4 g, 3 8 mmol) were added sequentially The biphasic mixture was shaken under hydrogen atmosphere (53 psi) for 14 days at rt The reaction mixture was filtered through a Celite®* pad The aq layer was separated and extracted with EtOAc (3 x 15 mL) The combined organic layers was washed with brine (-25 mL), dried over anhydrous MgSCU, filtered, and concentrated by rotary evaporation under reduced pressure The crude product was purified by flash silica gel chromatography (Isco Combiflash Rf®, 80 g RediSep silica gel cartridge, 0-100% EtOAc/hexanes over 20 column volumes @ 80 mL/min) Eluent from column volumes 1-6, containing unreacted Compound CD-1 , were discarded, while column volumes 7-20 were combined and concentrated to give desired product, Compound CD-2, as an off-white solid (667 g, 74% yield) Step 2
A solution of Compound CD-2 (6 67 g, 283 mmol) in dichloromethane (113 mL) was treated with solid Dess-Martin periodinane (18 g, 42 mmol) The reaction mixture was stirred overnight at rt The reaction mixture was diluted with diethyl ether (385 mL) and 1 N aq NaOH (185 mL) was added slowly The resulting solution was stirred at RT for 1 5 h The organic layer was separated and washed sequentially with 1 Naq NaOH (90 mL), brine (-50 mL), dried over anhydrous MgSO4, filtered, and concentrated by rotary evaporation under reduced pressure to afford the desired product, Compound K95, as a yellow oil (6 55 g, 99% yield) Compound K95 was used without subsequent purification
Scheme CE
Preparation of Example 1.966
Figure imgf000224_0001
Example 1 966
Step 1 Compound CE-1 was prepared following the procedure given in Step 1 of
Scheme CB, substituting Compound A5 (707 mg, 2.47 mmol) for Compound A6.
Step 2
In a 250-mL round-bottom flask, Compound CE-1 (1 08 g, 2.47 mmol) was dissolved in dichloromethane (10 ml_). Neat TFA (5 mL) was added and the resulting solution was stirred at RT for 16 h. The reaction mixture was concentrated by rotary evaporation under reduced pressure The resulting syrup was redissolved in dichloromethane (50 mL) and the solution was washed sequentially with 1 Naq NaOH (~25 mL), water (-25 mL), and brine (-25 mL) The organic layer was dried over anhydrous MgSCU, filtered, and concentrated to afford a clear, colorless oil. Said oil was redissolved in dichloromethane (25 mL). HCI solution (2.0 mL, 2 0 M in diethyl ether, 4.0 mmol) was added and the solvent was removed under reduced pressure to afford Compound CE-2 as a white solid (822 mg, 92% yield over two steps).
Step 3
In a Biotage® 5-mL microwave tube, Compound CE-2 (316 rng, 0.80 mmol) was dissolved in dry methanol (2.6 mL) with the aid of stirring and occasional sonication 4-lsopropylcyclohexanone (Compound K2, 891 mg, 6 37 mmol), triethylamine (0.447 mL, 322 mg, 3.18 mmol) and 4 A molecular sieves (1 3 g, 0.4-0.8 mm beads) were added. The reaction mixture was heated at 130 °C for 6 h under microwave conditions. The reaction mixture was diluted with dichloromethane (5 mL) and filtered through a Celite®* pad. The pad was rinsed with a further portion of dichloromethane (25 mL) and methanol (5 mL). The combined filtrates were concentrated under reduced pressure. The resulting orange, liquid residue was purified by flash silica gel chromatography (Isco Combiflash Rf*; 24 g RediSep silica gel cartridge, 0-30% EtOAc/hexanes over 12 column volumes @ 30 mL/min) to afford Compound CE-3 (667 mg), which was contaminated with an undetermined amount of Compound K2. Compound CE-3 was used without further purification.
Step 4
Compound CE-3 (667 mg, impure) was converted to Compound CE-4 following the procedure given in Scheme CA, Step 6. An undetermined amount of Compound K2 remained after chromatography, but the desired product Compound CE-4 (281 mg) was used without further purification.
Step 5
Compound CE-4 (281 mg, impure) was dissolved in methanol (1.5 mL) and 1 ,4-dιoxane (3 mL). 1 Naq NaOH (0.65 mL, 0 65 mmol) was added and the reaction flask was immersed into a preheated, 60 °C oil bath. The reaction was allowed to proceed at 60 °C for 22 h. The reaction mixture was concentrated to dryness under reduced pressure The residue was taken up in water (10 mL) and acidified with 1 N aq HCI (1 mL) The suspension was extracted with EtOAc (2 x -30 mL) The combined organic phases were washed with brine (-20 ml_), dried over anhydrous MgSO*, filtered, and concentrated under reduced pressure to afford an oily solid Purification by flash silica gel chromatography (Isco Combiflash Rf®, 40 g RediSep silica gel cartridge, 0-50% EtOAc/hexanes over 13 column volumes @ 30 mL/min, then 50-80% EtOAc/hexanes over 30 CV) gave pure Compound CE-5 as a white solid (151 mg, 41% yield over three steps)
Step 6
In a 50-mL round-bottom flask, Compound CE-5 (58 mg, 0 124 mmol) was dissolved in dry DMF (1 0 ml_) Aminomethyltetrazole hydrobromide (27 mg, 0 149 mmol), DIPEA (0 065 ml_, 48 mg, 0 373 mmol), and PyBOP (78 mg, 0 149 mmol) were added sequentially The reaction flask was immersed into a preheated 70 °C oil bath and the reaction was allowed to proceed with stirring at 70 °C for 4 h The reaction mixture was allowed to cool to rt, was filtered, and purified directly by reverse-phase, C-18 chromatography (40-100% MeCN (+0 05% TFA) in water
(+0 05% TFA) over 20 mm @ 20 mL/min) to afford Example 1.966 as a white solid (55 mg, 81 % yield)
Scheme CF
Preparation of Example 1.963
Figure imgf000226_0001
CF-1 Example 1 963
Step i
Compound CE-5 (50 mg, 0 11 mmol), prepared as described in Scheme CE, was dissolved in dichloromethane (1 1 mL) Triethylamine (0 060 ml_, 43 mg, 043 mmol), EDCI'HCI (25 mg, 0 13 mmol), H0BTΗ20 (20 mg, 0 13 mmol), and beta- alanine t-butyl ester hydrochloride (24 mg, 0 13 mmol) were added sequentially The reaction mixture was stirred overnight at rt The solvent was removed by rotary evaporation under reduced pressure The residue was purified by flash silica gel chromatography (Isco Combiflash Rf®, 4 g RediSep silica gel cartridge, 0-40% EtOAc/hexanes over 77 column volumes @ 18 ml_/mιn) to afford Compound CF-1 as a white solid (58 mg, 91% yield) Step 2
Compound CF-1 (56 mg, 0 094 mmol) was dissolved in dichloromethane (1 mL) and TFA (0 210 ml_, 323 mg, 2 83 mmol) was added The reaction mixture was stirred at RT for 18 h The reaction mixture was diluted with dichloromethane (~10 mL) and then concentrated by rotary evaporation to dryness The resulting syrup was co-evaporated with 1 1 dichloromethaπe-hexanes (20 mL) to afford a pale yellow foam The foam was purified by reverse-phase C-18 chromatography (Gilsoπ®, 20- 100% MeCN (+005% TFA) in water (+0 05% formic acid) over 20 mm @ 20 mL/min) to give Example 1.963 as a white solid (39 mg, 77% yield)
Scheme CG Preparation of M90
Figure imgf000227_0001
Step i
Figure imgf000227_0002
The imine (2604 g, 0 802 mol, prepared according to Scheme L Step 2) was dissolved in anhydrous dichloromethane (5 0 L) and the resulting solution was cooled to -73 °C (internal) using a Dry Ice/acetone bath n-Pentylmagnesιum bromide (765 mL, 2 M in diethyl ether, 1 53 mol) was added slowly over 1 h The reaction mixture was allowed to gradually warm to rt, and was stirred overnight at rt. The reaction mixture was poured slowly a mixture of cold, saturated aq. ammonium chloride (1 25 L) and ice (-500 mL). The mixture was stirred for 5 mm, and then extracted with EtOAc (1 x 5 L, 1 x 2 L). The organic layers were combined and washed sequentially with water (2 x 2.5 L) and brine (1 x 2 L), dried over anhydrous MgSO4, filtered, and concentrated by rotary evaporation under reduced pressure to afford the crude product (332 g, yellow oil) The crude product was purified by flash column chromatography [9.3 L silica gel pre-packed in hexanes (12 L), eluted with 15% EtOAc/hexanes, followed by 25% EtOAc/hexanes (24 L), then 30% EtOAc/hexanes (8 L), and finally 35% EtOAc/hexanes (48 L)] to obtain the desired product as a ~3 5:1 mixture of diastereomers (148.5 g, 46% yield)
The diastereomers were separated in two batches by SFC chromatography (Chiralpak® AD-H, 50 x 250 mm column; 15% MeOH/CO2, 100 bar back-pressure, 35 °C, 300 mL/min; UV detection at λ = 200 nm). In the first batch, a solution of crude product (25 g) was dissolved in MeOH (200 mL) and injected in 2.0 mL aliquots. Retention times for the two separated components were 1.97 mm and 2.70 mm In the second batch, a solution of crude product (118 g) was dissolved in MeOH (500 mL) and injected in 2 5 mL aliquots. Retention times for the two separated components were 2.03 mm and 2.73 mm All fractions that eluted at retention times 1 97 mm and 2.03 mm were combined and concentrated by rotary evaporation under reduced pressure to afford Compound CH-1 (74 g) as a white solid
Step 2
Figure imgf000228_0001
A solution of Compound CH-1 (1.53 g, 4.15 mmol) in methanol (14.4 mL) was treated with hydrogen chloride (2.2 mL; 4 M solution in 1 ,4-dιoxane; 8.7 mmol). The reaction mixture was stirred at RT for 40 mm. The solvents were removed by rotary evaporation under reduced pressure. The residue was suspended in diethyl ether (25 mL) Solvent was removed by rotary evaporation to afford the amine M90 as a yellow solid (1.24 g, 100% yield) Scheme TA
Figure imgf000229_0001
1 984
N-BOC glycine, the amine HCI salt, and ketone were processed according to Scheme AAE (Steps 1-6) to provide the tπflate
Ste i
Figure imgf000229_0002
The trifate (99 mg, 0 16 mmol), 2-phenylethanamιne (61 mg, 0 5 mmol), and 1Pr2NEt (83 mg, 0 64 mmol) were taken up in 2 ml of CH3CN and heated at 70 °C for 2 h The solution was concentrated The residue was purified via gradient flash chromatography (0-30% EtOAc in hexanes, S1O2) which provided 65 mg (58%) of the amino-imidazolone
The product of Step 1 was processed into Example 1.984 using conditions outlined in Scheme I Steps 5 and 6
In one embodiment, the compounds of the invention have the general structure shown in Table 1 below, and include pharmaceutically acceptable salts, solvates, esters, prodrugs, tautomers, and isomers of said compounds. The compounds of Table 1 were prepared according to the detailed procedures described above. The Schemes indicated in the Table by letter correspond to the procedures described above The ketones, amino acids, and amines used as indicated in Table 1 are depicted in Table 2.
