WO2013010453A1 - Chemoking receptor antagonists - Google Patents

Chemoking receptor antagonists Download PDF

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Publication number
WO2013010453A1
WO2013010453A1 PCT/CN2012/078586 CN2012078586W WO2013010453A1 WO 2013010453 A1 WO2013010453 A1 WO 2013010453A1 CN 2012078586 W CN2012078586 W CN 2012078586W WO 2013010453 A1 WO2013010453 A1 WO 2013010453A1
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WO
WIPO (PCT)
Prior art keywords
dihydro
trifluoromethyl
naphthyridin
methanone
hexahydropentalen
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Application number
PCT/CN2012/078586
Other languages
French (fr)
Inventor
Xueqing Wang
Michael Meyer
Betty YAO
Tao Guo
Guo Ping Robert WEI
Lijuan Jane Wang
Original Assignee
Abbott Laboratories
Abbott Laboratories Trading (Shanghai) Company, Ltd.
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Application filed by Abbott Laboratories, Abbott Laboratories Trading (Shanghai) Company, Ltd. filed Critical Abbott Laboratories
Publication of WO2013010453A1 publication Critical patent/WO2013010453A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids

Definitions

  • Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract leukocytes, as illustrated by macrophages, T cells, B cells, eosinophils, basophils, and neutrophils to and from sites of inflammation or within specific compartments, as illustrated by lymph nodes (reviewed in Schall, Cytokine 1991 ; 3: 165- 183; Schall, et al., Curr. Opin. Immunol. 1994; 6:865- 873; and Murphy, Rev. Immun. 1994; 12:593-633).
  • chemokines in addition to stimulating chemotaxis, other changes can be selectively induced by chemokines in responsive cells, including changes in cell shape, transient rises in the concentration of intracellular free calcium ions ([Ca 2+ ]), granule exocytosis, integrin upregulation, formation of bioactive lipids (e.g., leukotrienes), and respiratory burst, associated with leukocyte activation.
  • the chemokines are early modulators of inflammatory response, effecting inflammatory mediator release, chemotaxis and extravasation to sites of infection or inflammation.
  • CXC There are four classes of chemokines, CXC (a), CC ( ⁇ ), C ( ⁇ ), and CX 3 C ( ⁇ ), depending on whether the first two cysteines are separated by a single amino acid (C-X- C), are adjacent (C-C), have a missing cysteine pair (C), or are separated by three amino acids (CX 3 C).
  • a-chemokines such as interleukin-8 (IL-8), melanoma growth stimulatory activity protein (MGSA), and stromal cell derived factor 1 (SDF-1) are chemotactic primarily for neutrophils and lymphocytes
  • ⁇ -chemokines such as RANTES, ⁇ - ⁇ , ⁇ - ⁇ ⁇ , monocyte chemotactic protein- 1 (MCP-1), MCP-2, MCP-3, and eotaxin are chemotactic for macrophages, T-cells, eosinophils and basophils (Deng, et al., Naturel996; 381 :661-666).
  • the C chemokine lymphotactin shows specificity for lymphocytes (Kelner, et al., Science 1994; 266: 1395-1399) while the CX 3 C chemokine fractalkine shows specificity for lymphocytes and monocytes (Bazan, et al., Nature 1997; 385:640-644).
  • Chemokines bind specific cell-surface receptors belonging to the family of G- protein-coupled seven-transmembrane-domain proteins (reviewed in Horuk, Trends
  • chemokine receptors On binding their cognate ligands, chemokine receptors transduce an intracellular signal through the associated heterotrimeric G protein, resulting in a rapid increase in intracellular calcium concentration.
  • chemokine receptors There are at least twelve human chemokine receptors that bind or respond to ⁇ -chemokines with the following characteristic pattern: CCR1 (or "CKR-1 " or "CC- CKR-1 ”) ⁇ - ⁇ , ⁇ - ⁇ ⁇ , MCP-3, RANTES (Ben-Barruch, et al., J. Biol. Chem.
  • CCR2A and CCR2B (or "CKR- 2A'7"CKR-2A” or “CC-CKR-2A”/"CC-CKR2A") MCP-1, MCP-2, MCP-3, MCP-4; CCR3 (or “CKR-3” or "CC-CKR-3") eotaxin, RANTES, MCP; (Ponath, et al., J. Exp. Med. 1996; 183:2437-2448); CCR4 (or "CKR-4" or "CC-CKR-4") TARC, MDC (Imai, et al., J. Biol. Chem.
  • CCR5 or "CKR-5" or "CC-CKR-5" MIP- la, RANTES, MIP- ⁇ ⁇ ; (Sanson, et al., Biochemistry 1996; 35:3362-3367); CCR6 MIP-3a (Greaves, et al., J. Exp. Med. 1997; 186:837-844); CCR7 ⁇ -3 ⁇ and 6Ckine (Campbell, et al., J. Cell. Biol.
  • Chemokine receptors such as CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CX 3 CR1, and XCRl have been implicated as being important mediators of inflammatory and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis.
  • the CCR2 chemokine receptor is expressed primarily in monocytes and activated T lymphocytes, and its functional activity can be measured by cytosolic calcium elevation or chemotaxis.
  • CCR2 exists in two isoforms, CCR2A and CCR2B. These two isoforms are alternatively spliced variants of a single MCP- 1 receptor gene and differ only in the carboxyl-terminal tails. The chromosomal location of the CCR2 gene is localized to
  • the CC chemokines, MCP-1, MCP-2, MCP-3, and MCP-4, have been identified as the ligands that are selective and of high affinity to the CCR2 receptor.
  • CCR2 The highly selective expression of CCR2 makes it an ideal target for intervention to interrupt inappropriate monocyte and T cell trafficking.
  • the clinical indications for such intervention are in inflammatory diseases and T-cell mediated autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, asthma, allergy, chronic obstructive pulmonary disease, atherosclerosis, restinosis, type I and type II diabetes, metabolic syndrome, and pain.
  • Ectopic expression of MCP-1 and CCR2 in certain tumors indicates that selective modulation (such as antagonism or inhibition) of CCR2 can have value in tumor immunotherapy, particularly attenuation of metastasis.
  • the native peptide ligand of CCR2 is monocyte chemoattractant protein- 1 (MCP- 1 or CCL2) containing two adjacent disulfied bonds.
  • MCP- 1 or CCL2 monocyte chemoattractant protein- 1
  • CCR2 and MCP- 1 have limited expression levels in the CNS tissues under normal conditions, significant upregulation of CCR2 and MCP- 1 has been observed following a neuropathic injury in tissue relevant to pain, including neurons and glia in the spinal cord, rostroventromedial medulla (RVM) and DRG (Wang H., Zou S., Wei F., Dubner R., and Ren K., Soc for Neurosci Poster 2009; 72.3).
  • RVM rostroventromedial medulla
  • DRG rostroventromedial medulla
  • MCP- 1 has been shown to increase the excitability of neurons acutely dissociated from the DRG tissue (Sun J.H., Yang B., Donnelly D.F., Ma C, and LaMotte R.H., J Neurophysiol. 2006; 96:2189).
  • MCP- 1 direct injection of MCP- 1 in the spinal cord induces thermal hyperalgesia and mechanical allodynia (Dansereau et al. Neurochem. 2008; 106:7), and the MCP- 1 induced pronociception can be blocked by a CCR2 antagonist, INCB3344.
  • CCR2 antagonist INCB3344
  • the hyperalgesia induced by MCP-1 injection in the RVM is reversed by another CCR2 antagonist, RS I 02895 (Wang H., Zou S., Wei F., Dubner R. and Ren K., Soc for Neurosci Poster 2009; 72.3).
  • CCR2 knock out mice exhibit significantly reduced mechanical allydonia following nerve injury and reduced nocifensive behavior in the second phase of the formalin model, whereas they exhibit normal sensitivity to acute pain stimulation in the hot plate model (Abbadie C, Lindia J.A., Cumiskey A.M., Peterson L.B., Mudgett J.S., Bayne E.K., DeMartino J.A., Maclntyre D.E., and Forrest M.J., Proc Natl Aca Sci USA 2003; 100:7947). Treatment with AZ889 (Serrano A., Pare M., Mcintosh F., Elmes S.J.R.
  • AZ889 In vivo spinal intrathecal injection of AZ889 produced dose-dependent analgesia in chronic constriction injury rats (Serrano A., Pare M., Mcintosh F., Elmes S.J.R., Martino G., Jomphe C, Lessard E., Lembo P.M.C., Vaillancourt F., Perkins M.N., and Cao C.Q., Mol. Pain 2010; 6:90). Additionally, application of AZ889 to the exposed spinal cord inhibited evoked neuronal activity and confirmed that CCR2-mediated analgesia involved predominantly the spinal cord.
  • X 1 is CR 1 or N
  • X 2 is CR 2 or N
  • X 3 is CR 3 or N; with the proviso that no more than one of X 1 , X 2 , and X 3 is N; R 1 , R 2 , and R 3 are each independently hydrogen, -CN, halogen, alkyl, or haloalkyl;
  • G 1 is - 4 R 5 , formula (a), (b), or (c)
  • R 4 is hydrogen, C( 2 3 ⁇ 4) 3 , alkyl, haloalkyl, or alkoxyalkyl;
  • an heterocycle selected from the group consisting of a monocyclic heterocycle wherein one of the ring atoms is O, N, or NH and having zero or one double bond, optionally contains one or two additional heteroatoms selected from the group consisting of O, N, NH, and S, and optionally contains an C1-C4 alkylenyl bridge that links two non-adjacent carbon atoms within the ring; a bicyclic heterocycle, and a spiro heterocycle;
  • each of the R 5 phenyl, naphthyl, cycloalkyl, heteroaryl, heterocycle, and the heterocycle moiety of the heterocyclealkyl is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 R a ;
  • R 1 and R 3 are hydrogen, R 2 is haloalkyl, R 4 is alkyl, and R 5 is a monocyclic heterocycle or a heterocyclealkyl, then the heterocycle moiety of R 5 is substituted;
  • ring A 1 is 2,3-dihydro-lH-isoindolyl, decahydroisoquinolinyl, piperidinyl, or pyrrolidinyl, each of which is optionally further substituted with 1 , 2, or 3 substituents independently selected from the group consisting of CN, alkyl, oxo, halogen, haloalkyl, OH, O(alkyl), and 0(haloalkyl); with the proviso that when ring A 1 is piperidinyl, then G 2 and the optional substituent of ring A 1 do not reside on the same carbon atom;
  • G 2 is G 2a or -L'-G 2b ;
  • bicyclic aryl a bicyclic cycloalkyl, a bicyclic heterocycle, a spiro heterocycle, or an heteroaryl, each of which is optionally substituted with 1, 2, 3, 4, or 5 R b ; or
  • a phenyl a monocyclic cycloalkyl, or a monocyclic heterocycle, each of which is independently substituted with 1, 2, 3, 4, or 5 R b ;
  • G 2b is aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycle, each of which is optionally substituted with 1, 2, 3, 4, or 5 R b ;
  • R 6 is CN, OH, or halogen
  • each R 7 is an optional substituent on any substitutable carbon atom, and is independently alkyl, haloalkyl, halogen, oxo, or OH;
  • p 0, 1, 2, or 3;
  • L 1 and L 2 are independently O, N(J k ), or S; wherein J k , at each occurrence, is independently hydrogen, alkyl, haloalkyl, C(0)R k , S(0) 2 R k , or C 3 -C4 cycloalkyl; wherein the C 3 -C4 cycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independenly selected from the group consisting of alkyl, halogen, haloalkyl, oxo, hydroxy, and alkoxy, R k , at each occurrence, is independently alkyl or C3-C4 cycloalkyl; wherein the C3-C4 cycloalkyl is optionally with 1, 2, 3, or 4 substituents independenly selected from the group consisting of alkyl, halogen, haloalkyl, oxo, hydroxy, and alkoxy;
  • G 3a is aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycle, each of which is optionally substituted with 1, 2, 3, 4, or 5 R c ;
  • each ring A 2 is optionally substituted with 1, 2, 3, 4, or 5 R d ; with the proviso that ring A 2 is not 2,3-dihydro- lH-isoindolyl, decahydroisoquinolinyl, piperidinyl, or pyrrolidinyl;
  • R a , R b , R c , and R d are optional substituents on any substitutable atoms, and at each occurrence, are each independently alkyl, alkenyl, alkynyl, halogen, oxo, haloalkyl, CN, N0 2 , -OR f , -OC(0)R f , -OC(0)N(R f )(R s ), -S(0) 2 R e , -S(0) 2 N(R f )(R s ), -C(0)R f , -C(0)OR f , -C(0)N(R f )(R g ), -N(R f )(R g ), -N(R g )C(0)R f , -N(R g )S(0) 2 R e , -N(R g )C(0)0(R f ),
  • R e at each occurrence, is independently alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, G b , or -(C1-C6 alkylenyl)-G b ;
  • R f is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, G b , or -(C1-C6 alkylenyl)-G b ;
  • R g at each occurrence, is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, benzyl, or monocyclic cycloalkyl;
  • G a and G b are each independently aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycle, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, -CN, oxo, -OR h , -OC(0)R h , -OC(0)N(R h ) 2 , -SCO ⁇ R 1 , -S(0) 2 N(R h ) 2 , -C(0)R h , -C(0)OR h , -C(0)N(R h ) 2 , -N(R h ) 2 , -N(R h )C(0)R h , -N(R h )S(0) 2 R i ,
  • R x , R y , R xb , and R yb are each independently hydrogen, alkyl, halogen, or haloalkyl;
  • ql and q2, at each occurrence, are each independently 1, 2, 3, or 4;
  • R h at each occurrence, is independently hydrogen, alkyl, or haloalkyl
  • R 1 at each occurrence, is independently alkyl or haloalkyl.
  • compositions comprising therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or salt of a solvate thereof, in combination with a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier for treating or prevention of conditions and disorders associated to the expression or acitivity of CCR2.
  • the methods are useful for treating conditions such as, but not limited to, rheumatoid arthritis, osteoarthritis, asthma, chronic obstructive pulmonary disease, sepsis, psoriasis, psoriatic arthritis, inflammatory bowel disease, Crohn's disease, lupus, multiple sclerosis, juvenile chronic arthritis, Lyme arthritis, reactive arthritis, septic arthritis, spondyloarthropathy, systemic lupus erythematosus, an ocular condition, a cancer, a solid tumor, fibrosarcoma, osteoma, melanoma,
  • retinoblastoma a rhabdomyosarcoma
  • glioblastoma glioblastoma
  • neuroblastoma teratocarcinoma
  • an cancers such as lung, breast, stomach, bladder, colon, pancreas, ovarian, prostate and rectal cancer and hematopoietic malignancies (leukemia and lymphoma)
  • abetalipoprotemia acrocyanosis, acute and chronic parasitic or infectious processes, acute leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute or chronic bacterial infection, acute pancreatitis, acute renal failure, adenocarcinomas, aerial ectopic beats, AIDS dementia complex, alcohol-induced hepatitis, allergic conjunctivitis, allergic contact dermatitis, allergic rhinitis, alpha- 1 antitrypsin deficiency, amyotrophic lateral sclerosis, anemia, angina pectoris, anterior horn cell degeneration, anti cd3 therapy, antiphospholipid syndrome, anti-receptor hypersensitivity reactions, hypersensitivity reactions, hyperkinetic movement disorders, hypersensitivity pneumonitis, hypertension, hypokinetic movement disorders, aortic and peripheral aneurysms, hypothalamic-pituitary-adrenal axis evaluation, aortic dissection, arterial hypertension, arteriosclerosis
  • hematophagocytic lymphohistiocytosis fetal thymus implant rejection, Friedreich's ataxia, functional peripheral arterial disorders, fungal sepsis, gas gangrene, gastric ulcer, glomerular nephritis, gram negative sepsis, gram positive sepsis, granulomas due to intracellular organisms, hairy cell leukemia, Hallerrorden-Spatz disease, hay fever, heart transplant rejection, hemachromatosis, hemodialysis, hemolytic uremic
  • Hodgkin's disease lymphoma, myeloma, leukaemia, malignant ascites, hematopoietic cancers, Crow-Fukase (POEMS) syndrome (polyneuropathy, organomegaly,
  • a diabetic condition such as insulin-dependent diabetes mellitus glaucoma, diabetic retinopathy or microangiopathy, sickle cell anaemia, chronic inflammation, synovitis,
  • glomerulonephritis graft rejection
  • Lyme disease von Hippel Lindau disease
  • pemphigoid Paget' s disease
  • fibrosis sarcoidosis
  • cirrhosis thyroiditis
  • hyperviscosity syndrome Osier- Weber-Rendu disease
  • chronic occlusive pulmonary disease asthma or edema following burns, trauma, radiation, stroke, hypoxia, ischemia, ovarian
  • hyperstimulation syndrome post perfusion syndrome, post pump syndrome, post-MI cardiotomy syndrome, preeclampsia, menometrorrhagia, endometriosis, pulmonary hypertension, infantile hemangioma, or infection by Herpes simplex, Herpes Zoster, human immunodeficiency virus, parapoxvirus, protozoa or toxoplasmosis, Progressive supranucleo Palsy, primary pulmonary hypertension, radiation therapy, Raynaud's phenomenon and disease, Refsum's disease, regular narrow QRS tachycardia, renovascular hypertension, restrictive cardiomyopathy, sarcoma, senile chorea, Senile Dementia of Lewy body type, shock, skin allograft, skin changes syndrome, ocular or macular edema, ocular neovascular disease, scleritis, radial keratotomy, uveitis, vitritis, myopia, optic pits, chronic retina
  • hypogammaglobulinemia dilated cardiomyopathy
  • female infertility female infertility
  • ovarian failure premature ovarian failure
  • fibrotic lung disease chronic wound healing
  • cryptogenic fibrosing alveolitis post-inflammatory interstitial lung disease, interstitial pneumonitis, Pneumocystis carinii pneumonia, pneumonia, connective tissue disease associated interstitial lung disease, mixed connective tissue disease, lung disease, systemic sclerosis associated interstitial lung disease, rheumatoid arthritis associated interstitial lung disease, systemic lupus erythematosus associated lung disease, dermatomyositis/polymyositis associated lung disease, Sjogren's disease associated lung disease, ankylosing spondylitis associated lung disease, vasculitic diffuse lung disease, haemosiderosis associated lung disease, drug-induced interstitial lung disease, radiation fibrosis, bronchiolitis obliterans, chronic eosinophilic
  • glomerulonephritides microscopic vasulitis of the kidneys, Lyme disease, discoid lupus erythematosus, male infertility idiopathic or NOS, sperm autoimmunity, multiple sclerosis (all subtypes), sympathetic ophthalmia, pulmonary hypertension secondary to connective tissue disease, pain, Goodpasture's syndrome, pulmonary manifestation of polyarteritis nodosa, acute rheumatic fever, rheumatoid spondylitis, Still's disease, systemic sclerosis, Sjogren's syndrome, Takayasu's disease/arteritis, autoimmune thrombocytopaenia, toxicity, transplants, idiopathic thrombocytopaenia, autoimmune thyroid disease, hyperthyroidism, goitrous autoimmune hypothyroidism (Hashimoto's disease), atrophic autoimmune hypothyroidism, primary myxoedema, phacogenic u
  • such compounds may be useful in the treatment of disorders such as ascites, effusions, and exudates, including for example macular edema, cerebral edema, acute lung injury, adult respiratory distress syndrome, proliferative disorders such as restenosis, fibrotic disorders such as hepatic cirrhosis and atherosclerosis, mesangial cell proliferative disorders such as diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, and glomerulopathies, myocardial angiogenesis, coronary and cerebral collaterals, ischemic limb angiogenesis, ischemia/reperfusion injury, peptic ulcer Helicobacter related diseases, virally-induced angiogenic disorders, preeclampsia, menometrorrhagia, cat scratch fever, rubeosis, neovascular glaucoma and retinopathies such as those associated with diabetic retinopathy, retinopathy of prematurity, age-related
  • the methods are useful for treating conditions related to pain such as, but not limited to, neuropathic pain, nociceptive pain, inflammatory pain (e.g. osteoarthritic pain, rheumatoid arthritic pain), fibromyalgia, neuralgia such as postherpatic neuralgia and trigeminal neuralgia, diabatic neuropathic pain, HIV-related neuropathic pain, migraine, post-stroke pain, post-operative pain, multiple sclerosis pain, pain related to spinal cord injury, cancer pain, lower back pain, and eye pain; and inflammatory disorders (e.g rheumatoid arthritis, osteoarthritis).
  • inflammatory pain e.g. osteoarthritic pain, rheumatoid arthritic pain
  • fibromyalgia fibromyalgia
  • neuralgia such as postherpatic neuralgia and trigeminal neuralgia
  • diabatic neuropathic pain HIV-related neuropathic
  • present compounds or pharmaceutically acceptable salts, solvates, or salts of solvates thereof in the manufacture of medicaments for the treatment of the diseases or conditions described above, alone or in combination with a pharmaceutically acceptable carrier, particularly for the treatment of pain such as, but not limited to, neuropathic pain, nociceptive pain, inflammatory pain (e.g.
  • osteoarthritic pain rheumatoid arthritic pain
  • fibromyalgia neuralgia such as postherpatic neuralgia and trigeminal neuralgia
  • diabatic neuropathic pain HIV-related neuropathic pain
  • migraine post-stroke pain
  • post-operative pain multiple sclerosis pain
  • pain related to spinal cord injury cancer pain, lower back pain, and eye pain.
  • compositions comprising the compounds, and methods for treating or preventing conditions and disorders by administering the compounds are further described herein.
  • compositions comprising such compounds and methods for treating conditions and disorders using such compounds and compositions are also disclosed.
  • compounds described herein may contain variables that occur more than one time in any substituent or in the compound described or any other formula herein. Definition of a variable on each occurrence is independent of its definition at another occurrence. Further, combinations of variables are permissible only if such combinations result in stable compounds. Stable compounds are compounds that can be isolated from a reaction mixture.
  • alkenyl as used herein, means a straight or branched hydrocarbon chain containing from 2 to 10 carbons and containing at least one carbon-carbon double bond.
  • C2-C4 alkenyl means an alkenyl group containing 2-4 carbon atoms.
  • Non-limiting examples of alkenyl include buta-2,3-dienyl, ethenyl, 2-propenyl, 2-methyl- 2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl- 1-heptenyl, and 3- decenyl.
  • alkenylene means a divalent group derived from a straight or branched chain hydrocarbon of 2 to 4 carbon atoms and contains at least one carbon-carbon double.
  • alkoxy means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • C1-C4 alkoxy means a C1-C4 alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.
  • alkoxyalkyl as used herein, means an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkylenyl group, as defined herein.
  • alkoxyalkyl include tert-butoxymethyl, 2-ethoxyethyl, 2- methoxyethyl, and methoxymethyl.
  • alkyl as used herein, means a straight or branched, saturated hydrocarbon chain containing from 1 to 10 carbon atoms.
  • Cx-C y alkyl means a straight or branched chain, saturated hydrocarbon containing x to y carbon atoms.
  • C2-C10 alkyl means a straight or branched chain, saturated hydrocarbon containing 2 to 10 carbon atoms.
  • alkyl examples include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n- heptyl, n-octyl, n-nonyl, and n-decyl.
  • alkylene or "alkylenyl” means a divalent group derived from a straight or branched, saturated hydrocarbon chain, for example, of 1 to 10 carbon atoms or of 1 to 4 carbon atoms.
  • alkylene and alkylenyl include, but are not limited to, - CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, and -CH 2 CH(CH 3 )CH 2 -.
  • alkynyl as used herein, means a straight or branched chain
  • C 2 -C 4 alkynyl means a straight or branched chain hydrocarbon group containing from 2 to 4 carbon atoms.
  • Representative examples of alkynyl include, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2- pentynyl, and 1-butynyl.
  • aryl as used herein, means phenyl or a bicyclic aryl.
  • the bicyclic aryl is naphthyl, or a phenyl fused to a monocyclic cycloalkyl, or a phenyl fused to a monocyclic cycloalkenyl.
  • Non-limiting examples of the aryl groups include
  • bicyclic aryl is attached to the parent molecular moiety through any carbon atom contained within the bicyclic ring system and can be unsubstituted or substituted.
  • cycloalkyl or "cycloalkane” as used herein, means a monocyclic and a bicyclic cycloalkyl.
  • the monocyclic cycloalkyl is a carbocyclic ring system containing three to eight carbon atoms, zero heteroatoms and zero double bonds. Examples of monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • C3-C4 cycloalkyl as used herein, means a monocyclic carbocyclic ring containing three or four carbon atoms, zero heteroatom, and zero double bond.
  • the bicyclic cycloalkyl is a monocyclic cycloalkyl fused to a monocyclic cycloalkyl ring.
  • the monocyclic and the bicyclic cycloalkyl groups may contain one or two alkylene bridges of one, two, three, or four carbon atoms wherein each bridge links two non-adjacent carbon atoms of the ring system.
  • Non-limiting examples of bicyclic ring systems include bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane,
  • bicyclo[4.2. l]nonane examples include, but are not limited to, tricyclo[3.3.1.0 3 ' 7 ]nonane (octahydro-2,5- methanopentalene or noradamantane) and tricyclo[3.3.1. l 3 ' 7 ]decane (adamantane).
  • the monocyclic and the bicyclic groups can be unsubstituted or substituted, and are attached to the parent molecular moiety through any substitutable atom contained within the ring system.
  • cycloalkenyl or "cycloalkene” as used herein, means a monocyclic or a bicyclic hydrocarbon ring system.
  • the monocyclic cycloalkenyl has four-, five-, six-, seven- or eight carbon atoms and zero heteroatoms.
  • the four-membered ring systems have one double bond, the five-or six-membered ring systems have one or two double bonds, and the seven- or eight-membered ring systems have one, two, or three double bonds.
  • monocyclic cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • the bicyclic cycloalkenyl is a monocyclic cycloalkenyl fused to a monocyclic cycloalkyl group, or a monocyclic cycloalkenyl fused to a monocyclic cycloalkenyl group.
  • the monocyclic or bicyclic cycloalkenyl ring may contain one or two alkylene bridges, each consisting of one, two, or three carbon atoms, each linking two non-adjacent carbon atoms of the ring system.
  • Representative examples of the bicyclic cycloalkenyl groups include, but are not limited to, 4,5,6,7-tetrahydro-3aH-indene, octahydronaphthalenyl, and 1,6-dihydro-pentalene.
  • the monocyclic and bicyclic cycloalkenyl can be attached to the parent molecular moiety through any substitutable atom contained within the ring systems, and can be unsubstituted or substituted.
  • halo or halogen as used herein, means CI, Br, I, and F.
  • haloalkyl as used herein, means an alkyl group, as defined herein, in which one, two, three, four, five or six hydrogen atoms are replaced by halogen.
  • C1-C4 haloalkyl means a C1-C4 alkyl group, as defined herein, in which one, two, three, four, five or six hydrogen atoms are replaced by halogen.
  • haloalkyl include, but are not limited to, chloromethyl, fluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, 2-chloro-3- fluoropentyl, trifluorobutyl, and trifluoropropyl.
  • haloalkoxy means an alkoxy group, as defined herein, in which one, two, three, four, five or six hydrogen atoms are replaced by halogen.
  • C1-C4 haloalkoxy means a C1-C4 alkoxy group, as defined herein, in which one, two, three, four, five or six hydrogen atoms are replaced by halogen.
  • haloalkoxy include, but are not limited to, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, trifluoromethoxy, and difluoromethoxy.
  • haloalkoxyalkyl as used herein, means a haloalkoxy group, as defined herein, appended to the parent moiety through an alkylenyl group, as defined herein.
  • heterocycle or “heterocyclic” as used herein, means a monocyclic heterocycle, a bicyclic heterocycle, and a spiro heterocycle.
  • the monocyclic heterocycle is a three-, four-, five-, six-, seven-, or eight-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S.
  • the three- or four-membered ring contains zero or one double bond, and one heteroatom selected from the group consisting of O, N, and S.
  • the five-membered ring contains zero or one double bond and one, two, or three heteroatoms selected from the group consisting of O, N, and S.
  • the six-membered ring contains zero, one, or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S.
  • the seven- and eight-membered rings contains zero, one, two, or three double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S.
  • monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 2,3-dihydro-lH-pyrazolyl, 1,6-dihydropyridazinyl, 1,2- dihydropyridinyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxepanyl, oxetanyl, piperazinyl, piperidinyl, pyr
  • the bicyclic heterocycle is a monocyclic heterocycle fused to a phenyl group, or a monocyclic heterocycle fused to a monocyclic cycloalkyl, or a monocyclic heterocycle fused to a monocyclic cycloalkenyl, or a monocyclic heterocycle fused to a monocyclic heterocycle.
  • bicyclic heterocycles include, but are not limited to, benzopyranyl, benzothiopyranyl, 3,4-dihydro-2H-chromen-4-yl, 2,3- dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydro-lH-indolyl, 3,4- dihydroisoquinolin-2(lH)-yl, 1 ,2-dihydrophthalazinyl, 2,3,4,6-tetrahydro-lH-pyrido[l,2- a] pyrazin-2-yl, hexahydropyrano[4,3-b]pyrrol- l(4H)-yl, and hexahydropyrano[3,4- b] [l,4]oxazin-l(5H)-yl.
  • the monocyclic heterocycle and the bicyclic heterocycle may contain one or two alkylene bridges or alkenylene bridges, or mixture thereof, each consisting of 1, 2, 3, or 4 carbon atoms and each linking two non adjacent atoms of the ring system.
  • bridged heterocycle include, but are not limited to, 3- oxabicyclo[3.3.1]nonyl, azabicyclo[2.2. l]heptyl (including 2-azabicyclo[2.2.1]hept-2-yl), 8-azabicyclo[3.2.
  • l]oct-8-yl octahydro-2,5-epoxypentalene, hexahydro-2H-2,5- methanocyclopenta[0]furan, hexahydro- 1H- 1 ,4-methanocyclopenta[c]furan, aza- admantane (l-azatricyclo[3.3.1.1 3 ' 7 ]decane), and oxa-adamantane (2- oxatricyclo[3.3.1. l 3 ' 7 ]decane).
  • a spiro heterocycle is a monocyclic heterocycle wherein two substituents on the same carbon atom of the monocyclic heterocycle ring together with said carbon atom form a second ring system selected from a monocyclic cycloalkyl, a bicyclic cycloalkyl, a monocyclic heterocycle, or a bicyclic heterocycle.
  • spiro heterocycle examples include, but not limited to, 5-oxaspiro[2.5]octyl, 7-oxa- 1 - azaspiro[3.5]non-l-yl, 6-azaspiro[2.5]oct-6-yl, ⁇ , 4H-spiro[l,3-benzodioxine-2,4'- piperidin]-l '-yl, ⁇ , 3H-spiro[2-benzofuran-l,4'-piperidin]- -yl, and l,4-dioxa-8- azaspiro[4.5]dec-8-yl.
  • the monocyclic, the bicyclic, and the spiro heterocycles can be unsubstituted or substituted.
  • the monocyclic, the bicyclic and the spiro heterocycles are connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the rings except for those that are represented by ring A 2 wherein the point of connection is through a nitrogen atom within the monocyclic hetrocycle of the ring systems.
  • the nitrogen and sulfur heteroatoms in the heterocycle rings may optionally be oxidized and the nitrogen atoms may optionally be quarternized.
  • heterocyclealkyl as used herein, means a heterocycle group, as defined herein above, appended to the parent moiety through an alkylenyl group, as defined herein.
  • heteroaryl as used herein, means a monocyclic heteroaryl or a bicyclic heteroaryl.
  • the monocyclic heteroaryl is a five- or six-membered ring.
  • the five- membered ring contains two double bonds.
  • the five membered ring may contain one heteroatom selected from O or S; or one, two, three, or four nitrogen atoms and optionally one oxygen or one sulfur atom.
  • the six-membered ring contains three double bonds and one, two, three or four nitrogen atoms.
  • monocyclic heteroaryl include, but are not limited to, furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl (including 1,2,4-oxadiazolyl), 1,3-oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, 1,3-thiazolyl, thienyl, triazolyl (e.g. 1,2,4-triazolyl), and triazinyl.
  • furanyl imidazolyl
  • isoxazolyl isothiazolyl
  • oxadiazolyl including 1,2,4-oxadiazolyl
  • 1,3-oxazolyl 1,3-oxazolyl
  • pyridinyl pyridazinyl
  • pyrimidinyl pyraziny
  • the bicyclic heteroaryl consists of a monocyclic heteroaryl fused to a phenyl, or a monocyclic heteroaryl fused to a monocyclic cycloalkyl, or a monocyclic heteroaryl fused to a monocyclic cycloalkenyl, or a monocyclic heteroaryl fused to a monocyclic heteroaryl, or a monocyclic heteroaryl fused to a monocyclic heterocycle.
  • bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzoxadiazolyl, phthalazinyl, 2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)- yl, 6,7-dihydro-pyrazolo[l,5-a]pyrazin-5(4H)-yl, 6,7-dihydro-l,3-benzothiazolyl, 6,7- dihydro-4H-pyrano[4,3-d][l,3]thiazolyl, imidazo[l,2- ]pyridinyl, indazolyl, indolyl, isoindolyl, isoquinolinyl, naphthyridinyl, pyridoimidazolyl, quinolinyl, 2,4,6,7- tetrahydro-5H-pyrazolo[4,
  • the monocyclic and bicyclic heteroaryl groups can be substituted or unsubstituted and are connected to the parent molecular moiety through any substitutable carbon atom or any substitutable nitrogen atom contained within the ring systems, except for that represented by the ring A 2 wherein the point of connection is through a nitrogen atom of the monocyclic heterocycle of the ring systems.
  • heteroatom as used herein, means a nitrogen, oxygen, and sulfur.
  • hydroxyl or "hydroxy” means a -OH group.
  • a non-hydrogen radical is in the place of hydrogen radical any substitutable atom of the substituent.
  • a substituted heterocycle substituent is a heterocycle substituent in which at least one non- hydrogen radical is in the place of a hydrogen radical on the heterocycle substituent. It should be recognized that if there are more than one substitution on a substituent, each non-hydrogen radical may be identical or different (unless otherwise stated).
  • substituent may be either (1) not substituted or (2) substituted. If a substituent is described as being optionally substituted with up to a particular number of non-hydrogen radicals, that substituent may be either (1) not substituted; or (2) substituted by up to that particular number of non-hydrogen radicals or by up to the maximum number of substitutable positions on the substituent, whichever is less. Thus, for example, if a substituent is described as a heteroaryl optionally substituted with up to 3 non-hydrogen radicals, then any heteroaryl with less than 3 substitutable positions would be optionally substituted by up to only as many non-hydrogen radicals as the heteroaryl has substitutable positions.
  • tetrazolyl (which has only one substitutable position) would be optionally substituted with up to one non-hydrogen radical.
  • an amino nitrogen is described as being optionally substituted with up to 2 non-hydrogen radicals, then a primary amino nitrogen will be optionally substituted with up to 2 non-hydrogen radicals, whereas a secondary amino nitrogen will be optionally substituted with up to only 1 non-hydrogen radical.
  • treat refers to a method of alleviating or abrogating a disease and/or its attendant symptoms.
  • prevent refers to a method of preventing the onset of a disease and/or its attendant symptoms or barring a subject from acquiring a disease.
  • prevent also include delaying the onset of a disease and/or its attendant symptoms and reducing a subject's risk of acquiring a disease.
  • modulate refers to the ability of a compound to increase or decrease the function, or activity, of CCR.
  • Modulation as used herein in its various forms, is intended to encompass antagonism, inhibition, agonism, partial antagonism and/or partial agonism of the activity associated with chemokine receptor, CCR.
  • the chemokine receptor is CCR2.
  • composition as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the "subject” is defined herein to include animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In preferred embodiments, the subject is a human.
  • variable groups in compounds of formula (I) are as follows. Such values may be used where appropriate with any of the other values, definitions, claims or embodiments defined hereinbefore or hereinafter.
  • X 1 , X 2 , and X 3 have values as disclosed in the Summary.
  • X 1 is CR 1
  • X 2 is CR 2
  • X 3 is CR 3
  • R 1 , R 2 , and R 3 are the same or different, and are each independently hydrogen or haloalkyl.
  • R 1 and R 3 are hydrogen
  • R 2 is halogen (e.g. CI, Br, F), -CN, or haloalkyl (such as, but not limited to, trifluoromethyl, difluoromethyl).
  • R 1 and R 3 are hydrogen
  • R 2 is haloalkyl (such as, but not limited to, trifluoromethyl).
  • R 1 and R 3 are hydrogen, and R 2 is haloalkyl (such as, but not limited to, trifluoromethyl).
  • R 1 and R 3 are hydrogen, and R 2 is
  • G 1 is as described in the Summary. In certain embodiments, G 1 is NR 4 R 5 or formula (a). In other embodiments, G 1 is formula (b) or formula (c). R 4 , R 5 , ring A 1 and G 2 of formula (a), R 6 and G 3 of formula (b), and ring A 2 of formula (c) have meanings as described in the Summary and embodiments herein below.
  • G 1 is NR 4 R 5 and R 4 and R 5 are as described in the
  • examples of R 4 includes, but are not limited to, hydrogen, C( 2 ]3 ⁇ 4) 3 , d- C 4 alkyl (e.g. methyl, ethyl), haloalkyl (e.g. 2,2-difluoroethyl), and alkoxyalkyl (e.g. 2- methoxyethyl).
  • R 4 is hydrogen.
  • R 4 is Ci-C 4 alkyl (e.g. methyl, ethyl).
  • R 4 is methyl.
  • R 5 for example, is a heterocycle, a heteroaryl, or a cycloalkyl (e.g. monocyclic cycloalkyl), or for example, a heterocycle or a cycloalkyl (e.g. monocyclic cycloalkyl); each R 5 is optionally substituted as described in the Summary and herein.
  • R 5 is an optionally substituted monocyclic heterocycle (e.g. tetrahydropyranyl, 3- oxabicyclo[3.3.1]nonyl, oxepanyl, pyrrolidinyl, each of which is optionally substituted) as described in the Summary.
  • R 5 is an optionally substituted bicyclic heterocycle (e.g. optionally substituted 3,4-dihydro-2H-chromenyl).
  • R 5 is an optionally substituted spiro heterocycle (e.g. optionally substituted 5-oxaspiro[2.5]octyl).
  • R 5 is an optionally substituted heteroaryl (e.g. optionally substituted 6,7-dihydro-4H-pyrano[4,3-d][l,3]thiazolyl).
  • R 5 is an optionally substituted monocyclic cycloalkyl (e.g.
  • R 5 is a substituted heterocycle (e.g. tetrahydropyranyl, 3-oxabicyclo[3.3.1]nonyl, oxepanyl, pyrrolidinyl, 3,4-dihydro-2H-chromenyl, 5-oxaspiro[2.5]octyl), it is substituted with one or two substituents (R a ).
  • said substituents of the heterocycle of R 5 are selected from the group consisting of -CN, NO2, alkyl (e.g.
  • haloalkyl e.g. trifluoromethyl, difluoromethyl, fluoromethyl
  • halogen e.g. F, CI, Br
  • G a e.g. optionally substituted phenyl; optionally substituted heteroaryl such as, but not limited to, optionally substituted pyridinyl; optionally substituted monocyclic cycloalkyl such as, but not limited to, optionally substituted cyclopropyl
  • -(CR x R y ) q i-G a e.g. benzyl
  • -OR f e.g.
  • R 5 is optionally substituted tetrahydropyranyl. In yet other embodiments, R 5 is tetrahydropyranyl substituted with one or two substituents.
  • R 5 is a substituted tetrahydropyranyl
  • the optional substituents include, but are not limited to, optionally substtituted phenyl, optionally substituted heteroaryl such as, but not limited to, optionally substituted pyridinyl, -OR f and -(CR x R y ) q i-OR f wherein R f is C1-C4 alkyl (e.g. methyl, ethyl), R x and R y are hydrogen, and ql is 1.
  • R 5 is tetrahydropyranyl substituted with one -OR f group wherein R f is C1-C4 alkyl (e.g.
  • R 5 is tetrahydropyranyl substituted with one -OR f group wherein R f is methyl. In certain embodiments, R 5 is tetrahydropyranyl substituted with one C1-C4 alkyl group (e.g. methyl, ethyl). In certain embodiments, R 5 is
  • R 5 is optionally substituted pyrrolidinyl. Where R 5 is a substituted pyrrolidinyl, it is substituted with one or two substituents selected from the group consisting of oxo and G a wherein G a is as defined in the Summary. In yet other embodiments, R 5 is pyrrolidinyl substituted with one or two substituent selected from the group consisting of oxo and G a wherein G a is optionally substituted aryl (e.g. optionally substituted phenyl). In certain embodiments, R 5 is optionally substituted cycloalkyl (e.g.
  • R 5 is an optionally substituted cycloalkyl (including the exemplary rings mentioned), it is substituted with 1, 2, or 3 R a wherein R a is as described in the Summary.
  • R 5 is a monocyclic cycloalkyl (e.g.
  • R 5 is a monocyclic cycloalkyl (e.g. cyclobutyl, cyclohexyl, adamantyl) optionally substituted with two halogen groups.
  • G 1 is formula (a).
  • compounds of formula (la) are compounds of formula (la).
  • X 1 , X 2 , X 3 , A 1 , and G 2 have meanings as discussed in the Summary and embodiments herein above and below.
  • ring A 1 is pyrrolidinyl or piperidinyl, each of which is optionally further substituted as described in the Summary.
  • ring A 1 is pyrrolidinyl, optionally further substituted as described in the Summary and embodiments herein.
  • ring A 1 is piperidinyl, optionally further substituted as described in the Summary and embodiments herein.
  • ring A 1 is piperidinyl which is optionally further substituted with one or two substituents independently selected from the group consisting of alkyl (e.g. C1 -C4 alkyl such as, but not limited to methyl) or halogen (e.g. F).
  • alkyl e.g. C1 -C4 alkyl such as, but not limited to methyl
  • halogen e.g. F
  • ring A is piperidinyl which is further substituted with one methyl group.
  • G for any of the above and below embodiments is G 2a or -L'-G 2b .
  • G 2 is G 2a .
  • G 2 is -L'-G 2b .
  • G 2a , L 1 , and G 2b are as described in the Summary and herein below.
  • L 1 for example, is O.
  • G 2a in certain embodiments, is a substituted phenyl, an optionally substituted bicyclic aryl (e.g. optionally substituted naphthyl), an optionally substituted heteroaryl (e.g. pyridazinyl, phthalazinyl, pyrazolyl, pyridinyl, 1,2,4-oxadiazolyl, 1,2,4-triazolyl, tetrazolyl, each of which is optionally substituted), a substituted monocyclic heterocycle (e.g. substituted 1,6-dihydropyridazinyl, substituted 1,2-dihydropyridinyl), or an optionally substituted bicyclic heterocycle (e.g.
  • G 2a is substituted phenyl.
  • the substituents of G 2a are as described in the Summary and embodiments herein.
  • R b is G a (e.g. optionally substituted tetrazolyl), CN, COOR f , -(CR x R y ) q i-OR f , or -(CR x R y ) q i-C(0)OR f ; wherein R f is hydrogen or C1-C4 alkyl (e.g.
  • G 2a is a substituted phenyl, it is substituted with a COOH group.
  • G 2a is an optionally substituted heteroaryl (e.g. pyridazinyl, phthalazinyl, pyrazolyl, pyridinyl, 1 ,2,4-oxadiazolyl, 1 ,2,4-triazolyl, tetrazolyl, each of which is optionally substituted), it is optionally substituted with 1 , 2, or 3 substituents (R b ) as described in the Summary, for example, it is optionally substituted with 1 , 2, or 3 substituents (R b ) wherein R b is haloalkyl (e.g.
  • alkyl e.g. methyl, ethyl, isopropyl
  • OR f COOR f
  • G a e.g. optionally substituted phenyl
  • R f for example, is hydrogen or Ci-C 4 alkyl such as, but not limited to, methyl, ethyl.
  • G 2a is a monocyclic heterocycle or bicyclic heterocycle, it is substituted with an oxo group, and is optionally further substituted with one or two groups selected from alkyl (e.g. methyl, ethyl), halogen (e.g. F), or haloalkyl (e.g. trifluoromethyl).
  • G 2b is optionally substituted phenyl or optionally substituted naphthyl. In certain embodiments, G 2b is unsubstituted phenyl.
  • G 1 is formula (b).
  • compounds of formula (lb) are compounds of formula (lb).
  • R 6 is OH. In other embodiments, R 6 is CN or halogen (e.g. F).
  • G 3 is G 3a wherein G 3a is as described in the Summary and embodiments herein.
  • G 3a is aryl optionally substituted with 1 , 2, 3, 4, or 5 R c .
  • G 3a is phenyl optionally substituted with 1, 2, 3, 4, or 5 R c .
  • G 3 is -L 2 -G 3a wherein L 2 and G 3a are as described in the Summary and embodiments herein. In conjunction with any of the above and below embodiments wherein G 3 is -L 2 -G 3a , L 2 , for example, is O.
  • G 3a is aryl optionally substituted with 1 , 2, 3, 4, or 5 R c ; or for example, G 3a is phenyl optionally substituted with 1 , 2, 3, 4, or 5 R c .
  • R c has values as described in the Summary, for example, in conjunction with any of the above and below embodiments, each R c , for example, is independently alkyl, OR f , halogen (e.g. F, CI), COOR f , or haloalkyl, wherein each R f is, for example, independently hydrogen or C1 -C4 alkyl.
  • G 3a is phenyl, optionally substituted with one R c group wherein R c is halogen.
  • G 3a is phenyl, optionally substituted with one R c group wherein R c is F or CI.
  • G 1 is formula (c).
  • compounds of formula (Ic) are compounds of formula (Ic).
  • ring A 2 is a heterocycle, optionally substituted with 1, 2, 3, 4, or 5 R d groups.
  • ring A 2 is a monocyclic heterocycle (e.g. azetidinyl, piperazinyl, morpholinyl, tetrahydropyridinyl, 8-azabicyclo[3.2.1]oct-8-yl).
  • ring A 2 is substituted piperazinyl.
  • the monocyclic heterocycle of ring A (including the exemplary rings) is optionally substituted as described in the Summary and herein. For example, they are each independently unsubstituted or substituted with 1, 2, or 3 substituents (R d ).
  • the optional substituents (R d ) of the monocyclic rings are the same or different, and are selected from the group consisting of oxo, C1-C4 alkyl (e.g. methyl), halogen, haloalkyl (e.g. trifluoromethyl), G a (e.g optionally substituted aryl such as, but not limited to, optionally substituted phenyl; or optionally substituted heteroaryl such as, but not limited to, optionally substituted pyrazolyl), OR f , and -(CR x R y ) q i-OR f ; wherein each R f is independently hydrogen or alkyl.
  • C1-C4 alkyl e.g. methyl
  • halogen e.g. trifluoromethyl
  • G a e.g optionally substituted aryl such as, but not limited to, optionally substituted phenyl; or optionally substituted heteroaryl such as, but not limited to, optional
  • ring A 2 is an optionally substituted spiro heterocycle (e.g. H,4H-spiro[l,3-benzodioxine-2,4'-piperidin]- -yl, 6-azaspiro[2.5]oct-6-yl, l,4-dioxa-8-azaspiro[4.5]dec-8-yl, 1 'H,3H-spiro[2-benzofuran- l,4'-piperidin]-l '-yl, 7-oxa-l-azaspiro[3.5]non-l-yl, each of which is optionally substituted).
  • the optional substituents of the spiro heterocycles include, but are not limited to, alkyl, halogen, haloalkyl (e.g.
  • ring A 2 is l O,3H-spiro[2-benzofuran- l,4'-piperidin]- -yl.
  • ring A 2 is an optionally substituted bicyclic heterocycle (e.g.
  • Examples of the optional substituents of the bicyclic heterocycle include, but not limited to, oxo, alkyl, haloalkyl, or OR f wherein R f is hydrogen or alkyl.
  • ring A is hexahydropyrano[3,4-b][l,4]oxazin- l(5H)-yl.
  • ring A 2 is hexahydropyrano[4,3-b]pyrrol- 1 (4H)-yl.
  • ring A 2 is a monocyclic heteterocycle fused with a monocyclic heteroaryl, optionally substituted with 1, 2, 3, 4, or 5 R d groups.
  • ring A 2 is 2,4,6,7- tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl, 2,6-dihydro-pyrrolo[3,4-c]pyrazol-5(4H)-yl, 6,7-dihydro-pyrazolo[l,5-a]pyrazin-5(4H)-yl), or 6,7-dihydro-pyrano[4,3-b]pyrrol-l(4H)- yl.
  • the aforementioned rings in this paragraph are optionally substituted as described in the Summary. In certain embodiments, these rings are unsubstituted.
  • one aspect relates to a group of compounds of formula (I) wherein X 1 is CR 1 , X 2 is CR 2 , X 3 is CR 3 , and G 1 is NR 4 R 5 .
  • Another aspect is related to a group of compounds of formula (I) wherein X 1 is
  • R 5 is an optionally substituted heterocycle (e.g. tetrahydropyranyl, pyrrolidinyl, 3-oxabicyclo[3.3.1]nonyl, oxepanyl, 3,4-dihydro- 2H-chromenyl, 5-oxaspiro[2.5]octyl, each of which is optionally substituted) as described in the Summary, an optionally substituted heteroaryl (e.g. optionally substituted 6,7- dihydro-4H-pyrano[4,3-d][l,3]thiazolyl), or optionally substituted cycloalkyl (e.g.
  • Another aspect is related to a group of compounds of formula (I) wherein X 1 is CR 1 , X 2 is CR 2 , X 3 is CR 3 , G 1 is NR 4 R 5 , and R 5 is an optionally substituted heterocycle (e.g. tetrahydropyranyl, 3-oxabicyclo[3.3.1]nonyl, oxepanyl, pyrrolidinyl, 3,4-dihydro- 2H-chromenyl, 5-oxaspiro[2.5]octyl each of which is optionally substituted) as described in the Summary, or optionally substituted cycloalkyl (e.g. cyclobutyl, cyclohexyl, adamantyl, each of which is optionally substituted).
  • cycloalkyl e.g. cyclobutyl, cyclohexyl, adamantyl, each of which is optionally substituted.
  • Another aspect is related to a group of compounds of formula (I) wherein X 1 is CR 1 , X 2 is CR 2 , X 3 is CR 3 , G 1 is NR 4 R 5 , and R 5 is optionally substituted monocyclic heterocycle (e.g. tetrahydropyranyl, 3-oxabicyclo[3.3.1]nonyl, oxepanyl, pyrrolidinyl, each of which is optionally substituted).
  • monocyclic heterocycle e.g. tetrahydropyranyl, 3-oxabicyclo[3.3.1]nonyl, oxepanyl, pyrrolidinyl, each of which is optionally substituted.
  • Another aspect is related to a group of compounds of formula (I) wherein X 1 is CR 1 , X 2 is CR 2 , X 3 is CR 3 , G 1 is NR 4 R 5 , R 4 is hydrogen or C1-C4 alkyl, and R 5 is optionally substituted monocyclic heterocycle (e.g. tetrahydropyranyl, 3- oxabicyclo[3.3. l]nonyl, oxepanyl, pyrrolidinyl, each of which is optionally substituted).
  • monocyclic heterocycle e.g. tetrahydropyranyl, 3- oxabicyclo[3.3. l]nonyl, oxepanyl, pyrrolidinyl, each of which is optionally substituted.
  • Another aspect is related to a group of compounds of formula (I) wherein X 1 is CR 1 , X 2 is CR 2 , X 3 is CR 3 , G 1 is NR 4 R 5 , R 4 is hydrogen, and R 5 is optionally substituted tetrahydropyranyl.
  • Another aspect is related to a group of compounds of formula (I) wherein X is CR 1 , X 2 is CR 2 , X 3 is CR 3 , G 1 is NR 4 R 5 , R 4 is methyl, and R 5 is substituted
  • Another aspect is related to a group of compounds of formula (I) wherein X 1 is CR 1 , X 2 is CR 2 , X 3 is CR 3 , G 1 is NR 4 R 5 , R 4 is hydrogen or C1-C4 alkyl, and R 5 is optionally substituted pyrrolidinyl.
  • Another aspect is related to a group of compounds of formula (I) wherein X 1 is CR 1 , X 2 is CR 2 , X 3 is CR 3 , G 1 is NR 4 R 5 , and R 5 is optionally substituted cycloalkyl (e.g. cyclobutyl, cyclohexyl, adamantyl, each of which is optionally substituted).
  • X 1 is CR 1
  • X 2 is CR 2
  • X 3 is CR 3
  • G 1 is NR 4 R 5
  • R 5 is optionally substituted cycloalkyl (e.g. cyclobutyl, cyclohexyl, adamantyl, each of which is optionally substituted).
  • each R 5 is independently unsubstituted or substituted as described in the Summary and embodiments herein above.
  • Another aspect is related to a group of compounds of formula (I) and (la) wherein
  • X 1 is CR
  • X" is CR
  • X is CR J
  • ring A is pyrrolidinyl or piperidinyl, each of which is optionally further substituted.
  • Another aspect is related to a group of compounds of formula (I) and (la) wherein
  • X 1 is CR
  • X" is CR
  • X is CR J
  • ring A is pyrrolidinyl or piperidinyl, each of which is optionally further substituted
  • G 2 is G 2a or -L'-G 2b
  • L 1 is O.
  • Another aspect is related to a group of compounds of formula (I) and (la) wherein X 1 1 is CR 1 , X 2" is CR 2, X 3 is CR 3 J , ring A 1 is pyrrolidinyl or or piperidinyl, each of which is optionally further substituted, and G 2 is G 2a .
  • Another aspect is related to a group of compounds of formula (I) and (la) wherein X 1 is CR , X is CR X J is CR J , and ring A is piperidinyl which is optionally further substituted.
  • Another aspect is related to a group of compounds of formula (I) and (la) wherein
  • X 1 is CR
  • X" is CR
  • X is CR J
  • ring A is piperidinyl which is optionally further substituted
  • G 2 is G 2a or -L'-G 2b
  • L 1 is O.
  • Another aspect is related to a group of compounds of formula (I) and (la) wherein
  • X 1 is CR
  • ⁇ ⁇ is CR
  • X is CR
  • ring A is piperidinyl which is optionally further substituted
  • G 2 is G 2a .
  • Another aspect is related to a group of compounds of formula (I) and (la) wherein
  • X 1 is CR
  • X" is CR
  • X is CR J
  • ring A is piperidinyl which is optionally further substituted
  • G 2 is G 2a
  • G 2a is a substituted phenyl.
  • Another aspect is related to a group of compounds of formula (I) and (la) wherein
  • X 1 is CR
  • X" is CR
  • X is CR J
  • ring A is pyrrolidinyl which is optionally further substituted.
  • Another aspect is related to a group of compounds of formula (I) and (la) wherein
  • X 1 is CR 1
  • X" is CR
  • X is CR J
  • ring A is pyrrolidinyl which is optionally further substituted
  • G 2 is G 2a or -L'-G 2b
  • L 1 is O.
  • Another aspect is related to a group of compounds of formula (I) and (la) wherein
  • X 1 is CR
  • X" is CR
  • X is CR J
  • ring A is pyrrolidinyl which is optionally further substituted
  • G 2 is G 2a .
  • G 2a and G 2b the substituents of G 2a and G 2b , and the optional substituents of ring A 1 have values as described in the Summary and embodiments herein above.
  • Another aspect is related to a group of compounds of formula (I) and (lb) whererin X 1 is CR 1 , X 2 is CR 2 , X 3 is CR 3 , and G 3 is G 3a .
  • G 3a is optionally substituted aryl.
  • G 3a is optionally substituted phenyl.
  • Another aspect is related to a group of compounds of formula (I) and (lb) whererin X 1 is CR 1 , X 2 is CR 2 , X 3 is CR 3 , R 6 is OH, and G 3 is G 3a .
  • G 3a is optionally substituted aryl.
  • G 3a is optionally substituted phenyl.
  • Another aspect is related to a group of compounds of formula (I) and (lb) whererin X 1 is CR 1 , X 2 is CR 2 , X 3 is CR 3 , R 6 is CN or halogen, and G 3 is G 3a .
  • G 3a is optionally substituted aryl.
  • G 3a is optionally substituted phenyl.
  • Another aspect is related to a group of compounds of formula (I) and (lb) whererin X 1 is CR 1 , X 2 is CR 2 , X 3 is CR 3 , and G 3 is -L 2 -G 3a .
  • L 2 is O and G 3a is optionally substituted phenyl.
  • Another aspect is related to a group of compounds of formula (I) and (lb) whererin X 1 is CR 1 , X 2 is CR 2 , X 3 is CR 3 , R 6 is OH, and G 3 is -L 2 -G 3a .
  • L 2 is O and G 3a is optionally substituted phenyl.
  • Another aspect is related to a group of compounds of formula (I) and (lb) whererin X 1 is CR 1 , X 2 is CR 2 , X 3 is CR 3 , R 6 is CN or halogen, and G 3 is -L 2 -G 3a .
  • L 2 is O and G 3a is optionally substituted phenyl.
  • R 7 , p, and the optional substituents of G 3a have values as described in the Summary and embodiments herein above.
  • Another aspect is related to a group of compounds of formula (I) and (Ic) whererin
  • X 1 is CR 1
  • X" is CR
  • X is CR J
  • ring A is an optionally substituted heterocycle, with the proviso that ring A 2 is not an optionally substituted piperidinyl, an optionally substituted pyrrolidinyl, an optionally substituted 2,3-dihydroisoindolyl, or an optionally substituted decahydroisoquinolinyl.
  • the substituents of ring A 2 are as described in the Summary and embodiments herein above.
  • Another aspect is related to a group of compounds of formula (I) and (Ic) whererin
  • X 1 is CR
  • X" is CR
  • X is CR J
  • ring A is an optionally substituted monocyclic heterocycle, with the proviso that ring A 2 is not an optionally substituted piperidinyl or optionally substituted pyrrolidinyl.
  • ring A 2 is azetidinyl, piperazinyl, morpholinyl, tetrahydropyridinyl, or 8-azabicyclo[3.2.1]oct-8-yl, each of which is optionally substituted.
  • the substituents of ring A 2 are as described in the Summary and embodiments herein above.
  • Another aspect is related to a group of compounds of formula (I) and (Ic) whererin
  • X 1 is CR
  • X" is CR
  • X is CR J
  • ring A is substituted piperazinyl.
  • the substituents of ring A 2 are as described in the Summary and embodiments herein above.
  • Another aspect is related to a group of compounds of formula (I) and (Ic) whererin
  • X 1 is CR 1
  • X 2 is CR 2
  • X 3 is CR 3
  • ring A 2 is piperazinyl substituted with one G a group
  • G a is optionally substituted phenyl.
  • Another aspect is related to a group of compounds of formula (I) and (Ic) whererin
  • X 1 is CR
  • X" is CR
  • X is CR J
  • ring A is an optionally substituted spiro heterocycle.
  • ring A 2 is l 'H,4H-spiro[l,3-benzodioxine-2,4'- piperidin]-l '-yl, 6-azaspiro[2.5]oct-6-yl, l,4-dioxa-8-azaspiro[4.5]dec-8-yl, l 'H,3H- spiro[2-benzofuran-l,4'-piperidin]- -yl, or 7-oxa-l-azaspiro[3.5]non-l-yl, each of which is optionally substituted.
  • the substituents of ring A 2 are as described in the Summary and embodiments herein above.
  • Another aspect is related to a group of compounds of formula (I) and (Ic) whererin
  • X 1 is CR 1
  • X 2 is CR 2
  • X 3 is CR 3
  • ring A 2 is an optionally substituted 1 'H,3H-spiro[2- benzofuran-l,4'-piperidin]-l '-yl.
  • the substituents of ring A 2 are as described in the Summary and embodiments herein above.
  • ring A 2 is an unsubstituted 1 'H,3H-spiro[2-benzofuran- 1 ,4'-piperidin]- 1 '-yl.
  • Another aspect is related to a group of compounds of formula (I) and (Ic) whererin
  • X 1 is CR 1
  • X" is CR
  • X is CR ⁇
  • ring A is an optionally substituted bicyclic heterocycle with the proviso that ring A 2 is not an optionally substituted 2,3- dihydroisoindolyl or an optionally substituted decahydroisoquinolinyl.
  • ring A 2 is 3,4-dihydroisoquinolin-2(lH)-yl, 2,3,4,6-tetrahydro-lH- pyrido[l,2-a]pyrazin-2-yl, hexahydropyrano[3,4-b][l,4]oxazin-l(5H)-yl, or
  • Another aspect is related to a group of compounds of formula (I) and (Ic) whererin X 1 is CR 1 , X 2 is CR 2 , X 3 is CR 3 , and ring A is an optionally substituted
  • hexahydropyrana[3,4-b][l,4]-oxazin-l(5H)-yl The substituents of ring A 2 are as described in the Summary and embodiments herein above. In certain embodiments, ring A 2 is unsubstituted hexahydropyrana[3,4-b][l,4]-oxazin-l(5H)-yl.
  • Another aspect is related to a group of compounds of formula (I) and (Ic) whererin
  • X is CR , X is CR , X is CR , and ring A is an optionally substituted
  • hexahydropyrano[4,3-b]pyrrol-l(4H)-yl The substituents of ring A 2 are as described in the Summary and embodiments herein above. In certain embodiments, ring A 2 is unsubstituted hexahydropyrano[4,3-b]pyrrol- 1 (4H)-yl.
  • Another aspect is related to a group of compounds of formula (I) and (Ic) whererin
  • X 1 is CR
  • X" is CR%
  • X J is CR J
  • ring A is a monocyclic heterocycle fused with a monocyclic heteroaryl
  • ring A 2 is optionally substituted as described in the Summary and embodiments herein above.
  • R 1 , R 2 , and R 3 are as described in the Summary and embodiments herein above.
  • examples of a subgroup include but not limited to those whererin R 1 , R 2 , and R 3 are the same or different, and are each independently hydrogen or haloalkyl.
  • Examples of another subgroup include, but not limited to, those whererin R 1 and
  • R are hydrogen, and R is halogen (e.g. CI, Br, F), -CN, or haloalkyl (such as, but not limited to, trifluoromethyl, difluoromethyl).
  • halogen e.g. CI, Br, F
  • -CN e.g., benzyl
  • haloalkyl such as, but not limited to, trifluoromethyl, difluoromethyl
  • Examples of another subgroup include, but not limited to, those whererin R 1 and R 3 are hydrogen, and R 2 is haloalkyl.
  • Examples of yet another subgroup include, but not limited to, those whererin R 1 and R 3 are hydrogen, and R 2 is trifluoromethyl.
  • One embodiment is directed to compounds of formula (I) wherein
  • X 1 is CR 1 or N
  • X 2 is CR 2 or N
  • X 3 is CR 3 or N; with the proviso that no more than one of X 1 , X 2 , and X 3 is N; R 1 , R 2 , and R 3 are each independently hydrogen, halogen, alkyl, or haloalkyl;
  • G 1 is - 4 R 5 , formula (a), (b), or (c)
  • R 4 is hydrogen, alkyl, haloalkyl, or alkoxyalkyl
  • an heterocycle selected from the group consisting of a monocyclic heterocycle wherein one of the ring atoms is O, N, or NH and having zero or one double bond, optionally contains one or two additional heteroatoms selected from the group consisting of O, N, NH, and S; a bicyclic heterocycle, and a spiro heterocycle;
  • each of the R 5 phenyl, naphthyl, cycloalkyl, heteroaryl, heterocycle, and the heterocycle moiety of the heterocyclealkyl is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 R a ;
  • R 1 and R 3 are hydrogen, R 2 is haloalkyl, R 4 is alkyl, and R 5 is a monocyclic heterocycle or a heterocyclealkyl, then the heterocycle moiety of R 5 is substituted;
  • ring A 1 is 2,3-dihydro-lH-isoindolyl, decahydroisoquinolinyl, piperidinyl, or pyrrolidinyl, each of which is optionally further substituted with 1 , 2, or 3 substituents independently selected from the group consisting of CN, alkyl, oxo, halogen, haloalkyl, OH, O(alkyl), and 0(haloalkyl); with the proviso that when ring A 1 is piperidinyl, then G 2 and the optional substituent of ring A 1 do not reside on the same carbon atom;
  • G 2 is G 2a or -L'-G 2b ; a bicyclic aryl, a bicyclic cycloalkyl, a bicyclic heterocycle, a spiro heterocycle, or an heteroaryl, each of which is optionally substituted with 1, 2, 3, 4, or 5 R b ; or
  • a phenyl a monocyclic cycloalkyl, or a monocyclic heterocycle, each of which is independently substituted with 1, 2, 3, 4, or 5 R b ;
  • G 2b is aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycle, each of which is optionally substituted with 1, 2, 3, 4, or 5 R b ;
  • R 6 is CN, OH, or halogen
  • each R 7 is an optional substituent on any substitutable carbon atom, and is independently alkyl, haloalkyl, halogen, oxo, or OH;
  • p 0, 1, 2, or 3;
  • G 3 is G 3a or -L 2 -G 3a ;
  • L 1 and L 2 are independently O, N(J k ), or S; wherein J k , at each occurrence, is independently hydrogen, alkyl, haloalkyl, C(0)R k , S(0)2R k , or C 3 -C4 cycloalkyl; wherein the C 3 -C4 cycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independenly selected from the group consisting of alkyl, halogen, haloalkyl, oxo, hydroxy, and alkoxy,
  • R k at each occurrence, is independently alkyl or C 3 -C4 cycloalkyl; wherein the C 3 -C4 cycloalkyl is optionally with 1, 2, 3, or 4 substituents independenly selected from the group consisting of alkyl, halogen, haloalkyl, oxo, hydroxy, and alkoxy;
  • G 3a is aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycle, each of which is optionally substituted with 1, 2, 3, 4, or 5 R c ;
  • each ring A 2 is optionally substituted with 1, 2, 3, 4, or 5 R d ; with the proviso that ring A 2 is not 2,3-dihydro- lH-isoindolyl, decahydroisoquinolinyl, piperidinyl, or pyrrolidinyl;
  • R a , R , R c , and R a are optional substituents on any substitutable atoms, and at each occurrence, are each independently alkyl, alkenyl, alkynyl, halogen, oxo, haloalkyl, CN, N0 2 , -OR f , -OC(0)R f , -OC(0)N(R f )(R s ), -S(0) 2 R e , -S(0) 2 N(R f )(R s ), -C(0)R f , -C(0)OR f , -C(0)N(R f )(R g ), -N(R f )(R g ), -N(R g )C(0)R f , -N(R g )S(0) 2 R e , -N(R g )C(0)0(R f ),
  • R e at each occurrence, is independently alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, G b , or -(C1-C6 alkylenyl)-G b ;
  • R at each occurrence, is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, G b , or -(C1-C6 alkylenyl)-G b ;
  • R g at each occurrence, is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, benzyl, or monocyclic cycloalkyl;
  • G a and G b are each independently aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycle, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, -CN, oxo, -OR h , -OC(0)R h , -OC(0)N(R h ) 2 , -SCO ⁇ R 1 , -S(0) 2 N(R h ) 2 , -C(0)R h , -C(0)OR h , -C(0)N(R h ) 2 , -N(R h ) 2 , -N(R h )C(0)R h , -N(R h )S(0) 2 R i ,
  • R x , R y , R xb , and R yb are each independently hydrogen, alkyl, halogen, or haloalkyl;
  • ql and q2, at each occurrence, are each independently 1, 2, 3, or 4;
  • R h at each occurrence, is independently hydrogen, alkyl, or haloalkyl; and R 1 , at each occurrence, is independently alkyl or haloalkyl.
  • Exemplary compounds contemplated include, but are not limited to:
  • Compounds of formula (I) contain one or more chiral centers, and can exist in different optically active forms. When compounds of formula (I) contain one chiral center, the compounds exist in two enantiomeric forms and the present invention includes both enantiomers and mixtures of enantiomers, such as racemic mixtures.
  • the enantiomers may be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts which may be separated, for example, by crystallization; formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent.
  • enantiomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.
  • a compound of formula (I) When a compound of formula (I) contains more than one chiral center, it may exist in diastereoisomeric forms.
  • the diastereoisomeric compounds may be separated by methods known to those skilled in the art, for example chromatography or crystallization.
  • the present invention includes each diastereoisomer of compounds of formula (I) and mixtures of various ratios thereof.
  • Certain compounds of formula (I) may exist in different tautomeric forms or as different geometric isomers, and the present invention includes all tautomers and/or geometric isomers of compounds of formula (I) and mixtures thereof.
  • Isotopes of atoms such as hydrogen, carbon, phosphorous, sulfur, fluorine, chlorine, and iodine include, but are not limited to, 2 H, 3 H, 13 C, 14 C, 1 N, 18 0, 32 P, 3 S, 18 F, 36 C1, and 12 I. Compounds that contain other isotopes of these and/or other atoms are within the scope of this invention.
  • the isotope-labeled compounds contain deuterium ( 2 H), tritium ( 3 H) or 14 C isotopes.
  • Isotope-labeled compounds of this invention can be prepared by the general methods well known to persons having ordinary skill in the art. Such isotope-labeled compounds can be conveniently prepared by carrying out the procedures disclosed in the Examples and Schemes sections by substituting a readily available isotope-labeled reagent for a non-labeled reagent.
  • compounds may be treated with isotope-labeled reagents to exchange a normal atom with its isotope, for example, hydrogen for deuterium can be exchanged by the action of a deuteric acid such as D2SO4/D 2 O.
  • the isotope-labeled compounds of the invention may be used as standards to determine the effectiveness of CCR2 modulators in binding assays.
  • Isotope containing compounds have been used in pharmaceutical research to investigate the in vivo metabolic fate of the compounds by evaluation of the mechanism of action and metabolic pathway of the nonisotope-labeled parent compound (Blake et al. J. Pharm. Sci. 64, 3, 367-391 (1975)).
  • Such metabolic studies are important in the design of safe, effective therapeutic drugs, either because the in vivo active compound administered to the patient or because the metabolites produced from the parent compound prove to be toxic or carcinogenic (Foster et al., Advances in Drug Research Vol. 14, pp.
  • non-radioactive isotope-containing drugs such as deuterated drugs called “heavy drugs,” can be used for the treatment of diseases and conditions related to the modulation of CCR2 function. Increasing the amount of an isotope present in a compound above its natural abundance is called enrichment.
  • Examples of the amount of enrichment include from about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71, 75, 79, 84, 88, 92, 96, to about 100 mol %.
  • Replacement of up to about 15% of normal atom with a heavy isotope has been effected and maintained for a period of days to weeks in mammals, including rodents and dogs, with minimal observed adverse effects (Czajka D M and Finkel A J, Ann. N.Y. Acad. Sci. 1960 84: 770; Thomson J F, Ann. New York Acad. Sci 1960 84: 736; Czakja D M et al., Am. J.
  • Stable isotope labeling of a drug may alter its physico-chemical properties such as pKa and lipid solubility. These effects and alterations may affect the pharmacodynamic response of the drug molecule if the isotopic substitution affects a region involved in a ligand-receptor interaction. While some of the physical properties of a stable isotope- labeled molecule are different from those of the unlabeled one, the chemical and biological properties are the same, with one exception: because of the increased mass of the heavy isotope, any bond involving the heavy isotope and another atom will be stronger than the same bond between the light isotope and that atom. Accordingly, the incorporation of an isotope at a site of metabolism or enzymatic transformation will slow said reactions, potentially altering the pharmacokinetic profile or efficacy relative to the non-isotopic compound.
  • CHO cells expressing human CCR2B were generated as follows. cDNA for human CCR2B (cloned from human blood) was cloned into plasmid pcDNA3.1 (from Invitrogen). The resulting plasmids were separately transfected into CHO cells expressing human Gal 6 (from Molecular Devices). Sequences of the transfected CCR2 open reading frames in the resulting cell lines were identical to human CCR2B (NM 00648).
  • CHO cells expressing rat CCR2 (rCCR2) were generated as follows. cDNA for rat CCR2 (cloned from rat macrophage) was cloned into plasmid pEF- flag (from Chinese Academy of Science). The resulting plasmids were transfected into CHO cells expressing human Gal 6 (from Abbott). Sequences of the transfected CCR2 open reading frames in the resulting cell lines were identical to rat CCR2
  • Calcium flux assays were performed in CHO cells expressing human CCR2B and Gal 6 coupling protein, or rat CCR2 and Gal 6 coupling protein. All compounds were dissolved in DMSO and assays run at a final DMSO concentration of 0.25% (v/v).
  • Human MCP- 1 was purchased from PeproTech and used at a final assay concentration of 2 nM, while rat MCP- 1 was purchased from R&D and used at a final assay concentration of 4 nM. Assays with cells expressing human CCR2B were performed with human MCP- 1, while assays with cells expressing rat CCR2 were performed with rat MCP-1.
  • Calcium 4 dye (Molecular Probes) at 37 °C for 60 minutes.
  • Calcium flux assays were performed on a FLIPR Tetra instrument (Molecular Devices) by adding compound to the cells followed by addition of native agonist and measuring the change in fluorescence as a function of time. Maximal and minimal values for fluorescence were determined using native agonist (2 nM MCP-1) for human or rat CCR2, or buffer addition, respectively. Fluorescence values were used to calculate the percent inhibition at a given compound concentration and the data fit to a sigmoidal curve in a semi-log plot to determine IC50 values.
  • the invention provides a method for antagonizing CCR2 in a subject (e.g. human) suffering from a disorder in which CCR2 activity is detrimental, comprising administering to the subject a compound of formula (I), (la), (lb), or (Ic), or a pharmaceutical composition comprising the same, such that CCR2 activity in the human subject is inhibited and treatment is achieved.
  • a subject e.g. human
  • a disorder in which CCR2 activity is detrimental comprising administering to the subject a compound of formula (I), (la), (lb), or (Ic), or a pharmaceutical composition comprising the same, such that CCR2 activity in the human subject is inhibited and treatment is achieved.
  • autoimmune diseases and disease associated with chronic inflammation have been linked to activation of CCR2.
  • the present compounds are useful in the treatment of inflammatory disorders including, but not limited to rheumatoid arthritis, osteoarthritis, asthma, chronic obstructive pulmonary disease (COPD), sepsis, psoriasis, psoriatic arthritis, inflammatory bowel disease, Crohn's disease, lupus, multiple sclerosis, juvenile chronic arthritis, Lyme arthritis, reactive arthritis, septic arthritis, spondyloarthropathy and systemic lupus erythematosus.
  • COPD chronic obstructive pulmonary disease
  • present compounds or the pharmaceutical compositions comprising the same are also useful in the treatment of cardiovascular disorders, such as acute myocardial infarction, acute coronary syndrome, chronic heart failure, atherosclerosis, viral myocarditis, cardiac allograft rejection, and sepsis-associated cardiac dysfunction.
  • cardiovascular disorders such as acute myocardial infarction, acute coronary syndrome, chronic heart failure, atherosclerosis, viral myocarditis, cardiac allograft rejection, and sepsis-associated cardiac dysfunction.
  • the compounds of the present invention are also useful for the treatment of central nervous system disorders such as meningococcal meningitis, Alzheimer's disease and Parkinson's disease.
  • Compounds decribed herein or a pharmaceutically acceptable salt thereof or pharmaceutical compositions comprising a therapeutically effective amount thereof is useful in the treatment of a disorder selected from the group comprising CNS system disorders, arthritis, rheumatoid arthritis, osteoarthritis, juvenile chronic arthritis, Lyme arthritis, psoriatic arthritis, reactive arthritis, and septic arthritis, spondyloarthropathy, systemic lupus erythematosus, Crohn's disease, ulcerative colitis, inflammatory bowel disease, insulin dependent diabetes mellitus, thyroiditis, asthma, allergic diseases, psoriasis, dermatitis scleroderma, graft versus host disease, organ transplant rejection (including but not limited to bone marrow and solid organ rejection), acute or chronic immune disease associated with organ transplantation, sarcoidosis, atherosclerosis, disseminated intravascular coagulation, Kawasaki's disease, Grave's disease, nephrotic syndrome, chronic fatigue syndrome, Wegener'
  • autoimmune hepatitis dermatomyositis/polymyositis associated lung disease, Sjogren's disease associated lung disease, ankylosing spondylitis associated lung disease, vasculitic diffuse lung disease, haemosiderosis associated lung disease, drug-induced interstitial lung disease, radiation fibrosis, bronchiolitis obliterans, chronic eosinophilic pneumonia, lymphocytic infiltrative lung disease, postinfectious interstitial lung disease, gouty arthritis, autoimmune hepatitis, type- 1 autoimmune hepatitis (classical autoimmune or lupoid hepatitis), type-2 autoimmune hepatitis (anti-LKM antibody hepatitis), autoimmune mediated
  • hypoglycaemia type B insulin resistance with acanthosis nigricans, hypoparathyroidism, acute immune disease associated with organ transplantation, chronic immune disease associated with organ transplantation, osteoarthrosis, primary sclerosing cholangitis, psoriasis type 1 , psoriasis type 2, idiopathic leucopaenia, autoimmune neutropaenia, renal disease NOS, glomerulonephritides, microscopic vasulitis of the kidneys, Lyme disease, discoid lupus erythematosus, male infertility idiopathic or NOS, sperm autoimmunity, multiple sclerosis (all subtypes), sympathetic ophthalmia, pulmonary hypertension secondary to connective tissue disease, Goodpasture's syndrome, pulmonary
  • such compounds may be useful in the treatment of disorders such as edema, ascites, effusions, and exudates, including for example macular edema, cerebral edema, acute lung injury, adult respiratory distress syndrome (ARDS), proliferative disorders such as restenosis, fibrotic disorders such as hepatic cirrhosis and atherosclerosis, mesangial cell proliferative disorders such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, and
  • glomerulopathies myocardial angiogenesis, coronary and cerebral collaterals, ischemic limb angiogenesis, ischemia/reperfusion injury, peptic ulcer Helicobacter related diseases, virally-induced angiogenic disorders, Crow-Fukase syndrome (POEMS), preeclampsia, menometrorrhagia, cat scratch fever, rubeosis, neovascular glaucoma and retinopathies such as those associated with diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration or a central nervous system disorder.
  • POEMS Crow-Fukase syndrome
  • these compounds can be used as active agents against solid tumors, malignant ascites, von Hippel Lindau disease, hematopoietic cancers and hyperproliferative disorders such as thyroid hyperplasia (especially Grave's disease), and cysts (such as hypervascularity of ovarian stroma characteristic of polycystic ovarian syndrome (Stein-Leventhal syndrome) and polycystic kidney disease since such diseases require a proliferation of blood vessel cells for growth and/or metastasis.
  • thyroid hyperplasia especially Grave's disease
  • cysts such as hypervascularity of ovarian stroma characteristic of polycystic ovarian syndrome (Stein-Leventhal syndrome) and polycystic kidney disease since such diseases require a proliferation of blood vessel cells for growth and/or metastasis.
  • Another aspect relates to a method for the treatment of pain such as, but not limited to, neuropathic pain, nociceptive pain, inflammatory pain, osteoarthritic pain, fibromyalgia, neuralgia such as postherpatic neuralgia and trigeminal neuralgia, diabatic neuropathic pain, HIV-related neuropathic pain, migraine, post-stroke pain, post- operative pain, multiple sclerosis pain, pain related to spinal cord injury, cancer pain, lower back pain, and eye pain, comprising administering to a subject in need of such treatment compounds described herein, or pharmaceutically acceptable salts thereof, alone or in combination with a pharmaceutically acceptable carrier.
  • pain such as, but not limited to, neuropathic pain, nociceptive pain, inflammatory pain, osteoarthritic pain, fibromyalgia, neuralgia such as postherpatic neuralgia and trigeminal neuralgia, diabatic neuropathic pain, HIV-related neuropathic pain, migraine, post
  • Present compounds can be used alone or in combination with another therapeutic agent to treat such diseases, said additional agent being selected by the skilled artisan for its intended purpose.
  • the additional agent can be a therapeutic agent recognized as being useful to treat the disease or condition being treated by the compound of the present invention.
  • the additional agent also can be an agent that imparts a beneficial attribute to the therapeutic composition e.g., an agent that affects the viscosity of the composition.
  • the combinations which are to be included within this invention are those combinations useful for their intended purpose.
  • the agents set forth below are for illustrative purposes and not intended to be limited.
  • the combinations, which are part of this invention can be the compounds of the present invention and at least one additional agent selected from the lists below.
  • the combination can also include more than one additional agent, e.g., two or three additional agents if the combination is such that the formed composition can perform its intended function.
  • the present compounds may be used in conjunction or combination with an anti-inflammatory or analgesic agent such as an opiate agonist, a lipoxygenase inhibitor, such as an inhibitor of 5 -lipoxygenase, a cyclooxygenase inhibitor, such as a cyclooxygenase-2 inhibitor, an interleukin inhibitor, such as an interleukin- 1 inhibitor, an NMDA antagonist, an inhibitor of nitric oxide or an inhibitor of the synthesis of nitric oxide, a non-steroidal antiinflammatory agent, or a cytokine- suppressing anti-inflammatory agent, for example with a compound such as acetaminophen, aspirin, codeine, fentanyl, ibuprofen, indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, a steroidal analgesic, sufentanyl, sunlindac,
  • an anti-inflammatory or analgesic agent such
  • the instant compounds may be administered with a pain reliever; a potentiator such as caffeine, an H2- antagonist, simethicone, aluminum or magnesium hydroxide; a decongestant such as phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desoxy-ephedrine; an antiitussive such as codeine, hydrocodone, caramiphen, carbetapentane, or dextromethorphan; a diuretic; and a sedating or non-sedating antihistamine.
  • a pain reliever such as caffeine, an H2- antagonist, simethicone, aluminum or magnesium hydroxide
  • a decongestant such as phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine
  • compounds of the present invention may be used in combination with other drugs that are used in the treatment/prevention/suppression or amelioration of the diseases or conditions for which compounds of the present invention are useful.
  • Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention.
  • a pharmaceutical composition containing such other drugs in addition to the present compounds is preferred.
  • the pharmaceutical compositions include those that also contain one or more other active ingredients, in addition to a compound of formula (I), (la), (lb), or (Ic).
  • active ingredients include, but are not limited to: (a) VLA-4 antagonists, (b) steroids such as beclomethasone, methylprednisolone, betamethasone, prednisone, dexamethasone, and hydrocortisone; (c) immunosuppressants such as cyclosporine (cyclosporine A, Sandimmune®, Neoral®), tacrolimus (FK-506, Prograf®), rapamycin (sirolimus, Rapamune®) and other FK-506 type immunosuppressants, and mycophenolate, e.g., mycophenolate mofetil (CellCept®);
  • antihistamines such as bromopheniramine
  • trimeprazine azatadine, cyproheptadine, antazoline, pheniramine pyrilamine, astemizole, terfenadine, loratadine, cetirizine, fexofenadine, descarboethoxyloratadine, and the like;
  • non-steroidal anti-asthmatics such as beta.2-agonists (terbutaline, metaproterenol, fenoterol, isoetharine, albuterol, bitolterol, and pirbuterol), theophylline, cromolyn sodium, atropine, ipratropium bromide, leukotriene antagonists (zafirlukast, montelukast, pranlukast, iralukast, pobilukast, SKB- 106,203), leukotriene biosynthesis inhibitors (zileuton, BAY- 1005);
  • non- steroidal antiinflammatory agents such as propionic acid derivatives (alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indopro
  • NSAIDs non-
  • the weight ratio of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with an NSAID the weight ratio of the compound of the present invention to the NSAID will generally range from about 1000: 1 to about 1 : 1000, preferably about 200: 1 to about 1 :200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
  • Immunosuppressants within the scope of the present invention further include, but are not limited to, leflunomide, RAD001 , ERL080, FTY720, CTLA-4, antibody therapies such as orthoclone (OKT3), daclizumab (Zenapax®) and basiliximab (Simulect®), and antithymocyte globulins such as thymoglobulins.
  • antibody therapies such as orthoclone (OKT3), daclizumab (Zenapax®) and basiliximab (Simulect®
  • antithymocyte globulins such as thymoglobulins.
  • the present methods are also directed to the treatment or prevention of multiple sclerosis using a compound of the invention either alone or in combination with a second therapeutic agent selected from betaseron, avonex, azathioprene (Imurek®, Imuran®), capoxone, prednisolone and cyclophosphamide.
  • a second therapeutic agent selected from betaseron, avonex, azathioprene (Imurek®, Imuran®), capoxone, prednisolone and cyclophosphamide.
  • the practitioner can administer a combination of the therapeutic agents, or administration can be sequential.
  • the present methods are directed to the treatment or prevention of rheumatoid arthritis, wherein the compound of the invention is administered either alone or in combination with a second therapeutic agent selected from the group consisting of methotrexate, sulfasalazine, hydroxychloroquine, cyclosporine A, D- penicillamine, infliximab (Remicade®), etanercept (Enbrel®), adalimumab (Humira®), auranofin and aurothioglucose.
  • a second therapeutic agent selected from the group consisting of methotrexate, sulfasalazine, hydroxychloroquine, cyclosporine A, D- penicillamine, infliximab (Remicade®), etanercept (Enbrel®), adalimumab (Humira®), auranofin and aurothioglucose.
  • the present methods are directed to the treatment or prevention of an organ transplant condition wherein the compound of the invention is used alone or in combination with a second therapeutic agent selected from the group consisting of cyclosporine A, FK-506, rapamycin, mycophenolate, prednisolone, azathioprene, cyclophosphamide and an antilymphocyte globulin.
  • a second therapeutic agent selected from the group consisting of cyclosporine A, FK-506, rapamycin, mycophenolate, prednisolone, azathioprene, cyclophosphamide and an antilymphocyte globulin.
  • Present compounds can also be combined with a non-steroidal anti-inflammatory drug(s) also referred to as NSAIDS which include drugs like ibuprofen.
  • Non-limiting examples of therapeutic agents for rheumatoid arthritis with which a compound of Formula (I) of the invention can be combined include the following: cytokine suppressive anti-inflammatory drug(s) (CSAIDs); antibodies to or antagonists of other human cytokines or growth factors, for example, TNF, LT, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-12, IL- 15, IL- 16, IL-21 , IL-23, interferons, EMAP-II, GM-CSF, FGF, and PDGF.
  • CSAIDs cytokine suppressive anti-inflammatory drug
  • S/T kinase inhibitors of the invention can be combined with antibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD80 (B7.1), CD86 (B7.2), CD90, CTLA or their ligands including CD 154 (gp39 or CD40L).
  • cell surface molecules such as CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD80 (B7.1), CD86 (B7.2), CD90, CTLA or their ligands including CD 154 (gp39 or CD40L).
  • Preferred combinations of therapeutic agents may interfere at different points in the autoimmune and subsequent inflammatory cascade; preferred examples include TNF antagonists like chimeric, humanized or human TNF antibodies, D2E7 (HUMIRA®), (U.S. Patent No. US 6,090,382), CA2 (REMICADETM), CDP 571, and soluble p55 or p75 TNF receptors, derivatives, thereof, (p75TNFRlgG (ENBRELTM) or p55TNFRlgG (Lenercept), and also TNFa converting enzyme (TACE) inhibitors; similarly IL-1 inhibitors (Interleukin- 1 -converting enzyme inhibitors, IL-IRA etc.) may be effective for the same reason.
  • TNF antagonists like chimeric, humanized or human TNF antibodies, D2E7 (HUMIRA®), (U.S. Patent No. US 6,090,382), CA2 (REMICADETM), CDP 571, and soluble p55 or p75 TNF receptors, derivatives
  • Yet other preferred combinations are the other key players of the autoimmune response which may act parallel to, dependent on or in concert with IL- 18 function; especially preferred are IL- 12 antagonists including IL-12 antibodies or soluble IL-12 receptors, or IL-12 binding proteins. It has been shown that IL- 12 and IL- 18 have overlapping but distinct functions and a combination of antagonists to both may be most effective. Yet another preferred combination are non-depleting anti-CD4 inhibitors. Yet other preferred combinations include antagonists of the co-stimulatory pathway CD80 (B7.1) or CD86 (B7.2) including antibodies, soluble receptors or antagonistic ligands.
  • Present compounds may also be combined with agents, such as methotrexate, 6-
  • hydroxychloroquine pencillamine, aurothiomalate (intramuscular and oral), azathioprine, cochicine, corticosteroids (oral, inhaled and local injection), beta-2 adrenoreceptor agonists (salbutamol, terbutaline, salmeteral), xanthines (theophylline, aminophylline), cromoglycate, nedocromil, ketotifen, ipratropium and oxitropium, cyclosporin, FK506, rapamycin, mycophenolate mofetil, leflunomide, NSAIDs, for example, ibuprofen, corticosteroids such as prednisolone, phosphodiesterase inhibitors, adensosine agonists, antithrombotic agents, complement inhibitors, adrenergic agents, agents which interfere with signalling by proinflammatory cytokines such as TNFa or IL-1 (e.g.
  • IL- ⁇ ⁇ converting enzyme inhibitors T-cell signalling inhibitors such as kinase inhibitors, metalloproteinase inhibitors, sulfasalazine, 6-mercaptopurines, angiotensin converting enzyme inhibitors, soluble cytokine receptors and derivatives thereof (e.g. soluble p55 or p75 TNF receptors and the derivatives p75TNFRIgG (EnbrelTM and p55TNFRIgG (Lenercept)), sIL- lRI, sIL-lRII, sIL-6R), antiinflammatory cytokines (e.g.
  • IL-4, IL-10, IL-1 1, IL-13 and TGF celecoxib, folic acid, hydroxychloroquine sulfate, rofecoxib, etanercept, infliximab, naproxen, valdecoxib, sulfasalazine, methylprednisolone, meloxicam, methylprednisolone acetate, gold sodium thiomalate, aspirin, triamcinolone acetonide, propoxyphene napsylate/apap, folate, nabumetone, diclofenac, piroxicam, etodolac, diclofenac sodium, oxaprozin, oxycodone HC1, hydrocodone bitartrate/apap, diclofenac sodium/misoprostol, fentanyl, anakinra, tramadol HC1, salsalate, sulindac, cyano
  • acetaminophen alendronate sodium, prednisolone, morphine sulfate, lidocaine hydrochloride, indomethacin, glucosamine sulf/chondroitin, amitriptyline HC1, sulfadiazine, oxycodone HCl/acetaminophen, olopatadine HC1 misoprostol, naproxen sodium, omeprazole, cyclophosphamide, rituximab, IL- 1 TRAP, MRA, CTLA4-IG, IL- 18 BP, anti-IL-12, Anti-IL15, BIRB-796, SCIO-469, VX-702, AMG-548, VX-740, Roflumilast, IC-485, CDC-801, and Mesopram.
  • Preferred combinations include methotrexate or leflunomide and in moderate or severe rheumatoid arthritis cases, cyclo
  • Non-limiting examples of therapeutic agents for inflammatory bowel disease with which a compound of Formula (I) of the invention can be combined include the following: budenoside; epidermal growth factor; corticosteroids; cyclosporin, sulfasalazine; aminosalicylates; 6-mercaptopurine; azathioprine; metronidazole;
  • lipoxygenase inhibitors mesalamine; olsalazine; balsalazide; antioxidants; thromboxane inhibitors; IL-1 receptor antagonists; anti-IL- ⁇ ⁇ monoclonal antibodies; anti-IL-6 monoclonal antibodies; growth factors; elastase inhibitors; pyridinyl-imidazole compounds; antibodies to or antagonists of other human cytokines or growth factors, for example, TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-15, IL-16, EMAP-II, GM-CSF, FGF, and PDGF; cell surface molecules such as CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD90 or their ligands; methotrexate; cyclosporine; FK506; rapamycin; mycophenolate mofetil; leflunomide; NSAIDs, for
  • corticosteroids such as prednisolone; phosphodiesterase inhibitors; adenosine agonists; antithrombotic agents; complement inhibitors; adrenergic agents; agents which interfere with signalling by proinflammatory cytokines such as TNFa or IL-1 (e.g.
  • IL- ⁇ converting enzyme inhibitors include IL- ⁇ converting enzyme inhibitors; TNFa converting enzyme inhibitors; T-cell signalling inhibitors such as kinase inhibitors; metalloproteinase inhibitors; sulfasalazine; azathioprine; 6-mercaptopurines; angiotensin converting enzyme inhibitors; soluble cytokine receptors and derivatives thereof (e.g. soluble p55 or p75 TNF receptors, sIL-lRI, sIL- lRJI, sIL-6R) and antiinflammatory cytokines (e.g. IL-4, IL- 10, IL-1 1, IL-13 and TGF ).
  • TNF antagonists for example, anti-TNF antibodies, D2E7 (U.S. Patent No. 6,090,382; HUMIRA®), CA2 (REMICADETM), CDP 571, TNFR-Ig constructs, (p75TNFRJgG (ENBRELTM) and p55TNFRIgG (LENERCEPTTM)) inhibitors and PDE4 inhibitors.
  • a compound of Formula (I) can be combined with corticosteroids, for example, budenoside and dexamethasone; sulfasalazine, 5-aminosalicylic acid; olsalazine; and agents which interfere with synthesis or action of proinflammatory cytokines such as IL- 1 , for example, IL- ⁇ ⁇ converting enzyme inhibitors and IL-lra; T cell signaling inhibitors, for example, tyrosine kinase inhibitors 6-mercaptopurines; IL-1 1 ; mesalamine; prednisone;
  • corticosteroids for example, budenoside and dexamethasone
  • sulfasalazine 5-aminosalicylic acid
  • olsalazine and agents which interfere with synthesis or action of proinflammatory cytokines
  • IL- 1 for example, IL- ⁇ ⁇ converting enzyme inhibitors and IL-lra
  • diphenoxylate/atrop sulfate loperamide hydrochloride; methotrexate; omeprazole; folate; cipro floxacin/dextrose-water; hydrocodone bitartrate/apap; tetracycline hydrochloride; fluocinonide; metronidazole; thimerosal/boric acid; cholestyramine/sucrose; ciprofloxacin hydrochloride; hyoscyamine sulfate; meperidine hydrochloride; midazolam
  • hydrochloride oxycodone HCl/acetaminophen; promethazine hydrochloride; sodium phosphate; sulfamethoxazole/trimethoprim; celecoxib; polycarbophil; propoxyphene napsylate; hydrocortisone; multivitamins; balsalazide disodium; codeine phosphate/apap; colesevelam HC1; cyanocobalamin; folic acid; levofloxacin; methylprednisolone;
  • Non-limiting examples of therapeutic agents for multiple sclerosis with which present compounds can be combined include the following: corticosteroids; prednisolone; methylprednisolone; azathioprine; cyclophosphamide; cyclosporine; methotrexate; 4- aminopyridine; tizanidine; interferon- ia (AVONEX®; Biogen zu); anti-a4 antibody (Tysabri®; Biogen personally); inter feron- ⁇ lb (BETASERON®; Chiron/Berlex); interferon a- n3) (Interferon Sciences/Fujimoto), interferon-a (Alfa Wassermann/J&J), interferon ⁇ - IF (Serono/Inhale Therapeutics), Peginterferon a 2b (Enzon/Schering-Plough),
  • Copolymer 1 (Cop- 1; COPAXONE®; Teva Pharmaceutical Industries, Inc.); hyperbaric oxygen; intravenous immunoglobulin; clabribine; antibodies to or antagonists of other human cytokines or growth factors and their receptors, for example, TNF, LT, IL- 1 , IL-2, IL-6, IL-7, IL-8, IL-12, IL-23, IL- 15, IL-16, EMAP-II, GM-CSF, FGF, and PDGF.
  • cytokines or growth factors and their receptors for example, TNF, LT, IL- 1 , IL-2, IL-6, IL-7, IL-8, IL-12, IL-23, IL- 15, IL-16, EMAP-II, GM-CSF, FGF, and PDGF.
  • a compound of Formula (I) can be combined with antibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD 19, CD20, CD25, CD28, CD30, CD40, CD45, CD69, CD80, CD86, CD90 or their ligands.
  • cell surface molecules such as CD2, CD3, CD4, CD8, CD 19, CD20, CD25, CD28, CD30, CD40, CD45, CD69, CD80, CD86, CD90 or their ligands.
  • a compound of Formula (I) may also be combined with agents such as methotrexate, cyclosporine, FK506, rapamycin, mycophenolate mofetil, leflunomide, NSAIDs, for example, ibuprofen, corticosteroids such as prednisolone, phosphodiesterase inhibitors, adensosine agonists, antithrombotic agents, complement inhibitors, adrenergic agents, agents which interfere with signalling by proinflammatory cytokines such as TNFa or IL-1 (e.g.
  • IL- ⁇ ⁇ converting enzyme inhibitors TACE inhibitors, T-cell signaling inhibitors such as kinase inhibitors, metalloproteinase inhibitors, sulfasalazine, azathioprine, 6-mercaptopurines, angiotensin converting enzyme inhibitors, soluble cytokine receptors and derivatives thereof (e.g. soluble p55 or p75 TNF receptors, sIL- 1RI, sIL-lRJI, sIL-6R) and antiinflammatory cytokines (e.g. IL-4, IL-10, IL-13 and TGF ).
  • TACE inhibitors TACE inhibitors
  • T-cell signaling inhibitors such as kinase inhibitors, metalloproteinase inhibitors, sulfasalazine, azathioprine, 6-mercaptopurines, angiotensin converting enzyme inhibitors, soluble cytokine receptors and derivatives thereof (e.g. soluble
  • interferon- ⁇ for example, IFN ia and IFN ib
  • Copaxone corticosteroids
  • caspase inhibitors for example inhibitors of caspase-1, IL-1 inhibitors, TNF inhibitors, and antibodies to CD40 ligand and CD80.
  • Present compounds may also be combined with agents, such as alemtuzumab, dronabinol, daclizumab, mitoxantrone, xaliproden hydrochloride, fampridine, glatiramer acetate, natalizumab, sinnabidol, a-immunokine NNS03, ABR-215062, AnergiX.MS, chemokine receptor antagonists, BBR-2778, calagualine, CPI- 1189, LEM (liposome encapsulated mitoxantrone), THC.CBD (cannabinoid agonist), MBP-8298, mesopram (PDE4 inhibitor), MNA-715, anti-IL-6 receptor antibody, neurovax, pirfenidone allotrap 1258 (RDP- 1258), sTNF-Rl, talampanel, teriflunomide, TGF-beta2, tiplimotide, VLA-4 antagonists (for example,
  • Non-limiting examples of therapeutic agents for angina with which a compound of formula (I) of the invention can be combined include the following: aspirin, nitroglycerin, isosorbide mononitrate, metoprolol succinate, atenolol, metoprolol tartrate, amlodipine besylate, diltiazem hydrochloride, isosorbide dinitrate, clopidogrel bisulfate, nifedipine, atorvastatin calcium, potassium chloride, furosemide, simvastatin, verapamil HC1, digoxin, propranolol hydrochloride, carvedilol, lisinopril, spironolactone, hydrochlorothiazide, enalapril maleate, nadolol, ramipril, enoxaparin sodium, heparin sodium, valsartan, sotalol hydrochloride, fenofibrate
  • Non-limiting examples of therapeutic agents for ankylosing spondylitis with which a compound of formula (I) can be combined include the following: D2E7 (U.S. Patent No. 6,090,382; HUMIRA®), ibuprofen, diclofenac, misoprostol, naproxen, meloxicam, indomethacin, diclofenac, celecoxib, rofecoxib, sulfasalazine, methotrexate, azathioprine, minocyclin, prednisone, etanercept, and infliximab.
