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WO2022034568A1 - Composés d'acide azacyclohexyle acétique substitués par triazole-pyridinyle utilisés en tant qu'antagonistes du récepteur lpa - Google Patents

Composés d'acide azacyclohexyle acétique substitués par triazole-pyridinyle utilisés en tant qu'antagonistes du récepteur lpa Download PDF

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Publication number
WO2022034568A1
WO2022034568A1 PCT/IB2021/059266 IB2021059266W WO2022034568A1 WO 2022034568 A1 WO2022034568 A1 WO 2022034568A1 IB 2021059266 W IB2021059266 W IB 2021059266W WO 2022034568 A1 WO2022034568 A1 WO 2022034568A1
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Prior art keywords
compound
methyl
ealkyl
substituted
ring
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PCT/IB2021/059266
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English (en)
Inventor
Hongjian Zhang
Ping Chen
Zhenwei CAI
Fei Jiang
Peihua Sun
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Viva Star Biosciences Ltd
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Viva Star Biosciences Ltd
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Priority to KR1020237008152A priority Critical patent/KR20240068583A/ko
Priority to EP21791479.5A priority patent/EP4196220A1/fr
Priority to AU2021323515A priority patent/AU2021323515A1/en
Priority to MX2023001812A priority patent/MX2023001812A/es
Priority to CN202180067597.XA priority patent/CN116669727B/zh
Priority to JP2023510342A priority patent/JP2023544476A/ja
Priority to CA3191452A priority patent/CA3191452A1/fr
Priority to IL300525A priority patent/IL300525A/en
Publication of WO2022034568A1 publication Critical patent/WO2022034568A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • This application relates to novel substituted azacyclohexyl acetic acid compounds and analogues, their manufacture, pharmaceutical compositions comprising them, and their use as medicaments for treating a disease associated with dysregulation of lysophosphatidic acid receptors (LPAR).
  • LPAR lysophosphatidic acid receptors
  • Lysophosphatidic acid is a small glycerolphospholipid (1- or 2-acyl-sn-glycerol 3- phosphate) with a molecular weight of 430 - 480 Dalton, consisting of a glycerol backbone which is esterified with a phosphate group and a fatty acid with variable chain length and degree of saturation (Yang and Chen, World J Gastroenterol 24:4132-4151, 2018).
  • LPA can be formed from precursor molecules in plasma, serum or tissues (membrane phospholipids) via several pathways: (1) hydrolysis of the choline group off lysophosphatidylcholine by lysophospholipase D (lysoPLD or autotaxin); (2) hydrolysis of a fatty acyl chain from phosphatidic acid to produce 2-acyl or 1- acyl LPA by phospholipase Al or A2; and (3) de novo synthesis from glycerol-3 -phosphate by acyltransferases (Kihara et al., Experimental Cell Res 333: 171-177, 2015). In tissues or cells, LPA represents a mixture of 1- or 2-acyl-sn-glycerol 3-phosphates.
  • LPA Lysophosphatidic acid
  • LPAR G protein-coupled receptors
  • Fibrosis is a reparative (or “healing”) process characterized by the excessive accumulation of extracellular matrix (ECM).
  • ECM extracellular matrix
  • LPA levels increased significantly in the bronchoaveolar lavage fluid following lung injury, and mice lacking the LPAR1 gene (LPAR1-/- mice) were remarkably protected from fibrosis and mortality (Tager et al., Nat. Med. 14:45-54, 2008).
  • Treatment with small molecule LPAR1 antagonists could reduce the lung fibrosis in the bleomycin mouse model (Swanet et al., Br. J. Pharmacol. 160: 1699-1713, 2010).
  • the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:
  • L 1 is a covalent bond or CH2 optionally substituted with 1 or 2 methyl groups
  • L 2 is a covalent bond or (CR 7 R 7 ) P ;
  • L 3 is a covalent bond, O or NR 7 , provided that at least one of L 2 and L 3 is not a covalent bond;
  • X 1 is N, O or CR 6a ;
  • X 2 is N or NR 6 ;
  • X 3 is N, NR 6 or CR 6 , wherein the dashed circle denotes bonds forming a five-membered aromatic ring;
  • Y 1 , Y 2 , Y 3 and Y 4 are each independently N or CR 5 , provided that at least one but no more than two of Y 1 , Y 2 , Y 3 and Y 4 are N;
  • Z is CH2 or O
  • R 2 is (CR 7 R 7 ) q -R 8 ;
  • R 3 at each occurrence is independently hydrogen, halogen, CN, Ci-ealkyl, or C3-7cycloalkyl;
  • R 4 is independently hydrogen, halogen, Ci-ealkyl, haloCi-ealkyl, C2-ealkenyl, C2-ealkynyl, Ci- ealkoxy, (CH2)p-Ci-ealkoxy, phenyl, (CH2) P -phenyl, O(CH2) P -phenyl, CN, C3-7cycloalkyl, (CH2) P - C3-7cycloalkyl, C2-ealkenyl-C3-7cycloalkyl, C2-ealkynyl-C3-7cycloalkyl, O(CH2) P -C3-7cycloalkyl, (CH2)q-5-6-membered heteroaryl ring substituted with 1-4 R 11 , (CH2)q-5-7-membered heterocyclyl ring substituted with 1-4 R 11 , in which each phenyl is independently optionally substituted with 1-3 of halogen, Ci-ealkyl, or Ci-ealkoxy
  • R 5 at each occurrence is independently hydrogen, halogen, Ci-ealkyl, haloCi -ealkyl, OH, Ci- ealkyl-OH, Ci-ealkoxy, Ci-ealkyl-Ci-ealkoxy, haloCi-ealkoxy, CN, C3-7cycloalkyl, NR a R b , or Ci- 6 alkyl-NR a R b ; each occurrence of R 6a and R 6 is independently hydrogen, halogen, CN, methyl, ethyl, propyl, or cyclopropyl;
  • R 7 at each occurrence is independently hydrogen, Ci-4alkyl, C3-5cycloalkyl, or twoR 7 groups together with the carbon atom to which they are attached, form a 3-5-membered cycloalkyl ring;
  • R 11 at each occurrence is independently hydrogen, Ci-ealkyl, haloCi-ealkyl, C 2 -ealkenyl, C 2 - ealkynyl, Ci-ealkoxy, (CH 2 ) p -Ci-6alkoxy, phenyl, (CH 2 ) p -phenyl, O(CH 2 ) p -phenyl, CN, C3- 7cycloalkyl, (CH 2 ) p -C3-7cycloalkyl, C 2 -6alkenyl-C3-7cycloalkyl, C 2 -6alkynyl-C3-7cycloalkyl, O(CH 2 ) p -C3-7cycloalkyl, in which each phenyl is independently optionally substituted with 1-3 of halogen, Ci-ealkyl, or Ci-ealkoxy;
  • R 12 at each occurrence is independently hydrogen, Ci-4alkyl, C3-7cycloalkyl, or two R 12 groups, together with the carbon atom to which they are attached, form a 3-6-membered cycloalkyl ring; each occurrence of R a and R b is independently hydrogen or Ci-ealkyl, or R a and R b , together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of Cwalkyl, phenyl and benzyl; m is 1, or 2; n is 0, 1, or 2; p at each occurrence is independently 1, 2, 3 or 4; and q at each occurrence is independently 0, 1, 2, 3 or 4.
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), its manufacture and use as medicaments for treating a disease associated with dysregulation of lysophosphatidic acid receptor 1 (LPAi).
  • the compounds of formula (I) are useful for treatment of pathological fibrosis (e.g., pulmonary, liver, renal, cardiac, demal, ocular, or pancreatic fibrosis), idiopathic pulmonary fibrosis (IPF), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic kidney disease, or systemic sclerosis.
  • pathological fibrosis e.g., pulmonary, liver, renal, cardiac, demal, ocular, or pancreatic fibrosis
  • IPF idiopathic pulmonary fibrosis
  • NASH non-alcoholic steatohepatitis
  • NAFLD non-alcoholic fatty liver disease
  • chronic kidney disease diabetic
  • the present technology provides compounds, and their pharmaceutically acceptable forms, including, but not limited to, salts, hydrates, solvates, isomers, sterioisomers, enantiomers, prodrugs, and isotopically labeled derivatives thereof.
  • the present technology provides methods of treating and/or managing various diseases and disorders, which comprises administering to a patient a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable form (e.g., salts, hydrates, solvates, isomers, sterioisomers, enantiomers, prodrugs, and isotopically labeled derivatives) thereof.
  • a pharmaceutically acceptable form e.g., salts, hydrates, solvates, isomers, sterioisomers, enantiomers, prodrugs, and isotopically labeled derivatives
  • the present technology provides methods of preventing various diseases and disorders, which comprises administering to a patient in need of such prevention a prophylactically effective amount of a compound provided herein, or a pharmaceutically acceptable form (e.g., salts, hydrates, solvates, isomers, sterioisomers, prodrugs, and isotopically labeled derivatives) thereof.
  • a pharmaceutically acceptable form e.g., salts, hydrates, solvates, isomers, sterioisomers, prodrugs, and isotopically labeled derivatives
  • a compound provided herein, or a pharmaceutically acceptable form e.g., salts, hydrates, solvates, isomers, sterioisomers, prodrugs, and isotopically labeled derivatives
  • second active agents include small molecules and large molecules (e.g., proteins and antibodies).
  • compositions e.g., single unit dosage forms
  • pharmaceutical compositions comprise a compound provided herein, or a pharmaceutically acceptable form (e.g., salts, hydrates, solvates, isomers, sterioisomers, prodrugs, and isotopically labeled derivatives) thereof, and optionally one or more second active agents.