Figure imgf000230_0001
Figure imgf000231_0001
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Figure imgf000313_0001
NA* - not applicable/see indicated scheme for preparation
Figure imgf000313_0002
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Figure imgf000338_0001
Figure imgf000338_0002
Figure imgf000339_0001
Figure imgf000340_0001
Figure imgf000341_0001
LC refers to LCMS conditions LC
LC-1 : LCMS spectra were obtained on an Agilent 6140 Quadrupole LCMS, using a Zorbax SB-C-18 column (1.8 micron) and a flow rate of 1 0 mL/mm. The mobile phase consisted of acetonitrile and water, each of which contains 0.1% trifluoroacetic acid by volume. Gradient Table Time: 0 mm = 10 % CH3CN/ 90% water, 1.5 mm = 95% CH3CN/95% water, 2.7 mm = 95% CH3CN/5% water, 2.8 mm : 10% CH3CN/90% water Stop Time = 3 60 mm Post Time = 1 5 mm, Column Temperature = 50 °C
LC-2: LCMS spectra were obtained on an Agilent 6140 Quadrupole LCMS, using a Zorbax SB-C-18 column (1 8 micron) and a flow rate of 1 0 mL/min The mobile phase consisted of acetonitrile and water, each of which contains 0 1% trifluoroacetic acid by volume Gradient Table Time 0 mm = 10 % CH3CN/ 90% water, 5 30 mm = 95% CH3CN/95% water, 6 50 mm = 95% CH3CN/5% water, 6 56 mm = 10% CHsCN/90% water Stop Time = 7 5 mm Post Time = 1 5 mm, Column Temperature = 50 °C
LC-3 Column Agilent Zorbax SB-C18 (3 0 x 50 mm) 1 8 uM Mobile phase A
0 1 % Trifluoroacetic acid in water B 0 1 % Trifluoroacetic acid in acetonitrile Gradient 90 10 (A B) for 0 3 mm, 90 10 to 5 95 (A B) over 1 2 mm, 5 95 (A B) for 1 2 mm Flow rate 1 0 mL/min UV detection 254 and 220 nm Mass spectrometer Agilent 6140 quadrupole
LC-4: Column Gemini C-18, 50 x 4 6 mm, 5 micron, obtained from Phenomenex Mobile phase A 0 05% Trifluoroacetic acid in water B 0 05% Trifluofloacetic acid in acetonitrile Gradient 90 10 to 5 95 (A B) over 5 mm Flow rate
1 0 mL/min UV detection 254 nm ESI-MS Electro Spray Ionization Liquid chromatography-mass spectrometry (ESI-LC/MS) was performed on a PE SCIEX API-150EX, single quadrupole mass spectrometer LC-5 HPLC conditions for the retention time were as follows Column Luna
C18 100A, 5 μM A 0 025% TFA in water B 0 025% TFA in acetonitrile Gradient 982 to 2 98 (A B) over indicated time in parenthesis (below retention time provided in corresponding Table followed by a 2 minute gradient back to 98 2 (A B)) Flow rate 1 0 ml/mm UV detection 254 nm Mass spec were obtained by one of the following methods a) Multimode (ESI and APCI) b) ESI
The following amines were purchased from NetChem (New Brunswick, NJ) M2, M4, M7 M8, M9, M10, M12, M13, M15, M16, M17, and M51 The 4-TMS cyclohexanone K202 was prepared according to the literature procedure Tang, S -X , Li, Y -M , Cao, Y -R , Wang, X -L Chinese Journal of Chemistry 1991 , 68-75
Scheme 3.1
Example 7 SO
Figure imgf000343_0001
le 1 1
The acid (SM-Ex) Example 1.1 (300 mg, 0 52 mmol) was taken up in MeOH (50 mL), and O 51 mL of a O 1019 N NaOH(aq > solution was added The solution was stirred for a few minutes at room temperature The solution was filtered and concentrated which provided 227 mg (73 %) of the sodium salt Example 7.60 as a white solid
As stated above, in one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1 a), Formula (A-1 b), Formula (A-2a), Formula (A-2b), Formula (A-2c), Z contains a carboxylic acid moiety or a tetrazole moiety Pharmaceutically acceptable salts of such acids are also contemplated as being within the scope of the invention Table 3 depicts non-limiting examples of sodium salts prepared according the procedure outlined in Scheme 3.1 using the appropriate starting acid or tetrazole (SM)
Figure imgf000343_0002
Figure imgf000344_0001
Figure imgf000345_0001
Figure imgf000346_0001
Figure imgf000347_0001
Figure imgf000348_0001
Figure imgf000349_0001
Figure imgf000350_0001
Figure imgf000351_0001
Figure imgf000352_0001
Figure imgf000353_0001
Figure imgf000354_0001
Figure imgf000355_0001
Figure imgf000356_0002
Scheme 4.1
Figure imgf000356_0001
Example 1 220 Example 8.6
The tetrazole (SM-EX) Example 1.220 (110 mg, 0.17 mmol) was taken up in MeOH (10 mL), and 0.174 ml_ of a 1.00 N KOH(aq > solution was added. The solution was stirred for a few minutes at room temperature. The solution was filtered and concentrated which provided 102 mg (87 %) of the potassium salt Example 8.6 as a white solid
As stated above, in one embodiment, in each of Formula (A), Formula (A-1), Formula (A-1 a), Formula (A-1b), Formula (A-2a), Formula (A-2b), Formula (A-2c), Z contains a carboxylic acid or tetrazole moiety Pharmaceutically acceptable salts of such acids are also contemplated as being within the scope of the invention Table 4 depicts non-limiting examples of potassium salts prepared according the procedure outlined in Scheme 4.1 using the appropriate starting tetrazole (SM).
Figure imgf000357_0001
Figure imgf000358_0002
Scheme 4.1
Figure imgf000358_0001
Example 1 21 Example 95
The acid (SM-EX) Example 1.21 (32 mg, 0 056 mmol) was taken up in MeOH (10 mL), and 0 066 mL of a 10 % aqueous choline hydroxide solution was added The solution was stirred at RT for 18 h The solution was concentrated, and the residue was taken up in EtOH The EtOH was removed under reduced pressure Ethanol/hexanes has added to the residue, and the solution was concentrated and dried under high vaccuum This provided 38 mg (Quant ) of the choline salt Example 9.5 as a white solid
As stated above, in one embodiment, in each of Formula (A), Formula (A-1 ), Formula (A-1a), Formula (A-1b), Formula (A-2a), Formula (A-2b), Formula (A-2c), Z contains a carboxylic acid or tetrazole moiety Pharmaceutically acceptable salts of such acids are also contemplated as being within the scope of the invention Table 5 depicts non-limiting examples of choline salts prepared according the procedure outlined in Scheme 4.1 using the appropriate starting acid or tetrazole (SM-Ex).