  • Non-limiting examples of therapeutic agents for asthma with which a compound of formula (I) can be combined include the following: albuterol, salmeterol/fluticasone, montelukast sodium, fluticasone propionate, budesonide, prednisone, salmeterol xinafoate, levalbuterol HC1, albuterol sulfate/ipratropium, prednisolone sodium phosphate, triamcinolone acetonide, beclomethasone dipropionate, ipratropium bromide, azithromycin, pirbuterol acetate, prednisolone, theophylline anhydrous,
  • methylprednisolone sodium succinate clarithromycin, zafirlukast, formoterol fumarate, influenza virus vaccine, amoxicillin trihydrate, flunisolide, allergy injection, cromolyn sodium, fexofenadine hydrochloride, flunisolide/menthol, amoxicillin/clavulanate, levofloxacin, inhaler assist device, guaifenesin, dexamethasone sodium phosphate, moxifloxacin HC1, doxycycline hy elate, guaifenesin/d-methorphan, p- ephedrine/cod/chlorphenir, gatifloxacin, cetirizine hydrochloride, mometasone furoate, salmeterol xinafoate, benzonatate, cephalexin, pe/hydrocodone/chlorphenir, cetirizine HCl/ps
  • Non-limiting examples of therapeutic agents for COPD with which a compound of formula (I) can be combined include the following: LetairsTM (ambrisentan), albuterol sulfate/ipratropium, ipratropium bromide, salmeterol/fluticasone, albuterol, salmeterol xinafoate, fluticasone propionate, prednisone, theophylline anhydrous,
  • methylprednisolone sodium succinate montelukast sodium, budesonide, formoterol fumarate, triamcinolone acetonide, levofloxacin, guaifenesin, azithromycin,
  • methylprednisolone mometasone furoate, p-ephedrine/cod/chlorphenir, pirbuterol acetate, p-ephedrine/loratadine, terbutaline sulfate, tiotropium bromide, (R,R)-formoterol, TgAAT, cilomilast and roflumilast.
  • Non-limiting examples of therapeutic agents for HCV with which a compound of formula (I) can be combined include the following: Interferon-alpha-2a, Interferon-alpha- 2b, Interferon-alpha conl, Interferon-alpha-nl, pegylated interferon-alpha-2a, pegylated interferon-alpha-2b, ribavirin, peginterferon alfa-2b + ribavirin, ursodeoxycholic acid, glycyrrhizic acid, thymalfasin, Maxamine, VX-497 and any compounds that are used to treat HCV through intervention with the following targets: HCV polymerase, HCV protease, HCV helicase, and HCV IRES (internal ribosome entry site).
  • Non-limiting examples of therapeutic agents for Idiopathic Pulmonary Fibrosis with which a compound of Formula (I) can be combined include the following:
  • Non-limiting examples of therapeutic agents for myocardial infarction with which a compound of formula (I) can be combined include the following: aspirin, nitroglycerin, metoprolol tartrate, enoxaparin sodium, heparin sodium, clopidogrel bisulfate, carvedilol, atenolol, morphine sulfate, metoprolol succinate, warfarin sodium, lisinopril, isosorbide mononitrate, digoxin, furosemide, simvastatin, ramipril, tenecteplase, enalapril maleate, torsemide, retavase, losartan potassium, quinapril HCl/mag carb, bumetanide, alteplase, enalaprilat, amiodarone hydrochloride, tirofiban HCl m-hydrate, diltiazem hydrochloride, captopril
  • Non-limiting examples of therapeutic agents for psoriasis with which a compound of formula (I) can be combined include the following: calcipotriene, clobetasol propionate, triamcinolone acetonide, halobetasol propionate, tazarotene, methotrexate, fluocinonide, betamethasone diprop augmented, fluocinolone acetonide, acitretin, tar shampoo, betamethasone valerate, mometasone furoate, ketoconazole,
  • pramoxine/fluocinolone hydrocortisone valerate, flurandrenolide, urea, betamethasone, clobetasol propionate/emoll, fluticasone propionate, azithromycin, hydrocortisone, moisturizing formula, folic acid, desonide, pimecrolimus, coal tar, diflorasone diacetate, etanercept folate, lactic acid, methoxsalen, hc/bismuth subgal/znox/resor,
  • Non-limiting examples of therapeutic agents for psoriatic arthritis with which a compound of formula (I) can be combined include the following: D2E7 (U.S. Patent No. 6,090,382; HUMIRA®), methotrexate, etanercept, rofecoxib, celecoxib, folic acid, sulfasalazine, naproxen, leflunomide, methylprednisolone acetate, indomethacin, hydroxychloroquine sulfate, prednisone, sulindac, betamethasone diprop augmented, infliximab, methotrexate, folate, triamcinolone acetonide, diclofenac, dimethylsulfoxide, piroxicam, diclofenac sodium, ketoprofen, meloxicam, methylprednisolone, nabumetone, tolmetin sodium, calcipotriene, cyclosporine
  • Non-limiting examples of therapeutic agents for restenosis with which a compound of formula (I) can be combined include the following: sirolimus, paclitaxel, everolimus, tacrolimus, ABT-578, and acetaminophen.
  • Non-limiting examples of therapeutic agents for sciatica with which a compound of formula (I) can be combined include the following: hydrocodone bitartrate/apap, rofecoxib, cyclobenzaprine HC1, methylprednisolone, naproxen, ibuprofen, oxycodone HCl/acetaminophen, celecoxib, valdecoxib, methylprednisolone acetate, prednisone, codeine phosphate/apap, tramadol HCl/acetaminophen, metaxalone, meloxicam, methocarbamol, lidocaine hydrochloride, diclofenac sodium, gabapentin, dexamethasone, carisoprodol, ketorolac tromethamine, indomethacin, acetaminophen, diazepam, nabumetone, oxycodone HC1, tizanidine HC1,
  • Preferred examples of therapeutic agents for SLE (Lupus) with which a compound of formula (I) can be combined include the following: NSAIDS, for example, diclofenac, naproxen, ibuprofen, piroxicam, indomethacin; COX2 inhibitors, for example, celecoxib, rofecoxib, valdecoxib; anti-malarials, for example, hydroxychloroquine; steroids, for example, prednisone, prednisolone, budenoside, dexamethasone; cytotoxics, for example, azathioprine, cyclophosphamide, mycophenolate mofetil, methotrexate; inhibitors of PDE4 or purine synthesis inhibitor, for example Cellcept®.
  • NSAIDS for example, diclofenac, naproxen, ibuprofen, piroxicam, indomethacin
  • COX2 inhibitors for example, celecoxib,
  • a compound of Formula (I) may also be combined with agents such as sulfasalazine, 5-aminosalicylic acid, olsalazine, Imuran® and agents which interfere with synthesis, production or action of proinflammatory cytokines such as IL- 1 , for example, caspase inhibitors like IL- 1 ⁇ converting enzyme inhibitors and IL-lra.
  • agents such as sulfasalazine, 5-aminosalicylic acid, olsalazine, Imuran® and agents which interfere with synthesis, production or action of proinflammatory cytokines such as IL- 1 , for example, caspase inhibitors like IL- 1 ⁇ converting enzyme inhibitors and IL-lra.
  • a compound of Formula (I) may also be used with T cell signaling inhibitors, for example, tyrosine kinase inhibitors; or molecules that target T cell activation molecules, for example, CTLA-4-IgG or anti-B7
  • a compound of Formula (I) can be combined with IL- 1 1 or anti-cytokine antibodies, for example, fonotolizumab (anti-IFNg antibody), or anti-receptor receptor antibodies, for example, anti-IL-6 receptor antibody and antibodies to B-cell surface molecules.
  • a compound of Formula (I) may also be used with LJP 394 (abetimus), agents that deplete or inactivate B-cells, for example, Rituximab (anti-CD20 antibody), lymphostat-B (anti-BlyS antibody), TNF antagonists, for example, anti-TNF antibodies, D2E7 (U.S. Patent No. 6,090,382; HUMIRA ® ), CA2
  • REMICADETM CDP 571
  • TNFR-Ig constructs p75TNFRIgG (ENBRELTM)
  • p55TNFRIgG LENERCEPTTM
  • One or more compounds of this invention can be administered to a human patient by themselves or in pharmaceutical compositions where they are mixed with biologically suitable carriers or excipient(s) at doses to treat or ameliorate a disease or condition as described herein. Mixtures of these compounds can also be administered to the patient as a simple mixture or in suitable formulated pharmaceutical compositions.
  • therapeutically effective dose refers to that amount of the compound or compounds sufficient to result in the prevention or attenuation of a disease or condition as described herein.
  • Techniques for formulation and administration of the compounds of the instant application may be found in references well known to one of ordinary skill in the art, such as "Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, PA, latest edition.
  • Suitable routes of administration may, for example, include oral, eyedrop, rectal, transmucosal, topical, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections.
  • compositions may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • compositions for use in accordance with the present invention thus may be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • the agents may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • Pharmaceutical preparations for oral use can be obtained by combining the active compound with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol;
  • cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions which can be used orally include push- fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push- fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds may be delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the compounds can be formulated for parenteral administration by injection, e.g. bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g. in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly or by intramuscular injection).
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • An example of a pharmaceutical carrier for the hydrophobic compounds is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase.
  • the cosolvent system may be the VPD co- solvent system.
  • VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant polysorbate 80, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
  • the VPD co-solvent system (VPD:5W) consists of VPD diluted 1 : 1 with a 5% dextrose in water solution. This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration.
  • co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics.
  • identity of the co- solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.
  • Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as
  • dimethysulfoxide also may be employed, although usually at the cost of greater toxicity.
  • the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
  • sustained-release materials have been established and are well known by those skilled in the art.
  • Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days.
  • additional strategies for protein stabilization may be employed.
  • compositions also may comprise suitable solid or gel phase carriers or excipients.
  • suitable solid or gel phase carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
  • Many of the compounds may be provided as salts with pharmaceutically compatible counterions.
  • Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free base forms.
  • the therapeutically effective dose can be estimated initially from cellular assays.
  • a dose can be formulated in cellular and animal models to achieve a circulating concentration range that includes the IC 50 as determined in cellular assays (i.e., the concentration of the test compound which achieves a half-maximal inhibition of a given CCR2 activity).
  • the IC50 in the presence of 3 to 5% serum albumin since such a determination approximates the binding effects of plasma protein on the compound.
  • serum albumin i.e., the concentration of the test compound which achieves a half-maximal inhibition of a given CCR2 activity.
  • Such information can be used to more accurately determine useful doses in humans.
  • the most preferred compounds for systemic administration effectively inhibit CCR2 signaling in intact cells at levels that are safely achievable in plasma.
  • a therapeutically effective dose refers to that amount of the compound that results in amelioration of symptoms in a patient.
  • Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the maximum tolerated dose (MTD) and the ED 5 o (effective dose for 50% maximal response).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between MTD and ED50.
  • Compounds which exhibit high therapeutic indices are preferred.
  • the data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in humans.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 5 o with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. (See e.g. Fingl et al, 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 pi).
  • the administration of an acute bolus or an infusion approaching the MTD may be required to obtain a rapid response.
  • Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the CCR2 modulating effects, or minimal effective concentration (MEC).
  • MEC minimal effective concentration
  • the MEC will vary for each compound but can be estimated from in vitro data; e.g. the concentration necessary to achieve 50-90% inhibition of CCR2 using the assays described herein. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations.
  • Dosage intervals can also be determined using the MEC value.
  • Compounds should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90% until the desired amelioration of symptoms is achieved.
  • the effective local concentration of the drug may not be related to plasma concentration.
  • composition administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.
  • compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the pack may for example comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labelled for treatment of an indicated condition.
  • the compounds in the form of particles of very small size, for example as obtained by fluid energy milling.
  • active compound denotes any compound of the invention but particularly any compound which is the final product of one of the compounds listed in the Examples section.
  • capsules 10 parts by weight of active compound and 240 parts by weight of lactose can be de-aggregated and blended. The mixture can be filled into hard gelatin capsules, each capsule containing a unit dose or part of a unit dose of active compound.
  • Tablets can be prepared, for example, from the following ingredients. Parts by weight
  • the active compound, the lactose and some of the starch can be de-aggregated, blended and the resulting mixture can be granulated with a solution of the
  • Tablets can be prepared by the method described in (b) above.
  • the tablets can be enteric coated in a conventional manner using a solution of 20% cellulose acetate phthalate and 3% diethyl phthalate in ethanol: dichloromethane (1 : 1).
  • suppositories for example, 100 parts by weight of active compound can be incorporated in 1300 parts by weight of triglyceride suppository base and the mixture formed into suppositories each containing a therapeutically effective amount of active ingredient.
  • the active compound may, if desired, be associated with other compatible pharmacologically active ingredients.
  • the compounds of this invention can be administered in combination with another therapeutic agent that is known to treat a disease or condition described herein.
  • additional pharmaceutical agents that inhibit or prevent the production of VEGF or angiopoietins, attenuate intracellular responses to VEGF or angiopoietins, block intracellular signal transduction, inhibit vascular hyperpermeability, reduce inflammation, or inhibit or prevent the formation of edema or neovascularization.
  • the compounds of the invention can be administered prior to, subsequent to or simultaneously with the additional pharmaceutical agent, whichever course of administration is appropriate.
  • the additional pharmaceutical agents include, but are not limited to, anti-edemic steroids, NSAIDS, ras inhibitors, anti-TNF agents, anti-ILl agents, antihistamines, PAF-antagonists, COX- 1 inhibitors, COX-2 inhibitors, NO synthase inhibitors, Akt/PTB inhibitors, IGF- 1R inhibitors, PKC inhibitors, PI3 kinase inhibitors, calcineurin inhibitors and immunosuppressants.
  • the compounds of the invention and the additional pharmaceutical agents act either additively or synergistically.
  • the administration of such a combination of substances that inhibit angiogenesis, vascular hyperpermeability and/or inhibit the formation of edema can provide greater relief from the deletrious effects of a hyperproliferative disorder, angiogenesis, vascular hyperpermeability or edema than the administration of either substance alone.
  • combinations with antiproliferative or cytotoxic chemotherapies or radiation are included in the scope of the present invention.
  • a “therapeutically effective amount” is an amount of a compound of formula (I) or a combination of two or more such compounds, which inhibits, totally or partially, the progression of the condition or alleviates, at least partially, one or more symptoms of the condition.
  • a therapeutically effective amount can also be an amount which is prophylactically effective. The amount which is therapeutically effective will depend upon the patient's size and gender, the condition to be treated, the severity of the condition and the result sought. For a given patient, a therapeutically effective amount can be determined by methods known to those of skill in the art.
  • “Pharmaceutically acceptable salts” refers to those salts which retain the biological effectiveness and properties of the free bases and which are obtained by reaction with inorganic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid or organic acids such as sulfonic acid, carboxylic acid, organic phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, citric acid, fumaric acid, maleic acid, succinic acid, benzoic acid, salicylic acid, lactic acid, tartaric acid (e.g. (+) or (-)-tartaric acid or mixtures thereof), amino acids (e.g. (+) or (-)-amino acids or mixtures thereof), and the like.
  • These salts can be prepared by methods known to those skilled in the art.
  • Certain compounds of formula (I) which have acidic substituents may exist as salts with pharmaceutically acceptable bases.
  • the present invention includes such salts.
  • Examples of such salts include sodium salts, potassium salts, lysine salts and arginine salts. These salts may be prepared by methods known to those skilled in the art.
  • Certain compounds and their salts may exist in more than one crystal form and the present invention includes each crystal form and mixtures thereof.
  • Certain compounds and their salts may also exist in the form of solvates, for example hydrates, and the present invention includes each solvate and mixtures thereof. Certain compounds may exist in zwitterionic form and the present invention includes each zwitterionic form and mixtures thereof.
  • pro-drug refers to an agent which is converted into the parent drug in vivo by some physiological chemical process (e.g., a pro-drug on being brought to the physiological pH is converted to the desired drug form).
  • Pro-drugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not.
  • the pro-drug may also have improved solubility in pharmacological compositions over the parent drug.
  • pro-drug a compound of the present invention wherein it is administered as an ester (the "prodrug") to facilitate transmittal across a cell membrane where water solubility is not beneficial, but then it is metabolically hydrolyzed to the carboxylic acid once inside the cell where water solubility is beneficial
  • Pro-drugs have many useful properties. For example, a pro-drug may be more water soluble than the ultimate drug, thereby facilitating intravenous administration of the drug. A pro-drug may also have a higher level of oral bioavailability than the ultimate drug. After administration, the pro-drug is enzymatically or chemically cleaved to deliver the ultimate drug in the blood or tissue.
  • (Boc)20 for di-tert-butyl dicarbonate, n-BuLi for n- butyllithium, nB3 ⁇ 4N for tributylamine, DIBAL for diisobutylaluminum hydride, DMSO- ⁇ for deuterated dimethyl sulfoxide, DMAP for 4-(dimethylamino)pyridine, DME for dimethoxyethane, DMF for N,N-dimethylformamide, EDCI or EDC for l-ethyl-3-[3- (dimethylamino)propyl]-carbodiimide hydrochloride, EtOAc for ethyl acetate, Et 3 N for triethylamine, Et20 for diethyl ether, EtOH for ethanol, HATU for 0-(7-azabenzotriazol- l-yl)-N,N,
  • Pd(PPl3 ⁇ 4)4 for tetrakis(triphenylphosphine)palladium(0)
  • PdCl2(dppf) for [ 1 , 1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
  • PdCl2(PPli 3 )2 for bis(triphenylphosphine)palladium(II) dichloride
  • SFC Supercritical Fluid Chromatography
  • TFA for trifluoroacetic acid
  • TLC for thin layer chromatography
  • THF for tetrahydrofuran
  • Ti(iPrO) 4 for titanium(IV) isopropoxide
  • TsOH for para- toluenesulfonic acid
  • ZnEt2 for diethyl zinc.
  • Acid of formula (1) can be treated with amines of formula (2) under coupling conditions known to one skilled in the art, to provide compounds of formula (3).
  • Typical conditions for the coupling reaction include stirring about equimolar mixture of the compounds in a solvent such as, but not limited to, THF, ⁇ , ⁇ -dimethylacetamide, N,N- dimethylformamide, pyridine, chloroform, or mixture thereof, with a coupling reagent, optionally along with a coupling auxiliary, and in the presence or absence of a base.
  • Typical reactions can be carried out at temperature ranging from about 0 °C to about 65 °C or may be carried out in a microwave reactor to facilitate the coupling.
  • Examples of coupling reagents include, but are not limited to, bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPC1), 1,3-dicyclohexylcarbodiimide (DCC), polymer supported 1,3- dicyclohexylcarbodiimide (PS-DCC), 0-(7-azabenzotriazol- 1 -yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (HATU), 0-benzotriazol-l-yl-N,N,N',N'- tetramethyluronium tetrafluoroborate (TBTU), and 1 -propanephosphonic acid cyclic anhydride.
  • BOPC1 bis(2-oxo-3-oxazolidinyl)phosphinic chloride
  • DCC 1,3-dicyclohexylcarbodiimide
  • PS-DCC polymer supported 1,3-
  • Non-limiting examples of coupling auxiliary include l-hydroxy-7- azabenzotriazole (HOAT) and 1 -hydroxybenzotriazole hydrate (HOBT).
  • Suitable examples of bases include, but are not limited to, N-methyl morpholine and
  • Transformation of ketones (7) to amines of formula (8) can be achieved by treatment with amines of formula HNR A R B via reductive amination conditions known to one skilled in the art.
  • the starting materials and reagents are either commercially available or may be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature.
  • an optically active form of a compound of the invention When an optically active form of a compound of the invention is required, it may be obtained by carrying out one of the procedures described herein using an optically active starting material (prepared, for example, by asymmetric induction of a suitable reaction step), or by resolution of a mixture of the stereoisomers of the compound or intermediates using a standard procedure (such as chromatographic separation, recrystallization or enzymatic resolution).
  • a pure geometric isomer of a compound of the invention it may be obtained by carrying out one of the above procedures using a pure geometric isomer as a starting material, or by resolution of a mixture of the geometric isomers of the compound or intermediates using a standard procedure such as chromatographic separation.
  • Certain compounds in the Examples below can be purified using reverse-phase HPLC. Purification can be conducted using either a CI 8 or C8 reverse-phase column. Compounds can be eluted using a gradient of about 10-100% acetonitrile in 0.1% aqueous TFA or 0.1% aqueous formic acetate. For purifications conducted with TFA, the product thus obtained may be in the form of a TFA salt. Compounds may be characterized as the TFA salt or as the free base following neutralization, extraction and isolation.
  • a typical analytical reverse phase HPLC procedure was conducted as follows: SHIMADZU LC-20AB System; SEPAX-3 ⁇ , 2.1x30 mm ID column; Gradient 10-80% acetonitrile/H 2 0 (0.1% TFA); Flow rate: 1.0 mL/min; Back pressure: 5 ⁇ 25 MPa; Column temperature: 40 °C; Wavelength: 220 nm and 254 nm; Cycletime: 6 min; Sample preparation: compound was dissolved in acetonitrile to about 20 mg/mL; injection volume: 0.1 ⁇ per injection.
  • Certain compounds in the Examples below can be purified using normal phase silica gel chromatography including traditional flash chromatography or an automated purification system (e.g., Isco Combi-Flash, Analogix Intelliflash) using pre-packed silica gel columns (55 or 35 ⁇ silica gel, Isco gold columns). Compounds can also be purified by preparative-TLC.
  • normal phase silica gel chromatography including traditional flash chromatography or an automated purification system (e.g., Isco Combi-Flash, Analogix Intelliflash) using pre-packed silica gel columns (55 or 35 ⁇ silica gel, Isco gold columns).
  • Compounds can also be purified by preparative-TLC.
  • Typical solvents for silica gel chromatography include: ethyl acetate in hexanes, diethyl ether in hexanes, THF in hexanes, ethyl acetate in dichloromethane, methanol in dichloromethane, methanol in dichloromethane with NH 4 OH, acetone in hexanes, and dichloromethane in hexanes.
  • reaction mixture was neutralized, extracted with dichloromethane, ethyl acetate, or other organic solvents including diethyl ether, chloroform. The organic layers were combined, dried, and concentrated to obtain the free base, which can either be purfied on silica gel or used directly in subsequent reactions.
  • Example 1A 125 g, 61.35% as oil.
  • Example IB (27.75 g, 48.5%) as oil.
  • Example IB Ethyl 2-oxooctahydropentalene-3a-carboxylate
  • Pd/C 8 g
  • EtOH 500 mL
  • the mixture was filtered and concentrated in vacuum.
  • the residue was purified by column chromatography (S1O2, 0% to 10% EtOAc in petroleum ether) to give Example 1C (30 g, 58.8%) as light yellow oil.
  • Example ID (7.05 g, 80.4%) as grey oil, which was used in the next step directly.
  • the reaction mixture was charged to a 250 mL addition funnel and was added concurrently with a solution of sodium hydroxide solution (5 N, 65 mL) in another addition funnel to a solution of NaPF 6 (31.78 g) in water (230 mL) with cooling at 4 °C.
  • the addition rate was such that the internal temperature remained below 5 °C and the pH varied form 3.05 to 3.6.
  • the resulting yellow slurry was then stirred for 60 minutes at 0 °C.
  • the solids was filtered, slurry-washed with ice-cold water (2 x 100 mL) then dried with a stream of N2 under vacuum to provide Example IE.
  • tert-butyl 3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridine-6(5H)-carboxylate To a solution of tert-butyl 4-oxopiperidine- l-carboxylate (14.35 g, 0.072 mol) in THF (250 mL) was added lithium hexamethyldisilylamide (150 mL, 1 N, 0.15 mol) dropwise at -12 °C under N 2 . After the addition, the mixture was stirred for 1.5 hours at room temperature.
  • Example IE 25 g, 0.073 mol
  • THF 150 mL
  • Acetic acid 6.3 mL was added to the reaction mixture and gradually the temperature was allowed to warm to room
  • Example IF (13.5 g, 60.8%) as light yellow solid.
  • Example IF 3-(trifluoromethyl)-5,6,7,8-tetrahydro- 1 ,6-naphthyridine
  • dichloromethane 20 mL
  • HC1 dioxane
  • dioxane 4 N, 150 mL
  • the mixture was filtered, the solid was dried in vacuum to give Example 1G (14 g, 90.5%) as white solid.
  • the mixture was washed with water (100 mL) and extracted with dichloromethane (3 x 100 mL). The organic layer was dried over Na 2 S0 4 , filtered, and concentrated in vacuum. The residue was purified by chromatography on silica gel and followed by chiral SFC separation to give
  • Example 1H enantiomerically pure Example 1H (4.0 g, 27.1%) as light yellow solid.
  • Tert-butyl 4-(6-oxopyridazin-l(6H)-yl)piperidine-l-carboxylate was prepared and purified according to the procedure described in Example 4B, substituting tert-butyl 4- bromopiperidine- 1 -carboxylate for Example 4A, and pyridazin-3(2H)-one for 3- (trifluoromethyl)- 1 H-pyrazole.
  • Example 4C The title compound was prepared and purified according to the procedure described in Example 4C, substituting tert-butyl 4-(6-oxopyridazin- 1 (6H)-yl)piperidine- 1 -carboxylate for Example 4B.
  • Example II 2- ⁇ 1 -[(2S,3aR,6aR)-3a- ⁇ [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)- yl]carbonyl ⁇ octahydropentalen-2-yl]piperidin-4-yl ⁇ pyridazin-3(2H)-one
  • Example II 180 mg, 1.0 mmol
  • Example 1H 352 mg, 1.0 mmol
  • acetic acid 0.1 mL
  • Example 4C The title compound was prepared and purified according to the procedure described in Example 4C, substituting tert-butyl 4-(l-oxophthalazin-2(lH)-yl)piperidine- 1 -carboxylate for Example 4B.
  • Example 3A1 To a solution of Example 3A1 (0.8 g, 3.8 mmol) in methanol (5 mL) was added HCl(g)/methanol (10 mL) dropwise at room temperature. The resulting mixture was stirred for 1.5 hours at room temperature. TLC indicated the reaction was completed. The reaction mixture was concentrated in vacuum the residue was washed with aqueous NaHC0 3 (20 mL), extracted with EtOAc (3 x 20 mL), dried over Na 2 S0 4 , and filtered. The organic layer was concentrated in vacuum to give crude title compound (260 mg, 54%) as oil, which was used in the next step directly.
  • tert-butyl 4-(methylsulfonyloxy)piperidine- 1-carboxylate To mixture of tert-butyl 4-hydroxypiperidine- 1 -carboxylate (20 g, 99 mmol) and Et 3 N (14 mL, 100 mmol) in dichloromethane (400 mL) was added methanesulfonyl chloride (8.5 mL, 110 mmol) at 0 °C. The reaction mixture was stirred at room temperature overnight and diluted with dichloromethane (50 mL). The organic layer was separated and the aqueous phase was extracted with dichloromethane (2 x 500 mL). The combined organic layers were dried over MgS0 4 , filtered and concentrated. The crude product was used for next step without further purification.
  • Example 4C 160 mg, 0.67 mmol
  • Example 1H 200 mg, 0.57 mmol
  • dichloromethane 20 mL
  • Ti(i-OPr) 4 645 mg, 2.27 mmmol
  • ⁇ , ⁇ -diisopropylethyl amine 300 mg, 2.27 mmol
  • NaBH 4 86 mg, 2.27 mol
  • MeOH 0.5 mL
  • the succinate salt of the above compound was prepared as follows:
  • Example 4D A mixture of Example 4D (108 mg, 0.19 mmol), succinic acid (23 mg, 0.19 mmol) in MeOH (50 mL) was heated at 65 °C for 1 hour and then concentrated in vacuum. The residue was then washed by Et20 to afford off-white solid (130 mg, 86.4%).
  • Example 5 1 - ⁇ 1 -[(2R,3aR,6aR)-3a- ⁇ [3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)- yl]carbonyl ⁇ octahydropentalen-2-yl]piperidin-4-yl ⁇ pyridin-2(lH)-one
  • Example 4C The title compound was prepared and purified according to the procedure described in Example 4C, substituting tert-butyl 4-(2-oxopyridin- l(2H)-yl)piperidine- l- carboxylate for Example 4B. MS m/z 179 (M+H) + .
  • Example 4C The title compound was prepared and purified according to the procedure described in Example 4C, substituting tert-butyl 4-(4-(trifluoromethyl)-lH-pyrazol-l- yl)piperidine- l-carboxylate for Example 4B.
  • Example 6A The title compound was prepared and purified according to the procedure described in Example 1 J, substituting Example 6A for Example II.
  • ⁇ -NMR 400 MHz, CDC1 3 ) ⁇ 8.73 (s, 1H), 7.72 (m, 3H), 4.80 (m, 2H), 4.20 (m, 1H), 3.9 - 4.05 (m, 2H), 3.55 (m, 1H), 3.1 - 3.2 (m, 4H), 2.88 (m, 1H), 2.13 - 2.39 (m, 6H), 1.8 - 2.1 (m, 3H), 1.8 - 1.90 (m, 6H), 1.35 (m, 1H); LC/MS (ESI + ) m/z 556 (M+H) + .
  • Example 8A1 To a solution of Example 8A1 (2.6 g, 10.7mmol) in dichloromethane (100 mL) was added 4-(dimethylamino)pyridine (5.54 mmol), N-methylmorpholine (12.8mmol) , N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (12.8 mmol), and acetic acid (1 1.7 mmol). The reaction mixture was stirred at room temperature for 1 hour, washed with saturated brine, dried (MgS0 4 ), filtered, and concentrated. The residue was dissolved in toluene (30 mL) and heated under reflux for 24 hours.
  • Example 8A2 5-methyl-3-(piperidin-4-yl)- 1 ,2,4-oxadiazole
  • dichloromethane 3 mL
  • trifluoroacetic acid 100 ⁇
  • the reaction mixture was atirred for 12 hours at room temperature.
  • the mixtures were evaporated in vacuum to afford the Example 8A as trifluoroacetic acid salt.
  • tert-butyl 4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine- 1 (2H)-carboxylate Lithium bis(trimethylsilyl)amide (1 M, 40 mL) was added to a solution of tert- butyl-4-oxopiperidine- 1 -carboxylate (28 mmol) in dry THF (50 mL) at -78 °C under N 2 . The mixture was stirred at -78 °C for 1 hour. N-pheny-lbis(trifluoromethanesulfonimide) (28 mmol) was added as solid in one portion. The mixture was stirred at -78 °C for 1 hour. The solution was warmed up to room temperature over a period of 4 hours.
  • Example 9A2 ethyl tert-butyl 4-(3-(ethoxycarbonyl)phenyl)-5,6-dihydropyridine- 1 (2H)-carboxylate
  • a solution of Example 9A1 2.0g, 6 mmol
  • 3- (ethoxycarbonyl)phenylboronic acid 1.6 g, 8.34 mmol
  • LiCl 1.0 g
  • 2M Na2C(3 ⁇ 4 solution (1 1 mL) in dimethoxy ethane (100 mL) was added Pd(PPl3 ⁇ 4)4 and the resulting mixture was stirred at refluxing temperature for 30 hours under N 2 .
  • Example 9A2 A solution of Example 9A2 (1.0 g, 3.0 mmol) in EtOH (50 mL) was added Pd/C (0.1 g). Then the mixture was stirred at room temperature for 18 hours under 30 psi H 2 . The Pd/C was removed by filtration and the filtrate was concentrated in vacuum to afford Example 9A3.
  • Example 9A3 tert-butyl 4-(3-(2-hydroxypropan-2-yl)phenyl)piperidine- l-carboxylate
  • a solution of methyl magnesium bromide (14.8 mmol).
  • the resulting mixture was stirred at -25 °C for 0.5 hour and then stired at room temperature overnight.
  • the mixture was quenched with aqueous NH 4 C1, extracted with EtOAc, and concentrated.
  • the residue was purified by column chromatography on silica gel to give Example 9A4 in 80% yield as an oil.
  • Example 9A4 To a solution of Example 9A4 (1 g, 3.13mmol) in dioxane was added a solution of dioxane/HCl (20 mL, 4N) and the mixture was a stirred at room temperature for 1 hour. The solvent was removed in vacuum and give Example 9A as HC1 salt in 90% yield as a white solid. MS m/z 220 (M+H) + .
  • Example 9B [(2R,3aR,6aR)-2- ⁇ 4-[3-(2-hydroxypropan-2-yl)phenyl]piperidin- 1 -yl ⁇ hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]m
  • Example 9A The title compound was prepared and purified according to the procedure described in Example 1J, substituting free base of Example 9A for Example II.
  • Example 12A1 A mixture of Example 12A1 (28 g, 0.15 mol) in 6N HC1 (100 mL) was heated at reflux for 3 hours. After cooling to room temperature, the reaction mixture was partitioned between EtOAc (200 mL) and water (100 mL). The pH of the aqueous layer was adjusted to about 7 with solid NaHC(3 ⁇ 4 and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with a IN solution of NaHC(3 ⁇ 4, dried over Na 2 S0 4; filtered and concentrated in vaccum to give crude Example 12A2 (7.77 g, 38% for two steps) as an oil, which was used for the next step directly without further purification.
  • Example 4A To a solution of Example 4A (835 mg, 7.46 mmol) in DMF (20 mL) was added
  • Example 12A3 (1.2 g, 57%) as a colorless solid.
  • Example 12 A3 A solution of Example 12 A3 (1.2 g, 4 mmol) in HC1 / EtOAc (4 N, 50 mL) was stirred at room temperature overnight. The reaction mixture was concentrated in vaccum to give the HC1 salt of Example 12A4 (420 mg, 54%) as a white solid.
  • Example 14A1 4-(3-Ethoxycarbonyl-pyrazol- l-yl)-piperidine-l-carboxylic acid tert-butyl ester
  • Example 4A 4-(3-Ethoxycarbonyl-pyrazol- l-yl)-piperidine-l-carboxylic acid tert-butyl ester
  • DMF 20 mL
  • the reaction mixture was filtered and the filtrate was concentrated in vacuum and the residue was purified by chromatography on silica to give Example 14A2 (0.65 g, 56.5 %) as a colorless solid.
  • Example 14A2 ethyl l-(piperidin-4-yl)-lH-pyrazole-3-carboxylate
  • dichloromethane 5 mL
  • HCl(g)/methanol 20 mL
  • TLC TLC indicated that the reaction was completed.
  • the reaction mixture was concentrated in vacuum to give the HC1 salt of Example 14A (400 mg, 89%) as a white solid.
  • Example 15B ethyl 3-(l-((2R,3aR,6aR)-3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-l,6-naphthyridine-6- carbonyl)octahydropentalen-2-yl)piperidin-4-yl)benzoate
  • the title compound was prepared and purified according to the procedure described in Example 1J, substituting free base of Example 15A for Example II.
  • the mixture was acidified by 0.5 N aqueous HC1 to adjust the pH to about 5, extracted with dichloromethane (3 x 30 mL). The organic layer was dried over Na2S0 4 , filtered, and concentrated to give the title compound (600 mg, 97 %) as light yellow solid.

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Abstract

Disclosed herein are chemokine receptor antagonists of formula (I) wherein G1, X1, X2, and X3 are as defined in the specification. Compositions comprising such compounds; and methods for treating conditions and disorders using such compounds and compositions are also described.

Description

CHEMOKINE RECEPTOR ANTAGONISTS
BACKGROUND
Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract leukocytes, as illustrated by macrophages, T cells, B cells, eosinophils, basophils, and neutrophils to and from sites of inflammation or within specific compartments, as illustrated by lymph nodes (reviewed in Schall, Cytokine 1991 ; 3: 165- 183; Schall, et al., Curr. Opin. Immunol. 1994; 6:865- 873; and Murphy, Rev. Immun. 1994; 12:593-633). In addition to stimulating chemotaxis, other changes can be selectively induced by chemokines in responsive cells, including changes in cell shape, transient rises in the concentration of intracellular free calcium ions ([Ca2+]), granule exocytosis, integrin upregulation, formation of bioactive lipids (e.g., leukotrienes), and respiratory burst, associated with leukocyte activation. Thus, the chemokines are early modulators of inflammatory response, effecting inflammatory mediator release, chemotaxis and extravasation to sites of infection or inflammation.
There are four classes of chemokines, CXC (a), CC (β), C (γ), and CX3C (δ), depending on whether the first two cysteines are separated by a single amino acid (C-X- C), are adjacent (C-C), have a missing cysteine pair (C), or are separated by three amino acids (CX3C). The a-chemokines, such as interleukin-8 (IL-8), melanoma growth stimulatory activity protein (MGSA), and stromal cell derived factor 1 (SDF-1) are chemotactic primarily for neutrophils and lymphocytes, whereas β-chemokines, such as RANTES, ΜΙΡ-Ια, ΜΙΡ- Ι β, monocyte chemotactic protein- 1 (MCP-1), MCP-2, MCP-3, and eotaxin are chemotactic for macrophages, T-cells, eosinophils and basophils (Deng, et al., Naturel996; 381 :661-666). The C chemokine lymphotactin shows specificity for lymphocytes (Kelner, et al., Science 1994; 266: 1395-1399) while the CX3C chemokine fractalkine shows specificity for lymphocytes and monocytes (Bazan, et al., Nature 1997; 385:640-644).
Chemokines bind specific cell-surface receptors belonging to the family of G- protein-coupled seven-transmembrane-domain proteins (reviewed in Horuk, Trends
Pharm. Sci. 1994; 15: 159-165) termed "chemokine receptors." On binding their cognate ligands, chemokine receptors transduce an intracellular signal through the associated heterotrimeric G protein, resulting in a rapid increase in intracellular calcium concentration. There are at least twelve human chemokine receptors that bind or respond to β-chemokines with the following characteristic pattern: CCR1 (or "CKR-1 " or "CC- CKR-1 ") ΜΙΡ-Ια, ΜΙΡ-Ι β, MCP-3, RANTES (Ben-Barruch, et al., J. Biol. Chem. 1995; 270:22123-22128; Neote, et al., Cell 1993; 72:415425); CCR2A and CCR2B (or "CKR- 2A'7"CKR-2A" or "CC-CKR-2A"/"CC-CKR2A") MCP-1, MCP-2, MCP-3, MCP-4; CCR3 (or "CKR-3" or "CC-CKR-3") eotaxin, RANTES, MCP; (Ponath, et al., J. Exp. Med. 1996; 183:2437-2448); CCR4 (or "CKR-4" or "CC-CKR-4") TARC, MDC (Imai, et al., J. Biol. Chem. 1998; 273: 1764- 1768); CCR5 (or "CKR-5" or "CC-CKR-5") MIP- la, RANTES, MIP-Ι β; (Sanson, et al., Biochemistry 1996; 35:3362-3367); CCR6 MIP-3a (Greaves, et al., J. Exp. Med. 1997; 186:837-844); CCR7 ΜΙΡ-3β and 6Ckine (Campbell, et al., J. Cell. Biol. 1998; 141 : 1053- 1059); CCR8 I- 309, HHV8 vMIP-I, HHV-8 vMIP-II, MCV vMCC-I (Dairaghi, et al., J. Biol. Chem. 1999; 274:21569-21574); CCR9 TECK (Zaballos, et al., J. Immunol. 1999; 162:5671-5675), D6 MIP-1 beta, RANTES, and MCP-3 (Nibbs, et al., J. Biol. Chem. 1997; 272:32078-32083), and the Duffy blood-group antigen RANTES, MCP-1 (Chaudhun, et al., J. Biol. Chem. 1994; 269:7835-7838).
Chemokine receptors, such as CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CX3CR1, and XCRl have been implicated as being important mediators of inflammatory and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis.
The CCR2 chemokine receptor is expressed primarily in monocytes and activated T lymphocytes, and its functional activity can be measured by cytosolic calcium elevation or chemotaxis. CCR2 exists in two isoforms, CCR2A and CCR2B. These two isoforms are alternatively spliced variants of a single MCP- 1 receptor gene and differ only in the carboxyl-terminal tails. The chromosomal location of the CCR2 gene is localized to
3p21. The CC chemokines, MCP-1, MCP-2, MCP-3, and MCP-4, have been identified as the ligands that are selective and of high affinity to the CCR2 receptor.
The highly selective expression of CCR2 makes it an ideal target for intervention to interrupt inappropriate monocyte and T cell trafficking. The clinical indications for such intervention are in inflammatory diseases and T-cell mediated autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, asthma, allergy, chronic obstructive pulmonary disease, atherosclerosis, restinosis, type I and type II diabetes, metabolic syndrome, and pain. Ectopic expression of MCP-1 and CCR2 in certain tumors indicates that selective modulation (such as antagonism or inhibition) of CCR2 can have value in tumor immunotherapy, particularly attenuation of metastasis.
The native peptide ligand of CCR2 is monocyte chemoattractant protein- 1 (MCP- 1 or CCL2) containing two adjacent disulfied bonds. Ample evidence exists for the role of the CCR2/MCP-1 system in preclinical animal models of pain (White F.A., Jung F., and Miller R.J., Proc. Natl. Acad. Sci. USA 2007; 51 :20151). Although CCR2 and MCP- 1 have limited expression levels in the CNS tissues under normal conditions, significant upregulation of CCR2 and MCP- 1 has been observed following a neuropathic injury in tissue relevant to pain, including neurons and glia in the spinal cord, rostroventromedial medulla (RVM) and DRG (Wang H., Zou S., Wei F., Dubner R., and Ren K., Soc for Neurosci Poster 2009; 72.3). MCP- 1 has been shown to increase the excitability of neurons acutely dissociated from the DRG tissue (Sun J.H., Yang B., Donnelly D.F., Ma C, and LaMotte R.H., J Neurophysiol. 2006; 96:2189). In addition, direct injection of MCP- 1 in the spinal cord induces thermal hyperalgesia and mechanical allodynia (Dansereau et al. Neurochem. 2008; 106:7), and the MCP- 1 induced pronociception can be blocked by a CCR2 antagonist, INCB3344. Similarly, the hyperalgesia induced by MCP-1 injection in the RVM is reversed by another CCR2 antagonist, RS I 02895 (Wang H., Zou S., Wei F., Dubner R. and Ren K., Soc for Neurosci Poster 2009; 72.3). In addition, CCR2 knock out mice exhibit significantly reduced mechanical allydonia following nerve injury and reduced nocifensive behavior in the second phase of the formalin model, whereas they exhibit normal sensitivity to acute pain stimulation in the hot plate model (Abbadie C, Lindia J.A., Cumiskey A.M., Peterson L.B., Mudgett J.S., Bayne E.K., DeMartino J.A., Maclntyre D.E., and Forrest M.J., Proc Natl Aca Sci USA 2003; 100:7947). Treatment with AZ889 (Serrano A., Pare M., Mcintosh F., Elmes S.J.R. Martino G., Jomphe C, Lessard E., Lembo P.M.C., Vaillancourt F., Perkins M.N., and Cao C.Q., Mol. Pain 2010; 6:90), a CCR2 antagonist, abolished CCL2-evoked neuronal excitation, confirming that this activity is CCR2 -mediated. Neuronal and non-neuronal cells in the spinal cord were also excited by CCL2 applications indicating an important role of spinal CCR2 in neuropathic pain. In vivo spinal intrathecal injection of AZ889 produced dose-dependent analgesia in chronic constriction injury rats (Serrano A., Pare M., Mcintosh F., Elmes S.J.R., Martino G., Jomphe C, Lessard E., Lembo P.M.C., Vaillancourt F., Perkins M.N., and Cao C.Q., Mol. Pain 2010; 6:90). Additionally, application of AZ889 to the exposed spinal cord inhibited evoked neuronal activity and confirmed that CCR2-mediated analgesia involved predominantly the spinal cord. In view of the clinical importance of CCR2, the identification of compounds that modulate CCR2 function represents an attractive avenue into the development of new therapeutic agents that can be used to treat diseases such as inflammatory, autoimmune disease, cancer, and pain, that are associated with chemokine receptor expression or activity. Such compounds are provided herein.
SUMMARY
Disclosed herein are compounds of formula (I)
Figure imgf000005_0001
(I)
wherein
X1 is CR1 or N;
X2 is CR2 or N;
X3 is CR3 or N; with the proviso that no more than one of X1, X2, and X3 is N; R1, R2, and R3 are each independently hydrogen, -CN, halogen, alkyl, or haloalkyl;
G1 is - 4R5, formula (a), (b), or (c)
Figure imgf000005_0002
R4 is hydrogen, C(2¾)3, alkyl, haloalkyl, or alkoxyalkyl;
R5 is
an heterocycle selected from the group consisting of a monocyclic heterocycle wherein one of the ring atoms is O, N, or NH and having zero or one double bond, optionally contains one or two additional heteroatoms selected from the group consisting of O, N, NH, and S, and optionally contains an C1-C4 alkylenyl bridge that links two non-adjacent carbon atoms within the ring; a bicyclic heterocycle, and a spiro heterocycle;
a phenyl, a naphthyl,
a cycloalkyl,
an heteroaryl, or
an heterocyclealkyl; wherein
each of the R5 phenyl, naphthyl, cycloalkyl, heteroaryl, heterocycle, and the heterocycle moiety of the heterocyclealkyl, is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 Ra;
with the proviso that when X1 is CR1, X2 is CR2, X3 is CR3, R1 and R3 are hydrogen, R2 is haloalkyl, R4 is alkyl, and R5 is a monocyclic heterocycle or a heterocyclealkyl, then the heterocycle moiety of R5 is substituted;
ring A1 is 2,3-dihydro-lH-isoindolyl, decahydroisoquinolinyl, piperidinyl, or pyrrolidinyl, each of which is optionally further substituted with 1 , 2, or 3 substituents independently selected from the group consisting of CN, alkyl, oxo, halogen, haloalkyl, OH, O(alkyl), and 0(haloalkyl); with the proviso that when ring A1 is piperidinyl, then G2 and the optional substituent of ring A1 do not reside on the same carbon atom;
G2 is G2a or -L'-G2b;
G2a is
a bicyclic aryl, a bicyclic cycloalkyl, a bicyclic heterocycle, a spiro heterocycle, or an heteroaryl, each of which is optionally substituted with 1, 2, 3, 4, or 5 Rb; or
a phenyl, a monocyclic cycloalkyl, or a monocyclic heterocycle, each of which is independently substituted with 1, 2, 3, 4, or 5 Rb;
G2b is aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycle, each of which is optionally substituted with 1, 2, 3, 4, or 5 Rb;
R6 is CN, OH, or halogen;
each R7 is an optional substituent on any substitutable carbon atom, and is independently alkyl, haloalkyl, halogen, oxo, or OH;
p is 0, 1, 2, or 3;
Figure imgf000006_0001
L1 and L2 are independently O, N(Jk), or S; wherein Jk, at each occurrence, is independently hydrogen, alkyl, haloalkyl, C(0)Rk, S(0)2Rk, or C3-C4 cycloalkyl; wherein the C3-C4 cycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independenly selected from the group consisting of alkyl, halogen, haloalkyl, oxo, hydroxy, and alkoxy, Rk, at each occurrence, is independently alkyl or C3-C4 cycloalkyl; wherein the C3-C4 cycloalkyl is optionally with 1, 2, 3, or 4 substituents independenly selected from the group consisting of alkyl, halogen, haloalkyl, oxo, hydroxy, and alkoxy;
G3a is aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycle, each of which is optionally substituted with 1, 2, 3, 4, or 5 Rc;
ring A is
a heterocycle or
a monocyclic heterocycle fused to a monocyclic heteroaryl, each ring A2 is optionally substituted with 1, 2, 3, 4, or 5 Rd; with the proviso that ring A2 is not 2,3-dihydro- lH-isoindolyl, decahydroisoquinolinyl, piperidinyl, or pyrrolidinyl;
Ra, Rb, Rc, and Rd are optional substituents on any substitutable atoms, and at each occurrence, are each independently alkyl, alkenyl, alkynyl, halogen, oxo, haloalkyl, CN, N02, -ORf, -OC(0)Rf, -OC(0)N(Rf)(Rs), -S(0)2Re, -S(0)2N(Rf)(Rs), -C(0)Rf, -C(0)ORf, -C(0)N(Rf)(Rg), -N(Rf)(Rg), -N(Rg)C(0)Rf, -N(Rg)S(0)2Re, -N(Rg)C(0)0(Rf),
-N(Rg)C(0)N(Rf)(Rg), Ga, -(CRxRy)qi-ORf, -(CRxRy)qi-OC(0)Rf,
-(CRxRy)qi-OC(0)N(Rf)(Rg), -(CRxRy)qi-S(0)2Re, -(CRxRy)qi-S(0)2N(Rf)(Rg),
-(CRxRy)qi -C(0)Rf, -(CRxRy)qi-C(0)ORf, -(CRxRy)qi -C(0)N(Rf)(Rg),
-(CRxRy)qi -N(Rf)(Rg), -(CRxRy)qi-N(Rg)C(0)Rf, -(CRxRy)qi-N(Rg)S(0)2Re,
-(CRxRy)qi-N(Rg)C(0)0(Re), -(CRxRy)qi-N(Rg)C(0)N(Rf)(Rg), -(CRxRy)qi-CN, and -(CRxRy)qi-Ga;
Re, at each occurrence, is independently alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, Gb, or -(C1-C6 alkylenyl)-Gb;
Rf, at each occurrence, is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, Gb, or -(C1-C6 alkylenyl)-Gb;
Rg, at each occurrence, is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, benzyl, or monocyclic cycloalkyl;
Ga and Gb, at each occurrence, are each independently aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycle, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, -CN, oxo, -ORh, -OC(0)Rh, -OC(0)N(Rh)2, -SCO^R1, -S(0)2N(Rh)2, -C(0)Rh, -C(0)ORh, -C(0)N(Rh)2, -N(Rh)2, -N(Rh)C(0)Rh, -N(Rh)S(0)2Ri,
-N(Rh)C(0)0(Rh), -N(Rh)C(0)N(Rh)2, -(CRxbRyb)q2-ORf, -(CRxbRyb)q2-OC(0)Rh, -(CRxbRyb)q2-OC(0)N(Rh)2, -(CR'V^ SCO^R1, -(CRxbRyb)q2-S(0)2N(Rh)2, -(CRxbRyb)q2-C(0)Rh, -(CRxbRyb)q2-C(0)ORh, -(CRxbRyb)q2-C(0)N(Rh)2,
-(CRxbRyb)q2-N(Rh)2, -(CRxbRyb)q2-N(Rh)C(0)Rh, -(CRxbRyb)q2-N(Rh)S(0)2Ri,
-(CRxbRyb)q2-N(Rh)C(0)0(Rh), -(CRxbRyb)q2-N(Rh)C(0)N(Rh)2, and -(CRxbRyb)q2-CN;
Rx, Ry, Rxb, and Ryb, at each occurrence, are each independently hydrogen, alkyl, halogen, or haloalkyl;
ql and q2, at each occurrence, are each independently 1, 2, 3, or 4;
Rh, at each occurrence, is independently hydrogen, alkyl, or haloalkyl; and
R1, at each occurrence, is independently alkyl or haloalkyl.
Provided also is a pharmaceutical composition comprising therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or salt of a solvate thereof, in combination with a pharmaceutically acceptable carrier. The present compounds or compositions described herein can be administered in accordance with methods described herein, typically as part of a therapeutic regimen for treatment or prevention of conditions and disorders associated to the expression or acitivity of CCR2. More particularly, the methods are useful for treating conditions such as, but not limited to, rheumatoid arthritis, osteoarthritis, asthma, chronic obstructive pulmonary disease, sepsis, psoriasis, psoriatic arthritis, inflammatory bowel disease, Crohn's disease, lupus, multiple sclerosis, juvenile chronic arthritis, Lyme arthritis, reactive arthritis, septic arthritis, spondyloarthropathy, systemic lupus erythematosus, an ocular condition, a cancer, a solid tumor, fibrosarcoma, osteoma, melanoma,
retinoblastoma, a rhabdomyosarcoma, glioblastoma, neuroblastoma, teratocarcinoma, an cancers such as lung, breast, stomach, bladder, colon, pancreas, ovarian, prostate and rectal cancer and hematopoietic malignancies (leukemia and lymphoma),
abetalipoprotemia, acrocyanosis, acute and chronic parasitic or infectious processes, acute leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute or chronic bacterial infection, acute pancreatitis, acute renal failure, adenocarcinomas, aerial ectopic beats, AIDS dementia complex, alcohol-induced hepatitis, allergic conjunctivitis, allergic contact dermatitis, allergic rhinitis, alpha- 1 antitrypsin deficiency, amyotrophic lateral sclerosis, anemia, angina pectoris, anterior horn cell degeneration, anti cd3 therapy, antiphospholipid syndrome, anti-receptor hypersensitivity reactions, hypersensitivity reactions, hyperkinetic movement disorders, hypersensitivity pneumonitis, hypertension, hypokinetic movement disorders, aortic and peripheral aneurysms, hypothalamic-pituitary-adrenal axis evaluation, aortic dissection, arterial hypertension, arteriosclerosis, arteriovenous fistula, ataxia, spinocerebellar degenerations, streptococcal myositis, structural lesions of the cerebellum, Subacute sclerosing panencephalitis, Syncope, syphilis of the cardiovascular system, systemic anaphylaxis, systemic inflammatory response syndrome, systemic onset juvenile rheumatoid arthritis, T-cell or FAB ALL, Telangiectasia, thromboangitis obliterans, transplants,
trauma/hemorrhage, type III hypersensitivity reactions, type IV hypersensitivity, unstable angina, uremia, urosepsis, urticaria, valvular heart diseases, varicose veins, vasculitis, venous diseases, venous thrombosis, ventricular fibrillation, viral and fungal infections, vital encephalitis/aseptic meningitis, vital-associated hemaphagocytic syndrome, Wernicke- Korsakoff syndrome, Wilson's disease, xenograft rejection of any organ or tissue, atrial fibrillation (sustained or paroxysmal), atrial flutter, atrioventricular block, B cell lymphoma, bone graft rejection, bone marrow transplant (BMT) rejection, small bowel transplant rejection, spinal ataxia, bundle branch block, Burkitt's lymphoma, burns, cardiac arrhythmias, cardiac stun syndrome, cardiac tumors, cardiomyopathy, cardiopulmonary bypass inflammation response, cartilage transplant rejection, cerebellar cortical degenerations, cerebellar disorders, chaotic or multifocal atrial tachycardia, chemotherapy associated disorders, chromic myelocytic leukemia, chronic alcoholism, chronic inflammatory pathologies, chronic lymphocytic leukemia, chronic salicylate intoxication, colorectal carcinoma, congestive heart failure, conjunctivitis, cor pulmonale, coronary artery disease, Creutzfeldt- Jakob disease, culture negative sepsis, cystic fibrosis, cytokine therapy associated disorders, Dementia pugilistica, demyelinating diseases, dengue hemorrhagic fever, dermatitis, dermatologic conditions, diabetic ateriosclerotic disease, Diffuses Lewy body disease, dilated congestive cardiomyopathy, disorders of the basal ganglia, Down's Syndrome in middle age, drug- induced movement disorders induced by drugs which block CNS dopamine receptors, drug sensitivity, eczema, encephalomyelitis, endocarditis, endocrinopathy, epiglottitis, Epstein Barr virus infection, erythromelalgia, extrapyramidal and cerebellar disorders, familial
hematophagocytic lymphohistiocytosis, fetal thymus implant rejection, Friedreich's ataxia, functional peripheral arterial disorders, fungal sepsis, gas gangrene, gastric ulcer, glomerular nephritis, gram negative sepsis, gram positive sepsis, granulomas due to intracellular organisms, hairy cell leukemia, Hallerrorden-Spatz disease, hay fever, heart transplant rejection, hemachromatosis, hemodialysis, hemolytic uremic
syndrome/thrombolytic thrombocytopenic purpura, hemorrhage, idiopathic pulmonary fibrosis, antibody mediated cytotoxicity, Asthenia, infantile spinal muscular atrophy, inflammation of the aorta, influenza A, ionizing radiation exposure, iridocyclitis/uveitis/optic neuritis, juvenile rheumatoid arthritis, juvenile spinal muscular atrophy, kidney transplant rejection, legionella, leishmaniasis, lipedema, liver transplant rejection, lymphederma, malaria, malignant Lymphoma, malignant histiocytosis, malignant melanoma, meningococcemia, metabolic/idiopathic, migraine headache, mitochondrial multi-system disorder, monoclonal gammopathy, multiple myeloma, multiple systems degenerations (Mencel Dejerine- Thomas Shi-Drager and Machado- Joseph), myasthenia gravis, mycobacterium avium intracellulare, mycobacterium tuberculosis, myelodyplastic syndrome, myocardial ischemic disorders, nasopharyngeal carcinoma, neonatal chronic lung disease, nephritis, nephrosis, neurodegenerative diseases, neurogenic I muscular atrophies , neutropenic fever, non-Hodgkin's lymphoma, occlusion of the abdominal aorta and its branches, occulsive arterial disorders, okt3 therapy, orchitis/epidydimitis, orchitis/vasectomy reversal procedures, organomegaly, osteoporosis, pancreas transplant rejection, pancreatic carcinoma, paraneoplastic syndrome/hypercalcemia of malignancy, parathyroid transplant rejection, pelvic inflammatory disease, perennial rhinitis, pericardial disease, Kaposi's sarcoma,
Hodgkin's disease, lymphoma, myeloma, leukaemia, malignant ascites, hematopoietic cancers, Crow-Fukase (POEMS) syndrome (polyneuropathy, organomegaly,
endocrinopathy, monoclonal gammopathy, and skin changes syndrome), a diabetic condition such as insulin-dependent diabetes mellitus glaucoma, diabetic retinopathy or microangiopathy, sickle cell anaemia, chronic inflammation, synovitis,
glomerulonephritis, graft rejection, Lyme disease, von Hippel Lindau disease, pemphigoid, Paget' s disease, fibrosis, sarcoidosis, cirrhosis, thyroiditis, hyperviscosity syndrome, Osier- Weber-Rendu disease, chronic occlusive pulmonary disease, asthma or edema following burns, trauma, radiation, stroke, hypoxia, ischemia, ovarian
hyperstimulation syndrome, post perfusion syndrome, post pump syndrome, post-MI cardiotomy syndrome, preeclampsia, menometrorrhagia, endometriosis, pulmonary hypertension, infantile hemangioma, or infection by Herpes simplex, Herpes Zoster, human immunodeficiency virus, parapoxvirus, protozoa or toxoplasmosis, Progressive supranucleo Palsy, primary pulmonary hypertension, radiation therapy, Raynaud's phenomenon and disease, Refsum's disease, regular narrow QRS tachycardia, renovascular hypertension, restrictive cardiomyopathy, sarcoma, senile chorea, Senile Dementia of Lewy body type, shock, skin allograft, skin changes syndrome, ocular or macular edema, ocular neovascular disease, scleritis, radial keratotomy, uveitis, vitritis, myopia, optic pits, chronic retinal detachment, post-laser treatment complications, conjunctivitis, Stargardt's disease, Eales disease, retinopathy, macular degeneration, restenosis, ischemia/reperfusion injury, ischemic stroke, vascular occlusion, carotid obstructive disease, ulcerative colitis, inflammatory bowel disease, diabetes, diabetes mellitus, insulin dependent diabetes mellitus, allergic diseases, dermatitis scleroderma, graft versus host disease, organ transplant rejection (including but not limited to bone marrow and solid organ rejection), acute or chronic immune disease associated with organ transplantation, sarcoidosis, disseminated intravascular coagulation, Kawasaki's disease, nephrotic syndrome, chronic fatigue syndrome, Wegener's granulomatosis, Henoch- Schoenlein purpurea, microscopic vasculitis of the kidneys, chronic active hepatitis, septic shock, toxic shock syndrome, sepsis syndrome, cachexia, infectious diseases, parasitic diseases, acquired immunodeficiency syndrome, acute transverse myelitis, Huntington's chorea, stroke, primary biliary cirrhosis, hemolytic anemia, malignancies, Addison's disease, idiopathic Addison's disease, sporadic, polyglandular deficiency type I and polyglandular deficiency type II, Schmidt's syndrome, adult (acute) respiratory distress syndrome, alopecia, alopecia areata, seronegative arthropathy, arthropathy, Reiter's disease, psoriatic arthropathy, ulcerative colitic arthropathy, enteropathic synovitis, chlamydia, yersinia and salmonella associated arthropathy, atheromatous disease/arteriosclerosis, atopic allergy, autoimmune bullous disease, pemphigus vulgaris, pemphigus foliaceus, pemphigoid, linear IgA disease, autoimmune haemolytic anaemia, Coombs positive haemolytic anaemia, acquired pernicious anaemia, juvenile pernicious anaemia, peripheral vascular disorders, peritonitis, pernicious anemia, myalgic encephalitis/Royal Free Disease, chronic mucocutaneous candidiasis, giant cell arteritis, primary sclerosing hepatitis, cryptogenic autoimmune hepatitis, Acquired Immunodeficiency Disease Syndrome, Acquired Immunodeficiency Related Diseases, Hepatitis A, Hepatitis B, Hepatitis C, His bundle arrythmias, HIV infection/HIV neuropathy, common varied immunodeficiency (common variable
hypogammaglobulinemia), dilated cardiomyopathy, female infertility, ovarian failure, premature ovarian failure, fibrotic lung disease, chronic wound healing, cryptogenic fibrosing alveolitis, post-inflammatory interstitial lung disease, interstitial pneumonitis, Pneumocystis carinii pneumonia, pneumonia, connective tissue disease associated interstitial lung disease, mixed connective tissue disease, lung disease, systemic sclerosis associated interstitial lung disease, rheumatoid arthritis associated interstitial lung disease, systemic lupus erythematosus associated lung disease, dermatomyositis/polymyositis associated lung disease, Sjogren's disease associated lung disease, ankylosing spondylitis associated lung disease, vasculitic diffuse lung disease, haemosiderosis associated lung disease, drug-induced interstitial lung disease, radiation fibrosis, bronchiolitis obliterans, chronic eosinophilic pneumonia, lymphocytic infiltrative lung disease, postinfectious interstitial lung disease, gouty arthritis, autoimmune hepatitis, type- 1 autoimmune hepatitis (classical autoimmune or lupoid hepatitis), type-2 autoimmune hepatitis (anti- LKM antibody hepatitis), autoimmune mediated hypoglycaemia, type B insulin resistance with acanthosis nigricans, hypoparathyroidism, acute immune disease associated with organ transplantation, chronic immune disease associated with organ transplantation, osteoarthrosis, primary sclerosing cholangitis, psoriasis type 1 , psoriasis type 2, idiopathic leucopaenia, autoimmune neutropaenia, renal disease NOS,
glomerulonephritides, microscopic vasulitis of the kidneys, Lyme disease, discoid lupus erythematosus, male infertility idiopathic or NOS, sperm autoimmunity, multiple sclerosis (all subtypes), sympathetic ophthalmia, pulmonary hypertension secondary to connective tissue disease, pain, Goodpasture's syndrome, pulmonary manifestation of polyarteritis nodosa, acute rheumatic fever, rheumatoid spondylitis, Still's disease, systemic sclerosis, Sjogren's syndrome, Takayasu's disease/arteritis, autoimmune thrombocytopaenia, toxicity, transplants, idiopathic thrombocytopaenia, autoimmune thyroid disease, hyperthyroidism, goitrous autoimmune hypothyroidism (Hashimoto's disease), atrophic autoimmune hypothyroidism, primary myxoedema, phacogenic uveitis, primary vasculitis, vitiligo, acute liver disease, chronic liver diseases, alcoholic cirrhosis, alcohol-induced liver injury, choleosatatis, idiosyncratic liver disease, Drug-Induced hepatitis, Non-alcoholic Steatohepatitis, allergy and asthma, group B streptococci infection, mental disorders (e.g., depression and schizophrenia), Th2 Type and Thl Type mediated diseases,and diseases involving inappropriate vascularization for example diabetic retinopathy, retinopathy of prematurity, choroidal neovascularization due to age-related macular degeneration, and infantile hemangiomas in human beings. In addition, such compounds may be useful in the treatment of disorders such as ascites, effusions, and exudates, including for example macular edema, cerebral edema, acute lung injury, adult respiratory distress syndrome, proliferative disorders such as restenosis, fibrotic disorders such as hepatic cirrhosis and atherosclerosis, mesangial cell proliferative disorders such as diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, and glomerulopathies, myocardial angiogenesis, coronary and cerebral collaterals, ischemic limb angiogenesis, ischemia/reperfusion injury, peptic ulcer Helicobacter related diseases, virally-induced angiogenic disorders, preeclampsia, menometrorrhagia, cat scratch fever, rubeosis, neovascular glaucoma and retinopathies such as those associated with diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, acute idiopathic polyneuritis, acuter or chronic immune disease associated with organ transplantation, acute inflammatory demyelinating polyradiculoneuropathy, acute ischemia, adult Still's disease, allergy, anaphylaxis, anti-phospholipid antibody syndrome, aplastic anemia, atopic eczema, atopic dermatitis, autoimmune dermatitis, autoimmune diabetes, autoimmune disorder associated with streptococcus infection, autoimmune enteropathy, autoimmune hepatitis, autoimmune hearing loss, autoimmune lymphoproliferative syndrome, autoimmune myocarditis, autoimmune neutropenia, autoimmune premature ovarian failure, autoimmune thrombocytopenia, autoimmune uveitis, Behcet's disease, blepharitis, bronchiectasis, bullous pemphigoid, catastrophic antiphospholipid syndrome, celiac disease, cervical spondylosis, chronic ischemia, cicatricial pemphigoid, clinical isolated syndrome with risk for multiple sclerosis, childhood onset psychiatric disorder, dacrocystitis, dermatomyositis, disc herniation, disc prolapse, drug induced immune hemolytic anemia, endophthalmitis, episcleritis, erythema multiforme, erythema multiforme major, gestational pemphigoid, Guillain-Barre syndrome, heart failure, Hughes syndrome, idiopathic Parkinson's disease, idiopathic interstitial pneumonia, IgE- mediated allergy, immune hemolytic anemia, inclusion body myositis, infectious ocular inflammatory disease, inflammatory demyelinating disease, inflammatory heart disease, inflammatory kidney disease, IPF/UIP, iritis, keratitis, keratojuntivitis sicca, Kussmaul disease or Kussmaul-Meier disease, Landry's paralysis, Langerhan's cell hisiocytosis, livedo reticularis, microscopic polyangiitis, morbus bechterev, motor neuron disorders, mucous membrane pemphigoid, primary progressive multiple sclerosis, secondary progressive multiple sclerosis, relapsing remitting multiple sclerosis, multiple organ failure, myelodysplastic syndrome, nerve root disorder, neuropathy, Non-A Non-B hepatitis, osteolysis, ovarian cancer, pauciarticular JRA, peripheral artery occlusive disease (PAOD), peripheral vascular disease (PVD), peripheral artery disease, phlebitis, polychondritis, polymyalgia rheumatica, poliosis, polyarticular JRA, polyendocrine deficiency syndrome, polymyositis, post-pump syndrome, primary parkinsonism, prostatitis, psoratic arthropathy, pure red cell aplasia, primary adrenal insufficiency, Reiter's disease, recurrent neuromyelitis optica, rheumatic heart disease, SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis), scleroderma, secondary amyloidosis, shock lung, sciatica, secondary adrenal insufficiency, septic arthritis, seronegative arthopathy, silicone associated connective tissue disease, Sneddon- Wilkinson Dermatosis, spondilitis ankylosans, Stevens-Johnson Syndrome, systemic inflammatory response syndrome, temporal arteritis, toxoplasmic retinitis, toxic epidermal necrolysis, TRAPS (Tumor Necrosis factor receptor), type 1 allergic reaction, type II diabetes, urticaria, usual interstitial pneumonia, vernal conjunctivitis, viral retinitis, Vogt-Koyanagi-Harada syndrome (VKH syndrome) and wet macular degeneration. More particularly, the methods are useful for treating conditions related to pain such as, but not limited to, neuropathic pain, nociceptive pain, inflammatory pain (e.g. osteoarthritic pain, rheumatoid arthritic pain), fibromyalgia, neuralgia such as postherpatic neuralgia and trigeminal neuralgia, diabatic neuropathic pain, HIV-related neuropathic pain, migraine, post-stroke pain, post-operative pain, multiple sclerosis pain, pain related to spinal cord injury, cancer pain, lower back pain, and eye pain; and inflammatory disorders (e.g rheumatoid arthritis, osteoarthritis).
Further provided herein is the use of present compounds or pharmaceutically acceptable salts, solvates, or salts of solvates thereof, in the manufacture of medicaments for the treatment of the diseases or conditions described above, alone or in combination with a pharmaceutically acceptable carrier, particularly for the treatment of pain such as, but not limited to, neuropathic pain, nociceptive pain, inflammatory pain (e.g.
osteoarthritic pain, rheumatoid arthritic pain), fibromyalgia, neuralgia such as postherpatic neuralgia and trigeminal neuralgia, diabatic neuropathic pain, HIV-related neuropathic pain, migraine, post-stroke pain, post-operative pain, multiple sclerosis pain, pain related to spinal cord injury, cancer pain, lower back pain, and eye pain.
The compounds, compositions comprising the compounds, and methods for treating or preventing conditions and disorders by administering the compounds are further described herein.
These and other objectives of the invention are described in the following paragraphs. These objectives should not be deemed to narrow the scope of the invention.
DETAILED DESCRIPTION
Compounds of formula (I)
Figure imgf000015_0001
(I)
wherein G1, X1, X2, and X3 are as defined above in the Summary and below in the Detailed Description are disclosed. Compositions comprising such compounds and methods for treating conditions and disorders using such compounds and compositions are also disclosed.
In various embodiments, compounds described herein may contain variables that occur more than one time in any substituent or in the compound described or any other formula herein. Definition of a variable on each occurrence is independent of its definition at another occurrence. Further, combinations of variables are permissible only if such combinations result in stable compounds. Stable compounds are compounds that can be isolated from a reaction mixture.
a. Definitions
It is noted that, as used in this specification and the intended claims, the singular form "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a single compound as well as one or more of the same or different compounds, reference to "optional a pharmaceutically acceptable carrier" refers to a single optional pharmaceutically acceptable carrier as well as one or more pharmaceutically acceptable carriers, and the like.
As used in the specification and the appended claims, unless specified to the contrary, the following terms have the meaning indicated:
The term "alkenyl" as used herein, means a straight or branched hydrocarbon chain containing from 2 to 10 carbons and containing at least one carbon-carbon double bond. The term "C2-C4 alkenyl" means an alkenyl group containing 2-4 carbon atoms. Non-limiting examples of alkenyl include buta-2,3-dienyl, ethenyl, 2-propenyl, 2-methyl- 2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl- 1-heptenyl, and 3- decenyl.
The term "alkenylene" means a divalent group derived from a straight or branched chain hydrocarbon of 2 to 4 carbon atoms and contains at least one carbon-carbon double. Representative examples of alkenylene include, but are not limited to, -CH=CH- and -CH2CH=CH-.
The term "alkoxy" as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. The term "C1-C4 alkoxy" as used herein, means a C1-C4 alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.
The term "alkoxyalkyl" as used herein, means an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkylenyl group, as defined herein. Non-limiting examples of alkoxyalkyl include tert-butoxymethyl, 2-ethoxyethyl, 2- methoxyethyl, and methoxymethyl.
The term "alkyl" as used herein, means a straight or branched, saturated hydrocarbon chain containing from 1 to 10 carbon atoms. The term "Cx-Cy alkyl" means a straight or branched chain, saturated hydrocarbon containing x to y carbon atoms. For example "C2-C10 alkyl" means a straight or branched chain, saturated hydrocarbon containing 2 to 10 carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n- heptyl, n-octyl, n-nonyl, and n-decyl.
The term "alkylene" or "alkylenyl" means a divalent group derived from a straight or branched, saturated hydrocarbon chain, for example, of 1 to 10 carbon atoms or of 1 to 4 carbon atoms. Examples of alkylene and alkylenyl include, but are not limited to, - CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and -CH2CH(CH3)CH2-.
The term "alkynyl" as used herein, means a straight or branched chain
hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. The term "C2-C4 alkynyl" means a straight or branched chain hydrocarbon group containing from 2 to 4 carbon atoms. Representative examples of alkynyl include, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2- pentynyl, and 1-butynyl.
The term "aryl" as used herein, means phenyl or a bicyclic aryl. The bicyclic aryl is naphthyl, or a phenyl fused to a monocyclic cycloalkyl, or a phenyl fused to a monocyclic cycloalkenyl. Non-limiting examples of the aryl groups include
dihydroindenyl, indenyl, naphthyl, dihydronaphthalenyl, and tetrahydronaphthalenyl. The bicyclic aryl is attached to the parent molecular moiety through any carbon atom contained within the bicyclic ring system and can be unsubstituted or substituted.
The term "cycloalkyl" or "cycloalkane" as used herein, means a monocyclic and a bicyclic cycloalkyl. The monocyclic cycloalkyl is a carbocyclic ring system containing three to eight carbon atoms, zero heteroatoms and zero double bonds. Examples of monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The term "C3-C4 cycloalkyl" as used herein, means a monocyclic carbocyclic ring containing three or four carbon atoms, zero heteroatom, and zero double bond. The bicyclic cycloalkyl is a monocyclic cycloalkyl fused to a monocyclic cycloalkyl ring. The monocyclic and the bicyclic cycloalkyl groups may contain one or two alkylene bridges of one, two, three, or four carbon atoms wherein each bridge links two non-adjacent carbon atoms of the ring system. Non-limiting examples of bicyclic ring systems include bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane,
bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and
bicyclo[4.2. l]nonane. Examples of the cycloalkyl ring systems containing alkylene bridge(s) include, but are not limited to, tricyclo[3.3.1.03'7]nonane (octahydro-2,5- methanopentalene or noradamantane) and tricyclo[3.3.1. l3'7]decane (adamantane). The monocyclic and the bicyclic groups can be unsubstituted or substituted, and are attached to the parent molecular moiety through any substitutable atom contained within the ring system.
The term "cycloalkenyl" or "cycloalkene" as used herein, means a monocyclic or a bicyclic hydrocarbon ring system. The monocyclic cycloalkenyl has four-, five-, six-, seven- or eight carbon atoms and zero heteroatoms. The four-membered ring systems have one double bond, the five-or six-membered ring systems have one or two double bonds, and the seven- or eight-membered ring systems have one, two, or three double bonds. Representative examples of monocyclic cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. The bicyclic cycloalkenyl is a monocyclic cycloalkenyl fused to a monocyclic cycloalkyl group, or a monocyclic cycloalkenyl fused to a monocyclic cycloalkenyl group. The monocyclic or bicyclic cycloalkenyl ring may contain one or two alkylene bridges, each consisting of one, two, or three carbon atoms, each linking two non-adjacent carbon atoms of the ring system. Representative examples of the bicyclic cycloalkenyl groups include, but are not limited to, 4,5,6,7-tetrahydro-3aH-indene, octahydronaphthalenyl, and 1,6-dihydro-pentalene. The monocyclic and bicyclic cycloalkenyl can be attached to the parent molecular moiety through any substitutable atom contained within the ring systems, and can be unsubstituted or substituted.
The term "halo" or "halogen" as used herein, means CI, Br, I, and F.
The term "haloalkyl" as used herein, means an alkyl group, as defined herein, in which one, two, three, four, five or six hydrogen atoms are replaced by halogen. The term "C1-C4 haloalkyl" means a C1-C4 alkyl group, as defined herein, in which one, two, three, four, five or six hydrogen atoms are replaced by halogen. Representative examples of haloalkyl include, but are not limited to, chloromethyl, fluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, 2-chloro-3- fluoropentyl, trifluorobutyl, and trifluoropropyl.
The term "haloalkoxy" as used herein, means an alkoxy group, as defined herein, in which one, two, three, four, five or six hydrogen atoms are replaced by halogen. The term "C1-C4 haloalkoxy" as used herein, means a C1-C4 alkoxy group, as defined herein, in which one, two, three, four, five or six hydrogen atoms are replaced by halogen.
Representative examples of haloalkoxy include, but are not limited to, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, trifluoromethoxy, and difluoromethoxy.
The term "haloalkoxyalkyl" as used herein, means a haloalkoxy group, as defined herein, appended to the parent moiety through an alkylenyl group, as defined herein.
The term "heterocycle" or "heterocyclic" as used herein, means a monocyclic heterocycle, a bicyclic heterocycle, and a spiro heterocycle. The monocyclic heterocycle is a three-, four-, five-, six-, seven-, or eight-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S. The three- or four-membered ring contains zero or one double bond, and one heteroatom selected from the group consisting of O, N, and S. The five-membered ring contains zero or one double bond and one, two, or three heteroatoms selected from the group consisting of O, N, and S. The six-membered ring contains zero, one, or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. The seven- and eight-membered rings contains zero, one, two, or three double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. Representative examples of monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 2,3-dihydro-lH-pyrazolyl, 1,6-dihydropyridazinyl, 1,2- dihydropyridinyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxepanyl, oxetanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyridinyl (including 1,2,3,6-tetrahydropyridin- 1-yl), tetrahydropyranyl (including tetrahydro-2H-pyran-4-yl), tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, thiopyranyl, and trithianyl. The bicyclic heterocycle is a monocyclic heterocycle fused to a phenyl group, or a monocyclic heterocycle fused to a monocyclic cycloalkyl, or a monocyclic heterocycle fused to a monocyclic cycloalkenyl, or a monocyclic heterocycle fused to a monocyclic heterocycle. Representative examples of bicyclic heterocycles include, but are not limited to, benzopyranyl, benzothiopyranyl, 3,4-dihydro-2H-chromen-4-yl, 2,3- dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydro-lH-indolyl, 3,4- dihydroisoquinolin-2(lH)-yl, 1 ,2-dihydrophthalazinyl, 2,3,4,6-tetrahydro-lH-pyrido[l,2- a] pyrazin-2-yl, hexahydropyrano[4,3-b]pyrrol- l(4H)-yl, and hexahydropyrano[3,4- b] [l,4]oxazin-l(5H)-yl. The monocyclic heterocycle and the bicyclic heterocycle may contain one or two alkylene bridges or alkenylene bridges, or mixture thereof, each consisting of 1, 2, 3, or 4 carbon atoms and each linking two non adjacent atoms of the ring system. Examples of such bridged heterocycle include, but are not limited to, 3- oxabicyclo[3.3.1]nonyl, azabicyclo[2.2. l]heptyl (including 2-azabicyclo[2.2.1]hept-2-yl), 8-azabicyclo[3.2. l]oct-8-yl, octahydro-2,5-epoxypentalene, hexahydro-2H-2,5- methanocyclopenta[0]furan, hexahydro- 1H- 1 ,4-methanocyclopenta[c]furan, aza- admantane (l-azatricyclo[3.3.1.13'7]decane), and oxa-adamantane (2- oxatricyclo[3.3.1. l3'7]decane). A spiro heterocycle is a monocyclic heterocycle wherein two substituents on the same carbon atom of the monocyclic heterocycle ring together with said carbon atom form a second ring system selected from a monocyclic cycloalkyl, a bicyclic cycloalkyl, a monocyclic heterocycle, or a bicyclic heterocycle. Examples of spiro heterocycle include, but not limited to, 5-oxaspiro[2.5]octyl, 7-oxa- 1 - azaspiro[3.5]non-l-yl, 6-azaspiro[2.5]oct-6-yl, Η, 4H-spiro[l,3-benzodioxine-2,4'- piperidin]-l '-yl, Η, 3H-spiro[2-benzofuran-l,4'-piperidin]- -yl, and l,4-dioxa-8- azaspiro[4.5]dec-8-yl. The monocyclic, the bicyclic, and the spiro heterocycles can be unsubstituted or substituted. The monocyclic, the bicyclic and the spiro heterocycles are connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the rings except for those that are represented by ring A2 wherein the point of connection is through a nitrogen atom within the monocyclic hetrocycle of the ring systems. The nitrogen and sulfur heteroatoms in the heterocycle rings may optionally be oxidized and the nitrogen atoms may optionally be quarternized. The term "heterocyclealkyl" as used herein, means a heterocycle group, as defined herein above, appended to the parent moiety through an alkylenyl group, as defined herein.
The term "heteroaryl" as used herein, means a monocyclic heteroaryl or a bicyclic heteroaryl. The monocyclic heteroaryl is a five- or six-membered ring. The five- membered ring contains two double bonds. The five membered ring may contain one heteroatom selected from O or S; or one, two, three, or four nitrogen atoms and optionally one oxygen or one sulfur atom. The six-membered ring contains three double bonds and one, two, three or four nitrogen atoms. Representative examples of monocyclic heteroaryl include, but are not limited to, furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl (including 1,2,4-oxadiazolyl), 1,3-oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, 1,3-thiazolyl, thienyl, triazolyl (e.g. 1,2,4-triazolyl), and triazinyl. The bicyclic heteroaryl consists of a monocyclic heteroaryl fused to a phenyl, or a monocyclic heteroaryl fused to a monocyclic cycloalkyl, or a monocyclic heteroaryl fused to a monocyclic cycloalkenyl, or a monocyclic heteroaryl fused to a monocyclic heteroaryl, or a monocyclic heteroaryl fused to a monocyclic heterocycle. Representative examples of bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzoxadiazolyl, phthalazinyl, 2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)- yl, 6,7-dihydro-pyrazolo[l,5-a]pyrazin-5(4H)-yl, 6,7-dihydro-l,3-benzothiazolyl, 6,7- dihydro-4H-pyrano[4,3-d][l,3]thiazolyl, imidazo[l,2- ]pyridinyl, indazolyl, indolyl, isoindolyl, isoquinolinyl, naphthyridinyl, pyridoimidazolyl, quinolinyl, 2,4,6,7- tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl, thiazolo[5,4-b]pyridin-2-yl, thiazolo[5,4- d]pyrimidin-2-yl, and 5,6,7,8-tetrahydroquinolin-5-yl. The monocyclic and bicyclic heteroaryl groups can be substituted or unsubstituted and are connected to the parent molecular moiety through any substitutable carbon atom or any substitutable nitrogen atom contained within the ring systems, except for that represented by the ring A2 wherein the point of connection is through a nitrogen atom of the monocyclic heterocycle of the ring systems.
The term "heteroatom" as used herein, means a nitrogen, oxygen, and sulfur.
The term "hydroxyl" or "hydroxy" means a -OH group.
The term "oxo" as used herein, means a =0 group.
If a substituent is described as "substituted", a non-hydrogen radical is in the place of hydrogen radical any substitutable atom of the substituent. Thus, for example, a substituted heterocycle substituent is a heterocycle substituent in which at least one non- hydrogen radical is in the place of a hydrogen radical on the heterocycle substituent. It should be recognized that if there are more than one substitution on a substituent, each non-hydrogen radical may be identical or different (unless otherwise stated).
If a substituent is described as being "optionally substituted," the substituent may be either (1) not substituted or (2) substituted. If a substituent is described as being optionally substituted with up to a particular number of non-hydrogen radicals, that substituent may be either (1) not substituted; or (2) substituted by up to that particular number of non-hydrogen radicals or by up to the maximum number of substitutable positions on the substituent, whichever is less. Thus, for example, if a substituent is described as a heteroaryl optionally substituted with up to 3 non-hydrogen radicals, then any heteroaryl with less than 3 substitutable positions would be optionally substituted by up to only as many non-hydrogen radicals as the heteroaryl has substitutable positions. To illustrate, tetrazolyl (which has only one substitutable position) would be optionally substituted with up to one non-hydrogen radical. To illustrate further, if an amino nitrogen is described as being optionally substituted with up to 2 non-hydrogen radicals, then a primary amino nitrogen will be optionally substituted with up to 2 non-hydrogen radicals, whereas a secondary amino nitrogen will be optionally substituted with up to only 1 non-hydrogen radical.
The terms "treat," "treating," and "treatment" refer to a method of alleviating or abrogating a disease and/or its attendant symptoms.
The terms "prevent," "preventing," and "prevention" refer to a method of preventing the onset of a disease and/or its attendant symptoms or barring a subject from acquiring a disease. As used herein, "prevent," "preventing," and "prevention" also include delaying the onset of a disease and/or its attendant symptoms and reducing a subject's risk of acquiring a disease.
The term "modulate" refers to the ability of a compound to increase or decrease the function, or activity, of CCR. "Modulation", as used herein in its various forms, is intended to encompass antagonism, inhibition, agonism, partial antagonism and/or partial agonism of the activity associated with chemokine receptor, CCR. In certain embodiments, the chemokine receptor is CCR2.
The term "composition" as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The "subject" is defined herein to include animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In preferred embodiments, the subject is a human.
b. Compounds
Compounds of formula (I) are as described above.
Particular values of variable groups in compounds of formula (I) are as follows. Such values may be used where appropriate with any of the other values, definitions, claims or embodiments defined hereinbefore or hereinafter.
X1, X2, and X3 have values as disclosed in the Summary. In certain embodiments of compounds of formula (I), X1 is CR1, X2 is CR2, and X3 is CR3, wherein R1, R2, and R3 are as described in the Summary and herein. In certain embodiments, R1, R2, and R3 are the same or different, and are each independently hydrogen or haloalkyl. In certain embodiments, R1 and R3 are hydrogen, and R2 is halogen (e.g. CI, Br, F), -CN, or haloalkyl (such as, but not limited to, trifluoromethyl, difluoromethyl). In certain embodiments, R1 and R3 are hydrogen, and R2 is haloalkyl (such as, but not limited to, trifluoromethyl). In certain embodiments, R1 and R3 are hydrogen, and R2 is
trifluoromethyl.
G1 is as described in the Summary. In certain embodiments, G1 is NR4R5 or formula (a). In other embodiments, G1 is formula (b) or formula (c). R4, R5, ring A1 and G2 of formula (a), R6 and G3 of formula (b), and ring A2 of formula (c) have meanings as described in the Summary and embodiments herein below.
In certain embodiments, G1 is NR4R5 and R4 and R5 are as described in the
Summary and embodiments herein. In conjunction with any of the embodiments herein above and below, examples of R4 includes, but are not limited to, hydrogen, C(2]¾)3, d- C4 alkyl (e.g. methyl, ethyl), haloalkyl (e.g. 2,2-difluoroethyl), and alkoxyalkyl (e.g. 2- methoxyethyl). In certain embodiments R4 is hydrogen. In yet other embodiments, R4 is Ci-C4 alkyl (e.g. methyl, ethyl). In another embodiment, R4 is methyl. R5, for example, is a heterocycle, a heteroaryl, or a cycloalkyl (e.g. monocyclic cycloalkyl), or for example, a heterocycle or a cycloalkyl (e.g. monocyclic cycloalkyl); each R5 is optionally substituted as described in the Summary and herein. In certain embodiments, R5 is an optionally substituted monocyclic heterocycle (e.g. tetrahydropyranyl, 3- oxabicyclo[3.3.1]nonyl, oxepanyl, pyrrolidinyl, each of which is optionally substituted) as described in the Summary. In certain embodiments, R5 is an optionally substituted bicyclic heterocycle (e.g. optionally substituted 3,4-dihydro-2H-chromenyl). In other embodiments, R5 is an optionally substituted spiro heterocycle (e.g. optionally substituted 5-oxaspiro[2.5]octyl). In certain embodiments, R5 is an optionally substituted heteroaryl (e.g. optionally substituted 6,7-dihydro-4H-pyrano[4,3-d][l,3]thiazolyl). In other embodiments, R5 is an optionally substituted monocyclic cycloalkyl (e.g. cyclobutyl, cyclohexyl, adamantly, each of which is optionally substituted). Where R5 is a substituted heterocycle (e.g. tetrahydropyranyl, 3-oxabicyclo[3.3.1]nonyl, oxepanyl, pyrrolidinyl, 3,4-dihydro-2H-chromenyl, 5-oxaspiro[2.5]octyl), it is substituted with one or two substituents (Ra). In certain embodiments, said substituents of the heterocycle of R5 are selected from the group consisting of -CN, NO2, alkyl (e.g. methyl, ethyl, isopropyl), haloalkyl (e.g. trifluoromethyl, difluoromethyl, fluoromethyl), halogen (e.g. F, CI, Br), oxo, Ga (e.g. optionally substituted phenyl; optionally substituted heteroaryl such as, but not limited to, optionally substituted pyridinyl; optionally substituted monocyclic cycloalkyl such as, but not limited to, optionally substituted cyclopropyl), -(CRxRy)qi-Ga (e.g. benzyl), -ORf (e.g. OH, OCH3, OCH2CH3) and -(CRxRy)qi-ORf (e.g. -CH2OCH3). In certain embodiments, R5 is optionally substituted tetrahydropyranyl. In yet other embodiments, R5 is tetrahydropyranyl substituted with one or two substituents. Where R5 is a substituted tetrahydropyranyl, the optional substituents include, but are not limited to, optionally substtituted phenyl, optionally substituted heteroaryl such as, but not limited to, optionally substituted pyridinyl, -ORf and -(CRxRy)qi-ORf wherein Rf is C1-C4 alkyl (e.g. methyl, ethyl), Rx and Ry are hydrogen, and ql is 1. In certain embodiments, R5 is tetrahydropyranyl substituted with one -ORf group wherein Rf is C1-C4 alkyl (e.g. methyl, ethyl). In certain embodiments, R5 is tetrahydropyranyl substituted with one -ORf group wherein Rf is methyl. In certain embodiments, R5 is tetrahydropyranyl substituted with one C1-C4 alkyl group (e.g. methyl, ethyl). In certain embodiments, R5 is
tetrahydropyranyl substituted with one methyl group. In yet other embodiments, R5 is optionally substituted pyrrolidinyl. Where R5 is a substituted pyrrolidinyl, it is substituted with one or two substituents selected from the group consisting of oxo and Ga wherein Ga is as defined in the Summary. In yet other embodiments, R5 is pyrrolidinyl substituted with one or two substituent selected from the group consisting of oxo and Ga wherein Ga is optionally substituted aryl (e.g. optionally substituted phenyl). In certain embodiments, R5 is optionally substituted cycloalkyl (e.g. monocyclic cycloalkyl such as, but not limited to cyclobutyl, cyclohexyl, and adamantyl, each of which is optionally substituted) wherein the optional substituents are as described in the Summary and herein. Where R5 is an optionally substituted cycloalkyl (including the exemplary rings mentioned), it is substituted with 1, 2, or 3 Ra wherein Ra is as described in the Summary. In certain embodiments, R5 is a monocyclic cycloalkyl (e.g. cyclobutyl, cyclohexyl, adamantyl) optionally substituted with 1 , 2, or 3 substituents selected from the group consisting of alkyl, haloalkyl, halogen (e.g. F), Ga (e.g. optionally substituted heteroaryl such as, but not limited to, optionally substituted 1,3-thiazolyl, optionally substituted pyridinyl; or optionally substituted heterocycle such as, but not limited to, optionally substituted 1,3- benzodioxolyl), and -ORf (Rf, for example, is hydrogen, alkyl, or haloalkyl). In certain embodiments, R5 is a monocyclic cycloalkyl (e.g. cyclobutyl, cyclohexyl, adamantyl) optionally substituted with two halogen groups.
In certain embodiments, G1 is formula (a). Thus, included herein are compounds of formula (la)
Figure imgf000024_0001
(la)
wherein X1, X2, X3, A1, and G2 have meanings as discussed in the Summary and embodiments herein above and below.
In certain embodiments of compounds of formula (I) and (la), ring A1 is pyrrolidinyl or piperidinyl, each of which is optionally further substituted as described in the Summary.
In certain embodiments of compounds of formula (I) and (la), ring A1 is pyrrolidinyl, optionally further substituted as described in the Summary and embodiments herein.
In certain embodiments of compounds of formula (I) and (la), ring A1 is piperidinyl, optionally further substituted as described in the Summary and embodiments herein. For example, in certain embodiments, ring A1 is piperidinyl which is optionally further substituted with one or two substituents independently selected from the group consisting of alkyl (e.g. C1 -C4 alkyl such as, but not limited to methyl) or halogen (e.g. F). In certain embodiments, ring A is piperidinyl which is further substituted with one methyl group.
G for any of the above and below embodiments is G2a or -L'-G2b. In certain embodiments, G2 is G2a. In other embodiments, G2 is -L'-G2b. G2a, L1, and G2b are as described in the Summary and herein below. L1, for example, is O.
G2a, in certain embodiments, is a substituted phenyl, an optionally substituted bicyclic aryl (e.g. optionally substituted naphthyl), an optionally substituted heteroaryl (e.g. pyridazinyl, phthalazinyl, pyrazolyl, pyridinyl, 1,2,4-oxadiazolyl, 1,2,4-triazolyl, tetrazolyl, each of which is optionally substituted), a substituted monocyclic heterocycle (e.g. substituted 1,6-dihydropyridazinyl, substituted 1,2-dihydropyridinyl), or an optionally substituted bicyclic heterocycle (e.g. optionally substituted 1 ,2- dihydrophthalazinyl). In certain embodiments, G2a is substituted phenyl. The substituents of G2a are as described in the Summary and embodiments herein. For example, while G2a is a substituted phenyl, it is substituted with one substituent (Rb) wherein Rb is Ga (e.g. optionally substituted tetrazolyl), CN, COORf, -(CRxRy)qi-ORf, or -(CRxRy)qi-C(0)ORf; wherein Rf is hydrogen or C1-C4 alkyl (e.g. methyl, ethyl). In certain embodiments wherein G2a is a substituted phenyl, it is substituted with a COOH group. Where G2a is an optionally substituted heteroaryl (e.g. pyridazinyl, phthalazinyl, pyrazolyl, pyridinyl, 1 ,2,4-oxadiazolyl, 1 ,2,4-triazolyl, tetrazolyl, each of which is optionally substituted), it is optionally substituted with 1 , 2, or 3 substituents (Rb) as described in the Summary, for example, it is optionally substituted with 1 , 2, or 3 substituents (Rb) wherein Rb is haloalkyl (e.g. trifluoromethyl), alkyl (e.g. methyl, ethyl, isopropyl), ORf, COORf, Ga (e.g. optionally substituted phenyl); Rf, for example, is hydrogen or Ci-C4 alkyl such as, but not limited to, methyl, ethyl. While G2a is a monocyclic heterocycle or bicyclic heterocycle, it is substituted with an oxo group, and is optionally further substituted with one or two groups selected from alkyl (e.g. methyl, ethyl), halogen (e.g. F), or haloalkyl (e.g. trifluoromethyl).
In conjunction with any of the above or below embodiments, G2b, for example, is optionally substituted phenyl or optionally substituted naphthyl. In certain embodiments, G2b is unsubstituted phenyl.
In certain embodiments, G1 is formula (b). Thus, included herein are compounds of formula (lb)
Figure imgf000026_0001
(lb)
1 2 3 6 7 3
wherein X1, X X R°, R , p, and GJ have meanings as discussed in the Summary and embodiments herein above and below.
In certain embodiments of compounds of formula (I) and (lb), p is 0.
In certain embodiments of compounds of formula (I) and (lb), R6 is OH. In other embodiments, R6 is CN or halogen (e.g. F).
In certain embodiments of compounds of formula (I) and (lb), G3 is G3a wherein G3a is as described in the Summary and embodiments herein. For example, G3a is aryl optionally substituted with 1 , 2, 3, 4, or 5 Rc. For example, G3a is phenyl optionally substituted with 1, 2, 3, 4, or 5 Rc. In certain embodiments of compounds of formula (I) and (lb), G3 is -L2-G3a wherein L2 and G3a are as described in the Summary and embodiments herein. In conjunction with any of the above and below embodiments wherein G3 is -L2-G3a, L2, for example, is O. In certain embodiments of formula (I) and (lb) wherein G3 is -L2-G3a, G3a, for example, is aryl optionally substituted with 1 , 2, 3, 4, or 5 Rc; or for example, G3a is phenyl optionally substituted with 1 , 2, 3, 4, or 5 Rc.
Rc has values as described in the Summary, for example, in conjunction with any of the above and below embodiments, each Rc, for example, is independently alkyl, ORf, halogen (e.g. F, CI), COORf, or haloalkyl, wherein each Rf is, for example, independently hydrogen or C1 -C4 alkyl. In certain embodiments, G3a is phenyl, optionally substituted with one Rc group wherein Rc is halogen. In certain embodiments, G3a is phenyl, optionally substituted with one Rc group wherein Rc is F or CI.
In certain embodiments, G1 is formula (c). Thus, included herein are compounds of formula (Ic)
Figure imgf000026_0002
(Ic) wherein X1, X2, X3, and ring A2 have meanings as discussed in the Summary and embodiments herein above and below.
In certain embodiments of compounds of formula (I) and (Ic), ring A2 is a heterocycle, optionally substituted with 1, 2, 3, 4, or 5 Rd groups. For example, ring A2 is a monocyclic heterocycle (e.g. azetidinyl, piperazinyl, morpholinyl, tetrahydropyridinyl, 8-azabicyclo[3.2.1]oct-8-yl). In certain embodiments, ring A2 is substituted piperazinyl. The monocyclic heterocycle of ring A (including the exemplary rings) is optionally substituted as described in the Summary and herein. For example, they are each independently unsubstituted or substituted with 1, 2, or 3 substituents (Rd). In certain embodiments, the optional substituents (Rd) of the monocyclic rings are the same or different, and are selected from the group consisting of oxo, C1-C4 alkyl (e.g. methyl), halogen, haloalkyl (e.g. trifluoromethyl), Ga (e.g optionally substituted aryl such as, but not limited to, optionally substituted phenyl; or optionally substituted heteroaryl such as, but not limited to, optionally substituted pyrazolyl), ORf, and -(CRxRy)qi-ORf; wherein each Rf is independently hydrogen or alkyl. For example, ring A2 is an optionally substituted spiro heterocycle (e.g. H,4H-spiro[l,3-benzodioxine-2,4'-piperidin]- -yl, 6-azaspiro[2.5]oct-6-yl, l,4-dioxa-8-azaspiro[4.5]dec-8-yl, 1 'H,3H-spiro[2-benzofuran- l,4'-piperidin]-l '-yl, 7-oxa-l-azaspiro[3.5]non-l-yl, each of which is optionally substituted). Examples of the optional substituents of the spiro heterocycles (including the exemplary rings) include, but are not limited to, alkyl, halogen, haloalkyl (e.g.
trifluoromethyl), ORf wherein Rf is hydrogen or alkyl, or Ga (e.g. optionally substituted aryl such as, but not limited to, optionally substituted phenyl). In certain embodiments, ring A2 is l O,3H-spiro[2-benzofuran- l,4'-piperidin]- -yl. For example, ring A2 is an optionally substituted bicyclic heterocycle (e.g. 3,4-dihydroisoquinolin-2(lH)-yl, 2,3,4,6- tetrahydro- 1 H-pyrido[ 1 ,2-a]pyrazin-2-yl, hexahydropyrano [3 ,4-b] [ 1 ,4] oxazin- 1 (5H)-yl, hexahydropyrano[4,3-b]pyrrol-l(4H)-yl, each of which is optionally substitued).
Examples of the optional substituents of the bicyclic heterocycle include, but not limited to, oxo, alkyl, haloalkyl, or ORf wherein Rf is hydrogen or alkyl. In certain embodiments of compounds of formula (I) and (Ic), ring A is hexahydropyrano[3,4-b][l,4]oxazin- l(5H)-yl. In certain embodiments of compounds of formula (I) and (Ic), ring A2 is hexahydropyrano[4,3-b]pyrrol- 1 (4H)-yl.
In other embodiments of compounds of formula (I) and (Ic), ring A2 is a monocyclic heteterocycle fused with a monocyclic heteroaryl, optionally substituted with 1, 2, 3, 4, or 5 Rd groups. For example, in certain embodiments, ring A2 is 2,4,6,7- tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl, 2,6-dihydro-pyrrolo[3,4-c]pyrazol-5(4H)-yl, 6,7-dihydro-pyrazolo[l,5-a]pyrazin-5(4H)-yl), or 6,7-dihydro-pyrano[4,3-b]pyrrol-l(4H)- yl. The aforementioned rings in this paragraph are optionally substituted as described in the Summary. In certain embodiments, these rings are unsubstituted.
It is appreciated that compounds of formula (I), (la), (lb), and (Ic) with combinations of the above embodiments, including particular, more particular and preferred embodiments are contemplated.
Accordingly, one aspect relates to a group of compounds of formula (I) wherein X1 is CR1, X2 is CR2, X3 is CR3, and G1 is NR4R5.
Another aspect is related to a group of compounds of formula (I) wherein X1 is
CR1, X2 is CR2, X3 is CR3, G1 is NR4R5, and R5 is an optionally substituted heterocycle (e.g. tetrahydropyranyl, pyrrolidinyl, 3-oxabicyclo[3.3.1]nonyl, oxepanyl, 3,4-dihydro- 2H-chromenyl, 5-oxaspiro[2.5]octyl, each of which is optionally substituted) as described in the Summary, an optionally substituted heteroaryl (e.g. optionally substituted 6,7- dihydro-4H-pyrano[4,3-d][l,3]thiazolyl), or optionally substituted cycloalkyl (e.g.
cyclobutyl, cyclohexyl, adamantyl, each of which is optionally substituted).