  • a pharmaceutically acceptable form e.g., salts, hydrates, solvates, isomers, sterioisomers, prodrugs, and isotopically labeled derivatives
  • agent refers to a biological, pharmaceutical, or chemical compound or another moiety.
  • Non-limiting examples include simple or complex organic or inorganic molecules, a peptide, a protein, an oligonucleotide, an antibody, an antibody derivative, an antibody fragment, a vitamin, a vitamin derivative, a carbohydrate, a toxin, or a chemotherapeutic compound, and metabolites thereof.
  • Various compounds can be synthesized, for example, small molecules and oligomers (e.g., oligopeptides and oligonucleotides), and synthetic organic compounds based on various core structures.
  • various natural sources can provide active compounds, such as plant or animal extracts, and the like. A skilled artisan can readily recognize that there is no limit as to the structural nature of the agents of this disclosure.
  • administering of a disclosed compound encompasses the delivery to a subject of a compound as described herein, or a prodrug or other pharmaceutically acceptable derivative thereof, using any suitable formulation or route of administration, as discussed herein.
  • the term "co-administration,” “administered in combination with,” and their grammatical equivalents, as used herein, encompasses administration of two or more agents to the subject so that both agents and/or their metabolites are present in the subject at the same time. Coadministration includes simultaneous administration in separate compositions, administration at separate times in separate compositions, or administration in a composition in which both agents are present.
  • the term "effective amount” or “therapeutically effective amount” refers to that amount of a compound or pharmaceutical composition described herein that is sufficient to affect the intended application including, but not limited to, disease treatment, as illustrated below.
  • the amount is that effective for detectable inhibition of LPA1, which, for example, can be determined in an LPA1 functional antagonist assay.
  • the therapeutically effective amount can vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
  • the term also applies to a dose that will induce a response in target cells, e.g., reduction of cell migration.
  • the specific dose will vary depending on, for example, the compounds chosen, the species of subject and their age/existing health conditions or risk for health conditions, the dosing regimen to be followed, the severity of the disease, whether it is administered in combination with other agents, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.
  • treatment As used herein, the terms “treatment”, “treating”, “palliating” “managing” and “ameliorating” are used interchangeably herein. These terms refer to an approach for obtaining beneficial or desired results including, but not limited to, therapeutic benefit and/or a prophylactic benefit.
  • therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated.
  • a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient can still be afflicted with the underlying disorder.
  • the pharmaceutical compounds and/or compositions can be administered to a patient at risk of developing a disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
  • the terms “preventing” and “prophylaxis” as used herein refer to administering a pharmaceutical compound or medicament or a composition including the pharmaceutical compound or medicament to a subject before a disease, disorder, or condition fully manifests itself, to forestall the appearance and/or reduce the severity of one or more symptoms of the disease, disorder or condition.
  • the term “prevent” is not an absolute term. In the medical art it is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or seriousness of a disease, disorder or condition, or a symptom thereof, and this is the sense that such terms are used in this disclosure.
  • a prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
  • the "subjects" to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including rodents (e.g., mice, rats), cattle, pigs, horses, sheep, goats, cats, and/or dogs; and/or birds, including birds such as chickens, ducks, geese, quail, and/or turkeys.
  • humans i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or other
  • in vivo refers to an event that takes place in a subject’s body. In vivo also includes events occurring in rodents, such as rats, mice, guinea pigs, and the like.
  • in vitro refers to an event that takes places outside of a subject’s body.
  • an in vitro assay encompasses any assay conducted outside of a subject.
  • in vitro assays encompass cell-based assays in which cells, alive or dead, are employed.
  • In vitro assays also encompass cell-free assays in which no intact cells are employed.
  • the term "pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. (incorporated by referene herein) describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1-19.
  • Pharmaceutically acceptable salts of the compounds provided herein include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, besylate, benzoate, bisulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentane propionate, digluconate, dodecyl sulfate, ethane sulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemi sulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,
  • organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, lactic acid, trifluoracetic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid, and the like.
  • the salts can be prepared in situ during the isolation and purification of the disclosed compounds, or separately, such as by reacting the free base or free acid of a parent compound with a suitable base or acid, respectively.
  • Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (Ci-4alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.
  • compositions include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
  • the pharmaceutically acceptable base addition salt can be chosen from ammonium, potassium, sodium, calcium, and magnesium salts.
  • solvate refers to compounds that further include a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces.
  • the solvate can be of a disclosed compound or a pharmaceutically acceptable salt thereof. Where the solvent is water, the solvate is a "hydrate”.
  • Pharmaceutically acceptable solvates and hydrates are complexes that, for example, can include 1 to about 100, or 1 to about 10, or 1 to about 2, about 3 or about 4, solvent or water molecules. It will be understood that the term "compound” as used herein encompasses the compound and solvates of the compound, as well as mixtures thereof.
  • the pharmaceutically acceptable form is a prodrug.
  • prodrug refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable form of the compound.
  • a prodrug can be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis (e.g., hydrolysis in blood).
  • hydrolysis e.g., hydrolysis in blood
  • a prodrug has improved physical and/or delivery properties over the parent compound.
  • Prodrugs can increase the bioavailability of the compound when administered to a subject (e.g., by permitting enhanced absorption into the blood following oral administration) or which enhance delivery to a biological compartment of interest (e.g., the brain or lymphatic system) relative to the parent compound.
  • exemplary prodrugs include derivatives of a disclosed compound with enhanced aqueous solubility or active transport through the gut membrane, relative to the parent compound.
  • the prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7- 9, 21-24 (Elsevier, Amsterdam).
  • a discussion of prodrugs is provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein.
  • Exemplary advantages of a prodrug can include, but are not limited to, its physical properties, such as enhanced water solubility for parenteral administration at physiological pH compared to the parent compound, or it can enhance absorption from the digestive tract, or it can enhance drug stability for long-term storage.
  • prodrug is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a subject.
  • Prodrugs of an active compound, as described herein can be prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound.
  • Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively.
  • prodrugs examples include, but are not limited to, acetate, formate and benzoate derivatives of an alcohol or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound and the like.
  • Other examples of prodrugs include compounds that comprise -NO, -NO2, -ONO, or -ONO2moieties.
  • Prodrugs can typically be prepared using well known methods, such as those described in Burger ’s Medicinal Chemistry and Drug Discovery, 172-178, 949-982 (Manfred E. Wolff ed., 5th ed., 1995), and Design of Prodrugs (H. Bundgaard ed., Elselvier, New York, 1985).
  • a prodrug can comprise a pharmaceutically acceptable ester formed by the replacement of the hydrogen atom of the acid group with a group such as (Ci-s)alkyl, (Ci-i2)alkanoyloxymethyl, 1- (alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1 -methyl- l-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxy carbonyloxymethyl having from 3 to 6 carbon atoms, 1 -(alkoxy carbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl- 1 -(alkoxy carbonyl oxy )ethyl having from 5 to 10 carbon atoms, N-(alkoxycarbonyl)aminom ethyl having from 3 to 9 carbon atoms, 1-(N- (alk)alkyl, (Ci-i2)alkanoyloxymethyl, 1- (alkanoyloxy)ethyl
  • a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (Ci- 6)alkanoyloxymethyl, l-((Ci-6)alkanoyloxy)ethyl,l -methyl- l-((Ci-6)alkanoyloxy)ethyl, (Ci- 6)alkoxycarbonyloxymethyl, N-(Ci-6)alkoxycarbonylaminomethyl, succinoyl, (Ci- e)alkanoyl, a- amino(Ci-4)alkanoyl, arylacyl, and a-aminoacyl, or a-aminoacyl-a- aminoacyl, where each a- aminoacyl group is independently selected from the naturally occurring L-amino acids, - P(O)(OH)2, -P(O)(O(Ci-e)alkyl)2
  • a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as R-carbonyl, RO- carbonyl, NRR’ -carbonyl where R and R’ are each independently selected from (Ci-io)alkyl, (C3- ?)cycloalkyl, benzyl, a natural a-aminoacyl or natural a-aminoacyl-natural-a-aminoacyl,- C(OH)C(O)OY 1 wherein Y 1 is H, (Ci-e)alkyl or benzyl;-C(OY 2 )Y 3 wherein Y 2 is (Ci-4)alkyl and Y 3 is (Ci-e)alkyl, carboxy(Ci-e)alkyl, amino(Ci-4)alkyl or mono-N- or di-N,N-(Ci- 6)alkylaminoalky
  • the disclosed compounds may encompass an isomer.
  • “Isomers” are different compounds that have the same molecular formula.
  • “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space.
  • the term “isomer” includes any and all geometric isomers and stereoisomers.
  • “isomers” include geometric double bond cis- and trans-i somers, also termed E- and Z-isomers; R- and S-enantiomers; diastereomers, (d)-isomers and (l)-isomers, racemic mixtures thereof; and other mixtures thereof, as falling within the scope of this disclosure.
  • Geometric isomers can be represented by the symbol - which denotes a bond that can be a single, double or triple bond as described herein.
  • Substituents around a carbon-carbon double bond are designated as being in the "Z” or "E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the "E” and "Z” isomers.
  • Substituents around a carbon-carbon double bond alternatively can be referred to as “cis” or"trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond.
  • the arrangement of substituents around a carbocyclic ring can also be designated as “cis” or “trans.”
  • the term “cis” represents substituents on the same side of the plane of the ring, and the term “trans” represents substituents on opposite sides of the plane of the ring.
  • Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line.
  • Certain of the compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry at each asymmetric atom, as (R)- or (S)-.
  • the present chemical entities, pharmaceutical compositions and methods are meant to include all such possible isomers, including racemic mixtures, optically substantially pure forms and intermediate mixtures.
  • Optically active (R)- and (S)-isomers can be prepared, for example, using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • a mixture of a pair of enantiomers in any proportion can be known as a "racemic” mixture.