Figure imgf000359_0001
Figure imgf000360_0001
Microwave Reactions
All microwave reactions were performed using a Biotage Initiator Sixty microwave reactor, a Biotage Initiator Eight™ reactor, or a Biotage Creator Microwave™ reactor
Biological Assays
The ability of the compounds of the invention to inhibit the binding of glucagon and their utility in treating or preventing type 2 diabetes mellitus and related conditions can be demonstrated by the following in vitro assays
Glucagon Receptor Binding Assay
Recombinant human glucagon receptor (huGlucR) membranes and mouse glucagon receptor (mGlucR) membranes were prepared in-house from huGlucR/clone 103c/CHO and mouse liver tissue, respectively 0 03ug/lι huGluR membranes (or 0 5 ug/ml mGlucR) was incubated in assay buffer containing 0 05 nM 125I- Glucagon (Perkin Elmer, NEX 207) and varying concentrations of antagonist at room temperature for 60 to 90 mm (assay buffer 50 rtiM HEPES, 1 mM MgCI2, 1 mM CaCI2, 1 mg/ml BSA, COMPLETE protease inhibitor cocktail, pH 7 4) The total volume of the assay was 200 ul with 4% final DMSO concentration The assay was performed at room temperature using 96 -deep well plate Compound 4c, racemic diastereomer 1 (D1), (1 0 μM final concentration), described by G H Ladouceur et al in Bioorganic and Medicinal Chemistry Letters, 12 (2002), 3421-3424, was used to determine non-specific binding Following incubation, the reaction was stopped by rapid filtration through Unfιlter-96 GF/C glass fiber filter plates (Perkin Elmer) pre- soaked in 0 5 % polyethyleneimine The filtrate was washed using 50 mM Tris-HCI, pH 74 Dried filter plates containing bound radioactivity were counted in the presence of scintillation fluid (Microscint 0, Perkin-Elmer) using a Topcount scintillation counter Data was analyzed using the software program Prism (GraphPad) IC5O values were calculated using non-linear regression analysis assuming single site competition
Inhibition of Glucaqon-Stimulated Intracellular cAMP Assay
Chinese hamster ovary (CHO) cells expressing the recombinant human glucagon receptor were harvested with the aid of non-enzymatic cell dissociation solution (GIBCO 13151-014) The cells were then pelleted and suspended in the stimulation buffer (1 X HBSS, 5 mM Hepes, 0 1% BSA, pH7 4 in presence of complete protease inhibitor and phosphodiesterase inhibitor) The adenylate cyclase assay was conducted following the LANCE cAMP Kit (Perkin Elmer, AD0262) instructions Briefly, cells were preincubated with anti-cAMP antibody in the stimulation buffer with a final concentration of 3% DMSO for 30 minutes and then stimulated with 300 pM glucagon for 45 minutes The reaction was stopped by incubating with the detection buffer containing Europium chelate of the Eu-SA/Bιotιn- cAMP tracer for 20 hours The fluorescence intensity emitted from the assay was measured at 665 nm using PheraStar instruments Basal activity (100% inhibition) was determined using the DMSO control and 0% inhibition was defined as cAMP stimulation produced by 300 pM glucagon Standard cAMP concentrations were conducted concurrently for conversion of fluorescence signal to cAMP level Data was analyzed using GraphPad Prism IC50 values were calculated using non-linear regression analysis assuming single site competition IC50 values for all of the compounds of the invention shown in the examples measured less than about 10 μM in this functional assay Some of the compounds of the invention shown in the examples measured less than about 5 μM in this assay, other examples measured less than about 500 nM, others less than about 100 nM The IC50 results in this assay are given below for the indicated compound
Figure imgf000362_0001
Figure imgf000363_0001
In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of the invention described above in combination with a pharmaceutically acceptable carrier In another embodiment, the present invention provides a method for inhibiting glucagon receptors comprising exposing an effective amount of a compound or a composition comprising a compound of the invention to glucagon receptors In one embodiment, said glucagon receptors are part of a glucagon receptor assay Non - limiting examples of such assays include glucagon receptor assays and glucagon- stπmuloated intracellular cAMP formation assays such as those described above In one embodiment, said glucagon receptors are expressed in a population of cells In one embodiment, the population of cells is in in vitro In one embodiment, the population of cells is in ex vivo In one embodiment, the population of cells is in a patient Methods of Treatment. Compositions, and Combination Therapy
In another embodiment, the present invention provides a method of treating type 2 diabetes mellitus in a patient in need of such treatment comprising administering to said patient a compound of the invention or a composition comprising a compound of the invention in an amount effective to treat type 2 diabetes mellitus In another embodiment, the present invention provides a method of delaying the onset of type 2 diabetes mellitus in a patient in need of such treatment comprising administering to said patient a compound of the invention or a composition comprising a compound of the invention in an amount effective to delay the onset of type 2 diabetes mellitus
In another embodiment, the present invention provides a method of treating hyperglycemia, diabetes, or insulin resistance in a patient in need of such treatment comprising administering to said patient a compound of the invention, or a composition comprising a compound of the invention, in an amount that is effective to treat hyperglycemia, diabetes, or insulin resistance
In another embodiment, the present invention provides a method of treating non-insulin dependent diabetes mellitus in a patient in need of such treatment comprising administering to said patient an anti-diabetic effective amount of a compound of the invention or a composition comprising an effective amount of a compound of the invention
In another embodiment, the present invention provides a method of treating obesity in a patient in need of such treatment comprising administering to said patient a compound of the invention or a composition comprising a compound of the invention in an amount that is effective to treat obesity In another embodiment, the present invention provides a method of treating one or more conditions associated with Syndrome X (also known as metabolic syndrome, metabolic syndrome X, insulin resistance syndome, Reaven's syndrome) in a patient in need of such treatment comprising administering to said patient a compound of the invention or a composition comprising an effective amount of a compound of the invention in an amount that is effective to treat Syndrome X
In another embodiment, the present invention provides a method of treating a lipid disorder in a patient in need of such treatment comprising administering to said patient a compound of the invention, or a composition comprising a compound of the invention, in an amount that is effective to treat said lipid disorder Non-limiting examples of such lipid disorders include dyslipidemia, hyperhpidemia, hypertriglyceridemia, hypercholesterolemia, low HDL and high LDL, and metabolic syndrome
In another embodiment, the present invention provides a method of treating atherosclerosis in a patient in need of such treatment comprising administering to said patient a compound of the invention or a composition comprising a compound of the invention, in an amount effective to treat atherosclerosis
In another embodiment, the present invention provides a method of delaying the onset of, or reducing the risk of developing, atherosclerosis in a patient in need of such treatment comprising administering to said patient a compound of the invention or a composition comprising a compound of the invention, in an amount effective to delay the onset of, or reduce the risk of developing, atherosclerosis
In another embodiment, the present invention provides a method of treating a condition or a combination of conditions selected from hyperglycemia, low glucose tolerance, insulin resistance, obesity, abdominal obesity, lipid disorders, dyshpidemia, hyperhpidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels, high LDL levels, atherosclerosis, atherosclerosis and its sequelae, vascular restenosis, pancreatitis, neurodegenerative disease, retinopathy, nephropathy, neuropathy, Syndrome X and other conditions where insulin resistance is a component, in a patient in need thereof, comprising administering to said patient a compound of the invention, or a composition comprising a compound of the invention, in an amount that is effective to treat said condition or conditions
In another embodiment, the present invention provides a method of delaying the onset of a condition or a combination of conditions selected from hyperglycemia, low glucose tolerance, insulin resistance, obesity, abdominal obesity, lipid disorders, dyshpidemia, hyperhpidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels, high LDL levels, atherosclerosis, atherosclerosis and its sequelae, vascular restenosis, pancreatitis, neurodegenerative disease, retinopathy, nephropathy, neuropathy, Syndrome X and other conditions where insulin resistance is a component, in a patient in need thereof, comprising administering to said patient a compound of the invention, or a composition comprising a compound of the invention, in an amount that is effective to delay the onset said condition or conditions
In another embodiment, the present invention provides a method of reducing the risk of developing a condition or a combination of conditions selected from hyperglycemia, low glucose tolerance, insulin resistance, obesity, abdominal obesity, lipid disorders, dyshpidemia, hyperhpidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels, high LDL levels, atherosclerosis, atherosclerosis and its sequelae, vascular restenosis, pancreatitis, neurodegenerative disease, retinopathy, nephropathy, neuropathy, Syndrome X and other conditions where insulin resistance or hyperglycemia is a component, in a patient in need thereof, comprising administering to said patient a compound of the invention, or a composition comprising a compound of the invention, in an amount that is effective to reduce the risk of developing said condition or conditions
In another embodiment, the present invention provides a method of treating a condition selected from type 2 diabetes mellitus, hyperglycemia, low glucose tolerance, insulin resistance, obesity, abdominal obesity, lipid disorders, dyslipidemia, hyperlipemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels, high LDL levels, atherosclerosis, atherosclerosis and its sequelae, vascular restenosis, pancreatitis, neurodegenerative disease, retinopathy, nephropathy, neuropathy, Syndrome X and other conditions where insulin resistance is a component, in a patient in need thereof, comprising administering to said patient effective amounts of a compound of the invention and one or more additional active agents
Non-limiting examples of such additional active agents include the following DPP-IV inhibitors Non-limiting examples of DPP-IV inhibitors include alogliptin (Takeda), linagliptin, saxagliptin (Brystol-Myers Squibb), sitagliptin (Januvia™, Merck), vildagliptin (Galvus™, Novartis), denagliptin (GlaxoSmithKline), ABT-279 and ABT- 341 (Abbott), ALS-2-0426 (Alantos), ARI-2243 (Aπsaph), Bl-A and Bl-B (Boehπnger Ingelheim), SYR-322 (Takeda), compounds disclosed in US Patent No 6,699,871 , MP-513 (Mitsubishi), DP-893 (Pfizer), RO-0730699 (Roche) and combinations thereof Non-limiting examples of such combinations include Janumet™, a combination of sitagliptin/metformin HCI (Merck)