Another aspect is related to a group of compounds of formula (I) wherein X1 is CR1, X2 is CR2, X3 is CR3, G1 is NR4R5, and R5 is an optionally substituted heterocycle (e.g. tetrahydropyranyl, 3-oxabicyclo[3.3.1]nonyl, oxepanyl, pyrrolidinyl, 3,4-dihydro- 2H-chromenyl, 5-oxaspiro[2.5]octyl each of which is optionally substituted) as described in the Summary, or optionally substituted cycloalkyl (e.g. cyclobutyl, cyclohexyl, adamantyl, each of which is optionally substituted).
Another aspect is related to a group of compounds of formula (I) wherein X1 is CR1, X2 is CR2, X3 is CR3, G1 is NR4R5, and R5 is optionally substituted monocyclic heterocycle (e.g. tetrahydropyranyl, 3-oxabicyclo[3.3.1]nonyl, oxepanyl, pyrrolidinyl, each of which is optionally substituted).
Another aspect is related to a group of compounds of formula (I) wherein X1 is CR1, X2 is CR2, X3 is CR3, G1 is NR4R5, R4 is hydrogen or C1-C4 alkyl, and R5 is optionally substituted monocyclic heterocycle (e.g. tetrahydropyranyl, 3- oxabicyclo[3.3. l]nonyl, oxepanyl, pyrrolidinyl, each of which is optionally substituted).
Another aspect is related to a group of compounds of formula (I) wherein X1 is CR1, X2 is CR2, X3 is CR3, G1 is NR4R5, R4 is hydrogen, and R5 is optionally substituted tetrahydropyranyl. Another aspect is related to a group of compounds of formula (I) wherein X is CR1, X2 is CR2, X3 is CR3, G1 is NR4R5, R4 is methyl, and R5 is substituted
tetrahydropyranyl.
Another aspect is related to a group of compounds of formula (I) wherein X1 is CR1, X2 is CR2, X3 is CR3, G1 is NR4R5, R4 is hydrogen or C1-C4 alkyl, and R5 is optionally substituted pyrrolidinyl.
Another aspect is related to a group of compounds of formula (I) wherein X1 is CR1, X2 is CR2, X3 is CR3, G1 is NR4R5, and R5 is optionally substituted cycloalkyl (e.g. cyclobutyl, cyclohexyl, adamantyl, each of which is optionally substituted).
Within each of the aforementioned groups of compounds of formula (I), each R5 is independently unsubstituted or substituted as described in the Summary and embodiments herein above.
Another aspect is related to a group of compounds of formula (I) and (la) wherein
1 1 2 2 3 3 1
X1 is CR , X" is CR , X is CRJ, and ring A is pyrrolidinyl or piperidinyl, each of which is optionally further substituted.
Another aspect is related to a group of compounds of formula (I) and (la) wherein
1 1 2 2 3 3 1
X1 is CR , X" is CR , X is CRJ, ring A is pyrrolidinyl or piperidinyl, each of which is optionally further substituted, G2 is G2a or -L'-G2b, and L1 is O.
Another aspect is related to a group of compounds of formula (I) and (la) wherein X 11 is CR 1 , X 2" is CR 2, X 3 is CR 3J, ring A 1 is pyrrolidinyl or or piperidinyl, each of which is optionally further substituted, and G2 is G2a.
Another aspect is related to a group of compounds of formula (I) and (la) wherein X1 is CR , X is CR XJ is CRJ, and ring A is piperidinyl which is optionally further substituted.
Another aspect is related to a group of compounds of formula (I) and (la) wherein
1 1 2 2 3 3 1
X1 is CR , X" is CR , X is CRJ, ring A is piperidinyl which is optionally further substituted, G2 is G2a or -L'-G2b, and L1 is O.
Another aspect is related to a group of compounds of formula (I) and (la) wherein
1 1 2 2 3 3 1
X1 is CR , ΧΔ is CR , X is CR , ring A is piperidinyl which is optionally further substituted, and G2 is G2a.
Another aspect is related to a group of compounds of formula (I) and (la) wherein
1 1 2 2 3 3 1
X1 is CR , X" is CR , X is CRJ, ring A is piperidinyl which is optionally further substituted, G2 is G2a, and G2a is a substituted phenyl. Another aspect is related to a group of compounds of formula (I) and (la) wherein
1 1 2 2 3 3 1
X1 is CR , X" is CR , X is CRJ, and ring A is pyrrolidinyl which is optionally further substituted.
Another aspect is related to a group of compounds of formula (I) and (la) wherein
1 1 2 2 3 3 1
X1 is CR1, X" is CR , X is CRJ, ring A is pyrrolidinyl which is optionally further substituted, G2 is G2a or -L'-G2b, and L1 is O.
Another aspect is related to a group of compounds of formula (I) and (la) wherein
1 1 2 2 3 3 1
X1 is CR , X" is CR , X is CRJ, ring A is pyrrolidinyl which is optionally further substituted, and G2 is G2a.
Within each group of compounds of formula (I) and (la) described herein above,
G2a and G2b, the substituents of G2a and G2b, and the optional substituents of ring A1 have values as described in the Summary and embodiments herein above.
Another aspect is related to a group of compounds of formula (I) and (lb) whererin X1 is CR1, X2 is CR2, X3 is CR3, and G3 is G3a. In certain embodiments, G3a is optionally substituted aryl. In certain embodiments, G3a is optionally substituted phenyl.
Another aspect is related to a group of compounds of formula (I) and (lb) whererin X1 is CR1, X2 is CR2, X3 is CR3, R6 is OH, and G3 is G3a. In certain embodiments, G3a is optionally substituted aryl. In certain embodiments, G3a is optionally substituted phenyl.
Another aspect is related to a group of compounds of formula (I) and (lb) whererin X1 is CR1, X2 is CR2, X3 is CR3, R6 is CN or halogen, and G3 is G3a. In certain embodiments, G3a is optionally substituted aryl. In certain embodiments, G3a is optionally substituted phenyl.
Another aspect is related to a group of compounds of formula (I) and (lb) whererin X1 is CR1, X2 is CR2, X3 is CR3, and G3 is -L2-G3a. In certain embodiments, L2 is O and G3a is optionally substituted phenyl.
Another aspect is related to a group of compounds of formula (I) and (lb) whererin X1 is CR1, X2 is CR2, X3 is CR3, R6 is OH, and G3 is -L2-G3a. In certain embodiments, L2 is O and G3a is optionally substituted phenyl.
Another aspect is related to a group of compounds of formula (I) and (lb) whererin X1 is CR1, X2 is CR2, X3 is CR3, R6 is CN or halogen, and G3 is -L2-G3a. In certain embodiments, L2 is O and G3a is optionally substituted phenyl. Within each group of compounds of formula (I) and (lb) described herein above, R7, p, and the optional substituents of G3a have values as described in the Summary and embodiments herein above.
Another aspect is related to a group of compounds of formula (I) and (Ic) whererin
1 1 2 2 3 3 2
X1 is CR1, X" is CR , X is CRJ, and ring A is an optionally substituted heterocycle, with the proviso that ring A2 is not an optionally substituted piperidinyl, an optionally substituted pyrrolidinyl, an optionally substituted 2,3-dihydroisoindolyl, or an optionally substituted decahydroisoquinolinyl. The substituents of ring A2 are as described in the Summary and embodiments herein above.
Another aspect is related to a group of compounds of formula (I) and (Ic) whererin
1 1 2 2 3 3 2
X1 is CR , X" is CR , X is CRJ, and ring A is an optionally substituted monocyclic heterocycle, with the proviso that ring A2 is not an optionally substituted piperidinyl or optionally substituted pyrrolidinyl. In certain embodiments, ring A2 is azetidinyl, piperazinyl, morpholinyl, tetrahydropyridinyl, or 8-azabicyclo[3.2.1]oct-8-yl, each of which is optionally substituted. The substituents of ring A2 are as described in the Summary and embodiments herein above.
Another aspect is related to a group of compounds of formula (I) and (Ic) whererin
1 1 2 2 3 3 2
X1 is CR , X" is CR , X is CRJ, and ring A is substituted piperazinyl. The substituents of ring A2 are as described in the Summary and embodiments herein above.
Another aspect is related to a group of compounds of formula (I) and (Ic) whererin
X1 is CR1, X2 is CR2, X3 is CR3, ring A2 is piperazinyl substituted with one Ga group, and Ga is optionally substituted phenyl.
Another aspect is related to a group of compounds of formula (I) and (Ic) whererin
1 1 2 2 3 3 2
X1 is CR , X" is CR , X is CRJ, and ring A is an optionally substituted spiro heterocycle. In certain embodiments, ring A2 is l 'H,4H-spiro[l,3-benzodioxine-2,4'- piperidin]-l '-yl, 6-azaspiro[2.5]oct-6-yl, l,4-dioxa-8-azaspiro[4.5]dec-8-yl, l 'H,3H- spiro[2-benzofuran-l,4'-piperidin]- -yl, or 7-oxa-l-azaspiro[3.5]non-l-yl, each of which is optionally substituted. The substituents of ring A2 are as described in the Summary and embodiments herein above.
Another aspect is related to a group of compounds of formula (I) and (Ic) whererin
X1 is CR1, X2 is CR2, X3 is CR3, and ring A2 is an optionally substituted 1 'H,3H-spiro[2- benzofuran-l,4'-piperidin]-l '-yl. The substituents of ring A2 are as described in the Summary and embodiments herein above. In certain embodiments, ring A2 is an unsubstituted 1 'H,3H-spiro[2-benzofuran- 1 ,4'-piperidin]- 1 '-yl. Another aspect is related to a group of compounds of formula (I) and (Ic) whererin
1 1 2 2 3 3 2
X1 is CR1, X" is CR , X is CR\ and ring A is an optionally substituted bicyclic heterocycle with the proviso that ring A2 is not an optionally substituted 2,3- dihydroisoindolyl or an optionally substituted decahydroisoquinolinyl. In certain embodiments, ring A2 is 3,4-dihydroisoquinolin-2(lH)-yl, 2,3,4,6-tetrahydro-lH- pyrido[l,2-a]pyrazin-2-yl, hexahydropyrano[3,4-b][l,4]oxazin-l(5H)-yl, or
hexahydropyrano[4,3-b]pyrrol-l(4H)-yl, each of which is optionally substituted. The substituents of ring A2 are as described in the Summary and embodiments herein above.
Another aspect is related to a group of compounds of formula (I) and (Ic) whererin X1 is CR1, X2 is CR2, X3 is CR3, and ring A is an optionally substituted
hexahydropyrana[3,4-b][l,4]-oxazin-l(5H)-yl. The substituents of ring A2 are as described in the Summary and embodiments herein above. In certain embodiments, ring A2 is unsubstituted hexahydropyrana[3,4-b][l,4]-oxazin-l(5H)-yl.
Another aspect is related to a group of compounds of formula (I) and (Ic) whererin
1 1 2 2 3 3 2
X is CR , X is CR , X is CR , and ring A is an optionally substituted
hexahydropyrano[4,3-b]pyrrol-l(4H)-yl. The substituents of ring A2 are as described in the Summary and embodiments herein above. In certain embodiments, ring A2 is unsubstituted hexahydropyrano[4,3-b]pyrrol- 1 (4H)-yl.
Another aspect is related to a group of compounds of formula (I) and (Ic) whererin
1 1 2 2 3 3 2
X1 is CR , X" is CR% XJ is CRJ, ring A is a monocyclic heterocycle fused with a monocyclic heteroaryl, and ring A2 is optionally substituted as described in the Summary and embodiments herein above.
Within each of the aforementioned groups of compounds of formula (I), (la), (lb), and (Ic), R1, R2, and R3 are as described in the Summary and embodiments herein above. Thus, within each groups of of compounds of formula (I), (la), (lb), and (Ic) described above, examples of a subgroup include but not limited to those whererin R1, R2, and R3 are the same or different, and are each independently hydrogen or haloalkyl.
Examples of another subgroup include, but not limited to, those whererin R1 and
3 2
R are hydrogen, and R is halogen (e.g. CI, Br, F), -CN, or haloalkyl (such as, but not limited to, trifluoromethyl, difluoromethyl).
Examples of another subgroup include, but not limited to, those whererin R1 and R3 are hydrogen, and R2 is haloalkyl.
Examples of yet another subgroup include, but not limited to, those whererin R1 and R3 are hydrogen, and R2 is trifluoromethyl. One embodiment is directed to compounds of formula (I) wherein
X1 is CR1 or N;
X2 is CR2 or N;
X3 is CR3 or N; with the proviso that no more than one of X1, X2, and X3 is N; R1, R2, and R3 are each independently hydrogen, halogen, alkyl, or haloalkyl;
G1 is - 4R5, formula (a), (b), or (c)
Figure imgf000033_0001
R4 is hydrogen, alkyl, haloalkyl, or alkoxyalkyl;
R is
an heterocycle selected from the group consisting of a monocyclic heterocycle wherein one of the ring atoms is O, N, or NH and having zero or one double bond, optionally contains one or two additional heteroatoms selected from the group consisting of O, N, NH, and S; a bicyclic heterocycle, and a spiro heterocycle;
a phenyl,
a naphthyl,
a cycloalkyl,
an heteroaryl, or
an heterocyclealkyl; wherein
each of the R5 phenyl, naphthyl, cycloalkyl, heteroaryl, heterocycle, and the heterocycle moiety of the heterocyclealkyl, is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 Ra;
with the proviso that when X1 is CR1, X2 is CR2, X3 is CR3, R1 and R3 are hydrogen, R2 is haloalkyl, R4 is alkyl, and R5 is a monocyclic heterocycle or a heterocyclealkyl, then the heterocycle moiety of R5 is substituted;
ring A1 is 2,3-dihydro-lH-isoindolyl, decahydroisoquinolinyl, piperidinyl, or pyrrolidinyl, each of which is optionally further substituted with 1 , 2, or 3 substituents independently selected from the group consisting of CN, alkyl, oxo, halogen, haloalkyl, OH, O(alkyl), and 0(haloalkyl); with the proviso that when ring A1 is piperidinyl, then G2 and the optional substituent of ring A1 do not reside on the same carbon atom;
G2 is G2a or -L'-G2b; a bicyclic aryl, a bicyclic cycloalkyl, a bicyclic heterocycle, a spiro heterocycle, or an heteroaryl, each of which is optionally substituted with 1, 2, 3, 4, or 5 Rb; or
a phenyl, a monocyclic cycloalkyl, or a monocyclic heterocycle, each of which is independently substituted with 1, 2, 3, 4, or 5 Rb;
G2b is aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycle, each of which is optionally substituted with 1, 2, 3, 4, or 5 Rb;
R6 is CN, OH, or halogen;
each R7 is an optional substituent on any substitutable carbon atom, and is independently alkyl, haloalkyl, halogen, oxo, or OH;
p is 0, 1, 2, or 3;
G3 is G3a or -L2-G3a;
L1 and L2 are independently O, N(Jk), or S; wherein Jk, at each occurrence, is independently hydrogen, alkyl, haloalkyl, C(0)Rk, S(0)2Rk, or C3-C4 cycloalkyl; wherein the C3-C4 cycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independenly selected from the group consisting of alkyl, halogen, haloalkyl, oxo, hydroxy, and alkoxy,
Rk, at each occurrence, is independently alkyl or C3-C4 cycloalkyl; wherein the C3-C4 cycloalkyl is optionally with 1, 2, 3, or 4 substituents independenly selected from the group consisting of alkyl, halogen, haloalkyl, oxo, hydroxy, and alkoxy;
G3a is aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycle, each of which is optionally substituted with 1, 2, 3, 4, or 5 Rc;
ring A2 is
a heterocycle or
a monocyclic heterocycle fused to a monocyclic heteroaryl, each ring A2 is optionally substituted with 1, 2, 3, 4, or 5 Rd; with the proviso that ring A2 is not 2,3-dihydro- lH-isoindolyl, decahydroisoquinolinyl, piperidinyl, or pyrrolidinyl;
Ra, R , Rc, and Ra are optional substituents on any substitutable atoms, and at each occurrence, are each independently alkyl, alkenyl, alkynyl, halogen, oxo, haloalkyl, CN, N02, -ORf, -OC(0)Rf, -OC(0)N(Rf)(Rs), -S(0)2Re, -S(0)2N(Rf)(Rs), -C(0)Rf, -C(0)ORf, -C(0)N(Rf)(Rg), -N(Rf)(Rg), -N(Rg)C(0)Rf, -N(Rg)S(0)2Re, -N(Rg)C(0)0(Rf),
-N(Rg)C(0)N(Rf)(Rg), Ga, -(CRxRy)qi-ORf, -(CRxRy)qi-OC(0)Rf,
-(CRxRy)qi-OC(0)N(Rf)(Rg), -(CRxRy)qi-S(0)2Re, -(CRxRy)qi-S(0)2N(Rf)(Rg), -(CRxRy)qi -C(0)R -(CRxRy)qi-C(0)ORt, -(CRxRy)qi -C(0)N(Rt)(Rg),
-(CRxRy)qi -N(Rf)(Rs), -(CRxRy)qi-N(Rg)C(0)Rf, -(CRxRy)qi-N(Rg)S(0)2Re,
-(CRxRy)qi-N(Rg)C(0)0(Re), -(CRxRy)qi-N(Rg)C(0)N(Rf)(Rg), -(CRxRy)qi-CN, and -(CRxRy)ql-Ga;
Re, at each occurrence, is independently alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, Gb, or -(C1-C6 alkylenyl)-Gb;
R , at each occurrence, is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, Gb, or -(C1-C6 alkylenyl)-Gb;
Rg, at each occurrence, is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, benzyl, or monocyclic cycloalkyl;
Ga and Gb, at each occurrence, are each independently aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycle, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, -CN, oxo, -ORh, -OC(0)Rh, -OC(0)N(Rh)2, -SCO^R1, -S(0)2N(Rh)2, -C(0)Rh, -C(0)ORh, -C(0)N(Rh)2, -N(Rh)2, -N(Rh)C(0)Rh, -N(Rh)S(0)2Ri,
-N(Rh)C(0)0(Rh), -N(Rh)C(0)N(Rh)2, -(CRxbRyb)q2-ORf, -(CRxbRyb)q2-OC(0)Rh, -(CRxbRyb)q2-OC(0)N(Rh)2, -(CRxbRyb)q2-S(0)2Ri, -(CRxbRyb)q2-S(0)2N(Rh)2,
-(CRxbRyb)q2-C(0)Rh, -(CRxbRyb)q2-C(0)ORh, -(CRxbRyb)q2-C(0)N(Rh)2,
-(CRxbRyb)q2-N(Rh)2, -(CRxbRyb)q2-N(Rh)C(0)Rh, -(CRxbRyb)q2-N(Rh)S(0)2Ri,
-(CRxbRyb)q2-N(Rh)C(0)0(Rh), -(CRxbRyb)q2-N(Rh)C(0)N(Rh)2, and -(CRxbRyb)q2-CN;
Rx, Ry, Rxb, and Ryb, at each occurrence, are each independently hydrogen, alkyl, halogen, or haloalkyl;
ql and q2, at each occurrence, are each independently 1, 2, 3, or 4;
Rh, at each occurrence, is independently hydrogen, alkyl, or haloalkyl; and R1, at each occurrence, is independently alkyl or haloalkyl.
Exemplary compounds contemplated include, but are not limited to:
2- { l-[(2S,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)- yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}pyridazin-3(2H)-one;
2- { 1 - [(2R,3aR,6aR)-3a- { [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin- 6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}phthalazin- l(2H)-one;
[(2S,3aR,6aR)-2-[4-(lH-pyrazol- 1 -yl)piperidin- 1 -yl]hexahydropentalen-3a(lH)- yl] [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]methanone; [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl] [(2R,3aR,6aR)-2- {4- [3-(trifluoromethyl)-lH-pyrazol-l-yl]piperidin- l-yl}hexahydropentalen-3a(lH)- yl]methanone;
1 - { 1 - [(2R,3aR,6aR)-3a- { [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin- 6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}pyridin-2(lH)-one;
[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl] [(2R,3aR,6aR)-2- {4- [4-(trifluoromethyl)-lH-pyrazol-l-yl]piperidin- l-yl}hexahydropentalen-3a(lH)- yl]methanone;
[(2R,3aR,6aR)-2-(4-phenoxypiperidin- l-yl)hexahydropentalen-3a(lH)-yl][3- (trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-[4-(5-methyl- 1 ,2,4-oxadiazol-3-yl)piperidin- 1 - yl]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{4-[3-(2-hydroxypropan-2-yl)phenyl]piperidin- l- yl}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-[4-(lH-pyrazol-l-yl)piperidin-l-yl]hexahydropentalen-3a(lH)- yl] [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]methanone;
[(2S,3aR,6aR)-2-(4-phenoxypiperidin-l-yl)hexahydropentalen-3a(lH)-yl][3- (trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]methanone;
1 - { 1 - [(2R,3aR,6aR)-3a- { [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin- 6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}- l,2-dihydro-3H-pyrazol-3- one;
[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl] [(2S,3aR,6aR)-2- {4- [4-(trifluoromethyl)-lH-pyrazol-l-yl]piperidin- l-yl}hexahydropentalen-3a(lH)- yl]methanone;
ethyl l- { l-[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}-lH-pyrazole-3-carboxylate;
3- { 1 - [(2R,3aR,6aR)-3a- { [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin- 6(5H)-yl]carbonyl} octahydropentalen-2-yl]piperidin-4-yl}benzoic acid;
[(2S,3aR,6aR)-2-[4-(3-ethoxy- lH-pyrazol- 1 -yl)piperidin- 1 -yl]hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone; [(2R,3aR,6aR)-2-[4-(3-phenyl- 1 ,2,4-oxadiazol-5-yl)piperidin- 1 - yl]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[(2S,3aR,6aR)-2- {4-[3-(2-hydroxypropan-2-yl)phenyl]piperidin- 1 - yl}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl] [(2S,3aR,6aR)-2- {4- [3-(trifluoromethyl)-lH-pyrazol-l-yl]piperidin- l-yl}hexahydropentalen-3a(lH)- yl]methanone;
1 - { 1 - [(2S,3aR,6aR)-3a- { [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)- yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}pyridin-2(lH)-one;
[(2R,3aR,6aR)-2-[4-(3,5-dimethyl-4H- l,2,4-triazol-4-yl)piperidin-l- yl]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
1 - { 1 - [(2S,3aR,6aR)-3a- { [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)- yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}- l,2-dihydro-3H-pyrazol-3-one;
(2- { 1 -[(2S,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin- 6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}phenyl)acetic acid;
[(2R,3aR,6aR)-2-[4-(3-isopropyl-5-methyl-4H- 1 ,2,4-triazol-4-yl)piperidin- 1 - yl]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-[4-(3-ethoxy- 1 H-pyrazol- 1 -yl)piperidin- 1 -yl]hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone;
[(2S,3aR,6aR)-2-{4-[3-(lH-tetrazol-5-yl)phenyl]piperidin-l- yl}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
2- { 1 - [(2R,3aR,6aR)-3a- { [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin- 6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}pyridazin-3(2H)-one;
[(2S,3aR,6aR)-2-[4-(5-methyl-l,2,4-oxadiazol-3-yl)piperidin-l- yl]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
2- { l-[(2S,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)- yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}benzoic acid; 2- { 1 - [(2R,3aR,6aR)-3a- { [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin- 6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}benzoic acid;
3- { l-[(2S,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)- yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}benzoic acid;
1 - { 1 - [(2S,3aR,6aR)-3a- { [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)- yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}-lH-pyrazole-3-carboxylic acid;
(2- { 1 -[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin- 6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}phenyl)acetic acid;
[(2S,3aR,6aR)-2-[4-(3,5-dimethyl-4H- l,2,4-triazol-4-yl)piperidin-l- yl]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[(2S,3aR,6aR)-2-[4-(3-isopropyl-5-methyl-4H- l,2,4-triazol-4-yl)piperidin-l- yl]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[(2S,3aR,6aR)-2-[4-(3-phenyl-l,2,4-oxadiazol-5-yl)piperidin- l- yl]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-(4-hydroxy-4-phenylpiperidin-l-yl)hexahydropentalen-3a(lH)- yl] [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]methanone;
4-phenyl-l-[(2R,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin- 6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperidine-4-carbonitrile;
4- (4-chlorophenyl)-l-[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- l,6- naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperidine-4-carbonitrile;
4-(4-fluorophenoxy)- l-[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperidine-4-carbonitrile;
[(2R,3aR,6aR)-2-[4-fluoro-4-(4-fluorophenyl)piperidin-l-yl]hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone;
[(2S,3aR,6aR)-2-[4-fluoro-4-(4-fluorophenyl)piperidin-l-yl]hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone;
[(2S,3aR,6aR)-2-(4-fluoro-4-phenylpiperidin-l-yl)hexahydropentalen-3a(lH)- yl] [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-(4-fluoro-4-phenylpiperidin- l-yl)hexahydropentalen-3a(lH)- yl] [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]methanone; 4-(4-fluorophenyl)- 1 -[(2S,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperidine-4-carbonitrile;
4-(4-chlorophenyl)-l-[(2S,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro- l,6- naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperidine-4-carbonitrile;
[(2S,3aR,6aR)-2-(4-hydroxy-4-phenylpiperidin-l-yl)hexahydropentalen-3a(lH)- yl] [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]methanone;
4-phenyl- 1 -[(2S,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin- 6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperidine-4-carbonitrile;
4-(4-fluorophenoxy)- l-[(2S,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- l,6- naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2-yl]piperidine-4-carbonitrile;
[(2S,3aS,6aS)-2-(6-fluoro- 1 'H,4H-spiro[ 1 ,3-benzodioxine-2,4'-piperidin]- 1 '- yl)hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-(6-fluoro- 1 'H,4H-spiro[ 1 ,3-benzodioxine-2,4'-piperidin]- 1 '- yl)hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl] [(2R,3aR,6aR)-2- {3- [3-(trifluoromethyl)- lH-pyrazol- 1 -yl]azetidin- 1 -yl}hexahydropentalen-3a(lH)- yl]methanone;
l-(4-chlorophenyl)-4-[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- 1,6- naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperazin-2-one;
l-(4-fluorophenyl)-4-[(2R,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro- l,6- naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperazin-2-one;
[(2R,3aR,6aR)-2-(2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5- yl)hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-(2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-[(3R)-3-(methoxymethyl)morpholin-4-yl]hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone;
[(3aR,6aR)-2-(4-hydroxy-6-azaspiro[2.5]oct-6-yl)hexahydropentalen-3a(lH)- yl] [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]methanone; [(2R,3aR,6aR)-2-(6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)- yl)hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
l-(4-chlorophenyl)-4-[(2S,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro- l,6- naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperazin-2-one;
[(2S,3aR,6aR)-2-(2 -phenyl- 1, 4-dioxa-8-azaspiro[4.5]dec-8-yl)hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-[7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(lH)- yl]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
l-phenyl-4-((2R,3aR,6aR)-3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-l,6- naphthyridine-6-carbonyl)octahydropentalen-2-yl)piperazin-2-one;
[(2R,3aR,6aR)-2-(2-phenyl-l,4-dioxa-8-azaspiro[4.5]dec-8-yl)hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone;
l-(4-fluorophenyl)-4-[(2S,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperazin-2-one;
[(2S,3aR,6aR)-2-[7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(lH)- yl]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
2-[(2R,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)- yl]carbonyl} octahydropentalen-2-yl]- 1 ,2,3,4-tetrahydro-6H-pyrido[ 1 ,2-a]pyrazin-6-one;
[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl] [(2S,3aR,6aR)-2- {3- [3-(trifluoromethyl)-lH-pyrazol-l-yl]azetidin- l-yl}hexahydropentalen-3a(lH)- yl]methanone;
4-[(2S,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)- yl]carbonyl}octahydropentalen-2-yl]piperazin-2-one;
4- [(2R,3 aR,6aR)-3 a- { [3 -(trifluoromethyl)-7, 8-dihydro- 1 ,6-naphthyridin-6(5H)- yl]carbonyl}octahydropentalen-2-yl]piperazin-2-one;
[(2S,3aR,6aR)-2-(6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)- yl)hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[(2S,3aR,6aR)-2-[(3S)-3-(methoxymethyl)morpholin-4-yl]hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone; [(2S,3aR,6aR)-2-[(3R)-3-(methoxymethyl)morpholin-4-yl]hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone;
l-phenyl-4-[(2S,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperazin-2-one;
l,5-anhydro-2,3-dideoxy-4-0-methyl-3-{[(2S,3aR,6aR)-3a-{[3-(trifluoromethyl)- 7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2-yl]amino} -L- threo-pentitol;
l,5-anhydro-2,3-dideoxy-4-0-methyl-3-{[(2S,3aR,6aR)-3a-{[3-(trifluoromethyl)- 7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2-yl]amino} -D- erythro-pentitol;
l,5-anhydro-2,3-dideoxy-4-0-methyl-3-{[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)- 7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2-yl]amino} -L- threo-pentitol;
l,5-anhydro-2,3-dideoxy-4-0-methyl-3-{methyl[(2R,3aR,6aR)-3a- {[3- (trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2- yl]amino} -D-erythro-pentitol;
l,5-anhydro-2,3-dideoxy-4-0-methyl-3-{[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)- 7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2-yl]amino} -D- erythro-pentitol;
l,5-anhydro-2,3-dideoxy-4-0-methyl-3-{[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)- 7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2-yl]amino} -D- threo-pentitol;
(3S)-l-(4-fluorophenyl)-3- {[(2R,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]amino}pyrrolidin-2-one;
[(2R,3aR,6aR)-2-(tetrahydro-2H-pyran-4-ylamino)hexahydropentalen-3a(lH)- yl] [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]methanone;
((2R,3aR,6aR)-2-(4,4-difluorocyclohexylamino)octahydropentalen-3a-yl)(3- (trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl)methanone;
[(2R,3 aR,6aR)-2- [(3 ,3 -difluorocy clobutyl)amino]hexahydropentalen-3 a( 1 H)- yl] [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]methanone;
[(2S,3aR,6aR)-2-[(3,3-difluorocyclobutyl)amino]hexahydropentalen-3a(lH)- yl] [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]methanone;
(3S)-l-(4-fluorophenyl)-3-{[(2S,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]amino}pyrrolidin-2-one; (3S)-3- {[(2R,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin- 6(5H)-yl]carbonyl}octahydropentalen-2-yl]amino}pyrrolidin-2-one;
(3S)- l-phenyl-3-{[(2S,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]amino}pyrrolidin-2-one;
(3S)-3- {[(2S,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]carbonyl}octahydropentalen-2-yl]amino}pyrrolidin-2-one;
(3S)- l-phenyl-3-{[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]amino}pyrrolidin-2-one;
3- {(3R,4S)-3-methyl-l -[(3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro- l,6- naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2-yl]piperidin-4-yl}benzoic acid;
3-((3S,4R)-3-methyl- l-((3aR,6aR)-3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-l,6- naphthyridine-6-carbonyl)octahydropentalen-2-yl)piperidin-4-yl)benzoic acid;
3- {(3S,4R)-3-methyl- l-[(2S,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}benzoic acid;
3- {(3 S,4R)-3-methyl- 1 -[(2R,3aR,6aR)-3a- { [3-(trifluoromethyl)-7,8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}benzoic acid;
3- {(3R,4S)-3-methyl- l-[(2S,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}benzoic acid;
3- {(3R,4S)-3-methyl- 1 -[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2-yl]piperidin-4-yl}benzoic acid;
3- { l-[(2S,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)- yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}benzonitrile;
3- { 1 - [(2R,3aR,6aR)-3a- { [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin- 6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}benzonitrile;
[(3aR,6aR)-2-[4-(naphthalen-2-yl)piperidin-l-yl]hexahydropentalen-3a(lH)-yl][3- (trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2- {4-[3-(lH-tetrazol-5-yl)phenyl]piperidin- 1 - yl}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[(2S,3aR,6aR)-2-{4-[3-(lH-tetrazol-5-yl)phenyl]piperidin-l- yl}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-[4-(naphthalen-2-yl)piperidin-l-yl]hexahydropentalen-3a(lH)- yl] [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]methanone; [(2S,3aR,6aR)-2- {4-[3-methyl-5-(trifluoromethyl)- IH-pyrazol- 1 -yl]piperidin- 1 - yl}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[(2R,3aR,6aR)-2- {4-[3-methyl-5-(trifluoromethyl)- IH-pyrazol- 1 -yl]piperidin- 1 - yl}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[(2R,3aR,6aR)-2- {4-[5-methyl-3-(trifluoromethyl)- IH-pyrazol- 1 -yl]piperidin- 1 - yl}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[(2S,3aR,6aR)-2-{(3R,4S)-4-[3-(2-hydroxypropan-2-yl)phenyl]-3- methylpiperidin- 1 -yl} hexahy dropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- 1,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{(3R,4S)-4-[3-(2-hydroxypropan-2-yl)phenyl]-3- methylpiperidin- 1 -yl} hexahy dropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7,8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
3- { l-[(2S,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)- yl]carbonyl} octahydropentalen-2-yl]- 1 ,2,3,6-tetrahydropyridin-4-yl}benzonitrile;
3- { 1 - [(2R,3aR,6aR)-3a- { [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin- 6(5H)-yl]carbonyl} octahydropentalen-2-yl]- 1 ,2,3,6-tetrahydropyridin-4-yl}benzonitrile;
[(2S,3aR,6aR)-2-(3-phenylazetidin-l-yl)hexahydropentalen-3a(lH)-yl][3- (trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-(3-phenylazetidin- 1 -yl)hexahydropentalen-3a(lH)-yl] [3- (trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone;
[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl] [(2S,3aR,6aR)-2- {(3- endo)-3-[5-(trifluoromethyl)-lH-pyrazol-l-yl]-8-azabicyclo[3.2.1]oct-8- yl} hexahy dropentalen-3 a( 1 H)-yl]methanone;
[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl] [(2R,3aR,6aR)-2- {(3- endo)-3-[5-(trifluoromethyl)-lH-pyrazol-l-yl]-8-azabicyclo[3.2.1]oct-8- yl} hexahy dropentalen-3 a( 1 H)-yl]methanone;
[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl] [(2R,3aR,6aR)-2- {(3- endo)-3-[3-(trifluoromethyl)-lH-pyrazol-l-yl]-8-azabicyclo[3.2.1]oct-8- yl} hexahy dropentalen-3 a( 1 H)-yl]methanone; [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl] [(2S,3aR,6aR)-2- {(3- endo)-3-[3-(trifluoromethyl)-lH-pyrazol-l-yl]-8-azabicyclo[3.2.1]oct-8- yl} hexahydropentalen-3 a( 1 H)-yl]methanone;
[(2S,3aR,6aR)-2-(4-phenylpiperazin-l-yl)hexahydropentalen-3a(lH)-yl][3- (trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-(4-phenylpiperazin-l-yl)hexahydropentalen-3a(lH)-yl][3- (trifluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)-yl]methanone;
[(2S,3aR,6aR)-2-(l'H,3H-spiro[2-benzof ran-l,4'-piperidin]- l'- yl)hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-(l'H,3H-spiro[2-benzof ran- l,4'-piperidin]- l'- yl)hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-(hexahydropyrano[3,4-b][l,4]oxazin-l(5H)- yl)hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-[(4aS,8aR)-hexahydropyrano[3,4-b][l,4]oxazin-l(5H)- yl]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-[(4aR,8aS)-hexahydropyrano[3,4-b][l,4]oxazin- l(5H)- yl]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-[(4aS,8aS)-hexahydropyrano[3,4-b][l,4]oxazin-l(5H)- yl]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[(2R,3aR,6aR)-2- [(4aR,8aR)-hexahydropyrano[3,4-b] [ 1 ,4]oxazin- 1 (5H)- yl]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[(2S,3aR,6aR)-2-[(4aS,8aS)-hexahydropyrano[3,4-b][l,4]oxazin-l(5H)- yl]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[(2S,3aR,6aR)-2-[(4aR,8aS)-hexahydropyrano[3,4-b][l,4]oxazin-l(5H)- yl]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone; [(2R,3aR,6aR)-2-[tricyclo[3.3.1. l3'7]dec-2-ylamino]hexahydropentalen-3a(lH)- yl] [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphmyridin-6(5H)-yl]methanone;
l,5-anhydro-2,3-dideoxy-3-{ethyl[(2R,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8- dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2-yl]amino} -4-0- methyl-D-erythro-pentitol;
l,5-anhydro-2,3-dideoxy-3-{ethyl[(2R,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8- dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2-yl]amino} -4-0- methyl-D-threo-pentitol;
l,5-anhydro-2,3-dideoxy-4-0-methyl-3-{methyl[(2R,3aR,6aR)-3a-{[3- (trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2- yl] amino } -D-threo-pentitol;
l,5-anhydro-2,3-dideoxy-3-{(2,2-difluoroethyl)[(2R,3aR,6aR)-3a-{[3- (trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2- yl]amino}-4-0-methyl-D-threo-pentitol;
[(2R,3aR,6aR)-2-[(2-methoxyethyl)(tetrahydro-2H-pyran-4- yl)amino]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro- l,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(2S,4R)-2-phenyltetrahydro-2H-pyran-4- yl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(2R,4S)-2-phenyltetrahydro-2H-pyran-4- yl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone;
l,5-anhydro-2,3-dideoxy-3-{(2,2-difluoroethyl)[(2R,3aR,6aR)-3a-{[3- (trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2- yl]amino}-4-0-methyl-D-erythro-pentitol;
[(2R,3aR,6aR)-2-{[(2S,4S)-2-phenyltetrahydro-2H-pyran-4- yl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone;
l,5-anhydro-2,3-dideoxy-4-0-ethyl-3-{[(2R,3aR,6aR)-3a-{[3-(trifluoromethyl)- 7,8-dihydro-l,6-naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]amino}-D- eryi/zro-pentitol; l,5-anhydro-2,3-dideoxy-4-0-ethyl-3-{[(2R,3aR,6aR)-3a-{[3-(trifluoromethyl)- 7,8-dihydro-l,6-naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]amino}-L- i/zreo-pentitol;
l,5-anhydro-2,3-dideoxy-4-0-methyl-3-{(2H3)methyl[(2R,3aR,6aR)-3a-{[3- (trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2- yl]amino} -D-eryi zro-pentitol;
[(2R,3aR,6aR)-2-[(4R)-3,4-dihydro-2H-chromen-4-ylamino]hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(3S,4S)-3-methyltetrahydro-2H-pyran-4- yl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(3S,4R)-3-methyltetrahydro-2H-pyran-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-[(4R)-3,4-dihydro-2H-chromen-4- yl(methyl)amino]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(4R)-6-fluoro-3,4-dihydro-2H-chromen-4- yl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(2R,4R)-2-(pyridin-2-yl)tetrahydro-2H-pyran-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(3S,4S)-3-ethyltetrahydro-2H-pyran-4- yl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(3S,4R)-3-ethyltetrahydro-2H-pyran-4- yl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(4R)-8-fluoro-3,4-dihydro-2H-chromen-4- yl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone; [(2R,3aR,6aR)-2-[(3aS,7aS)-hexahydropyrano[4,3-b]pyrrol-l(4H)- yl]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-[(3aR,7aR)-hexahydropyrano[4,3-b]pyrrol-l(4H)- yl]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[(3aR,6aR)-2-(6,7-dihydro-4H-pyrano[4,3-d][l,3]thiazol-2- ylamino)hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2- {[trans-4-hydroxy-4-(6-methoxypyridin-3- yl)cyclohexyl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[trans-4-hydroxy-4-(l,3-thiazol-2- yl)cyclohexyl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[trans-4-(l,3-benzodioxol-5-yl)-4- hydroxycyclohexyl] amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8- dihydro- 1 ,6-naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(3R,4R)-3-fluorotetrahydro-2H-pyran-4- yl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(3S,4R)-3-fluorotetrahydro-2H-pyran-4- yl] amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(3R,4S)-3-fluorotetrahydro-2H-pyran-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(3S,4S)-3-fluorotetrahydro-2H-pyran-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[cis-4-hydroxy-4-(6-methoxypyridin-3- yl)cy clohexyl] amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone; [(2R,3aR,6aR)-2-{[cis-4-hydroxy-4-(l,3-thiazol-2- yl)cyclohexyl]amino}hexahydropentalen-3a(lH)-yl][3-(tri^
naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[cis-4-(l,3-benzodioxol-5-yl)-4- hydroxy cyclohexyl] amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8- dihydro- 1 ,6-naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(2R,4S)-2-benzyltetrahydro-2H-pyran-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(2R,4R)-2-benzyltetrahydro-2H-pyran-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(2S,4R)-2-benzyltetrahydro-2H-pyran-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-[(4S)-3,4-dihydro-2H-chromen-4-ylamino]hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-(7-oxa- 1 -azaspiro[3.5]non- 1 -yl)hexahy dropentalen-3 a(lH)- yl] [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]methanone;
[(2S,3aR,6aR)-2-(7-oxa-l-azaspiro[3.5]non-l-yl)hexahydropentalen-3a(lH)- yl] [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]methanone;
l,5-anhydro-2,3-dideoxy-3-{[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2-yl]amino} -D-erythro-pentitol;
[(2R,3aR,6aR)-2-{[(3R,4S)-3-methyltetrahydro-2H-pyran-4- yl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(3R,4R)-3-methyltetrahydro-2H-pyran-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
l,5-anhydro-2,3-dideoxy-4-C-(trifluoromethyl)-3-{[(2R,3aR,6aR)-3a- {[3-
(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2- yl]amino} -L-threo-pentitol; l,5-anhydro-2,3-dideoxy-4-C-(trifluoromethyl)-3-{[(2R,3aR,6aR)-3a- {[3- (trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2- yl]amino} -D-erythro-pentitol;
l,5-anhydro-3,4-dideoxy-2-C-(trifluoromethyl)-3-{[(2R,3aR,6aR)-3a- {[3- (trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2- yl]amino} -D-erythro-pentitol;
[(2R,3aR,6aR)-2-{[3-(methoxymethyl)tetrahydro-2H-pyran-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(3R,4R)-3-fluorotetrahydro-2H-pyran-4- yl] (methyl)amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7,8-dihydro- 1,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(3R)-4,4-dimethoxytetrahydro-2H-pyran-3- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(4S)-6-fluoro-3,4-dihydro-2H-chromen-4- yl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(4S)-6-chloro-3,4-dihydro-2H-chromen-4- yl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(4S)-6-bromo-3,4-dihydro-2H-chromen-4- yl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(3S,4R)-3-fluorotetrahydro-2H-pyran-4- yl] (methyl)amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- 1,6- naphthyridin-6(5H)-yl]methanone;
l,5-anhydro-2,3-dideoxy-3-{[(2R,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2-yl]amino} -L-threo-pentitol; l,5-anhydro-3,4-dideoxy-3-{[(2R,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2-yl]amino} -D-erythro-pentitol; l,5-anhydro-2,3-dideoxy-3-{[(2R,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]amino}-D-threo-pentitol; [(2R,3aR,6aR)-2-{[(3S)-4,4-dimethoxytetrahydro-2H-pyran-3- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(4R)-6-chloro-3,4-dihydro-2H-chromen-4- yl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(4R)-6-bromo-3,4-dihydro-2H-chromen-4- yl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(4S)-6-methyl-3,4-dihydro-2H-chromen-4- yl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(4R)-6-methyl-3,4-dihydro-2H-chromen-4- yl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphmyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2- {[(4S)-6-nitro-3,4-dihydro-2H-chromen-4- yl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro- l,6- naphmyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(4R)-6-nitro-3,4-dihydro-2H-chromen-4- yl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(2R,4S)-2-(pyridin-2-yl)tetrahydro-2H-pyran-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(4R)-6,7-difluoro-3,4-dihydro-2H-chromen-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(4S)-6,7-difluoro-3,4-dihydro-2H-chromen-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-[(9-anti)-3-oxabicyclo[3.3.1]non-9-ylamino]hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-[(9-syn)-3-oxabicyclo[3.3.1]non-9-ylamino]hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone; [(2R,3aR,6aR)-2-{[(3S,4S)-3-methoxy-3,4-dihydro-2H-chromen-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(3R,4S)-3-methoxy-3,4-dihydro-2H-chromen-4- yl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(3R,4R)-3-methoxy-3,4-dihydro-2H-chromen-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
(4S)-4- {[(2R,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin- 6(5H)-yl]carbonyl}octahydropentalen-2-yl]amino}-3,4-dihydro-2H-chromene-6- carbonitrile;
(4R)-4-{[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]carbonyl}octahydropentalen-2-yl]amino}-3,4-dihydro-2H-chromene-6- carbonitrile;
[(2R,3aR,6aR)-2-{[(4S)-8-fluoro-3,4-dihydro-2H-chromen-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(2R,4S)-2-(trifluoromethyl)-3,4-dihydro-2H-chromen-4- yl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(2S,4R)-2-(trifluoromethyl)-3,4-dihydro-2H-chromen-4- yl] amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(3R,4R)-3-cyclopropyltetrahydro-2H-pyran-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(3R,4S)-3-cyclopropyltetrahydro-2H-pyran-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(3S,4S)-3-cyclopropyltetrahydro-2H-pyran-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone; [(2R,3aR,6aR)-2-{[(3S,4R)-3-cyclopropyltetrahydro-2H-pyran-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[3-(fluoromethyl)tetrahydro-2H-pyran-4- yl] amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(3S,4R)-3-(difluoromethyl)tetrahydro-2H-pyran-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(3S,4S)-3-(difluoromethyl)tetrahydro-2H-pyran-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(4R)-3,3-dimethyltetrahydro-2H-pyran-4- yl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro- l,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(4S)-3,3-dimethyltetrahydro-2H-pyran-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-(6,7-dihydropyrano[4,3-b]pyrrol-l(4H)-yl)hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-[(4S)-oxepan-4-ylamino]hexahydropentalen-3a(lH)-yl][3- (trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-[(8R)-5-oxaspiro[2.5]oct-8-ylamino]hexahydropentalen-3a(lH)- yl] [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-[(8S)-5-oxaspiro[2.5]oct-8-ylamino]hexahydropentalen-3a(lH)- yl] [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(3R,4S)-3-(methoxymethyl)tetrahydro-2H-pyran-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(3R,4R)-3-(methoxymethyl)tetrahydro-2H-pyran-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
(3-chloro-7,8-dihydro-l,6-naphthyridin-6(5H)-yl)[(2R,3aR,6aR)-2-{[(3R,4S)-3- methyltetrahydro-2H-pyran-4-yl]amino } hexahydropentalen-3 a( 1 H)-yl]methanone; (3-chloro-7,8-dihydro-l,6-naphthyridin-6(5H)-yl)[(2R,3aR,6aR)-2-{[(3S,4S)-3- methyltetrahydro-2H-pyran-4-yl]amino } hexahydropentalen-3 a( 1 H)-yl]methanone;
(3-chloro-7,8-dihydro- l,6-naphthyridin-6(5H)-yl)[(2R,3aR,6aR)-2-{[(3S,4R)-3- methyltetrahydro-2H-pyran-4-yl]amino } hexahydropentalen-3 a( 1 H)-yl]methanone;
(3-chloro-7,8-dihydro-l,6-naphthyridin-6(5H)-yl)[(2R,3aR,6aR)-2-{[(3R,4R)-3- methyltetrahydro-2H-pyran-4-yl]amino } hexahydropentalen-3 a( 1 H)-yl]methanone; l,5-anhydro-3-({(2R,3aR,6aR)-3a-[(3-chloro-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl)carbonyl]octahydropentalen-2-yl}amino)-2,3-dideoxy-4-0-methyl-D-erythro- pentitol;
[3-(difluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl] [(2R,3aR,6aR)-2-
{[(3R,4S)-3-methyltetrahydro-2H-pyran-4-yl]amino}hexahydropentalen-3a(lH)- yl]methanone;
[3-(difluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl] [(2R,3aR,6aR)-2- {[(3S,4S)-3-methyltetrahydro-2H-pyran-4-yl]amino}hexahydropentalen-3a(lH)- yl]methanone;
[3-(difluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl] [(2R,3aR,6aR)-2- {[(3S,4R)-3-methyltetrahydro-2H-pyran-4-yl]amino}hexahydropentalen-3a(lH)- yl]methanone;
[3-(difluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl] [(2R,3aR,6aR)-2- { [(3R,4R)-3 -methyltetrahydro-2H-pyran-4-yl]amino } hexahydropentalen-3 a( 1 H)- yl]methanone;
(3-bromo-7,8-dihydro-l,6-naphthyridin-6(5H)-yl)[(2R,3aR,6aR)-2-{[(3S,4S)-3- methyltetrahydro-2H-pyran-4-yl]amino } hexahydropentalen-3 a( 1 H)-yl]methanone;
(3-bromo-7,8-dihydro-l,6-naphthyridin-6(5H)-yl)[(2R,3aR,6aR)-2-{[(3S,4R)-3- methyltetrahydro-2H-pyran-4-yl]amino } hexahydropentalen-3 a( 1 H)-yl]methanone;
6- {[(2R,3aR,6aR)-2- {[(3S,4R)-3-methyltetrahydro-2H-pyran-4- yl]amino}hexahydropentalen-3a(lH)-yl]carbonyl}-5,6,7,8-tetrahydro- l,6-naphthyridine- 3-carbonitrile;
6- {[(2R,3aR,6aR)-2- {[(3S,4S)-3-methyltetrahydro-2H-pyran-4- yl]amino}hexahydropentalen-3a(lH)-yl]carbonyl}-5,6,7,8-tetrahydro- l,6-naphthyridine- 3-carbonitrile;
l,5-anhydro-2,3-dideoxy-3-({(2R,3aR,6aR)-3a-[(3-fluoro-7,8-dihydro-l,6- naphthyridin-6(5H)-yl)carbonyl]octahydropentalen-2-yl}amino)-4-0-methyl-D-erythro- pentitol; and l,5-anhydro-2,3-dideoxy-3-({(2R,3aR,6aR)-3a-[(3-fluoro-7,8-dihydro-l,6- naphthyridin-6(5H)-yl)carbonyl]octahydropentalen-2-yl}amino)-4-0-methyl-D-threo- pentitol.
Compounds of formula (I) contain one or more chiral centers, and can exist in different optically active forms. When compounds of formula (I) contain one chiral center, the compounds exist in two enantiomeric forms and the present invention includes both enantiomers and mixtures of enantiomers, such as racemic mixtures. The enantiomers may be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts which may be separated, for example, by crystallization; formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where the desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired enantiomeric form. Alternatively, specific enantiomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.
When a compound of formula (I) contains more than one chiral center, it may exist in diastereoisomeric forms. The diastereoisomeric compounds may be separated by methods known to those skilled in the art, for example chromatography or crystallization. The present invention includes each diastereoisomer of compounds of formula (I) and mixtures of various ratios thereof.
Certain compounds of formula (I) may exist in different tautomeric forms or as different geometric isomers, and the present invention includes all tautomers and/or geometric isomers of compounds of formula (I) and mixtures thereof.
Though structural representations within this specification may show only one of the possible tautomeric or stereoisomeric forms, it is to be understood that the invention encompasses any tautomeric or stereoisomeric form, and mixtures thereof, and is not to be limited merely to any one tautomeric or stereoisomeric form utilized within drawings or the naming of the compounds. Compounds of the invention can exist in isotope-labeled or -enriched form containing one or more atoms having an atomic mass or mass number different from the atomic mass or mass number most abundantly found in nature. Isotopes can be radioactive or non-radioactive isotopes. Isotopes of atoms such as hydrogen, carbon, phosphorous, sulfur, fluorine, chlorine, and iodine include, but are not limited to, 2H, 3H, 13C, 14C, 1 N, 180, 32P, 3 S, 18F, 36C1, and 12 I. Compounds that contain other isotopes of these and/or other atoms are within the scope of this invention.
In another embodiment, the isotope-labeled compounds contain deuterium (2H), tritium (3H) or 14C isotopes. Isotope-labeled compounds of this invention can be prepared by the general methods well known to persons having ordinary skill in the art. Such isotope-labeled compounds can be conveniently prepared by carrying out the procedures disclosed in the Examples and Schemes sections by substituting a readily available isotope-labeled reagent for a non-labeled reagent. In some instances, compounds may be treated with isotope-labeled reagents to exchange a normal atom with its isotope, for example, hydrogen for deuterium can be exchanged by the action of a deuteric acid such as D2SO4/D2O. In addition to the above, relevant procedures and intermediates are disclosed, for instance, in Lizondo, J et al., Drugs Fut, 21(1 1), 1 1 16 (1996); Brickner, S J et al, J Med Chem, 39(3), 673 (1996); Mallesham, B et al., Org Lett, 5(7), 963 (2003); PCT publications WO 1997010223, WO2005099353, WO 1995007271, WO2006008754; US Patent Nos. 7538189; 7534814; 7531685; 7528131 ; 7521421 ; 7514068; 751 1013; and US Patent Application Publication Nos. 20090137457; 20090131485; 20090131363; 200901 18238; 200901 1 1840; 20090105338; 20090105307; 20090105147; 20090093422; 20090088416; and 20090082471, the methods are hereby incorporated by reference.
The isotope-labeled compounds of the invention may be used as standards to determine the effectiveness of CCR2 modulators in binding assays. Isotope containing compounds have been used in pharmaceutical research to investigate the in vivo metabolic fate of the compounds by evaluation of the mechanism of action and metabolic pathway of the nonisotope-labeled parent compound (Blake et al. J. Pharm. Sci. 64, 3, 367-391 (1975)). Such metabolic studies are important in the design of safe, effective therapeutic drugs, either because the in vivo active compound administered to the patient or because the metabolites produced from the parent compound prove to be toxic or carcinogenic (Foster et al., Advances in Drug Research Vol. 14, pp. 2-36, Academic press, London, 1985; Kato et al., J. Labelled Comp. Radiopharmaceut., 36(10):927-932 (1995); Kushner et al., Can. J. Physiol. Pharmacol, 77, 79-88 (1999). In addition, non-radioactive isotope-containing drugs, such as deuterated drugs called "heavy drugs," can be used for the treatment of diseases and conditions related to the modulation of CCR2 function. Increasing the amount of an isotope present in a compound above its natural abundance is called enrichment. Examples of the amount of enrichment include from about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71, 75, 79, 84, 88, 92, 96, to about 100 mol %. Replacement of up to about 15% of normal atom with a heavy isotope has been effected and maintained for a period of days to weeks in mammals, including rodents and dogs, with minimal observed adverse effects (Czajka D M and Finkel A J, Ann. N.Y. Acad. Sci. 1960 84: 770; Thomson J F, Ann. New York Acad. Sci 1960 84: 736; Czakja D M et al., Am. J.
Physiol. 1961 201 : 357). Acute replacement of as high as 15%-23% in human fluids with deuterium was found not to cause toxicity (Blagojevic N et al. in "Dosimetry &
Treatment Planning for Neutron Capture Therapy", Zamenhof R, Solares G and Harling O Eds. 1994. Advanced Medical Publishing, Madison Wis. pp.125-134; Diabetes Metab. 23: 251 (1997)).
Stable isotope labeling of a drug may alter its physico-chemical properties such as pKa and lipid solubility. These effects and alterations may affect the pharmacodynamic response of the drug molecule if the isotopic substitution affects a region involved in a ligand-receptor interaction. While some of the physical properties of a stable isotope- labeled molecule are different from those of the unlabeled one, the chemical and biological properties are the same, with one exception: because of the increased mass of the heavy isotope, any bond involving the heavy isotope and another atom will be stronger than the same bond between the light isotope and that atom. Accordingly, the incorporation of an isotope at a site of metabolism or enzymatic transformation will slow said reactions, potentially altering the pharmacokinetic profile or efficacy relative to the non-isotopic compound.
c. Biological Data
In Vitro Assay:
The in vitro potency of compounds in antagonizing CCR2 were determined by the procedures detailed below.
CHO cells expressing human CCR2B (hCCR2B) were generated as follows. cDNA for human CCR2B (cloned from human blood) was cloned into plasmid pcDNA3.1 (from Invitrogen). The resulting plasmids were separately transfected into CHO cells expressing human Gal 6 (from Molecular Devices). Sequences of the transfected CCR2 open reading frames in the resulting cell lines were identical to human CCR2B (NM 00648). CHO cells expressing rat CCR2 (rCCR2) were generated as follows. cDNA for rat CCR2 (cloned from rat macrophage) was cloned into plasmid pEF- flag (from Chinese Academy of Science). The resulting plasmids were transfected into CHO cells expressing human Gal 6 (from Abbott). Sequences of the transfected CCR2 open reading frames in the resulting cell lines were identical to rat CCR2
(NM_021866.1).
Inhibition of native agonist-induced intracellular calcium release in cells expressing hCCR2B, or rCCR2
Calcium flux assays were performed in CHO cells expressing human CCR2B and Gal 6 coupling protein, or rat CCR2 and Gal 6 coupling protein. All compounds were dissolved in DMSO and assays run at a final DMSO concentration of 0.25% (v/v).
Human MCP- 1 was purchased from PeproTech and used at a final assay concentration of 2 nM, while rat MCP- 1 was purchased from R&D and used at a final assay concentration of 4 nM. Assays with cells expressing human CCR2B were performed with human MCP- 1, while assays with cells expressing rat CCR2 were performed with rat MCP-1.
Briefly, cells were cultured overnight in a microtiter plate at 8000 per well. The next day, the resultant adherent cells were incubated in assay buffer (20 mM HEPES, pH 7.4, 0.1 % bovine serum albumin, and 2.5 mM probenocid in Hank's Buffered Saline
Solution) containing Calcium 4 dye (Molecular Probes) at 37 °C for 60 minutes. Calcium flux assays were performed on a FLIPRTetra instrument (Molecular Devices) by adding compound to the cells followed by addition of native agonist and measuring the change in fluorescence as a function of time. Maximal and minimal values for fluorescence were determined using native agonist (2 nM MCP-1) for human or rat CCR2, or buffer addition, respectively. Fluorescence values were used to calculate the percent inhibition at a given compound concentration and the data fit to a sigmoidal curve in a semi-log plot to determine IC50 values. The ¾ value was calculated as Kb=IC5o/(l+[agonist]/EC5o), where [agonist] is the concentration of agonist used and EC50 is the agonist potency determined in the previous experiments. The following Table demonstrates that present compounds when tested with the aforementioned assay, have activity in binding to the CCR2 receptor, indicating the intrinsic activity of the compounds in use as modulators of chemokine receptor activity. rCCR2 hCCR2B rCCR2 hCCR2B rCCR2 hCCR2B
Ex# Ex# Ex#
Κ¾ (μΜ) Κ¾ (μΜ) Κ¾ (μΜ) Κ¾ (μΜ) Κ¾ (μΜ) Κ¾ (μΜ)
1 -- 6.140 79 0.004 0.005 157 0.316 0.236
2 -- 0.561 80 0.054 0.016 158 0.386 0.384
3 -- 0.172 81 0.051 0.042 159 4.000 3.550
4 0.006 0.003 82 0.178 0.043 160 0.771 0.069
5 0.007 0.006 83 0.307 0.347 161 4.000 0.682
6 0.035 0.014 84 0.372 0.392 162 0.271 0.222
7 0.080 0.024 85 0.537 0.458 163 0.482 0.141
8 0.034 0.028 86 0.772 0.682 164 0.348 0.129
9 0.018 0.029 87 2.310 0.682 165 0.257 0.231
10 0.094 0.048 88 2.310 2.050 166 0.256 0.177
1 1 0.180 0.054 89 6.940 3.550 167 2.310 3.550
12 0.154 0.063 90 6.940 6.140 168 0.257 0.228
13 0.068 0.065 91 0.068 0.077 169 0.078 0.051
14 0.273 0.065 92 0.255 6.140 170 0.205 0.212
15 0.046 0.1 15 93 0.043 0.1 14 171 1.330 0.682
16 0.579 0.171 94 0.304 0.682 172 0.445 0.682
17 0.386 0.190 95 0.010 0.012 173 4.000 6.140
18 0.053 0.228 96 0.938 0.682 174 0.771 0.228
19 0.463 0.322 97 0.029 0.014 175 0.207 0.020
20 0.785 0.337 98 0.215 0.174 176 0.771 0.682
21 0.399 0.371 99 0.012 0.127 177 0.367 0.255
22 0.445 0.394 100 0.081 1.410 178 0.250 0.432
23 1.340 0.529 101 0.067 0.047 179 0.771 0.394
24 0.772 0.682 102 2.310 2.050 180 0.083 0.006
25 0.772 0.682 103 0.345 0.565 181 0.050 0.017 rCCR2 hCCR2B rCCR2 hCCR2B rCCR2 hCCR2B
Ex# Ex# Ex#
Κ¾ (μΜ) Κ¾ (μΜ) Κ¾ (μΜ) Κ¾ (μΜ) Κ¾ (μΜ) Κ¾ (μΜ)
26 0.081 1.410 104 0.183 0.233 182 0.640 0.314
27 0.772 1.050 105 0.041 0.061 183 0.214 0.046
28 0.772 1.180 106 0.038 0.029 184 2.310 1.180
29 1.160 3.070 107 0.772 0.682 185 0.024 0.071
30 3.470 3.070 108 0.1 13 0.032 186 0.035 0.059
31 0.445 3.550 109 0.014 2.050 187 0.669 0.394
32 0.372 3.550 1 10 0.259 0.146 188 0.013 0.058
33 4.000 5.740 1 1 1 1.340 0.682 189 0.771 0.682
34 6.940 6.140 1 12 0.530 0.717 190 0.106 0.058
35 6.940 6.140 1 13 0.455 0.309 191 2.310 0.682
36 6.940 6.140 1 14 0.445 0.682 192 0.041 0.031
37 0.019 0.006 1 15 0.771 0.682 193 0.284 0.204
38 0.074 0.024 1 16 0.197 0.036 194 0.025 0.006
39 0.1 19 0.039 1 17 0.120 0.131 195 0.009 0.005
40 0.352 0.084 1 18 0.007 0.004 196 0.014 0.020
41 0.199 0.086 1 19 0.028 0.020 197 0.032 0.042
42 0.134 0.1 10 120 0.220 0.163 198 0.618 1.180
43 0.463 0.1 14 121 0.404 0.082 199 0.682 0.728
44 0.231 0.1 18 122 0.014 0.008 200 0.057 0.120
45 0.434 0.255 123 2.310 0.394 201 0.081 0.085
46 0.496 0.335 124 6.940 2.050 202 0.682 2.050
47 0.370 0.343 125 0.771 0.682 203 2.050 6.140
48 0.843 0.669 126 0.096 0.131 204 0.537 0.510
49 0.772 2.050 127 0.051 0.019 205 0.215 0.563
50 -- 6.140 128 0.257 0.145 206 0.010 0.038 rCCR2 hCCR2B rCCR2 hCCR2B rCCR2 hCCR2B
Ex# Ex# Ex#
Κ¾ (μΜ) Κ¾ (μΜ) Κ¾ (μΜ) Κ¾ (μΜ) Κ¾ (μΜ) Κ¾ (μΜ)
51 -- 0.252 129 0.027 0.025 207 0.017 0.012
52 0.1 19 0.122 130 6.940 6.140 208 0.039 0.025
53 1.390 0.137 131 6.940 6.140 209 0.048 0.023
54 0.669 0.155 132 0.771 0.318 210 0.015 0.017
55 0.617 0.158 133 0.1 16 0.039 21 1 0.143 0.268
56 0.772 0.231 134 0.040 0.007 212 0.102 0.135
57 0.772 0.241 135 0.445 0.542 213 2.050 6.140
58 0.772 0.394 136 0.023 0.007 214 0.590 1.020
59 0.772 0.404 137 0.026 0.159 215 0.175 0.202
60 0.772 0.617 138 0.066 0.045 216 0.150 0.092
61 6.940 0.682 139 0.004 0.004 217 0.031 0.078
62 2.310 0.682 140 0.019 0.029 218 0.085 0.073
63 3.470 1.020 141 0.005 0.003 219 2.310 2.050
64 4.000 2.050 142 0.020 0.008 220 0.257 0.1 19
65 1.340 2.050 143 0.016 0.009 221 1.150 0.240
66 1.340 2.050 144 0.015 0.029 222 1.380 0.668
67 6.940 3.550 145 0.096 0.020 223 0.198 0.295
68 1.340 3.550 146 0.005 0.004 224 0.771 2.050
69 6.940 6.140 147 0.005 0.004 225 0.161 0.421
70 6.940 6.140 148 0.025 0.043 226 0.885 0.394
71 1.340 6.140 149 0.006 0.005 227 2.310 2.050
72 6.940 6.140 150 0.096 0.041 228 0.071 0.038
73 6.940 6.140 151 6.940 6.140 229 0.354 0.087
74 2.310 6.140 152 0.296 0.355 230 0.855 0.092
75 -- 0.682 153 1.390 0.410 231 1.543 0.402 rCCR2 hCCR2B rCCR2 hCCR2B rCCR2 hCCR2B
Ex# Ex# Ex#
Κ¾ (μΜ) Κ¾ (μΜ) Κ¾ (μΜ) Κ¾ (μΜ) Κ¾ (μΜ) Κ¾ (μΜ)
76 -- 0.439 154 0.154 0.128
77 0.036 0.012 155 0.051 0.005
78 0.008 0.005 156 0.054 0.009 d. Methods of Using the Compounds
In one aspect, the invention provides a method for antagonizing CCR2 in a subject (e.g. human) suffering from a disorder in which CCR2 activity is detrimental, comprising administering to the subject a compound of formula (I), (la), (lb), or (Ic), or a pharmaceutical composition comprising the same, such that CCR2 activity in the human subject is inhibited and treatment is achieved.
Many autoimmune diseases and disease associated with chronic inflammation, as well as acute responses, have been linked to activation of CCR2. The present compounds are useful in the treatment of inflammatory disorders including, but not limited to rheumatoid arthritis, osteoarthritis, asthma, chronic obstructive pulmonary disease (COPD), sepsis, psoriasis, psoriatic arthritis, inflammatory bowel disease, Crohn's disease, lupus, multiple sclerosis, juvenile chronic arthritis, Lyme arthritis, reactive arthritis, septic arthritis, spondyloarthropathy and systemic lupus erythematosus.
The present compounds or the pharmaceutical compositions comprising the same are also useful in the treatment of cardiovascular disorders, such as acute myocardial infarction, acute coronary syndrome, chronic heart failure, atherosclerosis, viral myocarditis, cardiac allograft rejection, and sepsis-associated cardiac dysfunction.
Furthermore, the compounds of the present invention are also useful for the treatment of central nervous system disorders such as meningococcal meningitis, Alzheimer's disease and Parkinson's disease.
Compounds decribed herein or a pharmaceutically acceptable salt thereof or pharmaceutical compositions comprising a therapeutically effective amount thereof is useful in the treatment of a disorder selected from the group comprising CNS system disorders, arthritis, rheumatoid arthritis, osteoarthritis, juvenile chronic arthritis, Lyme arthritis, psoriatic arthritis, reactive arthritis, and septic arthritis, spondyloarthropathy, systemic lupus erythematosus, Crohn's disease, ulcerative colitis, inflammatory bowel disease, insulin dependent diabetes mellitus, thyroiditis, asthma, allergic diseases, psoriasis, dermatitis scleroderma, graft versus host disease, organ transplant rejection (including but not limited to bone marrow and solid organ rejection), acute or chronic immune disease associated with organ transplantation, sarcoidosis, atherosclerosis, disseminated intravascular coagulation, Kawasaki's disease, Grave's disease, nephrotic syndrome, chronic fatigue syndrome, Wegener's granulomatosis, Henoch-Schoenlein purpurea, microscopic vasculitis of the kidneys, chronic active hepatitis, uveitis, septic shock, toxic shock syndrome, sepsis syndrome, cachexia, infectious diseases, parasitic diseases, acquired immunodeficiency syndrome, acute transverse myelitis, Huntington's chorea, Parkinson's disease, Alzheimer's disease, stroke, primary biliary cirrhosis, hemolytic anemia, malignancies, heart failure, myocardial infarction, Addison's disease, sporadic, polyglandular deficiency type I and polyglandular deficiency type II, Schmidt's syndrome, adult (acute) respiratory distress syndrome, alopecia, alopecia areata, seronegative arthopathy, arthropathy, Reiter's disease, psoriatic arthropathy, ulcerative colitic arthropathy, enteropathic synovitis, chlamydia, yersinia and salmonella associated arthropathy, atheromatous disease/arteriosclerosis, atopic allergy, autoimmune bullous disease, pemphigus vulgaris, pemphigus foliaceus, pemphigoid, linear IgA disease, autoimmune haemolytic anaemia, Coombs positive haemolytic anaemia, acquired pernicious anaemia, juvenile pernicious anaemia, myalgic encephalitis/Royal Free Disease, chronic mucocutaneous candidiasis, giant cell arteritis, primary sclerosing hepatitis, cryptogenic autoimmune hepatitis, Acquired Immunodeficiency Disease Syndrome, Acquired Immunodeficiency Related Diseases, Hepatitis B, Hepatitis C, common varied immunodeficiency (common variable hypogammaglobulinemia), dilated cardiomyopathy, female infertility, ovarian failure, premature ovarian failure, fibrotic lung disease, chronic wound healing, cryptogenic fibrosing alveolitis, post-inflammatory interstitial lung disease, interstitial pneumonitis, connective tissue disease associated interstitial lung disease, mixed connective tissue disease associated lung disease, systemic sclerosis associated interstitial lung disease, rheumatoid arthritis associated interstitial lung disease, systemic lupus erythematosus associated lung disease,
dermatomyositis/polymyositis associated lung disease, Sjogren's disease associated lung disease, ankylosing spondylitis associated lung disease, vasculitic diffuse lung disease, haemosiderosis associated lung disease, drug-induced interstitial lung disease, radiation fibrosis, bronchiolitis obliterans, chronic eosinophilic pneumonia, lymphocytic infiltrative lung disease, postinfectious interstitial lung disease, gouty arthritis, autoimmune hepatitis, type- 1 autoimmune hepatitis (classical autoimmune or lupoid hepatitis), type-2 autoimmune hepatitis (anti-LKM antibody hepatitis), autoimmune mediated
hypoglycaemia, type B insulin resistance with acanthosis nigricans, hypoparathyroidism, acute immune disease associated with organ transplantation, chronic immune disease associated with organ transplantation, osteoarthrosis, primary sclerosing cholangitis, psoriasis type 1 , psoriasis type 2, idiopathic leucopaenia, autoimmune neutropaenia, renal disease NOS, glomerulonephritides, microscopic vasulitis of the kidneys, Lyme disease, discoid lupus erythematosus, male infertility idiopathic or NOS, sperm autoimmunity, multiple sclerosis (all subtypes), sympathetic ophthalmia, pulmonary hypertension secondary to connective tissue disease, Goodpasture's syndrome, pulmonary
manifestation of polyarteritis nodosa, acute rheumatic fever, rheumatoid spondylitis, Still's disease, systemic sclerosis, Sjogren's syndrome, Takayasu's disease/arteritis, autoimmune thrombocytopaenia, idiopathic thrombocytopaenia, autoimmune thyroid disease, hyperthyroidism, goitrous autoimmune hypothyroidism (Hashimoto's disease), atrophic autoimmune hypothyroidism, primary myxoedema, phacogenic uveitis, primary vasculitis, vitiligo, acute liver disease, chronic liver diseases, alcoholic cirrhosis, alcohol- induced liver injury, choleosatatis, idiosyncratic liver disease, Drug-Induced hepatitis, Non-alcoholic Steatohepatitis, allergy and asthma, group B streptococci (GBS) infection, mental disorders (e.g., depression and schizophrenia), Th2 Type and Thl Type mediated diseases, acute and chronic pain (different forms of pain), and cancers such as lung, breast, stomach, bladder, colon, pancreas, ovarian, prostate and rectal cancer and hematopoietic malignancies (leukemia and lymphoma), and hematopoietic malignancies (leukemia and lymphoma), Abetalipoprotemia, Acrocyanosis, acute and chronic parasitic or infectious processes, acute leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute or chronic bacterial infection, acute pancreatitis, acute renal failure, adenocarcinomas, aerial ectopic beats, AIDS dementia complex, alcohol- induced hepatitis, allergic conjunctivitis, allergic contact dermatitis, allergic rhinitis, allograft rejection, alpha-1- antitrypsin deficiency, amyotrophic lateral sclerosis, anemia, angina pectoris, anterior horn cell degeneration, anti cd3 therapy, antiphospholipid syndrome, anti-receptor hypersensitivity reactions, aordic and peripheral aneuryisms, aortic dissection, arterial hypertension, arteriosclerosis, arteriovenous fistula, ataxia, atrial fibrillation (sustained or paroxysmal), atrial flutter, atrioventricular block, B cell lymphoma, bone graft rejection, bone marrow transplant (BMT) rejection, bundle branch block, Burkitt's lymphoma, Burns, cardiac arrhythmias, cardiac stun syndrome, cardiac tumors, cardiomyopathy, cardiopulmonary bypass inflammation response, cartilage transplant rejection, cerebellar cortical degenerations, cerebellar disorders, chaotic or multifocal atrial tachycardia, chemotherapy associated disorders, chromic myelocytic leukemia (CML), chronic alcoholism, chronic inflammatory pathologies, chronic lymphocytic leukemia (CLL), chronic obstructive pulmonary disease (COPD), chronic salicylate intoxication, colorectal carcinoma, congestive heart failure, conjunctivitis, contact dermatitis, cor pulmonale, coronary artery disease, Creutzfeldt- Jakob disease, culture negative sepsis, cystic fibrosis, cytokine therapy associated disorders, dementia pugilistica, demyelinating diseases, dengue hemorrhagic fever, dermatitis, dermatologic conditions, diabetes, diabetes mellitus, diabetic ateriosclerotic disease, Diffuse Lewy body disease, dilated congestive cardiomyopathy, disorders of the basal ganglia, Down's Syndrome in middle age, drug- induced movement disorders induced by drugs which block CNS dopamine receptors, drug sensitivity, eczema, encephalomyelitis, endocarditis, endocrinopathy, epiglottitis, epstein-barr virus infection, erythromelalgia, extrapyramidal and cerebellar disorders, familial hematophagocytic lymphohistiocytosis, fetal thymus implant rejection, Friedreich's ataxia, functional peripheral arterial disorders, fungal sepsis, gas gangrene, gastric ulcer, glomerular nephritis, graft rejection of any organ or tissue, gram negative sepsis, gram positive sepsis, granulomas due to intracellular organisms, hairy cell leukemia, Hallerrorden-Spatz disease, hashimoto's thyroiditis, hay fever, heart transplant rejection, hemachromatosis, hemodialysis, hemolytic uremic syndrome/thrombolytic thrombocytopenic purpura, hemorrhage, hepatitis (A), His bundle arrythmias, HIV infection/HIV neuropathy, Hodgkin's disease, hyperkinetic movement disorders, hypersensitivity reactions, hypersensitivity pneumonitis, hypertension, hypokinetic movement disorders, hypothalamic-pituitary- adrenal axis evaluation, idiopathic Addison's disease, idiopathic pulmonary fibrosis, antibody mediated cytotoxicity, Asthenia, infantile spinal muscular atrophy, inflammation of the aorta, influenza a, ionizing radiation exposure, iridocyclitis/uveitis/optic neuritis, ischemia- reperfusion injury, ischemic stroke, juvenile rheumatoid arthritis, juvenile spinal muscular atrophy, Kaposi's sarcoma, kidney transplant rejection, legionella, leishmaniasis, leprosy, lesions of the corticospinal system, lipedema, liver transplant rejection, lymphederma, malaria, malignant Lymphoma, malignant histiocytosis, malignant melanoma, meningitis, meningococcemia, metabolic/idiopathic, migraine headache, mitochondrial multisystem disorder, mixed connective tissue disease, monoclonal gammopathy, multiple myeloma, multiple systems degenerations (Mencel Dejerine- Thomas Shi-Drager and Machado-Joseph), myasthenia gravis, mycobacterium avium intracellulare, mycobacterium tuberculosis, myelodyplastic syndrome, myocardial infarction, myocardial ischemic disorders, nasopharyngeal carcinoma, neonatal chronic lung disease, nephritis, nephrosis, neurodegenerative diseases, neurogenic I muscular atrophies, neutropenic fever, non- Hodgkin's lymphoma, occlusion of the abdominal aorta and its branches, occulsive arterial disorders, okt3 therapy, orchitis/epidydimitis, orchitis/vasectomy reversal procedures, organomegaly, osteoporosis, pancreas transplant rejection, pancreatic carcinoma, paraneoplastic syndrome/hypercalcemia of malignancy, parathyroid transplant rejection, pelvic inflammatory disease, perennial rhinitis, pericardial disease, peripheral atherlosclerotic disease, peripheral vascular disorders, peritonitis, pernicious anemia, Pneumocystis carinii pneumonia, pneumonia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome), post perfusion syndrome, post pump syndrome, post-MI cardiotomy syndrome, preeclampsia, Progressive supranucleo Palsy, primary pulmonary hypertension, radiation therapy, Raynaud's phenomenon and disease, Raynoud's disease, Refsum's disease, regular narrow QRS tachycardia, renovascular hypertension, reperfusion injury, restrictive cardiomyopathy, sarcomas, scleroderma, senile chorea, Senile Dementia of Lewy body type, seronegative arthropathies, shock, sickle cell anemia, skin allograft rejection, skin changes syndrome, small bowel transplant rejection, solid tumors, specific arrythmias, spinal ataxia, spinocerebellar degenerations, streptococcal myositis, structural lesions of the cerebellum, Subacute sclerosing panencephalitis, Syncope, syphilis of the cardiovascular system, systemic anaphalaxis, systemic inflammatory response syndrome, systemic onset juvenile rheumatoid arthritis, T-cell or FAB ALL, Telangiectasia, thromboangitis obliterans, thrombocytopenia, toxicity, transplants, trauma/hemorrhage, type III hypersensitivity reactions, type IV hypersensitivity, unstable angina, uremia, urosepsis, urticaria, valvular heart diseases, varicose veins, vasculitis, venous diseases, venous thrombosis, ventricular fibrillation, viral and fungal infections, vital encephalitis/aseptic meningitis, vital-associated hemaphagocytic syndrome, Wernicke- Korsakoff syndrome, Wilson's disease, xenograft rejection of any organ or tissue, and diseases involving inappropriate vascularization for example diabetic retinopathy, retinopathy of prematurity, choroidal neovascularization due to age-related macular degeneration, and infantile hemangiomas in human beings. In addition, such compounds may be useful in the treatment of disorders such as edema, ascites, effusions, and exudates, including for example macular edema, cerebral edema, acute lung injury, adult respiratory distress syndrome (ARDS), proliferative disorders such as restenosis, fibrotic disorders such as hepatic cirrhosis and atherosclerosis, mesangial cell proliferative disorders such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, and
glomerulopathies, myocardial angiogenesis, coronary and cerebral collaterals, ischemic limb angiogenesis, ischemia/reperfusion injury, peptic ulcer Helicobacter related diseases, virally-induced angiogenic disorders, Crow-Fukase syndrome (POEMS), preeclampsia, menometrorrhagia, cat scratch fever, rubeosis, neovascular glaucoma and retinopathies such as those associated with diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration or a central nervous system disorder. In addition, these compounds can be used as active agents against solid tumors, malignant ascites, von Hippel Lindau disease, hematopoietic cancers and hyperproliferative disorders such as thyroid hyperplasia (especially Grave's disease), and cysts (such as hypervascularity of ovarian stroma characteristic of polycystic ovarian syndrome (Stein-Leventhal syndrome) and polycystic kidney disease since such diseases require a proliferation of blood vessel cells for growth and/or metastasis.
Another aspect relates to a method for the treatment of pain such as, but not limited to, neuropathic pain, nociceptive pain, inflammatory pain, osteoarthritic pain, fibromyalgia, neuralgia such as postherpatic neuralgia and trigeminal neuralgia, diabatic neuropathic pain, HIV-related neuropathic pain, migraine, post-stroke pain, post- operative pain, multiple sclerosis pain, pain related to spinal cord injury, cancer pain, lower back pain, and eye pain, comprising administering to a subject in need of such treatment compounds described herein, or pharmaceutically acceptable salts thereof, alone or in combination with a pharmaceutically acceptable carrier.
Present compounds can be used alone or in combination with another therapeutic agent to treat such diseases, said additional agent being selected by the skilled artisan for its intended purpose. For example, the additional agent can be a therapeutic agent recognized as being useful to treat the disease or condition being treated by the compound of the present invention. The additional agent also can be an agent that imparts a beneficial attribute to the therapeutic composition e.g., an agent that affects the viscosity of the composition.
It should further be understood that the combinations which are to be included within this invention are those combinations useful for their intended purpose. The agents set forth below are for illustrative purposes and not intended to be limited. The combinations, which are part of this invention, can be the compounds of the present invention and at least one additional agent selected from the lists below. The combination can also include more than one additional agent, e.g., two or three additional agents if the combination is such that the formed composition can perform its intended function.
For example, in the treatment or prevention of inflammation or pain, the present compounds may be used in conjunction or combination with an anti-inflammatory or analgesic agent such as an opiate agonist, a lipoxygenase inhibitor, such as an inhibitor of 5 -lipoxygenase, a cyclooxygenase inhibitor, such as a cyclooxygenase-2 inhibitor, an interleukin inhibitor, such as an interleukin- 1 inhibitor, an NMDA antagonist, an inhibitor of nitric oxide or an inhibitor of the synthesis of nitric oxide, a non-steroidal antiinflammatory agent, or a cytokine- suppressing anti-inflammatory agent, for example with a compound such as acetaminophen, aspirin, codeine, fentanyl, ibuprofen, indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, a steroidal analgesic, sufentanyl, sunlindac, tenidap, and the like. Similarly, the instant compounds may be administered with a pain reliever; a potentiator such as caffeine, an H2- antagonist, simethicone, aluminum or magnesium hydroxide; a decongestant such as phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desoxy-ephedrine; an antiitussive such as codeine, hydrocodone, caramiphen, carbetapentane, or dextromethorphan; a diuretic; and a sedating or non-sedating antihistamine. Likewise, compounds of the present invention may be used in combination with other drugs that are used in the treatment/prevention/suppression or amelioration of the diseases or conditions for which compounds of the present invention are useful. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the present compounds is preferred.
Accordingly, the pharmaceutical compositions include those that also contain one or more other active ingredients, in addition to a compound of formula (I), (la), (lb), or (Ic). Examples of other active ingredients that may be combined with a present compound, either administered separately or in the same pharmaceutical compositions, include, but are not limited to: (a) VLA-4 antagonists, (b) steroids such as beclomethasone, methylprednisolone, betamethasone, prednisone, dexamethasone, and hydrocortisone; (c) immunosuppressants such as cyclosporine (cyclosporine A, Sandimmune®, Neoral®), tacrolimus (FK-506, Prograf®), rapamycin (sirolimus, Rapamune®) and other FK-506 type immunosuppressants, and mycophenolate, e.g., mycophenolate mofetil (CellCept®);
(d) antihistamines (HI -histamine antagonists) such as bromopheniramine,
chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine, methdilazine, promethazine,
trimeprazine, azatadine, cyproheptadine, antazoline, pheniramine pyrilamine, astemizole, terfenadine, loratadine, cetirizine, fexofenadine, descarboethoxyloratadine, and the like;
(e) non-steroidal anti-asthmatics such as beta.2-agonists (terbutaline, metaproterenol, fenoterol, isoetharine, albuterol, bitolterol, and pirbuterol), theophylline, cromolyn sodium, atropine, ipratropium bromide, leukotriene antagonists (zafirlukast, montelukast, pranlukast, iralukast, pobilukast, SKB- 106,203), leukotriene biosynthesis inhibitors (zileuton, BAY- 1005); (f) non- steroidal antiinflammatory agents (NSAIDs) such as propionic acid derivatives (alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid, and tioxaprofen), acetic acid derivatives (indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin, and zomepirac), fenamic acid derivatives (flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid), biphenylcarboxylic acid derivatives (diflunisal and flufenisal), oxicams (isoxicam, piroxicam, sudoxicam and tenoxican), salicylates (acetyl salicylic acid, sulfasalazine) and the pyrazolones (apazone, bezpiperylon, feprazone, mofebutazone, oxyphenbutazone, phenylbutazone); (g) cyclooxygenase-2 (COX-2) inhibitors such as celecoxib
(Celebrex®) and rofecoxib (Vioxx®); (h) inhibitors of phosphodiesterase type IV (PDE- IV); (i) gold compounds such as auranofin and aurothioglucose, (j) inhibitors of phosphodiesterase type IV (PDE-IV); (k) other antagonists of the chemokine receptors, especially CCR1 , CCR2, CCR3, CCR5, CCR6, CCR8 and CCR10; (1) cholesterol lowering agents such as HMG-CoA reductase inhibitors (lovastatin, simvastatin and pravastatin, fluvastatin, atorvastatin, and other statins), sequestrants (cholestyramine and colestipol), nicotinic acid, fenofibric acid derivatives (gemfibrozil, clofibrat, fenofibrate and benzafibrate), and probucol; (m) anti-diabetic agents such as insulin, sulfonylureas, biguanides (metformin), a-glucosidase inhibitors (acarbose) and glitazones (troglitazone and pioglitazone); (n) preparations of interferon beta (interferon β-1 α; interferon β-lb); (o) etanercept (Enbrel®), (p) antibody therapies such as orthoclone (OKT3), daclizumab (Zenapax®), infliximab (Remicade®), basiliximab (Simulect®) and anti-CD40 ligand antibodies (e.g., MRP-1); and (q) other compounds such as 5 -aminosalicylic acid and prodrugs thereof, hydroxychloroquine, D-penicillamine, antimetabolites such as azathioprene and 6-mercaptopurine, and cytotoxic cancer chemotherapeutic agents. The weight ratio of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with an NSAID the weight ratio of the compound of the present invention to the NSAID will generally range from about 1000: 1 to about 1 : 1000, preferably about 200: 1 to about 1 :200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
Immunosuppressants within the scope of the present invention further include, but are not limited to, leflunomide, RAD001 , ERL080, FTY720, CTLA-4, antibody therapies such as orthoclone (OKT3), daclizumab (Zenapax®) and basiliximab (Simulect®), and antithymocyte globulins such as thymoglobulins.
The present methods are also directed to the treatment or prevention of multiple sclerosis using a compound of the invention either alone or in combination with a second therapeutic agent selected from betaseron, avonex, azathioprene (Imurek®, Imuran®), capoxone, prednisolone and cyclophosphamide. When used in combination, the practitioner can administer a combination of the therapeutic agents, or administration can be sequential.
In still other embodiments, the present methods are directed to the treatment or prevention of rheumatoid arthritis, wherein the compound of the invention is administered either alone or in combination with a second therapeutic agent selected from the group consisting of methotrexate, sulfasalazine, hydroxychloroquine, cyclosporine A, D- penicillamine, infliximab (Remicade®), etanercept (Enbrel®), adalimumab (Humira®), auranofin and aurothioglucose.
In yet other embodiments, the present methods are directed to the treatment or prevention of an organ transplant condition wherein the compound of the invention is used alone or in combination with a second therapeutic agent selected from the group consisting of cyclosporine A, FK-506, rapamycin, mycophenolate, prednisolone, azathioprene, cyclophosphamide and an antilymphocyte globulin. Present compounds can also be combined with a non-steroidal anti-inflammatory drug(s) also referred to as NSAIDS which include drugs like ibuprofen. Other combinations are corticosteroids including prednisolone; the well known side-effects of steroid use can be reduced or even eliminated by tapering the steroid dose required when treating patients in combination with the CCR2 antagonists. Non-limiting examples of therapeutic agents for rheumatoid arthritis with which a compound of Formula (I) of the invention can be combined include the following: cytokine suppressive anti-inflammatory drug(s) (CSAIDs); antibodies to or antagonists of other human cytokines or growth factors, for example, TNF, LT, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-12, IL- 15, IL- 16, IL-21 , IL-23, interferons, EMAP-II, GM-CSF, FGF, and PDGF. S/T kinase inhibitors of the invention can be combined with antibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD80 (B7.1), CD86 (B7.2), CD90, CTLA or their ligands including CD 154 (gp39 or CD40L).
Preferred combinations of therapeutic agents may interfere at different points in the autoimmune and subsequent inflammatory cascade; preferred examples include TNF antagonists like chimeric, humanized or human TNF antibodies, D2E7 (HUMIRA®), (U.S. Patent No. US 6,090,382), CA2 (REMICADE™), CDP 571, and soluble p55 or p75 TNF receptors, derivatives, thereof, (p75TNFRlgG (ENBREL™) or p55TNFRlgG (Lenercept), and also TNFa converting enzyme (TACE) inhibitors; similarly IL-1 inhibitors (Interleukin- 1 -converting enzyme inhibitors, IL-IRA etc.) may be effective for the same reason. Other preferred combinations include Interleukin 1 1. Yet other preferred combinations are the other key players of the autoimmune response which may act parallel to, dependent on or in concert with IL- 18 function; especially preferred are IL- 12 antagonists including IL-12 antibodies or soluble IL-12 receptors, or IL-12 binding proteins. It has been shown that IL- 12 and IL- 18 have overlapping but distinct functions and a combination of antagonists to both may be most effective. Yet another preferred combination are non-depleting anti-CD4 inhibitors. Yet other preferred combinations include antagonists of the co-stimulatory pathway CD80 (B7.1) or CD86 (B7.2) including antibodies, soluble receptors or antagonistic ligands.
Present compounds may also be combined with agents, such as methotrexate, 6-
MP, azathioprine sulphasalazine, mesalazine, olsalazine chloroquinine/
hydroxychloroquine, pencillamine, aurothiomalate (intramuscular and oral), azathioprine, cochicine, corticosteroids (oral, inhaled and local injection), beta-2 adrenoreceptor agonists (salbutamol, terbutaline, salmeteral), xanthines (theophylline, aminophylline), cromoglycate, nedocromil, ketotifen, ipratropium and oxitropium, cyclosporin, FK506, rapamycin, mycophenolate mofetil, leflunomide, NSAIDs, for example, ibuprofen, corticosteroids such as prednisolone, phosphodiesterase inhibitors, adensosine agonists, antithrombotic agents, complement inhibitors, adrenergic agents, agents which interfere with signalling by proinflammatory cytokines such as TNFa or IL-1 (e.g. IRAK, NIK, IKK , p38 or MAP kinase inhibitors), IL-Ι β converting enzyme inhibitors, T-cell signalling inhibitors such as kinase inhibitors, metalloproteinase inhibitors, sulfasalazine, 6-mercaptopurines, angiotensin converting enzyme inhibitors, soluble cytokine receptors and derivatives thereof (e.g. soluble p55 or p75 TNF receptors and the derivatives p75TNFRIgG (Enbrel™ and p55TNFRIgG (Lenercept)), sIL- lRI, sIL-lRII, sIL-6R), antiinflammatory cytokines (e.g. IL-4, IL-10, IL-1 1, IL-13 and TGF ), celecoxib, folic acid, hydroxychloroquine sulfate, rofecoxib, etanercept, infliximab, naproxen, valdecoxib, sulfasalazine, methylprednisolone, meloxicam, methylprednisolone acetate, gold sodium thiomalate, aspirin, triamcinolone acetonide, propoxyphene napsylate/apap, folate, nabumetone, diclofenac, piroxicam, etodolac, diclofenac sodium, oxaprozin, oxycodone HC1, hydrocodone bitartrate/apap, diclofenac sodium/misoprostol, fentanyl, anakinra, tramadol HC1, salsalate, sulindac, cyanocobalamin/fa/pyridoxine,
acetaminophen, alendronate sodium, prednisolone, morphine sulfate, lidocaine hydrochloride, indomethacin, glucosamine sulf/chondroitin, amitriptyline HC1, sulfadiazine, oxycodone HCl/acetaminophen, olopatadine HC1 misoprostol, naproxen sodium, omeprazole, cyclophosphamide, rituximab, IL- 1 TRAP, MRA, CTLA4-IG, IL- 18 BP, anti-IL-12, Anti-IL15, BIRB-796, SCIO-469, VX-702, AMG-548, VX-740, Roflumilast, IC-485, CDC-801, and Mesopram. Preferred combinations include methotrexate or leflunomide and in moderate or severe rheumatoid arthritis cases, cyclosporine and anti-TNF antibodies as noted above.
Non-limiting examples of therapeutic agents for inflammatory bowel disease with which a compound of Formula (I) of the invention can be combined include the following: budenoside; epidermal growth factor; corticosteroids; cyclosporin, sulfasalazine; aminosalicylates; 6-mercaptopurine; azathioprine; metronidazole;
lipoxygenase inhibitors; mesalamine; olsalazine; balsalazide; antioxidants; thromboxane inhibitors; IL-1 receptor antagonists; anti-IL-Ι β monoclonal antibodies; anti-IL-6 monoclonal antibodies; growth factors; elastase inhibitors; pyridinyl-imidazole compounds; antibodies to or antagonists of other human cytokines or growth factors, for example, TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-15, IL-16, EMAP-II, GM-CSF, FGF, and PDGF; cell surface molecules such as CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD90 or their ligands; methotrexate; cyclosporine; FK506; rapamycin; mycophenolate mofetil; leflunomide; NSAIDs, for example, ibuprofen;
corticosteroids such as prednisolone; phosphodiesterase inhibitors; adenosine agonists; antithrombotic agents; complement inhibitors; adrenergic agents; agents which interfere with signalling by proinflammatory cytokines such as TNFa or IL-1 (e.g. IRAK, NIK, IKK, or MAP kinase inhibitors); IL-Ιβ converting enzyme inhibitors; TNFa converting enzyme inhibitors; T-cell signalling inhibitors such as kinase inhibitors; metalloproteinase inhibitors; sulfasalazine; azathioprine; 6-mercaptopurines; angiotensin converting enzyme inhibitors; soluble cytokine receptors and derivatives thereof (e.g. soluble p55 or p75 TNF receptors, sIL-lRI, sIL- lRJI, sIL-6R) and antiinflammatory cytokines (e.g. IL-4, IL- 10, IL-1 1, IL-13 and TGF ). Preferred examples of therapeutic agents for Crohn's disease with which a compound of Formula (I) can be combined include the following: TNF antagonists, for example, anti-TNF antibodies, D2E7 (U.S. Patent No. 6,090,382; HUMIRA®), CA2 (REMICADE™), CDP 571, TNFR-Ig constructs, (p75TNFRJgG (ENBREL™) and p55TNFRIgG (LENERCEPT™)) inhibitors and PDE4 inhibitors. A compound of Formula (I) can be combined with corticosteroids, for example, budenoside and dexamethasone; sulfasalazine, 5-aminosalicylic acid; olsalazine; and agents which interfere with synthesis or action of proinflammatory cytokines such as IL- 1 , for example, IL-Ι β converting enzyme inhibitors and IL-lra; T cell signaling inhibitors, for example, tyrosine kinase inhibitors 6-mercaptopurines; IL-1 1 ; mesalamine; prednisone;
azathioprine; mercaptopurine; infliximab; methylprednisolone sodium succinate;
diphenoxylate/atrop sulfate; loperamide hydrochloride; methotrexate; omeprazole; folate; cipro floxacin/dextrose-water; hydrocodone bitartrate/apap; tetracycline hydrochloride; fluocinonide; metronidazole; thimerosal/boric acid; cholestyramine/sucrose; ciprofloxacin hydrochloride; hyoscyamine sulfate; meperidine hydrochloride; midazolam
hydrochloride; oxycodone HCl/acetaminophen; promethazine hydrochloride; sodium phosphate; sulfamethoxazole/trimethoprim; celecoxib; polycarbophil; propoxyphene napsylate; hydrocortisone; multivitamins; balsalazide disodium; codeine phosphate/apap; colesevelam HC1; cyanocobalamin; folic acid; levofloxacin; methylprednisolone;
natalizumab and interferon-gamma. Non-limiting examples of therapeutic agents for multiple sclerosis with which present compounds can be combined include the following: corticosteroids; prednisolone; methylprednisolone; azathioprine; cyclophosphamide; cyclosporine; methotrexate; 4- aminopyridine; tizanidine; interferon- ia (AVONEX®; Biogen Idee); anti-a4 antibody (Tysabri®; Biogen Idee); inter feron-β lb (BETASERON®; Chiron/Berlex); interferon a- n3) (Interferon Sciences/Fujimoto), interferon-a (Alfa Wassermann/J&J), interferon βΙΑ- IF (Serono/Inhale Therapeutics), Peginterferon a 2b (Enzon/Schering-Plough),
Copolymer 1 (Cop- 1; COPAXONE®; Teva Pharmaceutical Industries, Inc.); hyperbaric oxygen; intravenous immunoglobulin; clabribine; antibodies to or antagonists of other human cytokines or growth factors and their receptors, for example, TNF, LT, IL- 1 , IL-2, IL-6, IL-7, IL-8, IL-12, IL-23, IL- 15, IL-16, EMAP-II, GM-CSF, FGF, and PDGF. A compound of Formula (I) can be combined with antibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD 19, CD20, CD25, CD28, CD30, CD40, CD45, CD69, CD80, CD86, CD90 or their ligands. A compound of Formula (I) may also be combined with agents such as methotrexate, cyclosporine, FK506, rapamycin, mycophenolate mofetil, leflunomide, NSAIDs, for example, ibuprofen, corticosteroids such as prednisolone, phosphodiesterase inhibitors, adensosine agonists, antithrombotic agents, complement inhibitors, adrenergic agents, agents which interfere with signalling by proinflammatory cytokines such as TNFa or IL-1 (e.g. IRAK, NIK, IKK, p38 or MAP kinase inhibitors), IL-Ι β converting enzyme inhibitors, TACE inhibitors, T-cell signaling inhibitors such as kinase inhibitors, metalloproteinase inhibitors, sulfasalazine, azathioprine, 6-mercaptopurines, angiotensin converting enzyme inhibitors, soluble cytokine receptors and derivatives thereof (e.g. soluble p55 or p75 TNF receptors, sIL- 1RI, sIL-lRJI, sIL-6R) and antiinflammatory cytokines (e.g. IL-4, IL-10, IL-13 and TGF ).
Preferred examples of therapeutic agents for multiple sclerosis in which a compound of Formula (I) can be combined to include interferon-β, for example, IFN ia and IFN ib; Copaxone, corticosteroids, caspase inhibitors, for example inhibitors of caspase-1, IL-1 inhibitors, TNF inhibitors, and antibodies to CD40 ligand and CD80.
Present compounds may also be combined with agents, such as alemtuzumab, dronabinol, daclizumab, mitoxantrone, xaliproden hydrochloride, fampridine, glatiramer acetate, natalizumab, sinnabidol, a-immunokine NNS03, ABR-215062, AnergiX.MS, chemokine receptor antagonists, BBR-2778, calagualine, CPI- 1189, LEM (liposome encapsulated mitoxantrone), THC.CBD (cannabinoid agonist), MBP-8298, mesopram (PDE4 inhibitor), MNA-715, anti-IL-6 receptor antibody, neurovax, pirfenidone allotrap 1258 (RDP- 1258), sTNF-Rl, talampanel, teriflunomide, TGF-beta2, tiplimotide, VLA-4 antagonists (for example, TR-14035, VLA4 Ultrahaler, Antegran-ELAN/Biogen), interferon gamma antagonists and IL-4 agonists.
Non-limiting examples of therapeutic agents for angina with which a compound of formula (I) of the invention can be combined include the following: aspirin, nitroglycerin, isosorbide mononitrate, metoprolol succinate, atenolol, metoprolol tartrate, amlodipine besylate, diltiazem hydrochloride, isosorbide dinitrate, clopidogrel bisulfate, nifedipine, atorvastatin calcium, potassium chloride, furosemide, simvastatin, verapamil HC1, digoxin, propranolol hydrochloride, carvedilol, lisinopril, spironolactone, hydrochlorothiazide, enalapril maleate, nadolol, ramipril, enoxaparin sodium, heparin sodium, valsartan, sotalol hydrochloride, fenofibrate, ezetimibe, bumetanide, losartan potassium, lisinopril/hydrochlorothiazide, felodipine, captopril and bisoprolol fumarate.
