WO2013010453A1 - Antagonistes des récepteurs de chimiokines - Google Patents

Antagonistes des récepteurs de chimiokines 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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WIPO (PCT)
Prior art keywords
dihydro
trifluoromethyl
naphthyridin
methanone
hexahydropentalen
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PCT/CN2012/078586
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English (en)
Inventor
Xueqing Wang
Michael Meyer
Betty YAO
Tao Guo
Guo Ping Robert WEI
Lijuan Jane Wang
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Abbott Laboratories
Abbott Laboratories Trading (Shanghai) Company, Ltd.
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Publication of WO2013010453A1 publication Critical patent/WO2013010453A1/fr

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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.

Abstract

L'invention concerne des antagonistes des récepteurs de chimiokines de formule (I), G1, X1, X2 et X3 étant tels que définis dans la description. L'invention concerne également des compositions comprenant de tels composés; et des procédés de traitement d'états et de troubles utilisant de tels composés et de telles compositions.
PCT/CN2012/078586 2011-07-15 2012-07-13 Antagonistes des récepteurs de chimiokines WO2013010453A1 (fr)

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US8906911B2 (en) 2012-04-02 2014-12-09 Abbvie Inc. Chemokine receptor antagonists
WO2015019365A1 (fr) 2013-08-07 2015-02-12 Cadila Healthcare Limited N-cyanométhylamides comme inhibiteurs de la janus kinase
JP2015527323A (ja) * 2012-07-19 2015-09-17 ヤンセン ファーマシューティカ エヌ．ベー． Ｃｃｒ２のオクタヒドロ−シクロペンタピロリル拮抗薬
US9351954B2 (en) 2009-12-04 2016-05-31 Sunovion Pharmaceuticals Inc. Multicyclic compounds and methods of use thereof
US10196403B2 (en) 2016-07-29 2019-02-05 Sunovion Pharmaceuticals Inc. Compounds and compositions and uses thereof
CN110028469A (zh) * 2019-04-28 2019-07-19 南京药石科技股份有限公司 一种非阿片类镇痛药的关键中间体的制备方法及应用
US10780074B2 (en) 2017-08-02 2020-09-22 Sunovion Pharmaceuticals Inc. Compounds and uses thereof
US10815249B2 (en) 2018-02-16 2020-10-27 Sunovion Pharmaceuticals Inc. Salts, crystal forms, and production methods thereof
US11077090B2 (en) 2016-07-29 2021-08-03 Sunovion Pharmaceuticals Inc. Compounds and compositions and uses thereof
US11129807B2 (en) 2017-02-16 2021-09-28 Sunovion Pharmaceuticals Inc. Methods of treating schizophrenia
US11136304B2 (en) 2019-03-14 2021-10-05 Sunovion Pharmaceuticals Inc. Salts of a heterocyclic compound and crystalline forms, processes for preparing, therapeutic uses, and pharmaceutical compositions thereof
EP3981773A1 (fr) 2020-10-09 2022-04-13 Technische Universität Berlin Résolution cinétique dynamique d'alcools par silylation énantiosélective
WO2023067518A1 (fr) * 2021-10-20 2023-04-27 Assembly Biosciences, Inc. Procédé
US11738002B2 (en) 2020-04-14 2023-08-29 Sunovion Pharmaceuticals Inc. Methods of treating neurological and psychiatric disorders

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US9351954B2 (en) 2009-12-04 2016-05-31 Sunovion Pharmaceuticals Inc. Multicyclic compounds and methods of use thereof
US10085968B2 (en) 2009-12-04 2018-10-02 Sunovion Pharmaceuticals Inc. Multicyclic compounds and methods of use thereof
US8906911B2 (en) 2012-04-02 2014-12-09 Abbvie Inc. Chemokine receptor antagonists
JP2015527323A (ja) * 2012-07-19 2015-09-17 ヤンセン ファーマシューティカ エヌ．ベー． Ｃｃｒ２のオクタヒドロ−シクロペンタピロリル拮抗薬
US9556148B2 (en) 2013-08-07 2017-01-31 Cadila Healthcare Limited N-cyanomethylamides as inhibitors of janus kinase
WO2015019365A1 (fr) 2013-08-07 2015-02-12 Cadila Healthcare Limited N-cyanométhylamides comme inhibiteurs de la janus kinase
US11958862B2 (en) 2016-07-29 2024-04-16 Sumitomo Pharma America, Inc. Compounds and compositions and uses thereof
US11077090B2 (en) 2016-07-29 2021-08-03 Sunovion Pharmaceuticals Inc. Compounds and compositions and uses thereof
US10927124B2 (en) 2016-07-29 2021-02-23 Sunovion Pharmaceuticals Inc. Compounds and compositions and uses thereof
US10196403B2 (en) 2016-07-29 2019-02-05 Sunovion Pharmaceuticals Inc. Compounds and compositions and uses thereof
US11129807B2 (en) 2017-02-16 2021-09-28 Sunovion Pharmaceuticals Inc. Methods of treating schizophrenia
US10780074B2 (en) 2017-08-02 2020-09-22 Sunovion Pharmaceuticals Inc. Compounds and uses thereof
US11491133B2 (en) 2017-08-02 2022-11-08 Sunovion Pharmaceuticals Inc. Heteroaryl-isochroman compounds and uses thereof
US11440921B2 (en) 2018-02-16 2022-09-13 Sunovion Pharmaceuticals Inc. Salts, crystal forms, and production methods thereof
US10815249B2 (en) 2018-02-16 2020-10-27 Sunovion Pharmaceuticals Inc. Salts, crystal forms, and production methods thereof
US11136304B2 (en) 2019-03-14 2021-10-05 Sunovion Pharmaceuticals Inc. Salts of a heterocyclic compound and crystalline forms, processes for preparing, therapeutic uses, and pharmaceutical compositions thereof
CN110028469B (zh) * 2019-04-28 2022-08-09 南京药石科技股份有限公司 一种非阿片类镇痛药的关键中间体的制备方法及应用
CN110028469A (zh) * 2019-04-28 2019-07-19 南京药石科技股份有限公司 一种非阿片类镇痛药的关键中间体的制备方法及应用
US11738002B2 (en) 2020-04-14 2023-08-29 Sunovion Pharmaceuticals Inc. Methods of treating neurological and psychiatric disorders
WO2022074177A1 (fr) 2020-10-09 2022-04-14 Technische Universität Berlin Résolution cinétique dynamique d'alcools par silylation énantiosélective
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