Insulin sensitizers Non-limiting examples of insulin sensitizers include PPAR agonists and biguanides Non-limiting examples of PPAR agonists include ghtazone and thiaglitazone agents such as rosiglitazone, rosightazone maleate (AVANDIA™, GlaxoSmithKline), pioglitazone, pioglitazone hydrochloride (ACTOS™, Takeda), ciglitazone and MCC-555 (Mitstubishi Chemical Co ), troghtazone and englitazone Non-limiting example of biguanides include phenformin, metformin, metformin hydrochloride (such as GLUCOPHAGE®, Bristol-Myers Squibb), metformin hydrochloride with glyburide (such as GLUCOVANCE™, Bristol-Myers Squibb) and buformin Other non-limiting examples of insulin sensitizers include PTP-1 B inhibitors, and glucokinase activators, such as miglitol, acarbose, and voghbose
Insulin and insulin mimetics Non-limiting examples of orally administrable insulin and insulin containing compositions include AL-401 (Autoimmune), and the compositions disclosed in U S Patent Nos 4,579,730, 4,849,405, 4,963,526, 5 642,868, 5,763,396, 5,824,638, 5,843,866, 6,153,632, 6,191 ,105, and International Publication No WO 85/05029, each of which is incorporated herein by reference
Sulfonylureas and other insulin secretagogues Non-limiting examples of sulfonylureas and other secretagogues include glipizide, tolbutamide, glyburide, glimepiπde, chlorpropamide, acetohexamide, gliamihde, gliclazide, glibenclamide tolazamide, GLP-1 , GLP-1 mimetics, exendin, GIP, secretin, nateglmide, meglitinide, glibenclamide, and repaglinide Non-limiting examples of GLP-1 mimetics include Byetta™ (exenatide), hraglutide, CJC-1131 (ConjuChem), exenatide-LAR (Amylin), BIM-51077 (Ipsen/LaRoche), ZP-10 (Zealand Pharmaceuticals), and compounds disclosed in International Publication No WO 00/07617
Glucosidase inhibitors and alpha glucosidase inhibitors
Glucagon receptor antagonists other than compounds of the invention
Hepatic glucose output lowering agents other than a glucagon receptor antagonist Non-limiting examples of hepatic glucose output lowering agents include Glucophage and Glucophage XR
An antihypertensive agent Non-limiting examples of antihypertensive agents include beta-blockers and calcium channel blockers (for example diltiazem, verapamil, nifedipine, amlopidine, and mybefradil), ACE inhibitors (for example captopril, lismopril, enalapπl, spirapnl, ceranopril, zefenopπl, fosinopnl, cilazopril, and quinapril), AT-1 receptor antagonists (for example losartan, irbesartan, and valsartan), renin inhibitors and endothelin receptor antagonists (for example sitaxsentan)
A meglitinide Non-limiting examples of meglitinides useful in the present methods for treating diabetes include repaglinide and nateglmide
An agent that blocks or slows the breakdown of starches or sugars in vivo Non limiting examples of antidiabetic agents that slow or block the breakdown of starches and sugars in vivo include alpha-glucosidase inhibitors and certain peptides for increasing insulin production, Alpha-glucosidase inhibitors (which help the body to lower blood sugar by delaying the digestion of ingested carbohydrates, thereby resulting in a smaller rise in blood glucose concentration following meals) Non- limiting examples of alpha-glucosidase inhibitors include acarbose, miglitol, camiglibose, certain polyamines as disclosed in WO 01/47528 (incorporated herein by reference), and voglibose
Peptides for increasing insulin production Non-limiting examples of suitable peptides for increasing insulin production including amlintide (CAS Reg No 122384- 88-7, Amylin), pramhntide, exendin, certain compounds having Glucagon-like peptide- 1 (GLP-1) agonistic activity as disclosed in WO 00/07617 (incorporated herein by reference)
A histamine H3 receptor antagonist Non-limiting examples of histamine H3 receptor antagonist agents include the following compound
Figure imgf000368_0001
A sodium glucose uptake transporter 2 (SGLT-2) inhibitor Non-limiting examples of SGLT-2 inhibitors useful in the present methods include dapagliflozin and serglif lozin, AVE2268 (Sanofi-Aventis) and T- 1095 (Tanabe Seiyaku)
PACAP (pituitary adenylate cyclase activating polypeptide agonists) and PACAP mimetics Cholesterol lowering agents Non-limiting examples of cholesterol lowering agents include HMG-CoA reducatase inhibitors, sequestrants, nicotmyl alcohol, nicotinic acid and salts thereof, PPAR alpha agonists, PPAR alpha/gamma dual agonists, inhibitors of cholesterol absorption (such as ezetimibe (Zetia®)), combinations of HMG-CoA reductase inhibitors and cholesterol absorption agents (such as Vytorin®), acyl CoA cholesterol acyltransferase inhibitors, anti-oxidants, LXR modulators, and CETP (cholesterolester transfer protein) inhibitors such as Torcetrapib™ (Pfizer) and Anacetrapib™ (Merck)
Agents capable of raising serum HDL cholesterol levels Non-limiting examples include niacin (vitamin B-3), such as Niaspan™ (Kos) Niacin may be administered alone or optionally combined with one or more additional active agents such as niacin/lovastatin (Advicor™, Abbott), niacin/simvastatin (Simcor™, Abbott), and/or niacin/aspirin
PPAR delta agonists
Antiobesity agents Non-limiting examples of anti-obesity agents useful in the present methods for treating diabetes include a 5-HT2C agonist, such as lorcaserin, a neuropeptide Y antagonist, an MCR4 agonist, an MCH receptor antagonist, a protein hormone, such as leptin or adiponectin, an AMP kinase activator, and a lipase inhibitor, such as orlistat
Ileal bile acid transporter inhibitors
Anti-inflammatory agents, such as NSAIDs Non-limiting examples of NSAIDS include a salicylate, such as aspirin, amoxiprin, benorilate or diflunisal, an arylalkanoic acid, such as diclofenac, etodolac, indometacin, ketorolac, nabumetone, sulindac or tolmetin, a 2-arylpropιonιc acid (a "profen"), such as ibuprofen, carprofen, fenoprofen, flurbiprofen, loxoprofen, naproxen, tiaprofenic acid or suprofen, a fenamic acid, such as mefenamic acid or meclofenamic acid, a pyrazohdine derivative, such as phenylbutazone, azapropazone, metamizole or oxyphenbutazone, a coxib, such as celecoxib, etoricoxib, lumiracoxib or parecoxib, an oxicam, such as piroxicam, lornoxicam, meloxicam or tenoxicam, or a sulfonamide, such as nimesulide
Anti-pain medications, including NSAIDs as discussed above, and opiates Non-limiting examples of opiates include an anilidopiperidine, a phenylpipendine, a diphenylpropylamine derivative, a benzomorphane derivative, an oπpavine derivative and a morphinane derivative Additional illustrative examples of opiates include morphine, diamorphine, heroin, buprenorphme, dipipanone, pethidine, dextromoramide, alfentanil, fentanyl, remifentanil, methadone, codeine, dihydrocodeine, tramadol, pentazocine, vicodin, oxycodone, hydrocodone, percocet, percodan, norco, dilaudid, darvocet or lorcet
Antidepressants Non-limiting examples of tricyclic antidepressants useful in the present methods for treating pain include amitryptyline, carbamazepine, gabapentin or pregabalm
Protein tyrosine phosphatase-1 B (PTP-1 B) inhibitors CB1 antagonists/inverse agonists Non-limiting examples of CB1 receptor antagonists and inverse agonists include rimonabant and those disclosed in WO03/077847A2, published 9/25/2003, WO05/000809, published 1/6/2005, and WO2006/060461 , published June 8, 2006
In another embodiment, the present invention provides a method of treating a condition selected from hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperhpidemia, hypertriglyceridemia, and dyslipidemia, in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount or amounts of a compound of the invention, or a composition comprising a compound of the invention, and an HMG-CoA reductase inhibitor
In another embodiment, the present invention provides a method of treating a condition selected from hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperlipemia, hypertriglyceridemia, and dyslipidemia, in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount or amounts of a compound of the invention, or a composition comprising a compound of the invention, and an HMG-CoA reductase inhibitor, wherein the HMG-CoA reductase inhibitor is a statin In another embodiment, the present invention provides a method of treating a condition selected from hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperhpidemia, hypertriglyceridemia, and dyslipidemia, in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount or amounts of a compound of the invention, or a composition comprising a compound of the invention, and an HMG-CoA reductase inhibitor, wherein the HMG-CoA reductase inhibitor is a statin selected from lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, itavastatin, ZD-4522, and rivastatin In another embodiment, the present invention provides a method of reducing the risk of developing, or delaying the onset of, a condition selected from hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperhpidemia, hypertriglyceridemia, and dyslipidemia, in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount or amounts of a compound of the invention, or a composition comprising a compound of the invention, and an HMG-CoA reductase inhibitor In another embodiment, the present invention provides a method of reducing the risk of developing, or delaying the onset of, a condition selected from hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperhpidemia, hypertriglyceridemia, and dyslipidemia, in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount or amounts of a compound of the invention, or a composition comprising a compound of the invention, and an HMG-CoA reductase inhibitor, wherein the HMG-CoA reductase inhibitor is a statin
In another embodiment, the present invention provides a method of reducing the risk of developing, or delaying the onset of, a condition selected from hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperhpidemia, hypertriglyceridemia, and dyshpidemia, in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount or amounts of a compound of the invention, or a composition comprising a compound of the invention, and an HMG-CoA reductase inhibitor, wherein the HMG-CoA reductase inhibitor is a statin selected from lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, itavastatin, ZD-4522, and rivastatin In another embodiment, the present invention provides a method of reducing the risk of developing, or delaying the onset of atherosclerosis, high LDL levels, hyperhpidemia, and dyslipidemia, in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount or amounts of a compound of the invention, or a composition comprising a compound of the invention, and a cholesterol absorption inhibitor, optionally in further combination with a statin In another embodiment, the present invention provides a method of reducing the risk of developing, or delaying the onset of atherosclerosis, high LDL levels, hyperhpidemia, and dyshpidemia, in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount or amounts of a compound of the invention, or a composition comprising a compound of the invention, and a cholesterol absorption inhibitor, optionally in further combination with one or more statins, wherein the cholesterol absorption inhibitor is selected from ezetimibe, ezetimibe/simvastatin combination (Vytorin®), and a stanol
In another embodiment, the present invention provides a pharmaceutical composition comprising (1 ) a compound according to the invention, (2) one or more compounds or agents selected from DPP-IV inhibitors, insulin sensitizers, insulin and insulin mimetics, a sulfonylurea, an insulin secretagogue, a glucosidase inhibitor, an alpha glucosidase inhibitor a glucagon receptor antagonists other than a compound of the invention, a hepatic glucose output lowering agent other than a glucagon receptor antagonist, an antihypertensive agent, a meglitimde, an agent that blocks or slows the breakdown of starches or sugars in vivo, an alpha-glucosidase inhibitor, a peptide capable of increasing insulin production, a histamine H3 receptor antagonist, a sodium glucose uptake transporter 2 (SGLT-2) inhibitor, a peptide that increases insulin production, a GIP cholesterol lowering agent, a PACAP, a PACAP mimetic, a PACAP receptor 3 agonist, a cholesterol lowering agent, a PPAR delta agonist, an antiobesity agent, an ileal bile acid transporter inhibitor, an anti-inflammatory agent, an anti-pain medication, an antidepressant, a protein tyrosine phosphatase-1 B (PTP- 1 B) inhibitor, a CB1 antagonist, and a CB1 inverse agonist, and (3) one or more pharmaceutically acceptable carriers