  • the term “( ⁇ )” is used to designate a racemic mixture where appropriate.
  • a compound of the present technology is a racemic mixture of (S)- and (R)-isomers.
  • the racemic mixture has equal amounts of two enantiomers.
  • an enantiomer is provided partly or substantially free of the corresponding enantiomer, and may be referred to as “optically enriched,” “enantiomerically enriched,” “enantiomerically pure,” and “non-racemic,” as used interchangeably herein.
  • compositions described herein contain an enantiomeric excess of at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 99.5% of the S enantiomer, or a range between and including any two of the foregoing values (e.g., 50-99.5% ee).
  • the compositions contain an enantiomeric excess of the S enantiomer over the R enantiomer.
  • compositions described herein contain an enantiomeric excess of at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 99.5% of the R enantiomer or a range between any two of the foregoing values (e.g., 50-99.5% ee).
  • the compositions contain an enantiomeric excess of the R enantiomer over the S enantiomer.
  • compositions are referred to as “substantially enantiomerically enriched,” “substantially enantiomerically pure” or a “substantially non-racemic” preparation.
  • Enantiomers can be isolated from racemic mixtures by any method known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC), the formation and crystallization of chiral salts, or prepared by asymmetric syntheses. See, for example, Enantiomers, Racemates and Resolutions (Jacques, Ed., Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Stereochemistry of Carbon Compounds (E. L. Eliel, Ed., McGraw- Hill, NY, 1962); and Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. EIM, Ed., Univ, of Notre Dame Press, Notre Dame, Ind. 1972).
  • HPLC high-pressure liquid chromatography
  • Optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, e.g., by formation of diastereoisomeric salts, by treatment with an optically active acid or base.
  • appropriate acids include, but are not limited to, tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid.
  • the separation of the mixture of diastereoisomers by crystallization followed by liberation of the optically active bases from these salts affords separation of the isomers.
  • Another method involves synthesis of covalent diastereoisomeric molecules by reacting disclosed compounds with an optically pure acid in an activated form or an optically pure isocyanate.
  • the synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to deliver the enantiomerically enriched compound.
  • Optically active compounds can also be obtained by using active starting materials. In some embodiments, these isomers can be in the form of a free acid, a free base, an ester or a salt.
  • the pharmaceutically acceptable form is a tautomer.
  • tautomer is a type of isomer that includes two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa).
  • Tautomerization includes prototropic or proton-shift tautomerization, which is considered a subset of acid-base chemistry.
  • Prototropic tautomerization or"proton-shift tautomerization” involves the migration of a proton accompanied by changes in bond order.
  • Tautomerizations i.e., the reaction providing a tautomeric pair
  • Exemplary tautomerizations include, but are not limited to, keto-to-enol; amide-to-imide; lactam-to-lactim; enamine-to-imine; and enamine-to-(a different) enamine tautomerizations.
  • keto-enol tautomerization is the interconversion of pentane-2, 4-dione and 4-hydroxypent-3-en-2-one tautomers.
  • tautomerization is phenol-keto tautomerization.
  • phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(lH)-one tautomers.
  • structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C- or 14 C-enriched carbon are within the scope of this disclosure.
  • the disclosure also embraces pharmaceutically acceptable forms that are “isotopically labeled derivatives” which are compounds that are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2 H, 3 H, 13 C 14 C, 15 N, 18 0, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 C1, respectively.
  • isotopically-labeled disclosed compounds are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes can allow for ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) can afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). Isotopically labeled disclosed compounds can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • radiolabeled compounds are useful for studying metabolism and/or tissue distribution of the compounds or to alter the rate or path of metabolism or other aspects of biological functioning.
  • “Pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • the pharmaceutically acceptable carrier or excipient does not destroy the pharmacological activity of the disclosed compound and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions as disclosed herein is contemplated.
  • Non-limiting examples of pharmaceutically acceptable carriers and excipients include sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; glycols, such as polyethylene glycol and propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate; coloring
  • Cyclodextrins such as a-, P-, and y-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3- hydroxypropyl-cyclodextrins, or other solubilized derivatives can also be used to enhance delivery of compounds described herein.
  • Ci-6 alkyl is intended to encompass, Ci, C2, C3, C4, C5, Ce, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.
  • Alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to ten carbon atoms (e.g., Ci-10 alkyl). Whenever it appears herein, a numerical range such as “ 1 to 10" refers to each integer in the given range; e.g., " 1 to 10 carbon atoms” means that the alkyl group can consist of 1, 2, 3, ,4 5, 6, 7, 8, 9, or 10 carbon atoms, although the present definition also covers the occurrence of the term "alkyl” where no numerical range is designated. In some embodiments, alkyl groups have 1 to 10, 1 to 8, 1 to 6, or 1 to 3 carbon atoms.
  • saturated straight chain alkyls include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl groups; while saturated branched alkyls include, but are not limited to, isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl, 3 -methylbutyl, 2-methylpentyl, 3 -methylpentyl, 4-methylpentyl, 2- methylhexyl, 3 -methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, and the like.
  • alkyl is attached to the parent molecule by a single bond.
  • an alkyl group may be optionally substituted by one or more of substituents disclosed herein.
  • a substituted alkyl can be selected from fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3 -fluoropropyl, hydroxymethyl, 2-hydroxy ethyl, 3- hydroxypropyl, benzyl, and phenethyl.
  • alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, and having from two to ten carbon atoms (i.e., C2-10 alkenyl). Whenever it appears herein, a numerical range such as “2 to 10" refers to each integer in the given range; e.g., "2 to 10 carbon atoms” means that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. In any embodiments, an alkenyl comprises two to eight carbon atoms.
  • an alkenyl comprises two to six carbon atoms (e.g., C2-6 alkenyl).
  • the alkenyl is attached to the parent molecular structure by a single bond, for example, ethenyl (i.e., vinyl), prop-l-enyl (i.e., allyl), but- 1-enyl, pent-l-enyl, penta- 1,4-dienyl, and the like.
  • the one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl).
  • Examples of C2-4 alkenyl groups include ethenyl (C2), 1 -propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), 2-methylprop-2-enyl (C4), butadienyl (C4) and the like.
  • Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (Ce), 2,3-dimethyl-2-butenyl (Ce) and the like.
  • alkenyl examples include heptenyl (C7), octenyl (Cs), octatrienyl (Cs) and the like. Unless stated otherwise in the specification, an alkenyl group may be optionally substituted by one or more of substituents disclosed herein.
  • Alkynyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to ten carbon atoms (i.e., C2-10 alkynyl).
  • a numerical range such as “2 to 10” refers to each integer in the given range; e.g., "2 to 10 carbon atoms” means that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms.
  • an alkynyl comprises two to eight carbon atoms.
  • an alkynyl has two to six carbon atoms (e.g., C2-6 alkynyl).
  • the alkynyl is attached to the parent molecular structure by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, 3-methyl-4-pentenyl, hexynyl, and the like.
  • an alkynyl group may be optionally substituted by one or more of substituents disclosed herein.
  • Alkoxy refers to the group -O-alkyl, including from 1 to 10 carbon atoms of a straight, branched, saturated cyclic configuration and combinations thereof, attached to the parent molecular structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t- butoxy, pentoxy, cyclopropyloxy, cyclohexyloxy and the like.
  • Lower alkoxy refers to alkoxy groups containing one to six carbons. In some embodiments, Ci-4alkoxy is an alkoxy group which encompasses both straight and branched chain alkyls of from 1 to 4 carbon atoms.
  • alkoxy group may be optionally substituted by one or more of substituents disclosed herein.
  • alkenoxy and alkynoxy mirror the above description of “alkoxy” wherein the prefix “alk” is replaced with “alken” or “alkyn” respectively, and the parent “alkenyl” or “alkynyl” terms are as described herein.
  • Aromatic refers to a radical with 6 to 14 ring atoms (e.g., Ce-14 aromatic or Ce- 14 aryl) which has at least one ring having a conjugated pi electron system which is carbocyclic (e.g., phenyl, fluorenyl, and naphthyl).
  • the aryl is a Ce-io aryl group.
  • bivalent radicals formed from substituted benzene derivatives and having the free valences at ring atoms are named as substituted phenylene radicals.
  • bivalent radicals derived from univalent polycyclic hydrocarbon radicals whose names end in"-yl" by removal of one hydrogen atom from the carbon atom with the free valence are named by adding idene" to the name of the corresponding univalent radical, e.g., a naphthyl group with two points of attachment is termed naphthylidene.
  • the term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of ring atoms) groups.
  • Polycyclic aryl groups include bicycles, tricycles, tetracycles, and the like. In a multi-ring group, only one ring is required to be aromatic, so groups such as indanyl are encompassed by the aryl definition.
  • Non-limiting examples of aryl groups include phenyl, phenalenyl, naphthalenyl, tetrahydronaphthyl, phenanthrenyl, anthracenyl, fluorenyl, indolyl, indanyl, and the like. Unless stated otherwise in the specification, an aryl group may be optionally substituted by one or more of substituents disclosed herein.
  • Cycloalkyl and “carbocyclyl” each refer to a monocyclic or polycyclic radical that contains only carbon and hydrogen, and can be saturated or partially unsaturated. Partially unsaturated cycloalkyl groups can be termed “cycloalkenyl” if the carbocycle contains at least one double bond, or "cycloalkynyl” if the carbocycle contains at least one triple bond. Cycloalkyl groups include groups having from 3 to 13 ring atoms (i.e., C3-13 cycloalkyl).
  • a numerical range such as “3 to 10" refers to each integer in the given range; e.g., "3 to 13 carbon atoms” means that the cycloalkyl group can consist of 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, etc., up to and including 13 carbon atoms.
  • the term "cycloalkyl” also includes bridged and spiro-fused cyclic structures containing no heteroatoms.