Non-limiting examples of therapeutic agents for ankylosing spondylitis with which a compound of formula (I) can be combined include the following: D2E7 (U.S. Patent No. 6,090,382; HUMIRA®), ibuprofen, diclofenac, misoprostol, naproxen, meloxicam, indomethacin, diclofenac, celecoxib, rofecoxib, sulfasalazine, methotrexate, azathioprine, minocyclin, prednisone, etanercept, and infliximab.
Non-limiting examples of therapeutic agents for asthma with which a compound of formula (I) can be combined include the following: albuterol, salmeterol/fluticasone, montelukast sodium, fluticasone propionate, budesonide, prednisone, salmeterol xinafoate, levalbuterol HC1, albuterol sulfate/ipratropium, prednisolone sodium phosphate, triamcinolone acetonide, beclomethasone dipropionate, ipratropium bromide, azithromycin, pirbuterol acetate, prednisolone, theophylline anhydrous,
methylprednisolone sodium succinate, clarithromycin, zafirlukast, formoterol fumarate, influenza virus vaccine, amoxicillin trihydrate, flunisolide, allergy injection, cromolyn sodium, fexofenadine hydrochloride, flunisolide/menthol, amoxicillin/clavulanate, levofloxacin, inhaler assist device, guaifenesin, dexamethasone sodium phosphate, moxifloxacin HC1, doxycycline hy elate, guaifenesin/d-methorphan, p- ephedrine/cod/chlorphenir, gatifloxacin, cetirizine hydrochloride, mometasone furoate, salmeterol xinafoate, benzonatate, cephalexin, pe/hydrocodone/chlorphenir, cetirizine HCl/pseudoephed, phenylephrine/cod/promethazine, codeine/promethazine, cefprozil, dexamethasone, guaifenesin/pseudoephedrine, chlorpheniramine/hydrocodone, nedocromil sodium, terbutaline sulfate, epinephrine, methylprednisolone and
metaproterenol sulfate.
Non-limiting examples of therapeutic agents for COPD with which a compound of formula (I) can be combined include the following: Letairs™ (ambrisentan), albuterol sulfate/ipratropium, ipratropium bromide, salmeterol/fluticasone, albuterol, salmeterol xinafoate, fluticasone propionate, prednisone, theophylline anhydrous,
methylprednisolone sodium succinate, montelukast sodium, budesonide, formoterol fumarate, triamcinolone acetonide, levofloxacin, guaifenesin, azithromycin,
beclomethasone dipropionate, levalbuterol HC1, flunisolide, ceftriaxone sodium, amoxicillin trihydrate, gatifloxacin, zafirlukast, amoxicillin/clavulanate,
flunisolide/menthol, chlorpheniramine/hydrocodone, metaproterenol sulfate,
methylprednisolone, mometasone furoate, p-ephedrine/cod/chlorphenir, pirbuterol acetate, p-ephedrine/loratadine, terbutaline sulfate, tiotropium bromide, (R,R)-formoterol, TgAAT, cilomilast and roflumilast.
Non-limiting examples of therapeutic agents for HCV with which a compound of formula (I) can be combined include the following: Interferon-alpha-2a, Interferon-alpha- 2b, Interferon-alpha conl, Interferon-alpha-nl, pegylated interferon-alpha-2a, pegylated interferon-alpha-2b, ribavirin, peginterferon alfa-2b + ribavirin, ursodeoxycholic acid, glycyrrhizic acid, thymalfasin, Maxamine, VX-497 and any compounds that are used to treat HCV through intervention with the following targets: HCV polymerase, HCV protease, HCV helicase, and HCV IRES (internal ribosome entry site).
Non-limiting examples of therapeutic agents for Idiopathic Pulmonary Fibrosis with which a compound of Formula (I) can be combined include the following:
prednisone, azathioprine, albuterol, colchicine, albuterol sulfate, digoxin, gamma interferon, methylprednisolone sod succ, lorazepam, furosemide, lisinopril, nitroglycerin, spironolactone, cyclophosphamide, ipratropium bromide, actinomycin d, alteplase, fluticasone propionate, levofloxacin, metaproterenol sulfate, morphine sulfate, oxycodone HC1, potassium chloride, triamcinolone acetonide, tacrolimus anhydrous, calcium, interferon-alpha, methotrexate, mycophenolate mofetil and interferon-gamma-ΐ β.
Non-limiting examples of therapeutic agents for myocardial infarction with which a compound of formula (I) can be combined include the following: aspirin, nitroglycerin, metoprolol tartrate, enoxaparin sodium, heparin sodium, clopidogrel bisulfate, carvedilol, atenolol, morphine sulfate, metoprolol succinate, warfarin sodium, lisinopril, isosorbide mononitrate, digoxin, furosemide, simvastatin, ramipril, tenecteplase, enalapril maleate, torsemide, retavase, losartan potassium, quinapril HCl/mag carb, bumetanide, alteplase, enalaprilat, amiodarone hydrochloride, tirofiban HCl m-hydrate, diltiazem hydrochloride, captopril, irbesartan, valsartan, propranolol hydrochloride, fosinopril sodium, lidocaine hydrochloride, eptifibatide, cefazolin sodium, atropine sulfate, aminocaproic acid, spironolactone, interferon, sotalol hydrochloride, potassium chloride, docusate sodium, dobutamine HCl, alprazolam, pravastatin sodium, atorvastatin calcium, midazolam hydrochloride, meperidine hydrochloride, isosorbide dinitrate, epinephrine, dopamine hydrochloride, bivalirudin, rosuvastatin, ezetimibe/simvastatin, avasimibe, and cariporide.
Non-limiting examples of therapeutic agents for psoriasis with which a compound of formula (I) can be combined include the following: calcipotriene, clobetasol propionate, triamcinolone acetonide, halobetasol propionate, tazarotene, methotrexate, fluocinonide, betamethasone diprop augmented, fluocinolone acetonide, acitretin, tar shampoo, betamethasone valerate, mometasone furoate, ketoconazole,
pramoxine/fluocinolone, hydrocortisone valerate, flurandrenolide, urea, betamethasone, clobetasol propionate/emoll, fluticasone propionate, azithromycin, hydrocortisone, moisturizing formula, folic acid, desonide, pimecrolimus, coal tar, diflorasone diacetate, etanercept folate, lactic acid, methoxsalen, hc/bismuth subgal/znox/resor,
methylprednisolone acetate, prednisone, sunscreen, halcinonide, salicylic acid, anthralin, clocortolone pivalate, coal extract, coal tar/salicylic acid, coal tar/salicylic acid/sulfur, desoximetasone, diazepam, emollient, fluocinonide/emollient, mineral oil/castor oil/na lact, mineral oil/peanut oil, petroleum/isopropyl myristate, psoralen, salicylic acid, soap/tribromsalan, thimerosal/boric acid, celecoxib, infliximab, cyclosporine, alefacept, efalizumab, tacrolimus, pimecrolimus, PUVA, UVB, and sulfasalazine.
Non-limiting examples of therapeutic agents for psoriatic arthritis with which a compound of formula (I) can be combined include the following: D2E7 (U.S. Patent No. 6,090,382; HUMIRA®), methotrexate, etanercept, rofecoxib, celecoxib, folic acid, sulfasalazine, naproxen, leflunomide, methylprednisolone acetate, indomethacin, hydroxychloroquine sulfate, prednisone, sulindac, betamethasone diprop augmented, infliximab, methotrexate, folate, triamcinolone acetonide, diclofenac, dimethylsulfoxide, piroxicam, diclofenac sodium, ketoprofen, meloxicam, methylprednisolone, nabumetone, tolmetin sodium, calcipotriene, cyclosporine, diclofenac sodium/misoprostol, fluocinonide, glucosamine sulfate, gold sodium thiomalate, hydrocodone bitartrate/apap, ibuprofen, risedronate sodium, sulfadiazine, thioguanine, valdecoxib, alefacept and efalizumab.
Non-limiting examples of therapeutic agents for restenosis with which a compound of formula (I) can be combined include the following: sirolimus, paclitaxel, everolimus, tacrolimus, ABT-578, and acetaminophen.
Non-limiting examples of therapeutic agents for sciatica with which a compound of formula (I) can be combined include the following: hydrocodone bitartrate/apap, rofecoxib, cyclobenzaprine HC1, methylprednisolone, naproxen, ibuprofen, oxycodone HCl/acetaminophen, celecoxib, valdecoxib, methylprednisolone acetate, prednisone, codeine phosphate/apap, tramadol HCl/acetaminophen, metaxalone, meloxicam, methocarbamol, lidocaine hydrochloride, diclofenac sodium, gabapentin, dexamethasone, carisoprodol, ketorolac tromethamine, indomethacin, acetaminophen, diazepam, nabumetone, oxycodone HC1, tizanidine HC1, diclofenac sodium/misoprostol, propoxyphene napsylate/apap, asa/oxycod/oxycodone ter, ibuprofen/hydrocodone bit, tramadol HC1, etodolac, propoxyphene HC1, amitriptyline HC1, carisoprodol/codeine phos/asa, morphine sulfate, multivitamins, naproxen sodium, orphenadrine citrate, and temazepam.
Preferred examples of therapeutic agents for SLE (Lupus) with which a compound of formula (I) can be combined include the following: NSAIDS, for example, diclofenac, naproxen, ibuprofen, piroxicam, indomethacin; COX2 inhibitors, for example, celecoxib, rofecoxib, valdecoxib; anti-malarials, for example, hydroxychloroquine; steroids, for example, prednisone, prednisolone, budenoside, dexamethasone; cytotoxics, for example, azathioprine, cyclophosphamide, mycophenolate mofetil, methotrexate; inhibitors of PDE4 or purine synthesis inhibitor, for example Cellcept®. A compound of Formula (I) may also be combined with agents such as sulfasalazine, 5-aminosalicylic acid, olsalazine, Imuran® and agents which interfere with synthesis, production or action of proinflammatory cytokines such as IL- 1 , for example, caspase inhibitors like IL- 1 β converting enzyme inhibitors and IL-lra. A compound of Formula (I) may also be used with T cell signaling inhibitors, for example, tyrosine kinase inhibitors; or molecules that target T cell activation molecules, for example, CTLA-4-IgG or anti-B7 family antibodies, anti-PD- 1 family antibodies. A compound of Formula (I) can be combined with IL- 1 1 or anti-cytokine antibodies, for example, fonotolizumab (anti-IFNg antibody), or anti-receptor receptor antibodies, for example, anti-IL-6 receptor antibody and antibodies to B-cell surface molecules. A compound of Formula (I) may also be used with LJP 394 (abetimus), agents that deplete or inactivate B-cells, for example, Rituximab (anti-CD20 antibody), lymphostat-B (anti-BlyS antibody), TNF antagonists, for example, anti-TNF antibodies, D2E7 (U.S. Patent No. 6,090,382; HUMIRA®), CA2
(REMICADE™), CDP 571, TNFR-Ig constructs, (p75TNFRIgG (ENBREL™) and p55TNFRIgG (LENERCEPT™)).
e. Pharmaceutical Compositions
One or more compounds of this invention can be administered to a human patient by themselves or in pharmaceutical compositions where they are mixed with biologically suitable carriers or excipient(s) at doses to treat or ameliorate a disease or condition as described herein. Mixtures of these compounds can also be administered to the patient as a simple mixture or in suitable formulated pharmaceutical compositions. A
therapeutically effective dose refers to that amount of the compound or compounds sufficient to result in the prevention or attenuation of a disease or condition as described herein. Techniques for formulation and administration of the compounds of the instant application may be found in references well known to one of ordinary skill in the art, such as "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, latest edition.
Suitable routes of administration may, for example, include oral, eyedrop, rectal, transmucosal, topical, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections.
Alternatively, one may administer the compound in a local rather than a systemic manner, for example, via injection of the compound directly into an edematous site, often in a depot or sustained release formulation.
Furthermore, one may administer the drug in a targeted drug delivery system, for example, in a liposome coated with endothelial cell-specific antibody.
The pharmaceutical compositions may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
Pharmaceutical compositions for use in accordance with the present invention thus may be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
For injection, the agents may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
For oral administration, the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained by combining the active compound with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol;
cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
Pharmaceutical preparations which can be used orally include push- fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push- fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.
For administration by inhalation, the compounds may be delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
The compounds can be formulated for parenteral administration by injection, e.g. bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g. in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions.
Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly or by intramuscular injection). Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
An example of a pharmaceutical carrier for the hydrophobic compounds is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. The cosolvent system may be the VPD co- solvent system. VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant polysorbate 80, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol. The VPD co-solvent system (VPD:5W) consists of VPD diluted 1 : 1 with a 5% dextrose in water solution. This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration.
Naturally, the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics. Furthermore, the identity of the co- solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.
Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as
dimethysulfoxide also may be employed, although usually at the cost of greater toxicity. Additionally, the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.
The pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols. Many of the compounds may be provided as salts with pharmaceutically compatible counterions. Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free base forms.
For any compound used in a method of the present invention, the therapeutically effective dose can be estimated initially from cellular assays. For example, a dose can be formulated in cellular and animal models to achieve a circulating concentration range that includes the IC50 as determined in cellular assays (i.e., the concentration of the test compound which achieves a half-maximal inhibition of a given CCR2 activity). In some cases it is appropriate to determine the IC50 in the presence of 3 to 5% serum albumin since such a determination approximates the binding effects of plasma protein on the compound. Such information can be used to more accurately determine useful doses in humans. Further, the most preferred compounds for systemic administration effectively inhibit CCR2 signaling in intact cells at levels that are safely achievable in plasma.
A therapeutically effective dose refers to that amount of the compound that results in amelioration of symptoms in a patient. Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the maximum tolerated dose (MTD) and the ED5o (effective dose for 50% maximal response). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between MTD and ED50. Compounds which exhibit high therapeutic indices are preferred. The data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED5o with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. (See e.g. Fingl et al, 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 pi). In the treatment of crises, the administration of an acute bolus or an infusion approaching the MTD may be required to obtain a rapid response.
Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the CCR2 modulating effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vitro data; e.g. the concentration necessary to achieve 50-90% inhibition of CCR2 using the assays described herein. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations.
Dosage intervals can also be determined using the MEC value. Compounds should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90% until the desired amelioration of symptoms is achieved. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.
The amount of composition administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.
The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labelled for treatment of an indicated condition.
In some formulations it may be beneficial to use the compounds in the form of particles of very small size, for example as obtained by fluid energy milling.
The use of compounds of the present invention in the manufacture of pharmaceutical compositions is illustrated by the following description. In this description the term "active compound" denotes any compound of the invention but particularly any compound which is the final product of one of the compounds listed in the Examples section.
i) Capsules
In the preparation of capsules, 10 parts by weight of active compound and 240 parts by weight of lactose can be de-aggregated and blended. The mixture can be filled into hard gelatin capsules, each capsule containing a unit dose or part of a unit dose of active compound.
ii) Tablets
Tablets can be prepared, for example, from the following ingredients. Parts by weight
Active compound 10
Lactose 190
Maize starch 22
Polyvinylpyrrolidone 10
Magnesium stearate 3
The active compound, the lactose and some of the starch can be de-aggregated, blended and the resulting mixture can be granulated with a solution of the
polyvinylpyrrolidone in ethanol. The dry granulate can be blended with the magnesium stearate and the rest of the starch. The mixture is then compressed in a tabletting machine to give tablets each containing a unit dose or a part of a unit dose of active compound. iii) Enteric coated tablets
Tablets can be prepared by the method described in (b) above. The tablets can be enteric coated in a conventional manner using a solution of 20% cellulose acetate phthalate and 3% diethyl phthalate in ethanol: dichloromethane (1 : 1).
iv) Suppositories
In the preparation of suppositories, for example, 100 parts by weight of active compound can be incorporated in 1300 parts by weight of triglyceride suppository base and the mixture formed into suppositories each containing a therapeutically effective amount of active ingredient.
In the compositions of the present invention the active compound may, if desired, be associated with other compatible pharmacologically active ingredients. For example, the compounds of this invention can be administered in combination with another therapeutic agent that is known to treat a disease or condition described herein. For example, with one or more additional pharmaceutical agents that inhibit or prevent the production of VEGF or angiopoietins, attenuate intracellular responses to VEGF or angiopoietins, block intracellular signal transduction, inhibit vascular hyperpermeability, reduce inflammation, or inhibit or prevent the formation of edema or neovascularization. The compounds of the invention can be administered prior to, subsequent to or simultaneously with the additional pharmaceutical agent, whichever course of administration is appropriate. The additional pharmaceutical agents include, but are not limited to, anti-edemic steroids, NSAIDS, ras inhibitors, anti-TNF agents, anti-ILl agents, antihistamines, PAF-antagonists, COX- 1 inhibitors, COX-2 inhibitors, NO synthase inhibitors, Akt/PTB inhibitors, IGF- 1R inhibitors, PKC inhibitors, PI3 kinase inhibitors, calcineurin inhibitors and immunosuppressants. The compounds of the invention and the additional pharmaceutical agents act either additively or synergistically. Thus, the administration of such a combination of substances that inhibit angiogenesis, vascular hyperpermeability and/or inhibit the formation of edema can provide greater relief from the deletrious effects of a hyperproliferative disorder, angiogenesis, vascular hyperpermeability or edema than the administration of either substance alone. In the treatment of malignant disorders combinations with antiproliferative or cytotoxic chemotherapies or radiation are included in the scope of the present invention.
A "therapeutically effective amount" is an amount of a compound of formula (I) or a combination of two or more such compounds, which inhibits, totally or partially, the progression of the condition or alleviates, at least partially, one or more symptoms of the condition. A therapeutically effective amount can also be an amount which is prophylactically effective. The amount which is therapeutically effective will depend upon the patient's size and gender, the condition to be treated, the severity of the condition and the result sought. For a given patient, a therapeutically effective amount can be determined by methods known to those of skill in the art.
"Pharmaceutically acceptable salts" refers to those salts which retain the biological effectiveness and properties of the free bases and which are obtained by reaction with inorganic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid or organic acids such as sulfonic acid, carboxylic acid, organic phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, citric acid, fumaric acid, maleic acid, succinic acid, benzoic acid, salicylic acid, lactic acid, tartaric acid (e.g. (+) or (-)-tartaric acid or mixtures thereof), amino acids (e.g. (+) or (-)-amino acids or mixtures thereof), and the like. These salts can be prepared by methods known to those skilled in the art.
Certain compounds of formula (I) which have acidic substituents may exist as salts with pharmaceutically acceptable bases. The present invention includes such salts. Examples of such salts include sodium salts, potassium salts, lysine salts and arginine salts. These salts may be prepared by methods known to those skilled in the art.
Certain compounds and their salts may exist in more than one crystal form and the present invention includes each crystal form and mixtures thereof.
Certain compounds and their salts may also exist in the form of solvates, for example hydrates, and the present invention includes each solvate and mixtures thereof. Certain compounds may exist in zwitterionic form and the present invention includes each zwitterionic form and mixtures thereof.
As used herein the term "pro-drug" refers to an agent which is converted into the parent drug in vivo by some physiological chemical process (e.g., a pro-drug on being brought to the physiological pH is converted to the desired drug form). Pro-drugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. The pro-drug may also have improved solubility in pharmacological compositions over the parent drug. An example, without limitation, of a pro-drug would be a compound of the present invention wherein it is administered as an ester (the "prodrug") to facilitate transmittal across a cell membrane where water solubility is not beneficial, but then it is metabolically hydrolyzed to the carboxylic acid once inside the cell where water solubility is beneficial
Pro-drugs have many useful properties. For example, a pro-drug may be more water soluble than the ultimate drug, thereby facilitating intravenous administration of the drug. A pro-drug may also have a higher level of oral bioavailability than the ultimate drug. After administration, the pro-drug is enzymatically or chemically cleaved to deliver the ultimate drug in the blood or tissue.
f. General Synthesis
Compounds described herein when prepared by synthetic processes or by metabolic processes are encompassed in this application. Preparation of the compounds by metabolic processes includes those occurring in the human or animal body {in vivo) or processes occurring in vitro.
Compounds described herein can be prepared using readily available starting materials or known intermediates. The compounds and the intermediates can be prepared by a variety of processes well known for the preparation of compounds of this class. For example, the compounds of formula (I) wherein the groups X1, X2, X3, R4, R5, and formula (a), (b), and (c) have the meanings as set forth in the Summary and Detailed Description sections unless otherwise noted, can be synthesized, for example, as provided in Schemes 1 and 2.
Abbreviations which have been used in the descriptions of the Schemes and the Examples that follow are: (Boc)20 for di-tert-butyl dicarbonate, n-BuLi for n- butyllithium, nB¾N for tributylamine, DIBAL for diisobutylaluminum hydride, DMSO- ά for deuterated dimethyl sulfoxide, DMAP for 4-(dimethylamino)pyridine, DME for dimethoxyethane, DMF for N,N-dimethylformamide, EDCI or EDC for l-ethyl-3-[3- (dimethylamino)propyl]-carbodiimide hydrochloride, EtOAc for ethyl acetate, Et3N for triethylamine, Et20 for diethyl ether, EtOH for ethanol, HATU for 0-(7-azabenzotriazol- l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, HPLC for high-performance liquid chromatography, LC-MS for liquid chromatography-mass spectrometry, MeOH for methanol, NaBH(OAc)3 for sodium triacetoxyborohydride, OMs for
trifluoromethanesulfonate, Pd(PPl¾)4 for tetrakis(triphenylphosphine)palladium(0), PdCl2(dppf) for [ 1 , 1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(II),
PdCl2(PPli3)2 for bis(triphenylphosphine)palladium(II) dichloride, SFC for Supercritical Fluid Chromatography, TFA for trifluoroacetic acid, TLC for thin layer chromatography, THF for tetrahydrofuran, Ti(iPrO)4 for titanium(IV) isopropoxide, TsOH for para- toluenesulfonic acid, and ZnEt2 for diethyl zinc.
Compounds of general formula (6) wherein ring A is as defined as R5, can be prepared, for example, using the general method outlined in Scheme 1.
Scheme 1
Figure imgf000087_0001
(5)
Acid of formula (1) can be treated with amines of formula (2) under coupling conditions known to one skilled in the art, to provide compounds of formula (3). Typical conditions for the coupling reaction include stirring about equimolar mixture of the compounds in a solvent such as, but not limited to, THF, Ν,Ν-dimethylacetamide, N,N- dimethylformamide, pyridine, chloroform, or mixture thereof, with a coupling reagent, optionally along with a coupling auxiliary, and in the presence or absence of a base. Typical reactions can be carried out at temperature ranging from about 0 °C to about 65 °C or may be carried out in a microwave reactor to facilitate the coupling. Examples of coupling reagents include, but are not limited to, bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPC1), 1,3-dicyclohexylcarbodiimide (DCC), polymer supported 1,3- dicyclohexylcarbodiimide (PS-DCC), 0-(7-azabenzotriazol- 1 -yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (HATU), 0-benzotriazol-l-yl-N,N,N',N'- tetramethyluronium tetrafluoroborate (TBTU), and 1 -propanephosphonic acid cyclic anhydride. Non-limiting examples of coupling auxiliary include l-hydroxy-7- azabenzotriazole (HOAT) and 1 -hydroxybenzotriazole hydrate (HOBT). Suitable examples of bases include, but are not limited to, N-methyl morpholine and
diisopropylethylamine.
Conversion of (3) to the amines of formula (4) can be achieved by treatment with hydroxylamine at elevated temperature. Reductive amination of (4) with cyclic ketones of formula (5) affords compounds of formula (6) wherein R4 is hydrogen. The amines of formula (5) wherein R101 is hydrogen can be alkylated to those wherein R101 is alkyl, haloalkyl, or alkoxyalkyl in the presence of an appropriate base (e.g. diisopropylethyl amine) and R101OMs at about room temperature.
Compounds of general formula (8) wherein NRARB is NR4R5, or RA and RB together with the nitrogen atom form cyclic amines of formula (a), (b), or (c), can be synthesized using general procedure as illustrated in Scheme 2.
Scheme 2
Figure imgf000088_0001
Transformation of ketones (7) to amines of formula (8) can be achieved by treatment with amines of formula HNRARB via reductive amination conditions known to one skilled in the art.
It will be appreciated that the synthetic schemes and specific examples as illustrated in the Examples section are illustrative and are not to be read as limiting the scope of the invention as it is defined in the appended claims. All alternatives, modifications, and equivalents of the synthetic methods and specific examples are included within the scope of the claims. Optimum reaction conditions and reaction times for each individual step may vary depending on the particular reactants employed and substituents present in the reactants used. Unless otherwise specified, solvents, temperatures and other reaction conditions may be readily selected by one of ordinary skill in the art. Specific procedures are provided in the Examples section. Reactions may be worked up in the conventional manner, e.g. by eliminating the solvent from the residue and further purified according to methodologies generally known in the art such as, but not limited to, crystallization, distillation, extraction, trituration and chromatography. Unless otherwise described, the starting materials and reagents are either commercially available or may be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature.
Routine experimentations, including appropriate manipulation of the reaction conditions, reagents and sequence of the synthetic route, protection of any chemical functionality that may not be compatible with the reaction conditions, and deprotection at a suitable point in the reaction sequence of the method are included in the scope of the invention. Suitable protecting groups and the methods for protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rd ed.), John Wiley & Sons, NY (1999), which is incorporated herein by reference in its entirety. Synthesis of the compounds of the invention may be accomplished by methods analogous to those described in the synthetic schemes described hereinabove and in specific examples.
Starting materials, if not commercially available, may be prepared by procedures selected from standard organic chemical techniques, techniques that are analogous to the synthesis of known, structurally similar compounds, or techniques that are analogous to the above described schemes or the procedures described in the synthetic examples section.
When an optically active form of a compound of the invention is required, it may be obtained by carrying out one of the procedures described herein using an optically active starting material (prepared, for example, by asymmetric induction of a suitable reaction step), or by resolution of a mixture of the stereoisomers of the compound or intermediates using a standard procedure (such as chromatographic separation, recrystallization or enzymatic resolution). Similarly, when a pure geometric isomer of a compound of the invention is required, it may be obtained by carrying out one of the above procedures using a pure geometric isomer as a starting material, or by resolution of a mixture of the geometric isomers of the compound or intermediates using a standard procedure such as chromatographic separation.
g. Examples
Certain compounds in the Examples below can be purified using reverse-phase HPLC. Purification can be conducted using either a CI 8 or C8 reverse-phase column. Compounds can be eluted using a gradient of about 10-100% acetonitrile in 0.1% aqueous TFA or 0.1% aqueous formic acetate. For purifications conducted with TFA, the product thus obtained may be in the form of a TFA salt. Compounds may be characterized as the TFA salt or as the free base following neutralization, extraction and isolation.
A typical analytical reverse phase HPLC procedure was conducted as follows: SHIMADZU LC-20AB System; SEPAX-3 μηι, 2.1x30 mm ID column; Gradient 10-80% acetonitrile/H20 (0.1% TFA); Flow rate: 1.0 mL/min; Back pressure: 5~25 MPa; Column temperature: 40 °C; Wavelength: 220 nm and 254 nm; Cycletime: 6 min; Sample preparation: compound was dissolved in acetonitrile to about 20 mg/mL; injection volume: 0.1 μΕ per injection.
A typical preparative reverse phase HPLC procedure was conducted as follows: SHIMADZU LC-8A System System; LUNA C18-10 μηι, 250x50 mm ID column;
Gradient 10-50% acetonitrile/H20 (0.1% TFA); Flow rate: 70 mL/min; back pressure: 30- 100 bar; Column temperature: 20 °C; Wavelength: 220 nm and 254 nm; Cycletime: 30 min; Sample preparation: compound was dissolved in acetonitrile to about 180 mg/mL; Injection volume: 4 mL per injection.
A typical analytical chiral SFC procedure was conducted as follows:
Instrument: Berger MultiGram™ SFC, Mettler Toledo Co, Ltd; Column: Chiralpak AD- H 150x4.6 mm ID, 3 μιη; Mobile phase: iso-propanol (0.05% diethylamine as modifier) in CO2 from 5% to 40%; Flow rate: 2.5 mL/min; Wavelength: 220 nm.
Other columns for SFC analysis or purification include: Chiralcel OJ-H, Chiralcel OD-H, or Chiralpak AS-H. Mobile phases include methanol, ethanol, or iso-propanol with 0.05% diethylamine as the modifier.
A typical preparative chiral SFC procedure was conducted as follows:
Instrument: Berger MultiGram™ SFC , Mettler Toledo Co, Ltd; Column: Chiralcel AD 250x30 mm ID, 5 μιη; Mobile phase: A: Supercritical CO2 , B: iso-propanol (0.05% diethylamine as modifier), A:B =70:30 at 70 mL/min; Column Temp: 38 °C; Nozzle Pressure: lOOBar; Nozzle Temp: 60 °C; Evaporator Temp: 20 °C Trimmer Temp: 25 °C; Flow rate: 70 mL/min; Wavelength: 220 nm.
Certain compounds in the Examples below can be purified using normal phase silica gel chromatography including traditional flash chromatography or an automated purification system (e.g., Isco Combi-Flash, Analogix Intelliflash) using pre-packed silica gel columns (55 or 35 μιη silica gel, Isco gold columns). Compounds can also be purified by preparative-TLC.
Typical solvents for silica gel chromatography include: ethyl acetate in hexanes, diethyl ether in hexanes, THF in hexanes, ethyl acetate in dichloromethane, methanol in dichloromethane, methanol in dichloromethane with NH4OH, acetone in hexanes, and dichloromethane in hexanes.
For the deprotection of amines with acid-labile protective groups, unless otherwise noted, the reaction mixture was neutralized, extracted with dichloromethane, ethyl acetate, or other organic solvents including diethyl ether, chloroform. The organic layers were combined, dried, and concentrated to obtain the free base, which can either be purfied on silica gel or used directly in subsequent reactions.
Figure imgf000091_0001
Example 1
2- { 1 -[(2S,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)- yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}pyridazin-3(2H)-one
Example 1A
Ethyl 2-oxo- 1 -(2-oxopropyl)cyclopentanecarboxylate To a solution of ethyl 2-oxocyclopentanecarboxylate (150 g, 0.96 mol) in DMF (2000 mL) was added NaH (50 g, 0.88 mol) portion wise at 0 °C, followed by 1 - chloropropan-2-one (1 17.7 g, 1.24 mol). The mixture was stirred at room temperature for 24 hours under N2. TLC (petroleum ether :EtOAc = 5: 1) indicated the reaction was completed. The mixture was filtered and the filtrate was concentrated in vacuum. The residue was poured into water at 0 °C. Then the resulting aqueous layer was extracted with EtOAc (3 x 500 mL). Then the combined organic layers were dried over Na2S04, filtered, and the solvent was evaporated in vacuum. The residue was purified by column chromatography (S1O2, petroleum ethenEtOAc = 80: 1) to give Example 1A (125 g, 61.35%) as oil.
Example IB
Ethyl 5-oxo- 1 ,2,3,3a,4,5-hexahydropentalene-3a-carboxylate To a refluxing mixture of NaH (28.27 g, 0.706 mol) in toluene (2000 mL) was added a solution of Example 1A in toluene (250 mL) dropwise over 2 hours. After the addition, the mixture was stirred for 0.5 hour at refluxing. TLC (petroleum ethenEtOAc = 4: 1 ) indicated that the reaction was complete. The mixture was cooled to room temperature and poured into aqueous HC1 (1 N, 1500 mL), extracted with EtOAcD 3 x 500 mL). The combined organic layers was dried over Na2S04, filtered, concentrated, and the residue was purified by chromatography (S1O2, 0% to 10% EtOAc in petroleum ether) to give Example IB (27.75 g, 48.5%) as oil.
Example 1C
Ethyl 2-oxooctahydropentalene-3a-carboxylate A mixture of Example IB (50 g, 0.257 mol), Pd/C (8 g) in EtOH (500 mL) was stirred under hydrogen at 40 psi for 4 hours at room temperature. TLC (petroleum ethenEtOAc = 4: 1 ) indicated the reaction was complete. The mixture was filtered and concentrated in vacuum. The residue was purified by column chromatography (S1O2, 0% to 10% EtOAc in petroleum ether) to give Example 1C (30 g, 58.8%) as light yellow oil.
Example ID
2-oxooctahydropentalene-3a-carboxylic acid A solution of Example 1C (10 g, 0.051 mol) in HC1 (12 N, 150 mL) was heated at reflux for 4 hours. TLC (petroleum ether: EtOAc = 5: 1) indicated that the reaction was complete. The mixture was cooled to room temperature and extracted with
dichloromethane (3 x 30 mL). The organic layer was dried over Na2S04, filtered, and concentrated in vacuum to give Example ID (7.05 g, 80.4%) as grey oil, which was used in the next step directly.
Example IE
(Z)-N-(3-(dimethylamino)-2-(trifluoromethyl)allylidene)-N-methylmethanaminium POCI3 (35.67 mL) was added to DMF (100 mL) at 4 °C over 1 hour and the reaction mixture was allowed to warm to room temperature. 3,3,3-trifluoropropanoic acid (25 g) was added dropwise over 6 minutes, and the reaction mixture was stirred at about 50 °C to about 60 °C for 4 hours and then allowed to cool to room temperature. The reaction mixture was charged to a 250 mL addition funnel and was added concurrently with a solution of sodium hydroxide solution (5 N, 65 mL) in another addition funnel to a solution of NaPF6 (31.78 g) in water (230 mL) with cooling at 4 °C. The addition rate was such that the internal temperature remained below 5 °C and the pH varied form 3.05 to 3.6. The resulting yellow slurry was then stirred for 60 minutes at 0 °C. The solids was filtered, slurry-washed with ice-cold water (2 x 100 mL) then dried with a stream of N2 under vacuum to provide Example IE.
Example IF
tert-butyl 3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridine-6(5H)-carboxylate To a solution of tert-butyl 4-oxopiperidine- l-carboxylate (14.35 g, 0.072 mol) in THF (250 mL) was added lithium hexamethyldisilylamide (150 mL, 1 N, 0.15 mol) dropwise at -12 °C under N2. After the addition, the mixture was stirred for 1.5 hours at room temperature. The reaction mixture was added dropwise to a suspension of Example IE (25 g, 0.073 mol) in THF (150 mL) dropwise over 1 hour at -24 °C. After the addition, the mixture was stirred for 2 hours at -20 °C. Acetic acid (6.3 mL) was added to the reaction mixture and gradually the temperature was allowed to warm to room
temperature. Ammonium acetate (15.85 g, 0.205 mol) was added to the reaction mixture and the mixture was refluxed for 2 hours. The cooled mixture was washed with water (200 mL) and extracted with EtOAc (3 x 100 mL). The organic layer was dried over Na2S04, filtered, and concentrated in vacuum and the residue was purified by column chromatography to give Example IF (13.5 g, 60.8%) as light yellow solid.
Example 1G
3-(trifluoromethyl)-5,6,7,8-tetrahydro- 1 ,6-naphthyridine To a solution of Example IF (22 g, 0.065 mmol) in dichloromethane (20 mL) was added HC1 in dioxane (4 N, 150 mL) dropwise at room temperature. After the addition, the mixture was stirred for 2 hours at room temperature. TLC (petroleum ether: EtOAc = 5: 1) indicated that the reaction was complete. The mixture was filtered, the solid was dried in vacuum to give Example 1G (14 g, 90.5%) as white solid.
Example 1H (3aR,6aR)-3a-(3-(trifluoromethyl)-5,6,7,8 etrahydro-l,6-naphthyridine-6- carbonyl)hexahydropentalen-2( 1 H)-one
A mixture of Example ID (7.05 g, 0.042 mol), Example 1G (9 g, 0.037 mol), 1- ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (10.9 g, 0.056 mol), hydroxybenzotriazole (5.15 g, 0.037 mol), Et3N (21.9 ml, 0.151 mol) in dichloromethane (200 mL) was stirred for 12 hours at room temperature under N2. TLC (petroleum ether :EtOAc = 1 : 1) indicated the reaction was complete. The mixture was washed with water (100 mL) and extracted with dichloromethane (3 x 100 mL). The organic layer was dried over Na2S04, filtered, and concentrated in vacuum. The residue was purified by chromatography on silica gel and followed by chiral SFC separation to give
enantiomerically pure Example 1H (4.0 g, 27.1%) as light yellow solid.
Example II
2-(piperidin-4-yl)pyridazin-3(2H)-one
Tert-butyl 4-(6-oxopyridazin-l(6H)-yl)piperidine-l-carboxylate was prepared and purified according to the procedure described in Example 4B, substituting tert-butyl 4- bromopiperidine- 1 -carboxylate for Example 4A, and pyridazin-3(2H)-one for 3- (trifluoromethyl)- 1 H-pyrazole.
The title compound was prepared and purified according to the procedure described in Example 4C, substituting tert-butyl 4-(6-oxopyridazin- 1 (6H)-yl)piperidine- 1 -carboxylate for Example 4B.
Example 1J
2- { 1 -[(2S,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)- yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}pyridazin-3(2H)-one To a mixture of Example II (180 mg, 1.0 mmol) and Example 1H (352 mg, 1.0 mmol) in dichloroethane (5 mL) was added acetic acid (0.1 mL) at room temperature. The reaction mixture was stirred at room temperature for 24 hours before sodium triacetoxy borohydride (233 mg, 1.1 mmol) was added and the resulting mixture was stirred at room temperature over night, and concentrated in vacuum. The residue was purified by preparative reverse phase HPLC and followed by preparative chiral SFC to give the title compound (78.3 mg, 15.2%). Ή NMR: (400 MHz, CDC13 ) δ ppm 8.65 (s, 1H), 7.70 (m, 1H), 7.62 (s, 1H), 7.08(m, 1H), 6.80(m, 1H), 4.6 - 4.85 (m, 2H), 3.8 - 3.95 (m, 3H), 3.35 (m, 1H), 2.95 - 3.10 (m, 4H), 2.3 - 2.45 (m, 2H), 1.4 - 2.10 (m, 14H), 1.15 (m, 1H); MS (ESI) m/z 516 (M+H)+.
Figure imgf000095_0001
Example 2
2-{ l-[(2R,3aR,6aR)-3a- {[3-(trinuoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)- yl]carbonyl} octahydropentalen-2-yl]piperidin-4-yl}phthalazin- 1 (2H)-one
Example 2A
2-(piperidin-4-yl)phthalazin- 1 (2H)-one
Tert-butyl 4-(l-oxophthalazin-2(lH)-yl)piperidine-l-carboxylate was prepared and purified according to the procedure described in Example 4B, substituting phthalazin- l(2H)-one for 3-(trifluoromethyl)- lH-pyrazole.
The title compound was prepared and purified according to the procedure described in Example 4C, substituting tert-butyl 4-(l-oxophthalazin-2(lH)-yl)piperidine- 1 -carboxylate for Example 4B.
Example 2B
2-{ l-[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)- yl]carbonyl} octahydropentalen-2-yl]piperidin-4-yl}phthalazin- 1 (2H)-one The title compound was prepared and purified according to the procedure described in Example 1 J, substituting Example 2A for Example II.Ή NMR (400 MHz, CDC13) δ ppm 8.63 (s, 1H), 8.36 (d, J= 7.6Hz, 1H), 8.12 (s, 1H), 7.60 - 7.69 (m, 4H), 4.95 (m, 1H), 4.70 (m, 2H), 3.8 - 3.95 (m, 2H), 3.45 (m, 1H), 3.0-3.15 ( m, 4H), 2.7 - 2.9 (m, 3 H), 2.05 - 2.2 (m, 5H), 1.5 - 1.9 (m, 7H), 1.1 - 1.3 (m, 2H); MS (ESI) m/z 566 (M+H)+.
Figure imgf000095_0002
Example 3
[(2S,3aR,6aR)-2-[4-(lH-pyrazol- 1 -yl)piperidin- 1 -yl]hexahydropentalen-3a(lH)-yl] [3- (trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone Example 3A1
tert-butyl 4-( lH-pyrazol- 1 -yl)piperidine- 1 -carboxylate To a solution of lH-pyrazole (0.51 g, 7.46 mmol) in DMF (20 mL) was added NaH (0.43 g, 10.67 mmol) and Example 4A (2 g, 7.1 1 mmol) at room temperature. The mixture was stirred for 12 hours at 50 °C. TLC (petroleum ethenEtOAc = 1 : 1) indicated the reaction was completed. The reaction mixture was quenched with aqueous NH4CI4 (20 mL) and extracted with EtOAc (3X 50mL). The organic layer was dried over Na2S04, filtered, and concentrated in vacuum, the residue was purified by silica gel
chromatography to give the title compound (1.0 g, 55.9%) as a colorless solid. Ή NMR (400 MHz, CDCI3) δ 7.45 (d, IH), 7.35 (d, IH), 6.19 (t, IH), 4.21 (m, 3H), 2.82 (m, 2H), 2.03 (m, 2H), 1.84 (m, 2H), 1.40 (s, 9H).
Example 3A
4-( lH-pyrazol- 1 -yl)piperidine
To a solution of Example 3A1 (0.8 g, 3.8 mmol) in methanol (5 mL) was added HCl(g)/methanol (10 mL) dropwise at room temperature. The resulting mixture was stirred for 1.5 hours at room temperature. TLC indicated the reaction was completed. The reaction mixture was concentrated in vacuum the residue was washed with aqueous NaHC03 (20 mL), extracted with EtOAc (3 x 20 mL), dried over Na2S04, and filtered. The organic layer was concentrated in vacuum to give crude title compound (260 mg, 54%) as oil, which was used in the next step directly.
Example 3B
[(2S,3aR,6aR)-2-[4-(lH-pyrazol- 1 -yl)piperidin- 1 -yl]hexahydropentalen-3a(lH)-yl] [3- (trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone The title compound was prepared and purified according to the procedure described in Example 1 J, substituting Example 3A for Example II. Ή NMR (400 MHz, CD3OD) δ ppm 8.67 (s, IH), 8.04 (s, IH), 7.64 (s, IH), 7.45 (s, IH), 6.26 (s, IH), 5.49 (s, IH), 4.82 (m, IH), 4.17 (m, IH), 3.95 (m, 2H), 3.35 (m, IH), 3.10 (m, 4H), 2.50 (m, 2H), 2.2 (m, 3H), 2.08 (m, 5H), 1.5 - 1.9 (m, 6H), 1.22 (m, IH); MS (ESI) m/z 488 (M+H)+.
Figure imgf000097_0001
Example 4
[3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)-yl][(2R,3aR,6aR)-2- {4-[3- (trifluoromethyl)- lH-pyrazol- 1 -yl]piperidin- 1 -yl}hexahydropentalen-3a(lH)- yl]methanone
Example 4A
tert-butyl 4-(methylsulfonyloxy)piperidine- 1-carboxylate To mixture of tert-butyl 4-hydroxypiperidine- 1 -carboxylate (20 g, 99 mmol) and Et3N (14 mL, 100 mmol) in dichloromethane (400 mL) was added methanesulfonyl chloride (8.5 mL, 110 mmol) at 0 °C. The reaction mixture was stirred at room temperature overnight and diluted with dichloromethane (50 mL). The organic layer was separated and the aqueous phase was extracted with dichloromethane (2 x 500 mL). The combined organic layers were dried over MgS04, filtered and concentrated. The crude product was used for next step without further purification.
Example 4B
Tert-butyl 4-(3-(trifluoromethyl)- lH-pyrazol- 1 -yl) piperidine- 1-carboxylate A mixture of Example 4A (10 g, 36 mmol), 3-(trifluoromethyl)- lH-pyrazole (5.36 g, 39 mmol) and K2C03 (9.89 g, 72 mmol) in DMF was stirred at 100 °C overnight. The reaction mixture was poured into water and extracted with EtOAc. The combined organic layers were dried over MgS04, filtered, and concentrated. The residue was purified by column chromatography (S1O2, petroleum ethenEtOAc = 15: 1) to give title compound (5.3 g, 46%) as yellow oil.
Example 4C
4-(3-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)piperidine To a solution of Example 4B (5.3 g, 16.6 mmol) in EtOAc (20 mL) was added
HC1 (g) in EtOAc (10 mL). The mixture was stirred at room temperature for 6 hours. The solvent was removed to result in the title compound as HCl salt, which was used for next step. MS (ESI+) m/z 294 (M+H)+.
Example 4D
[3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)-yl][(2R,3aR,6aR)-2- {4-[3- (trifluoromethyl)- lH-pyrazol- 1 -yl]piperidin- 1 -yl}hexahydropentalen-3a(lH)- yl]methanone
To a solution of Example 4C (160 mg, 0.67 mmol) and Example 1H (200 mg, 0.57 mmol) in dichloromethane (20 mL) was added Ti(i-OPr)4 (645 mg, 2.27 mmmol) and Ν,Ν-diisopropylethyl amine (300 mg, 2.27 mmol). The mixture was stirred at room temperature for 18 hours and NaBH4 (86 mg, 2.27 mol) and MeOH (0.5 mL) was added. The mixture was stirred for additional 4 hours, then poured into NH4OH (30 mL). The mixture was stirred for 1.5 hours and filtered. The filtrate was extracted with
dichloromethane (2 x 20 mL). The combined extracts were concentrated, and the residue was purified by preparative HPLC, followed by preparative chiral SFC to afford the title compound (5 mg, 1.5%). Ή NMR (300 MHz, CDC13) δ ppm 1.2 (m, 1H), 1.5 (m, 1H), 1.55 - 1.8 (m, 6H), 1.9 (m, 3 H), 2.0-2.2 (m, 5H), 2.75 (m, 1H), 2.93 - 3.1 1 (m, 4 H), 3.45 (m, 1 H), 3.73 - 3.96 (m, 2 H), 4.15 (m, 1 H), 4.7 (m, 2 H), 6.45 (d, J=2.4 Hz, l H), 7.39 (d, J=2.4 Hz, l H), 7.62 (s, 1 H), 8.62 (s, 1 H); MS (ESI+) m/z 556 (M+H)+.
The succinate salt of the above compound was prepared as follows:
A mixture of Example 4D (108 mg, 0.19 mmol), succinic acid (23 mg, 0.19 mmol) in MeOH (50 mL) was heated at 65 °C for 1 hour and then concentrated in vacuum. The residue was then washed by Et20 to afford off-white solid (130 mg, 86.4%). Ή-NMR (400 MHz, CD3OD): δ ppm 8.67 (s, 1H), 8.02 (s, 1H), 7.80(s, 1H), 6.57 (d, J=2.0 Ηζ,ΙΗ), 4.85 (m, 2H), 4.45 (m, 1H), 3.87 - 4.00 (m, 2H), 3.45 (m, 3H), 3.1 (m, 2H), 2.8 (m, 2H), 2.57 (m, 1H), 2.54 (s, 4H), 2,25 (m, 5H), 1.6 - 2.0 (m, 6H), 1.2 - 1.5 (m, 3H).
Figure imgf000098_0001
Example 5 1 - { 1 -[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)- yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}pyridin-2(lH)-one
Example 5A
l-(piperidin-4-yl)pyridin-2(lH)-one
Tert-butyl 4-(2-oxopyridin-l(2H)-yl)piperidine-l-carboxylate was prepared and purified according to the procedure described in Example 4B, substituting pyridin-2(lH)- one for 3-(trifluoromethyl)-lH-pyrazole.
The title compound was prepared and purified according to the procedure described in Example 4C, substituting tert-butyl 4-(2-oxopyridin- l(2H)-yl)piperidine- l- carboxylate for Example 4B. MS m/z 179 (M+H)+.
Example 5B
1 - { 1 -[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)- yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}pyridin-2(lH)-one The title compound was prepared and purified according to the procedure described in Example 1 J, substituting Example 5B for Example II. Ή NMR (400 MHz, CDC13) δ ppm 8.72 (s, 1H), 8.25 (m, 1H), 7.95 (m, 1H), 7.91 (s, 1H), 7.2 (m, 1H), 6.95 (d, J=5.75 Ηζ,ΙΗ), 5.15 (m, 1H), 4.70 (m, 2H), 3.9(m, 1H), 2.6 - 3.8(m, 2H), 3.5 (m, 3H), 3.1-3.4(m, 4H), 2.2 - 2.4 (m, 4H), 2.15 (m, 2H), 1.9 - 2.1 (m, 4H), 1.5 - 1.85 (m, 3H), 1.2 (m, 1H); MS (ESI) m/z 515 (M+H)+.
Figure imgf000099_0001
Example 6
[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl][(2R,3aR,6aR)-2- {4-[4- (trifluoromethyl)- lH-pyrazol- 1 -yl]piperidin- 1 -yl}hexahydropentalen-3a(lH)- yl]methanone
Example 6A
4-(4-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)piperidine Tert-butyl 4-(4-(trifluoromethyl)- lH-pyrazol- l-yl)piperidine-l-carboxylate was prepared and purified according to the procedure described in Example 4B, substituting 4-(trifluoromethyl)- lH-pyrazole for 3-(trifluoromethyl)- lH-pyrazole.
The title compound was prepared and purified according to the procedure described in Example 4C, substituting tert-butyl 4-(4-(trifluoromethyl)-lH-pyrazol-l- yl)piperidine- l-carboxylate for Example 4B.
Example 6B
[3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)-yl][(2R,3aR,6aR)-2- {4-[4- (trifluoromethyl)- lH-pyrazol- 1 -yl]piperidin- 1 -yl}hexahydropentalen-3a(lH)- yl]methanone
The title compound was prepared and purified according to the procedure described in Example 1 J, substituting Example 6A for Example II. Ή-NMR (400 MHz, CDC13) δ 8.73 (s, 1H), 7.72 (m, 3H), 4.80 (m, 2H), 4.20 (m, 1H), 3.9 - 4.05 (m, 2H), 3.55 (m, 1H), 3.1 - 3.2 (m, 4H), 2.88 (m, 1H), 2.13 - 2.39 (m, 6H), 1.8 - 2.1 (m, 3H), 1.8 - 1.90 (m, 6H), 1.35 (m, 1H); LC/MS (ESI+) m/z 556 (M+H)+.
Figure imgf000100_0001
Example 7
[(2R,3aR,6aR)-2-(4-phenoxypiperidin-l-yl)hexahydropentalen-3a(lH)-yl][3-
(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone The title compound was prepared and purified according to the procedure described in Example 1 J, substituting 4-phenoxypiperidine for Example II. Ή-NMR (400 MHz, CDCI3) δ 8.67 (s, 1H), 7.66 (s, 1H), 7.25 (m, 2H), 6.89 (m ,3H), 4.75 (m, 2H), 4.26 (m, 1H), 3.8 - 3.95 (m, 2H), 3.5 (m, 1H), 3.10 (m, 2H), 2.65 - 2.90 (m, 3H), 2.05 - 2.39 (m, 3H),1.92 (m, 4H), 1.6 - 1.85 (m, 6H), 1.5 (m, 1H), 1.05 - 1.35 (m, 2H); LC/MS (ESI+) m/z 514 (M+H)+.
Figure imgf000101_0001
Example 8
[(2R,3aR,6aR)-2-[4-(5 -methyl- 1 ,2,4-oxadiazol-3-yl)piperidin- 1 -yl]hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone
Example 8A1
(E)-tert-butyl 4-(N'-hydroxycarbamimidoyl)piperidine- 1 -carboxylate
To a solution of tert-butyl-4-cyanopiperidine-l -carboxylate (4.5 g ,21.4mmol) in water (65 mL) and methanol (65 mL) was added hydroxylamine hydrochloride (128 mmol) and Na2C(¾ (1 1.34 g). Then the mixture was heated under reflux for 5 hours with stirring. The solvent was removed under vacuum and the reaction mixtures were diluted with dichloromethane and the organic layer was separated, the water phase was extracted with methelenechlorise. The combined organic layers were washed with saturated brine, dried (MgS04), filtered, and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether:EtOAc=5: l) to give Example 8A1 in 75% yield as a white solid. MS m/z 246 (M+H)+.
Example 8A2
tert-butyl 4-(5-methyl- l,2,4-oxadiazol-3-yl)piperidine- 1-carboxylate
To a solution of Example 8A1 (2.6 g, 10.7mmol) in dichloromethane (100 mL) was added 4-(dimethylamino)pyridine (5.54 mmol), N-methylmorpholine (12.8mmol) , N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (12.8 mmol), and acetic acid (1 1.7 mmol). The reaction mixture was stirred at room temperature for 1 hour, washed with saturated brine, dried (MgS04), filtered, and concentrated. The residue was dissolved in toluene (30 mL) and heated under reflux for 24 hours. The reaction mixtures were washed with saturated brine, dried (MgS04), filtered, and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether:EtOAc=l : 1) to give example 8A2 in 45% yield as a white solid. MS m/z 268 (M+H)+.
Example 8A
5-methyl-3-(piperidin-4-yl)- 1 ,2,4-oxadiazole To a solution of Example 8A2 (0.57 mmol) (0.57 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (100 μΕ). The reaction mixture was atirred for 12 hours at room temperature. The mixtures were evaporated in vacuum to afford the Example 8A as trifluoroacetic acid salt.
Example 8B
[(2R,3aR,6aR)-2-[4-(5 -methyl- 1 ,2,4-oxadiazol-3-yl)piperidin- 1 -yl]hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone The title compound was prepared and purified according to the procedure described in Example 1J, substituting Example free base of 8A for Example II. Ή NMR (400 MHz, CDC13) δ ppm 8.7 (s, 1H), 7.7(s, 1H), 4.65 - 4.9 (m, 2H), 3.85 (m, 2H), 3.35 (m, 1H), 3.05 - 3.20 (m, 4H), 2.7 - 2.95 (m, 2H), 2.55 (s, 3H), 2.45 (m, 1H), 1.95 - 2.25 (m, 8H), 1.50 - 1.90 (m, 7H); MS (ESI) m/z 504 (M+H)+.
ABS
Figure imgf000102_0001
Example 9
[(2R,3aR,6aR)-2- {4-[3-(2-hydroxypropan-2-yl)phenyl]piperidin- 1 -yl}hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone
Example 9A1
tert-butyl 4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine- 1 (2H)-carboxylate Lithium bis(trimethylsilyl)amide (1 M, 40 mL) was added to a solution of tert- butyl-4-oxopiperidine- 1 -carboxylate (28 mmol) in dry THF (50 mL) at -78 °C under N2. The mixture was stirred at -78 °C for 1 hour. N-pheny-lbis(trifluoromethanesulfonimide) (28 mmol) was added as solid in one portion. The mixture was stirred at -78 °C for 1 hour. The solution was warmed up to room temperature over a period of 4 hours.
Saturated NaHC(¾ was added and the aqueous layer was extracted by dichloromethane (5 x 100 mL) and dried over Na2S04, filtered, and dried. The residue was purified by column chromatography on silica gel (petroleum ether: EtOAc =80: 1) to give Example 9A1 in 85% yield as yellow liquid.
Example 9A2 ethyl tert-butyl 4-(3-(ethoxycarbonyl)phenyl)-5,6-dihydropyridine- 1 (2H)-carboxylate To a solution of Example 9A1 (2.0g, 6 mmol) and 3- (ethoxycarbonyl)phenylboronic acid (1.6 g, 8.34 mmol), LiCl (1.0 g) and 2M Na2C(¾ solution (1 1 mL) in dimethoxy ethane (100 mL) was added Pd(PPl¾)4 and the resulting mixture was stirred at refluxing temperature for 30 hours under N2. The resulting mixture was cooled to room temperature, stirred overnight, and partially concentrated to remove most of DME. To the remaining aqueous mixture was added dichloromethane, 2M Na2C(¾ solution, and 10 mL NH3.H2O solution. The mixture was extracted with dichloromethane (5 x 300 mL), dried over Na2S04, filtered, and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether: EtOAc =40: 1) to give Example 9A2 in 85% yield as colorless liquid.
Example 9A3
ethyl tert-butyl 4-(3-(ethoxycarbonyl)phenyl)piperidine- 1 -carboxylate
A solution of Example 9A2 (1.0 g, 3.0 mmol) in EtOH (50 mL) was added Pd/C (0.1 g). Then the mixture was stirred at room temperature for 18 hours under 30 psi H2. The Pd/C was removed by filtration and the filtrate was concentrated in vacuum to afford Example 9A3.
Example 9A4
tert-butyl 4-(3-(2-hydroxypropan-2-yl)phenyl)piperidine- l-carboxylate To a solution of Example 9A3 (lg, 3mmol) in dry THF (20 mL) was added a solution of methyl magnesium bromide (14.8 mmol). The resulting mixture was stirred at -25 °C for 0.5 hour and then stired at room temperature overnight. The mixture was quenched with aqueous NH4C1, extracted with EtOAc, and concentrated. The residue was purified by column chromatography on silica gel to give Example 9A4 in 80% yield as an oil.
Example 9A
2-(3-(piperidin-4-yl) phenyl) propan-2-ol
To a solution of Example 9A4 (1 g, 3.13mmol) in dioxane was added a solution of dioxane/HCl (20 mL, 4N) and the mixture was a stirred at room temperature for 1 hour. The solvent was removed in vacuum and give Example 9A as HC1 salt in 90% yield as a white solid. MS m/z 220 (M+H)+.
Example 9B [(2R,3aR,6aR)-2- {4-[3-(2-hydroxypropan-2-yl)phenyl]piperidin- 1 -yl}hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]m
The title compound was prepared and purified according to the procedure described in Example 1J, substituting free base of Example 9A for Example II. Ή NMR (400 MHz, CDC13) δ ppm 8.65 (s, 1H), 7.7(s, 1H), 7.62 (s, 1H), 7.20 - 7.20 (m, 3H), 7.03 (m, 1H), 4.65 - 4.80 (m, 2H), 3.80 - 4.00 (m, 2H), 3.65 (m, 2H), 3.40 (m, 1H), 3.05 (m, 3H), 2.80 (m, 1H), 2.65 (m, 1H), 2.50 (m, 1H), 2.00 - 2.20 (m, 3H), 1.55 - 1.9 (m, 8H), 1.50 (s, 6H), 1.25 (m, 4H); MS (ESI) m/z 556(M+H)+.
Figure imgf000104_0001
Example 10
[(2R,3aR,6aR)-2-[4-(lH-pyrazol-l-yl)piperidin-l-yl]hexahydropentalen-3a(lH)-yl][3- (trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone The title compound was isolated from the procedure of Example 3B. Ή NMR (400 MHz, CD3OD): δ ppm 8.72 (s, 1H), 8.05 (s, 1H), 7.65 (s, 1H), 7.55 (s, 1H), 6.30 (s, 1H), 4.85 (m, 1H),4.5 (m, 1H), 3.90 - 4.04 (m, 2H), 3.75 (m, 2H), 3.4-3.52 (m, 2H), 3.20 (m, 3H), 2.75 (m, 1H), 2.45 (m 1H), 1.7 - 2.37 (m, 12H), 1.35 - 1.55 (m, 2H); MS (ESI) m/z 488(M+H)+ .
Figure imgf000104_0002
Example 1 1
[(2S,3aR,6aR)-2-(4-phenoxypiperidin-l-yl)hexahydropentalen-3a(lH)-yl][3- (trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone The title compound was isolated from the procedure of Example 7. Ή-NMR (400 MHz, CDCI3) δ ppm 8.65 (s, 1H), 7.63 (s, 1H), 7.22 (m, 2H), 6.85 (m ,3H), 4.75 (m, 2H), 4.25 (m, 1H), 3.85 (m, 2H), 3.38 (m, 1H), 3.10 (m, 2H), 2.65 - 2.850.(m, 2H), 2.2 - 2.5 (m, 3H), 2.12 (m, 1H), 1.95 (m, 3H), 1.8 (m, 4H), 1.5 - 1.7 (m, 5H), 1.20 (m, 1H); LC/MS
Figure imgf000105_0001
Example 12
1 - { 1 -[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)- yl]carbonyl} octahydropentalen-2-yl]piperidin-4-yl} - 1 ,2-dihydro-3H-pyrazol-3-one
Example 12A1
3-ethoxy- lH-pyrazole-4-carboxylic acid ethyl ester A mixture of 2-ethoxymethylene-malonic acid diethyl ester (38.9 g, 179 mmol) and hydrazine monohydrochloride (12.69 g, 185 mmol) in ethanol (500 mL) was refluxed overnight. The mixture was concentrated in vaccum to afford crude Example 12A1 (28 g) as a brown oil, which was used for the next step directly without further purification.
Example 12A2
3-ethoxy-lH-pyrazole
A mixture of Example 12A1 (28 g, 0.15 mol) in 6N HC1 (100 mL) was heated at reflux for 3 hours. After cooling to room temperature, the reaction mixture was partitioned between EtOAc (200 mL) and water (100 mL). The pH of the aqueous layer was adjusted to about 7 with solid NaHC(¾ and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with a IN solution of NaHC(¾, dried over Na2S04; filtered and concentrated in vaccum to give crude Example 12A2 (7.77 g, 38% for two steps) as an oil, which was used for the next step directly without further purification.
Example 12A3
4-(3-ethoxy-pyrazol-l-yl)-piperidine-l-carboxylic acid tert-butyl ester
To a solution of Example 4A (835 mg, 7.46 mmol) in DMF (20 mL) was added
NaH (0.43 g, 10.67 mmol) and Example 12A2 (2 g, 7.1 1 mmol) at room temperature. The mixture was stirred for 12 hours at 50 °C. TLC (petroleum ether: EtOAc = 1 : 1) indicated the reaction was completed. The reaction mixture was quenched with aqeous NHztCl (20 mL) and extracted with EtOAc (350 x mL). The organic layer was dried over
filtered, and concentrated in vacuum, the residue was purified by silica gel
chromatography to give Example 12A3 (1.2 g, 57%) as a colorless solid.
Example 12A4
4-(3-ethoxy-pyrazol- 1 -yl)-piperidine
A solution of Example 12 A3 (1.2 g, 4 mmol) in HC1 / EtOAc (4 N, 50 mL) was stirred at room temperature overnight. The reaction mixture was concentrated in vaccum to give the HC1 salt of Example 12A4 (420 mg, 54%) as a white solid.
Example 12A
1 -piperidin-4-yl- 1 ,2-dihydro-pyrazol-3-one
Example 12A4 (590 mg, 2 mmol) and 48% HBr (30 mL) was heated in a sealed flask at 140 °C for 4 hours. The solution was dispersed in water and treated with a saturated Na2C(¾ solution and the aqueous layer was extracted with EtOAc (100 mL). The organic layer was dried over Na2S04 and concentrated in vacuum, the residue was purified by chromatography on silica (petroleum ether / EtOAc = 100: 1 - 1 : 1) to give Example 12A (207 mg, 62%) as a colorless oil.
Example 12B
1 - { 1 -[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)- yl]carbonyl} octahydropentalen-2-yl]piperidin-4-yl} - 1 ,2-dihydro-3H-pyrazol-3-one The title compound was prepared and purified according to the procedure described in Example 1 J, substituting Example 12A for Example II. Ή NMR (400 MHz, CDC13) δ ppm 8.63 (s, 1 H), 7.62 (s, 1 H), 7.09 (d, J=2.4 Hz, l H), 5.5 (d, J= 2.4Hz, l H), 4.7 (m, 2 H), 3.8 (m, 3 H), 3.45 (m, 1 H), 2.95 - 3.1 (m, 4H), 2.8 (m, 1H), 1.770 - 2.20 (m, 14 H), 1.50 (m, 2H), 1.35 (m, 1H); MS (ESI) m/z 504 (M+H)+.
Figure imgf000106_0001
Example 13 [3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl][(2S,3aR,6aR)-2- {4-[4- (trifluoromethyl)- lH-pyrazol- 1 -yl]piperidin- 1 -yl}hexahydropentalen-3a(lH)- yl]methanone
The title compound was isolated from the procedure of Example 6B. Ή-NMR (400 MHz, CDC13) δ ppm 8.70 (s, 1H), 7.68 (s, 3H), 4.65 - 4.86 (m, 2H), 4.15 (m, 1H), 3.90 (m, 2H), 3.40 (m, 1H), 3.05 - 3.15 (m, 4H), 2.45 - 2.50 (m, 2H), 1.90 - 2.20 (m, 7H), 1.52 - 1.87 (m, 7H) ,1.20 (m, 1H); LC/MS (ESI+) m/z 556 (M+H)+.
Figure imgf000107_0001
Example 14
ethyl 1 - { 1 - [(2R,3aR,6aR)-3a- { [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)- yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}-lH-pyrazole-3-carboxylate
Example 14A1
lH-Pyrazole-3-carboxylic acid ethyl ester
To a solution of lH-pyrazole-3-carboxylic acid (2.0 g, 17.8 mmol) in anhydrous ethanol (20 mL) was added concentrated H2SO4 (1 mL) at room temperature. The mixture was refluxed for 12 hours. TLC (neat EtOAc) indicated that the reaction was completed. The mixture was concentrated, the residue was washed with aqueous NaHC03 (20 mL), extracted with dichloromethane (50 mL x 3). The organic layer was dried over Na2S04, filtered, and concentrated in vacuum to give Example 14A1 (1.8 g, yield 72%) as a white solid.
Example 14A2
4-(3-Ethoxycarbonyl-pyrazol- l-yl)-piperidine-l-carboxylic acid tert-butyl ester A mixture of Example 14A1 (1 g, 3.55 mmol), Example 4A (0.498 g, 3.55 mmol) and K2CO3 (1.47 g, 10.67 mmol) in DMF (20 mL) was heated at 70 °C for 12 hours. TLC (Petroleum ether: EtOAc = 4: 1) indicated that the reaction was completed. The reaction mixture was filtered and the filtrate was concentrated in vacuum and the residue was purified by chromatography on silica to give Example 14A2 (0.65 g, 56.5 %) as a colorless solid.
Example 14A
ethyl l-(piperidin-4-yl)-lH-pyrazole-3-carboxylate To a solution of Example 14A2 (0.65 g, 2.0 mmol) in dichloromethane (5 mL) was added HCl(g)/methanol (20 mL) dropwise at room temperature. The resulting mixture was stirred for 1.5 hours at room temperature. TLC indicated that the reaction was completed. The reaction mixture was concentrated in vacuum to give the HC1 salt of Example 14A (400 mg, 89%) as a white solid.
Example 14B
ethyl l- { l-[(2R,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)- yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}-lH-pyrazole-3-carboxylate The title compound was prepared and purified according to the procedure described in Example 1J, substituting free base of Example 14A for Example II. Ή- NMR (400 MHz, CD3OD) δ ppm 8.65 (s, 1H), 8.02 (s, 1H), 7.50 (s, 1H), 6.82 (s, 1H), 5.45 (m, 1H), 4.80 (m, 2H), 4.28 (m, 2H), 3.965 - 4.0 (m, 4H), 3.50 (m, 1H), 3.22 (m, 1H), 3.10 (m, 2H), 2.70 (m, 1H), 1.8 - 2.4 (m, 12H), 1.75 (m, 1H), 1.50 (m, 1H) ,1.3 (m, 4H); LC/MS (ESI+) m/z 560 (M+H)+.
A
Figure imgf000108_0001
Example 15
3-{ l-[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)- yl]carbonyl} octahydropentalen-2-yl]piperidin-4-yl}benzoic acid
Example 15A
ethyl 3-(piperidin-4-yl)benzoate
The title compound was prepared and purified according to the procedure described in Example 4C, substituting Example 9A3 for Example 4B.
Example 15B ethyl 3-(l-((2R,3aR,6aR)-3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-l,6-naphthyridine-6- carbonyl)octahydropentalen-2-yl)piperidin-4-yl)benzoate The title compound was prepared and purified according to the procedure described in Example 1J, substituting free base of Example 15A for Example II.
Example 15C
3-{ l-[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)- yl]carbonyl} octahydropentalen-2-yl]piperidin-4-yl}benzoic acid To a solution of Example 15B (0.65 g, 1.14 mmol) in ethanol (5 mL) and water (3 mL) was added LiOH.ELO (191 mg, 4.56 mmol) in one portion. The mixture was stirred for 12 hours at room temperature. TLC (MeOH: CH2CI2 = 1 : 15) indicated the reaction was complete. The mixture was acidified by 0.5 N aqueous HC1 to adjust the pH to about 5, extracted with dichloromethane (3 x 30 mL). The organic layer was dried over Na2S04, filtered, and concentrated to give the title compound (600 mg, 97 %) as light yellow solid. Ή NMR (400 MHz, CD3OD) δ ppm 8.69 (s, 1H), 8.04 (s, 1H), 7.88 (m, 2H), 7.45 (m, 2H), 3.50 - 4.1 (m, 7H), 3.18 (m, 4H), 2.99 (m, 1H), 2.75 (m, 1H), 1.85 - 2.20 (m, 10H), 1.78 (m, 1H), 1.55 (m, 1H), 1.40 (m, 1H), 1.12 (m, 1H); MS (ESI) m/z 542 (M+H)+.
Figure imgf000109_0001
Example 16
[(2S,3 aR,6aR)-2- [4-(3 -ethoxy- 1 H-pyrazol- 1 -yl)piperidin- 1 -yl]hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone The title compound was prepared and purified according to the procedure described in Example 1J, substituting free base of Example 12A4 for Example II. Ή NMR (400 MHz, CDC13) δ ppm 8.63 (s, 1 H), 7.62 (s, 1 H), 7.13 (d, J= 2.4 Hz, 1 H), 5.54 (d, J= 2.4 Hz, 1 H), 4.62 - 4.76 (m, 2 H), 4.071 (m, 2 H), 3.84 (m, 3 H), 3.35 (m, 1 H), 3.05 (m, 3 H), 2.95 (m, 1H), 2.3 - 2.45 (m, 2 H), 2.0 - 2.2 (m, 5H), 1.55 - 1.95 (m, 9 H), 1.48 (m, 1 H), 1.346 (m, 3 H); MS (ESI) m/z 532 (M+H)+.
Figure imgf000110_0001
Example 17
[(2R,3aR,6aR)-2-[4-(3-phenyl- l,2,4-oxadiazol-5-yl)piperidin-l-yl]hexahydropentalen- 3a(lH)-yl][3-(trinuoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone
Example 17A1
1 -(2,2,2-trifluoroacetyl)piperidine-4-carboxylic acid To a solution of piperidine-4-carboxylic acid (4 g , 30.97mmol) in
dichloromethane (20 mL) was added dropwise triflate anhydride(7.8g). The resulting mixture was stirred at 0 °C overnight. Upon dilution with water, the combined organic layers were concentrated. The residue was purified by column chromatography on silica gel to give Example 17A1 in 70% yield as a white solid.
Example 17A2
2,2,2-trifluoro- 1 -(4-(3-phenyl- 1 ,2,4-oxadiazol-5-yl)piperidin- 1 -yl)ethanone To a solution of Example 17A1 (3 g , 133mmol) in dichloromethane (60 mL) was added (Z)-N'-hydroxybenzimidamide (2g) and N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (3.06g). The resulting mixture was stirred at room temperature overnight. The reaction mixture was washed with saturated brine, dried (MgS04), filtered, and concentrated and the crude product was purified by column chromatography on silica gel to give Example 17A2 in 80% yield as a white solid. MS m/z 326 (M+H)+.
Example 17A
3-phenyl-5-(piperidin-4-yl)- 1 ,2,4-oxadiazole To a solution of Example 17A2 (lg, 3.077mmol) in EtOH (20 mL) was added NaOH (4.62 mmol, 2 M). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture were diluted with water and extracted with dichloromethane. The combined organic layers were washed with saturated brine and dried. After removal of solvent in vavcuum, the residue was purified by column chromatography on silica gel (petroleum ethenEtOAc =1 : 1) to give Example 17A in 70% yield as a white solid. MS m/z 230 (M+H)+. Example 17B
[(2R,3aR,6aR)-2-[4-(3-phenyl- l,2,4-oxadiazol-5-yl)piperidin-l-yl]hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]metha
The title compound was prepared and purified according to the procedure described in Example 1J, substituting Example 17A for Example II. Ή NMR (400 MHz, CDC13) δ ppm 8.63 (s, 1 H), 7.98 (m, 2 H), 7.65 (s, 1H), 7.40 (m, 3H), 4.70 (m, 2 H), 3.80 (m„ 2 H), 3.35 (m, 1 H), 2.88 - 3.10 (m, 5 H), 2.30 - 2.50 (m, 2 H), 1.55 - 2.17 (m, 13 H), 1.49 (m, 1 H), 1.16 (m, 1 H); MS (ESI) m/z 566 (M+H)+.
ABS
Figure imgf000111_0001
Example 18
[(2S,3aR,6aR)-2-{4-[3-(2-hydroxypropan-2-yl)phenyl]piperidin- l-yl}hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone The title compound was isolated from the procedure of Example 9B. Ή NMR (400 MHz, CDCI3) δ ppm 8.68 (s, 1 H), 7.625 (s, 1 H), 7.35 (s, 1H), 7.25 (m, 2 H), 7.10 (m, 1H), 4.70 (m, 2 H), 3.90 (m, 2 H), 3.40 (m, 1 H), 3.00 - 3.20 (m, 5 H), 2.35 - 2.50 (m, 3 H), 1.60 - 2.15 (m, 14 H), 1.52 (s, 6 H), 1.25 (m, 1 H); MS (ESI) m/z 556 (M+H)+.
Figure imgf000111_0002
Example 19
[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl][(2S,3aR,6aR)-2-{4-[3- (trifluoromethyl)- lH-pyrazol- 1 -yl]piperidin- 1 -yl}hexahydropentalen-3a(lH)- yl]methanone
The title compound was isolated from the procedure of Example 4D. Ή NMR (300 MHz, CDCI3) δ ppm 1.15 (m, 1H), 1.45 - 2.17 (m, 14 H), 2.3 - 2.5 (m, 2H), 2.93 - 3.1 1 (m, 4 H), 3.35 (m, 1 H), 3.85 (m, 2 H), 4.12 (m, 1 H), 4.62 - 4.86 (m, 2 H), 6.45 (d, J= 2.0 Hz, l H), 7.4 (d, J=2.0 Hz, 1 H), 7.62 (s, 1 H), 8.62 (s, 1 H); MS (ESI) m/z 556 (M+H)+.
Figure imgf000112_0001
Example 20
1 - { 1 -[(2S,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)- yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}pyridin-2(lH)-one The title compound was isolated from the procedure of Example 5B. Ή NMR (400 MHz, CDC13) δ ppm 1.25 (m, 1 H), 1.6 (m, 1 H), 1.8 (m, 2 H), 1.85 - 2.5 (m, 1 1 H), 3.1 - 3.5 (m, 6 H), 3.6 - 3.95 (m, 3H), 4.8 (s, 2 H), 5.1 (s, 1 H), 6.9 (m, 1 H), 7.2 (m, 1H), 7.9 (m, 2H), 8.25 (m, 1H), 8.75 (s, 1H); MS (ESI) m/z 515 (M+H) +.
Figure imgf000112_0002
Example 21
[(2R,3aR,6aR)-2-[4-(3,5-dimethyl-4H- 1 ,2,4-triazol-4-yl)piperidin- 1 - yl]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-
6(5H)-yl]methanone
Example 21 A
N-(l-benzyl-piperidin-4-yl)-acetamide
To a solution of 1 -benzyl-piperidin-4-ylamine (8.0 g, 42 mmol) and Et3N (9.1 1 mL, 0.26 mol) in dichloromethane (40 mL) was added acetyl chloride (3.02 g, 44 mmol) dropwise at about 0 °C -10 °C. The mixture was stirred for 12 hours at room temperature. TLC (Petroleum ethenEtOAc = 1 : 1) indicated that the reaction was completed. The mixture was washed with aqueous 0.1 N HC1 (50 mL), extracted with EtOAc (3 x 100 mL). The pH of the aqueous layer was adjusted to about 10 and extracted with EtOAc (3 x 100 mL). The organic layer was dried over Na2S04, filtered, and concentrated in vacuum to give Example 21A (5.3 g, yield 54.25%).
Example 2 IB
N-( 1 -benzyl-piperidin-4-yl)-acetimidoyl chloride To a solution of Example 21A (1.0 g, 4.3 mmol) and pyridine (2 mL) in chloroform (15 mL) was added POCI3 (1.2 mL) dropwise at about 0 °C -10 °C. The mixture was stirred for 12 hours at room temperature. TLC (Petroleum ethenEtOAc = 1 : 1) indicated that the reaction was completed. The mixture was concentrated in vacuum to give Example 21B (1.1 g).
Example 21C
(Z)-N'-(l -(1 -benzylpiperidin-4-ylimino)ethyl)acetohydrazide A mixture of Example 21B (1.1 g, 4.38 mmol) and acetic acid hydrazide (0.389 g, 5.26 mmol) in chloroform (10 mL) was refluxed for 5 hours. TLC (Petroleum
ether :EtOAc = 1 : 1) indicated that the reaction was completed. The mixture was washed with aqueous NaHC(¾ (50 mL), extracted with dichloromethane (3 x 50 mL). The organic layer was dried over Na2S04, filtered, and concentrated in vacuum to give crude Example 21C (1.2 g).
Example 2 ID
l-Benzyl-4-(3,5-dimethyl-[l,2,4]triazol-4-yl)-piperidine A mixture of Example 21C (1.1 g, 4.38 mmol) in 6 N HQ (20 mL) was refluxed for 12 hours. The mixture was washed with aqueous NaOH solution, extracted with EtOAc (3 x 20 mL). The organic layer was dried over Na2S04, filtered, and concentrated in vacuum. The residue was purified by chromatography on silica to give Example 2 ID (0.234 g, yield: 20.8%).
Example 2 IE
4-(3,5-Dimethyl-[l,2,4]triazol-4-yl)-piperidine Example 21D (0.234 g, 0.856 mmol), Pd(OH)2/C (100 mg) in EtOH (20 mL) was hydrogenation under under 40 psi of ¾ for 12 hours at 40 °C. TLC (MeOH :
dichloromethane = 1 :8 ) indicated the reaction was complete, the mixture was filtered and the filtrate was concentrated in vacuum. The residue was dried to give Example 21E (140 mg, 89.7%).
Example 21 F [(2R,3aR,6aR)-2-[4-(3,5-dimethyl-4H- 1 ,2,4-triazol-4-yl)piperidin- 1 - yl]hexahydropentalen-3a( 1 H)-yl] [3-(trifl^
6(5H)-yl]methanone
The title compound was prepared and purified according to the procedure described in Example 1 J, substituting Example 21E for Example II. Ή NMR (400 MHz, CD3OD) δ ppm 8.69 (s, 1H), 8.05 (s, 1H), 4.81 (m, 2H), 4.10 (m, 1H), 3.94 (m, 2H), 3.35 (m, 2H), 3.05 - 3.25 (m, 4H), 2.53 (m, 1H), 2.50 (s, 6H), 2.05 - 2.3 (m, 6H), 1.60 - 1.95 (m, 7H), 1.56 (m, 1H), 1.25 (m, 1H); MS (ESI) m/z 517 (M+H)+.
Figure imgf000114_0001
Example 22
1 - { 1 -[(2S,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)- yl]carbonyl} octahydropentalen-2-yl]piperidin-4-yl} - 1 ,2-dihydro-3H-pyrazol-3-one The title compound was isolated from the procedure of Example 12B. Ή NMR (400 MHz, CDCI3): δ ppm 8.63 (s, 1 H), 7.63 (s, 1 H), 7.13 (d, J=2.4 Hz,l H), 5.58 (d, J=2.4 Hz,l H), 4.7 (m, 2 H), 3.83 (m, 3 H), 3.35 (m, 3 H), 3.05 (m, 2H), 2.40 (m, 2H), 1.95 - 2.20 (m, 9H), 1.50 - 1.85 (m, 6H), 1.20 (m, 1H); MS (ESI) m/z 504 (M+H)+ .
Figure imgf000114_0002
Example 23
(2- { 1 -[(2S,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)- yl]carbonyl} octahydropentalen-2-yl]piperidin-4-yl}phenyl)acetic acid
Example 23 A 1 tert-butyl 4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine- 1 (2H)- carboxylate
To a mixture of Example 9A1 (2 g, 6mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bi(l,3,2-dioxaborolane) (1.6 g, 7.2 mmol) and Na2CC"3 (2.5 g, 4 equivalents) in THF (25 mL) was added under nitrogen atmosphere PdCi2(dppf) (49 mg, 0.01 equivalent). The mixture was refreshed with nitrogen three times. The reaction mixture was stirred at 80 °C for 12 hours. The mixture was concentrated in vacuum and purified by column chromatography on silica gel to afford Example 23A1 (1.2 g).
Example 23A2
tert-Butyl 4-(2-(2-ethoxy-2-oxoethyl)phenyl)-5,6-dihydropyridine- 1 (2H)-carboxylate To a solution of ethyl 2-(2-bromophenyl)acetate (2480 mg, 2 mmol) and Example 23 Al (309 mg, 1.0 mmol), K2C03 (552 mg, 4 mmol) in DMF (15 ml) was added Pd(PPl¾)4 (12 mg, 0.01 mmol), the mixture was refreshed with nitrogen three time, and was heated with stirring at 80 °C for 14 hours under N2 condition. The reaction mixture was treated with EtOAc (25mL) and water (10 mL). The organic layer was separated and concentrated in vacuum, the crude product was purified by column chromatography on silica to give Example 23A2 (240 mg).
Example 23A3
tert-butyl 4-(2-(2-ethoxy-2-oxoethyl)phenyl)piperidine- 1 -carboxylate
To a solution of Example 23 A2 (240 mg, 0.7 mmol) in EtOH (10 mL) was added Pd/C (0.1 g). Then the mixture was stirred at 60 °C for 12 hours under ¾ (30 psi). The Pd/C was removed by filtration and the filtrate was evaporated in vacuum to afford Example 23A3 (240 mg).
Example 23A
ethyl 2-(2-(piperidin-4-yl)phenyl)acetate
To a solution of Example 23 A3 (240 mg, 0.7 mmol) in dioxane (1 mL) was added a solution of dioxane/HCl (10 mL, 4N) and the mixture was a stirred at room temperature overnight and concentrated to give the hydrochloride salt of Example 23 A( 170 mg).
Example 23B
ethyl 2-(2-(l-((2S,3aR,6aR)-3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro- l,6-naphthyridine- 6-carbonyl)octahydropentalen-2-yl)piperidin-4-yl)phenyl)acetate The title compound was prepared and purified according to the procedure described in Example 1J, substituting free base of Example 23 A for Example II. Example 23 C
(2- { 1 -[(2S,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)- yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}phenyl)acetic acid The title compound was prepared and purified according to the procedure described in Example 15C, substituting Example 23B for Example 15B. Ή NMR (400 MHz, CDC13) 8.69 (s, 1H), 7.71(s, 1H), 7.05-7.25 ( m, 4H), 4.75 (m, 2H), 3.82 (m, 1H), 3.55 (m, 2H), 3.35 (m, 3H), 3.10 (m, 2H), 2.85 - 3.05 (m, 2H), 2.25 - 2.55 (m, 3H), 1.95 - 2.17 (m, 4H), 1.60 - 1.90 (m, 7H), 1.55 (m, 1H), 1.25 (m, 2H); MS (ESI) m/z 556 (M+H)+.
Figure imgf000116_0001
Example 24
[(2R,3aR,6aR)-2-[4-(3-isopropyl-5-methyl-4H- l,2,4-triazol-4-yl)piperidin-l- yl]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-
6(5H)-yl]methanone
Example 24A 1
(Z)-N'-( 1 -(1 -benzylpiperidin-4-ylimino)ethyl)isobutyrohydrazide The title compound was prepared and purified according to the procedure described in Example 21 C, substituting isobutyrohydrazide for acetic acid hydrazide.
Example 24A2
1 -benzyl-4-(3-isopropyl-5-methyl-4H- 1 ,2,4-triazol-4-yl)piperidine The title compound was prepared and purified according to the procedure described in Example 2 ID, substituting Examle 24A1 for Example 21C.
Example 24A
4-(3-isopropyl-5-methyl-4H- 1 ,2,4-triazol-4-yl)piperidine The title compound was prepared and purified according to the procedure described in Example 2 IE, substituting Examle 24A2 for Example Example 2 ID.
Example 24B [(2R,3aR,6aR)-2-[4-(3-isopropyl-5-methyl-4H- l,2,4-triazol-4-yl)piperidin-l- yl]hexahydropentalen-3a( 1 H)-yl] [3-(trifl^
6(5H)-yl]methanone
The title compound was prepared and purified according to the procedure described in Example 1 J, substituting Example 24A for Example II. Ή NMR (400 MHz, CD3OD) δ ppm 8.70 (s, 1H), 8.05 (s, 1H), 4.90 (m, 1H), 4.78 (m, 3H), 4.03 (m, 1H), 3.75 - 3.92 (m, 4H), 3.55 (m, 1H), 3.45 (m, 1H), 3.15 (m, 2H), 2.74 (m, 1H), 2.72 (s, 3H), 2.55 (m, 2H), 2.35 (m, 2H), 2.10 - 2.29 (m ,3H), 2.00 (m, 3H), 1.80 (m, 1H), 1.55 (m, 1H), 1.45 (m, 8H); MS (ESI) m/z 545 (M+H)+.
Figure imgf000117_0001
Example 25
[(2R,3aR,6aR)-2-[4-(3-ethoxy- lH-pyrazol- l-yl)piperidin-l-yl]hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone The title compound was obtained from the procedure of Example 16. Ή NMR (400 MHz, CDCI3) δ ppm 8.63 (s, 1 H), 7.62 (s, 1 H), 7.20 (d, J= 2.4 Hz, 1 H), 5.54 (d, J= 2.4 Hz, 1 H), 4.6 (m, 2 H), 4.071 (q, J=3 Hz, 2 H), 3.84 (m, 2 H), 3.45 (m, 4 H), 3.05 (m, 2H), 2.45 (m, 3 H), 2.0 - 2.3 (m, 7H), 1.7 (m, 4 H), 1.5 (m, 1 H), 1.33 (t, J= 3Hz, 3 H), 1.2 (m, 2H); MS (ESI) m/z 532 (M+H)+.
Figure imgf000117_0002
Example 26 [(2S,3aR,6aR)-2-{4-[3-(lH-tetrazol-5-yl)phenyl]piperidin-l-yl}hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone
Example 26A 1
tert-butyl 4-(3-cyanophenyl)-5,6-dihydropyridine- 1 (2H)-carboxylate
To a solution of Example 9A1 (13.6 g , 41.09 mmol) in dimethoxyethane (60 mL) was added 3-cyanophenylboronic acid (6 g), Na2C(¾ (40 mL, 2 M), and Pd(PPtt3)4 (1.5 g). The resulting mixture was stirred under nitrogen and heated under reflux overnight. The reaction mixture was treated with EtOAc (25 mL) and water (10 mL). The organic layer was separated and concentrated in vacuum. The crude product was purified by column chromatography on silica gel (petroleum ether :EtOAc =10: 1) to afford Example 26A1 in 75% yield as a white solid. MS m/z 285 (M+H)+.
Example 26A2
tert-butyl 4-(3-(lH-tetrazol-5-yl)phenyl)-5,6-dihydropyridine- l(2H)-carboxylate To a solution of Example 26A1 (4 g, 14 mmol) in DMF (20 mL) was added NaN3 (1.36 g), and NH4Cl (1.2g, 22.43mmol). The resulting mixture was stirred and heated under reflux overnight, cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic layers were washed with saturated brine and dried over Na2S04, filtered, and concentrated. The residue was purified by column chromatography on silica gel (petroleum ethenEtOAc = 10: 1) to give Example 26A2 in 80% yield as a white solid. MS m/z 328 (M+H)+.
Example 26A3
tert-butyl 4-(3 -( 1 H-tetrazol-5 -yl)phenyl)piperidine- 1 -carboxylate A solution of Example 26A2 (1.5 g , 4.59 mmol) in EtOH (50 mL) was added Pd(OH)2 (0.1 g). Then the mixture was stirred at 45 °C for 18 hours under ¾ (30 psi). The Pd(OH)2 was removed by filtration and rinsed with EtOH (10 mL). The filtrate was concentrated in vacuum to give Example 26A3 in 90% yield. MS m/z 330 (M+H)+.
Example 26A
4-(3 -( 1 H-tetrazol-5 -yl)phenyl)piperidine
A solution of Example 26A3 (2 g , 6.1 mmol) in dioxane/HCl (50 mL) was a stirred at room temperature for lhour and concentrated in vaccum and give Example 26A in 90% yield as a white solid as a HC1 salt. MS m/z 230 (M+H)+.
Example 26B [(2S,3aR,6aR)-2-{4-[3-(lH-tetrazol-5-yl)phenyl]piperidin-l-yl}hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone The title compound was prepared and purified according to the procedure described in Example 1J, substituting free base of Example 26A for Example II. Ή NMR (400 MHz, CD3OD) δ ppm 8.7 (s, 1 H), 8.10 (s, 1H), 8.0 (s, 1H), 7.87 (m, 1 H), 7.50 - 7.60 (m, 2 H), 4.90 (m, 2H), 3.95 (m, 2H), 3.80 (m, 2 H), 3.45 (m, 3 H), 3.15 (m, 3 H), 3.05 (m, 1H), 2.78 (m, 1 H), 2.50 (m, 1H), 2.25 (m, 3H), 2.05 (m, 3H), 1.75 - 1.95 (m, 4 H), 1.65 (m, 1H), 1.52 (m, 1 H); MS (ESI) m/z 566 (M+H)+.
Figure imgf000119_0001
Example 27
2-{ l-[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)- yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}pyridazin-3(2H)-one The title compound was isolated from the procedure of Example 1J. Ή NMR (400 MHz, CDCI3). δ ppm 8.7 (s, 1H), 7.82 (m, 2H), 7.2 (m, 1H), 6.93 (m, 1H), 5.09 (m, 1H), 4.75 (m, 2H), 3.65 - 3.96 (m, 3H), 3.45 - 3.6 (m, 2H), 3.1 - 3.3 (m, 2H), 2.75 - 2.95 (m, 2H), 2.20 - 2.55 (m, 5H), 2.05 (m, 4H), 1.90 (m, 1H), 1.62 - 1.820 (m, 3H), 1.55 (m, 1H), 1.2 (m, 1H); MS (ESI) m/z 516 (M+H)+.
Figure imgf000119_0002
Example 28
[(2S,3aR,6aR)-2-[4-(5-methyl- 1 ,2,4-oxadiazol-3-yl)piperidin- 1 -yl]hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone The title compound was obtained as a side product of Example 8B. Ή NMR (400 MHz, CDCI3) δ ppm 8.7 (s, 1H), 7.7 (s, 1H), 4.65 - 4.9 (m, 2H), 3.87 (m, 2H), 3.35 (m, 1H), 3.10 - 3.20 (m, 4H), 2.7 - 2.95 (m, 2H), 2.55 (s, 3H), 2.45 (m, 1H), 1.93 - 2.25 (m, 8H), 1.50 - 1.90 (m, 7H); MS (ESI) m/z 504 (M+H)+.
Figure imgf000120_0001
Example 29
2- { 1 -[(2S,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)- yl]carbonyl} octahydropentalen-2-yl]piperidin-4-yl}benzoic acid
Example 29A 1
tert-butyl 4-(2-(methoxycarbonyl)phenyl)-5,6-dihydropyridine- 1 (2H)-carboxylate The title compound was prepared and purified according to the procedure described in Example 9A2, substituting 2-(methoxycarbonyl)phenylboronic acid for 3- (ethoxycarbonyl)phenylboronic acid.
Example 29A2
tert-butyl 4-(2-(methoxycarbonyl)phenyl)piperidine- 1 -carboxylate The title compound was prepared and purified according to the procedure described in Example 9A3, substituting Example 29A1 for Example 9A2.
Example 29A
methyl 2-(piperidin-4-yl)benzoate
The HC1 salt of the title compound was prepared and purified according to the procedure described in Example 4C, substituting Example 29A2 for Example 4B.
Example 29B
methyl 2-(l -((2S,3aR,6aR)-3a-(3-(triiluoromethyl)-5,6,7,8-tetrahydro- 1 ,6-naphthyridine- 6-carbonyl)octahydropentalen-2-yl)piperidin-4-yl)benzoate The title compound was prepared and purified according to the procedure described in Example 1J, substituting free base of Example 29A for Example II.
Example 29C
2- { 1 -[(2S,3aR,6aR)-3a- {[3-(triiluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)- yl]carbonyl} octahydropentalen-2-yl]piperidin-4-yl}benzoic acid The title compound was prepared and purified according to the procedure described in Example 15C, substituting Example 29B for Example 15B. Ή NMR (400 MHz, CDCI3) δ ppm 8.71 (s, 1H), 7.89 (d, J=7.6 Ηζ, ΙΗ), 7.73 (s, 1H), 7.44 (m ,2H), 7.23 (s, 1H), 4.77 (m, 2H), 3.90 (m, 2H), 3.60-3.80 (m, 4H), 3.37 (m, 1H), 3.10 - 3.20 (m, 3H), 2.65 - 2.85 (m, 2H), 2.36 - 2.58 (m, 2H), 2.3 (m, 1H), 2.17 (m, 1H), 1.90 - 2.10 (m, 4H), 1.58 - 1.90 (m, 4H), 1.3 (m, 1H); MS (ESI) m/z 542 (M+H)+.
Figure imgf000121_0001
Example 30
2-{ l-[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)- yl]carbonyl} octahydropentalen-2-yl]piperidin-4-yl}benzoic acid
Example 3 OA
methyl 2-(l-((2R,3aR,6aR)-3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-l,6-naphthyridine- 6-carbonyl)octahydropentalen-2-yl)piperidin-4-yl)benzoate The title compound was isolated from the procedure of Example 29B.
Example 30B
2-{ l-[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)- yl]carbonyl} octahydropentalen-2-yl]piperidin-4-yl}benzoic acid The title compound was prepared and purified according to the procedure described in Example 15C, substituting Example 30A for Example 15B. Ή NMR (400 MHz, CD3OD) δ ppm 8.70 (s, 1H), 8.05 (s, 1H), 7.86 (d, J=8.0 Ηζ,ΙΗ), 7.52 (m, 1H), 7.38 (d, J=8.0Hz, 1H), 7.32 (m, 1H), 4.80 (m, 2H), 4.02 (m, 1H), 3.93 (m, 1H), 3.82 (m, 2H), 3.68 (m, 2H), 3.55 (m, 1H), 3.10 - 3.20 (m, 3H), 2.72 (m, 1H), 1.85 - 2.18 (m, 1 1H), 1.75 (m, 1H), 1.55 (m, 1H), 1.39 (m, 1H); MS (ESI) m/z 542 (M+H)+.
Figure imgf000122_0001
Example 31
3- { 1 -[(2S,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)- yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}benzoic Acid
Example 31A
ethyl 3-(l-((2S,3aR,6aR)-3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-l,6-naphthyridine-6 carbonyl)octahydropentalen-2-yl)piperidin-4-yl)benzoate The title compound was isolated from the procedure of Example 15B.
Example 3 IB
3-{ l-[(2S,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)- yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}benzoic Acid The title compound was prepared and purified according to the procedure described in Example 15C, substituting Example 31A for Example 15B. Ή NMR (400 MHz, CD3OD) δ ppm 8.70 (s, 1H), 8.05 (s, 1H), 7.92 (m, 2H), 7.45 - 7.55 (m, 2H), 4.85 (m, 2H), 3.98 (m, 2H), 3.975 (m, 2H), 3.45 (m, 2H), 3.15 (m, 3H), 2.99 (m, 1H), 2.75 (m 1H), 2.748 (m, 1H), 1.70 - 2.24 (m, 1 1H), 1.55 - 1.70 (m, 2H); MS (ESI) m/z 542 (M+H)+.
ABS
Figure imgf000122_0002
Example 32
1 - { 1 -[(2S,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)- yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}-lH-pyrazole-3-carboxylic acid
Example 32A ethyl 1 -(1 -((2S,3aR,6aR)-3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro- 1 ,6-naphthyridine-6- carbonyl)octahydropentalen-2-yl)piperidin-4-yl)- lH-pyrazole-3-carboxylate The title compound was isolated from the procedure of Example 14B.
Example 32B
1 - { 1 -[(2S,3aR,6aR)-3a- {[3-(trifiuoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)- yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}-lH-pyrazole-3-carboxylic acid The title compound was prepared and purified according to the procedure described in Example 15C, substituting Example 32A for Example 15B. Ή NMR (400 MHz, CD3OD) δ ppm 8.70 (s, 1H), 8.05 (s, 1H), 7.55 (d, J=2.0Hz, 1H), 6.86 (s, 1H), 4.80 (m, 2H), 3.95 (m, 2H), 3.75 (m, 1H), 3.40 (m, 2H), 3.10 - 3.30 (m, 4H), 2.72 (m, 1H), 2.02 - 2.50 (m, 8H), 1.65 - 1.95 (m, 4H), 1.50 - 1.68 (m, 2H), 1.30 (m, 1H); MS (ESI) m/z 532 (M+H)+.
Figure imgf000123_0001
Example 33
(2- { 1 - [(2R,3aR,6aR)-3a- { [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)- yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}phenyl)acetic acid
Example 33 A
ethyl 2-(2-(l-((2R,3aR,6aR)-3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro- l,6- naphthyridine-6-carbonyl)octahydropentalen-2-yl)piperidin-4-yl)phenyl)acetate The title compound was isolated from the procedure of Example 23B.
Example 33B
(2- { 1 - [(2R,3aR,6aR)-3a- { [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)- yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}phenyl)acetic acid
The title compound was prepared and purified according to the procedure described in Example 15C, substituting Example 33A for Example 15B. Ή NMR (400 MHz, CDCI3) δ ppm 8.70 (s, 1H), 7.72 (s, 1H), 7.05 - 7.25 (m, 4H), 4.70 (m, 2H), 3.80 (m, 1H), 3.55 (m, 2H), 3.45 (m, 3H), 3.10 (m, 2H), 2.95 (m, 1H), 2.70 (m, 1H), 2.45 (m, 1H), 2.30 (m, 1H), 1.90 - 2.15 (m, 5H), 1.50 - 1.85 (m, 10H); MS (ESI) nVz 556 (M+H)+.
Figure imgf000124_0001
Example 34
[(2S,3aR,6aR)-2-[4-(3,5-dimethyl-4H- l,2,4-triazol-4-yl)piperidin- 1- yl]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro- l ,6-naphthyridin-
6(5H)-yl]methanone
The title compound was isolated from the procedure of Example 2 IF. Ή NMR (400 MHz, CD3OD) δ 8.70 (s, 1H), 8.05 (s, 1H), 4.75 (m, 2H), 3.75 - 4.05 (m, 6H), 3.55 (m, 1H), 3.12 - 3.25 (m, 3H), 2.70 (s, 6H), 2.50 (m, 2H), 2.35 (m, 2H), 2.15 (m, 4H), 2.0 (m, 4H), 1.80 (m, 1H), 1.60 (m, 1H), 1.40 (m, 1H); MS (ESI) m/z 517 (M+H)+.
Figure imgf000124_0002
Example 35
[(2S,3aR,6aR)-2-[4-(3-isopropyl-5-methyl-4H- 1 ,2,4-triazol-4-yl)piperidin- 1 - yl]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro- l ,6-naphthyridin-
6(5H)-yl]methanone
The title compound was isolated from the procedure of Example 24B. Ή NMR (400 MHz, CD3OD) δ ppm 8.70 (s, 1H), 8.07 (s, 1H), 4.80 (m, 2H), 3.95 (m, 2H), 3.80 (m, 2H), 3.35 - 3.50 (m, 3H), 3.10 - 3.30 (m, 4H), 2.75 (s, 3H), 2.55 - 2.75 (m, 3H), 2.45 (m, 1H), 2.35 (m, 2H), 2.1 - 2.25 (m, 2H), 1.60 - 1.95 (m ,7H), 1.42 (m, 6H); MS (ESI) m/z 545 (M+H)+.