When administering a combination therapy to a patient in need of such administration, the therapeutic agents in the combination, or a pharmaceutical composition or compositions comprising the therapeutic agents, may be administered in any order such as, for example, sequentially, concurrently, together, simultaneously and the like The amounts of the various actives in such combination therapy may be different amounts (different dosage amounts) or same amounts (same dosage amounts)
In one embodiment, the one or more compounds of the invention is administered during at time when the additional therapeutic agent(s) exert their prophylactic or therapeutic effect, or vice versa
In another embodiment, the one or more compounds of the invention and the additional therapeutic agent(s) are administered in doses commonly employed when such agents are used as monotherapy for treating a condition In another embodiment, the one or more compounds of the invention and the additional therapeutic agent(s) are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating a condition
In still another embodiment, the one or more compounds of the invention and the additional therapeutic agent(s) act synergistically and are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating a condition
In one embodiment, the one or more compounds of the invention and the additional therapeutic agent(s) are present in the same composition In one embodiment, this composition is suitable for oral administration In another embodiment, this composition is suitable for intravenous administration
The one or more compounds of the invention and the additional therapeutic agent(s) can act additively or synergistically A synergistic combination may allow the use of lower dosages of one or more agents and/or less frequent administration of one or more agents of a combination therapy A lower dosage or less frequent administration of one or more agents may lower toxicity of the therapy without reducing the efficacy of the therapy In one embodiment, the administration of one or more compounds of the invention and the additional therapeutic agent(s) may inhibit the resistance of a condition to the agent(s)
In one embodiment, when the patient is treated for diabetes, a diabetic complication, impaired glucose tolerance or impaired fasting glucose, the other therapeutic is an antidiabetic agent which is not a compound of the invention In another embodiment, when the patient is treated for pain, the other therapeutic agent is an analgesic agent which is not a compound of the invention
In another embodiment, the other therapeutic agent is an agent useful for reducing any potential side effect of a compound of the invention Non-limiting examples of such potential side effects include nausea, vomiting, headache, fever, lethargy, muscle aches, diarrhea, general pain, and pain at an injection site In one embodiment, the other therapeutic agent is used at its known therapeutically effective dose In another embodiment, the other therapeutic agent is used at its normally prescribed dosage In another embodiment, the other therapeutic agent is used at less than its normally prescribed dosage or its known therapeutically effective dose
The doses and dosage regimen of the other agents used in the combination therapies of the present invention for the treatment or prevention of a condition described herein can be determined by the attending clinician, taking into consideration the the approved doses and dosage regimen in the package insert, the age, sex and general health of the patient, and the type and severity of the viral infection or related disease or disorder When administered in combination, the compound(s) of the invention and the other agent(s) for treating diseases or conditions listed above can be administered simultaneously or sequentially This is particularly useful when the components of the combination are given on different dosing schedules, e g , one component is administered once daily and another every six hours, or when the preferred pharmaceutical compositions are different, e g one is a tablet and one is a capsule A kit comprising the separate dosage forms is therefore advantageous
Generally, a total daily dosage of the one or more compounds of the invention and the additional therapeutic agent(s) can, when administered as combination therapy, range from about 0 1 to about 2000 mg per day, although variations will necessarily occur depending on the target of the therapy, the patient and the route of administration In one embodiment, the dosage is from about 0 2 to about 100 mg/day, administered in a single dose or in 2-4 divided doses In another embodiment, the dosage is from about 1 to about 500 mg/day, administered in a single dose or in 2-4 divided doses In another embodiment, the dosage is from about 1 to about 200 mg/day, administered in a single dose or in 2-4 divided doses In still another embodiment, the dosage is from about 1 to about 100 mg/day, administered in a single dose or in 2-4 divided doses In yet another embodiment, the dosage is from about 1 to about 50 mg/day, administered in a single dose or in 2-4 divided doses In a further embodiment, the dosage is from about 1 to about 20 mg/day, administered in a single dose or in 2-4 divided doses
As indicated above, in one embodiment, the invention provides compositions comprising an effective amount of one or more compounds of the invention or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, and a pharmaceutically acceptable carrier
For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient Suitable solid carriers are known in the art, e g magnesium carbonate, magnesium stearate, talc, sugar or lactose Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A Gennaro (ed ), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co , Easton, PA
Liquid form preparations include solutions, suspensions and emulsions As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions Liquid form preparations may also include solutions for intranasal administration
Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e g nitrogen
Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration Such liquid forms include solutions, suspensions and emulsions
The compounds of the invention may also be deliverable transdermal^ The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose
In one embodiment, the compound of the invention is administered orally
In another embodiment, the compound of the invention is administered parenterally
In another embodiment, the compound of the invention is administered intravenously
In one embodiment, the pharmaceutical preparation is in a unit dosage form In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e g , an effective amount to achieve the desired purpose
The quantity of active compound in a unit dose of preparation is from about 0 1 to about 2000 mg Variations will necessarily occur depending on the target of the therapy, the patient and the route of administration In one embodiment, the unit dose dosage is from about 0 2 to about 1000 mg In another embodiment, the unit dose dosage is from about 1 to about 500 mg In another embodiment, the unit dose dosage is from about 1 to about 100 mg/day In still another embodiment, the unit dose dosage is from about 1 to about 50 mg In yet another embodiment, the unit dose dosage is from about 1 to about 10 mg The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated Determination of the proper dosage regimen for a particular situation is within the skill of the art For convenience, the total daily dosage may be divided and administered in portions during the day as required
The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated A typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 300 mg/day, preferably 1 mg/day to 75 mg/day, in two to four divided doses When the invention comprises a combination of at least one compound of the invention and an additional therapeutic agent, the two active components may be coadministered simultaneously or sequentially, or a single pharmaceutical composition comprising at least one compound of the invention and an additional therapeutic agent in a pharmaceutically acceptable carrier can be administered The components of the combination can be administered individually or together in any conventional dosage form such as capsule, tablet, powder, cachet, suspension, solution, suppository, nasal spray, etc The dosage of the additional therapeutic agent can be determined from published material, and may range from about 1 to about 1000 mg per dose In one embodiment, when used in combination, the dosage levels of the individual components are lower than the recommended individual dosages because of the advantageous effect of the combination
Thus, the term "pharmaceutical composition" is also intended to encompass both the bulk composition and individual dosage units comprised of more than one (e g , two) pharmaceutically active agents such as, for example, a compound of the present invention and an additional agent selected from the various the additional agents described herein, along with any pharmaceutically inactive excipients The bulk composition and each individual dosage unit can contain fixed amounts of the afore-said "more than one pharmaceutically active agents" The bulk composition is material that has not yet been formed into individual dosage units An illustrative dosage unit is an oral dosage unit such as tablets, pills and the like Similarly, the herein-described method of treating a patient by administering a pharmaceutical composition of the present invention is also intended to encompass the administration of the afore-said bulk composition and individual dosage units
In one embodiment, the components of a combination therapy regime are to be administered simultaneously, they can be administered in a single composition with a pharmaceutically acceptable carrier
In another embodiment, when the components of a combination therapy regime are to be administered separately or sequentially, they can be administered in separate compositions, each containing a pharmaceutically acceptable carrier
The components of the combination therapy can be administered individually or together in any conventional dosage form such as capsule, tablet, powder, cachet, suspension, solution, suppository, nasal spray, etc
Kits
In one embodiment, the present invention provides a kit comprising a effective amount of one or more compounds of the invention, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier, vehicle or diluent In another aspect the present invention provides a kit comprising an amount of one or more compounds of the invention, or a pharmaceutically acceptable salt or solvate thereof, and an amount of at least one additional therapeutic agent described above, wherein the combined amounts are effective for treating or preventing a condition described herein in a patient When the components of a combination therapy regime are to are to be administered in more than one composition, they can be provided in a kit comprising in a single package, one container comprising a compound of the invention in pharmaceutically acceptable carrier, and one or more separate containers, each comprising one or more additional therapeutic agents in a pharmaceutically acceptable carrier, with the active components of each composition being present in amounts such that the combination is therapeutically effective
The present invention is not to be limited by the specific embodiments disclosed in the examples that are intended as illustrations of a few aspects of the invention and any embodiments that are functionally equivalent are within the scope of this invention Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims
A number of references have been cited herein, the entire disclosures of which are incorporated herein by reference.