  • the term also includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of ring atoms) groups.
  • Polycyclic aryl groups include bicycles, tricycles, tetracycles, and the like.
  • cycloalkyl can be a C3-8 cycloalkyl radical. In some embodiments, “cycloalkyl” can be a C3-5 cycloalkyl radical.
  • Illustrative examples of cycloalkyl groups include, but are not limited to the following moieties: C3-6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce) and the like.
  • C3-7 carbocyclyl groups include norbornyl (C7).
  • Examples of C3-8 carbocyclyl groups include the aforementioned C3-7 carbocyclyl groups as well as cycloheptyl(C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, and the like.
  • C3-13 carbocyclyl groups include the aforementioned C3-8 carbocyclyl groups as well as octahydro- 1H indenyl, decahydronaphthal enyl, spiro[4.5]decanyl and the like.
  • a cycloalkyl group may be optionally substituted by one or more of substituents disclosed herein.
  • the terms “cycloalkenyl” and “cycloalkynyl” mirror the above description of “cycloalkyl” wherein the prefix “alk” is replaced with “alken” or “alkyn” respectively, and the parent “alkenyl” or “alkynyl” terms are as described herein.
  • a cycloalkenyl group can have 3 to 13 ring atoms, such as 5 to 8 ring atoms.
  • a cycloalkynyl group can have 5 to 13 ring atoms.
  • Halo means fluoro, chloro, bromo or iodo.
  • haloalkyl means alkyl, alkenyl, alkynyl and alkoxy structures that are substituted with one or more halo groups or with combinations thereof, preferably substituted with one, two, or three halo groups.
  • fluoroalkyl and fluoroalkoxy include haloalkyl and haloalkoxy groups, respectively, in which the halo is fluorine, such as, but not limited to, trifluoromethyl, difluoromethyl, 2,2,2- trifluoroethyl, l-fluoromethyl-2-fluoroethyl, -O-CHF2, and the like.
  • halo is fluorine, such as, but not limited to, trifluoromethyl, difluoromethyl, 2,2,2- trifluoroethyl, l-fluoromethyl-2-fluoroethyl, -O-CHF2, and the like.
  • alkyl, alkenyl, alkynyl and alkoxy groups are as defined herein and can be optionally further substituted as defined herein.
  • Heteroaryl or, alternatively, “heteroaromatic” refers to a refers to a radical of a 5-18 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic, tetracyclic and the like) aromatic ring system (e.g., having 6, 10 or 14 it electrons shared in a cyclic array) having ring carbon atoms and 1-6 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorous and sulfur ("5-18 membered heteroaryl").
  • Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings.
  • a numerical range such as “5 to 18” refers to each integer in the given range; e.g., "5 to 18 ring atoms” means that the heteroaryl group can consist of 5 ring atoms, 6 ring atoms, etc., up to and including 18 ring atoms. In some instances, a heteroaryl can have 5 to 14 ring atoms.
  • the heteroaryl has, for example, bivalent radicals derived from univalent heteroaryl radicals whose names end in "-yl" by removal of one hydrogen atom from the atom with the free valence are named by adding "-ene” to the name of the corresponding univalent radical, e.g., a pyridyl group with two points of attachment is a pyridylene.
  • an N-containing "heteroaromatic" or “heteroaryl” moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom.
  • One or more heteroatom(s) in the heteroaryl radical can be optionally oxidized.
  • Heteroaryl also includes ring systems substituted with one or more nitrogen oxide (-O-) substituents, such as pyridinyl N-oxides.
  • the heteroaryl is attached to the parent molecular structure through any atom of the ring(s).
  • Heteroaryl also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment to the parent molecular structure is either on the aryl or on the heteroaryl ring, or wherein the heteroaryl ring, as defined above, is fused with one or more cycloalkyl or heterocyclyl groups wherein the point of attachment to the parent molecular structure is on the heteroaryl ring.
  • the point of attachment to the parent molecular structure can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).
  • a heteroatom e.g., 2-indolyl
  • a heteroatom e.g., 5-indolyl
  • a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorous, and sulfur ("5-10 membered heteroaryl").
  • a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorous, and sulfur ("5-8 membered heteroaryl").
  • a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorous, and sulfur ("5-6 membered heteroaryl").
  • the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, phosphorous, and sulfur.
  • the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, phosphorous, and sulfur.
  • the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, phosphorous, and sulfur.
  • heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, benzo[b][l,4] oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodi oxolyl, benzodioxinyl, benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzopyranonyl, benzofurazanyl, benzothiazolyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d
  • Heterocyclyl each refer to any 3 to 18- membered non-aromatic radical monocyclic or polycyclic moiety comprising at least one carbon atom and at least one heteroatom selected from nitrogen, oxygen, phosphorous and sulfur.
  • a heterocyclyl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein the polycyclic ring systems can be a fused, bridged or spiro ring system.
  • Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings.
  • a heterocyclyl group can be saturated or partially unsaturated.
  • heterocycloalkenyl if the heterocyclyl contains at least one double bond
  • heterocycloalkynyl if the heterocyclyl contains at least one triple bond.
  • a numerical range such as “5 to 18” refers to each integer in the given range; e.g., "5 to 18 ring atoms” means that the heterocyclyl group can consist of 5 ring atoms, 6 ring atoms, etc., up to and including 18 ring atoms.
  • bivalent radicals derived from univalent heterocyclyl radicals whose names end in "-yl” by removal of one hydrogen atom from the atom with the free valence are named by adding "-ene” to the name of the corresponding univalent radical, e.g., a piperidine group with two points of attachment is a piperidylene.
  • An N-containing heterocyclyl moiety refers to a non-aromatic group in which at least one of the ring atoms is a nitrogen atom.
  • the heteroatom(s) in the heterocyclyl radical can be optionally oxidized.
  • One or more nitrogen atoms, if present, can be optionally quaternized.
  • Heterocyclyl also includes ring systems substituted with one or more nitrogen oxide (-O-) substituents, such as piperidinyl N-oxides.
  • the heterocyclyl is attached to the parent molecular structure through any atom of any of the ring(s).
  • Heterocyclyl also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment to the parent molecular structure is on the heterocyclyl ring.
  • a heterocyclyl group is a 5- 14 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorous and sulfur ("5-14 membered heterocyclyl").
  • a heterocyclyl group is a 3-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorous and sulfur ("3-10 membered heterocyclyl").
  • a heterocyclyl group is a 5-8 membered non- aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorous and sulfur ("5-8 membered heterocyclyl").
  • a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorous and sulfur ("5-6 membered heterocyclyl").
  • the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen phosphorous and sulfur.
  • the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, phosphorous and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, phosphorous and sulfur.
  • Examples of a ketone-contianing heterocycle include, without limitation, pyridin-2(lH)-one, pyrazin-2(lH)-one, pyrimidin-2(lH)-one, pyrimidin-4(3H)-one, pyridazin-3(2H)-one, pyridin- 4(lH)-one, imidazolidin-2-one, l,3-dihydro-2H-imidazol-2-one, 2,4-dihydro-3H-l,2,4-triazol-3- one, oxazol-2(3H)-one, and oxazolidin-2-one.
  • a ketone-containing heterocyclyl is obtainable by removing a hydrogen atom from its corepsonding ketone-contianing heterocycle at any available N-H or C-H position.
  • Exemplary 3-membered heterocyclyls containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, and thiorenyl.
  • Exemplary 4-membered heterocyclyls containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl.
  • Exemplary 5-membered heterocyclyls containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2, 5-dione.
  • Exemplary 5-membered heterocyclyls containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl, thiazolidinyl, and dithiolanyl.
  • Exemplary 5- membered heterocyclyls containing 3 heteroatoms include, without limitation, triazolinyl, diazol onyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6 membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, thiomorpholinyl, dithianyl, dioxanyl, and triazinanyl.
  • Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl.
  • Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl.
  • bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, benzoxanyl, benzopyrrolidinyl, benzopiperidinyl, benzoxolanyl, benzothiol any 1, benzothianyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, 3-lH-benzimidazol-2-one, (l-substituted)-2-oxo- benzimidazol-3-yl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl
  • a heterocyclyl group may be optionally substituted by one or more of substituents disclosed herein.
  • substituent groups are specified by their conventional chemical Formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2- .
  • a "leaving group or atom” is any group or atom that will, under the reaction conditions, cleave from the starting material, thus promoting reaction at a specified site. Suitable non-limiting examples of such groups unless otherwise specified include halogen atoms, mesyloxy, p- nitrobenzensulphonyloxy, trifluoromethyloxy, and tosyloxy groups.
  • Protecting group has the meaning conventionally associated with it in organic synthesis, i.e., a group that selectively blocks one or more reactive sites in a multifunctional compound such that a chemical reaction can be carried out selectively on another unprotected reactive site and such that the group can readily be removed after the selective reaction is complete.
  • functional groups that can be masked with a protecting group include an amine, hydroxy, thiol, carboxylic acid, and aldehyde.
  • a hydroxy protected form is where at least one of the hydroxy groups present in a compound is protected with a hydroxy protecting group.
  • protecting groups are disclosed, for example, Greene’s Protective Groups in Organic Synthesis, Fifth Edition, Wiley (2014), incorporated herein by reference in its entirety.
  • protecting group methodologies materials, methods and strategies for protection and deprotection
  • other synthetic chemistry transformations useful in producing the compounds described herein, see in R. Larock, Comprehensive organic Transformations, VCH Publishers (1989); Greene’s Protective Groups in Organic Synthesis, Fifth Edition, Wiley (2014); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995). These references are incorporated herein by reference in their entirety.
  • substituted or “substitution” mean that at least one hydrogen present on a group atom (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution for the hydrogen results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • a "substituted” group can have a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.