Figure imgf000125_0001
Example 36
[(2S,3aR,6aR)-2-[4-(3-phenyl- 1 ,2,4-oxadiazol-5-yl)piperidin- 1 -yl]hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]metha
The title compound was isolated from the procedure of Example 17B. Ή NMR
(400 MHz, CDC13) δ ppm 8.63 (s, 1 H), 7.98 (m, 2 H), 7.63 (s, 1H), 7.39 (m, 3H), 4.70 (m, 2 H), 3.82 (m, 2 H), 3.35 (m, 1 H), 2.85 - 3.10 (m, 5 H), 2.30 - 2.50 (m, 2 H), 1.55 - 2.17 (m, 13 H), 1.49 (m, 1 H), 1.16 (m, 1 H); MS (ESI) m/z 566 (M+H)+.
Figure imgf000125_0002
Example 37
[(2R,3aR,6aR)-2-(4-hydroxy-4-phenylpiperidin-l-yl)hexahydropentalen-3a(lH)-yl][3- (trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone The title compound was prepared and purified according to the procedure described in Example 1 J, substituting 4-phenylpiperidinyl-4-ol for Example II. Ή NMR (400 MHz, CDCI3) δ ppm 8.55 (s, 1H), 7.63 (s, 1H), 7.40 (m, 2H), 7.27 (m, 2H), 7.15 (m, 1H), 4.70 (m, 2H), 3.80 (m, 2H), 3.30 - 3.45 (m, 2H), 3.00 - 3.20 (m, 6H), 2.40 (m, 3H), 2.25 (m, 1H), 2.00 (m, 2H), 1.85 (m, 4H), 1.60 - 1.80 (m, 2H), 1.45 (m, 1H), 1.25 (m, 2H); MS (ESI) m/z 514 (M+H)+.
Figure imgf000126_0001
Example 38
4-phenyl- 1 -[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)- yl]carbonyl}octahydropentalen-2-yl]piperidine-4-carbonitrile The title compound was prepared and purified according to the procedure described in Example 1J, substituting 4-phenylpiperidinyl-4-carbonitrile for Example II. Ή NMR (400 MHz, CDC13) δ ppm 8.62 (s, 1H), 7.65 (s, 1H), 7.42 (m, 2H), 7.33 (m, 2H), 7.26 (m, 1H), 4.70 (m, 2H), 3.80 - 3.95 (m, 2H), 3.48 (m, 1H), 2.95 - 3.10 (m, 3H), 2.85 (m, 1H), 2.45 (m, 2H), 2.15 (m, 1H), 2.04 (m, 5H), 1.89 (m, 1H),1.55 - 1.80 (m, 6H), 1.49 (m, 1H), 1.25 (m, 1H); MS (ESI) m/z 523 (M+H)+.
Figure imgf000126_0002
Example 39
4-(4-chlorophenyl)- l-[(2R,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperidine-4-carbonitrile
Example 39A1
tert-butyl bis(2-chloroethyl)carbamate
To a mixture of bis(2-chloroethyl)amine hydrogen chloride (1 1 g, 62 mmol) and di-tert-butyl dicarbonate (14.8 g, 68.2 mmol) in dichloromethane (90 mL) was added triethylamine (7.5 g, 74.4 mmol) at 0 °C under nitrogen atmosphere. The mixture was warmed to room temperature and stirred overnight. The solid was filtered off and the cake was washed with dichloromethane. The filtrate was washed with IN HCl, saturated NaHC(¾ and brine. The organics was dried over Na2S04, filtered and concentrated to afford 39A1 (13 g, 87%) as colorless oil.
Example 39A2
tert-butyl 4-(4-chlorophenyl)-4-cyanopiperidine- 1 -carboxylate To a mixture of Example 39A1 (3.5 g, 14.5 mmol) and 4-Chloro-benzonitrile (2.0 g, 13.2 mmol) in DMF (50 ml) was added NaH (2.1 g, 43.5 mmol) in portions with ice- bath under nitrogen atmosphere. After addition, the mixture was heated to 60 °C and stirred overnight. After cooling to room temperature, the mixture was poured into ice water (200 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated. The residue was purified on silica column to afford Example 39A2 (1.8 g, 41%) as a white solid.
Example 39A
4-(4-chlorophenyl)piperidine-4-carbonitrile
To a solution of compound Example 39A2 (1.8 g, 5.6 mmol) in MeOH (5 mL) was added dropwise HCl/MeOH (20 mL) with ice-bath. After addition, the mixture was warmed to room temperature and stirred for 2 hours. The mixture was concentrated and the residue was dissolved in water (30 mL) and washed with ethyl acetate. The aqueous layers were basified to pH=9 with IN NaOH solution and then extracted with ethyl acetate (3 x 50 mL). The combined organics were washed with brine, dried over Na2S04, filtered, and concentrated to afford Example 39A (0.9 g, 73%) as a white solid.
Example 39B
4-(4-chlorophenyl)- l-[(2R,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperidine-4-carbonitrile The title compound was prepared and purified according to the procedure described in Example 1 J, substituting Example 39A for Example II. Ή NMR (400 MHz, CDC13) δ ppm 8.72 (s, 1H), 7.80 (s, 1H), 7.40 (m, 4H), 4.75 (m, 2H), 3.50 - 3.95 (m, 5H), 3.10 - 3.35 (m, 4H), 2.50 - 2.70 (m, 3H), 2.38 (m, 1H), 1.95 - 2.30 (m, 6H), 1.70 - 1.90 (m, 2H), 1.62 (m, 1H), 1.30 (m, 2H); MS (ESI) m/z 557 (M+H)+.
Figure imgf000128_0001
Example 40
4-(4-fluorophenoxy)- 1 -[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperidine-4-carbonitrile
Example 40A1
l-(tert-butoxycarbonyl)-4-(4-fluorophenoxy)piperidine-4-carboxylic acid To a mixture of 4-fluorophenol (4 g, 35.7 mmol) and NaOH (1.72 g, 42.8 mmol) in THF (10 mL) was added tert-butyl 4-oxopiperidine- 1 -carboxylate (71 g, 357 mmol) at 0 °C. The mixture was stirred at room temperature for 4 hours. CHCI3 (8.52 g, 71.4 mmol) was added and the reaction mixture was stirred at room temperature overnight. After removal of solvent, the residue was dissolved into dichloromethane (200 mL). The organic layer was washed with aqueous NaOH (4 N, 200 mL). The aqueous layer was acidified by 4 N HC1 until pH = 3, then extracted with dichloromethane. The combined extracts were dried over MgS04, filtered, and concentrated to give Example 40A1 (7.0 g, 57.8%) as white solid.
Example 40A2
tert-butyl 4-carbamoyl-4-(4-fluorophenoxy)piperidine- 1 -carboxylate
A mixture of Example 40A1 (2.4 g, 7 mmol), Di- tert-butyl dicarbonate (2.1 g, 9.1 mmol), pyridine (0.35 mL) and NH4HCO3 (700 mg, 9.1 mmol) in CH3CN (10 mL) was stirred at room temperature overnight. The mixture was diluted with water, and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over MgS04, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, eluted with ethyl acetate/hexanes 2:3) to provide Example 40A2 (1.8 g, 76%).
Example 40A3
tert-butyl 4-cyano-4-(4-fluorophenoxy)piperidine- 1 -carboxylate A mixture of Example 40A2 (1.8 g, 5.32 mmol), Et3N (2.42 g, 21.28 mmol) and trifluoroacetic anhydride (2.23 g, 10.6 mmol) in CH2CI2 (20 mL) was stirred at room temperature overnight. The mixture was poured into water. The organic layer was separated, washed with water and brine, dried over MgS04, filtered and concentrated in vaccum. The resulting residue was purified by flash chromatography (silica gel, eluted with ethyl acetate/hexanes 1 : 15) to giveExample 40A3 (1.1 g, 65%).
Example 40A
4-(4-fluorophenoxy) piperidine-4-carbonitrile A mixture of Example 40A3 (0.5 g, 1.6 mmol) in HCl/MeOH (10 mL) was stirred at room temperature overnight. After removal of the solvent, about 330 mg of Example 40A was obtained as a HC1 salt solid.
Example 40B
4-(4-fluorophenoxy)- 1 -[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperidine-4-carbonitrile The title compound was prepared and purified according to the procedure described in Example 1J, substituting free base of Example 40A for Example II. Ή NMR (400 MHz, CDC13) δ ppm 8.72 (s, 1H), 7.79 (s, 1H), 6.95 - 7.10 (m, 4H), 4.75 (m, 2H), 3.50 - 3.90 (m, 6H), 2.80 - 3.25 (m, 4H), 2.20 - 2.60 (m, 6H), 2.12 (m, 2H), 1.95 (m, 2H), 1.70 (m, 2H), 1.55 (m, 1H), 1.25 (m, 1H); MS (ESI) m/z 557 (M+H)+.
Figure imgf000129_0001
Example 41
[(2R,3aR,6aR)-2-[4-fluoro-4-(4-fluorophenyl)piperidin- l-yl]hexahydropentalen-3a(lH)- yl][3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)-yl]methanone
Example 41 A 1
tert-butyl 4-(4-fluorophenyl)-4-hydroxypiperidine- 1-carboxylate A mixture of bromo-4-fluoro-benzene (3.5 g, 20 mmol), Mg (487 mg, 20 mmol), I2 (9.6 mg) and THF (200 mL) was stirred at 70 °C for 2 hours and then cold to room temperature. A solution of 4-oxo-piperidine- 1 -carboxylic acid tert-butyl ester (2 g, 10 mmol) in THF (20 mL) was added to the reaction mixture at 0 °C. The mixture was stirred at the same temperature for 1 hour and at room temperature for 2 hours. A saturated aqueous ammonium chloride solution (100 mL) was added to the mixture at 0 °C. The solution was diluted with EtOAc (200 mL). The organic layer was washed with brine (6 x 50 mL), dried over Na2S04, filtered and concentrated in vaccum to give a brownish residue, which was purified by chromatography on silica-gel (petroleum ether / EtOAc = 100: 1 to 2: 1) to give Example 41A1 (2.1 g, 74%) as a white solid.
Example 41A2
tert-butyl 4-fluoro-4-(4-fluorophenyl)piperidine- 1 -carboxylate A solution of diethylaminosulfur trifluoride (420 mg, 2.6 mmol) in CH2CI2 (20 mL) was cooled to -78 °C and a solution of Example 41A1 (760 mg, 2.6 mmol) in CH2CI2 (10 mL) was added dropwise over 10 minutes. The mixture was stirred at the same temperature for 1 hour, and then allowed to warm at room temperature. A saturated NaHC(¾ solution (30 mL) was slowly poured into the reaction mixture. The aqueous phase was extracted with CH2CI2 (2 x 100 mL). The combined extracts were dried over Na2S04, filtered, and concentrated in vaccum to give crude Example 41A2 (650 mg) as a brown oil which was used for the next step without further purification.
Example 41 A
4-Fluoro-4-(4-fluoro-phenyl)-piperidine
A solution of Example 41 A2 (650 mg, 2.2 mmol) in HC1 /EtOAc (4 N, 150 mL) was stirred at room temperature overnight. The reaction mixture was cooled to 0 °C, and then basified to pH=9 with NaHC(¾. The aqueous phase was extracted with EtOAc (2 x 100 mL). The combined extracts were dried over Na2S04, filtered, and concentrated in vaccum to give crude Example 41A (340 mg) as a gale yellow oil which was used for the next step without further purification.
Example 4 IB
[(2R,3aR,6aR)-2-[4-fluoro-4-(4-fluorophenyl)piperidin- l-yl]hexahydropentalen-3a(lH)- yl][3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)-yl]methanone The title compound was prepared and purified according to the procedure described in Example 1J, substituting Example 41A for Example II. Ή NMR (400 MHz, CDCI3) δ ppm 8.72 (s, 1H), 7.79 (s, 1H), 7.32 (m, 2H), 7.08 (m, 2H), 4.75 (m, 2H), 3.90 (m, 2H), 3.65 (m, 1H), 3.05 - 3.30 (m, 4H), 2.35 - 2.65 (m, 4H), 1.70 - 2.20 (m, 10H), 1.62 (m, 1H), 1.25 (m, 2H); MS (ESI) m/z 534 (M+H)+.
Figure imgf000131_0001
Example 42
[(2S,3aR,6aR)-2-[4-fluoro-4-(4-fluorophenyl)piperidin-l-yl]hexahydropentalen-3a(lH) yl][3-(†jifluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)-yl]methanone The title compound was obtained from the procedure of Example 4 IB. Ή NMR
(400 MHz, CDC13) δ ppm 8.65 (s, 1H), 7.62 (s, 1H), 7.30 (m, 2H), 6.98 (m, 2H), 4.65 - 4.85 (m, 2H), 3.85 (m, 2H), 3.36 (m, 1H), 3.08 (m, 2H), 2.75 - 2.95 (m, 2H), 2.30 - 2.60 (m, 4H), 1.55 - 2.20 (m, 10H), 1.50 (m, 1H), 1.20 (m, 2H); MS (ESI) m/z 534 (M+H)+.
Figure imgf000131_0002
Example 43
[(2S,3aR,6aR)-2-(4-fluoro-4-phenylpiperidin-l-yl)hexahydropentalen-3a(lH)-yl][3- (trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone The title compound was prepared and purified according to the procedure described in Example 1J, substituting 4-fluoro 4-phenylpiperidine for Example II. Ή NMR (400 MHz, CDC13) δ ppm 8.70 (s, 1H), 7.70 (s, 1H), 7.38 (m, 4H), 7.30 (m, 1H), 4.70 - 4.90 (m, 2H), 3.90 (m, 2H), 3.45 (m, 1H), 3.15 (m, 2H), 2.85 - 2.98 (m, 2H), 2.40 2.60 (m, 4H), 2.20 (m, 2H), 2.00 (m, 4H), 1.65 - 1.90 (m, 6H), 1.25 (m, 1H); MS (ESI) m/z 516 (M+H)+.
Figure imgf000131_0003
Example 44
[(2R,3aR,6aR)-2-(4-fluoro-4-phenylpiperidin-l-yl)hexahydropentalen-3a(lH)-yl][3- (trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone The title compound was isolated from the procedure of Example 43. Ή NMR (400 MHz, CDC13) δ ppm 8.85 (s, 1H), 7.80 (s, 1H), 7.30 - 7.40 (m, 5H), 4.75 (m, 2H), 3.80 - 4.00 (m, 2H), 3.60 (m, 1H), 3.40 (m, 2H), 3.10 - 3.25 (m, 4H), 2.48 - 2.75 (m, 3H), 2.33 (m, 1H), 2.10 - 2.25 (m, 4H), 1.70 - 1.99 (m, 6H), 1.25 (m, 1H); MS (ESI) m/z 516 (M+H)+.
Figure imgf000132_0001
Example 45
4-(4-fluorophenyl)- 1 -[(2S,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperidine-4-carbonitrile The title compound was prepared and purified according to the procedure described in Example 1 J, substituting 4-(4-fluorophenyl) piperidinyl-4-carbonitrile for Example II. Ή NMR (400 MHz, CDCI3) δ ppm 8.72 (s, 1H), 8.30 (s, 1H), 7.75 (s, 1H), 7.48 (m, 2H), 7.10 (m, 2H), 4.70 - 4.90 (m, 2H), 3.90 (m, 2H), 3.55 (m, 2H), 3.43 (m, 1H), 3.15 (m, 2H), 3.02 (m, 1H), 2.88 (m, 2H), 2.55 (m, 3H), 2.30 (m, 1H), 2.20 (m, 3H), 2.05 (m, 1H), 1.60 - 1.90 (m, 6H); MS (ESI) m/z 541 (M+H)+.
Figure imgf000132_0002
Example 46
4-(4-chlorophenyl)-l-[(2S,3aR,6aR)-3a- {[3-(triiluoromethyl)-7,8-dihydro- l,6- naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperidine-4-carbonitrile The title compound was isolated from the procedure of Example 39B. Ή NMR (400 MHz, CDCI3) δ ppm 8.70 (s, 1H), 7.68 (s, 1H), 7.35 - 7.45 (m, 4H), 4.68 - 4.90 (m, 2H), 3.88 (m, 2H), 3.40 (m, 1H), 3.00 - 3.13 (m, 4H), 2.40 - 2.68 (m, 5H), 1.95 - 2.25 (m, 6H), 1.60 - 1.85 (m, 5H), 1.55 (m, 1H); MS (ESI) m/z 557 (M+H)+.
Figure imgf000133_0001
Example 47
[(2S,3aR,6aR)-2-(4-hydroxy-4-phenylpiperidin-l-yl)hexahydropentalen-3a(lH)-yl][3- (trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone The title compound was isolated from the procedure of Example 37. Ή NMR (400 MHz, CD3OD) δ ppm 8.65 (s, 1H), 7.65 (s, 1H), 7.45 (d, J=8 Hz, 2H), 7.30 (m, 2H), 7.25 (m, 1H), 4.65 - 4.80 (m, 2H), 3.82 (m, 2H), 3.37 (m, 1H), 3.05 (m, 2H), 2.75 - 2.90 (m, 2H), 2.30 - 2.55 (m, 4H), 2.15 (m, 3H), 1.90 (m, 1H), 1.50 - 1.80 (m, 9H), 1.20 (m, 1H); MS (ESI) m/z 514 (M+H)+.
Figure imgf000133_0002
Example 48
4-phenyl- 1 -[(2S,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)- yl]carbonyl}octahydropentalen-2-yl]piperidine-4-carbonitrile The title compound was isolated from the procedure of Example 38. Ή NMR (400 MHz, CDCI3) δ ppm 8.70 (s, 1H), 7.70 (s, 1H), 7.50 (m, 2H), 7.38 (m, 2H), 7.33 (m, 1H), 4.70 - 4.90 (m, 2H), 3.90 (m, 2H), 3.45 (m, 1H), 3.13 (m, 3H), 3.03 (m, 1H), 2.65 (m, 1H), 2.42 - 2.58 (m, 3H), 2.20 (m, 1H), 2.10 (m, 4H), 1.95 (m, 1H), 1.80 (m, 2H), 1.70 (m, 3H),1.55 (m, 1H), 1.25 (m, 1H); MS (ESI) m/z 523 (M+H)+.
Figure imgf000134_0001
Example 49
4-(4-fluorophenoxy)- l-[(2S,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperidine-4-carbonitrile The title compound was isolated from the procedure of Example 40B. Ή NMR
(400 MHz, CDC13) δ 8.65 (s, 1H), 7.65 (s, 1H), 7.07 (m, 2H), 6.90 (m, 2H), 4.65 - 4.85 (m, 2H), 3.85 (m, 2H), 3.35 (m, 1H), 3.05 (m, 2H), 2.75 (m, 2H), 2.25 - 2.50 (m, 4H), 1.85 - 2.15 (m, 6H), 1.55 - 1.80 (m, 5H), 1.45 (m, 1H), 1.15 (m, 1H); MS (ESI) m/z 557 (M+H)+.
Figure imgf000134_0002
Example 50
[(2S,3aS,6aS)-2-(6-fluoro- 1 'H,4H-spiro[ 1 ,3-benzodioxine-2,4'-piperidin]- 1 '- yl)hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin-
6(5H)-yl]methanone
Example 50A1
(tert-butyl 6-fluoro-4H-spiro[benzo[d][l,3]dioxine-2,4'-piperidine]- -carboxylate
6-fluoro-4H-spiro[benzo[d][l,3]dioxine-2,4'-piperidine] To a mixture of 4-fluoro-2-(hydroxymethyl)phenol (2.0 g, 13.99 mmol) and tert- butyl 4-oxopiperidine- 1 -carboxylate (4.0 g ,20.1 mmol) in CHCI3 (20 ml) was added p- TsOH.]¾0 (0.2 g, 1.05 mmol). The mixture was heated at reflux with azerotropic removal of water (Dean-Stark Trap) overnight. After cooling to room temperature, the solvent was evaporated in vaccum. The residue was purified by column chromatography to afford Example 50A1.
Example 5 OA
6-fluoro-4H-spiro[benzo[d][l,3]dioxine-2,4'-piperidine] To a solution of Example 50A (4.0g, 12.4 mmol) in dichloromethane (50 mL) was added ZnB¾ (4.0 g, 17.8 mmol) under nitrogen condition at room temperature. And the reaction mixture was stirred at the same temperature for 4 hours. TLC showed that the reaction was complete.The reaction mixture was treated with a solution of saturated Na2C(¾. And the separated organic layer was washed with brine, dried over Na2S04, filtered, and concentrated in vacuum to give the crude product which was purified by column chromatography to afford Example 50A (1.2g, yellow oil).
Example 50B
(3aS,6aS)-3a-(3-(triiluoromethyl)-5,6,7,8-tetrahydro-l,6-naphthyridine-6- carbonyl)hexahydropentalen-2( 1 H)-one
The title compound was isolated from the procedure of Example 1H.
Example 50C
[(2S,3aS,6aS)-2-(6-fluoro- 1 'H,4H-spiro[ 1 ,3-benzodioxine-2,4'-piperidin]- 1 '- yl)hexahydropentalen-3a(lH)-yl][3-(triiluoromethyl)-7,8-dihydro- l,6-naphthyridin-
6(5H)-yl]methanone
The title compound was prepared and purified according to the procedure described in Example 1 J, substituting Example 5 OA for Example II, and substituting Example 50B for Example 1H. Ή NMR (400 MHz, CDC13) δ ppm 8.68 (s, 1H), 7.68 (s, 1H), 6.80 (m, 1H), 6.75 (m, 1H), 6.65 (m, 1H), 4.75 (s, 2H), 4.70 (m, 2H), 3.85 (m, 2H), 3.36 (m, 1H), 3.09 (m, 2H), 2.50 - 2.70 (m, 4H), 2.40 (m, 1H), 2.12 (m, 1H), 1.60 - 1.95 (m, 1 1H), 1.55 (m, 1H), 1.30 (m, 1H); MS (ESI) m/z 560 (M+H)+.
Figure imgf000135_0001
Example 51
[(2R,3aR,6aR)-2-(6-fluoro- 1 'H,4H-spiro[l ,3-benzodioxine-2,4'-piperidin]- 1 '- yl)hexahydropentalen-3a(lH)-yl][3-(triiluoromethyl)-7,8-dihydro-l,6-naphthyridin-
6(5H)-yl]methanone
The title compound was prepared and purified according to the procedure described in Example 1 J, substituting Example 50A for Example II. Ή NMR (400 MHz, CDCI3) δ ppm 8.65 (s, 1H), 7.70 (s, 1H), 6.55-6.85 (m, 3H), 4.75 (s, 2H), 4.50 - 4.70 (m, 2H), 3.85 (m, 2H), 3.50 (m, 2H), 3.30 (m, 1H), 3.10 (m, 2H), 2.590 (m, 1H), 2.40 - 2.60 (m, 8H), 1.90 - 2.25 (m, 4H), 1.55 - 1.80 (m, 3H), 1.15 (m, 1H); MS (ESI) nVz 560 (M+H)+.
Figure imgf000136_0001
Example 52
[3-(trifluoromethyl)-7,8-dihydro ,6-naphthyridin-6(5H)-yl][(2R,3aR,6aR)-2- {3-[3- (trifluoromethyl)- lH-pyrazol- 1 -yl]azetidin- 1 -yl}hexahydropentalen-3a(lH)- yl]methanone
Example 52A 1
1 -benzhydrylazetidin-3 -yl methanesulfonate
1 -benzhydrylazetidin-3 -ol
To a solution of l-benzhydryl-azetidin-3-ol (1.5 g, 6.27 mmol) and triethylamine (0.95 g, 9.4 mmol) in dichloromethane (20 mL) was added methanesulfonyl chloride (0.86 g, 7.5 mmol) with ice-bath under nitrogen atmosphere. After addition, the mixture was stirred at room temperature for 3 hours. The mixture was diluted with
dichloromethane (30 mL) and washed with saturated citric acid solution, NaHC(¾ solution and brine. The organic was dried over Na2S04, filtered and concentrated in vacuum to afford Example 52A1 (1.8 g, 90%) as a white solid.
Example 52A2
1 -(1 -benzhydrylazetidin-3-yl)-3-(trifluoromethyl)- lH-pyrazole To a mixture of Example 52A1 (0.9 g, 2.8 mmol) and K2CO3 (0.77 g ,5.6 mmol) in DMF (15 ml) was added 3-trifluoromethyl-lH-pyrazole (0.42 g, 3.1 mmol) at room temperature under nitrogen atmosphere. Then the mixture was heated at 100 °C overnight. After cooling to room temperature, the mixture was quenched with water (30 ml) and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over Na2S04, filtered and concentrated. The residue was purified to afford Example 52A2 (0.6 g). LC/MS (ESI+) m/z 358 (M+H)+.
Example 52A
1 - (azetidin- 3 -yl)- 3 - (trifluoromethyl)- 1 H-pyrazole To a mixture of Pd(OH)2 (0.1 g) and methanol (20 mL) was added Example 52A2 (340 mg, 0.95 mmol) and concentrated HC1 solution (0.1 mL, 12N). The mixture was stirred under ¾ pressure (40 psi) at 40 °C overnight. The mixture was filtered and the filter cake was washed with methanol. The filtrate was concentrated dryness. The residue was dissolved in water (50 mL) and washed with ethyl acetate. The aqueous layer was basified to pH 9 with aqueous 2N NaOH solution and concentrated to dryness to afford Example 52A (80 mg).
Example 52B
[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl][(2R,3aR,6aR)-2- {3-[3- (trifluoromethyl)- lH-pyrazol- 1 -yl]azetidin- 1 -yl}hexahydropentalen-3a(lH)- yl]methanone
The title compound was prepared and purified according to the procedure described in Example 1 J, substituting Example 52A for Example II. Ή NMR (400 MHz, CD3OD) δ ppm 8.69 (s, 1H), 8.05 (s, 1H), 7.65 (s, 1H), 6.75 (m, 1H), 5.05 (m, 1H), 4.60 - 4.80 (m, 2H), 4.02 (m, 1H), 3.90 (m, 2H), 3.75 (m, 2H), 3.50 (m, 1H), 3.25 (m, 1H), 3.15 (m, 2H), 2.21 (m, 1H), 1.90 (m, 2H), 1.70 - 1.86 (m, 3H), 1.52 - 1.70 (m, 3H), 1.43 (m, 1H), 1.30 (m, 1H); MS (ESI) m/z 528 (M+H)+.
Figure imgf000137_0001
Example 53
1 -(4-chlorophenyl)-4-[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperazin-2-one The title compound was prepared and purified according to the procedure described in Example IJ, substituting l-(4-chlorophenyl) piperazin-2-one for Example II. Ή NMR (400 MHz, CDC13) δ ppm 8.65 (s, 1 H), 7.63 (s, 1 H), 7.230 (d, J= 6.4Hz, 2 H), 7.15 (d, J= 6.4 Hz, 2 H), 4.72 (m, 2 H), 3.72 - 3.95 (m, 4H), 3.45 - 3.65 (m, 3 H), 3.30 (m, 2H), 3.20 (m, 2H), 2.99 (m, 3H), 2.85 (m, 2H), 2.69 (m, 1 H), 2.15 (m, 1H), 1.60 - 1.90 (m, 4 H); MS (ESI) m/z 547 (M+H)+.
Figure imgf000138_0001
Example 54
1 -(4-fluorophenyl)-4-[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperazin-2-one The title compound was prepared and purified according to the procedure described in Example IJ, substituting l-(4-fluorophenyl) piperazin-2-one for Example II. 'H NMR (400 MHz, CDC13) δ ppm 8.65 (s, 1 H), 7.55 (s, 1 H), 7.17 (m, 2 H), 7.05 (m, 2 H), 4.72 (s, 2 H), 3.75 - 3.90 (m, 2H), 3.50 - 3.65 (m, 2 H), 3.30 (m, 2H), 3.07 (m, 2H), 2.97 (m, 1H), 2.85 (m, 2H), 2.71 (m, 1 H), 2.16 (m, 1H), 2.05 (m, 1H), 1.62 - 1.95 (m, 6 H), 1.25 - 1.35 (m, 2H); MS (ESI) m/z 531 (M+H)+.
A
Figure imgf000138_0002
Example 55
[(2R,3aR,6aR)-2-(2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone The title compound was prepared and purified according to the procedure described in Example 1 J, substituting 4,5,6,7-tetrahydro-2H-pyrazolo-[4,3,c]pyridine for Example II. Ή NMR (400 MHz, CD3OD) δ ppm 8.68 (s, 1 H), 8.05 (s, 1 H), 7.82 (s, 1 H), 4.85 (m, 2 H), 3.95 (m, 2H), 3.60 (m, 2 H), 3.46 (m, 1H), 3.10 (m,3H), 2.85 (m, 2H), 2.75 (m, 2H), 2.49 (m, 1 H), 2.10 (m, 1H), 1.9 (m, 3H), 1.65 - 1.85 (m, 3 H), 1.50 (m, 1H), 1.30 (m, 1H); MS (ESI) m/z 460 (M+H)+. A
Figure imgf000139_0001
Example 56
[(2R,3aR,6aR)-2-(2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)hexahydropentalen-3a(lH)- yl][3-(†jifluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)-yl]methanone The title compound was prepared and purified according to the procedure described in Example 1J, substituting 2,4,5, 6-tetrahydropyrrolo[3,4,c]pyrazole for Example II. Ή NMR (400 MHz, CD3OD) δ ppm 8.60 (s, 1 H), 7.95 (s, 1 H), 7.24 (s, 1 H), 4.75 (m, 2 H), 3.80 - 4.0 (m, 2H), 3.70 (m, 2 H), 3.40 (m, 1H), 3.05 (m,3H), 2.89 (m, 1H), 2.35 (m, 2H), 1.60 - 2.00 (m, 6 H), 1.30 - 1.46 (m, 2H), 1.30 (m, 1H); MS (ESI) m/z 446 (M+H)+.
Figure imgf000139_0002
Example 57
[(2R,3aR,6aR)-2-[(3R)-3-(methoxymethyl)morpholin-4-yl]hexahydropentalen-3a(lH)- yl][3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)-yl]methanone The title compound was prepared and purified according to the procedure described in Example 1 J, substituting (R)-3-(methoxymethyl) morpholine for Example II. Ή NMR (400 MHz, CDC13) δ ppm 8.63 (s, 1 H), 7.62 (s, 1 H), 4.60 - 4.80 (m, 2 H), 3.90 (m, 1H), 3.78 (m, 1H), 3.46 - 3.68 (m, 7H), 3.45 (s, 3 H), 3.03 (m, 2H), 2.75 (m, 1H), 2.60 (m, 1H), 2.40 (m, 1H), 2.05 (m, 2 H), 1.90 (m, 1H), 1.40 - 1.480 (m, 6H), 1.20 - 1.30 (m, 2H); MS (ESI) m/z 468 (M+H)+.
Figure imgf000140_0001
Example 58
[(3aR,6aR)-2-(4-hydroxy-6-azaspiro[2.5]oct-6-yl)hexahydropentalen-3a(lH)-yl][3- (trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone
Example 58A1
tert-butyl 3-hydroxy-4-methylenepiperidine- 1 -carboxylate To a suspension of Se02 (0.26 g, 2.3 mmol) in dichloromethane (15 mL) was added t-BuOOH (0.82 g, 9.2 mmol). After stirring for 30 minutes at 0 °C, tert-butyl 4- methylenepiperidine- 1 -carboxylate (0.9 g, 4.6 mmol) in dichloromethane (2 mL) was added and the mixture was stirred at 0 °C for 1 hour and warm to room temperature overnight. The reaction was quenched with ice and 10% NaHS03 (15 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over Na2S04, filtered and concentrated. The residue was purified on silica gel column o afford Example 58A1 (0.45 g, 46%) as a yellow solid.
Example 58 A2
tert-butyl 4-hydroxy-6-azaspiro[2.5]octane-6-carboxylate To a solution of diethyl zinc (1.88 mL, 1.88 mmol) in 1,2-dichloroethane (5 mL) was added diiodomethane (0.66 g, 3.76 mmol) at 0 °C under nitrogen atmosphere. After stirring for 1 hour, Example 58A1 (0.2 g, 0.94 mmol) in 1,2-dichloroethane (2 mL) was added. After stirring for 30 minutes at 0 °C, the mixture was warmed to room temperature and stirred overnight. The mixture was diluted with dichloromethane (20 mL) and washed with water, dried over Na2S04, filtered and concentrated to afford Example 58A2 (100 mg, 47%).
Example 58A
4-hydroxy-6-azaspiro[2.5]octane
To a solution of Example 58A2 (100 mg, 0.44 mmol) in dichloromethane (1 mL) was added HCl(g)/methanol (5 mL) dropwise at room temperature. After the addition, the mixture was stirred for 2 hours at room temperature. TLC indicated that the reaction was completed. The mixture was concentrated in vacuum to give Example 58A as HCl salt (74.3 mg, yield: 100%) as a white solid.
Example 58B
[(3aR,6aR)-2-(4-hydroxy-6-azaspiro[2.5]oct-6-yl)hexahydropentalen-3a(lH)-yl][3- (trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]methanone
The title compound was prepared and purified according to the procedure described in Example IJ, substituting free base of Example 58A for Example II. Ή NMR (400 MHz, CD3OD) δ ppm 8.70 (s, 1 H), 8.05 (s, 1 H), 4.85 (m, 2 H), 3.93 (m, 2H), 3.55 (m, 2 H), 3.38 (m, 2H), 3.00 - 3.25 (m, 5H), 2.60 - 2.75 (m, 2H), 2.30 - 2.45 (m, 1H), 1.70 - 2.18 (m, 7 H), 1.50 - 1.65 (m, 2H), 1.02 (m, 1H), 0.70 (m, 1H), 0.45 - 0.60 (m, 2H); MS (ESI) m/z 464 (M+H)+.
Figure imgf000141_0001
Example 59
[(2R,3aR,6aR)-2-(6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone The title compound was prepared and purified according to the procedure described in Example IJ, substituting 4,5,6,7-tetrahydropyrazolo[l,5,a]pyrazine for Example II. Ή NMR (400 MHz, CDCI3) δ ppm 8.65 (s, 1 H), 7.55 (s, 1 H), 7.36 (s, 1 H), 5.89 (s, 1H), 4.72 (s, 2 H), 4.10 (m, 2H), 3.75 - 3.95 (m, 2 H), 3.49 (m, 1H), 3.05 (m, 2H), 2.80 - 3.00 (m, 4H), 2.65 (m, 1H), 2.35 (m, 1H), 2.18 (m, 1H), 2.05 (m, 1 H), 1.45 - 1.95 (m, 5H), 1.10 - 1.30 (m, 2H); MS (ESI) m/z 460 (M+H)+.
Figure imgf000141_0002
Example 60 l-(4-chlorophenyl)-4-[(2S,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- l,6- naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperazin-2-one The title compound was isolated from the procedure of Example 53. Ή NMR (400 MHz, CDC13) δ ppm 8.70 (s, 1 H), 7.70 (s, 1 H), 7.37 (d, J= 6.8Hz, 2 H), 7.25 (d, J= 6.8 Hz, 2 H), 4.65 - 4.90 (m, 2 H), 3.92 (m, 2H), 3.68 (m, 2H), 3.45 (m,l H), 3.35 (m, 2H), 3.15 (m, 2H), 2.90 - 3.05 (m, 2H), 2.80 (m, 1H), 2.60 (m, 1 H), 2.45 (m, 1H), 2.22 (m, 1H), 1.95 (m, 1H), 1.50 - 1.90 (m, 5 H), 1.27 (m, 1H); MS (ESI) m/z 547 (M+H)+.
Figure imgf000142_0001
Example 61
[(2S,3aR,6aR)-2-(2-phenyl-l,4-dioxa-8-azaspiro[4.5]dec-8-yl)hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone The title compound was solated from the procedure of Example 64B. Ή NMR (400 MHz, CD3OD) δ ppm 8.70 (s, 1 H), 8.05 (s, 1 H), 7.25 - 7.40 (m, 5 H), 5.07 (m, 1H), 4.85 (m, 2 H), 4.30 (m, 1H), 3.95 (m, 2H), 3.65 (m, 1H), 3.10 (m, 2 H), 2.40 - 2.70 (m, 6H) , 2.10 - 2.20 (m, 2H), 1.40- 1.93 (m, 1 1H), 1.25 (m, 1H); MS (ESI) m/z 556 (M+H)+.
Figure imgf000142_0002
Example 62
[(2R,3aR,6aR)-2-[7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(lH)- yl]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone
The title compound was prepared and purified according to the procedure described in Example 1 J, substituting Example 1G for Example II. Ή NMR (400 MHz, CDCI3) δ ppm 8.70 (s, 1 H), 7.78 (s, 1 H), 7.50 (m, 1H), 7.20 - 7.35 (m, 2 H), 4.65 - 4.85 (m, 2 H), 3.80 (m, 4H), 3.55 (m, 2H), 3.16 (m, 4H), 2.65 (m, 1H), 2.40 (m, 1H), 2.20 (m, 1 H), 2.10 (m, 1H), 1.95 (m, 2H), 1.55 - 1.80 (m, 4H), 1.25 (m, 2H); MS (ESI) nVz 538 (M+H)+.
Figure imgf000143_0001
Example 63
1 -phenyl-4-((2R,3aR,6aR)-3a-(3-(triiluoromethyl)-5,6,7,8-tetrahydro- 1 ,6-naphthyridine- 6-carbonyl)octahydropentalen-2-yl)piperazin-2-one The title compound was prepared and purified according to the procedure described in Example 1 J, substituting l-phenylpiperazin-2-one for Example II. Ή NMR (400 MHz, CDC13) δ ppm 8.65 (s, 1 H), 7.65 (s, 1 H), 7.35 (m, 2 H), 7.20 (m, 3 H), 4.72 (s, 2 H), 3.75 - 3.92 (m, 2H), 3.55 - 3.70 (m, 2H), 3.50 (m, 1H), 3.30 (m, 2H), 3.06 (m,
2H), 2.85 (m, 2H), 2.70 (m, 1H), 2.30 (m, 1H), 2.15 (m, 1 H), 2.05 (m, 1H), 1.80-1.95 (m, 2H), 1.45 - 1.78 (m, 4H), 1.25 (m, 1H); MS (ESI) m/z 513 (M+H)+.
Figure imgf000143_0002
Example 64
[(2R,3aR,6aR)-2-(2 -phenyl- 1, 4-dioxa-8-azaspiro[4.5]dec-8-yl)hexahydropentalen-
3a(lH)-yl][3-(triiluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone
Example 64A 1
1 -Phenylethane- 1 ,2-diol
To a mixture of 2-hydroxy-2-phenylacetic acid (5.0 g, 32.8mmol) in MeOH (10 mL) was added concentrated H2SO4 (0.2 g) and then the reaction mixture was heated at reflux for 3 hours, cooled to room temperature, neutralized with aqueous 2 N NaOH solution, followed by addition of NaB¾ (1.25 g, 32.8 mmol) with cooling. The reaction mixture was stirred at room temperature overnight, neutralized with 2 N HCl, and concentrated in vacuum to remove most part of the methanol solution. The residue was extracted with dichloromethane, dried (MgS04), filtered, and concentrated in vacuum to give Example 64A1 (2.2g) which was used for next step without purification. Example 64A2 tert-Butyl 2-phenyl- l,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate To a solution of Example 64A1 (2.2 g, 15.9 mmol) in toluene (150 mL) was added tert-butyl 4-oxopiperidine- 1 -carboxylate (3.2g, 15.9 mmol) and toluene sulfonic acid (10 mg). The mixture was heated at reflux with Dean-stork condenser, after 15 hours the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (petroleum ethenEtOAc =3: 1) to give Example 64A2 (2.0 g).
Example 64A
2-Phenyl-l,4-dioxa-8-azaspiro[4.5]decane
To a solution of Example 64A2 (2.0g, 6.26mmol) in dichloromethane (20 mL) was added ZnB¾ (2.3 g, 9.39 mmol), then the mixture was stirred at room temperature for 12 hours. The solvent was removed under reduced pressure and the residue was diluted with water. The solution was adjusted to pH 9 with saturated Na2C(¾ solution, extracted with dichloromethane, dried over MgS04, filtered, and concentrated in vacuum to afford Example 64A which was used for next step without further purification (1.0 g).
Example 64B
[(2R,3aR,6aR)-2-(2 -phenyl- 1, 4-dioxa-8-azaspiro[4.5]dec-8-yl)hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone The title compound was prepared and purified according to the procedure described in Example 1 J, substituting Example 64A for Example II. Ή NMR (400 MHz, CD3OD) δ ppm 8.55 (s, 1 H), 7.90 (s, 1 H), 7.15 - 7.25 (m, 5 H), 4.95 (m, 1H), 4.75 (m, 2 H), 4.17 (m, 1H), 3.82 (m, 2H), 3.52 (m, 1H), 2.95 (m,2 H), 2.25 - 2.60 (m, 6H) , 1.90 - 2.10 (m, 2H), 1.40 - 1.80 (m, 1 1H), 1.10 (m, 1H); MS (ESI) m/z 556 (M+H)+.
Figure imgf000144_0001
Example 65 1 -(4-fluorophenyl)-4-[(2S,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperazin-2-one The title compound was isolated from the procedure of Example 54. Ή NMR (400 MHz, CDC13) δ ppm 8.65 (s, 1 H), 7.55 (s, 1 H), 7.18 (m, 2 H), 7.03 (m, 2 H), 4.60 - 4.90 (m, 2 H), 3.88 (m, 2H), 3.60 (m, 2 H), 3.40 (m, 1H), 3.25 (m, 2H), 3.08 (m, 2H),
2.95 (m, 1H), 2.85 (m, 1H), 2.70 (m, 1 H), 2.52 (m, 1H), 2.38 (m, 1H), 2.15 (m, 1H), 1.90 (m, 1 H), 1.45- 1.80 (m, 5H), 1.30 (m 1H); MS (ESI) m/z 531 (M+H)+.
Figure imgf000145_0001
Example 66
[(2S,3aR,6aR)-2-[7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(lH)- yl]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-
6(5H)-yl]methanone
The title compound was isolated from the procedure of Example 62. Ή NMR (400 MHz, CDCI3) δ ppm 8.65 (s, 1 H), 7.65 (s, 1 H), 7.30 (m, 1H), 7.10 - 7.20 (m, 2 H), 4.65 - 4.90 (m, 2 H), 3.87 (m, 2H), 3.65 (m, 2H), 3.40 (m, 1H), 3.10 (m, 2H), 2.87 (m, 2H), 2.75 (m, 2H), 2.62(m, 1 H), 2.48 (m, 1H), 2.22 (m, 1H), 1.90 (m, 1H), 1.60- 1.82 (m, 6H), 1.25 (m, 1H); MS (ESI) m/z 538 (M+H)+.
Figure imgf000145_0002
Example 67
2-[(2R,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)- yl]carbonyl} octahydropentalen-2-yl]- 1 ,2,3,4-tetrahydro-6H-pyrido[ l,2-a]pyrazin-6-one
Example 67A 1
2-tert-butoxy-6-chloropyridine
To a mixture of potassium tert-butoxide (18.2 g, 162 mmol) in toluene (300 ml) was added 2,6-dichloro-pyridine (20 g, 135 mmol) at room temperature under nitrogen atmosphere. The mixture was heated at 80 °C overnight. After cooling to room temperature, the solid was filtered off and the cake was washed with ethyl acetate. The filtrate was concentrated to dryness to afford Example 66A1 (21 g, 88%) as oil.
Example 67A2
6-tert-butoxypicolinonitrile
To a solution of Example 67A1 (15 g, 81 mmol) in DMF (100 mL) was added Zn(CN)2 (19 g, 162 mmol) and Pd(PPh3)4 (7.1 g, 6.48 mmol) under nitrogen atmosphere.
Then the mixture was stirred at 100 °C overnight. After cooling to room temperature, the mixture was filtered off and cake was washed with ethyl acetate. The filtrate was diluted with water (200 ml) and extracted with ethyl acetate. The organic layers were washed with water, brine, dried over Na2S04, filtered and concentrated. The residue was purified on silica gel column to afford Example 67A2 (3 g, 22%).
Example 67A3
(6-tert-butoxypyridin-2-yl) methanamine
To a solution of Example 67A2 (3 g, 17 mmol) in EtOH (50 ml) was added
Raney-Ni (0.5 g) under nitrogen. Then the mixture was stirred at 50 °C under ¾ pressure (50 psi) overnight. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to dryness to afford Example 67A3 (3.1 g, 95%).
Example 67A4
N-((6-tert-butoxypyridin-2-yl)methyl)-2-nitrobenzenesulfonamide
To a solution of Example 67A3 (3 g, 16.7 mmol) and diisopropylethyl amine (4.3 g, 33.4 mmol) in dichloromethane (50 mL) was added dropwise 2 -nitrobenzene- 1 - sulfonyl chloride (3.1 g, 16.7 mmol) in dichloromethane (10 mL) at 0 °C under nitrogen atmosphere. After addition, the mixture was stirred for 2 hours at room temperature. Water (20 mL) was added and the mixture was extracted with dichloromethane. The organics was washed with brine, dried over Na2S04, filtered, and concentrated to give Example 67A4 (5.7 g).
Example 67A5
N-(2-bromoethyl)-N-((6-tert-butoxypyridin-2-yl) methyl)-2-nitrobenzenesulfonamide To a solution of Example 67A4 (1.6 g, 4.4 mmol) in DMF (15 mL) was added
Cs2C03 (2.9 g, 8.8 mmol) followed by addition of BrCH2CH2Br (1.7 g, 8.8 mmol) at room temperature under nitrogen atmosphere. The mixture was stirred at room temperature overnight, diluted with water (20 mL), and extracted with ethyl acetate. The organic layers were washed with water, brine, dried over Na2S04, filtered, and concentrated to afford crude Example 67A5 (1.7 g) which was used in the next step without further purification.
Example 67A6
N-(2-bromoethyl)-N-((6-hydroxypyridin-2-yl)methyl)-2-nitrobenzenesulfonamide To a solution of 67A5 (1.7 g, 3.6 mmol) in dichloromethane (15 mL) was added trifluoroacetic acid (2 mL) at room temperature. After stirring for 2 hours, the mixture was concentrated to dryness to afford Example 67A6 (1.5 g) as brown oil.
Example 67A7
2-(2-nitrophenylsulfonyl)-3,4-dihydro-lH-pyrido[l,2-a]pyrazin-6(2H)-one To a solution of 67A6 (1.5 g, 3.6 mmol) in THF (15 mL) was added K2CO3 (1.0 g, 7.2 mmol) at room temperature under nitrogen atmosphere. The mixture was stirred for 3 hours and quenched with water (10 mL) and extracted with ethyl acetate. The residue was purified by silica column to afford Example 67A7 (0.8 g, 60%) as a light yellow solid.
Example 67 A 8
tert-butyl 6-oxo-3,4-dihydro-lH-pyrido[l,2-a]pyrazine-2(6H)-carboxylate To a solution of 67A7 (0.8 g, 2.4 mmol) in DMF (10 ml) was added K2CO3 (1.0 g, 7.2 mmol) followed by addition of PhSH (0.33 g, 3.0 mmol). The mixture was stirred at room temperature for 1 hour. Di-tert-butyl dicarbonate (1.57 g, 7.2 mmol) was added and the stirring was continued for 3 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated. The residue was purified on silica column to give Example 67A8 (0.48 g, 80 %) as a yellow solid.
Example 67A
3,4-dihydro- 1 H-pyrido [ 1 ,2-a]pyrazin-6(2H)-one To a solution of Example 67A8 (0.48 g, 1.9 mmol) in dioxane (2 mL) was added HCl/dioxane (20 mLl) with ice-bath under nitrogen atmosphere. The mixture was stirred for 2 hours and concentrated in vacuum to give Example 67A (0.4 g) as HC1 salt as solid.
Example 67B
2-[(2R,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)- yl]carbonyl} octahydropentalen-2-yl]- 1 ,2,3,4-tetrahydro-6H-pyrido[ l,2-a]pyrazin-6-one The title compound was prepared and purified according to the procedure described in Example 1J, substituting free base of Example 67A for Example II.Ή NMR (400 MHz, CDCI3) δ 8.65 (s, 1 H), 7.65 (s, 1 H), 7.20 (m, 1H), 6.35 (m, 1H), 5.85 (m, 1 H), 4.75 (m, 2 H), 3.70 - 4.00 (m, 4H), 3.45 - 3.65 (m, 3H), 3.10 (m, 2H), 2.82 (m, 2H), 2.20 (m, 1 H), 2.05 (m, 1H), 1.60 - 1.90 (m, 7H), 1.50 (m, 1H), 1.24 (m, 1H); MS (ESI) m/z 487 (M+H)+.
Figure imgf000148_0001
Example 68
[3-(trifluoromethyl)-7,8-dihydro-l,6-napM
(trifluoromethyl)- 1 H-pyrazol- 1 -yl]azetidin- 1 -yl}hexahydropentalen-3a(lH)- yl]methanone
The title compound was isolated from the procedure of Example 52B. Ή NMR (400 MHz, CDC13) δ ppm 8.65 (s, 1H), 7.62 (s, 1H), 7.48 (d, J=2.0 Hz, 1H), 6.53 (d, J=2.0 Hz, 1H), 5.0 (m, 1H), 4.65 - 4.85 (m, 2H), 3.85 (m, 1H), 3.72 (m, 2H), 3.57 (m, 2H), 3.4 (m, 1H), 3.05 (m, 2H), 2.72 (m, 1H), 2.18 (m, 1H), 1.82 - 2.05 (m, 3H), 1.75 (m, 2H), 1.65 (m, 2H), 1.49 (m, 2H), 1.10 (m, 1H). MS (ESI) m/z 528 (M+H)+.
Figure imgf000148_0002
Example 69
4-[(2S,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)- yl]carbonyl}octahydropentalen-2-yl]piperazin-2-one The title compound was prepared and purified according to the procedure described in Example 1J, substituting piperazin-2-one for Example II. Ή NMR (400 MHz, CDCI3) δ ppm 8.65 (s, 1 H), 7.64 (s, 1 H), 5.80 (m, 1H), 4.60 - 4.85 (m, 2 H), 3.82 (m, 2H), 3.30 - 3.40 (m, 3H), 3.05 - 3.15 (m, 4H), 2.70 (m, 1H), 2.45 - 2.60 (m, 2H), 2.35 (m, 1 H), 2.10 (m, lH), 1.90 (m, 1H), 1.45-1.80 (m, 6H), 1.15 (m, 1H); MS (ESI) m/z 437 (M+H)+.
Figure imgf000149_0001
Example 70
4-[(2R,3aR,6aR)-3a-{[3-(†jifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)- yl]carbonyl}octahydropentalen-2-yl]piperazin-2-one The title compound was obtained as a side product of Example 69. Ή NMR (400
MHz, CDC13) δ ppm 8.80 (s, 1 H), 8.00 (s, 1 H), 7.65 (s, 1H), 4.70 - 4.95 (m, 2 H), 3.25 - 4.00 (m, 1 1H), 2.45 (m, 2H), 1.95 - 2.15 (m, 4H), 1.60 - 1.90 (m, 4H), 1.30 (m, 1H); MS (ESI) m/z 437 (M+H)+.
Figure imgf000149_0002
Example 71
[(2S,3aR,6aR)-2-(6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone The title compound was obtained as a side product of Example 59. Ή NMR (400 MHz, CDCI3) δ ppm 8.65 (s, 1 H), 7.55 (s, 1 H), 7.36 (s, 1 H), 5.89 (s, 1H), 4.65 - 4.85 (m, 2 H), 4.12 (m, 2H), 3.85 (m, 2 H), 3.65 (m, 2H), 3.40 (m, 1H), 3.10 (m, 2H), 2.90 (m, 2H), 2.65 (m, 1H), 2.40 (m, 1H), 2.18 (m, 1 H), 1.90 (m, 1H), 1.55 - 1.80 (m, 4H), 1.50 (m, 1H), 1.22 (m, 2H); MS (ESI) m/z 460 (M+H)+.
Figure imgf000149_0003
Example 72 [(2S,3aR,6aR)-2-[(3S)-3-(methoxymeth^
yl][3-(†jifluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)-yl]m
The title compound was prepared and purified according to the procedure described in Example 1 J, substituting (S)-3-(methoxymethyl) morpholine for Example II. Ή NMR (400 MHz, CDC13) δ ppm 8.65 (s, 1 H), 7.55 (s, 1 H), 4.72 (s, 2 H), 3.50 - 3.90 (m, 9H), 3.42 (s, 3 H), 3.05 (m, 2H), 2.70 (m, lH), 2.65 (m, 1H), 2.45 (m, 1H), 1.55 - 2.10 (m, 9H), 1.25 (m, 2H); MS (ESI) m/z 468 (M+H)+.
Figure imgf000150_0001
Example 73
[(2S,3aR,6aR)-2-[(3R)-3-(methoxymethyl)morpholin-4-yl]hexahydropentalen-3a(lH)- yl][3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)-yl]methanone The title compound was isolated from the procedure of Example 57. Ή NMR (400 MHz, CDCI3) δ ppm 8.64 (s, 1 H), 7.62 (s, 1 H), 4.72 (s, 2 H), 3.55 - 3.90 (m, 9H), 3.45 (s, 3 H), 2.95 (m, 2H), 2.40 - 2.75 (m,3H), 2.07 (m, 1H), 1.92 (m, 1H), 1.40 - 1.80 (m, 7H), 1.28 (m, 2H); MS (ESI) m/z 468 (M+H)+.
Figure imgf000150_0002
Example 74
1 -phenyl-4-[(2S,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)- yl]carbonyl}octahydropentalen-2-yl]piperazin-2-one The title compound was obtained from the procedure of Example 63. Ή NMR
(400 MHz, CDCI3) δ ppm 8.70 (s, 1 H), 7.65 (s, 1 H), 7.35 (m, 2 H), 7.20 (m, 3 H), 4.60 - 4.90 (m, 2 H), 3.85 (m, 2H), 3.65 (m, 2H), 3.30 - 3.45 (m, 3H), 3.09 (m, 2H), 2.90 (m, 1H), 2.75 (m, 1H), 2.60 (m, 1H), 2.40 (m, 1H), 2.15 (m, 1H), 1.92 (m, 1H), 1.45 - 1.82 (m, 6H), 1.25 (m, 1H); MS (ESI) nVz 513 (M+H)+.
Figure imgf000151_0001
Example 75
l,5-anhydro-2,3-dideoxy-4-0-methyl-3-{[(2S,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8- dihydro-l,6-naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]amino}-L-threo- pentitol
Example 75A
(3R,4S)-3-methoxy-N-((S)-l-phenylethyl)tetrahydro-2H-pyran-4-amine The title compound was isolated from the procedure of Example 79E.
Example 75B
(3R,4S)-3-methoxytetrahydro-2H-pyran-4-amine The title compound was prepared according to the procedure described in Example 79F, substituting Example 75A for Example 79E.
Example 75 C
l,5-anhydro-2,3-dideoxy-4-0-methyl-3-{[(2S,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8- dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2-yl]amino} -L-threo- pentitol
The title compound was prepared according to method A of Example 79G, substituting Example 75B for Example 79F, and isolated as the major isomer. Ή NMR (400 MHz, CDC13) δ 8.68 (s, 1H), 7.66 (s, 1H), 4.75 (m, 2H), 4.10 (m, 1H), 3.78 - 3.95 (m, 3H), 3.52 (m, 2H), 3.40 (s, 3H), 3.30 (m, 2H), 3.02 - 3.16 (m, 3H), 2.96 (m, 1H), 2.00 - 2.17 (m, 3H), 1.55 - 1.95 (m, 8H), 1.30 (m, 2H); MS (ESI) m/z 468 (M+H)+.
Figure imgf000152_0001
Example 76
l,5-anhydro-2,3-dideoxy-4-0-methyl-3-{[(2S,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8- dihydro- l,6-naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]amino}-D-erythro- pentitol
The title compound was prepared and purified according to the method A described in Example 79G, and was isolated as the major product. Ή NMR (400 MHz, CDC13) δ 8.70 (s, 1H), 7.70 (s, 1H), 4.70 - 4.90 (m, 2H), 4.10 (m, 1H), 3.80 - 3.95 (m, 3H), 3.35 - 3.50 (m, 2H), 3.42 (s, 3H), 3.30 (m, 2H), 3.15 (m, 2H), 3.05 (m, 1H), 2.75 (m, lH), 2.35 (m, lH), 2.15 (m, 1H), 1.50 - 2.00 (m, 9H), 0.90-1.10 (m, 2H). MS (ESI) m/z 468 (M+H)+.
Figure imgf000152_0002
Example 77
l,5-anhydro-2,3-dideoxy-4-0-methyl-3- {[(2R,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8- dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]amino} -L-threo- pentitol
The title compound was isolated from the procedure of Example 75C. Ή NMR (400 MHz, CDCI3) δ 8.68 (s, 1H), 7.65 (s, 1H), 4.65 - 4.85 (m, 2H), 4.10 (dd, Ji = 12.0 Hz, h = 2.8 Hz, 1H), 3.80 - 3.95 (m, 3H), 3.30 - 3.45 (m, 2H), 3.38 (s, 3H), 3.25 (m, 2H), 3.12 (m, 2H), 3.00 (m, 1H), 2.70 (m, 1H), 2.35 (m, 1H), 2.10 (m, 1H), 1.48 - 1.95 (m, 9H), 1.20 (d, J= 6.0 Hz, 1H), 1.08 (m, 1H); MS (ESI) m/z 468 (M+H)+. ABS
Figure imgf000153_0001
Example 78
l,5-anhydro-2,3-dideoxy-4-0-methyl-3-{methyl[(2R,3aR,6aR)-3a-{[3-(trifluoromethyl)- 7,8-dihydro-l,6-naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]amino}-D- erythro-pentitol
To the solution of Example 79G (10 mg, 0.03 mmol) in dioxane (1 mL) was added formic acid (0.6 mL) and aqueous formalin solution (37%, 0.6 mL ). The mixture was heated at 80 °C overnight under nitrogen. The reaction mixture was concentrated in vaccum and was purified by HPLC to afford title compound as white solid (8.0 mg). Ή NMR (400 MHz, CD3OD) δ 8.70 (s, 1H), 8.06 (s, 1H), 4.75 - 4.90 (m, 2H), 4.30 (m, 1H), 3.90 - 4.10 (m, 4H), 3.50 - 3.72 (m, 4H), 3.45 (s, 3H), 3.15 (m, 2H), 2.78 (s, 3H), 2.60 (m, 1H), 1.85 - 2.20 (m, 9H), 1.80 (m, 1H), 1.58 (m, 1H), 1.42 (m, 1H); MS (ESI) m/z 482 (M+H)+.
To a solution of Example 78 (400 mg, 0.83 mmol) in MeOH (20 mL) was added succinic acid (98 mg 0.83 mmol) then the mixture was heated to 80 °C for 4 hours, then the solvent was concentrated under in vacuum to give the corresponding succinate salt (480 mg, 0.81 mmol, 96%). 'H NMR (400 MHz, CD3OD) δ 8.70 (s, 1H), 8.05 (s, 1H), 4.85 (m, 2H), 4.25 (m, 1H), 4.05 (m, 2H), 3.95 (m, 2H), 3.70 (s, 1H), 3.50 (m, 2H), 3.42 (s, 3H), 3.33 (m, 1H), 3.12 (m, 2H), 2.70 (s, 3H), 2.55 (m, 1H), 2.50 (s, 4H), 2.15 (m, 3H), 1.70 - 2.02 (m, 7H), 1.55 (m, 1H), 1.40 (m, 1H).
ABS
Figure imgf000153_0002
Example 79
l,5-anhydro-2,3-dideoxy-4-0-methyl-3- {[(2R,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8- dihydro- l,6-naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]amino}-D-erythro- pentitol
Method A
Example 79A
4,4-dimethoxytetrahydro-2H-pyran
To the solution of dihydro-2H-pyran-4(3H)-one (50 g, 0.5 mol) in MeOH (500 mL) was added TiCl4 (1 g, 5 mmol) and Et3N (500 mg, 5 mmol), and the mixture stirred at room temperature for 10 hours, followed by the addition of Et3N (2 g, 20 mmol). The mixture was concentrated to 100 mL, diluted by methyl tert-butyl ether (1.5 L) and washed with ¾0 (500 mL), and brine. The organic layer was dried over Na2S04, filtered, and concentrated to yield Example 79A (60 g, 84% yield). Example 79B
4,4-dimethoxytetrahydro-2H-pyran compound with 4-methoxy-3,6-dihydro-2H-pyran To the solution of Example 79A (60 g, 0.42 mol) in dichloromethane (800 mL) at -78 °C was added TiCl4 (84 g, 0.42 mol). The mixture was stirred at -78 °C for 1 hour, followed by the addition of pyridine (66 g, 0.84 mol) and KOH (47 g, 0.84 mol). The mixture was stirred at -78 °C for additional 0.5 hour then warmed to room temperature and stirred overnight. The mixture was filtered. The filtrate was washed with water (1 L), dried over MgS04, filtered, and concentrated to yield Example 79B (52 g, 100%).
Example 79C
4,4-dimethoxytetrahydro-2H-pyran-3-ol
To the solution of Example 79B (2 g, 17.5 mmol) in MeOH (50 mL) was added meta-chloroperoxy benzoic acid (6 g, 35 mmol) in MeOH (6 mL) at 0 - 6 °C via addition funnel. After addition, the mixture was stirred at 0 °C for 4 hours. Upon reaction completion, the mixture was concentrated to yield white solid, which was then dissolved in dichloromethane (40 mL). Calcium hydroxide (14.8 g, 200 mmol) was added to the solution, and the solution was stirred for an additional 2 hours. The mixture was filtered and the filtrate was concentrated to yield crude title compound (2 g, 66.7%), which was used into next step without further purification.
Example 79D 3-methoxydihydro-2H-pyran-4(3H)-one
To the mixture of NaH (60%, 5.04 g, 12.6 mmol) in THF (200 mL) was added Example 79C (20 g, 12.6 mmol) in THF (150 mL). The mixture was stirred at 0 °C for 0.5 hour, followed by addition of iodomethane (200 g, 15.5 mmol), and was stirred overnight. HC1 (12 M, 12 mL) was added to the mixture, stirred at room temperature for additional 1.5 hours and concentrated. The residue was purified by column
chromatography to Example 79D (20 g, 100%).
Example 79E
(3S,4S)-3-methoxy-N-((S)-l-phenylethyl)tetrahydro-2H-pyran-4-amine To the solution of Example 79D (20 g, 153.8 mmol) and (S)- 1 -phenylethanamine
(18.6 g, 153.8 mmol) in dichloromethane (200 mL) was added Ti(i-OPr)4 (87.7 g, 310 mmol) and diisopropylethyl amine (40 g, 310 mmoL). The mixture was then stirred at room temperature for 18 hours, following by addition of sodium triacetoxyborohydride (65.1 g, 310 mmol), and MeOH (15 mL). The mixture was stirred for additional 4 hours, then poured into saturated NaHC(¾ solution, stirred for 1.5 hours and filtered. The filtrate was extracted with dichloromethane (2 x 200 mL) and concentrated. The residue was purified by preparative HPLC followed by chiral SFC separation to yield title compound (10 g, 27.7%).
Example 79F
(3S,4S)-3-methoxytetrahydro-2H-pyran-4-amine
To the solution of Example 79E (5.8 g, 21.3 mmol) in EtOH (100 mL) was added Pd/C (6 g), and the mixture was then submitted to hydrogenolysis at 50 °C (¾, 50 Psi) for 48 hours. The mixture was filtered and the filtrate was concentrated to yield 1.5 g (55%) of Example 79F which was used into next step directly without further purification.
Example 79G
l,5-anhydro-2,3-dideoxy-4-0-methyl-3- {[(2R,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8- dihydro- l,6-naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]amino}-D-erythro- pentitol
To the mixture of Example 1H (4.8 g, 13.6 mmol), Example 79F (1.5 g, 0.87 mmol) in dichloroethane (120 mL) was added Ti(i-OPr)4 (974 mg, 3.48 mmol), N,N- diisopropylethyl amine (1.2 g, 10 mmol). The mixture was then stirred overnight followed by addition of NaBH4 (132 mg, 3.48 mmol) and MeOH (5 mL). The mixture was stirred for another 12 hours before it was poured into saturated NaHC(¾, stirred at room temperature for 2 hours, filtered, and the filtrate was extracted by dichloromethane (3 x 200 mL). The organic layer was concentrated and the residue was purified by preparative HPLC to afford a mixture of two diastereomers. This mixture was purified by chiral SFC to yield Exmaple 76 as the first eluent, as well as the title compound (600 mg) as the second eluent. Ή NMR (400 MHz, CDC13) δ 8.70 (s, 1H), 7.70 (s, 1H), 4.68 - 4.85 (m, 2H), 4.22 (m, 1H), 4.05 (m, 1H), 3.70 - 3.90 (m, 3H), 3.55 (m, 2H), 3.35 - 3.45 (m, 2H), 3.40 (s, 3H), 3.30 (m, 1H), 3.10 (m, 2H), 2.45 (m, 1H), 2.30 (m, 1H), 2.00 - 2.20 (m, 3H), 1.55 - 1.95 (m, 6H), 1.30 (m, 2H); MS (ESI) m/z 468 (M+H)+.
The succinate salt of the above compound was prepared as follows: A mixture of free base of Example 79G (600 mg, 1.25 mmol), succinic acid (152 mg, 1.25 mmol) in EtOH (50 mL) was heated at 65 °C for 2 hours and then concentrated. The residue was washed with Et20 (25 mL) to yield white solid (610 mg, 86.4%). Ή NMR (400 MHz, CD3OD) δ 8.70 (s, 1H), 8.05 (s, 1H), 4.85 (m, 2H), 4.22 (d, J= 14.8 Hz, 1H), 3.95 (m, 3H), 3.70 (m, 1H), 3.30 - 3.53 (m, 4H), 3.38 (s, 3H), 3.12 (m, 2H), 2.55 (m, 1H), 2.52 (s, 4H), 2.15 (m, 1H), 1.70 - 2.05 (m, 9H), 1.55 (m, 1H), 1.38 (m, 1H).
Method B
Example 79H
( 1 R,4S)-methyl 4-aminocyclopent-2-enecarboxylate To a cooled mixture of (lR,4S)-2-azabicyclo[2.2.1]hept-5-en-3-one (13 g, 1 19 mmol) in MeOH (150 mL) was added SOCI2 (20 mL) dropwise to keep the temperature of the reaction under 15 °C. Upon completion of addition, the mixture was stirred at 5 °C for 3 hours. The solvent was removed under reduced pressure to yield liquid, which was dried under high vacuum to give Example 79H as white solid (23 g).
Example 791
(lR,4S)-methyl 4-(2,5 -dimethyl- lH-pyrrol-l-yl)cyclopent-2-enecarboxylate To a mixture of Example 79H (23 g, 163 mmol) in MeOH (100 ml) was added diisopropylethyl amine (23 g, 179 mmol) and acetyl acetone (20 g, 170 mmol), then the mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure, and the crude product was purified by column chromatography (S1O2, petroleum ethenEtOAc = 20: 1) to give Example 791 as yellow oil (20 g).
Example 79J (lR,4S)-methyl 1 -(3-bromopropyl)-4-(2,5-dimethyl- lH-pyrrol- 1 -yl)cyclopent-2- enecarboxylate
To a solution of Example 791 (16.5 g, 74.4 mmol) in THF (200 ml) was added dropwise lithium hexamethyl bis(trimethylsilyl)amide (1 M, 1 19 mL) at -50 °C, stirredd for 1 hour, allowed to warm to -20 °C, followed by the dropwise addition of 1,3- dibromopropane (150 g, 744 mmol) over 1 hour. The reaction mixture was stirred at -20 °C for 1 hour, quenched with aqueous NH4C1 solution (6%, 600 mL), and extracted with ethyl acetate. The organic layer was washed with NH4CI solution, brine, dried over Na2S04, filtered, and concentrated. The residued was purified by silica gel column chromatography (petroleum ethenEtOAc = 80: 1) to give Example 79J (16 g).
Example 79K
(2R,3aR,6aR)-methyl 2-(2,5-dimethyl- lH-pyrrol- 1 -yl)octahydropentalene-3a-carboxylate To a solution of compound 79 J (16 g, 47 mmol) and azobisisobutyronitrile (1.6 g, 10 mmol) in toluene (1.8 L) was added a solution of tributyl tin hydride (32 mL) in toluene (200 mL) at 1 10 °C over 1 hour. After refluxing for 3 hours, the reaction mixture was quenched by saturated aqueous KF (200 mL), and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2S04; filtered, and concentrated. The residue was purified by column chromatography (S1O2, petroleum ethenEtOAc = 50: 1) to give compound Example 79K (8 g) as white solid.
Example 79L
(2R,3aR,6aR)-2-(2,5-dimethyl-lH-pyrrol-l-yl)octahydropentalene-3a-carboxylic acid To a solution of Example 79K (5.3 g, 20.3 mmol) in MeOH (33 mL) and water (15 mL) was added a aqueous solution of NaOH (3.2 g, 80 mmol in 4 mL water) and the mixture was heated at 65 °C for 16 hours. The mixture was cooled to room temperature, adjusted the pH to about 4 with HC1 solution (4 N) and filtered to collect Example 79L (4.5 g) as yellow solid and used in next step without purification.
Example 79M
((2R,3aR,6aR)-2-(2,5-dimethyl- lH-pyrrol- 1 -yl)octahydropentalen-3a-yl)(3- (trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl)methanone To a solution of compound Example 79L (5 g, 20.2 mmol) in dichloromethane (50 mL) was added hydroxybenzotriazole (4.2 g, 30.9 mmol), l-ethyl-3-(3- dimethylaminopropyl) carbodiimide hydrochloride (5.8 g, 30.4 mmol), and Et3N (6.0 g, 59.4 mmol), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was suspended in water and extracted with dichloromethane (3 x 300 mL). The combined organic layer was washed with brine, dried over Na2S04, filtered, and concentrated to result in the title compound (8 g), which was used in the next step without purification.
Example 79N
((2R,3aR,6aR)-2-aminooctahydropentalen-3a-yl)(3-(trifluoromethyl)-7,8-dihydro- l,6- naphthyridin-6(5H)-yl)methanone
To a solution of Example 79M (8.0 g, 18.6 mmol) in MeOH (100 mL) was added hydroxylamine hydrochloride (8.0 g, 1 15.9 mmol), 50% hydroxylamine hydrate (12 mL) and ¾0 (40 mL). The mixture was heated at reflux for 13 hours and cooled to room temperature. The mixture was treated with NaOH (10 N) to adjust the pH to about 1 1, and extracted with dichloromethane (3 x 300 mL). The combined organic layer was washed with brine, dried over MgS04, filtered, and concentrated. A solution of HCl in EtOAc (30 mL) was added to the residue with stirring at room temperature for 1 hour. The solvent was removed and the HCl salt of Example 79N (6.5 g) was used for next step without purification.
Example 790
tert-butyl(3,6-dihydro-2H-pyran-4-yloxy)dimethylsilane To a mixture of the tetrahydro-4H-pyran-4-one (38.9 g, 0.38 mol) and Et3N (76.8 g, 0.76 mol) in dichloromethane (800 mL) was added trimethyl trifluoromethanesulfonate (105.5 g, 0.399 mol) dropwise over 3 hours. After addition, the reaction was allowed to warm to room temperature and stirred overnight. Water was added and the resulting solution was extracted with dichloromethane (2 x 500 mL). The combined organic phase was washed with water (2 x 500 mL) and brine (2 x 200 mL), dried over Na2S04, filtered, and concentrated to give Example 790 (78 g, 85%) as an oil.
Example 79P
sodium (3R)-3,4-dihydroxytetrahydro-2H-pyran-4-sulfonate To a solution of (DHQD^PHAL (hydroquinidein 1 ,4-phthalazinediyl diether) (3.06 g, 3.93 mol), K20s04 (723 mg, 1.96 mol) and N-methylmorpholine-N-oxide (58.4 g, 0.432 mol) in acetone/H20 (700 mL, 10/1) at 0 °C was added slowly a solution of Example 790 (84 g, 0.393 mol) in acetone (100 mL) for 5 hours. The resulting solution was stirred at 10-20 °C overnight. A freshly prepared solution of Na2S20s (44.8 g, 0.236 mol) in water (315 mL) was added followed by acetic acid (67.3 mL). After stirring for 16 hours at room temperature, the solid was filtered and washed with isopropanol (400 mL) and dried to provide Example 79P (60 g, 73%) as a white solid.
Example 79Q
(R)-4,4-dimethoxytetrahydro-2H-pyran-3-ol To a solution of Example 79P (60 g, 0.294 mol) and HC(OCH3)3 (69.3 g, 0.647 mol) in MeOH (500 mL) at 50 °C was added HCl/MeOH (68 mL, 5-6 N) slowly over 30 minutes. Then the slurry was cooled to 5 °C and 50% of NaOH (100 mL in water) was added over 1 hour. The solid was filtered and the filtrate was concentrated. The resulting solution was washed with toluene for several times and then concentrated to give Example 79Q (38 g, yield: 88%) as an oil.
Example 79R
(R)-3-methoxydihydro-2H-pyran-4(3H)-one To a solution of Example 79Q (9.5 g, 64.68 mol) in THF (300 mL) was added sodium tert-butoxide (9.3 g, 97.02 mmol) at ice bath. Then dimethyl sulfate (13.4 g, 106 mmol) was added over 20 minutes, maintaining an interal temp below 36 °C. After addition, the reaction mixture was stirred for 4 hours at room temperature. Water (200 mL) was added followed by addition of 2N HC1 (100 mL). The apparent pH is below 1. After 16 hours of reaction, NaHC(¾ (20 g) was added and the mixture was extracted with EtOAc (4 x 300 mL), dried over Na2S04, filtered, and concentrated to give Example 79R (6 g, yield: 71 %) as an oil.
Example 79G
l,5-anhydro-2,3-dideoxy-4-0-methyl-3- {[(2R,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8- dihydro- l,6-naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]amino}-D-erythro- pentitol
A solution of Example 79N (3.2 g, 9.0 mmol) in isopropyl acetate (80 mL) was cooled with ice bath and tributylamine (3.3 g, 20.7 mmol) was added dropwise, followed by the addition of isopropyl alcohol (1.6 ml, 20.7 mmol). Sodium triacetoxyborohydride (4.4 g, 20.7 mmol) was added. After 1 hour at room temperature, a solution of Exampole 79R (1.75 g, 13 mmol) in isopropyl acetate (10 mL) was added to the mixture at 1 °C. Then the mixture was stirred at room temperature for 15 hours and partitioned between satureated aqueous NaHC(¾ (80 mL), water (50 mL) and EtOAc (400 mL). The aqueous phase was further extracted with EtOAc (200 mL). The combined organic phase was washed with saturated.aqeous NaHC03 solution, dried with Na2S04, filtered, concentrated. The residue was purified by column chromatography (S1O2,
dichloromethane:MeOH = 20: 1) to give Example 79G as a mixture of diastereomers, which was then further purified by chiral SFC to yield title compound as the first eluent and white solid upon concentration, as well as Example 80 as the second eluent.
Figure imgf000160_0001
Example 80
l ,5-anhydro-2,3-dideoxy-4-0-methyl-3- {[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8- dihydro- l ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2-yl]amino}-D-threo- pentitol
The title compound was obtained from the procedure of Example 79G via Method
B. Ή NMR (400 MHz, CD3OD) δ 8.60 (s, 1H), 7.95 (s, 1H), 4.60 - 4.85 (m, 2H), 4.12 (m, 1H), 3.85 (m, 3H), 3.65 (m, 1H), 3.30 - 3.45 (m, 4H), 3.30 (s, 3H), 3.20 (m, 2H), 2.98 (m, 2H), 2.45 (m, 1H), 1.60 - 1.95 (m, 8H), 1.45 (m, 1H), 1.25 (m, 1H); MS (ESI) m/z 468 (M+H)+.
Figure imgf000160_0002
Example 81
(3S)- 1 -(4-fluorophenyl)-3- {[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2-yl]amino}pyrrolidin-2-one
Example 81 A l
(S)-benzyl 1 -(4-fluorophenylamino)-4-(methylthio)- 1 -oxobutan-2-ylcarbamate To a solution of 4-fluoroaniline (2.0g, 18 mmol), N-carbobenzyloxy-L-methionine (5.03 g) in THF (80 ml) was added 4-(dimethylamino)pyridine (7.38 mmol), hydroxybenzotriazole (24.44 mmol), 2-(7-Aza- lH-benzotriazole-l- yl)- 1,1 ,3,3- tetramethyluronium hexafluorophosphate (21.053 mmol), and triethylamine (39.6 mmol). The resulting mixture was stirred at room temperature overnight. Upon completion of the reaction, the reaction mixture was concentrated and the residue partitioned between 20% Na2C03 (200 mL) and EtOAc (200 mL). The organic layer was washed with 20%
Na2C(¾ (2 x 60 mL), water (30 mL), brine, dried over Na2S04, filtered, and concentrated. The residue was purified by column chromatography on silica gel to give Example 81A1 in 70% yield as a white solid. MS m/z (M+H)+ 377.
Example 81A2
(S)-(3-(benzyloxycarbonylamino)-4-(4-fluorophenylamino)-4- oxobutyl)dimethylsulfonium iodide
A solution of Example 81A1 (1.5 g,3 .8 mmol) in CH3I (15 mL) was stirred at room temperature for 24 hours and filtered to yield Example 81A2 as yellow solid, which was used in the next step without purification.
Example 81 A3
(S)-benzyl l-(4-fluorophenyl)-2-oxopyrrolidin-3-ylcarbamate To a solution of Example 81A2 (800 mg, 2.84mmol) in THF (10 mL) was added NaH (6.75 mmol). The resulting mixture was stirred at room temperature overnight. Upon completion of the reaction, the mixture was partitioned between EtOAc (300 mL) and H2O (100 mL) and the organic layer was concentrated. The residue was purified by column chromatography on silica gel (petroleum ethenEtOAc 1 :2) to yield Example 81 A3 in 80% yield as a white solid. MS m/z (M+H)+ 329.
Example 81A
(S)-3-amino- 1 -(4-fluorophenyl)pyrrolidin-2-one To a solution of Example 81 A3 (3 g, 9.15 mmol) in EtOH (50 mL) was added
Pd(OH)2 (200 mg). The mixture was stirred at 50 °C for 18 hour under ¾ (50 psi ) and filtered. The filtrate was combined, concentrated in cavuum to give Example 81A in 80% yield as a white solid.
Example 8 IB
(3S)- 1 -(4-fluorophenyl)-3- {[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]amino}pyrrolidin-2-one The title compound was prepared and purified according to the procedure described in Example 1J, substituting Example 81A for Example II, and obtained as trifluoroacetic acid salt. 'H NMR (400 MHz, CDC13) δ 8.67 (s, 1H), 7.70 (s, 1H), 6.87 (m, 2H), 7.00 (m, 2H), 4.70 (m, 2H), 4.02 (m, 1H), 3.70 - 3.90 (m, 4H), 3.50 (m, 1H), 3.32 (m, 1H), 3.02 (m, 3H), 2.40 - 2.65 (m, 4H), 2.30 (m, 1H), 2.10 (m, 1H), 1.87 (m, 1H), 1.55 - 1.70 (m, 5H), 1.45 (m, 1H); MS (ESI) nVz 531 (M+H)+.
Figure imgf000162_0001
Example 82
[(2R,3aR,6aR)-2-(tetrahydro-2H-pyran-4-ylamino)hexahydropentalen-3a(lH)-yl][3- (trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone The title compound was prepared and purified according to the procedure described in Method B in Example 79G, substituting dihydro-2H-pyran-4(3H)-one for Example 79R. Ή NMR (400 MHz, CDC13) δ 8.72 (s, 1H), 7.80 (s, 1H), 4.70 - 4.85 (m, 2H), 4.05 (m, 1H), 3.70 - 3.90 (m, 2H), 3.30 - 3.45 (m, 3H), 3.20 (m, 3H), 3.02 (m, 2H), 240 (m, 1H), 2.15(m, 1H), 2.05 (m, 1H), 1.55 - 1.95 (m, 9H), 1.35 (m, 3H); MS (ESI) m/z 438 (M+H)+.
Figure imgf000162_0002
Example 83
((2R,3aR,6aR)-2-(4,4-difluorocyclohexylamino)octahydropentalen-3a-yl)(3- (trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl)methanone
The title compound was prepared and purified according to the procedure described in Example 1 J, substituting 4,4-difluorocyclohexylamine for Example II. Ή- NMR (400 MHz, CDCI3) δ 8.68 (s, 1H), 7.63 (s, 1H), 4.60 - 4.85 (m, 2H), 3.35 (m, 2H), 3.20 - 3.40 (m, 2H), 2.95 - 3.10 (m, 3H), 2.50 (m, 1H), 2.25 (m, 1H), 2.00 - 2.20 (m, 2H), 1.90 (m, IH), 1.60 - 1.80 (m, 6H), 1.50 (m, 2H), 1.30 (m, 6H); MS (ESI ) m/z 472 (M+H)+.
Figure imgf000163_0001
Example 84
[(2R,3aR,6aR)-2-[(3,3-difluorocyclobutyl)amino]hexahydropentalen-3a(lH)-yl][3- (trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone The title compound was prepared and purified according to the procedure described in Example 1 J, substituting 3,3-difluorocyclobutanamine for Example II. Ή NMR (400 MHz, CDC13) δ 8.65(s, IH), 7.62 (s, IH), 4.60 - 4.85 (m, 2H), 3.85 (m, 3H), 3.35 (m, IH), 3.20 (m, IH), 3.05 (m, 2H), 2.92 (m, lH), 2.75 (m, 2H), 2.35 (m, 3H), 2.15 (m, IH), 1.90 (m, IH), 1.50 - 1.80 (m, 6H), 1.10 (m, IH); MS (ESI) m/z 444 (M+H)+.
Figure imgf000163_0002
Example 85
[(2S,3aR,6aR)-2-[(3,3-difluorocyclobutyl)amino]hexahydropentalen-3a(lH)-yl][3- (trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]methanone
The title compound was obtained from the procedure of Example 84. Ή NMR (400 MHz, CDCI3) δ 8.64 (s, IH), 7.62 (s, IH), 4.60 - 4.80 (m, 2H), 3.82 (m, 2H), 3.48 (m, IH), 3.25 (m, 2H), 3.05 (m, 2H), 2.95 (m,lH), 2.75 (m, 2H), 2.45 (m, 3H), 1.50 - 2.10 (m, 8H), 1.20 (m, IH); MS (ESI) m/z 444 (M+H)+.
Figure imgf000163_0003
Example 86
(3S)- 1 -(4-fluorophenyl)-3- {[(2S,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2-yl]amino}pyrrolidin-2-one The title compound was obtained from the procedure of Example 8 IB. Ή NMR (400 MHz, CDC13) δ 8.70 (s, 1H), 7.65 (s, 1H), 7.50 (m, 2H), 7.03 (m, 2H), 4.65 - 4.85 (m, 2H), 3.75 - 3.95 (m, 5H), 3.45 (m, 1H), 3.30 (m, 1H), 3.10 (m, 2H), 2.50 (m, 2H), 2.34 (m, 1H), 2.20 (m, 1H), 1.60 - 2.00 (m, 6H), 1.55 (m, 1H), 1.30 (m, 2H); MS (ESI) m/z 531 (M+H)+.
A
Figure imgf000164_0001
Example 87
(3S)-3- {[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- l ,6-naphthyridin-6(5H)- yl]carbonyl} octahydropentalen-2-yl]amino}pyrrolidin-2-one The title compound was prepared and purified according to the procedure described in Example 1 J, substituting (S)-3-aminopyrrolidin-2-one for Example II. Ή NMR (400 MHz, CDC13) δ 8.65 (s, 1H), 7.63 (s, 1H), 5.65 (m, 1H), 4.72 (m, 2H), 3.80 (m, 2H), 3.20 - 3.50 (m, 5H), 3.05 (m, 2H), 2.40 (m, 1H), 2.15 (m, 1H), 1.50 - 1.95 (m, 9H), 1.30 (m, 2H); MS (ESI) m/z 437 (M+H)+.
Figure imgf000164_0002
Example 88
(3S)- l-phenyl-3- {[(2S,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- l ,6-naphthyridin- 6(5H)-yl]carbonyl} octahydropentalen-2-yl]amino}pyrrolidin-2-one
Example 88 A 1
(S)-benzyl 4-(methylthio)- 1 -oxo- 1 -(phenylamino)butan-2-ylcarbamate The title compound was prepared and purified according to the procedure described in Example 81A1, substituting aniline for 4-fluoroaniline.
Example 88A2
(S)-(3-(benzyloxycarbonylamino)-4-oxo-4-(phenylamino)butyl)dimethylsulfonium iodide The title compound was prepared and purified according to the procedure described in Example 81A2, substituting Example 88A1 for 81A1.
Example 88A3
(S)-benzyl l-(4-fluorophenyl)-2-oxopyrrolidin-3-ylcarbamate The title compound was prepared and purified according to the procedure described in Example 81 A3, substituting Example 88A2 for 81A2.
Example 88A
(S)-3 -amino- 1 -phenylpyrrolidin-2-one
The title compound was prepared and purified according to the procedure described in Example 81 A, substituting Example 88 A3 for 81 A3.
Example 88B
(3S)- l-phenyl-3-{[(2S,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]carbonyl}octahydropentalen-2-yl]amino}pyrrolidin-2-one The title compound was prepared and purified according to the procedure described in Example 1 J, substituting Example 88A for Example II. Ή NMR (400 MHz, CDC13) δ 8.70 (s, 1H), 7.75 (m, 1H), 7.45 (m, 2H), 7.35 (m, 2H), 7.18 (m, 1H), 4.65 -
4.90 (m, 2H), 4.10 (m, 1H), 3.90 (m, 1H), 3.80 (m, 2H), 3.70 (m, 1H), 3.45 (m, 2H), 3.05 (m, 2H), 2.55 (m, 3H), 2.25 (m, 2H), 2.05 (m, 1H), 1.55 - 1.85 (m, 6H), 1.50 (m, 1H); MS (ESI) m/z 513 (M+H)+.
Figure imgf000165_0001
Example 89
(3S)-3-{[(2S,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)- yl]carbonyl}octahydropentalen-2-yl]amino}pyrrolidin-2-one The title compound was obtained from the procedure of Example 87. Ή NMR (400 MHz, CDCI3) δ 8.65 (s, 1H), 7.62 (s, 1H), 6.15 (m, 1H), 4.65 - 4.85 (m, 2H), 3.80 (m, 2H), 3.20 - 3.45 (m, 4H), 2.90 - 3.10 (m, 3H), 1.50 - 2.45 (m, 11H), 1.48 (m, 1H), 1.10 (m, 1H); MS (ESI) nVz 437 (M+H)+.
Figure imgf000166_0001
Example 90
(3S)- 1 -phenyl-3- {[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin- 6(5H)-yl]carbonyl}octahydropentalen-2-yl]amino}pyrrolidin-2-one The title compound was obtained from the procedure of Example 88B. Ή NMR (400 MHz, CDC13) δ 8.65 (s, 1H), 7.65 (m, 1H), 7.52 (m, 2H), 7.30 (m, 2H), 7.05 (m, 1H), 4.60 - 4.85 (m, 2H), 3.50 - 3.95 (m, 5H), 3.40 (m, 1H), 2.85 - 3.08 (m, 3H), 2.20 - 2.45 (m, 3H), 1.45 - 1.95 (m, 8H), 1.00 - 1.25 (m, 2H); MS (ESI) m/z 513 (M+H)+.
Figure imgf000166_0002
Example 91
3-{(3R,4S)-3-methyl-l-[(3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}benzoic acid and
3-((3S,4R)-3-methyl-l-((3aR,6aR)-3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-l,6- naphthyridine-6-carbonyl)octahydropentalen-2-yl)piperidin-4-yl)benzoic acid
Example 91 A
methyl 3- {(3R,4S)-3-methyl- 1 -[(3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- 1,6- naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}benzoate and
methyl 3-{(3S,4R)-3-methyl-l-[(3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro- l,6- naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}benzoate The title compound was prepared according to the procedure described in Example 92E, substituting Example 92D 1 for Example 92D and purified by HPLC to provide a mixture of diasteoromers.
Example 9 IB
3-{(3R,4S)-3-methyl-l-[(3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}benzoic acid and
3-((3S,4R)-3-methyl-l-((3aR,6aR)-3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-l,6- naphthyridine-6-carbonyl)octahydropentalen-2-yl)piperidin-4-yl)benzoic acid The title compound was prepared and purified according to the procedure described in Example 92F, substituting Example 91 A for Example 92E. Ή NMR (400 MHz, CD3OD): 88.72 (s, 1H), 8.04 (s, 1H), 7.90 (m, 2H), 7.49 (m, 2H), 4.85 (m, 2H), 3.97 (m, 2H), 3.65 (m, 2H), 3.43 (m, 2H), 3.14 (m, 2H), 2.80 (m, 2H), 2.50 (m, 2H), 1.70 - 2.20 (m, 10H), 1.50 - 1.65 (m, 2H), 0.75 (d, J= 4.0Hz, 3H).
Figure imgf000167_0001
Example 92
3-{(3S,4R)-3-methyl-l-[(2S,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro- l,6- naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}benzoic acid
Example 92A
l-benzyl-3-methyl-l,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate
To a solution of lithium hexamethyl bis(trimethylsilyl)amide in THF (1M, 148 mL, 148 mmol) was added 150 mL of THF, followed by the addition of a solution of 1- benzyl-3-methylpiperidin-4-one (25 g, 123 mmol) in THF (120 mL) at -78 °C, maintaining the internal temperature < -65°C. After stirring for 2 hours at -78 °C, a solution of N-phenyl-trifluoromethansulfonimid (53 g, 148 mmol) in THF (200 mL) was added over 10 minutes. The mixture was allowed to warm to 0 °C and stirred for another 4 hours at 0 °C. The yellow solution was quenched with 1 mL of saturated ammonium chloride solution, diluted with ice-cold water and extracted three times with ethyl acetate. The organic layers were washed with brine, dried over sodium sulphate, filtered, and concentrated. The residue was taken into dichloromethane. The solid was filtered off and washed with dichloromethane two times. The filtrate was concentrated to give Example 92A (40g, yield 98%).
Example 92B
methyl 3-(l -benzyl-3-methyl- 1 ,2,3,6-tetrahydropyridin-4-yl)benzoate
To a solution of Example 92A (42 g, 125 mmol) and 3-(methoxycarbonyl) phenylboronic acid (26 g, 144 mmol) in toluene: EtOH (10: 1, 550 mL) was added PdCl2(PPli3)2 (4.23 g, 6.25 mmol) and potassium carbonate (33 g, 240 mmol). The mixture was heated at 100 °C for 6 hours. The cooled reaction mixture was partitioned between EtOAC and ¾0 and the aqueous layer was extracted with EtOAc (4.x). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with a gradient of hexanes: EtOAc to give Example 92B (30 g, yield 75%) as white solid.
Example 92C
trans-methyl 3-(l -benzyl-3-methylpiperidin-4-yl)benzoate A mixture of Example 92B (30 g, 93 mmol) in EtOAc (400 mL) was submitted to hydrogenolysis for 18 hours under ¾ (30 psi) in the presence of a catalytic amount (3 g) of platinum oxide. Platinum oxide was filtered through a celite plug and the filtrate was evaporated in vacuum to dryness. The resulting yellow oil was purified by column chromatography on silica gel eluting with a gradient of hexane: EtOAc to result a mixture of two trans- isomers.
Example 92D 1
trans-methyl 3-(l -benzyl-3-methylpiperidin-4-yl)benzoate
A mixture of Example 92C (5 g, 15.5 mmol) in EtOH (100 mL) was submitted to hydrogenolysis for 10 hours under ¾ (45 psi) in the presence of a catalytic amount (1 g) of Pd/C. The Pd/C was filtered through a celite plug and the filtrate was concentrated to give Example 92D 1 as a mixture of two trans diastereomers.
Example 92D
methyl 3-((3S,4R)3-methylpiperidin-4-yl)benzoate The title compound was obtained by chiral SFC separation of Example 92D 1 as one of the enantiomers. Example 92E
methyl 3-((3S,4R)-3-methyl- 1 -((2S,3aR,6aR)-3a-(3-(trifluoromethyl)-5,6,7,8-tetr ahydro- l,6-naphthyridine-6-carbonyl)octahydropentalen-2-yl)piperidin-4-yl)benzoate To a mixture of Example 92D (66 mg, 0.28 mmol), Example 1H (100 mg, 0.28 mmol), and diisopropylethyl amine (145 mg, 1 1.36 mmol) in dichloroethane (4 mL) was added Ti-(OiPr)4 (323 mg, 11.36 mmol) at room temperature. The mixture was stirred at room temperature for 12 hours. NaBH4 (54 mg, 14.2 mmol) and methanol (0.5 mL) was added to the resulting mixture and stirred for another 2 hours at room temperature, washed with aqueous NaHC(¾ (20 mL), and extracted with dichloromethane (3 x 30 mL). The organic layer was dried over Na2S04, filtered, and concentrated. The residue was purified by HPLC and SFC to give Example 92E (40 mg, 24.8%) as a light yellow solid.
Example 92F
3-{(3S,4R)-3-methyl-l-[(2S,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro- l,6- naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2-yl]piperidin-4-yl}benzoic acid To a solution of Example 92E (60 mg, 0.105 mmol) in ethanol (2 mL) and water (1 mL) was added LiOH.FLO (17.7 mg, 0.42 mmol) in one portion. The mixture was stirred for 12 hours at room temperature. TLC (MeOH: dichloromethane^ 1 : 15) indicated that the reaction was completed. The mixture was acidified by aqueous 0.5 N HC1 to adjust the pH to about 5, and extracted with dichloromethane (10 mLx3). The organic layer was dried over Na2S04, filtered, and concentrated to give Example 92 (10 mg, 17.1 %) as a white solid. Ή NMR (400 MHz, CD3OD) δ 8.70 (s, 1H), 8.06 (s, 1H), 7.92 (m, 2H), 7.48 (m, 2H), 4.85 (m, 2H), 3.95 (m, 2H), 3.65 (m, 2H), 3.41 (m, 2H), 3.10 (m, 2H), 2.78 (m, 2H), 2.50 (m, 2H), 2.0 - 2.3 (m, 5H), 1.55 - 1.95 (m, 7H), 0.76 (d, 3H); MS (ESI) m/z (M+H)+ 556.
Figure imgf000169_0001
Example 93 3- {(3S,4R)-3-methyl- 1 -[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}benzoic acid
Example 93A
methyl 3-((3S,4R)-3-methyl -((2R,3aR,6aR)-3a-(3-(†jifluoromethyl)-5,6,7,8-tetrahydro- l,6-naphthyridine-6-carbonyl)octahydropentalen-2-yl)piperidin-4-yl)benzoate The title compound was prepared and purified according to the procedure described in Example 92E.
Example 93B
3- {(3S,4R)-3-methyl- 1 -[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}benzoic acid The title compound was prepared and purified according to the procedure described in Example 92F, substituting Example 93 A for Example 92E. Ή NMR (400 MHz, CD3OD) δ 8.63 (s, 1H), 7.95 (s, 1H), 7.80 (m, 2H), 7.38 (m, 2H), 4.85 (m, 2H), 3.70 - 4.00 (m, 3H), 3.45 - 3.65 (m, 3H), 3.06 (m, 2H), 2.65 - 2.85 (m, 2H), 2.50 (m, 1H), 1.80 - 2.15 (m, 9H), 1.70 (m, 1H), 1.49 (m, 2H), 1.30 (m, 1H), 0.68 (d, J= 6.8 Hz, 3H); MS (ESI) nVz (M+H)+ 556.
Figure imgf000170_0001
Example 94
3-{(3R,4S)-3-methyl-l-[(2S,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro- l,6- naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}benzoic acid
Example 94A
methyl 3-((3R,4S)-3-methylpiperidin-4-yl)benzoate The title compound was obtained by chiral SFC separation of Example 92D 1 as the other enantiomers.
Example 94B
methyl 3-((3R,4S)-3-methyl- 1 -((2S,3aR,6aR)-3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro- l,6-naphthyridine-6-carbonyl)octahydropentalen-2-yl)piperidin-4-yl)benzoate The title compound was prepared and purified according to the procedure described in Example 92E substituting Example 94A for Example 92D.
Example 94C
3-{(3R,4S)-3-methyl-l-[(2S,3aR,6aR)-3a-{[3-(trifiuoromethyl)-7,8-dihydro- l,6- naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2-yl]piperidin-4-yl}benzoic acid The title compound was prepared and purified according to the procedure described in Example 92F, substituting Example 94B for Example 92E. Ή NMR (400 MHz, CD3OD) δ 8.70 (s, 1H), 8.05(s, 1H), 7.90 (m, 2H), 7.46 (m, 2H), 4.85 (m, 2H), 3.98 (m, 2H), 3.60-3.75 (m, 2H), 3.45 (m, 2H), 3.10-3.20 (m,2H), 2.70-2.90 (m, 2H), 2.40- 2.60 (m, 2H), 2.0-2.30 (m, 5H), 1.55-1.95 (m, 7H), 0.75 (d,J=6.0 Hz, 3H); MS (ESI) m/z (M+H)+ 556.
Figure imgf000171_0001
Example 95
3- {(3R,4S)-3-methyl- 1 -[(2R,3aR,6aR)-3a- { [3-(trifluoromethyl)-7,8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2-yl]piperidin-4-yl}benzoic acid
Example 95A
methyl 3-((3R,4S)-3-methyl- l-((2R,3aR,6aR)-3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro- l,6-naphthyridine-6-carbonyl)octahydropentalen-2-yl)piperidin-4-yl)benzoate The title compound was obtained from the procedure of Example 94B.
Example 95B
3- {(3R,4S)-3-methyl- 1 -[(2R,3aR,6aR)-3a- { [3-(trifluoromethyl)-7,8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}benzoic acid The title compound was prepared and purified according to the procedure described in Example 92F, substituting Example 95A for Example 92E. Ή NMR (400 MHz, CD3OD) δ 8.70 (s, 1H), 8.07 (s, 1H), 7.90 (m, 2H), 7.46 (m, 2H), 4.85 (m, 2H),
3.80 - 4.05 (m, 3H), 3.60 - 3.70 (m, 3H), 3.15 (m, 2H), 2.75 - 2.90 (m,2H), 2.55 (m, 1H), 1.90 - 2.20 (m, 8H), 1.80 (m, 1H), 1.55 (m, 1H), 1.40 (m, 1H), 0.75 (d, 3H); MS (ESI) m/z (M+H)+ 556. ABS
Figure imgf000172_0001
Example 96
3- { 1 -[(2S,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)- yl] carbonyl} octahydropentalen-2-yl]piperidin-4-yl} benzonitrile
Example 96A
tert-butyl 4-(3-cyanophenyl)-5,6-dihydropyridine- 1 (2H)-carboxylate
To a mixture of Example 9A1 (16 g, 49 mmol), 3-cyanophenylboronic acid (6 g, 41 mmol) and 2M Na2C03 (49 mL, 98 mmol) in DME (200 mL) was added Pd(PPh3)4 (1.6 g, 1.47 mmol) at room temperature under N2. Then the mixture was heated at 90 °C for 4 hours and stirred at room temperature overnight. The mixture was filtered and the filtrate was diluted with ethyl acetate and washed with brine, dried (MgS04), filtered, and concentrated. The residue was purifiedby lolumn chromatography on silica gel to afford Example 96A (10 g, 86%) as a white solid.
Example 96B
3-(l ,2,3,6-tetrahydropyridin-4-yl)benzonitrile
To a solution of Example 96A (5 g, 17.6 mmol) in dichloromethane (20 ml) was added trifluoroacetic acid (20 mL) and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated to afford Example 96B as trifluoroacetic acid salt (4 g).
Example 96C
3-(l-((2S,3aR,6aR)-3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-l,6-naphthyridine-6- carbonyl)octahydropentalen-2-yl)-l,2,3,6-tetrahydropyridin-4-yl)benzonitrile To a mixture of Example 96B (1.5 g, 4.26 mmol) and Example 1H (1.13 g, 5.1 1 mmol) in dichloroethane (50 mL) was added titanium(IV) isoprpoxide (4.8 g, 17 mmol) and diisopropylethyl amine (2.7 g, 21.3 mmol). The mixture was stirred at room temperature overnight. NaBH4 (0.81 g, 21.3 mmol) and methanol (3 mL) was added and stirred overnight. The reaction mixture was diluted with dichloromethane (30 mL) and quenched with saturated NaHC(¾ (20 mL). After stirring for 30 minutes, the mixture was filtered and rinsed with dichloromethane. The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated. The residue was purified by chiral SFC to afford Example 96C (1.0 g) as solid.