Claims

WE CLAIM:
1. A compound, or a pharmaceutically acceptable salt, solvate, tautomer, or isomer of said compound, said compound having the general structure shown in Formula (A):
Figure imgf000379_0001
(A) wherein ring A, ring B, L1, L2, R1, R3, and Z are selected independently of each other and wherein:
L1 is selected from the group consisting of a bond, -N(R4)-, -N(R4)-(C(R5A)2)-(C(R5)2)q-) -(C(R5A)2)-(C(R5)2)r-(C(R5A)2)-N(R4)-, -O-, -O-(C(R5A)2)-(C(R5)2)q-, -(C(R5A)2)-(C(R5)2)r-(C(R5A)2)-O-, and -(C(R5A)2)-(C(R5)2)S-, each q is independently an integer from 0 to 5; each r is independently an integer from 0 to 3; s is an integer from 0 to 5;
L2 is selected from the group consisting of a bond, -N(R4)-, -N(R4)-(C(R5A)2)-(C(R5)2),-, -(C(R5)2)U-(C(R5A)2)-N(R4)-, -O-, -O-(C(R5A)2)-(C(R5)2)r, -(C(R5)2)U-(C(R5A)2)-O-, -S-, -S-(C(R5A)2)-(C(R5)2)Γ, -(C(R5)2)u-(C(R5A)2)-S-, -S(O)-, -S(O)-(C(R5A)2)-(C(R5)2),-, -(C(R5)2)U-(C(R5A)2)-S(O)-, -S(O)2-, -S(O)2-(C(R5A)2)-(C(R5)2)r, -(C(R5)2)U-(C(R5A)2)-S(O)2-, -(C(R5)2)V-; each t is independently an integer from 0 to 3; each u is independently an integer from 0 to 3; v is an integer from 1 to 5; ring A represents a spirocycloalkyl ring or a spirocycloalkenyl ring, wherein said ring A is substituted on one or more available ring carbon atoms with from 0 to 5 independently selected R2 groups, or, alternatively, ring A represents a spiroheterocycloalkyl ring or a spiroheterocycloalkenyl ring, wherein said ring A is substituted on one or more available ring carbon atoms with from 0 to 5 independently selected R2 groups, and wherein said ring A is optionally further substituted on one or more available ring nitrogen atoms (when present) with from 0 to 3 R2A groups; ring B is a phenyl ring, wherein said phenyl ring is (in addition to the -L1- and -C(O)N(R3)-Z moieties shown) optionally further substituted with one or more substituents Ra, wherein each Ra (when present) is independently selected from the group consisting of halo, -OH, -SF5, -OSF5, alkyl, haloalkyl, heteroalkyl, hydroxyalkyl, alkoxy, and -O-haloalkyl, or ring B is a 5-membered heteroaromatic ring containing from 1 to 3 ring heteroatoms independently selected from N, O, and S, wherein said 5-membered heteroaromatic ring is (in addition to the -L1- and -C(O)N(R3)-Z moieties shown) optionally further substituted with one or more substituents Ra, wherein each Ra (when present) is independently selected from the group consisting of halo, -OH, -SF5, -OSF5, alkyl, haloalkyl, heteroalkyl, hydroxyalkyl, alkoxy, and -O-haloalkyl, or ring B is a 6-membered heteroaromatic ring containing from 1 to 3 ring nitrogen atoms, wherein said 6-membered heteroaromatic ring is (in addition to -L1- and -C(0)N(R3)Z moieties shown) optionally further substituted with one or more substituents Ra, wherein each Ra (when present) is independently selected from the group consisting of halo, -OH, -SF5, -OSF5, alkyl, haloalkyl, hydroxyalkyl, alkoxy, and - O-haloalkyl;
R1 is independently selected from the group consisting of aryl and heteroaryl, wherein said aryl and said heteroaryl of R1 are unsubstituted or substituted with one or more groups independently selected from:
(1) halo, -OH, -CO2R6, -C(O)R6, -SR7, -S(O)R7, -SO2R7, -SF5, -OSF5, CN, NO2, -C(O)NR8R9, -NR8R9, -NR10-C(O)-NR8R9, -NR10-CO2R6, -NR10-C(O)R6, -NR10-SO2R6, -SO2-NR8R9, -C(O)NR8R9, and -OC(O)NR8R9,
(2) alkyl, alkoxy, heteroalkyl, -O-heteroalkyl, alkenyl, heteroalkenyl, alkynyl, and heteroalkynyl, wherein each of said alkyl, alkoxy, heteroalkyl, -O-heteroalkyl, alkenyl, heteroalkenyl, alkynyl, and heteroalkynyl, are unsubstituted or optionally independently substituted with one or more groups each independently selected from: halo, OH, -CO2R6, -C(O)R6, -SR7, -S(O)R7, -SO2R7, CN, NO2, -C(O)NR8R9, -NR8R9, -O-haloalkyl, - NR10-C(O)-NR8R9, -NR10-CO2R6, -NR10-C(0)R6, -NR10-SO2R6, -SO2-NR8R9, -C(O)NR8R9, and -OC(O)NR8R9, and
(3) aryl, -O-aryl, -C(O)-aryl, -S-aryl, -S(O)-aryl, -S(O)2-aryl, -N(R4)-aryl, -C(O)-N(R4)-aryl, -N(R4)-C(O)-aryl, heteroaryl, -0-heteroaryl, -C(O)-heteroaryl, -S-heteroaryl, -S(O)-heteroaryl, -S(O)2-heteroaryl, -N(R4)-heteroaryl, -C(O)-N(R4)-heteroaryl, -N(R4)-C(O)-heteroaryl, cycloalkyl, -O- cycloalkyl, -C(O)- cycloalkyl, -S-cycloalkyl, -S(O)-cycloalkyl, -S(O)2-cycloalkyl, -N(R4)- cycloalkyl, -C(O)-N(R4)-cycloalkyl, -N(R4)-C(O)-cycloalkyl, heterocycloalkyl, -O- heterocycloalkyl, -C(O)- heterocycloalkyl, -S-heterocycloalkyl, -S(O)-heterocycloalkyl, -S(O)2-heterocycloalkyl, -N(R4)-heterocycloalkyl, -C(O)-N(R4)-heterocycloalkyl, -N(R4)-C(O)-heterocycloalkyl, cycloalkenyl, -O- cycloalkenyl, -C(O)- cycloalkenyl, -S-cycloalkenyl, -S(O)-cycloalkenyl, -S(O)2-cycloalkenyl, -N(R4)-cycloalkenyl, -C(O)-N(R4)-cycloalkenyl, -N(R4)-C(O)-cycloalkenyl, heterocycloalkenyl, -O- heterocycloalkenyl, -C(O)-heterocycloalkenyl, -S-heterocycloalkenyl, -S(O)-heterocycloalkenyl, -S(O)2-heterocycloalkenyl, -N(R4)-heterocycloalkenyl, -C(O)-N(R4)-heterocycloalkenyl, and -N(R4)-C(O)-heterocyctoalkenyl, each of which is unsubstituted or optionally independently substituted with from 1 to 2 groups each independently selected from (1) and (2) above; each R2 (when present) is independently selected from the group consisting of: (a) phenyl substituted with from 0 to 5 groups independently selected from -OH, halo, alkyl, haloalkyl, hydroxyalkyl, alkyl substituted with from 1 to 2 -CO2R6 groups, alkoxy, -O-haloalkyl, hydroxyalkoxy, alkoxy substituted with from 1 to 2 -CO2R6 groups, -C(O)R6, -CO2R6, CN, -SO2R7, -SF5, -OSF5, -C(O)NR8R9, and -NO2,
(b) alkyl or heteroalkyl, each substituted with from O to 5 groups independently selected from -OH, oxo, halo, heteroalkyl, deuteroalkyl, alkoxy, -O-haloalkyl, -CO2R6, and phenyl substituted with from O to 5 groups independently selected from -OH, halo, aryl, substituted aryl, alkyl, alkoxy, heteroalkyl, haloalkyl, -O-haloalkyl, haloheteroalkyl, -CO2R6, CN, -S(O)R7, -S(O)2R7, -SF5, -OSF5, -C(O)NR8R9, and -NO2,
(C) -NR10-C(O)-NR8R9, -NR10-CO2R6, -NR10-C(0)R6, -NR8R9, -NR10SO2R6, -SO2-NR8R9, -C(O)NR8R9, and -OC(O)-NR8R9;
(d) cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, each substituted with from O to 5 groups independently selected from -OH, oxo, halo, heteroalkyl, alkoxy, -O-haloalkyl, -CO2R6, and phenyl substituted with from O to 5 groups independently selected from -OH, halo, aryl, substituted aryl, alkyl, alkoxy, heteroalkyl, haloalkyl, -O-haloalkyl, haloheteroalkyl, -CO2R6, CN, -S(O)R7, -S(O)2R7, -SF5, -OSF5, -C(O)NR8R9, -NR10-C(O)R6, -SO2-NR8R9, and -NO2,
(e) heteroaryl substituted from O to 5 groups independently selected from -OH, oxo, halo, heteroalkyl, alkoxy, -O-haloalkyl, -CO2R6, and phenyl substituted with from O to 5 groups independently selected from -OH, halo, aryl, substituted aryl, alkyl, alkoxy, heteroalkyl, haloalkyl, -O-haloalkyl, haloheteroalkyl, -CO2R6, CN, -S(O)R7, -S(O)2R7, -C(O)NR8R9, -NR10-C(O)R6, -SO2-NR8R9, -SF5, -OSF5, and -NO2, and
(f) -Si(alkyl)3; or, alternatively, two R2 groups attached to the same atom of ring A are taken together to form a moiety selected from the group consisting of carbonyl, oxime, substituted oxime (said oxime substituents being independently selected from the group consisting of alkyl, haloalkyl, hydroxyl-substituted alkyl, and cycloalkyl), spirocycloalkyl, spiroheterocycloalkyl, spirocycloalkenyl, and spiroheterocycloalkenyl; or, alternatively, two R2 groups attached to adjacent ring atoms of ring A are taken together to form a 5-6-membered aromatic or heteroaromatic ring; each R2A (when present) is independently selected from the group consisting of -C(O)NR8R9, -CO2R6, -C(O)R6,-SO2R7, alkyl, heteroalkyl, haloalkyl, hydroxyl- substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl-, heteroaryl, R3 is selected from H and lower alkyl; Z is a moiety selected from -(C(R11)2)-(C(R12R13))m-C(O)OH, -(C(R11)2)-(C(R14)2)n-C(O)OHI from -(C(R11)2)-(C(R12R13))m-C(O)Oalkyl)
-(C(R11)2)-(C(R14)2)n-C(O)Oalkyl,
Figure imgf000383_0001
-(C(R11)2HC(R12R13))m-Q, and -(C(R11)2)-(C(R14)2)n-Q, wherein Q is a moiety selected from the group consisting of:
Figure imgf000383_0002
, and
Figure imgf000383_0003
Figure imgf000383_0004
; m is an integer from O to 5; n is an integer from O to 5; p is an integer from O to 5;
each R4 is independently selected from H, -OH, lower alkyl, haloalkyl, alkoxy, heteroalkyl, cyano-substituted lower alkyl, hydroxy-substituted lower alkyl, cycloalkyl, -O-cycloalkyl, -O-alkyl-cycloalkyl, and heterocycloalkyl, -O-heterocycloalkyl, and -O-alkyl-heterocycloalkyl; each R5A is independently selected from H, alkyl, -alkyl-Si(CH3)3, haloalkyl, heteroalkyl, cyano-substituted alkyl, hydroxy-substituted alkyl, cycloalkyl, -alkyl-cycloalkyl, and heterocycloalkyl, -alkyl-heterocycloalkyl, or, alternatively, two R5A groups are taken together with the carbon atom to which they are attached to form a carbonyl group, a spirocycloalkyl group, a spiroheterocycloalkyl group, an oxime group, or a substituted oxime group (said oxime substituents being independently selected from alkyl, haloalkyl, hydroxyl-substituted alkyl, and cycloalkyl); each R5 is independently selected from H, -OH, alkyl, -alkyl-Si(CH3)3, haloalkyl, alkoxy, heteroalkyl, cyano-substituted alkyl, hydroxy-substituted alkyl, cycloalkyl, -alkyl-cycloalkyl, -O-cycloalkyl, -O-alkyl-cycloalkyl, and heterocycloalkyl, -alkyl-heterocycloalkyl, -O-heterocycloalkyl, and -O-alkyl-heterocycloalkyl, or, alternatively, two R5 groups bound to the same carbon atom are taken together with the carbon atom to which they are attached to form a carbonyl group, a spirocycloalkyl group, a spiroheterocycloalkyl group, an oxime group, or a substituted oxime group (said oxime substituents being independently selected from alkyl, haloalkyl, hydroxyl-substituted alkyl, and cycloalkyl); each R6 is independently selected from H, alkyl, haloalkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, and heteroalkynyl; each R7 is independently selected from H, alkyl, heteroalkyl, and haloalkyl; each R8 is independently selected from H and alkyl; each R9 is independently selected from H and alkyl, or alternatively R8 and R9 are taken together with the nitrogen to which they are attached to form a 5-, 6-, or 7-membered saturated heterocyclic ring, or a 5-, 6-, or 7- membered unsaturated heterocyclic ring, which ring contains (including said nitrogen) from 1 to 2 ring heteroatoms each independently selected from N, N-oxide, O, S, S(O), or S(O)2, or alternatively R8 and R9 are taken together with the nitrogen to which they are attached to form a 5-membered heteroaromatic ring containing (including the nitrogen to which R8 and R9 are attached) from 1 to 3 ring nitrogens; each R10 is independently selected from H and alkyl; each R11 is independently selected from H and lower alkyl; each R12 is independently selected from H, lower alkyl, -OH, hydroxy- substituted lower alkyl; each R13 is independently selected from H, unsubstituted lower alkyl, lower alkyl substituted with one or more groups each independently selected from hydroxyl and alkoxy, or R and R are taken together to form an oxo; and each R14 is independently selected from H and fluoro.