  • Substituents include one or more group(s) individually and independently selected from acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo (i.e., F, Cl, Br, I), haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sul
  • a cycloalkyl substituent can have a halide substituted at one or more ring carbons, and the like.
  • the protecting groups that can form the protective derivatives of the above substituents are known to those of skill in the art and can be found in references such as Greene and Wuts, above.
  • a ring system e.g., cycloalkyl, heterocyclyl, aryl, or heteroaryl
  • substituents varying within an expressly defined range
  • the total number of substituents does not exceed the normal available valencies under the existing conditions.
  • a phenyl ring substituted with "p" substituents can have 0 to 5 substituents
  • a pyridinyl ring substituted with "p” substituents has several substituents ranging from 0 to 4.
  • the maximum number of substituents that a group in the disclosed compounds can have can be easily determined.
  • the substituted group encompasses only those combinations of substituents and variables that result in a stable or chemically feasible compound.
  • a stable compound or chemically feasible compound is one that, among other factors, has stability sufficient to permit its preparation and detection.
  • disclosed compounds are sufficiently stable that they are not substantially altered when kept at a temperature of 40° C or less, in the absence of moisture (e.g., less than about 10%, less than about 5%, less than about 2%, less than about 1%, or less than about 0.5%) or other chemically reactive conditions, for e.g., at least about 3 days, at least about a week, at least about 2 weeks, at least about 4 weeks, or at least about 6 weeks.
  • the terms “combine, combining, to combine, combination” refer to the action of adding at least one chemical substance to another chemical substance(s) either sequentially or simultaneously.
  • bringing these chemical substances together can result in transformation of the initial chemical substances into one or more different chemical substances. This transformation can occur through one or more chemical reactions, e.g., where covalent bonds are formed, broken, rearranged and the like.
  • a non-limiting example can include hydrolysis of an ester into an alcohol and carboxylic acid which can result from the combination of the ester with a suitable base.
  • an aryl fluoride can be combined with an amine to provide an aryl amine through a substitution process.
  • convert, converting, to convert, conversion refer to a subset of “combination” and its grammatical equivalents, where the action of one or more reagents transforms one or more functional groups on a chemical substance to another functional group(s).
  • a conversion includes, but is not limited to, transforming a nitro functional group on a chemical substance to an amine with a reducing agent.
  • Conversions also include changes in charged chemical substances, radical chemical substances and isotopically labeled chemical substances.
  • the term “convert” does not include alteration of conserved bonds in disclosed genuses and compounds.
  • the present invention relates to a compound of Formula (I):
  • Z is CH2 or O
  • Y 1 , Y 2 , Y 3 and Y 4 are each independently N or CR 5 , provided that at least one but no more than two of Y 1 , Y 2 , Y 3 and Y 4 are N;
  • X 1 is N, O or CR 6a ;
  • X 2 is N or NR 6 ;
  • X 3 is N, NR 6 or CR 6 , wherein the dashed circle denotes bonds forming a five-membered aromatic ring;
  • L 1 is a covalent bond or CH2 optionally substituted with 1 or 2 methyl groups
  • L 2 is a covalent bond or (CR 7 R 7 ) P ;
  • L 3 is a covalent bond, O or NR 7 , provided that at least one of L 2 and L 3 is not a covalent bond;
  • R 2 is (CR 7 R 7 ) q -R 8 ;
  • R 3 at each occurrence is independently hydrogen, halogen, CN, Ci-ealkyl, or C3-7cycloalkyl;
  • R 4 is independently hydrogen, halogen, Ci-ealkyl, haloCi-ealkyl, C2-ealkenyl, C2-ealkynyl, Ci- ealkoxy, (CH2)p-Ci-ealkoxy, phenyl, (CH2) P -phenyl, O(CH2) P -phenyl, CN, C3-7cycloalkyl, (CH2) P - C3-7cycloalkyl, C2-6alkenyl-C3-7cycloalkyl, C2-6alkynyl-C3-7cycloalkyl, O(CH2) P -C3-7cycloalkyl, (CH2)q-5-6-membered heteroaryl ring substituted with 1-4 R 11 , (CH2)q-5-7-membered heterocyclyl ring substituted with 1-4 R 11 , in which each phenyl is independently optionally substituted with 1-3 of halogen, Ci-ealkyl, or Ci-ealkoxy
  • R 5 at each occurrence is independently hydrogen, halogen, Ci-ealkyl, haloCi -ealkyl, OH, Ci- ealkyl-OH, Ci-ealkoxy, Ci-ealkyl-Ci-ealkoxy, haloCi-ealkoxy, CN, C3-7cycloalkyl, NR a R b , or Ci- 6 alkyl-NR a R b ; each occurrence of R 6a and R 6 is independently hydrogen, halogen, CN, methyl, ethyl, propyl, or cyclopropyl;
  • R 7 at each occurrence is independently hydrogen, Ci-4alkyl, C3-5cycloalkyl, or twoR 7 groups together with the carbon atom to which they are attached, form a 3-5-membered cycloalkyl ring;
  • R 12 at each occurrence is independently hydrogen, Ci-4alkyl, C3-7cycloalkyl, or two R 12 groups, together with the carbon atom to which they are attached, form a 3-6-membered cycloalkyl ring; each occurrence of R a and R b is independently hydrogen or Ci-ealkyl, or R a and R b , together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of Cwalkyl, phenyl and benzyl; m is 1, or 2; n is 0, 1, or 2; p at each occurrence is independently 1, 2, 3 or 4; and q at each occurrence is independently 0, 1, 2, 3 or 4.
  • the compound of Formula (I) includes a compound of Formula (II): or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein: L 1 is a covalent bond or CH2 optionally substituted with 1 or 2 methyl groups;
  • L 2 is a covalent bond or (CR 7 R 7 ) P ;
  • L 3 is a covalent bond, O or NR 7 , provided that at least one of L 2 and L 3 is not a covalent bond;
  • X 1 is N, or CR 6a ;
  • Z is CH2 or O
  • R 3 at each occurrence is independently hydrogen, halogen, CN, Ci-ealkyl, or C3-7cycloalkyl;
  • R 4 is independently hydrogen, halogen, Ci-ealkyl, haloCi-ealkyl, C2-ealkenyl, C2-ealkynyl, Ci- ealkoxy, (CH2)p-Ci-ealkoxy, phenyl, (CH2) P -phenyl, O(CH2) P -phenyl, CN, C3-7cycloalkyl, (CH2) P - C3-7cycloalkyl, C2-6alkenyl-C3-7cycloalkyl, C2-6alkynyl-C3-7cycloalkyl, O(CH2) P -C3-7cycloalkyl, (CH2)q-5-6-membered heteroaryl ring substituted with 1-4 R 11 , (CH2)q-5-7-membered heterocyclyl ring substituted with 1-4 R 11 , in which each phenyl is independently optionally substituted with 1- 3 of halogen, Ci-ealkyl, or Ci-ealkoxy
  • R 5 at each occurrence is independently hydrogen, halogen, Ci-ealkyl, haloCi-ealkyl, OH, Ci-ealkyl- OH, Ci-ealkoxy, Ci-ealkyl-Ci-ealkoxy, haloCi-ealkoxy, CN, C3-7cycloalkyl, NR a R b , or Ci-ealkyl- NR a R b ;
  • R 6a is hydrogen, or methyl
  • R 6 is hydrogen, halogen, CN, methyl, ethyl, propyl, or cyclopropyl;
  • R 7 at each occurrence is independently hydrogen, Ci-4alkyl, C3-5cycloalkyl, or R 7 andR 7 , together with the carbon atom to which they are attached, form a 3-5-membered cycloalkyl ring;
  • R 11 at each occurrence is independently hydrogen, Ci-ealkyl, haloCi -ealkyl, C2-ealkenyl, C2- ealkynyl, Ci-ealkoxy, (CH2)p-Ci-ealkoxy, phenyl, (CH2) P -phenyl, O(CH2) P -phenyl, CN, C3- vcycloalkyl, (CH2) P -C3-7cycloalkyl, C2-ealkenyl-C3-7cycloalkyl, C2-ealkynyl, O(CH2) P -C3- 7cycloalkyl, in which each phenyl is independently optionally substituted with 1-3 of halogen, Ci- e
  • R 13 at each occurrence is independently hydrogen, Ci-4alkyl, or C3-5cycloalkyl; each occurrence of Ra and Rb is independently hydrogen or Ci-ealkyl, or Ra and Rb, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of Cwalkyl, phenyl and benzyl; n is 0, 1 or 2; p at each occurrence is independently 1, 2, 3 or 4; t is 0, 1, 2 or 3; and w is 0 or 1, provided that when L 1 is a covalent bond, w is 1, and further provided that when L 1 is CH2 optionally substituted with 1 or 2 methyl groups, w is 0.