Example 96D
3- { 1 -[(2S,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)- yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}benzonitrile The mixture of Example 96C (0.5 g, 0.96 mmol) and Pd(OH)2 (0.2 g ) in ethanol (30 ml) was heated at 40 °C under ¾ (50 psi) overnight, and filtered. The filtrate was concentrated to afford Example 96D (90 mg, 18%). Ή NMR (400 MHz, CDC13) δ ppm 8.70 (s, 1 H), 7.81 (s, 1 H), 7.38 - 7.50 (m, 4 H), 4.65 - 4.88 (m, 2 H), 3.70 - 3.92 (m, 4H), 3.35 (m, 2H), 3.15 (m, 3H), 2.70 (m, 2H), 2.50 (m,lH), 2.10 - 2.40 (m, 3H), 1.92 - 2.06 (m, 3H),1.50 - 1.90 (m, 7H); MS (ESI+) m/z 523 (M+H)+.
ABS
Figure imgf000173_0001
Example 97
3-{ l-[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)- yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}benzonitrile The title compound was prepared and purified according to the procedure described in Example 96D, substituting Example 108 for Example 96C. Ή NMR (400 MHz, CDCI3) δ 8.67 (s, 1H), 7.80 (m, 1H), 7.40 (m, 3H), 7.15 (m, 1H), 4.75 (m, 2H), 3.40 - 4.0(m, 6H), 3.10 - 3.30 (m, 2H), 2.65 - 2.90 (m, 3H), 2.25 - 2.50 (m, 2H), 1.50 - 2.20 (m, 8H), 1.30 (m, 2H); MS (ESI) m/z 523 (M+H)+.
Figure imgf000173_0002
Example 98 [(3 aR,6aR)-2- [4-(naphthalen-2-yl)piperidin- 1 -yl]hexahy dropentalen-3 a( 1 H)-yl] [3 - (trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone
Example 98 A
4-naphthalen-2-yl-3,6-dihydro-2H-pyridine-l-carboxylic acid tert-butyl ester To a solution of example 9A1 (4.53 g, 13.7 mmol) in 1, 2- dimethoxy ethane (20 mL), was added sequentially 2-naphthaleneboronic acid (2 g, 1 1.6 mmol), Pd[(Ph)3P]4 (0.5 g, 4.3 mmol) and aqueous Na2C(¾ solution (13.3 mL, 0.027mol). The reaction mixture was stirred and refluxed for 16 hours. Then aqueous phase was extracted with dichloromethane (50 mLx3) and the organic phase was combined, washed with brine, dried over MgS04, filtered, and concentrated. The residue was purified on silica column to afford example 98A (2.6g , 72%) as white powder.
Example 98B
4-naphthalen-2-yl-piperidine- 1 -carboxylic acid tert-butyl ester To a solution of Exaple 98A (2.6 g, 8.4 mmol) in methanol (100 mL) was added Pd/C (0.26 g). The resulting mixture was agitated under hydrogen (50 psi) for 24 hours using a Parr apparatus, and filtrated. The filtrate was concentrated to afford example Example 98B (2.6 g).
Example 98C
4-naphthalen-2-yl-piperidine
To a satuated solution of HC1 in ethyl acetate (20 mL) was added Example 98B
(2.6 g, 8.4 mmol) and stirred at 25 °C for 5 hours, followed by addition of Na2C(¾ solution to basicify the solution. The separated aqueous layer was extracted with ethyl acetate (3 x 50 mL). The organic phases were combined, washed with brine, dried over MgS04, filtered, and concentrated to afford example 98 C (1.6 g , 90% yield) as white powder.
Example 98D
[(3 aR,6aR)-2-[4-(naphthalen-2-yl)piperidin-l-yl]hexahy dropentalen-3 a(lH)-yl] [3- (trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone The title compound was prepared according to the procedure described in Example 1 J, substituting Example 98C for Example II, purified by HPLC and isolated as a mixture of diasteomeric isomers. Ή NMR (400 MHz, CDC13) δ ppm 8.74 (s, 1H), 8.15 (m, 1H), 7.80 (m, 3H), 7.68 (m, 1H), 7.45 (m, 3H), 4.80 (m, 2H), 3.75 - 3.90 (m, 2H), 3.00 (m, 4H), 2.60 (m, 2H), 2.32 (m, 2H), 2.00 (m, 4H), 1.45 - 1.80 (m, 1 1H); MS (ESI) m/z 548 (M+H)+.
Figure imgf000175_0001
Example 99
[(2R,3aR,6aR)-2-{4-[3-(lH-tetrazol-5-yl)phenyl]piperidin-l-yl}hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone
Example 99A
tert-butyl 4-(3-cyanophenyl)piperidine- 1 -carboxylate The title compound was prepared and purified according to the procedure described in Example 96D, substituting Example 96A for Example 96C.
Example 99B
4-[3-(lH-Tetrazol-5-yl)-phenyl]-piperidine-l-carboxylic acid tert-butyl ester To a solution of 99A (4.7 g, 16.4 mmol) in DMF (50 mL) was added NH4C1 (1.4 g, 26 mmol) followed by NaN3 (1.6 g, 24.7 mmol) at room temperature under N2. The mixture was heated at 120 °C overnight, cooled to room temperature, followed by addition of water (100 mL). The aqueous solution was acidified to pH 5~6 with HC1 and extracted with ethyl acetate. The combined organic layerss were washed with water, brine, dried (MgS04), filtered, and concentrated in vacuum to afford Example 99B (6 g).
Example 99C
4-{3-[l-(4-Methoxy-benzyl)-lH-tetrazol-5-yl]-phenyl}-piperidine-l-carboxylic acid tert- butyl ester
To a solution of Example 99B (6 g, 18.2 mmol) in DMF (100 mL) was added NaH (1.1 g, 27.3 mmol) with cooling ice bath under N2. After the reaction mixture was stirred for 30 minutes, 4-methoxybenzyl chloride (4.3 g, 27.3 mmol) was added and the mixture stirred at room temperature overnight. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried (MgS04), filtered, and concentrated. The residue was purified on silica gel to afford Example 99C (6 g, 73%) as colorless oil.
Example 99D 4- {3-[l -(4-Methoxy-benzyl)- lH-tetrazol-5-yl]-phenyl} -piperidine
To a solution of Example 99C (0.2 g, 0.45 mmol) in dichloromethane (8.5 mL) was added trifluoroacetic acid (1.5 ml) at about 0 °C, stirred for 10 minutes at about 0 °C, and concentrated to dryness. The residue was dissolved indichloromethane and washed with saturated NaHC(¾, brine, dried (MgS04), filtered, and concentrated to afford Example 99D (0.15 g).
Example 99E
((2R,3aR,6aR)-2-(4-(3-(l-(4-methoxybenzyl)- lH-tetrazol-5-yl)phenyl)piperidin-l- yl)octahydropentalen-3a-yl)(3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)- yl)methanone
To a mixture of Example 1H (126 mg, 0.36 mmol) and Example 99D (150 mg, 0.43 mmol) in dichloroethane (5 mL) was added titanium (IV) isoprpoxide (409 mg, 1.44 mmol) and diisopropylethyl amine (230 g, 1.8 mmol). Then the mixture was stirred at room temperature overnight. NaBH4 (68 mg, 1.8 mmol) and methanol (1 mL) were added and stirred overnight. The reaction mixture was diluted with dichloromethane (10 ml) and quenched with saturated NaHC03 (10 mL). After stirring for 30 minutes, the mixture was filtered and the filter cake was washed with dichloromethane. The filtrate was extracted with dichloromethane and washed with brine, dried over Na2S04, filtered, and concentrated. The residue was purified by chiral SFC to afford Example 99E.
Example 99F
[(2R,3aR,6aR)-2-{4-[3-(lH-tetrazol-5-yl)phenyl]piperidin-l-yl}hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone The mixture of Example 99E (40 mg, 0.058 mmol) in trifluoroacetic acid (5 mL) was heated at 65-70 °C for7 hours, concentrated to dryness and recrystallized from dichloromethane to afford Example 99F (20 mg, 54%) as trifluoroacetic acid salt. Ή
NMR (400 MHz, CDC13) δ ppm 8.62 (s, 1 H), 7.92 - 8.10 (m, 2 H), 7.67 (s, 1 H), 7.25 (m, 1 H), 7.15 (m, 1 H), 4.75 (m, 2H), 3.50 - 3.90 (m, 4H), 2.70 - 3.20 (m, 7H), 2.40 (m, 2H), 2.25 (m, 2H), 1.90 - 2.10 (m, 7H), 1.50 - 1.85 (m, 4H); MS (ESI+) m/z 566 (M+H)+.
Figure imgf000176_0001
Example 100
[(2S,3aR,6aR)-2-{4-[3-(lH-tetrazol-5-yl)phenyl]piperidin-l-yl}hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone
Example 100A
((2S,3aR,6aR)-2-(4-(3-(l-(4-methoxybenzyl)-lH-tetrazol-5-yl)phenyl)piperidin- l- yl)octahydropentalen-3a-yl)(3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)- yl)methanone
The title compound was obtained from the procedure of Example 99E.
Example 100B
[(2S,3aR,6aR)-2-{4-[3-(lH-tetrazol-5-yl)phenyl]piperidin-l-yl}hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone The title compound was prepared using procedure similar to that of Example 99F, substituting Example 100A for Example 99E, and isolated as trifluoroacetic acid salt. Ή NMR (400 MHz, CDC13) δ ppm 8.64 (s, 1 H), 8.09 (s, 1 H), 7.98 (d, J=7.60 Hz, 1 H), 7.69 (s, 1 H), 7.30 (m, 1 H), 7.14 (m, 1H), 4.60 - 4.85 (m, 2H), 3.60 - 3.90 (m, 4H), 3.36 (m, 1H), 3.10 - 3.20 (m, 3H), 2.75 (m, 2H), 2.60 (m, 1H), 2.15 - 2.40 (m, 4H), 1.56 - 2.06 (m, 1 1H); MS (ESI ) m/z 566 (M+H)+.
Figure imgf000177_0001
Example 101
[(2R,3aR,6aR)-2-[4-(naphthalen-2-yl)piperidin-l-yl]hexahydropentalen-3a(lH)-yl][3- (trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone The title compound was obtained from purification of Example 98D using chiral SFC. 'H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (s, 1H), 8.16 (m, 1H), 7.40 - 7.85 (m, 7H), 4.73 - 4.79 (m, 2H), 3.75 - 3.90 (m, 2H), 3.00 (m, 4H), 2.60 (m, 2H), 2.32 (m, 2H), 1.97 - 2.03 (m, 4H), 1.60 - 1.85 (m, 9H), 1.45 (m, 2H); MS (ESI) m/z 548 (M+H)+.
Figure imgf000178_0001
Example 102
[(2S,3aR,6aR)-2- {4-[3-methyl-5-(triiluoromethyl)- lH-pyrazol- l-yl]piperidin- 1 - yl}hexahydropentalen-3a(lH)-yl][3-(triiluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone
Example 102A
4-(3-Methyl-5-triiluoromethyl-pyrazol-l-yl)-piperidine- l-carboxylic acid tert-butyl ester
To a solution of Example 4A (2.4 g, 9 mmol) in DMF (20 mL) was added 3- methyl-5-trifluoromethyl-lH-pyrazole (1.4 g, 9 mmol) and K2CO3 (1.9 g, 14 mmol). The mixture was stirred at 50 °C overnight. Sat NH4CI solution (100 mL) was added to quench the reaction; the aqueous layer was extracted with EtOAc (200 mL). The combined organic layer was washed with brine, dried over Na2S04, and concentrated in vaccum. The residue was purified by HPLC to give Example 102A (1.3 g, 43%) as a white solid.
Example 102B
4-(3-Methyl-5-trifluoromethyl-pyrazol- 1 -yl)-piperidine To a solution of Example 102 B (1.3 g, 4 mmol) in EtOAc (10 mL) was added HQ/ EtOAc (50 mL), stirred at room temperature overnight., and concentrated. The residue was washed with acetone (20 mL) to give Example 102B as HC1 salt (755 mg, 81 %) as a colorless solid.
Example 102C
[(2S,3aR,6aR)-2- {4-[3-methyl-5-(trifluoromethyl)- lH-pyrazol- l-yl]piperidin- 1 - yl}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-
6(5H)-yl]methanone
The title compound was prepared according to the procedure described in
Example 1J, substituting free base of Example 102B for Example II, and purified by HPLC as the trifluoroacetic acid salt. Ή NMR (400 MHz, CD3OD) δ 8.686(s, 1 H), 8.03 (s, 1 H), 6.52 (s, 1 H), 4.85 (m, 2 H), 4.56 (m, 1 H), 3.92 (m, 2 H), 3.75 (m, 2H), 3.35 - 3.40 (m, 2 H), 3.1 1 1 - 3.25 (m, 4 H), 2.70 (m, 1 H), 2.35-2.55 (m, 3 H), 2.26 (s, 3H), 1.95 - 2.25 (m, 4H), 1.50 - 1.96 (m, 6 H); MS (ESI) m/z 570 (M+H)+.
Figure imgf000179_0001
Example 103
[(2R,3aR,6aR)-2- {4- [3 -methy 1-5 -(trinuoromethyl)- 1 H-pyrazol- 1 -yl]piperidin- 1 - yl}hexahydropentalen-3a(lH)-yl][3-(triiluoromethyl)-7,8-dihydro-l,6-naphthyridin-
6(5H)-yl]methanone
The title compound was isolated from the procedure of Example 102C as the trifluoroacetic acid salt. 'H NMR (400 MHz, CD3OD) δ 8.69 (s, 1 H), 8.04 (s, 1 H), 6.54 (s, 1 H), 4.80 (m, 2 H), 4.55 (m, 1 H), 3.85-4.05 (m, 2 H), 3.72 (m, 3H), 3.55 (m, 1H), 3.10 - 3.25 (m, 3 H), 2.75 (m, 1 H), 2.40 (m, 3H), 2.25 (s, 3H), 1.72 - 2.15 (, 9H), 1.38 - 1.55 (m, 2 H); MS (ESI) m/z 570 (M+H)+.
ABS
Figure imgf000179_0002
Example 104
[(2R,3aR,6aR)-2- {4- [5 -methy 1-3 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl]piperidin- 1 - yl}hexahydropentalen-3a(lH)-yl][3-(triiluoromethyl)-7,8-dihydro-l,6-naphthyridin-
6(5H)-yl]methanone
Example 104A
tert-butyl 4-(5 -methyl-3 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)piperidine- 1 -carboxylate The title compound was isolated from the procedure for Example 102A.
Example 104B
4-(5-methyl-3-(triiluoromethyl)-lH-pyrazol- l-yl)piperidine The HC1 salt of the title compound was prepared according to Example 102B, substituting Example 104A for Example 102A
Example 104C
[(2R,3aR,6aR)-2- {4-[5-methyl-3-(trifluoromethyl)- lH-pyrazol- 1 -yl]piperidin- 1 - yl}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-
6(5H)-
The title compound was prepared and purified according to the procedure described in Example 1J, substituting the free base of Example 104B for Example II as the trifiuoroacetic acid salt. Ή NMR (400 MHz, CD3OD) δ 8.69 (s, 1 H), 8.03 (s, 1 H), 6.36 (s, 1 H), 4.85 (m, 2 H), 4.55 (m, 1 H), 3.90 - 4.00 (m, 2 H), 3.70 - 3.80 (m, 3H), 3.55 (m, 1H), 3.10 - 3.25 (m, 3 H), 2.75 (m, 1 H), 2.36 (s, 3 H), 1.73 - 2.32 (m, 12 H), 1.36 - 1.57 (m, 2 H); MS (ESI) m/z 570 (M+H)+.
Figure imgf000180_0001
Example 105
[(2S,3aR,6aR)-2- {(3R,4S)-4-[3-(2-hydroxypropan-2-yl)phenyl]-3-methylpiperidin- 1 - yl}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-
6(5H)-yl]methanone
Example 105 A
(3R,4S)-tert-butyl 4-(3-(methoxycarbonyl)phenyl)-3-methylpiperidine- 1 -carboxylate To a solution of Example 94A (250 mg, 1.07 mmol) in dichloromethane (2 mL) was added di-tert-butyl dicarbonate (280 mg, 1.28 mmol) and diisopropylethyl amine (210 mg, 1.60 mmol). The mixture was stirred for 12 hours at room temperature. TLC (petroleum ether: EtOAc = 4: 1) indicated that the reaction was completed. The reaction mixture was diluted with dichloromethane, washed with brine, and concentrated in vacuum to give Example 105A (330 mg, 92.4 %) as an oil.
Example 105B
(3R,4S)-tert-butyl 4-(3-(2-hydroxypropan-2-yl)phenyl)-3-methylpiperidine- 1 -carboxylate
To a solution of Example 105 A (250 mg, 1.07 mmol) in THF (2 mL) was added methyl magnesium bromide (1.65 mL, 4.95 mmol) at -20 °C. After the addition, the mixture was stirred for 12 hours at room temperature. TLC (petroleum ether: EtOAc = 4: 1) indicated that the reaction was completed. The mixture was quenched with aqueous NH4CI (20 mL), extracted with EtOAc (3 x 20 mL), and concentrated to give Examplae 105B (250 mg, 75.75 %) as an oil.
Example 105C
2-(3-((3R,4S)-3-methylpiperidin-4-yl)phenyl)propan-2-ol To a solution of Example 105B (250 mg, 0.75 mmol) in dichloromethane (5 mL) was added 4N HCl/dioxane (10 mL) at room temperature. After the addition, the mixture was stirred for 2 hours at room temperature. The mixture was concentrated in vacuum to give Example 105C as HC1 salt (230 mg) as an oil, which was used in the next step without further purification.
Example 105D
[(2S,3aR,6aR)-2- {(3R,4S)-4-[3-(2-hydroxypropan-2-yl)phenyl]-3-methylpiperidin- 1 - yl}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone
The title compound was prepared and purified according to the procedure described in Example 1J, substituting free base of Example 105C for Example II. Ή NMR (400 MHz, CD3OD) δ 8.68 (s, 1H), 8.05 (s, 1H), 7.23 (m, 3H), 7.08 (m, 1H), 5.31 (s, 1H), 5.07 (m, 1H), 4.60 (s, 1H), 3.98 (m, 2H), 3.35 (m, 3H), 3.05 - 3.20 (m, 4H), 2.50 (m, 2H),2.10 - 2.20 (m, 7H), 1.60 - 1.98 (m, 9H), 1.55 (m, 2H), 0.61 (d, 3H); MS (ESI) m/z 570 (M+H)+.
Figure imgf000181_0001
Example 106
[(2R,3aR,6aR)-2-{(3R,4S)-4-[3-(2-hydroxypropan-2-yl)phenyl]-3-methylpiperidin-l- yl}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-
6(5H)-yl]methanone
The title compound was isolated from the procedure of Example 105D. Ή NMR (400 MHz, CD3OD) δ 8.72 (s, 1H), 8.06 (s, 1H), 7.28 - 7.40 (m, 3H), 7.15 (d, J=7.6 Ηζ,ΙΗ), 5.35 (s, 1H), 5.09 (s, 1H), 3.55 - 4.10 (m, 6H), 3.05 - 3.20 (m, 4H), 3.25 - 3.38 (m, 2H), 2.45 (m, 1H), 2.15 (s, 6H), 1.89 - 2.25 (m, 4H), 1.80 (m, 1H), 1.30-1.60 (m, 7H), 0.75 (d, 3H); MS (ESI) nVz 570 (M+H)+.
Figure imgf000182_0001
Example 107
3- { 1 -[(2S,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)- yl]carbonyl} octahydropentalen-2-yl]- 1 ,2,3,6-tetrahydropyridin-4-yl}benzonitrile To a mixture of Example 96B (1.5 g, 4.26 mmol) and Example 1H (1.13 g, 5.1 1 mmol) in dichloroethane (50 mL) was added titanium(IV) isoprpoxide (4.8 g, 17 mmol) and diisopropylethyl amine (2.7 g, 21.3 mmol). The mixture was stirred at room temperature overnight. NaBH4 (0.81 g, 21.3 mmol) and methanol (3 mL) was added and stirred overnight. The reaction mixture was diluted with dichloromethane (30 mL) and quenched with saturated NaHC(¾ (20 mL). After stirring for 30 minutes, the mixture was filtered and rinsed with dichloromethane. The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated. The residue was purified by chiral SFC to afford Example 107 (1.0 g) as solid. Ή NMR (400 MHz, CDC13) δ 8.70 (s, 1 H), 7.69 (s, 1 H), 7.62 (s, 1 H), 7.61(m, 1 H), 7.59 (m, 1 H), 7.42 (m, 1H), 6.10 (s, 1H), 4.74 - 4.90 (m, 2H), 3.91 (m, 2H), 3.45 (m, 1H), 3.10 - 3.22 (m, 4H), 2.70 (m, 2H), 2.45 - 2.60 (m, 4H), 2.25 (m, 1H), 1.55 - 2.0 (m, 8H); MS (ESI+) m/z 521 (M+H)+.
ABS
Figure imgf000182_0002
Example 108
3-{ l-[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)- yl]carbonyl} octahydropentalen-2-yl]- 1 ,2,3,6-tetrahydropyridin-4-yl}benzonitrile The title compound was obtained from the procedure of Example 107. Ή NMR (400 MHz, CDCI3) δ 8.65 (s, 1 H), 7.62 (s, 1 H), 7.55 (s, 1 H), 7.52 (m, 1 H), 7.45 (m, 1 H), 7.35 (m, 1H), 6.04 (s, 1H), 4.70 (m, 2H), 3.80 - 3.95 (m, 2H), 3.48 (m, 1H), 3.05 3.15 (m, 4H), 2.89 (m, lH), 2.60 - 2.75 (m, 2H), 2.45 (m, 2H), 2.20 (m, 1H), 2.07(m, 1.60 - 1.95 (m, 6H), 1.50 (m, 1H), 1.35 (m, 1H); MS (ESI+) m/z 521 (M+H)+.
Figure imgf000183_0001
Example 109
[(2S,3aR,6aR)-2-(3-phenylazetidin-l-yl)hexahydropentalen-3a(lH)-yl][3- (trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone
Example 109A
1 -Benzhydryl-azetidin-3-one
To a solution of l-benzhydryl-azetidin-3-ol (2.5 g, 10.5 mmol) in
dichloromethane (20 ml) was added Dess-Martine reagent (6 g, 14.2 mmol) at room temperature under nitrogen. The mixture was stirred at room temperature overnight, quenched with Na2S(¾ solution, diluted with dichloromethane and partitioned. The organic layers were washed with NaHC(¾ solution, brine dried (MgS04), filtered, and concentrated. The residue was purified by silica gel column to afford Example 109A (1 g, 40%) as a light yellow solid.
Example 109B
l-Benzhydryl-3-phenyl-azetidin-3-ol
To a solution of Example 109A (0.85 g, 3.6 mmol) in anhydrous THF (10 ml) was added phenyl magnesium bromide (4.7 mL, 4.7 mmol) at -78°C under nitrogen. After addition, the mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was quenched with saturated NH4C1 with ice-bath and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgS04), filtered, and concentrated. The residue was purified on silica gel to afford Example 109B (1.0 g, 80%).
Example 109C
Dithiocarbonic acid 0-(l-benzhydryl-3-phenyl-azetidin-3-yl) ester S-methyl ester To a solution of NaH (270 mg, 6.7 mmol) in THF (100 mL) in an ice-bath was added dropwise Example 109B (lg, 3.2 mmol) in THF (10 mL) under nitrogen. After stirring for 3 hours at room temperature, CS2 (14.2 g, 0.18 mmol) and iodomethane (9 g, 63.4 mmol) was added dropwise sequentially. Then the reaction mixture was stirred at room temperature overnight. The mixture was concentrated to about 20 mL, diluted with water (30 mL), and extracted with ethyl acetate. The organic layers were washed with brine, dried (MgS04), filtered, and concentrated. The residue was purified on silica gel column to afford Example 109C (1.3 g, 95%).
Example 109D
1 -Benzhydryl-3-phenyl-azetidine
To a stirred solution of tributyl tin hydride (1.4 g, 4.8 mmol) in dry toluene (25 mL) at reflux under nitrogen was added dropwise over 1 hour a solution of Example 109C (1.3 g, 3.2 mmol) in toluene (25 mL). The reaction mixture was heated at reflux for another 2 hours, cooled to room temperature, and concentrated. The residue was purified by silica gel column and preparative HPLC to afford Example 109D (0.3 g, 31%).
Example 109E
3 -Phenyl- azetidine
A mixture of Example 109D (0.3 g, 1.0 mmol) and Pd(OFfj2 was stirred under ¾ atmosphere (50 psi) at 50 °C overnight. The mixture was filtered and the filter cake was washed with methanol. The filtrate was concentrated. The residue was washed with petroleum ether and dried to afford Example 109E (100 mg).
Example 109F
[(2S,3aR,6aR)-2-(3-phenylazetidin-l-yl)hexahydropentalen-3a(lH)-yl][3- (triiluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone The title compound was prepared and purified according to the procedure described in Example 1J, substituting Example 109E for Example II. Ή NMR (400 MHz, CDCI3) δ ppm 8.65 (s, 1 H), 7.65 (s, 1 H), 7.10 - 7.30 (m, 5 H), 4.65 - 4.85 (m, 2 H), 3.85 (m,2H), 3.45 (m, 2H), 3.05 - 3.15 (m, 4H), 2.60 (m, 2H), 2.15 (m, 1H), 1.50 - 2.00 (m, 10H); MS (ESI+) m/z 470 (M+H)+.
Figure imgf000185_0001
Example 1 10
[(2R,3aR,6aR)-2-(3-phenylazetidin- l-yl)hexahydropentalen-3a(lH)-yl][3- (triiluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone The title compound was isolated from the procedure of Example 109F. Ή NMR
(400 MHz, CDC13) δ ppm 8.65 (s, 1 H), 7.63 (s, 1 H), 7.10 - 7.35 (m, 5 H), 4.72 (m, 2 H), 3.90 (m, lH), 3.75 (m, 1H), 3.50 - 3.65 (m, 3H), 3.05 (m, 4H), 2.85 (m, 1H), 1.45 -1.90 (m, 1 1H); MS (ESI ) m/z 470 (M+H)+.
Figure imgf000185_0002
Example 1 1 1
[3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)-yl][(2S,3aR,6aR)-2-{(3-endo)- 3-[5-(triiluoromethyl)-lH-pyrazol- l-yl]-8-azabicyclo[3.2. l]oct-8-yl}hexahydropentalen-
3 a( 1 H)-yl]methanone
Example 11 1A
methanesulfonic acid 8-benzyl-8-aza-bicyclo[3.2.1]oct-3-yl ester To the mixture of dichloromethane (200 mL) and 8-benzyl-8- azabicyclo[3.2.1]octan-3-ol (5.4 g, 25 mmol), Et3N (3.74 g,3.7 mmol) was added methanesulfonyl chloride (3.7 g, 21 mmol) dropwise at 0 °C, the mixture was then stirred at room temperature for 2 hours. The reaction mixture was quenched with sat NH4CI (200 mL), 0.1 M HC1 (10 mL), extracted with dichloromethane (600 mL). The combined organic layer was washed with brine, dried over Na2S04, filtered, and concentrated in vaccum. The residue was purified by column chromatography to give Example 1 1 1 A (4.5 g, 61%) as a brown solid. Example 1 1 IB
8-benzyl-3-(5-(trifluoromethyl)- lH-pyrazol-l-yl)-8-azabicyclo[3.2.1]octane The title compound was isolated from the procedure of Example 1 13 A.
Example 1 1 1 C
8-benzyl-3-(5-(trifluoromethyl)- lH-pyrazol-l-yl)-8-azabicyclo[3.2.1]octane The title compound was prepared according to the procedure of Example 1 13B, substituting Example 11 IB for Example 1 13 A.
Example 11 ID
[3-(trifiuoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)-yl][(2S,3aR,6aR)-2-{(3-endo)- 3-[5-(trifluoromethyl)-lH-pyrazol- l-yl]-8-azabicyclo[3.2. l]oct-8-yl}hexahydropentalen-
3 a( 1 H)-yl]methanone
The title compound was prepared and purified according to the procedure described in Example 1 J, substituting Example 1 1 1C for Example II. Ή NMR (400 MHz, CD3OD) δ 8.68 (s, 1 H), 8.02 (s, 1 H), 7.65 (s, 1 H), 6.75 (s, 1 H), 4.80 (m, 2 H), 4.25 (m, 2 H), 3.90 (m, 2 H), 3.40 (m, 2 H), 3.12 (m, 2 H), 2.75 (m, 4 H), 1.55 - 2.45 (m, 15 H); MS (ESI) m/z 582 (M+H)+.
Figure imgf000186_0001
Example 1 12
[3-(trifiuoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl] [(2R,3aR,6aR)-2- {(3-endo)- 3-[5-(trifluoromethyl)-lH-pyrazol- l-yl]-8-azabicyclo[3.2. l]oct-8-yl}hexahydropentalen-
3 a( 1 H)-yl]methanone
The title compound was isolated from the procedure of Example 1 1 ID. Ή NMR (400 MHz, CD3OD) δ 8.68 (s, 1 H), 8.02 (s, 1 H), 7.65 (s, 1 H), 6.77 (s, 1 H), 4.80 (m, 2 H), 4.25 (m, 2 H), 3.95 (m, 2 H), 3.38 (m, 2 H), 3.12 (m, 2 H), 2.75 (m, 3H), 1.50 - 2.40 (m, 16 H); MS (ESI) m/z 582 (M+H)+. ABS
Figure imgf000187_0001
Example 1 13
[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl] [(2R,3aR,6aR)-2- {(3-endo)- 3-[3-(trifluoromethyl)-lH-pyrazol- l-yl]-8-azabicyclo[3.2. l]oct-8-yl}hexahydropentalen-
3 a( 1 H)-yl]methanone
Example 113A
8-benzyl-3-(3-trifluoromethyl-pyrazol- l-yl)-8-aza-bicyclo[3.2.1]octane To a solution of Example 11 1 A (2.5 g, 9.8 mmol) in DMF (100 mL) was added 3-trifluoromethyl-lH-pyrazole (1.1 g, 8 mmol) and K2CO3 (1.7 g, 12 mmol). The mixture was stirred at room temperature overnight. Saturated NH4CI solution (100 mL) was added to quench the reaction. The aqueous layer was extracted with EtOAc (200 mL). The combined organic layer was washed with brine, dried over Na2S04, filtered, and concentrated in vaccum. The residue was purified by preparative HPLC to give Example 1 13A (600 mg, 22%) as yellow oil.
Example 1 13B
3-(3-trifluoromethyl-pyrazol-l-yl)-8-aza-bicyclo[3.2.1]octane Example 1 13 A (600 mg, 1.8 mmol) was dissolved in EtOH (30 mL), followed by addition of ammonium formate (558 mg, 9 mmol) and Pd(OH)2/C (60 mg). The mixture was heated at reflux for 2 hours, and after cooling to room temperature, the reation mixture was filtered .The filtration was washed with sodium carbonate solution, dried over Na2S04, and concentrated in vaccum and purified using SFC to provide Example
1 13B.
Example 1 13C
[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl] [(2R,3aR,6aR)-2- {(3-endo)- 3-[3-(trifluoromethyl)-lH-pyrazol- l-yl]-8-azabicyclo[3.2. l]oct-8-yl}hexahydropentalen-
3 a( 1 H)-yl]methanone
The title compound was prepared and purified according to the procedure described in Example 1 J, substituting Example 1 13B for Example II. Ή NMR (400 MHz, CD3OD) δ 8.69 (s, 1 H), 8.05 (s, 1 H), 7.82 (s, 1 H), 6.60 (s, 1 H), 4.82 (m, 2 H), 4.24 (m, 2 H), 3.90 (m, 2 H), 3.38 (m, 2 H), 3.12 (m, 2 H), 2.75 (m, 1H), 2.60 (m, 2H), 1.50 - 2.45 (m, 16 H); MS (ESI) nVz 582 (M+H)+.
Figure imgf000188_0001
Example 1 14
[3-(trifluoromethyl)-7,8-dihydro ,6-naphthyridin-6(5H)-yl][(2S,3aR,6aR)-2-{(3-endo)- 3-[3-(trifluoromethyl)-lH-pyrazol- l-yl]-8-azabicyclo[3.2. l]oct-8-yl}hexahydropentalen-
3 a( 1 H)-yl]methanone
The title compound was isolated from procedure of Example 113C. Ή NMR (400 MHz, CDC13) δ 8.65 (s, 1 H), 7.65 (s, 1 H), 7.50 (s, 1 H), 6.55 (s, 1 H), 4.55 - 4.70 (m, 2 H), 3.85 (m, 4 H), 3.05 - 3.35 (m, 6 H), 2.35 - 2.60 (m, 5 H), 1.60 - 2.20(m, 12 H); MS (ESI) m/z 582 (M+H)+.
Figure imgf000188_0002
Example 1 15
[(2S,3aR,6aR)-2-(4-phenylpiperazin-l-yl)hexahydropentalen-3a(lH)-yl][3- (triiluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone
The title compound was prepared and purified according to the procedure described in Example 1 J, substituting phenyl piperazine for Example II. 'HNMR (400 MHz, CDCI3) δ ppm 8.70 (s, 1H), 7.71 (s, 1H), 7.28 (m, 2H), 6.93 (m, 3H), 4.75 (m, 2H), 3.85 (m, 2H), 3.40 - 3.60(m, 7H), 3.14 (m, 3H), 2.41 (m, 1H), 1.85 - 2.15 (m, 5H), 1.50 - 1.75 (m, 6H); MS (ESI) m/z 499 (M+H)+.
Figure imgf000189_0001
Example 1 16
[(2R,3aR,6aR)-2-(4-phenylpiperazin-l-yl)hexahydropentalen-3a(lH)-yl][3- (trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone The title compound was isolated from the procedure of Example 1 15. 'HNMR
(400 MHz, CDC13) δ ppm 8.72 (s, 1H), 7.70 (s, 1H), 7.30 (m, 2H), 6.90 - 7.00 (m, 3H), 4.75 (m, 2H), 3.90 (m, 2H), 3.65 (m, 6H), 3.40 (m, 1H), 3.15 (m, 3H), 2.95 (m, 2H), 2.80 (m, 1H), 2.55 (m, 1H), 2.35 (m, 1H), 2.10 - 2.30 (m, 4H), 1.60 - 1.90 (m, 3H); MS (ESI) m/z 499 (M+H)+.
Figure imgf000189_0002
Example 1 17
[(2S,3aR,6aR)-2-(lΉ,3H-spiro[2-benzofuran- l,4'-piperidin]-Γ-yl)hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone
Example 117A
1 -Benzyl-4-(2-hydroxymethyl-phenyl)-piperidin-4-ol
To a solution of (2-bromo-phenyl)-methanol (14.8 g, 79.3 mmol) in THF (100 mL) was added n-butyl lithium (67 mL, 132.25 mmol) at -78 °C under N2. After 2 hours, a solution of 1 -benzyl-piperidin-4-one (10 g, 52.9 mmol) in THF (10 mL) was added slowly at -78 °C. After addition, the mixture was stirred at room temperature for 10 hours. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgS04), filtered, and concentrated. The residue was purified by column chromatography on silical gel to afford Example 1 17A (9 g, 52%).
Example 1 17B 1 '-benzyl-3H-spiro[isobenzofuran- 1 ,4'-piperidine]
A solution of Example 1 17A (9 g, 30.3 mmol) and IN H2SO4 (100 mL) was stirred at 100 °C for 16 hours. The mixture was poured into ice water and the mixture was basified to pH 9 with saturated NaHC(¾ and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgS04), filtered, and concentrated. The residue was purified by column chromatography on silical gel to afford to afford Example 1 17B (8.9 g, 90%).
Example 1 17C
3H-spiro[isobenzofuran- 1 ,4'-piperidine]
A mixture of Example 1 17B (0.85 g, 3.05 mmol) and Pd/C (0.37 g, 10%) in ethanol (15 mL) was stirred under ¾ (45 psi) for 16 hours. The reaction mixture was filtered and rinsed with ethanol. The fitrate was concentrated in vacuum to afford Example 1 17C (490 mg, 75%).
Example 117D
[(2S,3aR,6aR)-2-(l'H,3H-spiro[2-benzofuran- 1 ,4'-piperidin]- l'-yl)hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone The title compound was prepared and purified according to the procedure described in Example 1 J, substituting Example 1 17C for Example II. Ή NMR (400 MHz, CDCI3) δ ppm 8.63 (s, 1 H), 7.62 (s, 1 H), 7.05 - 7.25 (m, 4 H), 4.98 (s, 2 H), 4.65 - 4.85 (m, 2 H), 3.85 (m, 2H), 3.35 (m, 1H), 3.05 (m, 2H), 2.79 - 2.92 (m, 2H), 2.55 (m, 1H), 2.36 (m, 3H), 2.12 (m, 1H), 1.90 (m, 3H), 1.50 - 1.85 (m, 9H); MS (ESI+) m/z 526 (M+H)+.
Figure imgf000190_0001
Example 1 18
[(2R,3aR,6aR)-2-(lΉ,3H-spiro[2-benzofuran-l,4'-piperidin]-Γ-yl)hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone The title compound was isolated from the procedure of Example 1 17D. Ή NMR (400 MHz, CDCI3) δ ppm 8.65 (s, 1 H), 7.62 (s, 1 H), 7.05 - 7.28 (m, 4 H), 5.00 (s, 2 H), 4.70 (s, 2 H), 3.75 - 3. 95 (m, 2H), 3.45 (m, 2H), 3.05 (m, 2H), 2.85 (m, 3H), 2.40 (m, 2H), 2.15 (m, 1H), 1.45 - 2.05 (m, 12H); MS (ESI+) nVz 526 (M+H)+.
Figure imgf000191_0001
Example 1 19
[(2R,3aR,6aR)-2-(hexahydropyrano[3,4-b] [1 ,4]oxazin- 1 (5H)-yl)hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone
Example 119A
3-(allyloxy)-4,4-dimethoxytetrahydro-2H-pyran NaH (1.63 g, 40.6 mmol) was suspended in THF (200 mL), and Example 79Q (3.0 g, 18.5 mmol) was added followed by addition of ally bromide (16 mL, 0.185 mol). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated in vacuum to dryness. The residue was diluted with CH2CI2, washed with brine, dried over MgS04, filtered, and concentrated in vaccum. The residue was purified by column (Hexanes: EtOAc = 20 : 1) to give Example 1 19A (2.7 g, 72%).
Example 1 19B
3-(allyloxy)dihydro-2H-pyran-4(3H)-one
A mixture of Example 1 19A (2.7 g, 13.3 mmol) in trifluoroacetic acid/ CH2CI2 (100 mL), was stirred at room temperature for 2 hours. After removal of solvent in vacuum, the residue was purified by column (S1O2, Hexanes: EtOAc = 10 : 1) to give Example 1 19B (1.5 g, 72%).
Example 1 19C
[(2R,3aR,6aR)-2-(hexahydropyrano[3,4-b] [1 ,4]oxazin- 1 (5H)-yl)hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone A solution of Example 1 19B (550 mg, 3.5 mmol) in CH2CI2 (50 ml) was cooled to -78 °C and O3 was passes through the solution until permanent blue color. The excess O3 was removed with N2 and a few drop of dimethylsulfide was added in to the solution at the same temperature and the mixture was allowed to warm to room temperature with stirring for 1 hour, dried over MgS04, filtered. To the filtrate Example 79N (985 mg, 2.79 mmol), diisopropylethyl amine (0.75 mL, 4.19 mmol), molecular sieves 4A, and sodium triacetoxyborohydride (3 g, 14 mmol) were added. The mixture was stirred at room temperature overnight, filtered, washed with sataturated aqueous NaHC(¾ solution and brine, dried over MgS04, filtered and concentrated in vaccum. The residue was purified by preparative HPLC to give the trifluoroacetic acid salt of Example 1 19C as a mixture of four isomers. Ή NMR (400 MHz, CD3OD) δ 8.70 (s, 1H), 8.05 (s, 1H), 4.85 (m, 2H), 3.67 - 4.15 (m, 8H), 3.35 -3.65 (m, 5H), 3.1 1 (m, 2H), 2.63 (m, 1H), 2.35 (m, 1H), 1.65 - 2.15 (m, 9H), 1.55 (m, 1H), 1.36 (m, 1H); MS (ESI) m/z 480 (M+H)+.
Examples 120- 123 were obtained from the purification of free base of Example 1 19C using chiral SFC.
tes
Figure imgf000192_0001
Example 120
[(2R,3aR,6aR)-2-[(4aS,8aR)-hexahydropyrano[3,4-b][ l ,4]oxazin- l (5H)- yl]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro- l ,6-naphthyridin-
6(5H)-yl]methanone
Ή NMR (400 MHz, CDC13) δ ppm 8.65 (s, 1H), 7.65 (s, 1H), 4.60 - 4.85 (m, 2H),
3.95 (m, 2H), 3.80 (m, 3H), 3.20 - 3.65 (m, 6H), 2.95 - 3.15 (m, 3H), 2.40 - 2.60 (m, 2H), 2.20 ( m, 2H), 1.30 - 2.10 (m, 10H); MS (ES ) m/z 480 (M+H)+.
Figure imgf000192_0002
Example 121
[(2R,3aR,6aR)-2-[(4aR,8aS)-hexahydropyrano[3,4-b][l ,4]oxazin- l (5H)- yl]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro- l ,6-naphthyridin-
6(5H)-yl]methanone
Ή NMR (400 MHz, CDCI3) δ ppm 8.65 (s, 1H), 7.65 (s, 1H), 4.72 (s, 2H), 4.02 i, 1H), 3.75 - 3.95 (m, 3H), 3.60 (m, 1H), 3.20 - 3.50 (m, 4H), 3.05 (m, 3H), 2.92 (m, 1H), 2.75 (m, 1H), 2.65 (m, 1H), 2.42 (m, 1H), 2.18 ( m, 1H), 2.02 (m, 2H), 1.90 (m, 1H), 1.75(m, 1H), 1.30-1.70 (m, 7 H); MS (ESI+) nVz 480 (M+H)+.
ABS
Figure imgf000193_0001
Example 122
[(2R,3aR,6aR)-2-[(4aS,8aS)-hexahydropyrano[3,4-b][l,4]oxazin- l(5H)- yl]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-
6(5H)-yl]methanone
Ή NMR (400 MHz, CDC13) δ ppm 8.65 (s, 1H), 7.65 (s, 1H), 4.65 - 4.85 (m, 2H), 3.75 - 3.95 (m, 4H), 3.65 (m, 2H), 3.05 - 3.46 (m, 6H), 2.75 (m, 2H), 2.65 (m, 1H), 2.45( m, 1H) , 2.29 (m, 1 H),2.10 (m, 2H), 1.45 - 1.95 (m, 8H), 1.30 (m, 1H); MS (ESI+) m/z 480 (M+H)+.
The succinate salt of Example 122 was prepared according to Example 4D. Ή NMR (400 MHz, CD3OD) δ 8.70 (s, 1H), 8.05 (s, 1H), 4.82 (m, 2H), 3.80 - 4.10 (m, 5H), 3.70 (m, 1H), 3.30 - 3.55 (m,5H), 3.12 (m, 3H), 2.85 (m, 1H), 2.75 (m, 1H), 2.53 ( s, 4H), 2.40 (m, 1H), 2.20 (m, 1H), 2.05 (m, 1H), 1.90 (m, 4H), 1.60-1.80 (m, 3H), 1.52 (m, 1H), 1.35 (m, 1H).
ABS
Figure imgf000193_0002
Example 123
[(2R,3aR,6aR)-2-[(4aR,8aR)-hexahydropyrano[3,4-b][l,4]oxazin-l(5H)- yl]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-
6(5H)-yl]methanone Ή NMR (400 MHz, CDC13) δ ppm 8.65 (s, 1H), 7.65 (s, 1H), 4.72 (s, 2H), 3.75 - 3.95 (m, 5H), 3.50 - 3.70 (m, 3H), 3.35 (m, 2H), 3.24 (m, 1H), 3.10 (m, 3H), 2.68 (m, 1H), 2.35 (m, 1H), 1.75 - 2.20 (m, 7H), 1.35- 1.70 (m, 4H), 1.28 (m, 1H); MS (ESI+) nVz 480 (M+H)+.
Figure imgf000194_0001
Example 124
[(2S,3aR,6aR)-2-[(4aS,8aS)-hexahydropyrano[3,4-b][l,4]oxazin- l(5H)- yl]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-
6(5H)-yl]methanone
Example 124 A
tert-butyl hydroxy(methyl)carbamate
K2CO3 (16.6 g, 120 mmol) was added to an ice-cold solution of N-methyl- hydroxylamine HC1 salt (20 g, 241 mmol) in THF/H20 (50 mL/50 mL). A solution of di- tert-butyl dicarbonate (1 15.5 g, 530 mmol) in THF (60 mL) was then added dropwise to the mixture and stirring was continued for 3 hours. The solution was concentrated in vaccum and the residue was dissolved in dichloromethane (300 mL) before washing with H2O (200 mL) and brine. The organic layer was concentrated in vaccum to give Example 124A (33 g, 92%) as an orange oil.
Example 124B
tert-butyl benzoyloxy(methyl)carbamate
A solution of Example 124A (33 g, 224 mmol) and benzoyl chloride (31.4 g, 224 mmol) in dry dichloromethane (300 mL) was cooled to 0 °C prior to slow addition of Et3N (22.6 g, 224 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 16 hours, then quenched with ¾0 (20 mL) and extracted with dichloromethane (400 mL). The organic layer was dried over Na2S04, concentrated in vaccum, the residue was purified by column chromatography to give Example 124B (45 g, 80%) as a colorless oil.
Example 124C O-benzoyl-N-methylhydroxylamine
To a solution of Example 124B (5 g, 20 mmol) in EtOAc (10 mL) was added HQ/ EtOAc (4N, 20 mL). The reaction was stirred at room temperature for 5 hours, and then concentrated in vaccum. The residue was washed with acetone (20 mL) to give Example 124C (1.3 g, 36%) as a white solid.
Example 124D
4-oxotetrahydro-2H-pyran-3-yl benzoate
Example 124C (1 g, 5 mmol) and tetrahydro-pyran-4-one (500 mg, 5 mmol) were dissolved in DMSO (10 mL) and stirred at room temperature for 16 hours. After this period, the reaction mixture was diluted with EtOAc (50 mL) and washed with brine. The organic layer was dried over Na2S04, filtered, and then concentrated in vaccum. The residue was purified by column chromatography to give Example 124D (792 mg, 72%) as a white solid.
Example 124E
(4S)-4-((S)- 1 -phenylethylamino) tetrahydro-2H-pyran-3-yl benzoate
A mixture of Example 124D (200 mg, 0.568 mmol), (S)- 1 -phenylethanamine (141 mg, 1.15 mmol) in dichloroethane (10 mL) was added Ti(iPrO)4 (0.878 g, 3.09 mmol) at room temperature. The reaction mixture was stirred at room temperature for 12 hours. NaBH4 (146 mg, 3.86 mmol) and methanol (2 mL) was added to the resulting mixture and stirred for another 2 hours. LCMS indicated that the reaction was complete, the mixture was diluted with dichloromethane and washed with aqueous NaHC(¾ (20 mL), the aqueous layer was extracted with methylene dichloride (3 x 30 mL). The organic layer was dried over Na2S04, filtered, and concentrated. The residue was purified by preparative HPLC to give Example 124E (100 mg) as a light yellow solid.
Example 124F
(4S)-4-((S)- 1 -phenylethylamino) tetrahydro-2H-pyran-3-ol To a solution of Example 124E (0.51 g, 1.57 mmol) in MeOH (8 mL) was added sodium methoxide (0.102 g, 1.88 mmol) at room temperature. After the addition, the mixture was stirred for 2 hours at room temperature. TLC (MeOH: dichloromethane^ 1 : 10) indicated that the reaction was completed. The mixture was concentrated in vaccum, the residue was purified by chromatography on silica to give Example 124F (240 mg, 69.2 %) as a white solid.
Example 124G
2-chloro-N-((4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-N-((S)- 1 -phenylethyl) acetamide To a solution of Example 124F (0.16 g, 0.72 mmol) in THF (10 mL) was added Et3N (0.1 15 mL, 0.79 mmol) and chloro- acetyl chloride (81.76 mg, 0.72 mmol) at room temperature. After the addition, the reaction mixture was stirred for 2 hours at room temperature. TLC (petroleum ethenEtOAc = 1 : 1) indicated that the reaction was completed. The mixture was concentrated in vaccum, the residue was treated with aqueous NaHC03 (20 mL), extracted with EtOAc (3 x 30 mL), the comnined organic layer was dried and concentrated in vaccum to give Example 124G (200 mg) as an oil which was used in the next step without further purification.
Example 124H
(4aS,8aS)- 1 -((S)- 1 -phenylethyl) hexahydropyrano[3,4-b] [ 1 ,4]oxazin-2(l H)-one
To a solution of Example 124G (3.4 g, 12 mmol) in THF (60 mL) was added potassium tert-butoxide ( 2.73g, 24 mmol). After the addition, the mixture was stirred for 12 hours at room temperature. TLC (neat EtOAc) indicated that the reaction was completed. The mixture was concentrated in vaccum, the residue was treated with water (20 mL), extracted with EtOAc (3 x 30 mL), dried (MgSC^), filtered, and concentrated in vaccum, and the residue was purified by chromatography on silica to give Example 124H (600mg, yield 22.7%) as an oil and another pure chiral isomer, (4aR,8aS)-l-((S)-l- phenylethyl)hexahydropyrano[3,4-b][l,4]oxazin-2(lH)-one (800 mg).
Example 1241
(4aS,8aS)- 1 -((S)- 1 -phenylethyl)octahydropyrano[3,4-b][ 1 ,4]oxazine
To a solution of Example 124H (0.25 g, 0.95 mmol) in THF (10 mL) was added L1AIH4 (91 mg, 2.39 mmol). After the addition, the mixture was refluxed for 2 hours. TLC (petroleum ethenEtOAc = 4: 1) indicated that the reaction was completed. The mixture was quenched with water (0.2 mL) and IN NaOH (0.3 mL), filtered, rinsed with THF (10 mL) and the filtrate was concentrated in vaccum and the residue was purified by chromatography on silica to give Example 1241 (150 mg, 63.4%) as an oil.
Example 124 J
(4aS,8aS)-octahydropyrano[3,4-b][l,4]oxazine A solution of Example 1241 (0.15 g, 0.607 mmol), Pd(OH)2/C (200 mg), con. HC1 (2 drops) in EtOH (15 mL) was submitted for hydrogenation at 50 psi of ¾ at 50 °C for 12 hours. The mixture was filtered and the filtrate was concentrated in vaccum, the residue was dried in vaccum to give Example 124J (100 mg, yield 91.7%) as a white solid.
Example 124K [(2S,3aR,6aR)-2-[(4aS,8aS)-hexahydropyrano[3,4-b][l,4]oxazin- l(5H)- yl]hexahydropentalen-3a( 1 H)-yl] [3-(triflu^^
6(5H)-yl]methanone
The title compound was purified according to the procedure described in Example 1H substituting Example 124J for II. Ή NMR (400 MHz, CD3OD) δ ppm 8.67 (s, 1H), 8.03 (s, 1H), 4.83 (s, 2H), 3.80 - 4.00 (m, 5H), 3.62 (m, 1H), 3.30 - 3.50 (m, 3H), 3.24 (m, 2H), 3.06 (m, 3H), 2.75 (m, 1H), 2.55 (m, 1H), 2.38 (m, 1H), 2.15 (m, 1H), 1.40-2.10 (m, 9H), 1.32 (m, 1H); MS (ESI+) m/z 480 (M+H)+.
ABS
Figure imgf000197_0001
Example 125
[(2S,3aR,6aR)-2-[(4aR,8aS)-hexahydropyrano[3,4-b][l,4]oxazin- l(5H)- yl]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-
6(5H)-yl]methanone
Example 125 A
(4aR,8aS)- l-((S)-l-phenylethyl)hexahydropyrano[3,4-b][l,4]oxazin-2(lH)-one The title compound was isolated from the procedure of Example 124H.
Example 125B
(4aR,8aS)- 1 -((S)- 1 -phenylethyl)octahydropyrano[3,4-b] [ 1 ,4]oxazine
The title compound was prepared and isolated according to procedure for Example 1241, substituting Example 125 A for Example 124H.
Example 125C
(4aR,8aS)-octahydropyrano[3,4-b][l,4]oxazine The title compound was prepared and isolated according to procedure for Example 124 J, substituting Example 125B for Example 1241.
Example 125D
[(2S,3aR,6aR)-2-[(4aR,8aS)-hexahydropyrano[3,4-b][l,4]oxazin- l(5H)- yl]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-
6(5H)-yl]methanone The title compound was purified according to the procedure described in Example 1H substituting Example 125C for II. Ή NMR (400 MHz, CD3OD) δ ppm 8.70 (s, 1H), 8.05 (s, 1H), 4.85 (s, 2H), 3.80 - 4.05 (m, 6H), 3.55 - 3.70 (m, 2H), 3.30 - 3.50 (m, 2H), 3.05 - 3.25 (m, 3H), 2.85 (m, 1H), 2.65 (m, 1H), 2.55 (m, 1H), 2.35(m, 2H), 2.00 - 2.20 (m, 2H), 1.92 (m, 2H), 1.40 - 1.83 (m, 5H), 1.35 (m, 1H); MS (ESI+) m/z 480 (M+H)+.
Figure imgf000198_0001
Example 126
[(2R,3aR,6aR)-2-[tricyclo[3.3.1.13'7]dec-2-ylamino]hexahydropentalen-3a(lH)-yl][3- (trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone The title compound was prepared and purified according to the procedure described in method B of Example 79G, substituting 2-adamentanone for Example 79R. 'H NMR (400 MHz, CD3OD) δ 8.75 (s, 1H), 8.05 (s, 1H), 3.98 (m, 2H), 3.85 (m, 1H), 3.58 (m, 1H), 3.39 (m, 2H), 3.12 (m, 2H), 2.55 (m, 1H), 1.7 - 2.15 (m, 22H), 1.60 (m, 1H), 1.38 (m, 1H); MS (ESI+) m/z 488 (M+H)+.
Figure imgf000198_0002
Example 127
l,5-anhydro-2,3-dideoxy-3- {ethyl[(2R,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2-yl] amino } -4-O-methyl-D- erythro-pentitol
To a solution of Example 79G (75 mg, 0.16 mmol) in anhydrous DMF (4 mL) was added potassium carbonate (1 10 mg, 0.9 mmol) and iodoethane (250 mg, 1.6 mmol) and the mixtures were stired at 50 °C overnight. LC-MS showed that the reaction was complete. After aqueous work-up, the crude product was purified by HPLC to afford title compound (40 mg). ¾ NMR (400 MHz, CD3OD) δ 8.70 (s, 1H), 8.06 (s, 1H), 4.85 (m, 2H), 4.30 (m, 1H), 3.90 - 4.10 (m, 4H), 3.46 - 3.75 (m, 4H), 3.45 (s, 3H), 3.35 (m, 1H), 3.05 - 3.20 (m, 3H), 2.58 (m, 1H), 1.85 - 2.20 (m, 8H), 1.75 (m, 1H), 1.55 (m, 1H), 1.25 - 1.40 (m, 5H); MS (ESI) m/z 496 (M+H)+.
The succinate salt of the above compound was prepared according to the procedure of preparation of succinate salt of Example 79G, substituting Example 127 for Example 79G. Ή NMR (400 MHz, CD3OD) δ 8.70 (s, 1H), 8.06 (s, 1H), 4.85 (m, 2H), 4.25 (d, J=13.6 Ηζ,ΙΗ), 3.95 (m, 4H), 3.65 (m, 1H), 3.40 - 3.50 (m, 3H), 3.40 (s, 3H), 3.35 (m, 1H), 3.06 - 3.28 (m, 3H), 2.50 (s, 4H), 2.48 (m, 1H), 2.10 - 2.25 (m, 2H), 1.90 (m, 5H), 1.25 (m, 2H), 1.55 (m, 1H), 1.18-1.40 (m, 5H); MS (ESI+) m/z 496 (M+H)+.
Figure imgf000199_0001
Example 128
l,5-anhydro-2,3-dideoxy-3- {ethyl[(2R,3aR,6aR)-3a-{[3-(triiluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2-yl] amino } -4-O-methyl-D- threo-pentitol
A mixture of Example 80 (200 mg, 0.4 mmol), ethyl iodide (100 mg, 0.6 mmol) and K2CO3 (125 mg, 0.9 mmol) in DMF (5 ml) was stirred at 100 °C overnight. The mixture was poured into water, extracted with EtOAc. The combined organic layer was washed with brine and water, dried over MgS04, filtered and concentrated in vaccum. The residue was purified by preparative HPLC to give Example 128 (15 mg) as trifluoroacetic acid salt. Ή NMR (400 MHz, CD3OD) δ ppm 8.72 (s, 1H), 8.05 (s, 1H), 4.85 (m, 2H), 4.30 (m, 1H), 4.02 (m, 4H), 3.45 - 3.75 (5H), 3.44 (s, 3H), 3.15 (m, 3H), 2.60 (m, 1H), 1.70 - 2.24 (m, 10H), 1.20 - 1.60 (m, 5H); MS (ESI+) m/z 496 (M+H)+.
Figure imgf000200_0001
Example 129
l,5-anhydro-2,3-dideoxy-4-0-methyl-3-{methyl[(2R,3aR,6aR)-3a-{[3-(trifluoromethyl)- 7,8-dihydro-l,6-naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]amino}-D- threo-pentitol
The title compound was prepared according to the procedure described in Example 78, substituting Example 80 for Example 79G, and isolated as trifluoroacetic acid salt. Ή NMR (400 MHz, CD3C1) δ 8.65 (s, 1H), 7.63 (s, 1H), 4.70 - 4.82 (m, 2H), 3.80 - 4.15 (m, 4H), 3.35 - 3.45 (m, 4H), 3.32 (s, 3H), 3.05 - 3.20 (m, 3H), 2.60 (m, 1H), 2.27 (s, 3H), 2.03 - 2.15 (m, 3H), 1.45 - 1.95 (m, 9H); MS (ESI) m/z 482 (M+H)+.
ABS
Figure imgf000200_0002
Example 130
l,5-anhydro-2,3-dideoxy-3- {(2,2-difluoroethyl)[(2R,3aR,6aR)-3a-{[3-(trifluoromethyl)- 7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2-yl] amino} -4-0- methyl-D-threo-pentitol
To a solution of Example 80 (100 mg, 0.21 mmol) in anhydrous dichloromethane (10 mL) was added 2,2-difluoroethyl trifluoromethanesulfonate (100 mg, 0.46 mmol) and diisopropylethyl amine (0.3 mL) and the reaction mixtures were stired at room temperature for 72 hours. After aqueous work-up, the crude product was purified by HPLC to afford title compound (50 mg) as trifluoroacetic acid salt. Ή NMR (400 MHz, CD3OD) δ 8.70 (s, 1H), 8.05 (s, 1H), 6.12(t, J= 40 .0 Hz, 2H), 4.85 (m, 2H), 4.28 (d, J=13.2 Hz, 1H), 3.90 - 4.10 (m, 4H), 3.75 (m, 3H), 3.60 (m, 1H), 3.50 (m, 2H), 3.36 (s, 3H), 3.10 (m, 2H), 2.58 (m, 1H), 1.86 - 2.27 (m, 8H), 1.75 (m, 2H), 1.56 (m, 1H), 1.34 (m, 1H); MS (ESI) m/z 532 (M+H)+.
Figure imgf000201_0001
Example 132
[(2R,3aR,6aR)-2-[(2-methoxyethyl)(tetrahydro-2H-pyran-4-yl)am
3a(lH)-yl][3-(trifluoromethyl)-7,8-dm^
To a solution of Example 82 (30 mg, 0.069 mmol) in anhydrous DMF (5 mL) was added potassium carbonate (100 mg, 0.72 mmol) and 1 -bromo-2-methoxy ethane (30 mg, 0.22 mmol) and the mixtures were stired at 60 °C for 72 hours. After aqueous work-up, the crude product was purified by HPLC to afford title compound as trifluoroacetic acid salt (2.5 mg). 'H NMR (400 MHz, CD3OD) δ 8.71 (s, 1H), 8.06 (s, 1H), 4.85 (m, 2H), 3.96 - 4.14 (m, 5H), 3.38 - 3.70 (m, 6H), 3.30 (s, 3H), 3.15 (m, 3H), 2.50 - 2.70 (m, 2H), 1.70 - 2.15 (m, 1 1H), 1.55 (m, 1H), 1.35 (m, 1H); MS (ESI) m/z 496 (M+H)+.
Figure imgf000201_0002
Example 133
[(2R,3aR,6aR)-2-{[(2S,4R)-2-phenyltetrahydro-2H-pyran-4-yl]amino}hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone The title compound was isolated from the procedure of Example 136C. Ή NMR: (400 MHz, CDC13) δ ppm 8.66 (s, 1H), 7.68 (s, 1H), 7.25 - 7.35 (m, 5H), 4.75 - 4.85 (m, 3H), 3.75 - 4.00(m, 4H), 3.40 - 3.55 (m, 2H), 2.90 - 3.20(m, 3H), 1.30 - 2.30(m, 15H); MS (ESI) m/z 514 (M+H)+.
Figure imgf000202_0001
Example 134
[(2R,3aR,6aR)-2-{[(2R,4S)-2-phenyltetrahydro-2H-pyran-4-y^
3a(lH)-yl][3-(trifluoromethyl)-7,8-dih^
Example 134A
(R)-2-phenyldihydro-2H-pyran-4(3H)-one
The title compound was isolated from the procedure of Example 136B.
Example 134B
[(2R,3aR,6aR)-2-{[(2R,4S)-2-phenyltetrahydro-2H-pyran-4-yl]amino}hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone The title compound was prepared and purified according to the procedure described in method B of Example 79G, substituting Example 134A for Example 79R. Ή NMR: (400 MHz, CDC13 ) δ ppm 8.63 (s, 1H), 7.53 (s, 1H), 7.25 - 7.35 (m, 5H), 4.65 - 4.90 (m, 3H), 3.70 - 4.00 (m, 4H), 3.52 (m, 2H), 3.25 (m, 1H), 3.06 (m, 2H), 1.30 - 2.10 (m, 15H); MS (ESI) m/z 514 (M+H)+.
Figure imgf000202_0002
Example 135
l,5-anhydro-2,3-dideoxy-3- {(2,2-difluoroethyl)[(2R,3aR,6aR)-3a-{[3-(trifluoromethyl)- 7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2-yl]amino} -4-0- methyl-D-erythro-pentitol
The title compound was prepared and purified according to the procedure described in Example 130, substituting Example 79G for Example 80, and isolated as trifluoroacetic acid salt. 'H NMR (400 MHz, CD3OD) δ 8.69 (s, 1H), 8.04 (s, 1H), 6.15 (t, J= 40.0 Hz, 1H), 4.84 (m, 2H), 4.25 (d, J=13.2 Hz, 1H), 3.90 - 4.10 (m, 4H), 3.52 - 3.80 (m, 6H), 3.45 (s, 3H), 3.10 (m, 2H), 2.62 (m, 1H), 1.90 - 2.27 (m, 8H), 1.75 (m, 2H), 1.55 (m, 1H), 1.39 (m, 1H); MS (ESI) nVz 532 (M+H)+.
Figure imgf000203_0001
Example 136
[(2R,3 aR,6aR)-2- { [(2S,4S)-2-phenyltetrahydro-2H-pyran-4-yl] amino } hexahydropentalen- 3a(lH)-yl][3-(triiluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone
2-phenyltetrahydro-2H-pyran-4-ol
Example 136A
Sulfuric acid (3 mL) was added at 0 °C to a mixture of 3-butenol (4.0 g, 55.4 mmol) and benzaldehyde (3.0 g, 28.2 mmol) and the reaction mixture was stirred for 16 hours, during which time it was allowed to warm to room temperature. The mixture was poured into crushed ice, neutralized by the addition of solid sodium bicarbonate and extracted with dichloromethane (2 x 50 mL). The organic layer was combined, dried over Na2S04, filtrated, and concentrated. The residue was purified by chromatography (S1O2, 0% to 25% EtOAc in petroleum ether) to afford example 136A (1.4g, 28%yield) as oil.
Example 136B
(S)-2-phenyldihydro-2H-pyran-4(3H)-one
Dimethyl sulphoxide (4.6 g, 60 mmol) was added dropwise into a solution of oxalyl chloride (1.7 g, 13 mmol) at -78 °C. The mixture was stirred at -78 °C for 15 minutes, then Example 136A (1.4 g, 8 mmol) in dichloromethane (5 mL) was added dropwise. The mixture was stirred at -78 °C for 30 minutes, then diisopropylethylamine (8 mL) was added dropwise at -78 °C and the resulting mixture was stirred for additional 3 hours. Water (lOmL) and dichloromethane (20 mL) were added, and the reaction mixture was stirred at room temperature for 15 minutes. Two phases were separated and the organic fraction was washed with water, dried over Na2S04, filtered, and
concentrated. The residue was purified by chromatography (S1O2, 0% to 30% EtOAc in petroleum ether), followed by chiral SFC separation to give Example 136B (0.4 g, 28%) as oil.
Example 136C
[(2R,3 aR,6aR)-2- { [(2S,4S)-2-phenyltetrahydro-2H-pyran-4-yl] amino } hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone
The title compound was prepared and purified according to method B for Example 79G, substituting Example 136B for Example 79R. Ή NMR: (400 MHz, CDC13) δ ppm 8.63 (s, 1H), 7.60 (s, 1H), 7.25 - 7.35 (m, 5H), 4.66 - 4.90 (m, 3H), 3.75 - 3.95(m, 4H), 3.50 (m, 2H), 3.21(m, 1H), 3.07 (m, 2H), 1.30 - 2.05 (m, 15H); MS (ESI) m/z 514 (M+H)+.
Figure imgf000204_0001
Example 137
l,5-anhydro-2,3-dideoxy-4-0-ethyl-3-{[(2R,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8- dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2-yl] amino } -O-erythro- pentitol
The title compound was isolated from the procedure of Example 138D. Ή NMR (400 MHz, CD3OD) δ 8.70 (s, 1H), 8.05 (s, 1H), 4.85 (m, 2 H), 4.15 (d, J=12.4 Hz, 1H), 3.97 (m, 3 H), 3.35 - 3.75 (m, 5H), 3.10 (m, 2 H), 3.03 (q, J=7.2Hz, 2H), 2.49 (m, 1 H), 1.65 - 2.10 (m, 10 H), 1.55 (m, 1H), 1.45 (m, 1H), 1.25 (t, J=7.2 Hz, 3 H); MS (ESI) m/z 482 (M+H)+.
Figure imgf000204_0002
Example 138
l,5-anhydro-2,3-dideoxy-4-0-ethyl-3-{[(2R,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8- dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2-yl]amino} - -threo- pentitol
Example 138A
4,4-Dimethoxy-tetrahydro-pyran-3-ol To a 0 °C solution of KOH (96 g, 1.4 mol) in MeOH (800 mL) was added tetrahydro-pyran-4-one (60 g, 0.6mmol) over 0.5 hour. After stirring for 1 hour, a solution of iodine (96 g, 0.7 mol) in MeOH (1.2 L) was added over 2 hours. Upon completion of the addition, the solution was gradually warmed to room temperature and stirred for additional 10 hours. The resulting solution was then concentrated, and the residue was purified by column chromatography to give Example 138A (70 g, 72%) as a yellow oil.
Example 138B
3-Ethoxy-4,4-dimethoxy-tetrahydro-pyran
To a suspension of NaH (144 mg, 6 mmol) in THF (50 mL) was added Example 138A (486 mg, 3 mmol), followed by iodoethane (2.8 g, 18 mmol). The mixture was stirred at room temperature overnight and concentrated. The residue was diluted with EtOAc (100 mL) and ¾0 (50 mL) .The organic layer was washed with brine, dried over Na2S04, filtered, and concentrated. The residue was purified by column chromatography to give Example 138B (410 mg, 72%) as a gale yellow oil.
Example 138C
3-Ethoxy-tetrahydro-pyran-4-one
A mixture of Example 138B (410 mg, 2.16 mmol) in dichloromethane (20 mL) and trifluoroacetic acid (2 mL) was stirred at room temperature for 3 hours and concentrated to provide Example 138C, which was directly into the next step without further purification.
Example 138D
l,5-anhydro-2,3-dideoxy-4-0-ethyl-3-{[(2R,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8- dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2-yl]amino} - -threo- pentitol
The title compound was prepared and purified according method B of Example 79G, substituting Example 138C for Example 79R. Ή NMR (400 MHz, CD3OD): δ 8.70 (s, 1H), 8.05 (s, 1H), 4.87 (m, 2 H), 4.20 (d, J=13.2 Hz, 1H), 3.97 (m, 3 H), 3.35 - 3.78 (m,5H), 3.10 (m, 2 H), 3.05 (q, J=7.2Hz, 2H), 2.59 (m, 1 H), 1.70 - 2.10 (m, 10 H), 1.55 (m, 1H), 1.48 (m, 1H), 1.28 (t, J=7.2 Hz, 3 H); MS (ESI) m/z 482 (M+H)+.
Figure imgf000205_0001
Example 139
l ,5-anhydro-2,3-dideoxy-4-0-methyl-3- {(2H3)methyl[(2R,3aR,6aR)-3a- {[3- (trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2- yl]amino} -D-eryi/zro-pentitol
To a solution of Example 79G (50 mg, 0.107 mmol) in dioxane (2 mL) was added
CD2O2 (30 mg, 0.63 mmol) and CD2O (30 mg, 0.93 mmol) then the mixture was heated at 80 °C overnight under nitrogen. LC-MS showed that the reaction was complete. The pH of the mixture was adjusted to about 10 with the addition of aqueous NaHC(¾ solution and the layers separated. The aqueous layer was extracted with CH2CI2. The combined organic layers were washed with brine, dried (MgSC^), filtered, and concentrated. The residue was purified by HPLC to afford the title compound (50 mg) as white solid. Ή NMR (400 MHz, CDCI3) δ 8.69 (s, 1H), 7.67 (s, 1H) , 4.75(s, 2H), 4.01 - 4.48 (m, 2H), 3.50-4.00 (m, 4H), 3.48-3.50 (m, 7H), 3.01 -3.38 (m, 2H), 2.64 (m, 1H), 2.04-2.36 (m, 3H), 1.70-2.02 (m, 2H), 1.48- 1.68 (m, 4H), 1.20- 1.49 (m, 2H); MS (ESI) m/z 485(M+H)+.
fes
Figure imgf000206_0001
Example 140
[(2R,3aR,6aR)-2-[(4R)-3,4-dihydro-2H-chromen-4-ylamino]hexahydropentalen-3a(lH)- yl][3-(trifluoromethyl)-7,8-dihydro- l ,6-naphthyridin-6(5H)-yl]methanone The title compound (retention time 8.68 minute, 27 mg) was prepared and isolated according to the procedure described in Example 148C, substituting chroman-4-one for Example 148B. The diastereomeric isomer Example 165 (retention time 9.01 minute, 30 mg) was also isolated Ή NMR (400 MHz, CDC13) δ 8.62 (s, 1H), 8.52 (d, 1H), 7.05-7.19 (m, 2H), 6.68-6.81 (m, 2H), 4.70(s, 2H), 4.28 (t, 1H), 4.12 (m, 1H), 3.61 -3.81 (m, 2H), 3.36-3.55 (m, 2H), 2.91 -3.04 (m, 3H), 1.46-2.14 (m, 10H), 1.04 - 1.42 (m, 4H); MS (ESI) m/z 485(M+H)+.
Figure imgf000207_0001
Example 141
[(2R,3aR,6aR)-2-{[(3S,4S)-3-methyltetrahydro-2H-pyran-4- yl]amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(triiluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone
Example 141 A
3-Methyldihydro-2H-pyran-4(3H)-one
To a mixture of tetrahydropyranone (42 g, 0.419 mol) and
hexamethylphosphoramide (72 mL) in tetrahydrofuran (400 mL) was added lithium diisopropylamide (262 mL, 0.524 mol) dropwise at -78 °C under N2. After the addition the mixture was stirred for 0.5 hour at -78 °C. Iodomethane (250 g, 1.67 mol, 4.0 equivalents) was added to the mixture dropwise. The resulting mixture was stirred for 12 hours at room temperature. TLC (petroleum ether: ethyl acetate = 4: 1) indicated that the reaction was not complete. The mixture was quenched with aqueous NH4C1 (100 mL) and extracted with ethyl acetate (3x150 mL). The combined organic layers was concentrated in vacuum and the residue was purified by chromatography on silica to provide the title compound (1 1 g, 22.3%) as a colorless liquid. Ή NMR (400 MHz, CDC13) δ 4.25 (m, 1H), 4.17 (m, 1H),3.72 (m, 1H), 3.30 (m, 1H), 2.65 (m, 2H), 2.40 (m, 1H), 0.98(d, J = 6.8Hz, 3H); MS (ESI) m/z 452 (M+H)+.
Example 14 IB
[(2R,3aR,6aR)-2-{[(3S,4S)-3-methyltetrahydro-2H-pyran-4- yl]amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(triiluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone
To a solution of Example 79N (0.37g, 0.87 mmol) in isopropyl acetate (3 mL) was added isopropanol (0.2 mL), nBu3N (0.39 g, 2.1 mmol) and NaBH(OAc)3 (0.4 lg, 1.9 mmol). The reaction mixture was stirred at 0 °C for 1 hour, followed by the addition of Example 141A (0.1 g, 0.87 mmol) in isopropyl acetate (2 mL). The reaction mixture was stirred at room temperature for 48 hours. The mixture was partitioned between saturated NaHC(¾ solution (6 mL), water (6 mL) and ethyl acetate (20 mL). The separated aqueous layer was extracted with ethyl acetate (20 mLx3). The combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated in vacuuo. The residue was purified by preparative TLC (CH2CI2: MeOH, 20: 1) to afford product of four diastereoisomers (0.1 g). The four diastereoisomers were further purified by chiral SFC using a preparative ChiralCel AD 250mm*30mm,5um eluting with mobile A:
Supercritical CO2, B: ethanol (0.05% diethylamine), A:B =80:20 at 70ml/min; Column Temp: 38 °C; Nozzle Pressure: lOOBar; Nozzle Temp: 60 °C; Evaporator Temp: 20 °C Trimmer Temp: 25 °C; Flow rate: 70 mL/min; Wavelength: 220 nm to yield Example 169 (peak 1, Retention time 6.6 minute, 5.22 mg), the title compound (peak 2, Retention time 7.39 minute, 8.97 mg), Example 142( peak 3, Retention time 7.93 minute, 7.96 mg) and Example 170 (peak 4, Retention time 9.23minute, 2.55 mg). Ή NMR (400 MHz, CDC13) δ 8.70 (s, 1H), 7.68(s, 1H), 4.80 (m, 2H), 3.90 (m,3H), 3.65 (m, 1H), 3.55 (m, 1H), 3.35- 3.48 (m, 3H), 3.15 (m, 2H), 2.78 (m, 1H), 2.10 (m, 1H), 1.45-2.05 (m, 12H), 1.35 (m, 1H), 0.94 (d, J=7.20 Hz, 3H).
To a solution of Example 141B (3.90 g, 8.64 mmol) in ethanol (50 mL) was added dropwise a solution of succinic acid (1.02g 8.64 mmol) in ethanol (50 mL) at room temperature. The resulting mixture was stirred for 1 hour at ambient temperature. The solvent was removed in vacuum to give the corresponding succinate salt. The solid was dissolved in water ( 100 mL) and lyophilized to afford the succinate salt of the title compound as light yellow compound (4.9 g, 8.1 mmol, 96%). Ή NMR (400 MHz,
CD3OD) δ 8.73 (s, 1H), 8.09 (s, 1H), 4.82 (m, 2H), 4.00 (m, 3H), 3.74 (m, 2H), 3.55 (m, 2H), 3.49 (m, 1H), 3.14 (m, 2H), 2.56 (m, 1H), 2.53 (m, 4H), 1.75-2.20 (m, 1 1H), 1.60 (m, 1H), 1.40 (m, 1H),1.10 (d, J= 7.0 Hz, 3H).
Figure imgf000208_0001
Example 142
[(2R,3aR,6aR)-2-{[(3S,4R)-3-methyltetrahydro-2H-pyran-4- l]amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- naphthyridin-6(5H)-yl]methanone The title compound (peak 3, retention time 7.93 minute) was isolated from the chiral SFC purification of Example 141B. 'H NMR (400 MHz, CDC13) δ (ppm): 8.65 (s, 1H), 7.68(s, 1H), 4.73 (s, 2H), 3.90 (m,3H), 3.65 (m, 1H), 3.50 (m, 1H), 3.28-3.45 (m, 3H), 3.09 (m, 2H), 2.72 (m, 1H), 1.90-2.05 (m, 2H), 1.36-1.90 (m, 11H), 1.25 (m, 1H), 0.89(d, J=6.56 Hz, 3H); MS (ESI) m/z 452(M+H)+.
Figure imgf000209_0001
Example 143
[(2R,3aR,6aR)-2-[(4R)-3,4-dihydro-2H-chromen-4-yl(methyl)amino]hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone The title compound was prepared and isolated according to the procedure described in Example 78, substituting Example 140 for Example 79G. Ή NMR (400 MHz, CDCI3) δ (ppm) 8.68 (s, 1H), 7.66 (d, 1H) , 7.47 (d, 1H), 7.05 (t, 1H), 6.84 (s, 1H), 6.71(d, 1H), 4.70 (m, 2H), 4.30-4.33 (m, 1H), 3.75-4.1 1 (m, 4H), 3.50 (m, 1H), 3.06-3.19 (m, 2H), 1.98-2.24 (m, 6H), 1.71-1.92 (m, 3H), 1.41 -1.70 (m, 2H), 1.15 -1.40 (m, 4H), 0.94 (m, 1H); MS (ESI) m/z 500 (M+H)+.
Figure imgf000209_0002
Example 144
[(2R,3aR,6aR)-2-{[(4R)-6-fluoro-3,4-dihydro-2H-chromen-4- yl]amino}hexahydropentalen-3a(lH)-yl] [3-(trifluoromethyl)-7,8-dihydro- 1 ,6- naphthyridin- 6(5H) -yl]methanone
Example 144 A
6-fluorochroman-4-one
The title compound was prepared and isolated according to the procedure described in Example 148A and 148B, substituting 4-fluorophenol for 2-fluorophenol.
Example 144B [(2R,3aR,6aR)-2-{[(4R)-6-iluoro-3,4-dihydro-2H-chromen-4- yl]amino}hexahydropentalen-3a(lH)-yl] [3-(trifluoromethyl)-7,8-dihydro- 1 ,6- naphthyridin- 6(5H) -yl]methanone
The title compound was prepared and isolated according to the procedure described in Example 148C, substituting Example 144A for Example 148B to provide the title compound (peak 1, retention time 7.12 minute, 22 mg), as well as the diastereomeric isomer Example 177 (peak 2, retention time 8.05 minute, 17 mg). Ή NMR (400 MHz, CDC13) δ 8.68 (s, 1H), 7.67 (s, 1H) , 6.95 (m, 1H), 6.82 (m, 1H), 6.69 (m, 1H), 4.77(s, 2H), 4.38 (m, 1H), 4.12 (m, 1H), 3.82-3.96 (m, 2H), 3.66 (m, 1H), 3.51-3.61 (m, 1H), 3.45-3.49 (m, 1H), 3.15 (t, 2H), 2.01-2.21 (m, 4H), 1.91-2.03 (m, 2H), 1.60-1.89 (m, 4H), 1.50- 1.59 (m, 1H), 1.20-1.48 (m, 2H); MS (ESI) m/z 504(M+H)+.
Figure imgf000210_0001
Example 145
[(2R,3aR,6aR)-2-{[(2R,4R)-2-(pyridin-2-yl)tetrahydro-2H-pyran-4- yl]amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- 1,6- naphthyridin-6(5H)-yl]methanone
Example 145 A
2-(pyridin-2-yl)tetrahydro-2H-pyran-4-ol
To a solution of picolinaldehyde (4.6 g, 43 mmol) in dichloromethane (10 mL) was added but-3-en-l-ol (3.1 g, 43 mmol) at 0 °C, followed by drop wise addition of H2SO4 (15 mL ) over 40 minutes. After the addition was completed, the mixture was stirred at room temperature for 14 hours under N2. TLC indicated that the reaction was completed. The mixture was pour into ice-water, then adjusted to pH=7 with 2N aqueous NaOH. Then the resulting aqueous layer was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over Na2S04, filtered, and the solvent was evaporated in vacuum. The residue was purified by column chromatography to provide the title compound (1.0 g, 13 %).
Example 145B
2-(pyridin-2-yl)dihydro-2H-pyran-4(3H)-one A mixture of Example 145A (1 g, 5.6 mmol) in tetrahydrofuran (30 mL) was added Dess-Martin reagent (4.8 g, 1 1.2 mmol), then the mixture reaction was heated at reflux for 5 hours. To the mixture was added saturated aqueous NaHC(¾ solution (50 mL). The resulting aqueous layer was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over Na2S04, filtered, and concentrated. The residue was purified by column chromatography with (petroleum ether: ethyl aceate = 10:3) to provide the title compound (200 mg, 20%).
Example 145C
[(2R,3aR,6aR)-2-{[(2R,4R)-2-(pyridin-2-yl)tetrahydro-2H-pyran-4- yl]amino}hexahydropentalen-3a(lH)-yl] [3-(triiluoromethyl)-7,8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone
To an ice-cold solution of compound 79N (0.226 g, 0.46 mmol) in isopropyl acetate (15 mL) was added η-Β¾Ν (0.226 g, 1.225 mmol) followed by addition of isopropanol (1.0 mL). Sodium triacetoxyborohydride (0.25 g, 1.225 mmol) was added at 5 °C. After 1 hour, a solution of Example 145B (0.166 g, 1 mmol) in isopropyl acetate (5 mL) was added to the mixture at 1 °C. The reaction mixture was stirred at room temperature for 15 hours. The mixture was partitioned between saturated aqueous NaHC(¾ (10 mL) and ethyl acetate (40 mL). The organic phase was dried with Na2S04, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel chromatography (CFLC^MeOH = 20: 1). The fractions collected were concentrated. The crude product was further purified by chiral SFC (Instrument: Berger MultiGram™ SFC , Mettler Toledo Co, Ltd; Column: Chiralcel OJ 250x30 mm ID, 20 μιη; Mobile phase: A: Supercritical CO2, B: isopropanol (0.05% diethylamine as modifier), A:B =70:30 at 80 mL/min; Column Temp: 38 °C; Nozzle Pressure: lOOBar; Nozzle Temp: 60 °C;
Evaporator Temp: 20 °C Trimmer Temp: 25 °C; Flow rate: 80 mL/min; Wavelength: 220 nm) to provide the title compound (retention time 6.38 minute, 2.076 mg, 2.6%) as white solid, as well as Example 191 (retention time 7.42 minute, 2.26 mg). Ή NMR (400 MHz, CDCI3) δ 8.69 (s, 1H), 8.52 (d, 1H) 7.71 (m, 2H), 7.47 (d, 1H), 7.17 (t, 1H), 5.03 (s, lH),4.82(m, 2H), 3.93-4.00 (m, 3H), 3.50-3.70 (m, 3H), 3.42 (s, 1H), 3.28 (s, 2H), 2.01 - 2.44 (m, 7H), 1.86 -1.99 (m, 4H), 1.50-1.80 (m, 3H), 1.23-1.50 (m, 3H); MS (ESI) m/z 515 (M+H)+.
Figure imgf000212_0001
Example 146
[(2R,3aR,6aR)-2-{[(3S,4S)-3-ethyltetrahydro-2H-pyran-4-yl]amino}hexahydropentalen- 3a(lH)-yl][3-(trinuoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone The title compound (peak 1, retention time 5.32 minute) was isolated from the
SFC purification of Example 147B. Ή NMR (400 MHz, CD3OD): 88.72 (s, 1H), 8.07 (s, 1H), 4.87 (m, 2H), 4.00 (m, 4H), 3.75 (m, 1H), 3.50 (m, 4H), 3.12 (m, 3H), 2.55 (m, 1H), 2.1 1 (m, 1H), 1.50-2.00 (m, 10H), 1.30 (m, 3H), 1.01 (m, 3H); MS (ESI) m/z 466 (M+H)+.
Figure imgf000212_0002
Example 147
[(2R,3aR,6aR)-2-{[(3S,4R)-3-ethyltetrahydro-2H-pyran-4-yl]amino}hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone
Example 147A
3-ethyldihydro-2H-pyran-4(3H)-one
To a mixture of dihydro-2H-pyran-4(3H)-one (5 g, 0.05 mol) and
hexamethylphosphoramide (9 mL) in tetrahydrofuran (100 mL) was added lithium diisopropylamide (34.7 mL, 0.062 mol) dropwise at -78 °C under N2. After the addition the mixture was stirred for 0.5 hour at -78 °C. Iodo ethane (7.78 g, 0.199 mol) was added to the mixture dropwise. The resulting mixture was stirred for 12 hours at room temperature. TLC (petroleum ether: ethyl acetate = 4: 1) indicated that the reaction was still not complete, the mixture was quenched with aqueous NH4CI (100 mL), extracted with ethyl acetate (3 x 50 mL), the combined organic layers was concentrated in vacuo and the residue was purified by chromatography on silica to yield title compound (2.5 g, 39.1%) as a colorless liquid.
Example 147B [(2R,3aR,6aR)-2-{[(3S,4R)-3-ethyltetrahydro-2H-pyran-4-yl]amino}hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone A mixture of Example 79N (0.14 g, 0.35 mol), n-Bu3N (0.135 g, 0.71 mmol) and propan-2-ol (1 mL) in isopropyl acetate (15 mL) was added NaBH(OAc)3 (0.31 g, 1.43 mmol) at 0-10 °C The mixture was stirred at 0 °C for 1 hour. Example 146A (0.069 g, 0.54 mmol) was added to the reaction mixture and stirred for 12 hours at room temperature. LC-MS indicated that the reaction was complete. The mixture was washed with aqueous NaHC(¾ (15 mL). The aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over Na2S04, filtered, and concentrated in vacuum. The residue was purified by chromatography on silica and then SFC
(Instrument: Berger MultiGram™ SFC, Mettler Toledo Co, Ltd; Column: Chiralcel AD 250 mm x 30 mm, ID 5 μιη; Mobile phase: A: Supercritical CO2, B: isopropanol (0.05% diethylamine as modifier), A:B =70:30 at 70 mL/min; Column Temp: 38 °C; Nozzle Pressure: lOOBar; Nozzle Temp: 60 °C; Evaporator Temp: 20 °C; Trimmer Temp: 25 °C; Flow rate: 70 mL/min; Wavelength: 220 nm) to provide the title compound (peak 2, retention time 6.81 minute) as a white solid. Ή NMR (400 MHz, CD3OD) δ 8.72 (s, 1H), 8.07 (s, 1H), 4.87 (m, 2H), 4.00 (m, 4H), 3.40-3.75 (m, 4H), 3.15 (m, 2H), 2.87 (m, 1H), 2.30 (m, 1H), 1.30-2.10 (m, 16H), 0.98 (m, 3H); MS (ESI) m/z 466 (M+H)+.
Figure imgf000213_0001
Example 148
[(2R,3aR,6aR)-2- {[(4R)-8-fluoro-3,4-dihydro-2H-chromen-4- yl]amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone
Example 148 A
3-(2-fluorophenoxy)propanoic acid
To a mixture of 2-fluorophenol (15 g, 0.33 mol) and 3-bromopropanoic acid (20.1 1 g, 0.12 mol) in water (50 mL) was added NaOH (11 g, 0.275 mol) in one portion. After the addition the mixture was refluxed for 12 hours. The mixture was acidified to about H 2 by addition of 2N HC1 solution, the solid was filtered and dried to yield title compound (5 g, 20.2%) as a white solid.
Example 148B
8-fluorochroman-4-one
To a solution of Example 148A (0.9 g, 4.88 mmol) in dichloromethane (15 mL) was added (COCl)2 (0.93 g, 7.33 mmol) and N,N- dimethyl formamide (2 drops). The mixture was stirred at room temperaturefor 1 h, cooled to 0 °C, followed by the addition of AICI3 (0.977 g, 7.33 mmol). The reaction mixture was stirred for 12 hours at room temperature, washed with aqueous NaOH (1 N, 20 mL), and extracted with ethyl acetate (3 x 50 mL). The organic layer was dried over Na2S04, filtered, and concentrated in vacuum to give title compound (0.6 g, 74%) as a light yellow solid.
Example 148C
[(2R,3aR,6aR)-2- {[(4R)-8-fluoro-3,4-dihydro-2H-chromen-4- yl]amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone
A mixture of Example 148B (85.1 mg, 0.51 mmol) and Example 79N (0.2 g, 0.51 mol) in Ti-(OiPr)4 (5 mL) was added N,N-diisopropylethylamine (0.196 g, 1.53 mmol) dropwise at room temperature. The mixture was stirred at room temperature for 12 hours. NaBH4 (0.197 g, 5.1 mmol) was added to the reaction mixture, followed by addition of methanol (10 mL) and stirred for 2 hours at room temperature. LC-MS indicated that the reaction was complete, the mixture was washed with aqueous NaHC(¾ (15 mL), the aqueous layer was extracted with ethyl acetate (3 x 50 mL). The organic layer was dried over Na2S04,concentrated in vacuum and purified by chromatography on silica and then SFC (Instrument: Berger MultiGram™ SFC, Mettler Toledo Co, Ltd; Column: Chiralcel OJ 250x30 mm ID, 5 μιη; Mobile phase: A: Supercritical CO2, B: isopropanol (0.05% diethylamine as modifier), A:B =70:30 at 60 mL/min; Column Temp: 38 °C; Nozzle Pressure: 100 Bar; Nozzle Temp: 60 °C; Evaporator Temp: 20 °C Trimmer Temp: 25 °C; Flow rate: 60 mL/min; Wavelength: 220 nm.) to afford the title compound as a white solid (peak 1, retention time 6.5 minute, 2.31 mg), as well as Example 201 (peak 2, retention time 7.22 minute, 0.98 mg). Ή NMR (400 MHz, CD3OD): δ 8.68 (s, 1H), 8.04 (s, 1H), 6.95 (m, 3H), 4.70 (m, 2H), 4.25 (m, 2H), 4.31 (m, 1H), 3.95 (m, 3H), 3.51 (m, 2H), 3.10 (m, 2H), 2.29 (m, 1H), 1.90 (m, 9H), 1.55 (m, 1H), 1.31 (m, 2H); MS (ESI) m/z 503 (M+H)+.
Figure imgf000215_0001
Example 149
[(2R,3aR,6aR)-2-[(3aS,7aS)-hexahydropyrano[4,3-b]pyrrol-l(4H)-yl]hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone
Example 149A
3-allyldihydro-2H-pyran-4(3H)-one
To a solution of lithium diisopropylamide (prepared from disopropylamine (21 mL, 0.15 mol) and n-BuLi (60 mL, 0.15 mmol)) in tetrahydrofuran (350 mL) at -78 °C was slowly added tetrhydropyan-4-one (10 g, 0.1 mol) and hexamethyl phosphoramide (18 mL, 0.09 mol). The resultant solution was stirred for 60 min at -78 °C. Then the mixture was quenched with allyl bromide (36.3 g, 0.3 mol). The resulting solution was gradually warmed to 0 °C and held there for additional 3 hours. The reaction solution was quenched with water at 0 °C and extracted with ethyl acetate (3 x 150 mL). The combined organic phase was washed with brine, dried over Na2S04, filtered, and concentrated to give a crude product, which was purified by column chromatography (S1O2, 10% petroleum ether/ethyl acetate) to give Example 149A (4 g, yield 35%).
Example 149B
2-(4-oxotetrahydro-2H-pyran-3-yl) acetaldehyde To a solution of Example 149 A (1 g, 7.09 mmol) in dichloromethane (5 mL) with stirring at -78 °C was bubbled with O3. After 5 minutes, TLC showed starting material was consumed. The mixture was concentrated to afford Example 149B (1 g, yield 96%).
Example 149C
((2R,3aR,6aR)-2-((3aS,7aS)-hexahydropyrano[4,3-b]pyrrol-l(6H)-yl)octahydropentalen- 3a-yl)(3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl)methanone A solution of Example 149B (300 mg, 2.1 1 mmol) and Example 79N (500 mg, 1.8 mmol) in dichloromethane (2 mL) was stirred at room temperature for 1 hour. Then, NaBH(OAc)3 (895 mg, 4.22 mmol) was added at 0 °C. After addition, the reaction solution was stirred at room temperature for 16 hours. The reaction mixture was extracted with ethyl acetate (2 x 10 ml). The organic phase was washed with brine, dried over Na2S04, filtered, and concentrated to give a crude product, which was purified by preparative HPLC to afford a mixture of isomers. These isomers were further purified by chiral SFC with a preparative ChiralCel AD column (250mm*30mm^m) eluting with mobile phase: A, Supercritical CO2; B, EtOH (0.2% diethylamine), A:B=75:25 with a flow rate of 60 mL/min (Nozzle pressure: 100 bar; Nozzle temperature: 60 °C, wavelength: 220 nm, column temperature: 38 °C, Instrument: Thar 200 ) to afford the title compound ( peak 2, retention time 5.68 minute, 50 mg), as well as Example 150 (peak 1, retention time, 5.25 minutes, 40 mg). Ή NMR (400 MHz, CD3OD) δ 8.74 (s, 1 H), 8.09 (s, 1 H), 4.86 (m, 2H), 3.70-4.10 (m, 7H), 3.35-3.64 (m, 3 H), 3.15 (s, 2 H), 2.35-2.78 (m, 4 H), 1.70-2.25 (m, 10 H), 1.60 (m, 1H), 1.35 (m, 1H); MS (ESI) m/z 464 (M+H)+.
The succinate salt of the title compound (2.6 g) was prepared by heating a mixture of Example 149C (2.16 g, 4.67 mmol) and succinic acid (0.551 g, 4.67 mmol) in ethanol (100 mL) at 45 °C for 30 minutes and concentrated in vacuo. 'HNMR δ 8.68 (s, 1 H), 8.03 (s, 1 H), 4.8 (m, 2 H), 3.90 (m, 3 H), 3.82 (m, 1 H), 3.69 (m, 4 H), 3.50 (m, 1 H), 3.10 (m, 2 H), 2.50(m, 6 H), 1.60-2.20 m, 12 H) , 1.5 (m, 1 H), 1.31 (m, 1 H).
Figure imgf000216_0001
Example 150
[(2R,3aR,6aR)-2-[(3aR,7aR)-hexahydropyrano[4,3-b]pyrrol- l(4H)- yl]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-
6(5H)-yl]methanone
The title compound (retention time, 5.25 minutes) was isolated from the SFC purification of Example 149C. Ή NMR (400 MHz, CD3OD) δ 8.75 (s, 1 H), 8.10 (s, 1 H), 4.86 (m, 2H), 3.60-4.15 (m, 7H), 3.35-3.58 (m, 3 H), 3.15 (s, 2 H), 2.68 (m, 1H), 2.35-2.55 (m, 2 H), 1.70-2.23 (m, 1 1 H), 1.60 (m, 1H), 1.45 (m, 1H); MS (ESI) m/z 464 (M+H)+.
Figure imgf000217_0001
Example 151
[(3aR,6aR)-2-(6,7-dihydro-4H-pyrano[4,3-d][l,3]thiazol-2-ylamino)hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone
Example 151 A
3-chlorodihydro-2H-pyran-4(3H)-one
To a solution of tetrhydropyan-4-one (5.0 g, 50 mmol) in CCI4 (100 mL) at 0 °C, SO2CI2 (7.4 g, 55 mmol) was added slowly. After the addition, the reaction mixture was stirred at room temperature for 4 hours and then carefully quenched with ice-cold water. The reaction mixture was washed with brine, dried over MgS04, filtered, and concentrated. The colorless oil (6 g) obtained was used for next step without purification.
Example 15 IB
6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-amine To a solution of Example 151A (6.0 g, 44 mmol) in tetrahydrofuran (60 mL), ethanol (30 mL) was added thiourea (4.0 g, 52 mmol). The mixture was refluxed for 12 hours. TLC showed that the reaction was completed. The reaction mixture was cooled to room temperature and the white solid was separated by filtration (4.0 g).
Example 151C
[(3aR,6aR)-2-(6,7-dihydro-4H-pyrano[4,3-d][l,3]thiazol-2-ylamino)hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone The title compound was prepared and purified according to the method A described for Example 79G, substituting Example 15 IB for Example 79F. The crude product was purified by HPLC (ASB CI 8 Column: 150*25mm ID, 5μιη; Mobile phase A: Water (0.1% TFA,V/V), mobile phase B acetonitrile (Neutral), flow rate: 25 mL/min; Gradient: 24 %-40 % acetonitrile; Wavelength: 220 nm and 254nm; retention time 12 minute). 'H NMR (400 MHz, CD3OD) δ 8.93 (s, 1H), 8.44 (s, 1H), 45.14 (m, 2H), 4.51 (s, 2H), 4.07 (m, 3H), 3.86 (m, 1H), 3.51 (m, 1H), 3.28-3.40 (m, 2H), 2.51-2.89 (m, 3H), 2.48 (m, 1H), 2.21 (m, 1H), 1.56-1.87 (m, 5H), 1.58 (m, 1H), 1.45 (m, 1H); MS (ESI) m/z 493 (M+H)+.
Figure imgf000218_0001
Example 152
[(2R,3aR,6aR)-2-{[trans-4-hydroxy-4-(6-methoxypyridin-3- yl)cyclohexyl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone
Example 152A
8-(6-methoxypyridin-3-yl)-l,4-dioxaspiro[4.5]decan-8-ol A mixture of 5-bromo-2-methoxypyridine (5.0 g, 26.6 mmol) in tetrahydrofuran (30 mL) was cooled to -78 °C, followed by drop wise additon of n-BuLi (12 mL, 30 mmol, 2.5M) over 10 minutes. The reaction mixture was stirred for an additional 20 minutes at -78 °C. A solution of compound l,4-dioxaspiro[4.5]decan-8-one (4.37 g, 28 mmol) in tetrahydrofuran 10 mL was slowly added into the reaction mixture. The resulting mixture was stirred for another 2 hours at -78 °C, quenched with water, and warmed to room temperature. The solvent was removed in vacuum and the residue was partitioned between ethyl acetate and water. The organic layer was wash with brine, dried over Na2S04, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether/ethyl aceatate: 10/3) to give title compound (8 g).
Example 152B
4-hydroxy-4-(6-methoxypyridin-3-yl)cyclohexanone To a mixture of Example 152A (8.0 g, 36.1 mmol) in tetrahydrofuran (50 mL) was added 2M HC1 (50 mL), and the mixture reaction was stirred for 12 hours at room temperature. The solvent was removed under reduced pressure to give compound the title compound (6 g). The crude product was used for next step without purification.