2. A compound of claim 1 , or a pharmaceutically acceptable salt, solvate, tautomer, or isomer of said compound, said compound having the general structure shown in Formula (A-1):
Figure imgf000385_0001
(A-I).
3. A compound of claim 1 , or a pharmaceutically acceptable salt, solvate, tautomer, or isomer of said compound, said compound having the general structure shown in Formula (A-1a):
Figure imgf000386_0001
(A-Ia).
4. A compound of claim 1 , or a pharmaceutically acceptable salt, solvate, tautomer, or isomer of said compound, said compound having the general structure shown in Formula (A-1b):
Figure imgf000386_0002
(A-1 b). 386
5. A compound according to Claim 1 , or a pharmaceutically acceptable salt, solvate, tautomer, or isomer of said compound, said compound having the general structure shown in Formula (I):
Figure imgf000387_0001
(I) wherein ring A, L1, L2, R1, R3, and Z are selected independently of each other and wherein:
L1 is selected from the group consisting of: a bond, -N(R4)-, -N(R4)-(C(R5A)2)-, -O-, -O-(C(R5A)2)-, and -(C(R5A)2)-(C(R5)2)S-; s is 0-3;
L2 is selected from the group consisting of bond, -N(R4)-, -N(R4)-(C(R5A)2)-, -(C(R5A)2)-N(R4)-, -(C(R5)2)U-(C(R5A)2)-N(R4)-, -O-, -O-(C(R5A)2)-, -(C(R5A)2)-O- and -(C(R5)2)v-, wherein u is 0 to 2 and v is 1-3;
R3 is selected from the group consisting of H and lower alkyl;
Z is a moiety selected from -(C(R11)2)-(C(R12R13))m-C(O)OH, -(C(R11)2)-(C(R14)2)n-C(O)OH, and
Figure imgf000387_0002
m is an integer from 0 to 5; n is an integer from 0 to 5; p is an integer from 0 to 5; each R4 is independently selected from H, lower alkyl, cycloalkyl, heterocycloalkyl, heteroalkyl, and haloalkyl; each R5A is independently selected from H, lower alkyl, -lower alkyl-Si(CH3)3, lower haloalkyl, and hydroxy-substituted lower alkyl; each R5 is independently selected from H, -OH, lower alkyl, -lower alkyl-Si(CH3)3, lower haloalkyl, and hydroxy-substituted lower alkyl; each R6 is independently selected from H, alkyl, and haloalkyl; each R7 is independently selected from H, alkyl, heteroalkyl, and haloalkyl; each R8 is independently selected from H and alkyl; each R9 is independently selected from H and alkyl, each R11 is independently selected from H and lower alkyl; each R12 is independently selected from H, lower alkyl, -OH, hydroxy- substituted lower alkyl; each R13 is independently selected from H, unsubstituted lower alkyl, lower alkyl substituted with one or more groups each independently selected from hydroxyl and alkoxy, or R12 and R13 are taken together to form an oxo; and each R14 is independently selected from H and fluoro.
6. A compound of Claim 5, or a pharmaceutically acceptable salt, solvate, tautomer, or isomer of said compound, wherein: ring A represents a spirocycloalkyl ring or a spirocycloalkenyl ring, wherein said ring A is substituted on one or more available ring carbon atoms with from 0 to 5 independently selected R2 groups;
R1 is selected from the group consisting of: aryl and heteroaryl, wherein each of said aryl and said heteroaryl are unsubstituted or substituted with from 1 to 3 groups each independently selected from:
(1 ) halo, -SO2R7, -SF5, -OSF5, CN,
(2) alkyl, alkoxy, heteroalkyl, -O-heteroalkyl, wherein each of said alkyl, alkoxy, heteroalkyl, and -O-heteroalkyl, is unsubstituted or optionally independently substituted with from 1 to 3 groups each independently selected from: halo, OH, -CO2R6, -C(O)R6, -SR7, -S(O)R7, -SO2R7, CN, NO2, -C(O)NR8R9, -NR8R9, -O-haloalkyl, - NR10-C(O)-NR8R9, -NR10-CO2R6, -NR10-C(O)R6, -NR10-SO2R6, -SO2-NR8R9, -C(O)NR8R9, and -OC(O)NR8R9, and
(3) aryl, -0-aryl, -S-aryl, -S(O)-aryl, -S(O)2-aryl, heteroaryl, cycloalkyl, cycloalkenyl, and heterocycloalkenyl, each of which is unsubstituted or optionally independently substituted with from 1 to 2 groups each independently selected from (1 ) and (2) above; and each R2 (when present) is independently selected from the group consisting of -Si(CH3)3 and alkyl, wherein said alkyl is substituted with from 0 to 5 groups independently selected from -OH, oxo, halo, heteroalkyl, alkoxy, -O-haloalkyl, -CO2R6, and phenyl substituted with from O to 5 groups independently selected from -OH, halo, aryl, substituted aryl, alkyl, alkoxy, -O-haloalkyl, heteroalkyl, haloalkyl, haloheteroalkyl, -CO2R6, CN, -S(O)R7, -S(O)2R7, -SF5, -OSF5, -C(O)NR8R9, and -NO2.
7. A compound, or a pharmaceutically acceptable salt, solvate, tautomer, or isomer of said compound, having the general structure shown in Formula (II):
Figure imgf000389_0001
(II) wherein L1, L2, R1, each R2, R3, and Z are selected independently of each other and wherein:
L1 is selected from the group consisting of: a bond, and -(C(R5A)2)-(C(R5)2)S-; s is 0-1 ;
L2 is selected from the group consisting of: a bond, -(C(R5)2)U-(C(R5A)2)-N(R4)-, and -(C(R5)2)v-; u is 0-2; v is 1-2; R1 is selected from the group consisting of: phenyl, wherein said phenyl is unsubstituted or substituted with one or more groups each independently selected from: halo, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, alkoxy, -O-haloalkyl, and cycloalkyl; each R2 is independently selected from the group consisting of -Si(CH3)3 and alkyl, wherein said alkyl is substituted with from 0 to 5 groups independently selected from -OH, halo, alkyl, haloalkyl, hydroxyalkyl, alkyl substituted with from 1 to 2 -CO2R6 groups, alkoxy, -O-haloalkyl, hydroxyalkoxy, alkoxy substituted with from 1 to 2 -CO2R6 groups, -CO2R6, CN, -SO2R7, -C(O)NR8R9, and -NO2;
R3 is selected from the group consisting of H and lower alkyl; Z is a moiety selected from the group consisting of: -(CH2)-(CH(CH3))-C(O)OH, -(CH2)-(CH2)-(CH2)-C(O)OH, -(CH2)-C(CH3)2-C(O)OH, -(CH2)-C(CH3)(OH)-C(O)OH, -CH2-CH2-C(O)OH, -CH2-CH(OH)-C(O)OH, -CH(CH3)-CH2-C(O)OH, -C(CHg)2-CH2-C(O)OH, -CH2-CH(F)-C(O)OH, -CH2-CF2-C(O)OH, -CH(CH3)-
CF2-C(O)OH, -CH2-CH2-CF2-C(O)OH, and
Figure imgf000390_0001
, wherein p is an integer from O to 1 , and R11 (when present) is selected from the group consisting of H and lower alkyl; each R5A is independently selected from H, lower alkyl, -lower alkyl-Si(CH3)3, lower haloalkyl, and lower alkyl substituted with from 1 to 2 hydroxyl; each R5 is independently selected from H, -OH, lower alkyl, -lower alkyl-Si(CH3)3, lower haloalkyl, and lower alkyl substituted with from 1 to 2 hydroxyl; each R6 is independently selected from H, alkyl, and haloalkyl; each R7 is independently selected from H, alkyl, heteroalkyl, and haloalkyl; each R8 is independently selected from H and alkyl; and each R9 is independently selected from H and alkyl.
8. A compound of Claim 7, or a pharmaceutically acceptable salt, solvate, tautomer, or isomer of said compound, said compound having the general structure shown in Formula (ll-a):
Figure imgf000391_0001
(II-a).
9. A compound of Claim 7, or a pharmaceutically acceptable salt, solvate, tautomer, or isomer of said compound, said compound having the general structure shown in Formula (ll-b):
Figure imgf000391_0002
( II-b).