  • the compound of Formula I includes a compound of Formula (Ila) or (Ilaa): or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein: L 2 is a covalent bond or (CR 7 R 7 ) P ;
  • L 3 is a covalent bond, O or NR 7 , provided that at least one of L 2 and L 3 is not a covalent bond;
  • Q is a ring selected from the group consisting of 5-membered heteroaryl, 5-membered heterocyclyl, 6-membered heteroaryl, and 6-membered heterocyclyl, wherein the ring comprises at least one carbon atom, at least one nitrogen atom and optionally 1-4 additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein oxygen may be a ring member and/or an oxo attached to a ring member, and wherein the ring is substituted with (R 3 )n and one R 4 ;
  • X 1 is N, or CR 6a ;
  • R 3 at each occurrence is independently hydrogen, halogen, CN, Ci-ealkyl, or C3-7cycloalkyl;
  • R 4 is independently hydrogen, halogen, Ci-ealkyl, haloCi-ealkyl, C2-ealkenyl, C2-ealkynyl, Ci- ealkoxy, (CH2)p-Ci-ealkoxy, phenyl, (CH2) P -phenyl, O(CH2) P -phenyl, CN, C3-7cycloalkyl, (CH2) P - C3-7cycloalkyl, C2-ealkenyl-C3-7cycloalkyl, C2-ealkynyl-C3-7cycloalkyl, O(CH2) P -C3-7cycloalkyl, (CH2)q-5-6-membered heteroaryl ring substituted with 1-4 R 11 , (CH2)q-5-7-membered heterocyclyl ring substituted with 1-4 R 11 , in which each phenyl is independently optionally substituted with 1- 3 of halogen, Ci-ealkyl, or Ci-ealkoxy
  • R 5 at each occurrence is independently hydrogen, halogen, Ci-ealkyl, haloCi-ealkyl, OH, Ci-ealkyl- OH, Ci-ealkoxy, Ci-ealkyl-Ci-ealkoxy, haloCi-ealkoxy, CN, C3-7cycloalkyl, NR a R b , or Ci-ealkyl- NR a R b ;
  • R 6a is hydrogen, or methyl
  • R 6 is hydrogen, halogen, CN, methyl, ethyl, propyl, or cyclopropyl;
  • R 7 at each occurrence is independently hydrogen, Ci-4alkyl, C3-5cycloalkyl, or R 7 andR 7 , together with the carbon atom to which they are attached, form a 3-5-membered cycloalkyl ring;
  • R 11 at each occurrence is independently hydrogen, Ci-ealkyl, haloCi -ealkyl, C2-ealkenyl, C2- ealkynyl, Ci-ealkoxy, (CH2) P -Ci-ealkoxy, phenyl, (CH2) P -phenyl, O(CH2) P -phenyl, CN, C3- vcycloalkyl, (CH2) P -C3-7cycloalkyl, C2-6alkenyl-C3-7cycloalkyl, C2-6alkynyl-C3-7cycloalkyl, O(CH2)p-C3-7cycloalkyl, in which each phenyl is independently optionally substituted with 1-3 of halogen, Ci-ealkyl, or Ci-ealkoxy;
  • R 13 at each occurrence is independently hydrogen, Ci-4alkyl, or C3-5cycloalkyl; each occurrence of Ra and Rb is independently hydrogen or Ci-ealkyl, or Ra and Rb, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of Cwalkyl, phenyl and benzyl; n is 0, 1 or 2; p at each occurrence is independently 1, 2, 3 or 4; and t is 0, 1, 2 or 3.
  • the compound of Formula I includes a compound of Formula (lib) or (Ilbb): or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:
  • L 2 is a covalent bond or (CR 7 R 7 ) P ;
  • L 3 is a covalent bond, O or NR 7 , provided that at least one of L 2 and L 3 is not a covalent bond;
  • Q is a ring selected from the group consisting of 5-membered heteroaryl, 5-membered heterocyclyl, 6-membered heteroaryl, and 6-membered heterocyclyl, wherein the ring comprises at least one carbon atom, at least one nitrogen atom and optionally 1-4 additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and wherein the ring is substituted with (R 3 ) n and one R 4 ;
  • X 1 is N, or CR 6a ;
  • R 3 at each occurrence is independently hydrogen, halogen, CN, Ci-ealkyl, or C3-7cycloalkyl;
  • R 4 is independently hydrogen, halogen, Ci-ealkyl, haloCi-ealkyl, C2-ealkenyl, C2-ealkynyl, Ci- ealkoxy, (CH2)p-Ci-ealkoxy, phenyl, (CH2) P -phenyl, O(CH2) P -phenyl, CN, C3-7cycloalkyl, (CH2) P - C3-7cycloalkyl, C2-6alkenyl-C3-7cycloalkyl, C2-6alkynyl-C3-7cycloalkyl, O(CH2) P -C3-7cycloalkyl, (CH2)q-5-6-membered heteroaryl ring substituted with 1-4 R 11 , (CH2)q-5-7-membered heterocyclyl ring substituted with 1-4 R 11 , in which each phenyl is independently optionally substituted with 1- 3 of halogen, Ci-ealkyl, or Ci-ealkoxy
  • R 5 at each occurrence is independently hydrogen, halogen, Ci-ealkyl, haloCi-ealkyl, OH, Ci-ealkyl- OH, Ci-ealkoxy, Ci-ealkyl-Ci-ealkoxy, haloCi-ealkoxy, CN, C3-7cycloalkyl, NR a R b , or Ci-ealkyl- NR a R b ;
  • R 6a is hydrogen, or methyl
  • R 6 is hydrogen, halogen, CN, methyl, ethyl, propyl, or cyclopropyl;
  • R 7 at each occurrence is independently hydrogen, Ci-4alkyl, C3-5cycloalkyl, or R 7 andR 7 , together with the carbon atom to which they are attached, form a 3-5-membered cycloalkyl ring;
  • R 11 at each occurrence is independently hydrogen, Ci-ealkyl, haloCi -ealkyl, C2-ealkenyl, C2- ealkynyl, Ci-ealkoxy, (CH2) P -Ci-ealkoxy, phenyl, (CH2) P -phenyl, O(CH2) P -phenyl, CN, C3- 7cycloalkyl, (CH2) P -C3-7cycloalkyl, C2-ealkenyl-C3-7cycloalkyl, C2-ealkynyl-C3-7cycloalkyl, O(CH2) P -C3-7cycloalkyl, in which each phenyl is independently optionally substituted with 1-3 of halogen, Ci-ealkyl, or Ci-ealkoxy;
  • R 13 at each occurrence is independently hydrogen, Ci-4alkyl, or C3-5cycloalkyl; each occurrence of Ra and Rb is independently hydrogen or Ci-ealkyl, or Ra and Rb, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of Cwalkyl, phenyl and benzyl; n is 0, 1 or 2; p at each occurrence is independently 1, 2, 3 or 4; and t is 0, 1, 2 or 3.
  • the compound of Formula I includes a compound of Formula (lie) or (IIcc): or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:
  • L 2 is a covalent bond or (CR 7 R 7 ) P ;
  • L 3 is a covalent bond, O or NR 7 , provided that at least one of L 2 and L 3 is not a covalent bond;
  • Q is a ring selected from the group consisting of 5-membered heteroaryl, 5-membered heterocyclyl, 6-membered heteroaryl, and 6-membered heterocyclyl, wherein the ring contains at least one carbon atom, at least one nitrogen atom, and optionally contains 1-4 additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and wherein the ring is substituted with (R 3 )n and one R 4 ;
  • X 1 is N, or CR 6a ;
  • R 3 at each occurrence is independently hydrogen, halogen, CN, Ci-ealkyl, or C3-7cycloalkyl;
  • R 4 is hydrogen, halogen, Ci-ealkyl, haloCi-ealkyl, C2-ealkenyl, C2-ealkynyl, Ci-ealkoxy, (CH2)p-Ci- ealkoxy, phenyl, (CH2) P -phenyl, O(CH2) P -phenyl, CN, C3-7cycloalkyl, (CH2) P -C3-7cycloalkyl, C2- 6alkenyl-C3-7cycloalkyl, C2-ealkynyl, O(CH2) P -C3-7cycloalkyl, (CH2)q-5-6-membered heteroaryl ring substituted with 1-4 R 11 , or (CH2)q-5-7-membered heterocyclyl ring substituted with 1-4 R 11 , in which each phenyl is independently optionally substituted with 1-3 of halogen, Ci-ealkyl, or Ci- ealkoxy;
  • R 5 at each occurrence is independently hydrogen, halogen, Ci-ealkyl, haloCi-ealkyl, OH, Ci-ealkyl- OH, Ci-ealkoxy, Ci-ealkyl-Ci-ealkoxy, haloCi-ealkoxy, CN, C3-7cycloalkyl, NR a R b , or Ci-ealkyl- NR a R b ;
  • R 6a is hydrogen, or methyl
  • R 6 is hydrogen, halogen, CN, methyl, ethyl, propyl, or cyclopropyl;
  • R 7 at each occurrence is independently hydrogen, Ci-4alkyl, C3-5cycloalkyl, or R 7 andR 7 , together with the carbon atom to which they are attached, form a 3-5-membered cycloalkyl ring;
  • R 11 at each occurrence is independently hydrogen, Ci-ealkyl, haloCi -ealkyl, C2-ealkenyl, C2- ealkynyl, Ci-ealkoxy, (CH2)p-Ci-ealkoxy, phenyl, (CH2) P -phenyl, O(CH2) P -phenyl, CN, C3- 7cycloalkyl, (CH2) P -C3-7cycloalkyl, C2-ealkenyl-C3-7cycloalkyl, C2-ealkynyl, O(CH2) P -C3- 7cycloalkyl, in which each phenyl is independently optionally substituted with 1-3 of halogen, Ci- ealkyl, or Ci-ealkoxy;
  • R 13 at each occurrence is independently hydrogen, Ci-4alkyl, or C3-5cycloalkyl; each occurrence of Ra and Rb is independently hydrogen or Ci-ealkyl, or Ra and Rb, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of Cwalkyl, phenyl and benzyl; n is 0, 1 or 2; p at each occurrence is independently 1, 2, 3 or 4; and t is 0, 1, 2 or 3.