Example 152C
[(2R,3aR,6aR)-2-{[trans-4-hydroxy-4-(6-methoxypyridin-3- yl)cyclohexyl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone
To an ice cold solution of Example 152B (0.3 g, 0.7 mmol) in isopropyl acetate (15 mL) was added η-Β¾Ν (0.323 g 1.75 mmol) followed by addition of isopropanol (1.5 mL 1.75 mmol). Sodium triacetoxyborohydride (0.371g, 1.75mmol) was added at 5 °C. After 1 hour, a solution of Example 79N (0.23 g, 1 mmol) in 10 mL isopropyl acetate was added at 1 °C. The mixture was stirred at room temperature for 15 hours, and partitioned between saturated aqueous NaHC(¾ (10 mL), water (10 mL) and ethyl acetate (40 mL). The aqueous phase was further extract with ethyl acetate (20 mL). The combined organic phases were washed with saturated aqueous NaHC(¾, dried with Na2S04, filtered, and concentrated in vacuo. The resulting residue was purified by HPLC to give title compound as crude product, then purified by SFC (Instrument: Thar 80 SFC, Column: AD 250x20 mm ID, 20 μηι; Mobile phase: A: Supercritical C02, B: MeOH (0.05 % diethylamine as modifier), A:B =60:40 at 80 mL/min; Column Temp: 38 °C; Nozzle Pressure: lOOBar; Nozzle Temp: 60 °C; Evaporator Temp: 20 °C Trimmer Temp: 25 °C; Flow rate: 80 mL/min; Wavelength: 220 nm) to provide the title compound (peak 1, 70 mg, retention time 4.17 minute) as white solid, and Example 159 (peak 2, 80 mg, retention time 5.29 minute). Ή NMR (400 MHz, CDC13) δ 8.65 (s, 1H), 8.29 (s, 1H), 7.65-7.73 (m, 2H), 6.55 (d, 1H), 4.81 (s, 2H), 3.73-4.05 (m, 5H), 3.62 (m, 2H), 3.31-3.60 (m, 2H), 2.85-3.15 (m, 5H), 2.21-2.45 (t, 2H), 2.1 1 (m, 1H), 1.80- 1.95 (m, 3H), 1.50-1.80 (m, 6H), 1.35-1.46 (m, 5H); MS (ESI) m/z 559 (M+H)+.
Figure imgf000219_0001
Example 153
[(2R,3aR,6aR)-2-{[trans-4-hydroxy-4-(l,3-thiazol-2- yl)cyclohexyl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone
Example 153 A
8-(thiazol-2-yl)-l,4-dioxaspiro[4.5]decan-8-ol To a mixture of 2-bromothiazole (5.0 g, 30 mmol) in tetrahydrofuran (50 mL) was added n-BuLi solution (14.6 mL, 36 mmol, 2.5 M) dropwise over 10 minutes at -78 °C. The reaction mixture was stirred for additional 20 minutes at -78 °C. A solution of 1,4- dioxaspiro[4.5]decan-8-one (4.76 g, 30 mmol) in tetrahydrofuran (10 mL) was added dropwise into the reaction mixture. The reaction mixture was stirred for another 2 hours at -78 °C, then quenched with water and warmed to room temperature. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was wash with brine dried over Na2S04, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate: 10/3) to afford the title compound (4.8 g, 65.3%) as a brown solid.
Example 153B
4-hydroxy-4-(thiazol-2-yl)cyclohexanone
To a solution of Example 153A (2.0 g, 8.28 mmol) in tetrahydrofuran (20 mL) was added 2M HC1 (20 mL). The mixture reaction was stirred for 12 hours at room temperature. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2S04, filtered, and concentrated to give title compound (0.6 g, 33.4%) as a white solid.
Example 153C
[(2R,3aR,6aR)-2-{[trans-4-hydroxy-4-(l,3-thiazol-2- yl)cyclohexyl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone
To an ice cold solution of Example 79N (0.3 g, 0.7 mmol) in isopropyl acetate (15 mL) was added n-B¾N (0.323 g 1.75 mmol) followed by addition of isopropanol (1.5 mL), sodium triacetoxyborohydride (0.371 g, 1.75 mmol) was added at about 5 °C. After 1 hour, a solution of Example 153B (0.179 g, 0.84 mmol) in 10 mL isopropyl acetate was added to the reaction mixture at about 1 °C. The reaction mixture was stirred at room temperature for 15 hours. The mixture was partitioned between saturated aqueous NaHC(¾ (10 mL), water (10 mL) and ethyl acetate (40 mL). The aqueous phase was further extracted with ethyl acetate (20 mL). The combined organic phases were washed with saturated aqueous NaHC03, dried with Na2S04, and concentrated in vacuo. The resulting residue was purified by HPLC. The fractions collected was concentrated and the residue purified by SFC (Instrument: Berger MultiGram™ SFC, Mettler Toledo Co, Ltd; Column: Chiralcel OJ 250x30 mm ID, 5 μιη; Mobile phase: A: Supercritical CO2, B: isopropanol (0.05% diethylamine as modifier), A:B =70:30 at 60 mL/min; Column Temp: 38 °C; Nozzle Pressure: lOOBar; Nozzle Temp: 60 °C; Evaporator Temp: 20 °C Trimmer Temp: 25 °C; Flow rate: 60 mL/min; Wavelength: 220 nm) to provide the title compound (105 mg, peak 1, retention time 6.02 minute) as white solid, and Example 160 (peak 2, retention time 7.95 minute). Ή NMR (400 MHz, CD3OD) δ 8.68 (s, 1H), 8.01 (s, 1H), 7.65 (s, 1H), 7.41 (s, 1H), 3.66 (s, 1H),3.65 (m, 1H), 3.50 (m, 1H), 3.10 (m, 2H), 2.90 (m, 1H), 2.39 (m, 1H), 1.30-2.10 (m, 18H). MS (ESI) nVz 535 (M+H)+.
Figure imgf000221_0001
Example 154
[(2R,3aR,6aR)-2-{[trans-4-(l,3-benzodioxol-5-yl)-4- hydroxycyclohexyl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8- dihydro- 1 ,6-naphthyridin-6(5H)-yl]methanone
Example 154A
8-(benzo[d][l,3]dioxol-5-yl)-l,4-dioxaspiro[4.5]decan-8-ol To a mixture of 5-bromobenzo[d][l,3]dioxole (5.0 g, 24 mmol) in tetrahydrofuran (50 mL ) was treated with drop wise addition of n-BuLi (12 mL, 30 mmol, 2.5 M) over 10 minutes at -78 °C. The reaction mixture was stirred for additional 20 minutes at -78 °C. A solution of l,4-dioxaspiro[4.5]decan-8-one (3.89 g, 24 mmol) in tetrahydrofuran (10 mL) was slowly addeded into the mixture. The reaction mixture was stirred for another 2 hours at -78 °C after complete addition, quenched with water, and warmed to room temperature. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was wash with brine, dried over Na2S04, filtered, and concentrated. The residue was purified by silica gel chromatography with (petroleum ether/ethyl acetate: 10/3) to give title compound (4.8 g, 69.3%) as a white solid.
Example 154B
4-(benzo[d][l,3]dioxol-5-yl)-4-hydroxycyclohexanone To a solution of Example 154A (2.0 g, 7.18 mmol) in tetrahydrofuran (20 mL) was added 2M HC1 (20 mL). The mixture reaction was stirred for 12 hours at room temperature and concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine dried over Na2S04, filtered, and concentrated in vacuo to afford the title compound (0.6 g, 33.4%) as a white solid.
Example 154C [(2R,3aR,6aR)-2-{[trans-4-(l,3-benzodioxol-5-yl)-4- hydroxycyclohexyl] amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8- dihydro- 1 ,6-naphthyridin-6(5H)-yl]methanone To an ice cold solution of Example 79N (0.3 g, 0.7 mmol) in isopropyl acetate (15 mL) was added η-Β¾Ν (0.323 g, 1.75 mmol) followed by addition of isopropanol (1.5 mL). Sodium triacetoxyborohydride (0.371 g, 1.75 mmol) was added at about 5 °C. After stirring for 1 hour, a solution of Example 154B (0.21 1 g, 0.84 mmol) in 10 mL isopropyl acetate was added to the reaction mixture at about 1 °C. The mixture was stirred at room temperature for 15 hours, and partitioned between saturated aqueous NaHC(¾ (10 mL), water (10 mL) and ethyl acetate (40 mL). The aqueous phase was further extracted with ethyl acetate (20 mL). The combined organic phases were washed with saturated aqueous NaHC(¾ dried with Na2S04, filtered, and concentrated. The resulting residue was purified by HPLC and the fractions were collected and concentrated. The residue was purified by SFC (Instrument: Berger MultiGram™ SFC, Mettler Toledo Co, Ltd;
Column: Chiralcel OJ 250 x 30 mm ID, 5 μιη; Mobile phase: A: Supercritical CO2, B: isopropanol (0.05% diethylamine as modifier), A:B =70:30 at 60 mL/min; Column Temp: 38 °C; Nozzle Pressure: 100 Bar; Nozzle Temp: 60 °C; Evaporator Temp: 20 °C Trimmer Temp: 25 °C; Flow rate: 60 mL/min; Wavelength: 220 nm) to provide the title compound (70 mg, retention time 5.87 minute) as white solid and Example 161 (retention time 6.88 minute). Ή NMR (400 MHz, CD3OD) δ 8.65 (s, 1H), 8.01 (s, 1H), 7.00 (m, 2H), 6.72 (d, 1H), 5.90 (s, 2H), 3.90 (m, 2H), 3.65 (s, 1H), 3.48 (m, 2H), 3.10 (m, 2H), 2.95 (m, 1H), 2.30 (m, 3H), 1.35-2.10 (m, 15H); MS (ESI) m/z 572 (M+H)+.
Figure imgf000222_0001
Example 155
[(2R,3aR,6aR)-2-{[(3R,4R)-3-fluorotetrahydro-2H-pyran-4- yl]amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone
The title compound (peak 4, retention time 8.951 minute) was isolated from the chiral SFC purification of Example 158D. Ή NMR (400 MHz, CDCI3) δ 8.633 (s, 1 H), 7.612 (s, 1 H), 4.513-4.759 (m, 3 H), 3.790-4.104 (m, 4 H), 3.294-3.440 (m, 4 H), 3.021- 3.091 (m, 2 H), 2.630-2.787 (m, 1 H), 1.139-2.050 (m, 13 H); MS (ESI) m/z 456 (M+H)+.
Figure imgf000223_0001
Example 156
[(2R,3aR,6aR)-2-{[(3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl]amino}hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone The title compound (peak 3, retention time 8.349 minutes) was isolated from the chiral SFC purification of Example 158D. 'H NMR (400 MHz, CDC13) δ 8.631 (s, 1 H), 7.610 (s, 1 H), 4.532-4.756 (m, 3 H), 3.759-4.102 (m, 4 H), 3.267-3.515 (m, 4 H), 3.01 1-3.123 (m, 2 H), 2.700-2.801 (m, 1 H), 1.1 17-2.080 (m, 13 H); MS (ESI) m/z 456 (M+H)+.
Figure imgf000223_0002
Example 157
[(2R,3aR,6aR)-2-{[(3R,4S)-3-fluorotetrahydro-2H-pyran-4-yl]amino}hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone
The title compound (peak 1, retention time 5.592 minute) was isolated from the chiral SFC purification of Example 158D. Ή NMR (400 MHz, CDC13): δ 8.636 (s, 1 H), 7.620 (s, 1 H), 4.681-4.840 (m, 3 H), 3.765-4.114 (m, 4 H), 2.996-3.537 (m, 7 H), 1.251- 2.020 (m, 13 H), MS (ESI) m/z 456 (M+H)+.
Figure imgf000223_0003
Example 158
[(2R,3aR,6aR)-2-{[(3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl]amino}hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone
Example 158A
4,4-dimethoxytetrahydropyran To a solution of dihydro-2H-pyran-4(3H)-one (300 g, 3 mol) in MeOH (5L) was added TEA (36.4 g, 0.12 mol) at room temperature. The resulting solution was cooled to -
78 °C, followed by the addition of TiC (5.7 g, 0.03 mol) was added. This reaction mixture was stirred at -78 °C for 2 hours, and filtered. The filtrate was concentrated and the residue was distilled under reduced pressure to provide the titled product (157 g, 30 %).
Example 158B
4-methoxy-3,6-dihydro-2H-pyran
To a stirred solution of 4,4-dimethoxytetrahydropyran ( 50.2 g, 0.34 mol) in CH2C12 (500 mL) at -78 °C was added TiCl4 (41.4 mL, 0.38 mol) over 2 minutes. After 1 hour, pyridine (137.5 mL, 1.7 mol) was added followed by ground KOH (108 g, dried at
100 °C). After 20 minutes the reaction mixture was warmed to room temperature and stirred for another hour. The reaction mixture was poured into Et20 (1 L), then filtered through Celite and the filter bed washed with Et20 (0.25 L). The combined filtrates were washed with water (0.25 L) and brine (0.25 L) sequentially, dried (MgS04), and concentrated under reduced pressure (water bath <30 °C, >1 cm/Hg). To the residue was added triethylamine (5 mL) and this was distilled under reduced pressure to provide the title compound (33.6 g, 86 %), bp 60-62 °C /15 mmHg.
Example 158C
3-fluorodihydro-2H-pyran-4(3H)-one
To a mixture of Example 158B (16g, 0.138 mol) in CH3CN/H20 (480 mL, 1 : 1) at room temperature was added Selectfluor (49 g, 0.138 mol) in one lot and the resulting reaction mixture was stirred at room temperature until completion. Solid NaCl was then added and the reaction mixture was then extracted with ethyl acetate (4 x 50 mL). The combined organic layers were dried (MgS04), filtered, and concentrated to yield 7 g of the title compound.
Example 158D
((2R,3aR,6aR)-2-(3-fluorotetrahydro-2H-pyran-4-ylamino)octahydropentalen-3a-yl)(3- (trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl)methanone The title compound was prepared according Example 154C, substituting Example 158C for Example 154B, and purified by preparative HPLC to provide the title compound as a mixture of diasteromers.
Example 158E
[(2R,3aR,6aR)-2-{[(3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl]amino}hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone Example 158D was purified by chiral SFC (Instrument: Berger MultiGram™ SFC, Mettler Toledo Co, Ltd; Column: Chiralcel IC 250 4.6 mm ID, 5 μηι; Mobile phase: A: Supercritical CO2, B: methanol (0.05% diethylamine as modifier), A:B =95:5 to 60:40 at 2.35 mL/min; Wavelength: 220 nm) to provide the title compound as the second peak (retention time 8.195 minute, 9.35 mg), as well as Example 155 (peak 4, retention time 8.951 minute, 1.43 mg), Example 156 (peak 3, retention time 8.349 minute, 1.24 mg), and Example 157 (peak 1, retention time 5.592 minute, 10.58 mg). Ή NMR (400 MHz, CDCI3) δ 8.632 (s, 1 H), 7.615 (s, 1 H), 4.581-4.983 (m, 3 H), 3.730-4.172 (m, 4 H), 2.866-3.556 (m, 7 H), 1.183-2.181 (m, 13 H), MS (ESI) m/z 456 (M+H)+.
Figure imgf000225_0001
Example 159
[(2R,3aR,6aR)-2-{[cis-4-hydroxy-4-(6-methoxypyridin-3- yl)cyclohexyl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone
The title compound (peak 2, retention time 5.29 minute) was isolated from the SFC purification of Example 152C. Ή NMR (400 MHz, CDC13) δ 8.64 (s, IH), 8.24 (s, IH), 7.65-7.73 (m, 2H), 6.68 (d, IH), 4.81 (m, 2H), 3.73-4.05 (m, 5H), 3.62(m, 2H), 3.28- 3.60 (m, 2H), 2.875-3.2(m, 4H), 2.64(m, IH), 2.31 (m, IH), 1.89-2.03 (m, 2H), 1.50- 1.80 (m, 7H), 1.25-1.48 (m, 6H); MS (ESI) m/z 559 (M+H)+.
Figure imgf000225_0002
Example 160
[(2R,3aR,6aR)-2-{[cis-4-hydroxy-4-(l,3-thiazol-2- yl)cyclohexyl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone
The title compound (peak 2, retention time 7.95 minute) was isolated from the SFC purification of Example 153C. Ή NMR (400 MHz, CD3OD) δ 8.70 (s, 1H), 8.06 (s, 1H), 7.72 (s, 1H), 7.51 (s, 1H), 4.00 (m, 2H),3.65 (s, 1H), 3.50 (m, 2H), 3.1 1 (m, 2H), 2.89 (m, 1H), 2.33 (m, 3H), 1.30-2.10 (m, 13H); MS (ESI) m/z 535 (M+H)+.
Figure imgf000226_0001
Example 161
[(2R,3aR,6aR)-2-{[cis-4-(l,3-benzodioxol-5-yl)-4- hydroxycyclohexyl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8- dihydro- 1 ,6-naphthyridin-6(5H)-yl]methanone The title compound (retention time 6.88 minute) was isolated from the SFC purification of Example 154C. Ή NMR (400 MHz, CD3OD) δ 8.71 (s, 1H), 8.01 (s, 1H), 7.00 (m, 2H), 6.72 (d, 1H), 5.90 (s, 2H), 3.90 (m, 1H), 3.70 (s, 2H), 3.60 (m, 2H), 3.15 (m, 2H), 2.71 (m, 1H), 2.31 (m, 1H), 1.00-2.00 (m, 13H); MS (ESI) m/z 572 (M+H)+.
Figure imgf000226_0002
Example 162
[(2R,3aR,6aR)-2-{[(2R,4S)-2-benzyltetrahydro-2H-pyran-4- I amino } hexahy dropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- naphthyridin-6(5H)-yl]methanone
Example 162A
2-benzyl-2H-pyran-4(3H)-one 2 A solution of boron trifluoride diethyl etherate (1.4 g, 10 mmol) in dry ether (6 mL) was added to a stirred mixture of phenyl acetaldehyde (1.2 g, 10 mmol) and (1- methoxymethylene-allyloxy)-trimethyl-silane (1.5 g, 9 mmol) and dry ether (60 mL) cooled to -78 °C. After 1 hour, the mixture was allowed to reach 0 °C and stirred for 3 hours. The deep red reaction mixture was quenched with saturated aqueous NaHC(¾ (20 mL) and the mixture was allowed to warm to 25 °C. The aqueous phase was extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with brine, dried over Na2S04, filtered, and concentrated. The residue was purified by silica column (20% ethyl acetate in petroleum ether) to afford title compound (0.5g) as colorless oil.
Example 162B
2-Benzyl-tetrahydro-pyran-4-one
Pd/C (0.12 g) was added to ethyl acetate (20 mL) under nitrogen, followed by addition of Example 162A (0.5 g, 2.6 mmol). The mixture was stirred at 50 psi of hydrogen gas at 25 °C for 24 hour using a Parr apparatus. Then the reaction mixture was filtrated and concentrated to afford the title compound (0.5g) as colorless oil.
Example 162C
[(2R,3aR,6aR)-2-{[(2R,4S)-2-benzyltetrahydro-2H-pyran-4- yl]amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone
To a solution of example 79N (0.43g, 1 mmol) in isopropyl acetate (4 mL) was added isopropanol (0.2 mL), and NaBH(OAc)3 (0.44g, 2.4mmol) at 0 °C. After stirring for 1 hour, a solution of Example 162B (0.19 g, 1 mmol) in isopropyl acetate (2 mL) was added to the reaction mixture at 0 °C. After 16 hours, the mixture was partitioned between saturated aqueous NaHC(¾ solution (6 mL), water (16 mL) and ethyl acetate (20 mL). The aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC and followed by chiral SFC (Column: Chiralcel OJ 250x30 mm ID, 5 μιη; Mobile phase: A: Supercritical C(¾, B: EtOH (0.05% diethylamine as modifier), A:B =75:25 at 60 mL/min; Flow rate: 60 mL/min; Wavelength: 220 nm.) to provide the title compound (peak 1, retention time 3.62 minute, 0.3 g), as well as
Example 163 (retention time 5.06 minute) and Example 164 (retention time 5.73 minute). 'H NM : (400 MHz, CDC13 ) δ ppm 8.69 (s, 1H), 7.68 (s, 1H), 7.26-7.3 l(m, 2H), 7.19- 7.22 (m, 3H), 4.68-4.87 (m, 2H), 3.60-4.05 (m, 4H), 3.49 (m, 2H), 3.31 (m, 1H), 3.13 (m, 2H), 2.60-2.90 (m, 3H), 1.45-2.03 (m, 13H), 1.15- 1.35 (m, 3H); MS (ESI) nVz 528 (M+H)+.
Figure imgf000228_0001
Example 163
[(2R,3aR,6aR)-2-{[(2R,4R)-2-benzyltetrahydro-2H-pyran-4- yl]amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone
The title compound (retention time 5.06 minute) was isolated from the chiral SFC purification of Example 162C. Ή NMR: (400 MHz, CDC13) δ ppm 8.70 (s, IH), 7.66 (s, IH), 7.15-7.28 (m, 5H), 4.74 (s, 2H), 3.69-3.92 (m, 4H), 3.46-3.48 (m, 2H), 3.01-3.18 (m, 4H), 2.82-2.87 (m, IH), 2.59-2.65 (m, IH), 1.60-2.05 (m, 9H), 1.15-1.58 (m, 6H); MS (ESI) m/z 528 (M+H)+.
Figure imgf000228_0002
Example 164
[(2R,3aR,6aR)-2-{[(2S,4R)-2-benzyltetrahydro-2H-pyran-4- yl]amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone
The title compound (retention time 5.73 minute) was isolated from the chiral SFC purification of Example 162C. Ή NMR (400 MHz, CDCI3 ) δ ppm 8.69 (s, IH), 7.68 (s, IH), 7.18-7.30 (m, 5H), 4.72-4.86 (m, 2H), 3.73-3.90 (m, 4H), 3.46-3.48 (m, 2H), 2.89- 3.12 (m, 4H), 2.67 (m, IH), 1.54-1.90 (m, 13H), 1.23-1.27 (m, 2H); MS (ESI) m/z 528 (M+H)+.
Figure imgf000229_0001
Example 165
[(2R,3aR,6aR)-2-[(4S)-3,4-dihydro-2H-chromen-4-ylamino]hexahydropentalen-3a(lH)- yl][3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)-yl]methanone The title compound (retention time 9.01 minute) was isolated from the chiral SFC purification of Example 140. 'H NMR (400 MHz, CDC13) δ 8.69 (s, 1H), 7.68 (s, 1H) , 7.05-7.19 (m, 2H), 6.72-6.89 (m, 2H), 4.79(s, 2H), 4.35 (t, 1H), 4.22 (m, 1H), 3.81-3.98 (m, 2H), 3.75 (s, 1H), 3.61 (m, 1H), 3.48 (m, 1H), 3.04 (m, 2H), 1.46-2.24 (m, 13H), 1.04 - 1.42 (m, 3H); MS (ESI) m/z 485(M+H)+.
Figure imgf000229_0002
Example 166
[(2R,3 aR,6aR)-2-(7-oxa- 1 -azaspiro [3.5 ]non- 1 -yl)hexahydropentalen-3 a( 1 H)-yl] [3 - (trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone
Example 166A
4-methylenetetrahydro-2H-pyran
To a solution of methyltriphenylphosphonium bromide (17.84 g, 0.05 mmol) in tetrahydrofuran (150 mL) was added drop wise n-Buli (20 mL, 0.05 mmol) at -40 °C, 30 minutes later, dihydro-2H-pyran-4(3H)-one (5 g, 0.05 mol) was added drop wise at -40 °C. The resulting mixture was stirred for 12 hours, quenched with aqueous NH4CI (50 mL), extracted with ethyl acetate(3 x 100 mL), dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica (petroleum ether/ ethyl acetate: 30/1) to afford the title compound (2 g, yield 40.81%) as a liquid.
Example 166B
7-oxa-l-azaspiro[3.5]nonan-2-one
Chlorosulfonyl isocyanate (2.89 g, 20.41 mmol) was added dropwise at 0 °C to a solution of Example 166A (2 g, 20.4 mmol) in dry Et20 (20 mL). The resulting mixture was stirred for 2 hours at 0 °C, followed by addition of aqueous Na2S(¾ (20 mL) and 10% KOH (20 mL). The mixture was stirred for 1 hour, extracted with Et20, dried (Na2S04), filtered, and concentrated in vacuo. The residue was purified by
chromatography on silica (petroleum ether/ethyl acetate: 10/l)to afford the title compound (0.4 g, yield 13.9%) as a liquid.
Example 166C
7-oxa- 1 -azaspiro[3.5 ]nonane
To an ice-cold solution of Example 166B (0.4 g, 2.83 mmol) in anhydrous tetrahydrofuran (20 mL) was added LiAlH4 (0.27 g, 7.08 mmol). The resulting mixture was refluxed for 2 hours. After cooling, the reaction mixture was quenched with 15%
NaOH (0.27 g), and filtered. The filtrate was concentrated to afford title compound (0.2 g, yield 36%) as an oil.
Example 166D
[(2R,3 aR,6aR)-2-(7-oxa- 1 -azaspiro [3.5 ]non- 1 -yl)hexahydropentalen-3 a( 1 H)-yl] [3 - (trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]methanone
To a mixture of Example 166C (87 mg, 0.681 mmol) and Example 1H (0.2 g, 0.56 mmol) in dichloroethane (15 mL) was added acetic acid (100 mg) at room temperature. The mixture was stirred at room temperature for 12 hours. NaBH(OAc)3 (240 mg, 1.13 mmol) was added to the resulting mixture and stirred for another 2 hours. LC-MS indicated that the reaction was completed. The mixture was washed with water (10 mL). The aqueous layer was extracted with ethyl acetate (30 mL). The organic layer was dried over Na2S04, filtered, and concentrated in vacuum. The residue was purified by preperative HPLC and SFC (Instrument: Berger MultiGram™ SFC, Mettler Toledo Co, Ltd; Column: Chiralcel AD 250 x 30 mm ID, 5 μιη; Mobile phase: A: Supercritical CO2, B: isopropanol (0.05% diethylamine as modifier), A:B =70:30 at 70 mL/min; Column Temp: 38 °C; Nozzle Pressure: lOOBar; Nozzle Temp: 60 °C; Evaporator Temp: 20 °C Trimmer Temp: 25 °C; Flow rate: 70 mL/min; Wavelength: 220 nm) to provide the title compound (peak 2, retention time 7.56 minute, 30 mg) as a light yellow solid, as well as Example 167 (peak 1, retention time 6.85 minute). Ή NMR (400 MHz, CD3OD): 88.68 (s, 1H), 8.05 (s, 1H), 4.78 (m, 1H), 3.9 (m, 5H), 3.4 (m, 3H), 3.05 (m, 2H), 2.25 (m, 1H),1.5- 2.1 (m, 17H), 1.4 (m, 1H); MS (ESI) m/z 464 (M+H)+.
Figure imgf000231_0001
Example 167
[(2S,3 aR,6aR)-2-(7-oxa- 1 -azaspiro [3.5 ]non- 1 -yl)hexahy dropentalen-3 a( 1 H)-yl] [3 - (triiluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone The title compound (peak 1, retention time 6.85 minute) was isolated from the
SFC purification of Example 166D. 'H NMR (400 MHz, CD3OD) δ 8.67 (s, 1H), 8.05 (s, 1H), 4.78 (m, 1H), 4.08 (m, 1H), 3.80 (m, 4H), 3.15 (m, 4H), 2.80 (m, 1H), 2.1 (m, 6H), 1.7 (m, 9H), 1.5 (m, 3H), 1.05 (m, 1H); MS (ESI) m/z 464 (M+H)+.
Figure imgf000231_0002
Example 168
l,5-anhydro-2,3-dideoxy-3-{[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]amino}-D-erythro-pentitol The title compound (peak 1, retention time 7.25 minute) was isolated from the chiral SFC purification of Example 183C. 'H NMR (400 MHz, CDC13) δ 8.687 (s, 1 H), 7.698 (s, 1 H), 4.698-4.903 (m, 2 H), 3.580-4.035 (m, 7 H), 2.998-3.328 (m, 4 H), 2.371- 2.644 (m, 2 H), 1.357-2.086 (m, 1 1 H); MS (ESI) m/z 454 (M+H)+.
Figure imgf000231_0003
Example 169
[(2R,3aR,6aR)-2- {[(3R,4S)-3-methyltetrahydro-2H-pyran-4- yl]amino } hexahy dropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone
The title compound (peak 1, retention time 6.6 minute) was isolated from the SFC purification of Example 141B. Ή NMR (400 MHz, CDC13) δ ppm 0.8 -1.1 (m, 3 H), 1.2 -1.4 (m, 1 H), 1.50 -2.20 (m, 13 H), 2.86 (s, 1 H), 3.12(s, 2H), 3.30-3.50(m, 3H), 3.50 - 3.60 (m, 1 H), 3.60 - 3.75 (m, 1 H), 3.80 - 4.05 (m,3 H), 4.78 (s, 2 H), 7.68 (s, 1 H), 8.69 (s, 1 H); MS (ESI) nVz 452 (M+H)+.
Figure imgf000232_0001
Example 170
[(2R,3aR,6aR)-2-{[(3R,4R)-3-methyltetrahydro-2H-pyran-4- yl]amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone
The title compound (retention time, 9.23 minute) was isolated from the SFC purification of Example 141B. Ή NMR (400 MHz, CDC13) δ ppm 0.92 (s, 3 H), 1.40 - 1.50 (m, 3 H), 1.5 -2.1 (m, 10 H), 2.3 -2.70 (m, 1 H), 2.90-3.0 (m, 1 H), 3.15 (s, 2H), 3.30-3.50 (m, 1H), 3.30 - 3.40 (m, 1 H), 3.50 - 3.70 (m, 1 H), 3.80 - 4.10 (m,4 H), 7.69 (s, 1 H), 8.70 (s, 1 H); MS (ESI) m/z 452 (M+H)+.
Figure imgf000232_0002
Example 171
l,5-anhydro-2,3-dideoxy-4-C-(trifluoromethyl)-3-{[(2R,3aR,6aR)-3a- {[3- (trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2- yl]amino} -L-threo-pentitol
Example 171 A
4,4-Dimethoxy-tetrahydro-pyran-3-ol
To a 0 °C solution of KOH (96 g, 1.4 mol) in MeOH (800 mL) was added tetrahydro-pyran-4-one (60 g, 0.6 mmol) over 0.5 hour. After stirring for 1 hour, a solution of iodine (96 g, 0.7 mol) in MeOH (1.2 L) was added over 2 hours. Upon completion of the addition, the solution was gradually warmed to room temperature and stirred for additional 10 hours. The resulting solution was then concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/ethyl acetate) to provide the title compound (70 g, 72%) as a yellow oil.
Example 17 IB
4,4-Dimethoxy-dihydro-pyran-3-one
To a solution of Example 171 A (8.1 g, 50 mmol) in anhydrous dichloromethane (200 mL) was added Dess-Martin periodinane (42.8 g, 100 mmol) at room temperature in one portion. The reaction mixture was stirred for two hours, and then aqueous NaHC(¾ (100 mL) was added to quench the reaction. The aqueous layer was extracted with dichloromethane (90 mL). The combined organic layers were washed with brine, dried over Na2SC"4, filtered, and concentrated in vacuo. The residue was purified by column chromatography to provide the title compound (4.3 g, 54%) as yellow oil.
Example 171C
(4,4-Dimethoxy-3-trifluoromethyl-tetrahydro-pyran-3-yloxy)-trimethyl-silane To a solution of Example 171B (1.6 g, 10 mmol) in tetrahydrofuran (20 mL) was added tetra-n-butyl ammonium fluoride (15 mg) and trimethyl-trifluoromethyl-silane (2.1 g, 15 mmol) at 0 °C, and then the reaction mixture was allowed to warm to room temperature and stirred overnight. After removal of the solvent, the residue was purified by column chromatography to provide the title compound (2.1 g, 70%) as a yellow oil.
Example 17 ID
3 -Hydroxy-3 -trifluoromethyl-tetrahydro-pyran-4-one A mixture of Example 171C (2.1 g, 7 mmol) and trifluoroacetic acid (2 mL) in dichloromethane (10 mL) was stirred at room temperature overnight. The reaction was concentrated in vacuo, and then the residue was purified by column chromatography (petroleum/ethyl acetate) to afford the title compound (580 mg, 45%) as yellow oil. Ή NMR (400 MHz, CDC13) δ 8.713 (s, 1 H), 7.702 (s, 1 H), 4.715-4.882 (m, 2 H), 3.358- 3.970 (m, 8 H), 3.020-3.260 (m, 4 H), 1.355-1.966 (m, 11 H); MS (ESI) m/z 522 (M+H)+.
Example 17 IE
l,5-anhydro-2,3-dideoxy-4-C-(trifluoromethyl)-3-{[(2R,3aR,6aR)-3a-{[3- (trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2- yl]amino} -L-threo-pentitol
The title compound was prepared according Example 154C, substituting Example 17 ID for Example 154B, and purified by chiral SFC (Column: Chiralpak AD-H IC 250 4.6 mm ID, 5 μιη; Mobile phase: A: Supercritical CO2, B: methanol (0.05% diethylamine as modifier), A:B =95:5 to 60:40 at 2.35 mL/min; Wavelength: 220 nm) to provide the title compound as peak 2 (retention time 6.43 minute), as well as Example 172 (peak 1, retention time 6.26 minute), and Example 173 (peak 3, retention time 6.81 minute). Ή NMR (400 MHz, CDC13): δ 8.713 (s, 1 H), 7.702 (s, 1 H), 4.715-4.882 (m, 2 H), 3.358- 3.970 (m, 8 H), 3.020-3.260 (m, 4 H), 1.355-1.966 (m, 11 H); MS (ESI) m/z 522 (M+H)+.
Figure imgf000234_0001
Example 172
l,5-anhydro-2,3-dideoxy-4-C-(trifluoromethyl)-3-{[(2R,3aR,6aR)-3a-{[3- (trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2- yl]amino}-D-erythro-pentitol
The title compound (peak 1, retention time 6.26 minute) was obtained from the SFC purification of Example 171E. 'H NMR (400 MHz, CDC13) δ 8.706 (s, 1 H), 7.689 (s, 1 H), 4.684-4.899 (m, 2 H), 3.643-4.234 (m, 5 H), 2.971-3.419 (m, 4 H), 1.460-2.582 (m, 13 H), 0.864-0.973 (m, 2 H); MS (ESI) m/z 522 (M+H)+.
Figure imgf000234_0002
Example 173
l,5-anhydro-3,4-dideoxy-2-C-(trifluoromethyl)-3-{[(2R,3aR,6aR)-3a-{[3- (trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2- yl]amino} -D-erythro-pentitol
The title compound (peak 3, retention time 6.81 minute) was obtained from the
SFC purification of Example 171E. 'H NMR (400 MHz, CDC13) δ 8.714 (s, 1 H), 7.693 (s, 1 H), 4.731-4.806 (m, 2 H), 3.337-3.949 (m, 1 1 H), 3.063-3.129 (m, 2 H), 1.322-2.198 (m, 12 H); MS (ESI) m/z 522 (M+H)+.
Figure imgf000235_0001
Example 174
[(2R,3aR,6aR)-2-{[3-(methoxymethyl)tetrahydro-2H-pyran-4- yl]amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone
To a solution of Example 79N (444 mg, 1.1 mmol), isopropanol (0.2 mL) and n- BU3N (0.6 mL) in isopropyl acetate (3 mL) was added NaBH(OAc)3 (0.51 g, 2.4 mmol) at 0 °C. After 1 hour, Example 217B (318 mg, 2.1 mmol) was added at 0 °C and stirred for 6 hours. The mixture was washed with aqueous NaHC03 and the aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC to provide the title compound as a mixture of diasteromers. Ή NMR (400 MHz, CD3OD) δ 8.72 (s, 1 H), 8.15 (s, 1 H), 4.92 (m, 2 H), 3.3-4.3 (m, 15 H), 1.5-2.6 (m, 12 H); MS (ESI) m/z 482 (M+H)+.
Figure imgf000235_0002
Example 175
[(2R,3aR,6aR)-2-{[(3R,4R)-3-fluorotetrahydro-2H-pyran-4- yl](methyl)amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone
To a mixture of formaldehyde (1 mL), formic acid (1 mL) and Example 158D
(1.02 g, 2 mmol) in 1,4-dioxane (20 mL) was heated to reflux overnight. The pH of the reaction mixture was adjusted to about 9 with saturated NaHCC"3, extracted with dichloromethane (60 mL), washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC, followed by chiral SFC (Column: Chiralpak AD-H IC 250 4.6 mm ID, 5 μπι; Mobile phase: A:
Supercritical CO2, B: isopropanol (0.05% diethylamine as modifier), A:B =95:5 to 60:40 at 2.5 mL/min; Wavelength: 220 nm) to afford the title compound (peak 1, retention time 4.46 minute, 30 mg), as well as Example 180 (peak 2, retention time 4.73 minute, 50 mg), both as white solid. Ή NMR (400 MHz, CDC13) δ 8.706 (s, 1 H), 7.699 (s, 1 H), 4.701- 4.865 (m, 2 H), 3.841-4.163 (m, 4 H), 3.1 13-3.544 (m, 6 H), 1.569-2.590 (m, 15 H), 1.231- 1.322 (m, 2 H); MS (ESI) m/z 470 (M+H)+.
Figure imgf000236_0001
Example 176
[(2R,3aR,6aR)-2-{[(3R)-4,4-dimethoxytetrahydro-2H-pyran-3- yl]amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone
The title compound was prepared according Example 154C, substituting Example 17 IB for Example 154B, and purified by chiral SFC (Column: Chiralpak AD-H IC 250 x 4.6 mm ID, 5 μιη; Mobile phase: A: Supercritical C(¾, B: methanol (0.05% diethylamine as modifier), A:B =95:5 to 60:40 at 2.35 mL/min; Wavelength: 220 nm) to provide the title compound (retention time 7.18 minute, 6.3 mg), as well as Example 184 (retention time 6.22 minute, 3.25 mg). Ή NMR (400 MHz, CDCI3) δ 8.792 (s, 1 H), 7.934 (s, 1 H),
4.794-4.920 (m, 2 H), 3.498-4.034 (m, 8 H), 3.239 (d, 9 H), 2.167-2.652 (m, 3 H), 1.735- 2.049 (m, 8 H), 1.380- 1.427 (m, 1 H); MS (ESI) m/z 498 (M+H)+.
Figure imgf000236_0002
Example 177
[(2R,3aR,6aR)-2- {[(4S)-6-fiuoro-3,4-dihydro-2H-chromen-4- yl]amino}hexahydropentalen-3a(lH)-yl] [3-(trifluoromethyl)-7,8-dihydro- 1 ,6- naphthyridin- 6(5H) -yl]methanone
The title compound (peak 2, retention time 8.05 minute) was obtained from the SFC purification of Example 144B. Ή NMR (400 MHz, CDCI3) δ 8.68 (s, 1H), 7.68 (s, 1H) , 6.71-6.92 (m, 2H), 6.61 (m, 1H), 4.87(m, 2H), 4.41 (m, 1H), 4.12 (m, 1H), 3.82- 3.96 (m, 2H), 3.56-3.70 (m, 2H), 3.48 (m, 1H), 3.15 (t, 2H), 2.01-2.21 (m, 4H),1.91-2.03 (m, 4H), 1.50-1.89 (m, 5H), 1.30-1.49 (m, 2H); MS (ESI) m/z 504(M+H)+.
Figure imgf000237_0001
Example 178
[(2R,3aR,6aR)-2-{[(4S)-6-chloro-3,4-dihydro-2H-chromen-4- yl]amino}hexahydropentalen-3a(lH)-yl] [3-(trifluoromethyl)-7,8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone
Example 178A
6-chlorochroman-4-one
The title compound was prepared and isolated according to the procedure described in Example 148A and 148B, substituting 4-chlorophenol for 2-fluorophenol.
Example 178B
[(2R,3aR,6aR)-2-{[(4S)-6-chloro-3,4-dihydro-2H-chromen-4- yl]amino}hexahydropentalen-3a(lH)-yl] [3-(trifluoromethyl)-7,8-dihydro- 1 ,6- naphthyridin- 6(5H) -yl]methanone
The title compound was prepared and isolated according to the procedure described in Example 148C, substituting Example 178A for Example 148B to provide the title compound (retention time 7.81 minute, 7.06 mg), as well as Example 185 (retention time 9.54 minute, 4.84 mg). Ή NMR (400 MHz, CDC13) δ 8.68 (s, 1H), 7.68 (s, 1H) , 7.00-7.26 (m, 2H), 6.62-6.77 (m, 2H), 4.78(m, 2H), 4.35 (m, 1H), 4.22 (m, 1H), 3.81-3.98 (m, 2H), 3.54-3.75 (m, 2H), 3.45(m, 1H), 3.28 (m, 2H), 1.56-2.14 (m, 12H), 1.04 -1.42 (m, 2H); MS (ESI) m/z 520 (M+H)+.
Figure imgf000237_0002
Example 179
[(2R,3aR,6aR)-2- {[(4S)-6-bromo-3,4-dihydro-2H-chromen-4- |amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro- naphthyridin- 6(5H) -yl]methanone
Example 179A 6-bromochroman-4-one
The title compound was prepared and isolated according to the procedure described in Example 148A and 148B, substituting 4-bromophenol for 2-fluorophenol.
Example 179B
[(2R,3aR,6aR)-2- {[(4S)-6-bromo-3,4-dihydro-2H-chromen-4- yl]amino}hexahydropentalen-3a(lH)-yl] [3-(trifluoromethyl)-7,8-dihydro- 1 ,6- naphthyridin- 6(5H) -yl]methanone
The title compound was prepared according to the procedure described in
Example 148C, substituting Example 179A for Example 148B. The residue was diluted with CH3CN and extracted with heptane. The acetonitrile phase was concentrated to give crude compound as a mixture of two diastereoisomers, which was then further purified by chiral SFC with a preparative ChiralCel AD 250 mm*30 mm, 5 μιη eluting with mobile A: Supercritical C02, B: ethanol (0.05% diethylamine), A:B = 90: 10 at 70 mL/min Column Temp: 38 °C; Nozzle Pressure: lOOBar; Nozzle Temp: 60 °C; Evaporator Temp: 20 °C; Trimmer Temp: 25 °C; Flow rate: 70 mL/min; Wavelength: 220 nm to yield the title compound (peak 1, retention time 9.045 minute, 5.02 mg) and Example 186 (peak 2, retention time 18.09 minute, 4.35 mg). Ή NMR (400 MHz, CDC13) δ ppm 1.30 -1.45 (m, 1 H), 1.60-2.00 (m, 1 1 H), 3.13(s, 2H), 3.40 - 3.50 (m, 1 H), 3.60 - 3.75 (m, 2 H), 3.80 - 4.00 (m,2 H), 4.10 - 4.20 (m, lH), 4.20 - 4.30 (m, l H),4.84 (s,2 H), 6.60 - 6.70 (m, l H), 7.10 - 7.20 (m, l H), 7.25 (s, 1 H), 7.69 (s, 1 H), 8.69 (s, 1 H); MS (ESI) m/z 566 (M+H)+.
Figure imgf000238_0001
Example 180
[(2R,3aR,6aR)-2- {[(3S,4R)-3-fluorotetrahydro-2H-pyran-4- yl](methyl)amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro- l,6- naphthyridin-6(5H)-yl]methanone
The title compound (peak 2, retention time 4.73 minute) was isolated from the chiral SFC purification of Example 175. Ή NMR (400 MHz, CDC13) δ 8.706 (s, 1 H), 7.692 (s, 1 H), 4.726-4.889 (m, 2 H), 3.835-4.148 (m, 4 H), 3.125-3.517 (m, 6 H), 1.562- 2.365 (m, 15 H), 1.229- 1.304 (m, 2 H); MS (ESI) m/z 470 (M+H)+.
Figure imgf000239_0001
Example 181
l,5-anhydro-2,3-dideoxy-3-{[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]amino}-L-threo-pentitol The title compound (peak 2, retention time 7.38 minute) was obtained from the chiral SFC purification of Example 183C. Ή NMR (400 MHz, CDC13) δ 8.610 (s, 1 H), 7.680 (s, 1 H), 4.651-4.906 (m, 2 H), 3.648-3.998 (m, 7 H), 2.649-3.517 (m, 9 H), 1.594- 2.304 (m, 9 H), 1.234- 1.296 (m, 1 H); MS (ESI) m/z 454 (M+H)+.
Figure imgf000239_0002
Example 182
l,5-anhydro-3,4-dideoxy-3-{[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]amino}-D-erythro-pentitol The title compound (peak 3, retention time 7.81 minute) was obtained from the chiral SFC purification of Example 183C. 'H NMR (400 MHz, CD3OD) δ 8.600 (s, 1 H), 7.959 (s, 1 H), 4.782-4.826 (m, 2 H), 3.662-3.915 (m, 7 H), 3.325-3.591 (m, 6 H), 3.020 (s, 2 H), 2.444-2.494 (m, 1 H), 1.258-1.975 (m, 11 H); MS (ESI) m/z 454 (M+H)+.
Figure imgf000239_0003
Example 183
l,5-anhydro-2,3-dideoxy-3-{[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2-yl]amino} -D-threo-pentitol
Example 183 A
3-hydroxydihydro-2H-pyran-4(3H)-one
Example 183 A
4,4-Dimethoxy-tetrahydro-pyran-3-ol To a solution of KOH (96 g, 1.4 mmol) in MeOH (800 mL) was added tetrahydro- pyran-4-one (60 g, 0.6 mmol) over 0.5 hour. A solution of h (96 g, 0.7 mmol) in MeOH (1200 mL) was added over 2 hours, the solution was gradually warmed to room temperature and stirred for additional 15 hours. The resulting solution was concentrated in vacuo. The residue was purified by column chromatography, eluted with 5 % ethyl acetate in hexanea to provide the title compound (70 g, 72 %) as a yellow oil.
Example 183B
3-hydroxydihydro-2H-pyran-4(3H)-one
A mixture of Example 183A (3.2 g, 20 mmol) and TFA (2 mL) in
dichloromethane (10 mL) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, and the residue was purified by column
chromatography, eluted with 5-10 % ethyl acetate in hexanes to provide the title compound (1.6 g, 70%) as a yellow oil.
Example 183C
1 ,5-anhydro-2,3-dideoxy-3- {[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]amino}-D-threo-pentitol The title compound was prepared according to Example 14 IB, substituting Example 183B for Example 141 A, and purified by chiral SFC (Column: Chiralpak AD-H IC 250 4.6 mm ID, 5 μπι; Mobile phase: A: Supercritical C02, B: ethanol (0.05% diethylamine as modifier), A:B =95:5 to 60:40 at 2.35 mL/min; Wavelength: 220 nm) to provide the title compound (peak 4, retention time 9.25 minute), as well as Example 168 (peak 1, retention time 7.25 minute), Example 181 (peak 2, retention time 7.38 minute), and Example 182 (peak 3, retention time 7.81 minute). Ή NMR (400 MHz, CDC13) δ 8.681 (s, 1 H), 7.708 (s, 1 H), 4.758-4.854 (m, 2 H), 3.515-3.971 (m, 7 H), 3.024-3.515 (m, 5 H), 1.291-2.284 (m, 1 1 H), 0.861-0.918 (m, 1 H); MS (ESI) m/z 454 (M+H)+.
Figure imgf000240_0001
Example 184
[(2R,3aR,6aR)-2-{[(3S)-4,4-dimethoxytetrahydro-2H-pyran-3- yl]amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone The title compound (retention time 6.22 minute) was obtained from the chiral SFC purification of Example 176. Ή NMR (400 MHz, CDC13) δ 8.780 (s, 1 H), 7.887 (s, 1 H), 4.672-5.151 (m, 2 H), 3.475-4.078 (m, 8 H), 3.127-3.375 (m, 9 H), 2.875 (s, 1 H), 2.284 (s, 1 H), 1.458-2.090 (m, 10 H); MS (ESI) m/z 498 (M+H)+.
Figure imgf000241_0001
Example 185
[(2R,3aR,6aR)-2-{[(4R)-6-chloro-3,4-dihydro-2H-chromen-4- yl]amino}hexahydropentalen-3a(lH)-yl] [3-(trifluoromethyl)-7,8-dihydro- 1 ,6- naphthyridin- 6(5H) -yl]methanone
The title compound (retention time 9.54 minute) was obtained from the chiral SFC purification of Example 178B. Ή NMR (400 MHz, CDC13) δ 8.69 (s, 1H), 7.68 (s, 1H) , 7.19 (m, 1H), 7.02 (m, 1H), 6.63 (m, 1H), 4.70(s, 2H), 4.35 (m, 1H), 4.22 (m, 1H), 3.81- 3.98 (m, 2H), 3.75 (m, 1H), 3.61 (m, 1H), 3.48 (m, 1H), 3.04 (m, 2H), 1.46-2.24 (m, 14H), 1.14 -1.45 (m, 2H); MS (ESI) m/z 520 (M+H)+.
Figure imgf000241_0002
Example 186
[(2R,3aR,6aR)-2-{[(4R)-6-bromo-3,4-dihydro-2H-chromen-4- yl]amino}hexahydropentalen-3a(lH)-yl] [3-(trifluoromethyl)-7,8-dihydro- 1 ,6- naphthyridin- 6(5H) -yl]methanone
The title compound (peak 2, retention time 18.09 minute) was obtained from the chiral SFC purification of Example 179B. Ή NMR (400 MHz, CDCI3) δ ppm 1.20 -1.40 (m, 2 H), 1.55-2.15 (m, 10 H), 3.12(s, 2H), 3.40 - 3.70 (m,2H), 3.70 - 4.00 (m,3H), 4.00 - 4.40 (m,2 H), 4.79 (s,2 H), 6.60 - 6.75 (m, l H), 7.15 - 7.25 (m,l H), 7.35 (s, 1 H), 7.67 (s, 1 H), 8.69 (s, 1 H); MS (ESI) m/z 566 (M+H)+.
Figure imgf000242_0001
Example 187
[(2R,3aR,6aR)-2-{[(4S)-6-methyl-3,4-dihydro-2H-chromen-4- yl]amino}hexahydropentalen-3a(lH)-yl] [3-(trifluoromethyl)-7,8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone
Example 187A
6-methylchroman-4-one
The title compound was prepared and isolated according to the procedure described in Example 148A and 148B, substituting 4-methylphenol for 2-fluorophenol.
Example 187B
[(2R,3aR,6aR)-2-{[(4S)-6-methyl-3,4-dihydro-2H-chromen-4- yl]amino}hexahydropentalen-3a(lH)-yl] [3-(trifluoromethyl)-7,8-dihydro- 1 ,6- naphthyridin- 6(5H) -yl]methanone
The title compound was prepared according to the procedure described in Example 148C, substituting Example 187A for Example 148B. The residue was diluted with CH3CN and extracted with heptane. The acetonitrile phase was concentrated to give crude compound as a mixture of two diastereoisomers, which was then further purified by chiral SFC with a preparative ChiralCel AD 250 mm*30 mm, 5 μιη eluting with mobile A: Supercritical C02, B: ethanol (0.05% diethylamine), A:B = 90: 10 at 70 mL/min Column Temp: 38 °C; Nozzle Pressure: lOOBar; Nozzle Temp: 60 °C; Evaporator Temp: 20 °C; Trimmer Temp: 25 °C; Flow rate: 70 mL/min; Wavelength: 220 nm to yield the title compound (peak 1, retention time 8.215 min, 5.22 mg) and Example 188 (peak 2, retention time 1 1.638 minute, 4.55 mg). Ή NMR (400 MHz, CDCI3) δ ppm 1.20 -2.20 (m, 13 H), 2.25 (s, 3 H), 3.12 (s, 2H), 3.40 - 3.70 (m,2H), 3.70 - 4.00 (m,3H), 4.10 - 4.40 (m,2 H),4.78 (s,2 H), 6.60 - 6.75 (m, l H), 6.90 - 7.05 (m,2 H), 7.72 (s, 1 H), 8.72 (s, 1 H); MS (ESI) m/z 500(M+H)+.
Figure imgf000243_0001
Example 188
[(2R,3aR,6aR)-2-{[(4R)-6-methyl-3,4-dihydro-2H-chromen-4- yl]amino}hexahydropentalen-3a(lH)-yl] [3-(trifluoromethyl)-7,8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone
The title compound (peak 2, retention time 1 1.638 minute) was obtained from the chiral SFC purification of Example 187B. Ή NMR (400 MHz, CDC13) δ ppml .20 -2.20 (m, 13 H), 2.23 (s, 3 H), 3.13 (s, 2H), 3.40 - 3.70 (m,2H), 3.70 - 4.00 (m,3H), 4.10 - 4.40 (m,2 H), 4.80 (s,2 H), 6.60 - 6.70(m, l H), 6.92 (s,2 H), 7.68 (s, 1 H), 8.68(s, 1 H); MS (ESI) m/z 500 (M+H)+.
Figure imgf000243_0002
Example 189
[(2R,3aR,6aR)-2-{[(4S)-6-nitro-3,4-dihydro-2H-chromen-4-yl]amino}hexahydropentalen- 3a(lH)-yl] [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]methanone
Example 189A
6-nitrochroman-4-one
The title compound was prepared and isolated according to the procedure described in Example 148A and 148B, substituting 4-nitrophenol for 2-fluorophenol.
Example 189B
[(2R,3aR,6aR)-2-{[(4S)-6-nitro-3,4-dihydro-2H-chromen-4-yl]amino}hexahydropentalen- 3a(lH)-yl] [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]methanone The title compound was prepared according to the procedure described in Example 148C, substituting Example 189A for Example 148B. The residue was diluted with CH3CN and extracted with heptane. The acetonitrile phase was concentrated to give crude compound as a mixture of two diastereoisomers, which was then further purified chiral SFC with a preparative ChiralCel AD 250 mm*30 mm, 5 μιη eluting with mobile A: Supercritical CO2, B: isopropanol (0.05% diethylamine), A:B = 60:40 at 70 mL/min Column Temp: 38 °C; Nozzle Pressure: lOOBar; Nozzle Temp: 60 °C; Evaporator Temp: 20 °C; Trimmer Temp: 25 °C; Flow rate: 70 mL/min; Wavelength: 220 nm to yield the title compound (peak 1, retention time 8.309 minute, 5.66 mg) and Example 190 (peak 2, retention time 12.04 minute, 4.40 mg). Ή NMR (400 MHz, CDC13) δ ppm 1.10 -2.10 (m, 12 H), 3.13 (s,2H), 3.40 - 4.00 (m,6H), 4.20 - 4.45 (m,2 H), 4.88 (s,2 H), 6.70 - 6.80 (m,l H), 7.70 (s, l H), 8.00-8.05 (m, 1 H), 8.1 1 (s, 1 H), 8.69(s, 1 H); MS (ESI) m/z 531(M+H)+.
Figure imgf000244_0001
Example 190
[(2R,3aR,6aR)-2-{[(4R)-6-nitro-3,4-dihydro-2H-chromen-4- yl]amino}hexahydropentalen-3a(lH)-yl] [3-(trifluoromethyl)-7,8-dihydro- 1 ,6- naphthyridin- 6(5H) -yl]methanone
The title compound (peak 2, retention time 12.04 minute) was obtained from the chiral SFC purification of Example 189B. 'H NMR (400 MHz, CDC13) δ ppm 1.10 -2.10 (m, 12 H) 3.13 (s,2H), 2.90 - 3.10 (m,3H) 3.40 - 4.00 (m,5H), 4.20 - 4.45 (m,2 H), 4.80 (s,2 H), 6.84 - 6.85 (m,l H), 7.69 (s, l H), 8.00-8.10 (m, 1 H), 8.18 (s, 1 H), 8.69(s, 1 H); MS (ESI) m/z 531 (M+H)+.
Figure imgf000244_0002
Example 191
[(2R,3aR,6aR)-2- {[(2R,4S)-2-(pyridin-2-yl)tetrahydro-2H-pyran-4- l]amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- naphthyridin-6(5H)-yl]methanone The title compound (retention time 7.42 minute) was obtained from the SFC purification of Example 145C. Ή NMR (400 MHz, CDC13) δ 8.69 (s, 1H), 8.52 (d, 1H) 7.71 (m, 2H), 7.47 (d, 1H), 7.17 (t, 1H), 5.03 (s, lH),4.82(m, 2H), 3.93-4.00 (m, 3H), 3.50-3.70 (m, 3H), 3.42 (s, 1H), 3.28 (s, 2H), 2.01 - 2.44 (m, 7H), 1.86 - 1.99 (m, 4H), 1.50- 1.80 (m, 3H), 1.23-1.50 (m, 3H); MS (ESI) m/z 515 (M+H)+.
Figure imgf000245_0001
Example 192
[(2R,3aR,6aR)-2-{[(4R)-6,7-difluoro-3,4-dihydro-2H-chromen-4- yl]amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone
3 -(3 ,4-difluoro-phenoxy)-propionic acid
Example 192A
A mixture of 3,4-difluoro-phenol (5 g, 38 mmol), 3-bromo-propionic acid (6.2 g, 41 mmol) and NaOH (3 g, 76 mmol) in ¾0 ( 50 mL) was refluxed overnight. After cooling to room temperature, the pH of the reaction mixture was adjusted to about 2 with the addition of 3 M HC1, and then extracted with ethyl acetate (200 mL). The combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/ethyl acetate: 1/1) to provide the title compound (2 g, 26 %) as a white solid.
6,7-difluoro-chroman-4-one
Example 192B
To a solution of Example 192A (1 g, 5 mmol) in dry dichloromethane (50 mL) was added oxalyl dichloride (1 mL) and one drop Ν,Ν-dimethyl formamide at 0 °C. The mixture was stirred for 2 hours, followed by the addition of AICI3 (700 mg, 5 mmol), and stirring at room temperature overnight. The mixture was poured into ice-bath water and extracted with dichloromethane (300 mL). The combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/ethyl acetate: 10/2) to give title compound (600 mg, 65%) as a yellow solid.
Example 192C [(2R,3aR,6aR)-2-{[(4R)-6,7-difluoro-3,4-dihydro-2H-chromen-4- yl]amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone
A mixture of N,N-diisopropylethylamine (192 mg. 1.5 mmol), Ti(OiPr)4 (710 mg, 2.5 mmol), Example 79N (177 mg, 0.5 mmol) and Example 192B (138 mg, 0.75 mmol) was stirred at room temperature overnight. NaBH4 (76 mg, 2 mmol) was added and stirred overnight. The reaction mixture was filtered, and then concentrated in vacuo. The residue was diluted with dichloromethane (100 mL) and ¾0 (50 mL), and partitioned. The organic layer was washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC, followed by chiral SFC (Chiralpak AD-H 50 mm*4.6 mm, 3 μιη eluting with mobile A: Supercritical CO2, B: ethanol (0.05% diethylamine), A:B from 95:5 to 40:60; Wavelength: 220 nm) to obtain title compound (peakl, retention time 7.36 minute, 5 mg), as well as Example 193 (peak 2, retention time 7.77 minute, 6 mg) both as a white solid. Ή NMR (400 MHz, CDCI3) δ 8.620 (s, 1 H), 7.61 1 (s, 1 H), 7.141-7.179 (m, 1 H), 6.566-6.663 (m, 1 H), 4.632-4.796 (m, 2 H), 3.057-4.166 (m, 1 1 H), 1.636-1.965 (m, 10 H), 1.120- 1.156 (m, 1 H); MS (ESI) m/z 522 (M+H)+.
Figure imgf000246_0001
Example 193
[(2R,3aR,6aR)-2-{[(4S)-6,7-difluoro-3,4-dihydro-2H-chromen-4- yl]amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone
The title compound (peak 2, retention time 7.77 minute) was obtained from the chiral SFC purificaiton of Example 192C. Ή NMR (400 MHz, CDCI3) δ 8.629 (s, 1 H), 7.628 (s, 1 H), 6.851-6.994 (m, 1 H), 6.458-6.514 (m, 1 H), 4.704-4.804 (m, 2 H), 3.067- 4.146 (m, 9 H), 1.338-2.042 (m, 12 H), 1.143-1.237 (m, 1 H); MS (ESI) m/z 522 (M+H)+
Figure imgf000246_0002
Example 194
[(2R,3aR,6aR)-2-[(9-anti)-3-oxabicyclo[3.3.1]non-9-ylamino]hexahydropentalen-3a(lH)- yl][3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)-yl]methanone
Example 194A
6-hydroxy-3-oxabicyclo[3.3.1]nonan-9-one
A mixture of dihydro-2H-pyran-4(3H)-one (1.0 g, 10 mmol) and pyrrolidine (1.05 g, 15 mmol) was stirred at room temperature for 1.5 hours. After removal of excess pyrrolidine, the residue was diluted with Et20 (9 mL) and acrolein (0.74 mL) was added. The mixture was stirred at room temperature overnight, and quenched with water (10 mL) and concentrated H2SO4 (1.4 mL). After removal of Et20, the mixture was refluxed for 30 minutes, cooled, and extracted with CH2CI2. The organic layer was dried over MgS04, filtered, and concentrated in vacuo. The residue was purified by silica gel
chromatography (hexanes: ethyl acetate = 3 : 1) to provide the title compound (400 mg).
Example 194B
3-oxabicyclo[3.3.1 ]non-6-en-9-one
To a solution of Example 194A (400 mg, 2.6 mmol), l,8-diazabicycloundec-7-ene (1.16 g, 7.7 mol) in toluene (4 ml) was added triflic anhydride (1.47 g, 5.2 mol) at 0 °C. The mixture was stirred at room temperature for 2 hours and purified by silica gel chromatography (hexanes : ethyl acetate = 10 : 1) to afford 140 mg of the title compound.
Example 194C
3-oxabicyclo[3.3.1]nonan-9-one
A mixture of Example 194B (140 mg, 1 mmol) and Pd/C (14 mg) in ethyl acetate (5 mL) was stirred at room temperature for 2 hours under ¾ (50 Psi). The catalyst was removed by filtration. The filtrate was concentrated in vacuo. The residue was used for the next step.
Example 194D
[(2R,3aR,6aR)-2-[(9-anti)-3-oxabicyclo[3.3.1]non-9-ylamino]hexahydropentalen-3a(lH)- yl][3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)-yl]methanone A mixture of Example 194C (87 mg, 0.6 mmol), Example 79N (1 17 mg, 0.3 mmol), N,N-diisopropylethylamine (78 mg, 0.6 mmol), molecular sieves 4A (200 mg) and NaBH(OAc)3 (125 mg, 0.6 mmol) in CH2CI2 (10 ml) was stirred at room temperature overnight. The reaction was quenched with saturated aqueous Na2C(¾, and filtered to remove molecular sieves. The filtrate was partitioned. The organic layer was concentrated in vacuo. The residue of two diastereoisomers was further purified by chiral SFC with a preparative ChiralCel AD column (250 mm*30mm, ID 5 μιη) eluting with mobile phase: A, Supercritical C02; B, MeOH (0.05% diethylamine), A:B= 70:30 with a flow rate of 65 mL/min to provide the title compound (Peak 1, retention time 6.61 minute, 6.79 mg) and Example 195 (peak 2, retention time 7.01 minute, 16.67 mg). Ή NMR (400 MHz, CDC13) δ ρριη 1.12 - 1.33 (m, 3H), 1.37 - 1.89 (m, 13H), 1.91 - 2.01 (m, 1H), 2.03 - 2.18 (m, 2H), 2.764 (s, 1H), 2.85 - 2.93 (m, 1H), 2.98 - 3.15 (m, 1H), 3.23 - 3.37 (m, 1H), 3.39 - 3.55 (m, 1H), 3.56 - 3.68 (m, 2H), 3.74 - 4.01 (m, 3H), 4.717 (m, 2H), 7.618 (s, 1H), 8.632 (s, 1H). MS (ESI) m/z 478 (M+H)+.
Figure imgf000248_0001
Example 195
[(2R,3aR,6aR)-2-[(9-syn)-3-oxabicyclo[3.3.1]non-9-ylamino]hexahydropentalen-3a(lH)- yl][3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)-yl]methanone The title compound (peak 2, retention time 7.01 minute) was obtained from the chiral SFC purification of Example 194D. Ή NMR (400 MHz, CDC13) δ ppm 1.22 - 2.12 (m, 18H), 2.15 - 2.28 (m, 1H), 2.62 - 2.73 (m, 1H), 3.08 - 3.19 (m, 2H), 3.33 - 3.47 (m, 1H), 3.51 - 3.62 (m, 1H), 3.82 - 3.95 (m, 2H), 4.02 - 4.1 1 (m, 2H), 4.780 (m, 2H), 7.675 (s, 1 H), 8.683 (s, 1H); MS (ESI) m/z 478 (M+H)+.
Figure imgf000248_0002
Example 196
[(2R,3aR,6aR)-2-{[(3S,4S)-3-methoxy-3,4-dihydro-2H-chromen-4- yl]amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone
Example 196A
4,4-dimethoxychroman-3-ol
To a 0 °C solution of KOH (1.68 g, 30 mmol) in MeOH (100 mL) was added chroman-4-one (1.48 g, 10 mmol) over 0.5 hour. PhI(OAc)2 (3.5 g, 1 1 mmol) was added in one portions. Upon completion of the addition, the solution was gradually warmed to room temperature and aged for additional 10 hours. The resulting solution was then concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/ethyl acetate: 10/2) to afford the title compound (1.8 g, 86%) as a colorless solid.
Example 196B
3 ,4,4-trimethoxy chroman
To a solution of Example 196B (1.8 g, 8.6 mmol) in tetrahydrofuran (100 mL) was slowly added NaH (312 mg, 13 mmol) at 0 °C, and the resulting slurry was stirred for 1 hour, followed by the addition of iodomethane (1 1 mL, 17 mmol). The resulting mixture was allowed to warm to room temperature overnight, quenched with saturated NH4CI solution (100 mL) solution, and extracted with ethyl acetate (300 mL). The combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo to provide the crude product, which was used directly in the next step without further purification.
Example 196C
3 -methoxychroman-4-one
To a solution of Example 196B (1.9 g, 8.6 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (3 mL). The mixture was stirred at room temperature overnight. TLC showed completion of the reaction. The reaction mixture was concentrated in vacuo, and the residue purified by column chromatography (petroleum ether/ethyl acetate: 10/2) to provide the title compound (1.3 g, 87%) as a yellow oil. The mixtures of enantiomers were separated by SFC to afford 3(R)-methoxychroman-4-one (peak 1) and 3(S)-methoxychroman-4-one (peak 2).
Example 196D
[(2R,3aR,6aR)-2-{[(3S,4S)-3-methoxy-3,4-dihydro-2H-chromen-4- yl]amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone
The title compound was prepared according to the procedure described in Example 148C, substituting 3(R)-methoxychroman-4-one (peak 1 of Example 196C) for Example 148B. The residue was diluted with CH3CN and extracted with heptane. The acetonitrile phase was concentrated to give crude compound, which was further purified by chiral SFC with a preparative Chiralpak AD-H 250 mm*30 mm, 5 μιη eluting with mobile A: Supercritical C02, B: ethanol (0.05% diethylamine), A:B = 95:5 to 60:40 at 4 mL/min,; Wavelength: 220 nm) to yield the title compound (one peak only, 3.0 mg). Ή NMR (400 MHz, CDC13) δ 8.668 (s, 1 H), 8.048 (s, 1 H), 7.379 (d, 1 H), 7.065 (t, 1 H), 6.803 (t, 1 H), 6.686 (d, 1 H), 4.812-4.915 (m, 2 H), 3.353-4.382 (m, 1 1 H), 3.088-3.129 (m, 2 H), 1.340-2.360 (m, 10 H); MS (ESI) m/z 516 (M+H)+.
Figure imgf000250_0001
Example 197
[(2R,3aR,6aR)-2-{[(3R,4S)-3-methoxy-3,4-dihydro-2H-chromen-4- yl]amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone
The title compound was prepared according to the procedure described in
Example 148C, substituting 3(S)-methoxychroman-4-one (peak 2 of Example 196C) for Example 148B. The residue was diluted with CH3CN and extracted with heptane. The acetonitrile phase was concentrated to give crude compound as a mixture of two diastereoisomers, which was then further purified by chiral SFC with a preparative Chiralpak AD-H 250 mm*30 mm, 5 μιη eluting with mobile A: Supercritical CO2, B: ethanol (0.05% diethylamine), A:B = 95:5 to 60:40 at 4 mL/min; Wavelength: 220 nm) to yield title compound (peak 2, Retention time 1.935 minute, 7.0 mg), as well as Example 198 (peak 1, Retention time 1.413 minute, 3.0 mg). ¾ NMR (400 MHz, CD3OD) δ 8.618 (s, 1 H), 7.953 (s, 1 H), 7.254 (d, 1 H), 7.004 (t, 1 H), 6.722 (t, 1 H), 6.601 (d, 1 H), 4.815-4.915 (m, 2 H), 3.464-4.362 (m, 11 H), 2.953-3.082 (m, 2 H), 1.272-2.047 (m, 1 1 H); MS (ESI) m/z 516 (M+H)+.
Figure imgf000250_0002
Example 198
[(2R,3aR,6aR)-2-{[(3R,4R)-3-methoxy-3,4-dihydro-2H-chromen-4- yl]amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone The title compound (peak 1 , Retention time 1.413 minute) was isolated from the chiral SFC purification of Example 197. Ή NMR (400 MHz, CDC13): δ 8.671 (s, 1 H), 8.046 (s, 1 H), 7.382 (d, 1 H), 7.074 (t, 1 H), 6.812 (t, 1 H), 6.694 (d, 1 H), 4.816-4.916 (m, 2 H), 3.341-4.383 (m, 1 1 H), 3.084-3.132 (m, 2 H), 1.348-2.369 (m, 10 H); MS (ESI) m/z 516 (M+H)+.
Figure imgf000251_0001
Example 199
(4S)-4-{[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)- yl]carbonyl}octahydropentalen-2-yl]amino}-3,4-dihydro-2H-chromene-6-carbonitrile
Example 199A
6-methylchroman-4-one
The title compound was prepared and isolated according to the procedure described in Example 148A and 148B, substituting 4-cyanophenol for 2-fluorophenol.
Example 199B
(4S)-4- {[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)- yl]carbonyl}octahydropentalen-2-yl]amino}-3,4-dihydro-2H-chromene-6-carbonitrile The title compound was prepared according to the procedure described in Example 148C, substituting Example 199A for Example 148B. The residue was diluted with CH3CN and extracted with heptane. The acetonitrile phase was concentrated to give crude compound as a mixture of two diastereoisomers, which was then further purified by chiral SFC (preparative ChiralCel AD 250 mm*30 mm, 5 μιη eluting with mobile A: Supercritical CO2, B: ethanol (0.05% diethylamine), A:B = 65 :35; Column Temp: 38 °C; Nozzle Pressure: 100 Bar; Nozzle Temp: 60 °C; Evaporator Temp: 20 °C; Trimmer Temp: 25 °C; Flow rate: 70 mL/min; Wavelength: 220 nm) to yield the title compound (peak 1, retention time 4.45 minute, 5.53 mg) and Example 200 (peak 2, retention time 5.47 minute, 3.07 mg). Ή NMR (400 MHz, CDC13) δ ppm 1.10 -2.10 (m, 12 H) 3.13 (s,2H), 2.90 - 3.10 (m,3H) 3.30 - 4.00 (m,5H), 4.10 - 4.40 (m,2 H), 4.70 - 4.90 (m,2 H), 6.70 - 6.80 (m, l H), 7.30-7.40 (m, 1 H), 7.43 (s, 1 H), 7.66 (s, 1 H), 8.62(s, 1 H); MS (ESI) m/z 51 1 (M+H)+.
Figure imgf000252_0001
Example 200
(4R)-4- {[(2R,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro ,6-naphthyridin-6(5H)- yl]carbonyl} octahydropentalen-2-yl]amino}-3,4-dihydro-2H-chromene-6-carbonitrile The title compound (peak 2, retention time 5.47 minute) was obtained from the chiral SFC purification of Example 199B. 'H NMR (400 MHz, CDC13) δ ppm 1.10 -2.10 (m, 13 H) 3.13 (s,2H), 2.90 - 3.10 (m,2H) 3.30 - 4.00 (m,5H), 4.10 - 4.40 (m,2 H), 4.70 - 4.90 (m,2 H), 6.70 - 6.80(m,l H), 7.30-7.35(m, 1 H), 7.51 (s, 1 H), 7.63 (s, 1 H), 8.62(s, 1 H); MS (ESI) m/z 51 1 (M+H)+.
Figure imgf000252_0002
Example 201
[(2R,3aR,6aR)-2-{[(4S)-8-fluoro-3,4-dihydro-2H-chromen-4- yl]amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone
The title compound (retention time 7.22 minute) was isolated from the chiral SFC purification of Example 148C. Ή NMR (400 MHz, CD3OD) δ 8.66 (s, 1H), 8.34 (s, 1H), 6.89 (m, 2H), 6.75 (m, 1H), 4.87 (m, 2H), 4.44 (m, 1H), 4.31 (m, 1H), 4.00 (m, 2H), 3.78 (m, 1H), 3.50 (m, 2H), 3.10 (m, 2H), 2.18 (m, 1H), 1.98 (m, 5H), 1.75 (m, 4H), 1.60 (m, 1H), 1.42 (m, 1H); MS (ESI) m/z 504 (M+H)+.
Figure imgf000252_0003
Example 202
[(2R,3aR,6aR)-2-{[(2R,4S)-2-(trifluoromethyl)-3,4-dihydro-2H-chromen-4- yl]amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone
Example 202A
2-(trifluoromethyl)-4H-chromen-4-one
To a mixture of 1 -(2-hydroxyphenyl)ethanone (5.0 g, 37mmol) in trifluoroacetic anhydride (15 g, 74 mmol) was added pyridine (2.9 g, 37 mmol). The mixture was heated to 80 °C and stirred for 5 hours. After cooling, the reaction mixture was treated with 1M hydrochloric acid (15 mL) and CH2CI2 (15 mL), and washed thoroughly with water. The organic layer was wash with brine, dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (CH2CI2: MeOH = 80: 1) to afford the title compound (1 g).
Example 202B
2-(trifluoromethyl)chroman-4-ol
To a mixture of Example 202A (1.0 g, 4.7 mmol) in ethyl acetate (30 mL) was added 10% Pd/C (0.1 g). The reaction mixture was hydrogenated at 45 psi ¾ for 12 hours at room temperature, filtered, and concentrated under reduced pressure to provide the title compound (0.7g). The crude product was used in the next step without purification.
Example 202C
2-(trifluoromethyl)chroman-4-one
To a solution of Example 202B (0.5g, 2.3mmol) in CH2CI2 (40 ml) was added Dess-Martin reagent (1.9 g, 4.6 mmol) at room temperature. The mixture was stirred at room temperature for 16 hour. Then the reaction mixture was suspended in saturated aqueous NaHC03 and extracted with dichloromethane (50 mL x 2). The combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated. The crude product was purified by silica gel chromatography to provide the title compound (100 mg).
Example 202D
[(2R,3aR,6aR)-2-{[(2R,4S)-2-(trifluoromethyl)-3,4-dihydro-2H-chromen-4- yl]amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone To a mixture of Example 79N (0.17g, 0.398mmol) in ethanol (10 mL) was added N,N-diisopropylethylamine (0.15g 1.99mmol), Example 202C (0.17g 0.796 mmol), and Ti (OiPr)4 (0.565 g 1.99 mmol). The mixture was stirred at room temperature for 16 hours, followed by addition of NaBH4 (0.075 g 1.99 mmol). The reaction mixture was stirred at room temperature for another 13 hours, treated with saturated aqueous NaHC(¾, and filtered. The filtrate was partitioned. The aqueous layer was extracted with CH2CI2. The combined organic layers were washed with saturated brine, dried (Na2S04), and concentrated. The residue was purified by HPLC and SFC (Column: Chiralcel AD 250 x 30 mm ID 5 μιη; Mobile phase: A: Supercritical C(¾, B: isopropanol (0.05%
diethylamine as modifier), A:B =75:25 at 60 mL/min; Flow rate: 60 mL/min;
Wavelength: 220 nm) to give title compound (peak 1, retention time 5.94 minute, 20 mg) as white solid, as well as Example 203 (peak 2, retention time 7.62 minute, 27.5 mg). Ή NMR (400 MHz, CDCI3) δ 8.69 (s, 1H), 8.04 (b, 1H), 7.48 (m, 1H), 7.25 (s, 1H), 6.64- 7.02 (m, 2H), 4.91(m, 2H), 4.58 (m, 1H), 3.99-4.38 (m, 3H), 3.44-3.74 (m, 2H), 3.00-3.35 (m, 2H), 2.54 (m, 1H), 1.98-2.38 (m, 3H), 1.72-1.90 (m, 4H), 1.62-1.70 (m, 3H), 1.42- 1.50 (m, 1H); MS (ESI) m/z 554 (M+H)+.
Figure imgf000254_0001
Example 203
[(2R,3aR,6aR)-2-{[(2S,4R)-2-(trifluoromethyl)-3,4-dihydro-2H-chromen-4- yl]amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone
The title compound (peak 2, retention time 7.62 minute) was obtained from the SFC purification of Example 202D. Ή NMR (400 MHz, CDC13) δ 8.70 (s, 1H), 8.40 (s, 1H), 8.05 (d, 1H), 7.51 (t, 1H), 7.18 (t, 1H) , 6.87 (d, 1H), 4.84(m, 2H), 4.68 (m, 1H), 4.41 (m, 1H), 4.02 (m, 2H), 3.50-3.55 (m, 2H), 3.21 (m, 2H), 2.54 (m, 1H), 2.30 (m, 1H), 1.46-2.14 (m, 8H), 1.62 (m, 1H), 1.42- 1.50 (m, 1H); MS (ESI) m/z 554 (M+H)+.
Figure imgf000255_0001
Example 204
[(2R,3aR,6aR)-2- {[(3R,4R)-3-cyclopropyltetrahydro-2H-pyran-4- yl]amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone
Example 204A
methyl 4-oxotetrahydro-2H-pyran-3-carboxylate To a mixture of NaH (20 g, 500 mmol) in tetrahydrofuran (600 mL) at room temperature was added tetrahydro-pyran-4-one (20 g, 200 mmol), 2 hours later followed by the addition of carbonic acid dimethyl ester (42 mL, 500 mL).The mixture was refluxed overnight. After cooling to room temperature, the mixture was poured into 0.1 N HC1 (50 mL) and ethyl acetate (200 mL), filtered, and then extracted with ethyl acetate (300 mL). The combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/ethyl acetate: 10/2) to provide the title compound (5 g, 16 %) as a red oil.
Example 204B
3,3-Dimethyl- l,5,9-trioxa-spiro[5.5]undecane-7-carboxylic acid methyl ester A mixture of Example 204A (5 g, 31 mmol), 2,2-dimethyl-propane-l,3-diol (4.27 g, 41 mmol) and toluene-4-sulfonic acid (200 mg) in toluene (60 mL) was refluxed overnight using Dean- Stark trap. After cooling to room temperature, the reaction mixture was quenched with a saturated NaHC(¾ (100 mL) solution. The aqeous layer was extracted with ethyl acetate (200 mL). The combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/ethyl acetate: 10/2) to provide the title compound (5 g, 65%) as a red oil.
Example 204C
(3,3-Dimethyl-l,5,9-trioxa-spiro[5.5]undec-7-yl)-methanol To a solution of Example 204B (2.4 g, 10 mmol) in dichloromethane (50 mL) was added dropwise DIBAL-H (22 mL, 22 mmol) at -78 °C. The resulting mixture was stirred at -78 °C for 2 hours, followed by the addition of ¾0 (2 mL) and NaOH solution (1 M, 2 mL). The resulting white suspension was filtered. The filtrate was concentrated in vacuo to provide the title compound (2.14 g), which was used directly in the next step without further purification.
Example 204D
3,3-Dimethyl-l,5,9-trioxa-spiro[5.5]undecane-7-carbaldehyde To a solution of Example 204C (2.14 g, 10 mmol) in dichloromethane (50 mL) was added Dess-Martin reagent (8.5 g, 20mmol) in small portions. The mixture was stirred at room temperature overnight and quenched with a saturated NaHC03 (50 mL) solution. The reaction mixture was stirred for 0.5 hour and partitioned. The aqueous layer was extracted with dichloromethane (60 mL). The combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/ethyl acetate: 10/3) to provide title compound (1.5 g, 70%) as a pale yellow oil.
Example 204E
3 ,3 -Dimethyl-7-vinyl- 1 ,5 ,9-trioxa-spiro [5.5 ]undecane To a solution of ΡΡ1¾ΜεΒΓ (3.75 g, 10.5 mmol) in tetrahydrofuran (30 mL) was added dropwise n-BuLi (4 mL, 10.5 mmol) at 0 °C. After the addition, the mixture was stirred for 0.5 hour at 0 °C, followed by the addition of Example 204D (1.5 g, 7 mmol) in tetrahydrofuran (30 mL), and stirred at room temperature overnight. A saturated NH4C1 solution (50 mL) was added to quench the reaction. The aqeous layer was extracted with ethyl acetate (200 mL). The combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/ethyl acetate: 10/2) to give Example E (1.2 g, 80%) as a colorless oil.
Example 204F
7-Cyclopropyl-3,3-dimethyl- l,5,9-trioxa-spiro[5.5]undecane CH2I2 (1.2 g, 6 mmol) was added to a stirred solution of ZnEt2 (12 mL, 12 mmol) in dichloromethane (30 mL) at -78 °C under N2. The mixture was allowed to warm to 0 °C and stirred for 1 hour. A solution of Example 204E (1.2 g, 6 mmol) in
dichloromethane (20 mL) was added, the resulting suspension was stirred at room temperature for 5 hours. Concentrated Na2EDTA (100 mL) solution and saturated NaHC(¾ (100 mL) solution was added to quench the reaction. The mixture was filtered, and the filtrate was extracted with ethyl acetate (200 mL). The combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. The residue was diluted with petroleum ether, filtered, and the filtrate was concentrated in vacuo to provide the title compound (0.8 g, 5.9%) as a yellow oil.
Example 204G
3-Cyclopropyl-tetrahydro-pyran-4-one
A mixture of Example 204F (563 mg, 2.5 mmol) and toluene-4-sulfonic acid (160 mg) in acetone (30 mL) was stirred at room temperature for 3 hours. After concentrated in vacuo, the residue was purified by Preparative TLC to provide the title compound (100 mg, 10%) as a colorless oil. Ή NMR (400 MHz, CD3OD) δ 8.723 (s, 1 H), 8.085 (s, 1 H), 3.923-4.010 (m, 4 H), 3.468-3.769 (m, 7 H), 2.491-3.320 (m, 3 H), 1.378-2.1 10 (m, 12 H), 0.166-1.159 (m, 8 H): MS (ESI) m/z 478 (M+H)+.
Example 204H
[(2R,3aR,6aR)-2- {[(3R,4R)-3-cyclopropyltetrahydro-2H-pyran-4- yl]amino}hexahydropentalen-3a(lH)-yl] [3-(trifluoromethyl)-7,8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone
The title compound was prepared according Example 14 IB, substituting Example 204G for Example 141 A, and purified by chiral SFC (Column: Chiralpak AD-H 250 4.6 mm ID, 5 μιη; Mobile phase: A: Supercritical CO2, B: isopropanol (0.05%
diethylamine as modifier), A:B = 95:5 to 60:40 at 2.35 mL/min; Wavelength: 220 nm) to provide the title compound (peak 4, retention time 6.856 minute, 3.19 mg), Example 205 (peak 3, retention time 6.18 minute, 2.32 mg), Example 206 (peak 2, retention time 5.934 minute, 2.28 mg), and Example 207 (peak 1, retention time 5.304 minute, 2.55 mg). 'HNMR (400 MHz, CD3OD) δ 8.723 (s, 1H), 8.085 (s, 1H), 3.923-4.010 (m, 4H), 3.468- 3.769 (m, 7H), 2.491-3.320 (m, 3H), 1.378-2.1 10 (m, 12H), 0.166-1.159 (m, 8H); MS (ESI) m/z 478 (M+H)+.
Figure imgf000257_0001
Example 205
[(2R,3aR,6aR)-2-{[(3R,4S)-3-cyclopropyltetrahydro-2H-pyran-4- l]amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- naphthyridin-6(5H)-yl]methanone The title compound (peak 3, retention time 6.18 minute) was obtained from the chiral SFC purification of Example 204H. Ή NMR (400 MHz, CD3OD) δ 8.673 (s, 1 H), 8.042 (s, 1 H), 3.828-3.993 (m, 6 H), 3.424-3.553 (m, 4 H), 3.079-3.186 (m, 2 H), 1.440- 2.285 (m, 14 H), 0.028-0.753 (m, 6 H); MS (ESI) m/z 478(M+H)+.
Figure imgf000258_0001
Example 206
[(2R,3aR,6aR)-2- {[(3S,4S)-3-cyclopropyltetrahydro-2H-pyran-4- yl]amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone
The title compound (peak 2, retention time 5.934 minute) was obtained from the chiral SFC purification of Example 204H. Ή NMR (400 MHz, CD3OD) δ 8.691 (s, 1 H), 8.046 (s, 1 H), 3.766-3.991 (m, 6 H), 3.459-3.512 (m, 4 H), 3.027-3.150 (m, 2 H), 1.584- 2.220 (m, 14 H), 0.028- 1.427 (m, 6 H); MS (ESI) m/z 478 (M+H)+.
Figure imgf000258_0002
Example 207
[(2R,3aR,6aR)-2- {[(3S,4R)-3-cyclopropyltetrahydro-2H-pyran-4- yl]amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone
The title compound (peak 1, retention time 5.304 minute) was obtained from the chiral SFC purification of Example 204H. Ή NMR (400 MHz, CD3OD) δ 8.720 (s, 1 H), 8.089 (s, 1 H), 3.899-4.048 (m, 4 H), 3.406-3.899 (m, 5 H), 2.469-3.245 (m, 3 H), 1.386- 2.250 (m, 12 H), 0.028- 1.067 (m, 8 H), MS (ESI) m/z 478(M+H)+
Figure imgf000259_0001
Example 208
[(2R,3 aR,6aR)-2- { [3 -(fluoromethyl)tetrahydro-2H-pyran-4-yl]amino } hexahy dropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone
Example 208A
7-(fluoromethyl)-3,3-dimethyl-l,5,9-trioxaspiro[5.5]undecane
To a mixture of Example 204C in CH2CI2 (30 mL) was added diethylaminosulfur trifluoride (4.7 mL, 28 mmol). The reaction mixture was stirred at room temperature for 16 hours. TLC indicated that the reaction was complete. The reaction mixture was quenched with saturated aqueous NaHC(¾ (30 mL) solution and partitioned. The aqueous layer was extracted with CH2CI2 (3 x 30 mL). The combined organic layers were dried over Na2S04, filtered, and concentrated. The residue was purified by column
chromatography on silica gel (petroleum ether: ethyl acetate = 10: 1) to provide the title compound (1.0 g)
Example 208B
3-(fluoromethyl)dihydro-2H-pyran-4(3H)-one
A solution of Example 208A (1.0 g, 4.58 mmol) in formic acid (15 mL) was stirred for 2 hours at room temperature, and extracted with ethyl acetate (3 x 20 mL). The organic phase was dried (Na2S04), filtered, and concentrated in vacuo to afford the title compound (500 mg), which was used in the next step directly.
Example 208C
[(2R,3 aR,6aR)-2- { [3 -(fluoromethyl)tetrahydro-2H-pyran-4-yl]amino } hexahy dropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone A mixture of Example 79N (0.15 g, 0.35 mmol) in dichloroethane (10 mL) was added N,N-diisopropylethylamine (0.9 g 0.7 mmol) and Example 208B (0.95 g 0.7 mmol) and Ti(OiPr)4 (0.5 g 1.76 mmol). The mixture was stirred at room temperature for 16 hours, followed by the addition of NaBH4 (0.053 g 1.4 mmol), and stirred at room temperature for another 13 hours. The mixture was then treated with saturated aqueous NaHC(¾, filtered, and partitioned. The aqueous layer was extracted with CH2CI2. The combined organic layers were washed with brine, dried, filtered, and concentrated in vacuo. The residue was purified by HPLC (Phenomenex Synergi CI 8, Column:
150*30mm ID, 4μηι; Mobile phase: A Water (0.1 % TFA, V/V), B: acetonitrile (Neutral), flow rate: 25 mL/min; 24 %-40 % acetonitrile; Wavelength: 220 nm and 254nm) to provide the title compound (retention time 13 minute, 2.21 mg) as white solid. Ή NMR (400 MHz, CD3OD) δ 8.70 (s, 1H), 8.01 (s, 1H), 4.80 (m, 2H), 3.8 (m, 4H), 3.50 (m, 3H), 3.1 (m, 3H), 2.50 (m, 2H), 2.0 (m, 13H), 1.55 (m, 2H), 1.35 (m, 3H), 1.0 (m, 1H); MS (ESI) m/z 470(M+H)+.
Figure imgf000260_0001
Example 209
[(2R,3aR,6aR)-2-{[(3S,4R)-3-(difluoromethyl)tetrahydro-2H-pyran-4- yl]amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(triiluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone
Example 209A
7-(difluoromethyl)-3,3-dimethyl- 1 ,5,9-trioxaspiro[5.5]undecane
To a mixture of Example 204D (3.0 g, 14 mmol) in CH2CI2 (30 mL) was added diethylaminosulfur triiluoride (4.7 mL, 28 mmol), and stirred at room temperature for 16 hours. TLC indicated that the reaction was complete. A saturated aqueous NaHC(¾ (30 mL) was added and partitioned. The resulting aqueous layer was extracted with CH2CI2 (3 x 30 mL). The combined organic layers were dried over Na2S04, filtered, and the solvent was evaporated in vacuum. The residue was purified by column chromatography
(petroleum ether/ethyl acetate: 10: 1) to provide the title compound (1.0 g).
Example 209B
3-(difluoromethyl)dihydro-2H-pyran-4(3H)-one A mixture of Example 209A (250 mg, 1.1 mmol) was dissolved in 20 mL
HCOOH:CH2Cl2=5 : 1 , and stirred at room temperature for 18 hours. TLC indicated that the reaction was complete. A brine solution was added and the resulting aqueous layer was extracted with CH2CI2 (2 x 20 mL). The combined organic layers were dried over Na2S04, filtered, the solvent was removed under reduced pressure to give the title compound (100 mg) which was used in the next step without purification. Example 209C
[(2R,3aR,6aR)-2- {[(3S,4R)-3-(difluoromethyl)tetrahydro-2H-pyran-4- yl]amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone
To a mixture of Example 79N (0.15 g, 0.35 mmol) in dichloroethane (10 mL) was added N,N-diisopropylethylamine (0.9 g, 0.7 mmol), Example 209B (0.1 1 g, 0.7 mmol) and Ti(OiPr)4 (0.5 g, 1.76 mmol). The reaction mixture was stirred at room temperature for 16 hours, followed by the addition of NaBH4 (0.053 g 1.4 mmol). The reaction mixture was stirred at room temperature for another 13 hours. To the reaction mixture was then added saturated aqueous NaHC(¾ and filtered. The filtrate was partitioned. The aqueous layer was extracted with CH2CI2. The combined organic layers were washed with saturated brine, dried over Na2S04, and concentrated. The residue was purified by HPLC and SFC (Instrument: Thr 80 SFC , Column: Chiralcel AD 250 x 20 mm ID 20μηι; Mobile phase: A: Supercritical C02, B: ethanol (0.05% diethyl amine) A:B =75:25 at 60 mL/min; Column Temp: 38 °C; Nozzle Pressure: 100 Bar; Nozzle Temp: 60 °C;
Evaporator Temp: 20 °C Trimmer Temp: 25 °C;Wavelength: 220 nm) to provide the title compound (peak 1 , retention time 4.98 minute, 2.65 mg) as white solid and Example 210 (peak 2, retention time 6.53 minute, 2.21 mg). 'HNMR (400MHZ, CDCI3) δ 8.69 (s, 1H), 7.68 (d, 1H), 5.61 -5.98 (m, 1H), 4.74 (m, 2H), 3.74-3.915 (m, 2H), 3.51 -3.71 (m, 5H), 3.35 (m, 1H), 3.28 (m, 2H), 2.90 (m, 1H), 2.00-2.20 (m, 1H), 1.90-2.00 (m, 3H), 1.81 - 1.86 (m, 1H), 1.63- 1.80 (m, 5H), 1.23- 1.47 (m, 4H); MS (ESI) m/z 488 (M+H)+.
Figure imgf000261_0001
Example 210
[(2R,3aR,6aR)-2- {[(3S,4S)-3-(difluoromethyl)tetrahydro-2H-pyran-4- yl]amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone
The title compound (retention time 6.53 minute) was obtained from the SFC purification of Example 209C. 'HNMR (400MHZ, CDCI3) δ 8.70(s, 1H), 7.68 (d, 1H), 5.77-6.07 (m, 1H), 4.77 (s, 2H), 3.60-3.91 (m, 5H), 3.49-3.52 (m, 3H), 3.31 (m, 1H), 3.28 (m, 2H), 3.0-3.07 (m, 1H), 1.86-2.20 (m, 4H), 1.63- 1.84 (m, 5H), 1.23-1.42 (m, 4H); MS (ESI) nVz 488 (M+H)+.
Figure imgf000262_0001
Example 21 1
[(2R,3aR,6aR)-2-{[(4R)-3,3-dimethyltetrahydro-2H-pyran-4- yl]amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone
The title compound (peak 2, retention time 7.18 minute) was obtained from the SFC purification of Example 212G. Ή NMR (400 MHz, CD3OD) δ 8.90 (s, 1H), 8.35 (s, 1H), 5.00 (m, 2H), 4.00 (m, 4H), 3.50 (m, 3H), 3.25 (m, 4H), 2.50 (m, 1H), 2.25 (m, 1H), 1.9 (m, 9H), 1.68 (m, 1H), 1.48 (m, 1H), 1.1 (m, 6H); MS (ESI) m/z 466 (M+H)+.
Figure imgf000262_0002
Example 212
[(2R,3aR,6aR)-2-{[(4S)-3,3-dimethyltetrahydro-2H-pyran-4- yl]amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone
Example 212A
ethyl 2,2-dimethyl-3-oxobutanoate
To a suspension of NaH (38.4 g, 0.96 mol) in tetrahydrofuran (500 mL) was added ethyl 3-oxobutanoate (50 g, 0.384 mol) dropwise, followed by addition of iodomethane (172 g, 1.15 mol) at room temperature. The reaction mixture was stirred for 12 hours at room temperature, poured into aqueous NH4CI (150 mL), and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2S04, filtered, and concentrated in vacuo to give the title compound (75 g) as a liquid, which was used in the next step directly.
Example 212B
ethyl 2-methyl-2-(2-methyl- 1 ,3-dioxolan-2-yl)propanoate A mixture of Example 212A (25 g, 0.158 mol), ethane- 1,2-diol (29.87 g, 0.474 mol), 4-methyl-benzenesulfonic acid (0.6 g, 3.6 mmol) in toluene (400 ml) was refluxed in a Dean-stark apparatus with continous removal of water for 12 hours. The reaction mixture was washed with water and extracted with ethyl acetate (3 x 150 mL). The combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica eluted with ethyl acetate in petroleum ether (0%-25%) to afford the title compound (1 1 g, yield: 34.4%) as a liquid.
Example 212C
2-methyl-2-(2-methyl- 1 ,3-dioxolan-2-yl)propan- 1 -ol To a suspension of LiAlH4 (3.3 g, 0.087 mol) in tetrahydrofuran (150 mL) was added Example 212B (1 1 g, 0.054 mol) in tetrahydrofuran (20 mL) dropwise at 0 °C. After addition, the reaction mixture was stirred for 2 hours at 0 °C. The mixture was quenched with water (9 mL) and aqueous 1 N sodium hydroxide (3.3 mL), and filtered. The filtrate was concentrated in vacuum to afford the title compound (7 g, yield: 80.45%) as an oil.
Example 212D
4-hydroxy-3,3-dimethylbutan-2-one
To a solution of Example 212C (4 g, 0.025 mol) in dichloromethane (20 mL) was added silica (12 g) and oxalic acid (10%, 7 mL). After the addition, the mixture was stirred for 12 hours at room temperature, and filtered. The filtrate was concentrated in vacuo to afford the title compound (0.6 g, yield: 82.6%) as a liquid.
Example 212E
3,3-dimethyl-2H-pyran-4(3H)-one
To a solution of triethyl orthoformate (1.53 g, 0.33 mol) in dichloromethane (20 mL) was added SnCl4 (2.69 g, 10.33 mmol) dropwise at -40 °C, followed by the addition of a solution of Example 212D (0.6 g, 5.16 mmol) in dichloromethane (5 mL). After the addition, the mixture was stirred for 2 hours at about -20 °C to about 0 °C. The mixture was washed with aqueous NaHC(¾ (50 mL), extracted with dichloromethane (3 x 15 mL), dried over (Na2S04), filtered, and concentrated in vacuo to afford the title compound (0.45 g, yield: 69.2%) as a liquid.
Example 212F
3,3-dimethyldihydro-2H-pyran-4(3H)-one
A mixture of Example 212E (0.45 g, 3.57 mmol) and Pd/C (100 mg) in ethyl acetate (30 mL) was hydrogenated under 15 psi of ¾ for 2.5 hours at room temperature, and filtered. The filtrate was concentrated in vacuum to afford the title compound (0.4 g, yield: 80%) as a liquid.
Example 212G
[(2R,3aR,6aR)-2-{[(4S)-3,3-dimethyltetrahydro-2H-pyran-4- yl]amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone
To a mixture of Example 79N (0.22 g, 0.56 mmol) in dichloroethane (10 mL) was added Ν,Ν-diisopropylethylamine (0.9g 0.7mmol), Example 212F (0.1 lg 0.85 mmol) and Ti(OiPr)4 (0.5 mL). The mixture was stirred at room temperature for 12 hours, followed by the addition of NaBH4 (0.107g 2.82 mmol). The reaction mixture was stirred at room temperature for another 12 hours, followed by the addition of saturated aqueous NaHC(¾, filtered, and partitioned. The aqueous layer was extracted with CH2CI2. The combined organic layers were washed with brine, dried (Na2S04), and concentrated. The residue was purified by HPLC and SFC (Instrument: Berger MultiGram™ SFC, Mettler Toledo Co, Ltd; Column: Chiralcel OJ 250 x 30 mm ID, 5 μιη; Mobile phase: A: Supercritical CO2, B: isopropanol (0.05% diethylamine as modifier), A:B =70:30 at 60 mL/min;
Column Temp: 38 °C; Nozzle Pressure: lOOBar; Nozzle Temp: 60 °C; Evaporator Temp: 20 °C Trimmer Temp: 25 °C; Flow rate: 60 mL/min; Wavelength: 220 nm.) to provide title compound (peak 1, retention time 5.85 minute, 10 mg), as well as Example 21 1
(peak 2, retention time 7.18 minute, 10 mg). 'H NMR (400 MHZ, CD3OD) δ 8.99 (s, 1H), 8.51 (s, 1H), 5.00 (m, 2H), 4.00 (m, 4H), 3.50 (m, 3H), 3.25 (m, 3H), 2.75 (m, 1H), 2.0 (m, 8H), 1.60 (m, 1H), 1.42 (m, 1H), 1.09 (m, 6H); MS (ESI) m/z 466 (M+H)+.
Figure imgf000264_0001
Example 213
[(2R,3aR,6aR)-2-(6,7-dihydropyrano[4,3-b]pyrrol- l(4H)-yl)hexahydropentalen-3a(lH)- yl][3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)-yl]methanone The title compound was obtained as a byproduct from Example 149C. Ή NMR (400 MHz, CD3OD) δ 8.66 (s, 1 H), 8.01 (s, 1 H), 6.56 (s, 1H), 5.75 (s, 1H), 4.88-4.4.93 (m, 2 H), 4.48-4.54 (m, 3H), 3.88-4.01 (m, 4H), 3.52-3.56 (m, 1H), 3.05-3.1 1 (m, 2H), 2.51- 2.64 (m, 3H), 1.82-2.09 (m, 7H), 1.76- 1.79 (m, 2H); MS (ESI) m/z 460 (M+H)+.