10. A compound of Claim 9, or a pharmaceutically acceptable salt, solvate, tautomer, or isomer of said compound, wherein:
L1 is selected from the group consisting of: a bond, straight or branched lower alkyl, and -CH(lower alkyl-Si(CH3)3)-; L2 is selected from the group consisting of: a bond and straight or branched lower alkyl;
R1 is selected from the group consisting of: phenyl, wherein said phenyl is unsubstituted or substituted with from 1 to
3 groups each independently selected from: halo, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, alkoxy, and
-O-haloalkyl; each R2 is independently selected from the group consisting of H, straight or branched lower alkyl, and -Si(CH3)3;
R3 is selected from the group consisting of H and lower alkyl;
Z is a moiety selected from the group consisting of: -(CH2)-(CH(CH3))-C(O)OH, -(CH2)-(CH2)-(CH2)-C(O)OH, -(CH2)-C(CH3)2-C(O)OH, -(CHa)-C(CH3)(OH)-C(O)OH, -CH2-CH2-C(O)OH, -CH2-CH(OH)-C(O)OH, -CH(CH3)-CH2-C(O)OH, -C(CH3)2-CH2-C(O)OH, -(C(R11)2)-(C(R14)2)n-C(O)OH, -CH2-CH(F)-C(O)OH, -CH2-CF2- C(O)OH, -CH(CHs)-CF2-C(O)OH, -CH2-CH2-CF2-C(O)OH, -(CH2)-(CH(CH3))-C(O)OCH3, -(CH2)-(CH2)-(CH2)-C(O)OCH3, -(CH2)-C(CH3)2-C(O)OCH3, -(CH2)-C(CH3)(OH)-C(O)OCH3, -CH2-CH2-C(O)OCH3, -CH2-CH(OH)-C(O)OCH3, -CH(CH3)-CH2-C(O)OCH3, -C(CH3)2-CH2-C(O)OCH3, -(C(R11)2)-(C(R14)2)n-C(O)OCH3, -CH2-CH(F)-C(O)OCH3, -CH2-CF2-C(O)OCH3, -CH(CH3)-CF2-C(O)OCH3, -CH2-CH2-CF2-C(O)OCH3, and
Figure imgf000392_0001
, wherein p is an integer from O to 1 , and R11 (when present) is selected from the group consisting of H and lower alkyl; each R5 is independently selected from H, -OH, lower alkyl, lower haloalkyl, and lower alkyl substituted with from 1 to 2 hydroxyl; each R6 is independently selected from H, alkyl, and haloalkyl; each R7 is independently selected from H, alkyl, heteroalkyl, and haloalkyl; each R8 is independently selected from H and alkyl; and each R9 is independently selected from H and alkyl.
11. A compound of Claim 10, or a pharmaceutically acceptable salt, solvate, tautomer, or isomer of said compound, wherein:
L1 is selected from the group consisting of: a bond,
Figure imgf000393_0004
,
Figure imgf000393_0005
, and -(CH2)1-3-.
12. A compound of Claim 10, or a pharmaceutically acceptable salt, solvate, tautomer, or isomer of said compound, wherein:
L1 is selected from the group consisting of
Figure imgf000393_0001
Figure imgf000393_0002
Z is selected from the group consisting of -Ch^-CH2-C(O)OH and
Figure imgf000393_0003
, wherein p is 1 and R11 is. H.
13. A compound of claim 1 , or a pharmaceutically acceptable salt or tautomer of said compound, said compound selected from the group consisting of:
Figure imgf000394_0001
Figure imgf000395_0001
Figure imgf000396_0001
Figure imgf000397_0001
Figure imgf000398_0001
Figure imgf000399_0001
Figure imgf000400_0001
Figure imgf000401_0001
Figure imgf000402_0001
Figure imgf000403_0001
Figure imgf000404_0001
Figure imgf000405_0001
Figure imgf000406_0001
Figure imgf000407_0001
Figure imgf000408_0001
Figure imgf000409_0001
Figure imgf000410_0001
Figure imgf000411_0001
Figure imgf000412_0001
Figure imgf000413_0001
Figure imgf000414_0001
Figure imgf000415_0001
Figure imgf000416_0001
Figure imgf000417_0001
Figure imgf000418_0001
Figure imgf000419_0001
Figure imgf000420_0001
Figure imgf000421_0001
Figure imgf000422_0001
Figure imgf000423_0001
Figure imgf000424_0001
Figure imgf000425_0001
Figure imgf000426_0001
Figure imgf000427_0001
Figure imgf000428_0001
Figure imgf000429_0001
Figure imgf000430_0001
Figure imgf000431_0001
Figure imgf000432_0001
Figure imgf000433_0001
Figure imgf000434_0001
Figure imgf000435_0001
Figure imgf000436_0001
Figure imgf000437_0001
Figure imgf000438_0001
Figure imgf000439_0001
Figure imgf000440_0001
Figure imgf000441_0001
Figure imgf000442_0001
Figure imgf000443_0001
Figure imgf000444_0001
Figure imgf000445_0001
Figure imgf000446_0001
Figure imgf000447_0001
Figure imgf000448_0002
14. A compound of claim 1 , or a pharmaceutically acceptable salt or tautomer of said compound, said compound selected from the group consisting of:
Figure imgf000448_0001
Figure imgf000449_0001
Figure imgf000450_0001
Figure imgf000451_0001
Figure imgf000452_0001
Figure imgf000453_0001
Figure imgf000454_0001
15. A compound of claim 1 , or a pharmaceutically acceptable salt or tautomer of said compound, said compound selected from the group consisting of:
Figure imgf000454_0002
Figure imgf000455_0001
Figure imgf000456_0001
Figure imgf000457_0002
16. A compound of claim 1 , or a pharmaceutically acceptable salt or tautomer of said compound, said compound selected from the group consisting of:
Figure imgf000457_0001
Figure imgf000458_0001
Figure imgf000459_0001
17. A compound of claim 1 , or a pharmaceutically acceptable salt or tautomer of said compound, said compound selected from the group consisting of:
Figure imgf000460_0001
18. A compound of claim 1 , or a pharmaceutically acceptable salt or tautomer of said compound, said compound having the structure:
Figure imgf000460_0002
19. A compound of claim 1 , or a pharmaceutically acceptable salt or tautomer of said compound, said compound having the structure:
Figure imgf000461_0002
20. A compound of claim 1 , or a pharmaceutically acceptable salt or tautomer of said compound, said compound having the structure:
Figure imgf000461_0003
21. A compound of claim 1 , or a pharmaceutically acceptable salt or tautomer of said compound, said compound having the structure:
Figure imgf000461_0001
22. A compound of claim 1 , or a pharmaceutically acceptable salt or tautomer of said compound, said compound having the structure:
Figure imgf000461_0004
23. A compound of claim 1 , or a pharmaceutically acceptable salt or tautomer of said compound, said compound having the structure:
Figure imgf000461_0005
Figure imgf000462_0003
24. A compound of claim 1 , or a pharmaceutically acceptable salt or tautomer of said compound, said compound having the structure:
Figure imgf000462_0002
25. A compound of claim 1 , or a pharmaceutically acceptable salt or tautomer of said compound, said compound having the structure:
Figure imgf000462_0001
26. A composition comprising a compound according to any one of claims 1 -25 and a pharmaceutically acceptable carrier.
27. A composition of claim 26, further comprising one or more antidiabetic agents other than a compound of claim 1.
28. A composition of claim 27, further comprising at least one pharmaceutically acceptable carrier.
29. A composition of claim 26, further comprising at least one additional therapeutic agent selected from the group consisting of: DPP-IV inhibitor, an insulin sensitizer, insulin, an insulin mimetic, an insulin secretagogue, a GLP-1 mimetic, a glucosidase inhibitor, an alpha glucosidase inhibitor, a glucagon receptor antagonist other than a compound of claim 1 , glucophage, glucophage XR, an antihypertensive agent, a meglitinide, an alpha-glucosidase inhibitor, amlintide, pramlintide, exendin, a histamine H3 receptor antagonist, dapagliflozin, sergliflozin, AVE2268 (Sanofi-Aventis) and T-1095 (Tanabe Seiyaku), a cholesterol lowering agent, a PACAP, a PACAP mimetic, a PACAP receptor 3 agonist, a PPAR delta agonist, an antiobesity agent, an ileal bile acid transporter inhibitor, an NSAID, and a CB1 receptor antagonist, and a CB1 receptor inverse agonist.
30. A method for treating type 2 diabetes mellitus in a patient in need thereof, comprising administering to said patient at least one compound according to any one of claims 1 -25 in an amount that is effective to treat type 2 diabetes mellitus.
31. A method for delaying the onset of type 2 diabetes mellitus in a patient in need thereof, comprising administering to said patient a composition according to claim 26 in an amount that is effective to delay the onset of type 2 diabetes mellitus.
32. A method for treating hyperglycemia, diabetes, or insulin resistance in a patient in need thereof comprising administering to said patient an effective amount of a composition of claim 26.
33. A method for treating non-insulin dependent diabetes mellitus in a patient in need thereof comprising administering to said patient a composition of claim 26 in an amount that is effective to treat non-insulin dependent diabetes mellitus.
34. A method for treating obesity in a patient in need thereof comprising administering to said patient a composition of claim 26 in an amount that is effective to treat obesity.
35. A method for Syndrome X in a patient in need thereof comprising administering to said patient a composition of claim 26 in an amount that is effective to treat Syndrome X.
36. A method for treating a lipid disorder in a patient in need thereof comprising administering to said patient a composition of claim 26 in an amount that is effective to treat a lipid disorder.
37. A method of claim 36, wherein said lipid disorder is selected from the group consisting of dyslipidemia, hyperlipidemia, hypertriglyceridemia, low HDL and high LDL, and hypercholesterolemia.
38. A method for treating atherosclerosis in a patient in need thereof comprising administering to said patient a composition of claim 26 in an amount effective to treat atherosclerosis.
39. A method for delaying the onset of atherosclerosis in a patient in need thereof comprising administering to said patient a composition of claim 26 in an amount effective to delay the onset of atherosclerosis.
40. A method for treating a condition, or a combination of conditions, selected from hyperglycemia, low glucose tolerance, insulin resistance, obesity, abdominal obesity, lipid disorders, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels and/or high LDL levels, atherosclerosis, atherosclerosis and its sequelae, vascular restenosis, pancreatitis, neurodegenerative disease, retinopathy, nephropathy, neuropathy, Syndrome X and other conditions where insulin resistance or hyperglycemia is a component, in a patient in need thereof, comprising administering to said patient a composition of claim 26 in an amount effective to treat said condition.
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