  • the compound of Formula I includes a compound of Formula (lid) or (Ildd):
  • L 2 is a covalent bond or (CR 7 R 7 ) P ;
  • L 3 is a covalent bond, O or NR 7 , provided that at least one of L 2 and L 3 is not a covalent bond;
  • X 1 is N, or CR 6a ;
  • R 3 at each occurrence is independently hydrogen, halogen, CN, Ci-ealkyl, or C3-7cycloalkyl;
  • R 4 is independently hydrogen, halogen, Ci-ealkyl, haloCi-ealkyl, C2-ealkenyl, C2-ealkynyl, Ci- ealkoxy, (CH2)p-Ci-ealkoxy, phenyl, (CH2) P -phenyl, O(CH2) P -phenyl, CN, C3-7cycloalkyl, (CH2) P - C3-7cycloalkyl, C2-ealkenyl-C3-7cycloalkyl, C2-ealkynyl, O(CH2) P -C3-7cycloalkyl, (CH2)q-5-6- membered heteroaryl ring substituted with 1-4 R 11 , (CH2)q-5-7-membered heterocyclyl ring substituted with 1-4 R 11 , in which each phenyl is independently optionally substituted with 1-3 of halogen, Ci-ealkyl, or Ci-ealkoxy;
  • R 5 at each occurrence is independently hydrogen, halogen, Ci-ealkyl, haloCi-ealkyl, OH, Ci-ealkyl- OH, Ci-ealkoxy, Ci-ealkyl-Ci-ealkoxy, haloCi-ealkoxy, CN, C3-7cycloalkyl, NR a R b , or Ci-ealkyl- NR a R b ;
  • R 6a is hydrogen, or methyl
  • R 6 is hydrogen, halogen, CN, methyl, ethyl, propyl, or cyclopropyl;
  • R 7 at each occurrence is independently hydrogen, Ci-4alkyl, C3-5cycloalkyl, or two R 7 groups together with the carbon atom to which they are attached, form a 3-5-membered cycloalkyl ring;
  • R 11 at each occurrence is independently hydrogen, Ci-ealkyl, haloCi -ealkyl, C2-ealkenyl, C2- ealkynyl, Ci-ealkoxy, (CH2)p-Ci-ealkoxy, phenyl, (CH2) P -phenyl, O(CH2) P -phenyl, CN, C3- vcycloalkyl, (CH2) P -C3-7cycloalkyl, C2-ealkenyl-C3-7cycloalkyl, C2-ealkynyl-C3-7cycloalkyl, O(CH2) P -C3-7cycloalkyl, in which each phenyl is independently optionally substituted with 1-3 of halogen, Ci-ealkyl, or Ci-ealkoxy; each occurrence of Ra and Rb is independently hydrogen or Ci-ealkyl, or Ra and Rb, together with the nitrogen atom to which they are attached, form a saturated or unsaturated
  • the compound of Formula I includes a compound of Formula (III):
  • X 1 is N, or CR 6a ;
  • Z is CH2 or O
  • L 1 is a covalent bond or CH2 optionally substituted with 1 or 2 methyl groups
  • L 2 is a covalent bond or (CR 7 R 7 ) P ;
  • L 3 is a covalent bond, O or NR 7 , provided that at least one of L 2 and L 3 is not a covalent bond;
  • R 5 at each occurrence is independently hydrogen, halogen, Ci-ealkyl, haloCi-ealkyl, OH, Ci-ealkyl- OH, Ci-ealkoxy, Ci-ealkyl-Ci-ealkoxy, haloCi-ealkoxy, CN, C3-7cycloalkyl, NR a R b , or Ci-ealkyl- NR a R b ;
  • R 6a is hydrogen, or methyl
  • R 6 is hydrogen, halogen, CN, methyl, ethyl, propyl, or cyclopropyl;
  • R 7 at each occurrence is independently hydrogen, Ci-4alkyl, C3-5cycloalkyl, or two R 7 groups together with the carbon atom to which they are attached, form a 3-5-membered cycloalkyl ring; each occurrence of R 9 and R 10 is independently hydrogen, Ci-ealkyl substituted with 1-4 R 11 , (CR 12 R 12 )q-C2-ealkenyl substituted with 1-4 R 11 , (CR 12 R 12 )q-C2-ealkynyl substituted with 1-4 R 11 , (CR 12 R 12 )q-C3-7cycloalkyl substituted with 1-4 R 11 , (CR 12 R 12 )q-phenyl substituted with 1-4 R 11 , (CR 12 R 12 )q-5-6-membered heteroaryl ring substituted with 1-4 R 11 , (CR 12 R 12 )q-5-7-membered heterocyclyl ring substituted with 1-4 R 11 ; or R 9 and R 10 , together with the nitrogen
  • R 11 at each occurrence is independently hydrogen, Ci-ealkyl, haloCi -ealkyl, C2-ealkenyl, C2- ealkynyl, Ci-ealkoxy, (CH2)p-Ci-ealkoxy, phenyl, (CH2) P -phenyl, O(CH2) P -phenyl, CN, C3- vcycloalkyl, (CH2) P -C3-7cycloalkyl, C2-ealkenyl-C3-7cycloalkyl, C2-ealkynyl-C3-7cycloalkyl, O(CH2) P -C3-7cycloalkyl, in which each phenyl is independently optionally substituted with 1-3 of halogen, Ci-ealkyl, or Ci-ealkoxy;
  • R 12 at each occurrence is independently hydrogen, Ci-4alkyl, C3-7cycloalkyl, or two R 12 groups, together with the carbon atom to which they are attached, form a 3-6-membered cycloalkyl ring;
  • R 13 at each occurrence is independently Ci-4alkyl, or C3-5cycloalkyl; each occurrence of Ra and Rb is independently hydrogen or Ci-ealkyl, or Ra and Rb, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of Cwalkyl, phenyl and benzyl; p at each occurrence is independently 1, 2, 3 or 4; q at each occurrence is independently 0, 1, 2, 3 or 4; t is 0, 1, 2 or 3; and w is 0 or 1, provided that when L 1 is a covalent bond, w is 1, and further provided that when L 1 is CH2 optionally substituted with 1-2 methyl, w is 0. [0082]
  • the compound of Formula I includes
  • L 2 is a covalent bond or (CR 7 R 7 ) P ;
  • L 3 is a covalent bond, O or NR 7 , provided that at least one of L 2 and L 3 is not a covalent bond;
  • X 1 is N, or CR 6a ;
  • R 5 at each occurrence is independently hydrogen, halogen, Ci-ealkyl, haloCi -ealkyl, OH, Ci- ealkyl-OH, Ci-ealkoxy, Ci-ealkyl-Ci-ealkoxy, haloCi-ealkoxy, CN, C3-7cycloalkyl, NR a R b , or Ci- ealkyl-NR a R b ;
  • R 6 is hydrogen, halogen, CN, methyl, ethyl, propyl, or cyclopropyl;
  • R 7 at each occurrence is independently hydrogen, Ci-4alkyl, C3-5cycloalkyl, or twoR 7 groups together with the carbon atom to which they are attached, form a 3-5-membered cycloalkyl ring; each occurrence of R 9 and R 10 is independently hydrogen, Ci-ealkyl substituted with 1-4 R 11 , (CR 12 R 12 )q-C2-ealkenyl substituted with 1-4 R 11 , (CR 12 R 12 )q-C2-ealkynyl substituted with 1-4 R 11 , (CR 12 R 12 )q-C3-7cycloalkyl substituted with 1-4 R 11 , (CR 12 R 12 )q-phenyl substituted with 1-4 R 11 , (CR 12 R 12 )q-5-6-membered heteroaryl ring substituted with 1-4 R 11 , (CR 12 R 12 )q-5-7-membered heterocyclyl ring substituted with 1-4 R 11 ; or R 9 and R 10 , together with the nitrogen
  • R 11 at each occurrence independently hydrogen, Ci-ealkyl, haloCi-ealkyl, C2-ealkenyl, C2-ealkynyl, Ci-ealkoxy, (CH2)p-Ci-ealkoxy, phenyl, (CH2) P -phenyl, O(CH2) P -phenyl, CN, C3-7cycloalkyl, (CH2) P -C3-7cycloalkyl, C2-6alkenyl-C3-7cycloalkyl, C2-6alkynyl-C3-7cycloalkyl, O(CH2) P -C3- 7cycloalkyl, in which each phenyl is independently optionally substituted with 1-3 of halogen, Ci- ealkyl, or Ci-ealkoxy;
  • R 12 at each occurrence is independently hydrogen, Ci-4alkyl, C3-7cycloalkyl, or R 12 and R 12 , together with the carbon atom to which they are attached, form a 3-6-membered cycloalkyl ring;
  • R 13 at each occurrence is independently hydrogen, Ci-4alkyl, or C3-5cycloalkyl; each occurrence of Ra and Rb is independently hydrogen or Ci-ealkyl, or R a and Rb, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of Cwalkyl, phenyl and benzyl; t is 0, 1, 2 or 3; p at each occurrence is independently 1, 2, 3 or 4; and q at each occurrence is independently 0, 1, 2, 3 or 4.
  • the compound of Formula I includes a compound of Formula (Illb) or (Ilbb) :
  • L 2 is a covalent bond or (CR 7 R 7 ) P ;
  • L 3 is a covalent bond, O or NR 7 , provided that at least one of L 2 and L 3 is not a covalent bond;
  • X 1 is N, or CR 6a ;
  • R 5 at each occurrence is independently hydrogen, halogen, Ci-ealkyl, haloCi-ealkyl, OH, Ci-ealkyl- OH, Ci-ealkoxy, Ci-ealkyl-Ci-ealkoxy, haloCi-ealkoxy, CN, C3-7cycloalkyl, NR a R b , or Ci-ealkyl- NR a R b ;
  • R 6a is hydrogen, or methyl
  • R 6 is hydrogen, halogen, CN, methyl, ethyl, propyl, or cyclopropyl; each occurrence of R 7 is independently hydrogen, Ci-4alkyl, C3-5cycloalkyl, or R 7 andR 7 , together with the carbon atom to which they are attached, form a 3-5-membered cycloalkyl ring; each occurrence of R 9 and R 10 is independently hydrogen, Ci-ealkyl substituted with 1-4 R 11 , (CR 12 R 12 )q-C2-ealkenyl substituted with 1-4 R 11 , (CR 12 R 12 )q-C2-ealkynyl substituted with 1-4 R 11 , (CR 12 R 12 )q-C3-7cycloalkyl substituted with 1-4 R 11 , (CR 12 R 12 )q-phenyl substituted with 1-4 R 11 , (CR 12 R 12 )q-5-6-membered heteroaryl ring substituted with 1-4 R 11 , (CR 12 R 12
  • R 13 at each occurrence is independently hydrogen, Ci-4alkyl, or C3-5cycloalkyl; each occurrence of Ra and Rb is independently hydrogen or Ci-ealkyl, or Ra and Rb, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of Cwalkyl, phenyl and benzyl; t is 0, 1, 2 or 3; p at each occurrence is independently 1, 2, 3 or 4; and q at each occurrence is independently 0, 1, 2, 3 or 4.