Figure imgf000265_0001
Example 214
[(2R,3aR,6aR)-2-[(4S)-oxepan-4-ylamino]hexahydropentalen-3a(lH)-yl][3- (triiluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone
Example 214A
l,6-dioxaspiro[2.5]octane
To the solution of MesOI (12.1 g, 55 mmol) in 200 mL of THF was added KOtBu (6.17 g, 55mmol) at 0 °C over 1 hour, followed by the addition of dihydro-2H-pyran- 4(3H)-one (5.0 g, 50 mmol), and stirred at 0 °C for 5 hours. The mixture was treated with ice water and extracted with ethyl acetate (100 mLx3). The combined organic layerw were washed with water (20 mL), dried over with Na2S04, filtered, and concentrated to a brown oil (3.5 g).
Example 214B
4-(aminomethyl)tetrahydro-2H-pyran-4-ol
To the solution of Example 214A (3.5 g, 30.7mmol) in 40 mL of MeOH was added NH3.H2O (20 mL) at 0 °C over lhour. The mixture was stirred at room temperature overnight. After the reaction was complete, the mixture was treated with ice water and extracted with ethyl acetate (100 mLx3). The combined organic layers were washed with water (20 mL), dried over with Na2S04, filtered, and concentrated to brown oil (1.0 g).
Example 214C
oxepan-4-one To the solution of Example 214B (l .Og, 30.7mmol) in 10 mL of acetic acid (3 mL) at 0□ was added dropwise NaN02 (4.2 g, 61.4 mmol) in water (2 ml) at -10 °C for 30 minutes . After the reaction was complete, the mixture was treated with ice water and extracted with ethyl acetate (20 mLx3). The combined organic layers were washed with water (20 mL), dried over with Na2S04, filtered, and concentrated to afford a yellow oil (400 mg).
Example 214D
[(2R,3aR,6aR)-2-[(4S)-oxepan-4-ylamino]hexahydropentalen-3a(lH)-yl][3- (trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone To a solution of Example 79N (0.22 g, 0.56 mmol) in dichloroethane (10 mL) was added diisopropylethylamine (0.9 g, 0.7 mmol), Example 214C (0.4 g, 3.5 mmol), and Ti(iPrO)4 (0.5 mL). The mixture was stirred at room temperature for 12 hours, followed by the addition of NaBH4 (0.107 g, 2.82 mmol). After stirring at room temperature for another 12 hours, saturated NaHC(¾ solution was added. The mixture was filtered and partitioned. The aqueous layer was extracted with CH2CI2, The combined organic layers were washed with brine, dried (Na2S04), filtered, and concentrated. The residue was purified by HPLC to provide the title compound (30 mg). Ή NMR (400 MHz, CDC13) δ 8.73 (s, 1H), 8.45 (s, 1H), 4.80-4.90(m, 2H), 3.73-4.15 (m, 3H), 3.52(m, 1H),3.1 1-3.32 (m, 3H), 2.51(m, 1H), 1.88-2.14 (m, 7H), 1.80-1.85 (m, 4H), 1.50-1.75 (m, 10H), 1.35- 1.46 (m, 1H); MS (ESI) m/z 450 (M+H)+.
Figure imgf000266_0001
Example 215
[(2R,3aR,6aR)-2-[(8R)-5-oxaspiro[2.5]oct-8-ylamino]hexahydropentalen-3a(lH)-yl][3- (trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone
Example 215 A
4,4-Dimethoxy-dihydro-pyran-3-one
To a solution of 183A (8.1 g, 50 mmol) in dichloromethane (200 mL) was added Dess-martin (42.8 g, 100 mmol) in small portions. The mixture was stirred at room temperature overnight. A saturated NaHC03 (50 mL) was added to quench the reaction and stirred for 0.5 hour. After filtration, the filtrate was extracted with dichloromethane (60 mL). The combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo to provide the title compound (6 g), which was used directly into next step without further purification.
Example 215B
4,4-Dimethoxy-3-methylene-tetrahydro
To a solution of ΡΡ1¾ΜεΒΓ (3.75 g, 10.5 mmol) in THF (60 mL) was added dropwise n-BuLi (4 mL, 10.5 mmol) at 0 °C. After the addition, the mixture was stirred for 0.5 hour at that temperature, followed by the addition of Example 215A (1.12 g, 7 mmol) in THF (30 mL). The reaction mixture was stirred at room temperature overnight, and quenched with a saturated NH4C1 solution (50 mL). The aqeous layer was extracted with EtOAc (200 mL). The combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by column chromatography to provide the title compound (750 mg, 80 %) as a yellow oil.
Example 215C
8,8 -Dimethoxy- 5 -oxa- spiro [2.5 ] o ctane
Mel2 (2 mL, 40 mmol) was added to a stirred solution of ZnEt2 (20 mL, 20 mmol) in dichloromethane (150 mL) at -78 °C under N2. The mixture was allowed to warm to 0 °C and stirred for 1 hour. A solution of Example 215B (1.58 g, 10 mmol) in
dichloromethane (50 mL) was added, the resulting suspension was stirred at room temperature for 5 hours. Na2EDTA (100 mL) solution and NaHC03 (100 mL) solution were added to quench the reaction. The mixture was filtered, and the filtrate was extracted with EtOAc (200 mL). The combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by preparative.TLC with 5 % ethyl acetate in hexanes to provide the title compound (200 mg, 12 %) as a yellow oil.
Example 215D
5-Oxa-spiro[2.5]octan-8-one
A mixture of Example 215C (l g, 6 mmol) and TFA (3 mL) in dichloromethane (200 mL) was stirred at room temperature overnight, and concentrated in vacuo. The residue was purified by preparative TLC with 10 % ethyl acetate in hexanes to provide the title compound (60 mg, 8 %) as a colorless oil.
Example 215E [(2R,3aR,6aR)-2-[(8R)-5-oxaspiro[2.5]oct-8-ylamino]hexahydropentalen-3a(lH)-yl][3- (trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone The title compound was prepared according to the procedure described in Example 218C (please check), and purified by SFC separation (Column: IC 250x4.6mm I.D., 5um; Mobile phase: methanol (0.05% diethylamine) in CO2 from 5 % to 40 %, Flow rate: 2.35mL/min, Wavelength: 205 nm) to provide the title compound (retention time 8.365 minute, 4.85 mg) and Example 216 (retention time 8.074 minute, 4.83 mg). Ή NMR (400 MHz, CD3OD) δ 8.840 (s, 1 H), 8.271 (s, 1 H), 4.909-4.967 (m, 2 H), 3.800- 4.012 (m, 6 H), 2.545-3.529 (m, 6 H), 1.359-2.229 (m, 12 H), 0.629-0.756 (m, 4 H); MS (ESI) m/z 464 (M+H)+.
Figure imgf000268_0001
Example 216
[(2R,3aR,6aR)-2-[(8S)-5-oxaspiro[2.5]oct-8-ylamino]hexahydropentalen-3a(lH)-yl][3- (trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone The title compound (retention time 8.074 minute) was obtained from the SFC purification of Example 215E. H NMR (400 MHz, CD3OD) δ 9.021 (d, 1 H), 8.578 (d, 1 H), 4.965-5.01 1 (m, 2 H), 3.866-4.016 (m, 6 H), 2.615-3.538 (m, 6 H), 1.393-2.306 (m, 12 H), 0.602-0.905 (m, 4 H); MS (ESI) m/z 464 (M+H)+.
Figure imgf000268_0002
Example 217
[(2R,3aR,6aR)-2- {[(3R,4S)-3-(methoxymethyl)tetrahydro-2H-pyran-4 yl]amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- naphthyridin-6(5H)-yl]methanone
Example 217A
7-(methoxymethyl)-3,3-dimethyl-l,5,9-trioxaspiro[5.5]undecane To a suspension of Example 204C (1.7 g) and NaH (0.468 g) in tetrahydrofuran (20 mL) was added iodomethane (1.33 g) at 0 °C. The mixture was stirred at room temperature overnight, quenched with water, and extracted with ethyl acetate (20 mL). The extracts were washed with brine, water, dried over MgS04, filtered, and concentrated in vacuo. The residue was purified by column chromatography (hexane:ethyl acetate = 10 : 1) to provide the title compound (0.83 g).
Example 217B
3-(methoxymethyl)dihydro-2H-pyran-4(3H)-one A mixture of Example 217A (480 mg, 2.1 mmol), p-toluenesulfonic acid (200 mg) in CH2CI2 (50 ml) was stirred at room temperature for 3 hours. The mixture was concentrated in vacuo. The residue was used in the next step without purification.
Example 217C
[(2R,3aR,6aR)-2-{[3-(methoxymethyl)tetrahydro-2H-pyran-4- yl]amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone
To a solution of Example 79N (444 mg, 1.1 mmol), isopropanol (0.2 mL) and BU3N (0.6 mL) in isopropyl acetate (3 mL) was added NaBH(OAc)3 (0.51 g, 2.4 mmol) at 0 °C. After 1 hour, Example 217B (318 mg, 2.1 mmol) was added at 0 °C and stirred for 6 hours. The mixture was washed with aqueous NaHC03 (20 mL) and the aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic layer was dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC to provide the title compound as a mixture of diasteromers.
Example 217D
[(2R,3aR,6aR)-2- {[(3R,4S)-3-(methoxymethyl)tetrahydro-2H-pyran-4- yl]amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone
Example 217C was purified using chiral SFC with a preparative ChiralCel AD column (250mm*30mm, ID 5 μιη) eluting with mobile phase: A, Supercritical CO2; B, ethanol (0.05% diethylamine), A:B= 80:20 with a flow rate of 60 mL/min to yield the title compound (Peak 1, retention time 6.41 minute, 6.79 mg), as well as Example 218 (peak 2, retention time 6.83 minute, 16.67 mg). Ή NMR (400 MHz, CDCI3) δ ppm 1.24 - 1.49 (m, 2H), 1.58 - 1.67 (m, 2H), 1.68 - 1.85 (m, 6H), 1.88 - 2.08 (m, 2H), 2.08 - 2.32 (m, 2H), 3.08 - 3.18 (m, 3H), 3.28 - 3.62 (m, 8H), 3.62 - 3.75 (m, 3H), 3.52 - 4.05 (m, 4H), 4.65 - 4.89 (m, 2H), 7.695 (s, 1H), 8.692 (s, 1H); MS (ESI) m/z 482 (M+H)+.
Figure imgf000270_0001
Example 218
[(2R,3aR,6aR)-2-{[(3R,4R)-3-(methoxymethyl)tetrahydro-2H-pyran-4- yl]amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(triiluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone
The title compound (peak 2, retention time 6.83 minute) was obtained from the SFC purification of Example 217C. Ή NMR (400 MHz, CDC13) δ ppm 1.24 - 1.49 (m, 2 H), 1.55 - 2.09 (m, 10 H), 2.08 - 2.32 (m, 2 H), 3.08 - 3.29 (m, 4 H), 3.31 - 3.49 (m, 4 H), 3.52 - 3.61 (m, 2 H), 3.62 - 3.68 (m, 1 H), 3.72 - 4.05 (m, 4 H), 4.72 - 4.93 (m, 2 H), 7.698 (s, 1 H), 8.687 (s, 1 H); MS (ESI) m/z 482(M+H)+.
Figure imgf000270_0002
Example 219
(3-chloro-7,8-dihydro-l,6-naphthyridin-6(5H)-yl)[(2R,3aR,6aR)-2-{[(3R,4S)-3- methyltetrahydro-2H-pyran-4-yl] amino }hexahydropentalen-3 a( 1 H)-yl]methanone
Example 219A
(Z)-N-(3-(dimethylamino)-2-(Chloro)allylidene)-N-methylmethanaminium Reagent A: POCI3 (48 mL) was added to Ν,Ν-dimethyl formamide (1 14 mL) at 4 °C over 1 hour and the reaction mixture was allowed to warm to room temperature. Chloro acetic acid (25 g, 265 mmol) was added dropwise over 6 minutes, and the reaction mixture was aged at 50 to 60 °C for 4 hours and then allowed to warm to room temperature. The reaction mixture was charged to a 250 mL addition funnel. HPF6 (43 mL) was added to water (312 mL) with cooling at 4 °C. Sodium hydroxide solution (5 N, 130 mL) was added slowly keeping the internal temperature below 15 °C. The solution was then cooled to 0 °C. To the solution was added reagent A and sodium hydroxide solution (5N) concurrently at a rate such that the internal temperature remained below 5 °C and the pH maintained at about 3.05 to about 3.6. The resulting yellow slurry was then stirred for 60 minutes at 0 °C. The solids was filtered and the slurry was washed with ice-cold water (200 mL) then dried with a stream of N2 under vacuum to provide the title compound (20 g) as a yellow solid, which was used in the next step without purification.
Example 219B
3-Chloro-7,8-dihydro-5H-[l,6]naphthyridine-6-carboxylic acid tert-butyl ester To a solution of tert-butyl 4-oxopiperidine- l-carboxylate (13 g, 0.065 mol) in tetrahydrofuran (200 mL) was added lithium hexamethyldisilylamide (68 mL, 1 N, 0.068 mol) dropwise at - 12 °C under N2. After the addition, the mixture was stirred for 1.5 hours at room temperature. The reaction mixture was added dropwise to a suspension of Example 219A (20 g, 0.065 mol) in tetrahydrofuran (100 mL) over 1 hour at -24 °C. After the addition, the mixture was stirred for 2 hours at -20 °C. Acetic acid (5.6 mL) was added to the reaction mixture and the temperature was gradually allowed to warm to room temperature. NH4OAc (13.86 g) was added to the reaction mixture and the mixture was refluxed for 2 hours. The cooled mixture was washed with water (200 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by column chromatography (S1O2, petroleum ether/ethyl acetate: 10/3) to provide the title compound (7.6 g, 43%) as light yellow solid.
Example 219C
3-Chloro-5,6,7,8-tetrahydro-[l,6]naphthyridine Hydrochloride salt To a solution of Example 219B (7.6 g, 0.028 mmol) in dichloromethane (20 mL) was added HC1 in dioxane (4 N, 150 mL) dropwise at room temperature. After the addition, the mixture was stirred for 2 hours at room temperature. TLC (petroleum ether: ethyl acetate = 5: 1) indicated that the reaction was complete. The mixture was filtered and the solid was dried in vacuum to provide the hydrochloride salt of the title compound (4.5 g, 79%).
Example 219D (3-Chloro-7,8-dihydro-5H-[l,6]naphthyridin-6-yl)-[2-(2,5-dimethyl-pyrrol-l-yl)- hexahydro-pentalen-3a-yl]-methanone
To a solution of 79L (247 mg, 1 mmol) in dichloromethane (50 mL) was added hydroxybenzotriazole (204 mg, 1 mmol), l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (287 mg, 1.5 mmol), Example 219C (204 mg, 1 mmol) and triethylamine (303 mg, 3 mmol). The mixture was stirred at room temperature for 16 hours, suspended in water and extracted with dichloromethane (3 x 300 mL). The combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated to afford the title compound (800 mg), which was used in the next step without purification.
Example 219E
(2-Amino-hexahydro-pentalen-3a-yl)-(3-chloro-7,8-dihydro-5H-[l,6]naphthyridin-6-yl)- methanone
To a solution of Example 219D (800 mg, 2 mmol) in MeOH (30 mL) was added hydroxylamine hydrochloride (828 mg, 12 mmol), 50% hydroxylamine hydrate (2 mL) and ¾0 (8 mL). The mixture was refluxed for 13 hours. After cooling to room temperature the pH of the reaction mixture was adjusted to about 1 Imixture by treating with NaOH (10 N). The mixture was extracted with dichloromethane (3 x 300 mL). The combined organic layers were washed with brine, dried over MgS04, filtered, and concentrated to afford the title compound (500 mg), which was used in the next step without purification.
Example 219F
(3-chloro-7,8-dihydro-l,6-naphthyridin-6(5H)-yl)[(2R,3aR,6aR)-2-{[(3R,4S)-3- methyltetrahydro-2H-pyran-4-yl] amino }hexahydropentalen-3 a( 1 H)-yl]methanone The title compound was prepared according Example 141B, substituting Example
219E for Example 79N, and purified by chiral SFC (Column: Chiralpak AD-H IC 250 4.6 mm ID, 5 μιη; Mobile phase: A: Supercritical CO2, B: ethanol (0.05% diethylamine as modifier), A:B =95:5 to 60:40 at 2.35 mL/min; Wavelength: 220 nm) to provide the title compound (peak 1, retention time 8.88 minute), as well as Exmaple 220 (peak 2, retention time 9.33 minute), Example 221 (peak 3, retention time 9.68 minute), and
Example 222 (peak 4, retention time 10.56 minute). Ή NMR (400 MHz, CDC13) δ 8.399 (s, 1 H), 7.438 (s, 1 H), 4.652-4.721 (m, 2 H), 3.788-4.236 (m, 5 H), 3.382-3.648 (m, 3 H), 2.979-3.035 (m, 3 H), 1.825-2.287 (m, 7 H), 1.305-1.489 (m, 7 H), 0.845-0.942 (m, 3 H); MS (ESI) m/z 418 (M+H)+.
Figure imgf000273_0001
Example 220
(3-chloro-7,8-dihydro-l,6-naphthyridin-6(5H)-yl)[(2R,3aR,6aR)-2-{[(3S,4S)-3- methyltetrahydro-2H-pyran-4-yl] amino } hexahydropentalen-3 a( 1 H)-yl]methanone The title compound (peak 2, retention time 9.33 minute) was obtained from the chiral SFC purification of Example 219F. Ή NMR (400 MHz, CDC13) δ 8.388 (d, 1 H), 7.450 (d, 1 H), 4.652-4.758 (m, 2 H), 3.521-3.918 (m, 5 H), 3.356-3.474 (m, 3 H), 2.903- 3.022 (m, 3 H), 1.538-2.297 (m, 13 H), 1.256-1.429 (m, 2 H), 0.965-1.158 (m, 3 H); MS (ESI) m/z 418 (M+H)+.
Figure imgf000273_0002
Example 221
(3-chloro-7,8-dihydro-l,6-naphthyridin-6(5H)-yl)[(2R,3aR,6aR)-2-{[(3S,4R)-3- methyltetrahydro-2H-pyran-4-yl] amino }hexahydropentalen-3 a( 1 H)-yl]methanone
The title compound (peak 3, retention time 9.68 minute) was obtained from the chiral SFC purification of Example 219F. Ή NMR (400 MHz, CDCI3) δ 8.386 (d, 1 H), 7.451 (d, 1 H), 4.652-4.710 (m, 2 H), 3.640-3.931 (m, 4 H), 3.319-3.535 (m, 6 H), 2.886- 3.037 (m, 3 H), 1.538-2.162 (m, 14 H), 1.286-1.459 (m, 2 H), 0.965-1.168 (m, 3 H); MS (ESI) m/z 418 (M+H)+.
Figure imgf000273_0003
Example 222 (3-chloro-7,8-dihydro-l,6-naphthyridin-6(5H)-yl)[(2R,3aR,6aR)-2- {[(3R,4R)-3- methyltetrahydro-2H-pyran-4-yl] amino }hexahydropentalen-3 a( 1 H)-yl]methanone The title compound (peak 4, retention time 10.56 minute) was obtained from the chiral SFC purification of Example 219F. Ή NMR (400 MHz, CDC13) δ 8.403 (s, 1 H), 7.454 (s, 1 H), 4.705-4.712 (m, 2 H), 3.760-4.235 (m, 5 H), 3.342-3.589 (m, 3 H), 2.883- 3.024 (m, 3 H), 1.660-2.135 (m, 6 H), 1.322-1.461 (m, 7 H), 0.765-0.835 (m, 3 H); MS (ESI) m/z 418 (M+H)+.
Figure imgf000274_0001
Example 223
l,5-anhydro-3-({(2R,3aR,6aR)-3a-[(3-chloro-7,8-dihydro-l,6-naphthyridin-6(5H)- yl)carbonyl]octahydropentalen-2-yl}amino)-2,3-dideoxy-4-0-methyl-D-erythro-pentitol
The title compound was prepared according to Example 14 IB, substituting Example 219E for Example 79N, and Example 79R for Example 141 A, and purified by chiral SFC (Column: Chiralpak AD-H IC 250 x 4.6 mm ID, 5 μπι; Mobile phase: A: Supercritical CO2, B: methanol (0.05% diethylamine as modifier), A:B =95:5 to 60:40 at 2.35 mL/min; Wavelength: 220 nm) to provide the title compound (peak 2, retention time 9.42 min). Ή NMR (400 MHz, CDC13) δ 8.320 (d, 1 H), 7.383 (d, 1 H), 4.602-4.686 (m, 2 H), 3.814-4.163 (m, 4 H), 3.211-3.448 (m, 6 H), 2.929-3.035 (m, 3 H), 1.662-2.054 (m, 1 1 H), 1.206-1.289 (m, 4 H), MS (ESI) m/z 434 (M+H)+.
Figure imgf000274_0002
Example 224
[3-(difluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl][(2R,3aR,6aR)-2-{[(3R,4S)- 3 -methyltetrahydro-2H-pyran-4-yl]amino } hexahydropentalen-3 a( 1 H)-yl]methanone
Example 224A
(Z)-N-(3-(dimethylamino)-2-(bromo)allylidene)-N-methylmethanaminium POCI3 (48.7 g, 0.32 mol) was added dropwise to N,N-dimethyl formamide (67 mL) at 0°C. The mixture was gradually warmed to room temperature. Bromo acetic acid (20 g, 0.143 mol) was added to the reaction mixture and stirred for 4 hours at about 50-60 °C. After cooling to room temperature, the reaction mixture was added to a solution of HPF6 (13.9 g, 0.095 mol) in water (184 mL). The pH value was kept around 3.5 with addition of aqueous NaOH (10N) at 0 °C. After the addition, the mixture was stirred for 30 hours at 0 °C, The solid was collected by filtration and dried to afford the title compound (8 g, 15.3 %) as a white solid.
Example 224B
tert-butyl 3-bromo-7,8-dihydro- 1 ,6-naphthyridine-6(5H)-carboxylate
To a solution of 4-oxo-piperidine- 1 -carboxylic acid tert-butyl ester (4.3 g, 0.021 mol) in tetrahydrofuran (20 mL) was added lithium bistrimethylsilyl amide (22.6 mL, IN, 22.6 mmol) dropwise at - 12 °C under N2. After the addition, the mixture was stirred for 1.5 hours at room temperature. The reaction mixture was added to a suspension of Example 224A (8 g, 0.022 mol) in tetrahydrofuran (25 mL) dropwise at -24 °C. After the addition, the mixture was stirred for 2 hours at -20 °C. Acetic acid (2.2 mL) was added to the reaction mixture and the mixture was gradually warmed to room temperature.
NH4OAC (4.75 g, 0.061 mol) was added to the reaction mixture and the mixture was refluxed for 2 hours. The reaction mixture was cooled to room temperature, washed with water (150 mL), and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over Na2S04, filtered, and concentrated in vacuum. The residue was purified by chromatography on silica (dichloromethane/MeOH: 50 /l) to afford the title compound (2.9 g, 46.9 %) as a light yellow oil.
Example 224C
tert-butyl 3-cyano-7,8-dihydro- 1 ,6-naphthyridine-6(5H)-carboxylate
To a mixture of Example 224B (2.17 g, 6.95 mmol), dimethylacetamide (13 mL) under N2 was added Pd/C (148 mg, 0.14 mmol), 1 , 1 '-bis(diphenylphosphino)ferrocene (152 mg, 0.28 mmol) and ZnCN2 (0.48 g, 4.18 mmol). The slurry was sprayed with subsurface N2 for 10 minutes and ZnCN2 was added (133 mg, 0.71 mmol). Slurry was sprayed with subsurface N2 for another 10 minutes, then the mixture was heated under N2 at 1 10-120 °C overnight. The reaction mixture was cooled to room temperature and diluted with tetrahydrofuran (15 mL), and the resulting slurry was filtered. The filtrate was washed with water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over Na2S04, filtered, and concentrated in vacuum. The residue was purified by chromatography on silica (dichloromethane/MeOH: 50 /l) to afford the title compound (0.7 g, 39 %) as a light yellow solid.
Example 224D
tert-butyl 3-formyl-7,8-dihydro- 1 ,6-naphthyridine-6(5H)-carboxylate
To a solution of Example 224C (0.14 g, 0.447 mmol) in tetrahydrofuran (10 mL) was added DIBAL-H (1.34 ml, 1.34 mmol) at -50 °C. After the addition, the mixture was stirred for 2 hours at about -50 to about 0 °C. TLC (petroleum ethenethyl acetate = 4: 1) indicated that the reaction was completed. The mixture was quenched with water (0.2 mL) and IN NaOH (0.3 mL), and filtered. The filtrate was concentrated in vacuo and the residue was purified by preparative- TLC (petroleum ether/ethyl acetate: 4/1) to afford the title compound (30 mg, 21.2 %) as a white solid.
Example 224E
tert-butyl 3-(difluoromethyl)-7,8-dihydro- 1 ,6-naphthyridine-6(5H)-carboxylate To a solution of Example 224D (0.3 g, 1.14 mmol) in dichloromethane (5 mL) was added diethylaminosulfur trifluoride (1 mL) dropwise at 0 °C. After the addition, the mixture was stirred for 12 hours at room temperature, the mixture was poured into aqueous NaHC03 (5 mL), the aqueous layer was extracted with dichloromethane (3 x 50 mL). The organic layer was dried over Na2S04, concentrated in vacuum and the residue was purified by chromatography on silica (dichloromethane/MeOH: 50 /l) to give title compound (150 mg, 46.4 %) as an oil.
Example 224F
3-(difluoromethyl)-5,6,7,8-tetrahydro- l,6-naphthyridine To a solution of 224E (150 mg, 0.53 mmol) in dichloromethane (2 mL) was added HCl(g)/dioxane (5 mL, 2N) dropwise at room temperature. After the addition, the mixture was stirred for 4 hours at room temperature. TLC (Petroleum ethenethyl acetate = 10: 1) indicated that the reaction was completed. The mixture was concentrated in vacuum to afford the HC1 salt of the title compound (1 16 mg) as a light yellow solid which was used in the next step directly.
Example 224G
(3-(difluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl)((2R,3aR,6aR)-2-(2,5- dimethyl- 1 H-pyrrol- 1 -yl)octahydropentalen-3 a-yl)methanone A mixture of Example 224F, Example 79L (131.08 mg, 0.53 mmol), l-ethyl-3-(3- dimethylaminopropyl) carbodiimide (108.12 mg, 0.795 mmol), hydroxybenzotriazole (152 mg, 0.795 mmol), triethylamine (0.23 ml, 1.15 mmol) in dichloromethane (10 mL) was stirred for 12 hours at room temperature under N2. TLC (petroleum ethenethyl acetate = 1 : 1) indicated that the reaction was complete. The mixture was washed with water (50 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic layers were dried over Na2S04, filtered, and concentrated in vacuum. The residue was purified by chromatography on silica (petroleum ethenethyl acetate = 1 : 1) to afford the title compound (1 16 mg, 73.5%) as an oil.
Example 224H
((2R,3aR,6aR)-2-aminooctahydropentalen-3a-yl)(3-(difluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl)methanone
A mixture of Example 224G (1 16 mg, 0.389 mmol), NH4OH.HCl (161.2 mg, 2.336 mmol), NH2OH.H20 (266 mg, 2.608 mmol, 50%) in MeOH was refluxed for 12 hours under N2. TLC (petroleum ether: ethyl acetate = 1 : 1) indicated that the reaction was complete. The mixture was basified to pH around 1 land extracted with dichloromethane (3 x 15 mL). The combined organic layers were dried over Na2S04, filtered, and concentrated in vacuum to provide the title compound (130 mg) as a grey solid, which was used in the next step directly.
Example 2241
[3-(difluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl][(2R,3aR,6aR)-2-{[(3R,4S)- 3 -methyltetrahydro-2H-pyran-4-yl]amino } hexahydropentalen-3 a( 1 H)-yl]methanone To a solution of Example 224H (130.7 mg, 0.389 mmol) in dichloromethane (10 mL) was added NaBH(OAc)3 (329.8 mg, 1.56 mmol) and isopropanol (0.3 mL) at 0 °C. The mixture was stirred at 0 °C for 1 hour. Example 141A (88.8 mg, 0.778 mmol) was added to the resulting mixture and stirred for another 12 hours. LC-MS indicated that the reaction was complete, the mixture was washed with aqueous NaHC(¾ (20 mL), the aqueous layer was extracted with dichloromethane (3 x 30 mL). The combined organic layers were dried over Na2S04, filtered, and concentrated in vacuum. The residue was purified by preparative HPLC and SFC (Instrument: Berger MultiGram™ SFC, Mettler Toledo Co, Ltd; Column: Chiralcel AD 250 x 30 mm ID, 5 μιη; Mobile phase: A:
Supercritical CO2, B: isopropanol (0.05% diethylamine as modifier), A:B =70:30 at 60 mL/min; Column Temp: 38 °C; Nozzle Pressure: lOOBar; Nozzle Temp: 60 °C; Evaporator Temp: 20 °C Trimmer Temp: 25 °C; Flow rate: 60 mL/min; Wavelength: 220 nm) to provide the title compound (peak 1, retention time 5.49 minute, 4 mg) as a light yellow solid, as well as Example 225 (peak 2, retention time 6.10 minute), Example 226 (peak 3, retention time 7.75 minute), and Example 227 (peak 4, retention time 8.20 minute). Ή NMR (400 MHz, CD3OD) δ 8.541 (s, 1H), 7.879 (s, 1H), 6.882 (m, 1H), 4.85 (m, 2H), 4.55 (s, 1H), 3.95 (m, 3H), 3.80 (m, 1H), 3.65 (s, 1H), 3.49 (m, 4H), 2.50 (m, 1H), 2.22 (m, 1H), 1.70-2.10 (m, 8H), 1.51 (m, 2H), 1.40 (m, 2H), 0.9 (d, 3H); MS (ESI) m/z 434 (M+H)+.
Figure imgf000278_0001
Example 225
[3-(difluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)-yl][(2R,3aR,6aR)-2-{[(3S,4S)-3- methyltetrahydro-2H-pyran-4-yl] amino }hexahydropentalen-3 a( 1 H)-yl]methanone The title compound (peak 2, retention time 6.10 minute) was obtained from the SFC purification of Example 2241. Ή NMR (400 MHz, CD3OD) δ 8.540 (s, 1H), 7.90 (s, 1H), 6.883 (m, 1H), 4.85 (m, 2H), 3.95 (m, 3H), 3.60 (m, 1H), 3.40 (m, 5H), 3.10 (m, 2H), 2.82 (m, 1H), 2.25 (m, 1H), 1.68-2.10 (m, 7H), 1.55 (m, 4H), 1.35 (m, 1H), 0.91 (d, 3H); MS (ESI) m/z 434 (M+H)+.
Figure imgf000278_0002
Example 226
[3-(difiuoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl][(2R,3aR,6aR)-2- {[(3S,4R)- 3 -methyltetrahydro-2H-pyran-4-yl]amino } hexahydropentalen-3 a( 1 H)-yl]methanone The title compound (peak 3, retention time 7.75 minute) was obtained from the SFC purification of Example 2241.Ή NMR (400 MHz, CD3OD) δ 8.454 (s, 1H), 7.792 (s, 1H), 6.795 (m, 1H), 4.75 (m, 2H), 3.80 (m, 3H), 3.51 (m, 2H), 3.30 (m, 4H), 3.00 (m, 2H), 2.65 (m, 1H), 2.11 (m, 1H), 1.55-2.00 (m, 9H), 1.48 (m, 4H), 1.25 (m, 2H), 0.85 (d, 3H); MS (ESI) nVz 434 (M+H)+.
Figure imgf000279_0001
Example 227
[3-(difluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl][(2R,3aR,6aR)-2- {[(3R,4R)- 3 -methyltetrahydro-2H-pyran-4-yl]amino } hexahy dropentalen-3 a( 1 H)-yl]methanone The title compound (peak 4, retention time 8.20 minute) was obtained from the SFC purification of Example 2241. Ή NMR (400 MHz, CD3OD) δ 8.552 (s, 1H), 7.891 (s, 1H), 6.891 (m, 1H), 4.78 (m, 2H), 3.95 (m, 3H), 3.70 (m, 2H), 3.55 (m, 2H), 3.35 (m, 1H), 3.08 (m, 2H), 2.90 (m, 1H), 1.60-2.10 (m, 9H),1.55 (m, 2H), 1.35 (m, 4H), 0.75 (d, 3H); MS (ESI) m/z 434 (M+H)+.
Figure imgf000279_0002
Example 228
(3-bromo-7,8-dihydro-l,6-naphthyridin-6(5H)-yl)[(2R,3aR,6aR)-2-{[(3S,4S)-3- methyltetrahydro-2H-pyran-4-yl] amino }hexahy dropentalen-3 a( 1 H)-yl]methanone
Example 228 A
3-Bromo-5,6,7,8-tetrahydro-[l,6]naphthyridine To a solution of Example 224B (0.5 g, 1.6 mmol) in MeOH (10 mL) was added HQ in MeOH (15 mL) dropwise at room temperature. After the addition, the reaction mixture was stirred for 2 hours at room temperature. TLC (petroleum ether: ethyl acetate = 5: 1) indicated that the reaction was complete. The mixture was filtered; the solid was dried in vacuum to afford the HC1 salt of the title compound (0.5 g, 100 %) as a solid.
Example 228B
(3-bromo-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl)((2R,3aR,6aR)-2-(2,5-dimethyl- 1H- pyrrol- 1 -yl)octahy dropentalen-3 a-yl)methanone To a solution of Example 79L (0.5 g, 2.02 mmol) in dichloromethane (5 mL) was added hydroxybenzotriazole (0.42 g, 3.09 mmol), l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.58 g, 3.04 mmol), Example 228A (0.5 g, 2.02 mmol) and triethylamine (0.6 g, 5.94 mmol), and the mixture was stirred at room temperature for 16 hours under nitrogen. The reaction mixture was suspended in water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo to afford the title compound (0.56 g, 63 %), which was used in the next step without purification.
Example 228 C
((2R,3aR,6aR)-2-aminooctahydropentalen-3a-yl)(3-bromo-7,8-dihydro- l,6-naphthyridin-
6(5H)-yl)methanone
To a solution of Example 228B (560 mg, 1.26 mmol) in MeOH (4 mL) was added hydroxylamine hydrochloride (560 mg, 8.0 mmol), 50% hydroxylamine hydrate (3 mL), and ¾0 (1 mL). The mixture was refluxed for 13 hours, cooled to room temperature, basified to pH 1 1 with NaOH (10 N), and extracted with dichloromethane (3 x 300 mL). The combined organic layers were washed with brine, dried over MgS04, filtered, and concentrated to provide the title compound (402 mg, 87 %), which was used for next step without purification.
Example 228D
(3-bromo-7,8-dihydro-l,6-naphthyridin-6(5H)-yl)[(2R,3aR,6aR)-2-{[(3S,4S)-3- methyltetrahydro-2H-pyran-4-yl] amino }hexahydropentalen-3 a( 1 H)-yl]methanone The title compound was prepared and purified according to Example 2241, substituting Example 228C for Example 224H to provide the title compound (retention time 10.164 minute), as well as Example 229 (retention time 10.517 minute). Ή NMR (400 MHz, CDC13) δ 8.425 (s, 1 H), 7.526 (s, 1 H), 4.584-4.677 (m, 2 H), 3.773-3.821 (m, 3 H), 3.229-3. 608 (m, 8 H), 2.671-2.932 (m, 3 H), 1.483-1.991 (m, 14 H); MS (ESI) m/z 464 (M+H)+.
Figure imgf000280_0001
Example 229 (3-bromo-7,8-dihydro-l,6-naphthyridin-6(5H)-yl)[(2R,3aR,6aR)-2-{[(3S,4R)-3- methyltetrahydro-2H-pyran-4-yl]amino}hexahydropentalen-3a(lH)-yl]methanoneO The title compound (retention time 10.517 minute) was obtained from the purification of Example 228D. Ή NMR (400 MHz, CDC13) δ 8.414 (s, 1 H), 7.525 (s, 1 H), 4.538-4.617 (m, 2 H), 3.563-4.963 (m, 5 H), 3.202-3.436 (m, 4 H), 2.893-2.929 (m, H), 2.156-2.258 (m, 2 H), 1.563-2.024 (m, 1 1 H); MS (ESI) m/z 464 (M+H)+.
Figure imgf000281_0001
Example 230
6- { [(2R,3aR,6aR)-2- { [(3 S,4R)-3-methyltetrahydro-2H-pyran-4- yl]amino}hexahydropentalen-3a(lH)-yl]carbonyl} -5,6,7,8-tetrahydro- 1 ,6-naphthyridine-
3-carbonitrile
To a diastereomeric mixture of Example 228 and Example 229 (prior to their separation by SFC) (450 mg, 0.97 mmol) in Ν,Ν-dimethyl formamide (5 mL) was added CuCN (0.25 g). The mixture was heated at reflux (190 °C) under nitrogen for 12 hours. After cooling to room termperature, the reaction mixture was treated with ethyl acetate. And the solid was filtered and the filtrate was washed with water, dried over Na2S04, filtered, and concentrated in vacuum. The residue was purified by HPLC to afford the mixture of diastereomers (30 mg). Further SFC purification (Column: Chiralpak AD-H IC 250 4.6 mm ID, 5 μιη; Mobile phase: A: Supercritical CO2, B: ethanol (0.05% diethylamine as modifier), A:B =65 to 35 at 55 mL/min; Wavelength: 220 nm) provided the title compound (peak 1, retention time 8.81 minute, 1.5 mg), Example 231 (peak 2, retention time 9.23 minute, 2.1 mg).. 'H NMR (400 MHz, CDC13) δ 8.699 (s, 1 H), 7.716 (s, 1 H), 4.750 (s, 2 H), 3.670-3.922 (m, 3 H), 3.300-3.661 (m, 5 H), 3.117-3.130 (d, 2 H), 2.743-2.767 (t, 3 H), 1.561-2.095 (m, 19 H); MS (ESI) m/z 409 (M+H)+.
Figure imgf000281_0002
Example 231 6-{[(2R,3aR,6aR)-2-{[(3S,4S)-3-methyltetrahydro-2H-pyran-4- yl]amino}hexahydropentalen-3a(lH)-yl]carbonyl}-5,6,7,8-tetrahydro-l,6-naphthyridine-
3-carbonitrile
The title compound (peak 2, retention time 9.23 minute) was obtained from the SFC purification of Example 230. Ή NMR (400 MHz, CDC13) δ 8.641 (s, 1 H), 7.670 (s, 1 H), 4.609-4.748 (m, 2 H), 3.768-4.163 (m, 9 H), 3.053 (s, 2 H), 2.404 (m, 1 H), 1.557- 2.145 (m, 14 H); MS (ESI) m/z 409 (M+H)+.
Figure imgf000282_0001
Example 232
l,5-anhydro-2,3-dideoxy-3-({(2R,3aR,6aR)-3a-[(3-fluoro-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl)carbonyl]octahydropentalen-2-yl}amino)-4-0-methyl-D-erythro-pentitol
Example 232 A
2-Chloro-5-fluoro-6-(4-methoxy-benzyloxy)-nicotinonitrile To a mixture of (4-methoxy-phenyl)-methanol (1. Og, 7.37mmol) in
tetrahydrofuran (5 mL) was added potassium tert-butoxide (0.91, 8.1 1 mmol) at 0 °C over 30 minutes. This reaction mixture was then added dropwise to 2,6-dichloro-5-fluoro- nicotinonitrile(1.4 g,7.37 mmol) in tetrahydrofuran(10 mL) at -78 °C over 10 minutes . The mixture was stirred at -78 °C for 30 minutes, allowed to warm to 0 °C for 3 hours. TLC showed that the reaction was completed. The combined organic layers were washed with brine, dried (Na2S04), filtered, and concentrated. The residue was purified by column chromatography in silica gel (petroleum ether: ethyl acetate = 10: 1) to provide the title compound (1.55g ,70%) as an off white solid.
Example 232B
5-Fluoro-6-(4-methoxy-benzyloxy)-2-vinyl-nicotinonitrile To a solution of Example 232A (1.0 g, 3.42 mmol) in tolune (25 mL) and
Pd(PPli3)4 (200 mg), was added dropwise tributyl-vinyl-stannane (2.4 g). The mixture was stirred at 125 °C for 24 hours. TLC showed that the reaction was completed. The combined organic layers were washed with brine, dried (Na2S04), filtered, and concentrated. The residue was purified by column chromatography in silica gel
(petroleum ether: ethyl acetate =10: 1) to give title compound (300 mg) as a white solid. Example 232C
3-Fluoro-6-(4-methoxy-benzyl)-2-(4-methoxy-benzyloxy)-7,8-dihydro-6H-
[ 1 ,6]naphthyridin-5 -one
To a solution of Example 232B (300 mg, 1.056 mmol) in MeOH (10 mL) was added 4-methoxy-benzylamine (3.60 g, 26.28 mmol) and ¾0(2 mL). The mixture was stirred at 100 °C for 24 hours. The TLC showed that the reaction was completed. The combined organic layers were washed with brine, dried (Na2S04), filtered, and concentrated. The residue was purified by column chromatography in silica gel
(petroleum ethenethyl acetae = 10:3) to provide the title compound (200 mg) as a white solid.
Example 232D
3-Fluoro-6-(4-methoxy-benzyl)-2-(4-methoxy-benzyloxy)-5,6,7,8-tetrahydro-
[ 1 ,6]naphthyridine
To a solution of Example 232C (200 mg, 0.474 mmol) in tetrahydrofuran (25 mL) was added lithium aluminum hydride (36 mg), and the reaction mixture was refluxed for 24 hours. The TLC showed that the reaction was completed. The reaction mixture was poured into ice water and extracted with ethyl acetate (20 mL). The combined organic layers were washed with brine, dried (Na2S04), filtered, and concentrated. The residue was purified by column chromatography in silica gel (petroleum ethenethyl acetate = 10:3) to afford the title compound (180 mg) as a white solid.
Example 232E
3-Fluoro-5,6,7,8-tetrahydro-[ 1 ,6]naphthyridin-2-ol To a solution of Example 232D (180 mg, 0.44 mmol) in MeOH (10 mL) was added Pd/C (0.1 g). The reaction was stirred at room temperature under ¾ of 40 psi overnight. TLC showed that the reaction was completed. The reaction mixture was filtered through celite pad and rinsed with MeOH. The filtrate was diluted with ethyl acetate. The organic layers were washed with brine, dried (Na2S04), filtered, and concentrated. The residue was purified by column chromatography in silica gel
(dichloromethane:MeOH=10: 1) to afford the title compound (60 mg) as a yellow oil.
Example 232F
2-Chloro-3-fluoro-5,6,7,8-tetrahydro-[l,6]naphthyridine A solution of Example 232E (0.5 g, 2.98 mmol) in POCI3 (10 mL) was stirred at 1 10 °C for 24 hours. The TLC showed that the reaction was completed. After removal of solvent, the reaction mixture was poured into icewater and extracted with ethyl acetate(20 mL). The combined organic layers were washed with washed with brine, dried (Na2S04), filtered, and concentrated in vacuo to afford the title compound (0.55 g) as a yellow oil which was used in the next step without further purification.
Example 232G
3-Fluoro-5,6,7,8-tetrahydro-[l,6]naphthyridine To a solution of Example 232F (0.55g, 2.97mmol) in MeOH (10 mL) was added Pd/C (0.1 g). The reaction mixture was stirred at room temperature under ¾ with 40 psi overnight. TLC showed that the reaction was completed. The reaction mixture was filtered through celite pad and rinsed with MeOH. The filtrate was diluted with ethyl acetate. The combined organic layers were washed with washed with brine, dried (Na2S04), filtered, and concentrated. The residue was purified by column
chromatography in silica gel (dichloromethane:MeOH=10: 1) to afford the title compound (400 mg) as a yellow oil.
Example 232H
((2R,3aR,6aR)-2-(2,5-dimethyl- lH-pyrrol- 1 -yl)octahydropentalen-3a-yl)(3-fluoro-7,8- dihydro- 1 ,6-naphthyridin-6(5H)-yl)methanone To a solution of Example 79L (0.49g ) in dichloromethane (30 mL) was added Example 232G (0.3 g), hydroxybenzotriazole (0.4 g), triethylamine (0.6 g), and 1 -ethyl- 3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.57 g). The resulting mixture was stirred at room temperature overnight. TLC showed that the reaction was completed. The reaction mixture was washed with washed with brine, dried (Na2S04), filtered, and concentrated.The residue was purified by column chromatography in silica gel
(dichloromethane:MeOH=10: 1) to afford the title compoundDO.4 gDas a yellow oil.
Example 2321
((2R,3aR,6aR)-2-aminooctahydropentalen-3a-yl)(3-fluoro-7,8-dihydro-l,6-naphthyridin-
6(5H)-yl)methanone
To a solution of Example 232H (0.4 g, 1.05 mmol) in MeOH (10 mL) was added NH2OH.H20 (0.4 mL), and NH2OH.HCI (0.5 g). The mixture was stirred at 1 10 °C for 3 hours. The TLC showed that the reaction was completed. The solvent was removed in vacuo and the mixture was basified to pH>l 1 by NaOH. The mixture was extracted with dichloromethane (3 x 50mL). The combined organic layers were washed with washed with brine, dried (Na2S04), filtered, and concentrated to afford the title compound (0.3 g) as yellow oil which was used in the next step without further purification.
Example 232J
l ,5-anhydro-2,3-dideoxy-3-({(2R,3aR,6aR)-3a-[(3-fluoro-7,8-dihydro- l ,6-naphthyridin- 6(5H)-yl)carbonyl]octahydropentalen-2-yl} amino)-4-0-methyl-D-erythro-pentitol
To a solution of Example 2321 (0.2 g, 0.66 mmol) and Example 79R (0.17g, 1.32 mmol) in dichloromethane (3 ml) was added CH3COOH (100 μΕ). The resulting mixture was stirred at room temperature overnight, followed by the addition of NaBH(OAc)3 (0.68 mmol). After stirring at room temperature overnight, the LC-MS showed that the reaction was completed. Saturated aqueous NaHC03 solution was added to the reaction mixture and diluted with dichloromethane. The organic layer was washed with brine, dried over MgS04, filtered, and concentrated in vacuo. The residue was diluted with CH3CN and extracted with heptane. The acetonitrile phase was concentrated to provide a mixture of two diastereoisomers, which was then further purified by chiral SFC using chiral SFC with a preparative ChiralCel AD 250 mm*30 mm, 5 μιη eluting with mobile phase: A, Supercritical CO2; B: isopropanol (0.05% diethylamine), A:B =80:20 at 70 ml=L/min to afford the title compound (peak 1 , retention time 6.30 minute, 5.22 mg) and Example 233 (peak 2, retention time 6.77 minute, 4.55 mg). Ή NMR (400 MHz, CDCI3) δ 1.20 -2.00(m, 12 H), 2.40 -2.50 (m, 1 H), 3.00 - 3.10 (m, 2 H), 3.30-3.45(m, 5 H), 3.50-3.60 (m, 3H), 3.70-3.80 (m, 2H), 3.95-4.15 (m, 2H), 4.15 - 4.25 (m, 2 H), 4.60-4.85 (m, 1 H), 7.10-7.20 (m, 1 H), 8.30 (s, 1 H); MS (ESI) m/z 418 (M+H)+.
Figure imgf000285_0001
Example 233
l ,5-anhydro-2,3-dideoxy-3-({(2R,3aR,6aR)-3a-[(3-fluoro-7,8-dihydro- l ,6-naphthyridin- 6(5H)-yl)carbonyl]octahydropentalen-2-yl} amino)-4-0-methyl-D-threo-pentitol The title compound (peak 2, retention time 6.77 minute) was obtained from the SFC purification of Example 232J. Ή NMR (400 MHz, CDCI3) δ ppm 0.80 -0.90(m, 1 H), 1.20 -1.40 (m, 3 H), 1.60 -2.30 (m, 9 H), 3.30-3.45 (m, 9H), 3.50-3.90 (m, 4H), 4.00 - 4.10 (d, 1 H), 4.15 - 4.25 (d, 1 H), 4.50-4.80 (m, 2 H), 7.15-7.25 (m, 1 H), 8.35 (s, 1 H); MS (ESI) m/z 418 (M+H)+. It is understood that the foregoing detailed description and accompanying examples are merely illustrative and are not to be taken as limitations upon the scope of the invention, which is defined solely by the appended claims and their equivalents. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including without limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations and/or methods of use of the invention, may be made without departing from the spirit and scope thereof.

Claims

CLAIMS:
1. A compound of formula (I)
Figure imgf000287_0001
(I)
or a pharmaceutically acceptable salt, solvate, or pro-drug thereof, wherein
X1 is CR1 or N;
X2 is CR2 or N;
X3 is CR3 or N; with the proviso that no more than one of X1, X2, and X3 is N;
R1, R2, and R3 are each independently hydrogen, -CN, halogen, alkyl, or haloalkyl;
G1 is - 4R5, formula (a), (b), or (c)
Figure imgf000287_0002
(a) (b) (c) .
R4 is hydrogen, C(2¾)3, alkyl, haloalkyl, or alkoxyalkyl;
R is
an heterocycle selected from the group consisting of a monocyclic heterocycle wherein one of the ring atoms is O, N, or NH and having zero or one double bond, optionally contains one or two additional heteroatoms selected from the group consisting of O, N, NH, and S, and optionally contains an C1-C4 alkylenyl bridge that links two non-adjacent carbon atoms within the ring; a bicyclic heterocycle, and a spiro heterocycle;
a phenyl,
a naphthyl,
a cycloalkyl,
an heteroaryl, or
an heterocyclealkyl; wherein each of the R5 phenyl, naphthyl, cycloalkyl, heteroaryl, heterocycle, and the heterocycle moiety of the heterocyclealkyl, is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 Ra;
with the proviso that when X1 is CR1, X2 is CR2, X3 is CR3, R1 and R3 are hydrogen, R2 is haloalkyl, R4 is alkyl, and R5 is a monocyclic heterocycle or a heterocyclealkyl, then the heterocycle moiety of R5 is substituted;
ring A1 is 2,3-dihydro-lH-isoindolyl, decahydroisoquinolinyl, piperidinyl, or pyrrolidinyl, each of which is optionally further substituted with 1 , 2, or 3 substituents independently selected from the group consisting of CN, alkyl, oxo, halogen, haloalkyl, OH, O(alkyl), and 0(haloalkyl); with the proviso that when ring A1 is piperidinyl, then G2 and the optional substituent of ring A1 do not reside on the same carbon atom;
G2 is G2a or -L'-G2b;
G2a is
a bicyclic aryl, a bicyclic cycloalkyl, a bicyclic heterocycle, a spiro heterocycle, or an heteroaryl, each of which is optionally substituted with 1, 2, 3, 4, or 5 Rb; or
a phenyl, a monocyclic cycloalkyl, or a monocyclic heterocycle, each of which is independently substituted with 1, 2, 3, 4, or 5 Rb;
G2b is aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycle, each of which is optionally substituted with 1, 2, 3, 4, or 5 Rb;
R6 is CN, OH, or halogen;
each R7 is an optional substituent on any substitutable carbon atom, and is independently alkyl, haloalkyl, halogen, oxo, or OH;
p is 0, 1, 2, or 3;
G3 is G3a or -L2-G3a;
L1 and L2 are independently O, N(Jk), or S; wherein Jk, at each occurrence, is independently hydrogen, alkyl, haloalkyl, C(0)Rk, S(0)2Rk, or C3-C4 cycloalkyl; wherein the C3-C4 cycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independenly selected from the group consisting of alkyl, halogen, haloalkyl, oxo, hydroxy, and alkoxy, Rk, at each occurrence, is independently alkyl or C3-C4 cycloalkyl; wherein the
C3-C4 cycloalkyl is optionally with 1, 2, 3, or 4 substituents independenly selected from the group consisting of alkyl, halogen, haloalkyl, oxo, hydroxy, and alkoxy;
G3a is aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycle, each of which is optionally substituted with 1, 2, 3, 4, or 5 Rc; 2
ring A is
a heterocycle or
a monocyclic heterocycle fused to a monocyclic heteroaryl, each ring A2 is optionally substituted with 1, 2, 3, 4, or 5 Rd; with the proviso that ring A2 is not 2,3-dihydro- lH-isoindolyl, decahydroisoquinolinyl, piperidinyl, or pyrrolidinyl;
Ra, R , Rc, and Ra are optional substituents on any substitutable atoms, and at each occurrence, are each independently alkyl, alkenyl, alkynyl, halogen, oxo, haloalkyl, CN, N02, -ORf, -OC(0)Rf, -OC(0)N(Rf)(Rs), -S(0)2Re, -S(0)2N(Rf)(Rs), -C(0)Rf, -C(0)ORf, -C(0)N(Rf)(Rg), -N(Rf)(Rg), -N(Rg)C(0)Rf, -N(Rg)S(0)2Re, -N(Rg)C(0)0(Rf),
-N(Rg)C(0)N(Rf)(Rg), Ga, -(CRxRy)qi-ORf, -(CRxRy)qi-OC(0)Rf,
-(CRxRy)qi-OC(0)N(Rf)(Rg), -(CRxRy)qi-S(0)2Re, -(CRxRy)qi-S(0)2N(Rf)(Rg),
-(CRxRy)qi -C(0)Rf, -(CRxRy)qi-C(0)ORf, -(CRxRy)qi -C(0)N(Rf)(Rg),
-(CRxRy)qi -N(Rf)(Rg), -(CRxRy)qi-N(Rg)C(0)Rf, -(CRxRy)qi-N(Rg)S(0)2Re,
-(CRxRy)qi-N(Rg)C(0)0(Re), -(CRxRy)qi-N(Rg)C(0)N(Rf)(Rg), -(CRxRy)qi-CN, and -(CRxRy)ql-Ga;
Re, at each occurrence, is independently alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, Gb, or -(C1-C6 alkylenyl)-Gb;
Rf, at each occurrence, is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, Gb, or -(C1-C6 alkylenyl)-Gb;
Rg, at each occurrence, is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, benzyl, or monocyclic cycloalkyl;
Ga and Gb, at each occurrence, are each independently aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycle, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, -CN, oxo, -ORh, -OC(0)Rh, -OC(0)N(Rh)2, -SCO^R1, -S(0)2N(Rh)2, -C(0)Rh, -C(0)ORh, -C(0)N(Rh)2, -N(Rh)2, -N(Rh)C(0)Rh, -N(Rh)S(0)2Ri,
-N(Rh)C(0)0(Rh), -N(Rh)C(0)N(Rh)2, -(CRxbRyb)q2-ORf, -(CRxbRyb)q2-OC(0)Rh, -(CRxbRyb)q2-OC(0)N(Rh)2, -(CR'V^ SCO^R1, -(CRxbRyb)q2-S(0)2N(Rh)2,
-(CRxbRyb)q2-C(0)Rh, -(CRxbRyb)q2-C(0)ORh, -(CRxbRyb)q2-C(0)N(Rh)2,
-(CRxbRyb)q2-N(Rh)2, -(CRxbRyb)q2-N(Rh)C(0)Rh, -(CRxbRyb)q2-N(Rh)S(0)2Ri,
-(CRxbRyb)q2-N(Rh)C(0)0(Rh), -(CRxbRyb)q2-N(Rh)C(0)N(Rh)2, and -(CRxbRyb)q2-CN;
Rx, Ry, Rxb, and Ryb, at each occurrence, are each independently hydrogen, alkyl, halogen, or haloalkyl; ql and q2, at each occurrence, are each independently 1, 2, 3, or 4;
Rh, at each occurrence, is independently hydrogen, alkyl, or haloalkyl; and
R1, at each occurrence, is independently alkyl or haloalkyl.
A compound of formula (I)
Figure imgf000290_0001
(I)
or a pharmaceutically acceptable salt, solvate, or pro-drug thereof, wherein
X1 is CR1 or N;
X2 is CR2 or N;
X3 is CR3 or N; with the proviso that no more than one of X1, X2, and X3 is N; R1, R2, and R3 are each independently hydrogen, halogen, alkyl, or haloalkyl; G1 is -NR4R5, formula (a), (b), or (c)
Figure imgf000290_0002
(a) (b) (c) .
R4 is hydrogen, alkyl, haloalkyl, or alkoxyalkyl;
R is
an heterocycle selected from the group consisting of a monocyclic heterocycle wherein one of the ring atoms is O, N, or NH and having zero or one double bond, optionally contains one or two additional heteroatoms selected from the group consisting of O, N, NH, and S; a bicyclic heterocycle, and a spiro heterocycle;
a phenyl,
a naphthyl,
a cycloalkyl,
an heteroaryl, or
an heterocyclealkyl; wherein each of the R5 phenyl, naphthyl, cycloalkyl, heteroaryl, heterocycle, and the heterocycle moiety of the heterocyclealkyl, is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 Ra;
with the proviso that when X1 is CR1, X2 is CR2, X3 is CR3, R1 and R3 are hydrogen, R2 is haloalkyl, R4 is alkyl, and R5 is a monocyclic heterocycle or a heterocyclealkyl, then the heterocycle moiety of R5 is substituted;
ring A1 is 2,3-dihydro-lH-isoindolyl, decahydroisoquinolinyl, piperidinyl, or pyrrolidinyl, each of which is optionally further substituted with 1 , 2, or 3 substituents independently selected from the group consisting of CN, alkyl, oxo, halogen, haloalkyl, OH, O(alkyl), and 0(haloalkyl); with the proviso that when ring A1 is piperidinyl, then G2 and the optional substituent of ring A1 do not reside on the same carbon atom;
G2 is G2a or -L'-G2b;
G2a is
a bicyclic aryl, a bicyclic cycloalkyl, a bicyclic heterocycle, a spiro heterocycle, or an heteroaryl, each of which is optionally substituted with 1, 2, 3, 4, or 5 Rb; or
a phenyl, a monocyclic cycloalkyl, or a monocyclic heterocycle, each of which is independently substituted with 1, 2, 3, 4, or 5 Rb;
G2b is aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycle, each of which is optionally substituted with 1, 2, 3, 4, or 5 Rb;
R6 is CN, OH, or halogen;
each R7 is an optional substituent on any substitutable carbon atom, and is independently alkyl, haloalkyl, halogen, oxo, or OH;
p is 0, 1, 2, or 3;
G3 is G3a or -L2-G3a;
L1 and L2 are independently O, N(Jk), or S; wherein Jk, at each occurrence, is independently hydrogen, alkyl, haloalkyl, C(0)Rk, S(0)2Rk, or C3-C4 cycloalkyl; wherein the C3-C4 cycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independenly selected from the group consisting of alkyl, halogen, haloalkyl, oxo, hydroxy, and alkoxy, Rk, at each occurrence, is independently alkyl or C3-C4 cycloalkyl; wherein the
C3-C4 cycloalkyl is optionally with 1, 2, 3, or 4 substituents independenly selected from the group consisting of alkyl, halogen, haloalkyl, oxo, hydroxy, and alkoxy;
G3a is aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycle, each of which is optionally substituted with 1, 2, 3, 4, or 5 Rc; 2
ring A is
a heterocycle or
a monocyclic heterocycle fused to a monocyclic heteroaryl, each ring A2 is optionally substituted with 1, 2, 3, 4, or 5 Rd; with the proviso that ring A2 is not 2,3-dihydro- lH-isoindolyl, decahydroisoquinolinyl, piperidinyl, or pyrrolidinyl;
Ra, R , Rc, and Ra are optional substituents on any substitutable atoms, and at each occurrence, are each independently alkyl, alkenyl, alkynyl, halogen, oxo, haloalkyl, CN, N02, -ORf, -OC(0)Rf, -OC(0)N(Rf)(Rs), -S(0)2Re, -S(0)2N(Rf)(Rs), -C(0)Rf, -C(0)ORf, -C(0)N(Rf)(Rg), -N(Rf)(Rg), -N(Rg)C(0)Rf, -N(Rg)S(0)2Re, -N(Rg)C(0)0(Rf),
-N(Rg)C(0)N(Rf)(Rg), Ga, -(CRxRy)qi-ORf, -(CRxRy)qi-OC(0)Rf,
-(CRxRy)qi-OC(0)N(Rf)(Rg), -(CRxRy)qi-S(0)2Re, -(CRxRy)qi-S(0)2N(Rf)(Rg),
-(CRxRy)qi -C(0)Rf, -(CRxRy)qi-C(0)ORf, -(CRxRy)qi -C(0)N(Rf)(Rg),
-(CRxRy)qi -N(Rf)(Rg), -(CRxRy)qi-N(Rg)C(0)Rf, -(CRxRy)qi-N(Rg)S(0)2Re,
-(CRxRy)qi-N(Rg)C(0)0(Re), -(CRxRy)qi-N(Rg)C(0)N(Rf)(Rg), -(CRxRy)qi-CN, and -(CRxRy)ql-Ga;
Re, at each occurrence, is independently alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, Gb, or -(C1-C6 alkylenyl)-Gb;
Rf, at each occurrence, is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, Gb, or -(C1-C6 alkylenyl)-Gb;
Rg, at each occurrence, is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, benzyl, or monocyclic cycloalkyl;
Ga and Gb, at each occurrence, are each independently aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycle, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, -CN, oxo, -ORh, -OC(0)Rh, -OC(0)N(Rh)2, -SCO^R1, -S(0)2N(Rh)2, -C(0)Rh, -C(0)ORh, -C(0)N(Rh)2, -N(Rh)2, -N(Rh)C(0)Rh, -N(Rh)S(0)2Ri,
-N(Rh)C(0)0(Rh), -N(Rh)C(0)N(Rh)2, -(CRxbRyb)q2-ORf, -(CRxbRyb)q2-OC(0)Rh, -(CRxbRyb)q2-OC(0)N(Rh)2, -(CR'V^ SCO^R1, -(CRxbRyb)q2-S(0)2N(Rh)2,
-(CRxbRyb)q2-C(0)Rh, -(CRxbRyb)q2-C(0)ORh, -(CRxbRyb)q2-C(0)N(Rh)2,
-(CRxbRyb)q2-N(Rh)2, -(CRxbRyb)q2-N(Rh)C(0)Rh, -(CRxbRyb)q2-N(Rh)S(0)2Ri,
-(CRxbRyb)q2-N(Rh)C(0)0(Rh), -(CRxbRyb)q2-N(Rh)C(0)N(Rh)2, and -(CRxbRyb)q2-CN;
Rx, Ry, Rxb, and Ryb, at each occurrence, are each independently hydrogen, alkyl, halogen, or haloalkyl; ql and q2, at each occurrence, are each independently 1 ,
2, 3, or 4;
Rh, at each occurrence, is independently hydrogen, alkyl, or haloalkyl; and
R1, at each occurrence, is independently alkyl or haloalkyl. 3. The compound of formula (I) according to claim 2 or a pharmaceutically
1 1 2 2 3 3 acceptable salt, solvate, or pro-drug thereof, wherein X is CR , X is CR , and X is CR .
4. The compound of formula (I) according to claim 2 or a pharmaceutically acceptable salt, solvate, or pro-drug thereof, wherein G1 is NR4R5.
5. The compound of formula (I) according to claim 2 or a pharmaceutically
1 1 2 2 3 3 acceptable salt, solvate, or pro-drug thereof, wherein X is CR , X is CR , X is CR , and G1 is NR4R5.
6. The compound of formula (I) according to claim 5 or a pharmaceutically acceptable salt, solvate, or pro-drug thereof, wherein R5 is an optionally substituted heterocycle or optionally substituted cycloalkyl.
7. The compound of formula (I) according to claim 6 or a pharmaceutically acceptable salt, solvate, or pro-drug thereof, wherein R5 is an optionally substituted monocyclic heterocycle wherein one of the ring atoms is O, N, or NH and having zero or one double bond, optionally contains one or two additional heteroatoms selected from the group consisting of O, N, NH, and S.
8. The compound of formula (I) according to claim 6 or a pharmaceutically acceptable salt, solvate, or pro-drug thereof, wherein R4 is hydrogen, and R5 is optionally substituted tetrahydropyranyl.
9. The compound of formula (I) according to claim 6 or a pharmaceutically acceptable salt, solvate, or pro-drug thereof, wherein R4 is methyl, and R5 is substituted tetrahydropyranyl.
10. The compound of formula (la) according to claim 2 or a pharmaceutically acceptable salt, solvate, or pro-drug thereof
Figure imgf000294_0001
(la)
wherein X1, X2, X3, A1, and G2 are as set forth in claim 2. 1 1. The compound of formula (la) according to claim 10 or a pharmaceutically
1 1 2 2 3 3 acceptable salt, solvate, or pro-drug thereof wherein X is CR , X is CR , and X is CR .
12. The compound of formula (la) according to claim 1 1 or a pharmaceutically acceptable salt, solvate, or pro-drug thereof wherein ring A1 is pyrrolidinyl or piperidinyl, each of which is optionally further substituted.
13. The compound of formula (la) according to claim 12 or a pharmaceutically acceptable salt, solvate, or pro-drug thereof wherein G2 is G2a or -L'-G2b, and L1 is O.
14. The compound of formula (la) according to claim 13 or a pharmaceutically acceptable salt, solvate, or pro-drug thereof wherein G2 is G2a.
15. The compound of formula (la) according to claim 1 1 or a pharmaceutically acceptable salt, solvate, or pro-drug thereof wherein ring A1 is piperidinyl which is optionally further substituted, G2 is G2a, and G2a is a substituted phenyl.
16. The compound of formula (lb) according to claim 2 or a pharmaceutically acceptable salt, solv
Figure imgf000294_0002
(lb)
wherein X 1 , X 2 , X 3 , R 6 , R 7 , p, and G 3 are as set forth in claim 2.
17. The compound of formula (lb) according to claim 16 or a pharmaceutically
1 1 2 2 3 3 acceptable salt, solvate, or pro-drug thereof wherein X is CR , X is CR , and X is CR .
18. The compound of formula (lb) according to claim 17 or a pharmaceutically acceptable salt, solvate, or pro-drug thereof wherein G3 is G3a.
19. The compound of formula (lb) according to claim 18 or a pharmaceutically acceptable salt, solvate, or pro-drug thereof wherein R6 is OH.
20. The compound of formula (Ic) according to claim 2 or a pharmaceutically
Figure imgf000295_0001
21. The compound of formula (Ic) according to claim 20 or a pharmaceutically
1 1 2 2 3 3 acceptable salt, solvate, or pro-drug thereof wherein X is CR , X is CR , and X is CR .
22. The compound of formula (Ic) according to claim 21 or a pharmaceutically acceptable salt, solvate, or pro-drug thereof wherein ring A2 is an optionally substituted heterocycle with the proviso that ring A2 is not an optionally susbtituted 2,3-dihydro-lH- isoindolyl, an optionally susbtituted decahydroisoquinolinyl, an optionally susbtituted piperidinyl, or an optionally susbtituted pyrrolidinyl.
23. The compound of formula (Ic) according to claim 21 or a pharmaceutically acceptable salt, solvate, or pro-drug thereof wherein ring A2 is unsubstituted
hexahydropyrano[4,3-b]pyrrol- 1 (4H)-yl.
24. The compound according to any one of claims 1-23 or a pharmaceutically acceptable salt, solvate, or pro-drug thereof, wherein R1, R2, and R3 are the same or different, and are each independently hydrogen or haloalkyl.
25. The compound according to any one of claims 1-23 or a pharmaceutically acceptable salt, solvate, or pro-drug thereof, wherein R1 and R3 are hydrogen, and R2 is haloalkyl.
26. The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of
2- { l-[(2S,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)- yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}pyridazin-3(2H)-one;
2- { 1 - [(2R,3aR,6aR)-3a- { [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin- 6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}phthalazin- l(2H)-one;
[(2S,3aR,6aR)-2-[4-(lH-pyrazol- 1 -yl)piperidin- 1 -yl]hexahydropentalen-3a(lH)- yl] [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]methanone;
[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl] [(2R,3aR,6aR)-2- {4- [3-(trifluoromethyl)-lH-pyrazol-l-yl]piperidin- l-yl}hexahydropentalen-3a(lH)- yl]methanone;
1 - { 1 - [(2R,3aR,6aR)-3a- { [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin- 6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}pyridin-2(lH)-one;
[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl] [(2R,3aR,6aR)-2- {4- [4-(trifluoromethyl)-lH-pyrazol-l-yl]piperidin- l-yl}hexahydropentalen-3a(lH)- yl]methanone;
[(2R,3aR,6aR)-2-(4-phenoxypiperidin- l-yl)hexahydropentalen-3a(lH)-yl][3- (trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-[4-(5-methyl- 1 ,2,4-oxadiazol-3-yl)piperidin- 1 - yl]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{4-[3-(2-hydroxypropan-2-yl)phenyl]piperidin- l- yl}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-[4-(lH-pyrazol- 1 -yl)piperidin- 1 -yl]hexahydropentalen-3a(lH)- yl] [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]methanone; [(2S,3aR,6aR)-2-(4-phenoxypiperidin- l-yl)hexahydropentalen-3a(lH)-yl][3- (trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone;
1 - { 1 - [(2R,3aR,6aR)-3a- { [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin- 6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}- l,2-dihydro-3H-pyrazol-3- one;
[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl] [(2S,3aR,6aR)-2- {4- [4-(trifluoromethyl)-lH-pyrazol-l-yl]piperidin- l-yl}hexahydropentalen-3a(lH)- yl]methanone;
ethyl l- { l-[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]carbonyl} octahydropentalen-2-yl]piperidin-4-yl} - 1 H-pyrazole-3-carboxylate;
3- { 1 - [(2R,3aR,6aR)-3a- { [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin- 6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}benzoic acid;
[(2S,3aR,6aR)-2-[4-(3-ethoxy- 1 H-pyrazol- 1 -yl)piperidin- 1 -yl]hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-[4-(3-phenyl- 1 ,2,4-oxadiazol-5-yl)piperidin- 1 - yl]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[(2S,3aR,6aR)-2- {4-[3-(2-hydroxypropan-2-yl)phenyl]piperidin- 1 - yl}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl] [(2S,3aR,6aR)-2- {4- [3-(trifluoromethyl)-lH-pyrazol-l-yl]piperidin- l-yl}hexahydropentalen-3a(lH)- yl]methanone;
1 - { 1 - [(2S,3aR,6aR)-3a- { [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)- yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}pyridin-2(lH)-one;
[(2R,3aR,6aR)-2-[4-(3,5-dimethyl-4H- l,2,4-triazol-4-yl)piperidin-l- yl]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
l- { l-[(2S,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)- yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}- l,2-dihydro-3H-pyrazol-3-one;
(2- { 1 -[(2S,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin- 6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}phenyl)acetic acid; [(2R,3aR,6aR)-2-[4-(3-isopropyl-5-methyl-4H- 1 ,2,4-triazol-4-yl)piperidin- 1 - yl]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-[4-(3-ethoxy- 1 H-pyrazol- 1 -yl)piperidin- 1 -yl]hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone;
[(2S,3aR,6aR)-2-{4-[3-(lH-tetrazol-5-yl)phenyl]piperidin-l- yl}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
2- { 1 - [(2R,3aR,6aR)-3a- { [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin- 6(5H)-yl]carbonyl} octahydropentalen-2-yl]piperidin-4-yl}pyridazin-3(2H)-one;
[(2S,3aR,6aR)-2-[4-(5-methyl-l,2,4-oxadiazol-3-yl)piperidin-l- yl]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
2- { l-[(2S,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)- yl]carbonyl} octahydropentalen-2-yl]piperidin-4-yl}benzoic acid;
2- { 1 - [(2R,3aR,6aR)-3a- { [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin- 6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}benzoic acid;
3- { l-[(2S,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)- yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}benzoic acid;
1 - { 1 - [(2S,3aR,6aR)-3a- { [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)- yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}- lH-pyrazole-3-carboxylic acid;
(2- { 1 -[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin- 6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}phenyl)acetic acid;
[(2S,3aR,6aR)-2-[4-(3,5-dimethyl-4H- l,2,4-triazol-4-yl)piperidin-l- yl]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[(2S,3aR,6aR)-2-[4-(3-isopropyl-5-methyl-4H-l,2,4-triazol-4-yl)piperidin-l- yl]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[(2S,3aR,6aR)-2-[4-(3-phenyl-l,2,4-oxadiazol-5-yl)piperidin- l- yl]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-(4-hydroxy-4-phenylpiperidin-l-yl)hexahydropentalen-3a(lH)- yl] [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]methanone; 4-phenyl-l-[(2R,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin- 6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperidine-4-carbonitrile;
4-(4-chlorophenyl)-l-[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- l,6- naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperidine-4-carbonitrile;
4-(4-fluorophenoxy)- l-[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperidine-4-carbonitrile;
[(2R,3aR,6aR)-2-[4-fluoro-4-(4-fluorophenyl)piperidin-l-yl]hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone;
[(2S,3aR,6aR)-2-[4-fluoro-4-(4-fluorophenyl)piperidin-l-yl]hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone;
[(2S,3aR,6aR)-2-(4-fluoro-4-phenylpiperidin-l-yl)hexahydropentalen-3a(lH)- yl] [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-(4-fluoro-4-phenylpiperidin- l-yl)hexahydropentalen-3a(lH)- yl] [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]methanone;
4-(4-fluorophenyl)- 1 -[(2S,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperidine-4-carbonitrile;
4-(4-chlorophenyl)-l-[(2S,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro- l,6- naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperidine-4-carbonitrile;
[(2S,3aR,6aR)-2-(4-hydroxy-4-phenylpiperidin-l-yl)hexahydropentalen-3a(lH)- yl] [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]methanone;
4-phenyl- 1 -[(2S,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin- 6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperidine-4-carbonitrile;
4-(4-fluorophenoxy)- l-[(2S,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- l,6- naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperidine-4-carbonitrile;
[(2S,3aS,6aS)-2-(6-fluoro- 1 'H,4H-spiro[ 1 ,3-benzodioxine-2,4'-piperidin]- 1 '- yl)hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-(6-fluoro- 1 'H,4H-spiro[ 1 ,3-benzodioxine-2,4'-piperidin]- 1 '- yl)hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl] [(2R,3aR,6aR)-2- {3- [3-(trifluoromethyl)- IH-pyrazol- 1 -yl]azetidin- 1 -yl}hexahydropentalen-3a(lH)- yl]methanone; l-(4-chlorophenyl)-4-[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- l,6- naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperazin-2-one;
l-(4-fluorophenyl)-4-[(2R,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro- l,6- naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperazin-2-one;
[(2R,3aR,6aR)-2-(2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5- yl)hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-(2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-[(3R)-3-(methoxymethyl)morpholin-4-yl]hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone;
[(3aR,6aR)-2-(4-hydroxy-6-azaspiro[2.5]oct-6-yl)hexahydropentalen-3a(lH)- yl] [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-(6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)- yl)hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
l-(4-chlorophenyl)-4-[(2S,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro- l,6- naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperazin-2-one;
[(2S,3aR,6aR)-2-(2 -phenyl- l,4-dioxa-8-azaspiro[4.5]dec-8-yl)hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-[7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(lH)- yl]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
l-phenyl-4-((2R,3aR,6aR)-3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-l,6- naphthyridine-6-carbonyl)octahydropentalen-2-yl)piperazin-2-one;
[(2R,3aR,6aR)-2-(2-phenyl-l,4-dioxa-8-azaspiro[4.5]dec-8-yl)hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone;
1- (4-fluorophenyl)-4-[(2S,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperazin-2-one;
[(2S,3aR,6aR)-2-[7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(lH)- yl]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
2- [(2R,3 aR,6aR)-3 a- { [3 -(trifluoromethyl)-7, 8-dihydro- 1 ,6-naphthyridin-6(5H)- yl]carbonyl} octahydropentalen-2-yl]- 1 ,2,3,4-tetrahydro-6H-pyrido[ 1 ,2-a]pyrazin-6-one; [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl] [(2S,3aR,6aR)-2- {3- [3-(trifluoromethyl)- IH-pyrazol- 1 -yl]azetidin- 1 -yl}hexahydropentalen-3a(lH)- yl]methanone;
4-[(2S,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)- yl]carbonyl} octahydropentalen-2-yl]piperazin-2-one;
4-[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)- yl]carbonyl}octahydropentalen-2-yl]piperazin-2-one;
[(2S,3aR,6aR)-2-(6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)- yl)hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[(2S,3aR,6aR)-2-[(3S)-3-(methoxymethyl)morpholin-4-yl]hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone;
[(2S,3aR,6aR)-2-[(3R)-3-(methoxymethyl)morpholin-4-yl]hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone;
l-phenyl-4-[(2S,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-
6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperazin-2-one;
l,5-anhydro-2,3-dideoxy-4-0-methyl-3-{[(2S,3aR,6aR)-3a-{[3-(trifluoromethyl)- 7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2-yl]amino} -L- threo-pentitol;
l,5-anhydro-2,3-dideoxy-4-0-methyl-3-{[(2S,3aR,6aR)-3a-{[3-(trifluoromethyl)- 7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2-yl]amino} -D- erythro-pentitol;
l,5-anhydro-2,3-dideoxy-4-0-methyl-3-{[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)- 7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2-yl]amino} -L- threo-pentitol;
l,5-anhydro-2,3-dideoxy-4-0-methyl-3-{methyl[(2R,3aR,6aR)-3a- {[3- (trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2- yl]amino} -D-erythro-pentitol;
l,5-anhydro-2,3-dideoxy-4-0-methyl-3-{[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)- 7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2-yl]amino} -D- erythro-pentitol;
l,5-anhydro-2,3-dideoxy-4-0-methyl-3-{[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)- 7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2-yl]amino} -D- threo-pentitol; (3S)- l -(4-fluorophenyl)-3- {[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- l ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2-yl]amino}pyrrolidin-2-one;
[(2R,3aR,6aR)-2-(tetrahydro-2H-pyran-4-ylamino)hexahydropentalen-3a(lH)- yl] [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]methanone;
((2R,3aR,6aR)-2-(4,4-difluorocyclohexylamino)octahydropentalen-3a-yl)(3- (trifluoromethyl)-7,8-dihydro- l ,6-naphthyridin-6(5H)-yl)methanone;
[(2R,3 aR,6aR)-2- [(3 ,3 -difluorocy clobutyl)amino]hexahydropentalen-3 a( 1 H)- yl] [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]methanone;
[(2S,3aR,6aR)-2-[(3,3-difluorocyclobutyl)amino]hexahydropentalen-3a(lH)- yl] [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]methanone;
(3S)- l -(4-fluorophenyl)-3- {[(2S,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- l ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2-yl]amino}pyrrolidin-2-one;
(3S)-3- {[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin- 6(5H)-yl]carbonyl} octahydropentalen-2-yl]amino}pyrrolidin-2-one;
(3S)- l-phenyl-3- {[(2S,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- l ,6- naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2-yl]amino}pyrrolidin-2-one;
(3S)-3- {[(2S,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- l ,6-naphthyridin- 6(5H)-yl]carbonyl} octahydropentalen-2-yl]amino}pyrrolidin-2-one;
(3S) - 1 -phenyl-3- {[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2-yl]amino}pyrrolidin-2-one;
3- {(3R,4S)-3-methyl- l -[(3aR,6aR)-3a- {[3-(triiluoromethyl)-7,8-dihydro- l,6- naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2-yl]piperidin-4-yl}benzoic acid;
3-((3S,4R)-3-methyl- l-((3aR,6aR)-3a-(3-(triiluoromethyl)-5,6,7,8-tetrahydro- l ,6- naphthyridine-6-carbonyl)octahydropentalen-2-yl)piperidin-4-yl)benzoic acid;
3- {(3S,4R)-3-methyl- l -[(2S,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- l ,6- naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2-yl]piperidin-4-yl}benzoic acid;
3- {(3 S,4R)-3-methyl- 1 -[(2R,3aR,6aR)-3a- { [3-(trifluoromethyl)-7,8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2-yl]piperidin-4-yl}benzoic acid;
3- {(3R,4S)-3-methyl- l -[(2S,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- l ,6- naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2-yl]piperidin-4-yl}benzoic acid;
3- {(3R,4S)-3-methyl- 1 -[(2R,3aR,6aR)-3a- {[3-(triiluoromethyl)-7,8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2-yl]piperidin-4-yl}benzoic acid;
3- { l-[(2S,3aR,6aR)-3a- {[3-(triiluoromethyl)-7,8-dihydro- l ,6-naphthyridin-6(5H)- yl]carbonyl} octahydropentalen-2-yl]piperidin-4-yl}benzonitrile; 3- { 1 - [(2R,3aR,6aR)-3a- { [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin- 6(5H)-yl]carbonyl}octahydropentalen-2-yl]piperidin-4-yl}benzonitrile;
[(3aR,6aR)-2-[4-(naphthalen-2-yl)piperidin-l-yl]hexahydropentalen-3a(lH)-yl][3- (trifluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2- {4-[3-(lH-tetrazol-5-yl)phenyl]piperidin- 1 - yl}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[(2S,3aR,6aR)-2-{4-[3-(lH-tetrazol-5-yl)phenyl]piperidin-l- yl}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-[4-(naphthalen-2-yl)piperidin-l-yl]hexahydropentalen-3a(lH)- yl] [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]methanone;
[(2S,3aR,6aR)-2- {4-[3-methyl-5-(trifluoromethyl)- lH-pyrazol- 1 -yl]piperidin- 1 - yl}hexa ydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[(2R,3aR,6aR)-2- {4-[3-methyl-5-(trifluoromethyl)- lH-pyrazol- 1 -yl]piperidin- 1 - yl}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[(2R,3aR,6aR)-2- {4-[5-methyl-3-(trifluoromethyl)- lH-pyrazol- 1 -yl]piperidin- 1 - yl}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[(2S,3aR,6aR)-2-{(3R,4S)-4-[3-(2-hydroxypropan-2-yl)phenyl]-3- methylpiperidin- 1 -yl} hexahy dropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7,8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{(3R,4S)-4-[3-(2-hydroxypropan-2-yl)phenyl]-3- methylpiperidin- 1 -yl} hexahy dropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- 1,6- naphthyridin-6(5H)-yl]methanone;
3- { l-[(2S,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)- yl]carbonyl} octahydropentalen-2-yl]- 1 ,2,3,6-tetrahydropyridin-4-yl}benzonitrile;
3- { l-[(2R,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-
6(5H)-yl]carbonyl} octahydropentalen-2-yl]- 1 ,2,3,6-tetrahydropyridin-4-yl}benzonitrile;
[(2S,3aR,6aR)-2-(3-phenylazetidin-l-yl)hexahydropentalen-3a(lH)-yl][3- (trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone; [(2R,3aR,6aR)-2-(3-phenylazetidin- 1 -yl)hexahydropentalen-3a(lH)-yl] [3- (trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone;
[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl] [(2S,3aR,6aR)-2- {(3- endo)-3-[5-(trifluoromethyl)-lH-pyrazol-l-yl]-8-azabicyclo[3.2.1]oct-8- yl} hexahydropentalen-3 a( 1 H)-yl]methanone;
[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl] [(2R,3aR,6aR)-2- {(3- endo)-3-[5-(trifluoromethyl)-lH-pyrazol-l-yl]-8-azabicyclo[3.2.1]oct-8- yl} hexahydropentalen-3 a( 1 H)-yl]methanone;
[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl] [(2R,3aR,6aR)-2- {(3- endo)-3-[3-(trifluoromethyl)-lH-pyrazol-l-yl]-8-azabicyclo[3.2.1]oct-8- yl} hexahydropentalen-3 a( 1 H)-yl]methanone;
[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl] [(2S,3aR,6aR)-2- {(3- endo)-3-[3-(trifluoromethyl)-lH-pyrazol-l-yl]-8-azabicyclo[3.2.1]oct-8- yl} hexahydropentalen-3 a( 1 H)-yl]methanone;
[(2S,3aR,6aR)-2-(4-phenylpiperazin-l-yl)hexahydropentalen-3a(lH)-yl][3- (triiluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-(4-phenylpiperazin-l-yl)hexahydropentalen-3a(lH)-yl][3- (triiluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)-yl]methanone;
[(2S,3aR,6aR)-2-(l'H,3H-spiro[2-benzofuran-l,4'-piperidin]- l'- yl)hexahydropentalen-3a(lH)-yl][3-(triiluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-(l'H,3H-spiro[2-benzofuran- l,4'-piperidin]- l'- yl)hexahydropentalen-3a(lH)-yl][3-(triiluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-(hexahydropyrano[3,4-b][l,4]oxazin-l(5H)- yl)hexahydropentalen-3a(lH)-yl][3-(triiluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-[(4aS,8aR)-hexahydropyrano[3,4-b][l,4]oxazin-l(5H)- yl]hexahydropentalen-3a(lH)-yl][3-(triiluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-[(4aR,8aS)-hexahydropyrano[3,4-b][l,4]oxazin- l(5H)- yl]hexahydropentalen-3a(lH)-yl][3-(triiluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone; [(2R,3aR,6aR)-2-[(4aS,8aS)-hexahydropyrano[3,4-b][l,4]oxazin-l(5H)- yl]hexahydropentalen-3a(lH)-yl][3-(trifluorom
6(5H)-yl]methanone;
[(2R,3aR,6aR)-2- [(4aR,8aR)-hexahydropyrano[3,4-b] [ 1 ,4]oxazin- 1 (5H)- yl]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[(2S,3aR,6aR)-2-[(4aS,8aS)-hexahydropyrano[3,4-b][l,4]oxazin-l(5H)- yl]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[(2S,3aR,6aR)-2-[(4aR,8aS)-hexahydropyrano[3,4-b][l,4]oxazin-l(5H)- yl]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-[tricyclo[3.3.1. l3'7]dec-2-ylamino]hexahydropentalen-3a(lH)- yl] [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]methanone;
l,5-anhydro-2,3-dideoxy-3-{ethyl[(2R,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8- dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2-yl]amino} -4-0- methyl-D-erythro-pentitol;
l,5-anhydro-2,3-dideoxy-3-{ethyl[(2R,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8- dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2-yl]amino} -4-0- methyl-D-threo-pentitol;
l,5-anhydro-2,3-dideoxy-4-0-methyl-3-{methyl[(2R,3aR,6aR)-3a-{[3- (trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2- yl] amino } -D-threo-pentitol;
l,5-anhydro-2,3-dideoxy-3-{(2,2-difluoroethyl)[(2R,3aR,6aR)-3a-{[3- (trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2- yl]amino}-4-0-methyl-D-threo-pentitol;
[(2R,3aR,6aR)-2-[(2-methoxyethyl)(tetrahydro-2H-pyran-4- yl)amino]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(2S,4R)-2-phenyltetrahydro-2H-pyran-4- yl] amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone; [(2R,3aR,6aR)-2-{[(2R,4S)-2-phenyltetrahydro-2H-pyran-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
l,5-anhydro-2,3-dideoxy-3-{(2,2-difluoroethyl)[(2R,3aR,6aR)-3a-{[3- (trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2- yl]amino}-4-0-methyl-D-erythro-pentitol;
[(2R,3aR,6aR)-2-{[(2S,4S)-2-phenyltetrahydro-2H-pyran-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
l,5-anhydro-2,3-dideoxy-4-0-ethyl-3-{[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)- 7,8-dihydro-l,6-naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]amino}-D- eryi/zro-pentitol;
l,5-anhydro-2,3-dideoxy-4-0-ethyl-3-{[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)- 7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2-yl]amino} -L- i/zreo-pentitol;
l,5-anhydro-2,3-dideoxy-4-0-methyl-3-{(2H3)methyl[(2R,3aR,6aR)-3a-{[3- (trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2- yl]amino} -D-eryi zro-pentitol;
[(2R,3aR,6aR)-2-[(4R)-3,4-dihydro-2H-chromen-4-ylamino]hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(3S,4S)-3-methyltetrahydro-2H-pyran-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(3S,4R)-3-methyltetrahydro-2H-pyran-4- yl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-[(4R)-3,4-dihydro-2H-chromen-4- yl(methyl)amino]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(4R)-6-fluoro-3,4-dihydro-2H-chromen-4- yl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone; [(2R,3aR,6aR)-2-{[(2R,4R)-2-(pyridin-2-yl)tetrahydro-2H-pyran-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2- {[(3S,4S)-3-ethyltetrahydro-2H-pyran-4- yl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(3S,4R)-3-ethyltetrahydro-2H-pyran-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(4R)-8-fluoro-3,4-dihydro-2H-chromen-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-[(3aS,7aS)-hexahydropyrano[4,3-b]pyrrol-l(4H)- yl]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-[(3aR,7aR)-hexahydropyrano[4,3-b]pyrrol-l(4H)- yl]hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]methanone;
[(3aR,6aR)-2-(6,7-dihydro-4H-pyrano[4,3-d][l,3]thiazol-2- ylamino)hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2- {[trans-4-hydroxy-4-(6-methoxypyridin-3- yl)cyclohexyl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[trans-4-hydroxy-4-(l,3-thiazol-2- yl)cyclohexyl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[trans-4-(l,3-benzodioxol-5-yl)-4- hydroxycyclohexyl] amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8- dihydro- 1 ,6-naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(3R,4R)-3-fluorotetrahydro-2H-pyran-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone; [(2R,3aR,6aR)-2-{[(3S,4R)-3-fluorotetrahydro-2H-pyran-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(3R,4S)-3-fluorotetrahydro-2H-pyran-4- yl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(3S,4S)-3-fluorotetrahydro-2H-pyran-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[cis-4-hydroxy-4-(6-methoxypyridin-3- yl)cyclohexyl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[cis-4-hydroxy-4-(l,3-thiazol-2- yl)cyclohexyl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[cis-4-(l,3-benzodioxol-5-yl)-4- hydroxycyclohexyl] amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8- dihydro- 1 ,6-naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(2R,4S)-2-benzyltetrahydro-2H-pyran-4- yl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(2R,4R)-2-benzyltetrahydro-2H-pyran-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(2S,4R)-2-benzyltetrahydro-2H-pyran-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-[(4S)-3,4-dihydro-2H-chromen-4-ylamino]hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-(7-oxa-l-azaspiro[3.5]non-l-yl)hexahydropentalen-3a(lH)- yl] [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]methanone;
[(2S,3aR,6aR)-2-(7-oxa-l-azaspiro[3.5]non-l-yl)hexahydropentalen-3a(lH)- yl] [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]methanone; l,5-anhydro-2,3-dideoxy-3-{[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2-yl]amino} -D-erythro-pentitol;
[(2R,3aR,6aR)-2-{[(3R,4S)-3-methyltetrahydro-2H-pyran-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(3R,4R)-3-methyltetrahydro-2H-pyran-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
l,5-anhydro-2,3-dideoxy-4-C-(trifluoromethyl)-3-{[(2R,3aR,6aR)-3a- {[3- (trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2- yl]amino} -L-threo-pentitol;
l,5-anhydro-2,3-dideoxy-4-C-(trifluoromethyl)-3-{[(2R,3aR,6aR)-3a- {[3- (trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2- yl]amino} -D-erythro-pentitol;
l,5-anhydro-3,4-dideoxy-2-C-(trifluoromethyl)-3-{[(2R,3aR,6aR)-3a- {[3-
(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2- yl]amino} -D-erythro-pentitol;
[(2R,3aR,6aR)-2-{[3-(methoxymethyl)tetrahydro-2H-pyran-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(3R,4R)-3-fluorotetrahydro-2H-pyran-4- yl] (methyl)amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7,8-dihydro- 1,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(3R)-4,4-dimethoxytetrahydro-2H-pyran-3- yl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(4S)-6-fluoro-3,4-dihydro-2H-chromen-4- yl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(4S)-6-chloro-3,4-dihydro-2H-chromen-4- yl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone; [(2R,3aR,6aR)-2-{[(4S)-6-bromo-3,4-dihydro-2H-chromen-4- yl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(3S,4R)-3-fluorotetrahydro-2H-pyran-4- yl] (methyl)amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- 1,6- naphthyridin-6(5H)-yl]methanone;
l,5-anhydro-2,3-dideoxy-3-{[(2R,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2-yl]amino} -L-threo-pentitol; l,5-anhydro-3,4-dideoxy-3-{[(2R,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin-6(5H)-yl]carbonyl}octahydropentalen-2-yl]amino}-D-erythro-pentitol; l,5-anhydro-2,3-dideoxy-3-{[(2R,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]carbonyl} octahydropentalen-2-yl]amino} -D-threo-pentitol;
[(2R,3aR,6aR)-2-{[(3S)-4,4-dimethoxytetrahydro-2H-pyran-3- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(4R)-6-chloro-3,4-dihydro-2H-chromen-4- yl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(4R)-6-bromo-3,4-dihydro-2H-chromen-4- yl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(4S)-6-methyl-3,4-dihydro-2H-chromen-4- yl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(4R)-6-methyl-3,4-dihydro-2H-chromen-4- yl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(4S)-6-nitro-3,4-dihydro-2H-chromen-4- yl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(4R)-6-nitro-3,4-dihydro-2H-chromen-4- yl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone; [(2R,3aR,6aR)-2-{[(2R,4S)-2-(pyridin-2-yl)tetrahydro-2H-pyran-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(4R)-6,7-difluoro-3,4-dihydro-2H-chromen-4- yl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(4S)-6,7-difluoro-3,4-dihydro-2H-chromen-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-[(9-anti)-3-oxabicyclo[3.3.1]non-9-ylamino]hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-[(9-syn)-3-oxabicyclo[3.3.1]non-9-ylamino]hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(3S,4S)-3-methoxy-3,4-dihydro-2H-chromen-4- yl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro- l,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(3R,4S)-3-methoxy-3,4-dihydro-2H-chromen-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(3R,4R)-3-methoxy-3,4-dihydro-2H-chromen-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
(4S)-4- {[(2R,3aR,6aR)-3a-{[3-(trifluoromethyl)-7,8-dihydro- l,6-naphthyridin- 6(5H)-yl]carbonyl}octahydropentalen-2-yl]amino}-3,4-dihydro-2H-chromene-6- carbonitrile;
(4R)-4-{[(2R,3aR,6aR)-3a- {[3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl]carbonyl}octahydropentalen-2-yl]amino}-3,4-dihydro-2H-chromene-6- carbonitrile;
[(2R,3aR,6aR)-2-{[(4S)-8-fluoro-3,4-dihydro-2H-chromen-4- yl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(2R,4S)-2-(trifluoromethyl)-3,4-dihydro-2H-chromen-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone; [(2R,3aR,6aR)-2-{[(2S,4R)-2-(trifluoromethyl)-3,4-dihydro-2H-chromen-4- yl] amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(3R,4R)-3-cyclopropyltetrahydro-2H-pyran-4- yl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(3R,4S)-3-cyclopropyltetrahydro-2H-pyran-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(3S,4S)-3-cyclopropyltetrahydro-2H-pyran-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(3S,4R)-3-cyclopropyltetrahydro-2H-pyran-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[3-(fluoromethyl)tetrahydro-2H-pyran-4- yl] amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(3S,4R)-3-(difluoromethyl)tetrahydro-2H-pyran-4- yl]amino}hexahydropentalen-3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(3S,4S)-3-(difluoromethyl)tetrahydro-2H-pyran-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(4R)-3,3-dimethyltetrahydro-2H-pyran-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(4S)-3,3-dimethyltetrahydro-2H-pyran-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-(6,7-dihydropyrano[4,3-b]pyrrol-l(4H)-yl)hexahydropentalen- 3a(lH)-yl][3-(trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-[(4S)-oxepan-4-ylamino]hexahydropentalen-3a(lH)-yl][3- (trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone; [(2R,3aR,6aR)-2-[(8R)-5-oxaspiro[2.5]oct-8-ylamino]hexahydropentalen-3a(lH)- yl] [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-[(8S)-5-oxaspiro[2.5]oct-8-ylamino]hexahydropentalen-3a(lH)- yl] [3-(trifluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(3R,4S)-3-(methoxymethyl)tetrahydro-2H-pyran-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
[(2R,3aR,6aR)-2-{[(3R,4R)-3-(methoxymethyl)tetrahydro-2H-pyran-4- yl] amino } hexahy dropentalen-3 a( 1 H)-yl] [3-(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanone;
(3-chloro-7,8-dihydro-l,6-naphthyridin-6(5H)-yl)[(2R,3aR,6aR)-2-{[(3R,4S)-3- methyltetrahydro-2H-pyran-4-yl]amino } hexahydropentalen-3 a( 1 H)-yl]methanone;
(3-chloro-7,8-dihydro-l,6-naphthyridin-6(5H)-yl)[(2R,3aR,6aR)-2-{[(3S,4S)-3- methyltetrahydro-2H-pyran-4-yl]amino } hexahydropentalen-3 a( 1 H)-yl]methanone;
(3-chloro-7,8-dihydro- l,6-naphthyridin-6(5H)-yl)[(2R,3aR,6aR)-2-{[(3S,4R)-3- methyltetrahydro-2H-pyran-4-yl]amino } hexahydropentalen-3 a( 1 H)-yl]methanone;
(3-chloro-7,8-dihydro-l,6-naphthyridin-6(5H)-yl)[(2R,3aR,6aR)-2-{[(3R,4R)-3- methyltetrahy dro-2H-pyran-4-yl]amino } hexahydropentalen-3 a( 1 H)-yl]methanone; l,5-anhydro-3-({(2R,3aR,6aR)-3a-[(3-chloro-7,8-dihydro-l,6-naphthyridin- 6(5H)-yl)carbonyl]octahydropentalen-2-yl}amino)-2,3-dideoxy-4-0-methyl-D-erythro- pentitol;
[3-(difluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl] [(2R,3aR,6aR)-2- {[(3R,4S)-3-methyltetrahydro-2H-pyran-4-yl]amino}hexahydropentalen-3a(lH)- yl]methanone;
[3-(difluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl] [(2R,3aR,6aR)-2-
{[(3S,4S)-3-methyltetrahydro-2H-pyran-4-yl]amino}hexahydropentalen-3a(lH)- yl]methanone;
[3-(difluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl] [(2R,3aR,6aR)-2- {[(3S,4R)-3-methyltetrahydro-2H-pyran-4-yl]amino}hexahydropentalen-3a(lH)- yl]methanone;
[3-(difluoromethyl)-7,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl] [(2R,3aR,6aR)-2- { [(3R,4R)-3 -methyltetrahydro-2H-pyran-4-yl]amino } hexahydropentalen-3 a( 1 H)- yl]methanone; (3-bromo-7,8-dihydro-l,6-naphthyridin-6(5H)-yl)[(2R,3aR,6aR)-2-{[(3S,4S)-3- methyltetrahydro-2H-pyran-4-yl]amino } hexahydropentalen-3 a( 1 H)-yl]methanone;
(3-bromo-7,8-dihydro-l,6-naphthyridin-6(5H)-yl)[(2R,3aR,6aR)-2-{[(3S,4R)-3- methyltetrahydro-2H-pyran-4-yl]amino } hexahydropentalen-3 a( 1 H)-yl]methanone;
6- {[(2R,3aR,6aR)-2- {[(3S,4R)-3-methyltetrahydro-2H-pyran-4- yl]amino}hexahydropentalen-3a(lH)-yl]carbonyl}-5,6,7,8-tetrahydro- l,6-naphthyridine- 3-carbonitrile;
6- {[(2R,3aR,6aR)-2- {[(3S,4S)-3-methyltetrahydro-2H-pyran-4- yl]amino}hexahydropentalen-3a(lH)-yl]carbonyl}-5,6,7,8-tetrahydro- l,6-naphthyridine- 3-carbonitrile;
l,5-anhydro-2,3-dideoxy-3-({(2R,3aR,6aR)-3a-[(3-fluoro-7,8-dihydro-l,6- naphthyridin-6(5H)-yl)carbonyl]octahydropentalen-2-yl}amino)-4-0-methyl-D-erythro- pentitol; and
l,5-anhydro-2,3-dideoxy-3-({(2R,3aR,6aR)-3a-[(3-fluoro-7,8-dihydro-l,6- naphthyridin-6(5H)-yl)carbonyl]octahydropentalen-2-yl} amino)-4-0-methyl-D-threo- pentitol.
27. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to claim 2 or a pharmaceutically acceptable salt, solvate, or pro-drug thereof, in combination with a pharmaceutically acceptable carriers.
28. A method for treating pain in a subject in need of such treatment comprising administering to the subject a therapeutically effective amount of a compound of formula (I) according to claim 2, or a pharmaceutically acceptable salt, solvate, or pro-drug thereof, alone or in combination with a pharmaceutically acceptable carrier.
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