  • the compound of Formula I includes a compound of Formula (IIIc) or (IIIcc): or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein: L 2 is a covalent bond or (CR 7 R 7 ) P ;
  • L 3 is a covalent bond, O or NR 7 , provided that at least one of L 2 and L 3 is not a covalent bond;
  • X 1 is N, or CR 6a ;
  • R 5 at each occurrence is independently hydrogen, halogen, Ci-ealkyl, haloCi-ealkyl, OH, Ci-ealkyl- OH, Ci-ealkoxy, Ci-ealkyl-Ci-ealkoxy, haloCi-ealkoxy, CN, C3-7cycloalkyl, NR a R b , or Ci-ealkyl- NR a R b ;
  • R 6a is hydrogen, or methyl
  • R 6 is hydrogen, halogen, CN, methyl, ethyl, propyl, or cyclopropyl;
  • R 7 at each occurrence is independently hydrogen, Ci-4alkyl, C3-5cycloalkyl, or R 7 andR 7 , together with the carbon atom to which they are attached, form a 3-5-membered cycloalkyl ring; each occurrence of R 9 and R 10 is independently hydrogen, Ci-ealkyl substituted with 1-4 R 11 , (CR 12 R 12 )q-C2-ealkenyl substituted with 1-4 R 11 , (CR 12 R 12 )q-C2-ealkynyl substituted with 1-4 R 11 , (CR 12 R 12 )q-C3-7cycloalkyl substituted with 1-4 R 11 , (CR 12 R 12 )q-phenyl substituted with 1-4 R 11 , (CR 12 R 12 )q-5-6-membered heteroaryl ring substituted with 1-4 R 11 , (CR 12 R 12 )q-5-7-membered heterocyclyl ring substituted with 1-4 R 11 ; or R 9 and R 10 , together
  • R 11 at each occurrence is independently hydrogen, Ci-ealkyl, haloCi -ealkyl, C2-ealkenyl, C2- ealkynyl, Ci-ealkoxy, (CH2)p-Ci-ealkoxy, phenyl, (CH2) P -phenyl, O(CH2) P -phenyl, CN, C3- 7cycloalkyl, (CH2) P -C3-7cycloalkyl, C2-ealkenyl-C3-7cycloalkyl, C2-ealkynyl-C3-7cycloalkyl, O(CH2) P -C3-7cycloalkyl, in which each phenyl is independently optionally substituted with 1-3 of halogen, Ci-ealkyl, or Ci-ealkoxy;
  • R 12 at each occurrence is independently hydrogen, Ci-4alkyl, C3-7cycloalkyl, or R 12 and R 12 , together with the carbon atom to which they are attached, form a 3-6-membered cycloalkyl ring;
  • R 13 at each occurrence is independently hydrogen, Ci-4alkyl, or C3-5cycloalkyl; each occurrence of Ra and Rb is independently hydrogen or Ci-ealkyl, or Ra and Rb, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of Cwalkyl, phenyl and benzyl; t is 0, 1, 2 or 3; p at each occurrence is independently 1, 2, 3 or 4; and q at each occurrence is independently 0, 1, 2, 3 or 4.
  • the compound of Formula I includes a compound of Formula (Hid) or (Illdd): wherein:
  • L 2 is a covalent bond or (CR 7 R 7 ) P ;
  • L 3 is a covalent bond, O or NR 7 , provided that at least one of L 2 and L 3 is not a covalent bond;
  • X 1 is N, or CR 6a ;
  • R 5 at each occurrence is independently hydrogen, halogen, Ci-ealkyl, haloCi-ealkyl, OH, Ci-ealkyl- OH, Ci-ealkoxy, Ci-ealkyl-Ci-ealkoxy, haloCi-ealkoxy, CN, C3-7cycloalkyl, NR a R b , or Ci-ealkyl- NR a R b
  • R 6a is hydrogen, or methyl
  • R 6 is hydrogen, halogen, CN, methyl, ethyl, propyl, or cyclopropyl; each occurrence of R 7 is independently hydrogen, Ci-4alkyl, C3-5cycloalkyl, or R 7 andR 7 , together with the carbon atom to which they are attached, form a 3-5-membered cycloalkyl ring; each occurrence of R 9 and R 10 is independently hydrogen, Ci-ealkyl substituted with 1-4 R 11 , (CR 12 R 12 )q-C2-ealkenyl substituted with 1-4 R 11 , (CR 12 R 12 )q-C2-ealkynyl substituted with 1-4 R 11 , (CR 12 R 12 )q-C3-7cycloalkyl substituted with 1-4 R 11 , (CR 12 R 12 )q-phenyl substituted with 1-4 R 11 , (CR 12 R 12 )q-5-6-membered heteroaryl ring substituted with 1-4 R 11 , (CR 12 R 12
  • Z is CH2. In certain other embodiments, Z is O.
  • L 1 is a covalent bond. In certain other embodiments, L 1 is CH2 optionally substituted with 1-2 methyl. In yet other embodiments, L 1 is CH2.
  • L 1 is a covalent bond, and w is 1.
  • L 1 is CH2 optionally substituted with 1-2 methyl, and w is 0.
  • each occurrence of R 1 is independently hydrogen. In certain other embodiments, each occurrence of R 1 is independently halogen. In yet other embodiments, m is 2, one R 1 is hydrogen, and the other R 1 is halogen. In yet other embodiments, m is 2, one R 1 is hydrogen, and the other R 1 is F. In yet other embodiments, each occurrence of R 1 is independently F.
  • Y 2 is N, and each of Y 1 , Y 3 and Y 4 is independently CR 5 .
  • Y 1 is CR 5
  • Y 2 is N
  • each of Y 3 and Y 4 is independently CH.
  • Y 1 is CR 5
  • Y 2 is N
  • Y 3 is N
  • Y 4 CH is independently CH.
  • R 5 is methyl or ethyl. In certain other embodiments, R 5 is CHF2 or CF3. In yet other embodiments, R 5 is hydrogen, or CN.
  • t is 0. In certain other embodiments, t is 1. In yet other embodiments, t is 2. In yet other embodiments, t is 3.
  • X 1 is N, X 2 is N, and X 3 is NR 6 .
  • X 1 is CH, X 2 is N, and X 3 is NR 6 .
  • X 1 is O, X 2 is N, and X 3 is CR 6 .
  • R 6 is hydrogen. In certain other embodiments, R 6 is methyl. In yet other embodiments, R 6 is ethyl. In yet other embodiments, R 6 is cyclopropyl.
  • R 6a is hydrogen. In certain other embodiments, R 6a is methyl. In yet other embodiments, R 6a is ethyl. In yet other embodiments, R 6a is cyclopropyl. [0097] In any embodiments, L 2 is a covalent bond. In certain other embodiments, L 2 is (CR 7 R 7 ) P . In yet other embodiments, L 2 is CH2.
  • L 3 is a covalent bond. In certain other embodiments, L 3 is O. In yet other embodiments, L 3 is NR 7 .
  • each occurrence of R 7 is independently hydrogen. In certain other embodiments, each occurrence of R 7 is independently Ci-4alkyl. In yet other embodiments, each occurrence of R 7 is independently C3-5cycloalkyl. In yet other embodiments, each occurrence of R 7 is independently hydrogen or methyl.
  • q is 0. In certain other embodiments, q is 1. In yet other embodiments, q is 2.
  • R 8 is COOH
  • R 9 is Ci-4alkyl. In certain other embodiments, R 9 is methyl. In yet other embodiments, R 9 is ethyl.
  • R 10 is Ci-ealkyl substituted with 1-4 R 11 , (CR 12 R 12 )q-C2-ealkenyl substituted with 1-4 R 11 , (CR 12 R 12 )q-C2-ealkynyl substituted with 1-4 R 11 , (CR 12 R 12 )q-C3- vcycloalkyl substituted with 1-4 R 11 , (CR 12 R 12 )q-phenyl substituted with 1-4 R 11 , (CR 12 R 12 )q-5-6- membered heteroaryl ring substituted with 1-4 R 11 , (CR 12 R 12 )q-5-7-membered heterocyclyl ring substituted with 1-4 R 11 .
  • R 10 is Ci-ealkyl.
  • R 10 is (CH2)p-C3- vcycloalkyl.
  • R 9 and R 10 together with the nitrogen atom to which they are attached, form a saturated or unsaturated 3-7-membered heterocyclic ring substituted with 1-4 R 11 , which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
  • Q is a ring (also referred to herein the “Q ring”) selected from the group consisting of 5-membered heteroaryl, 5- membered heterocyclyl, 6-membered heteroaryl, and 6-membered heterocyclyl, wherein the ring comprises at least on carbon atom, at least one nitrogen atom and optionally 1-3 heteroatoms selected from nitrogen, oxygen and sulfur wherein oxygen may be a ring member and/or an oxo attached to a ring member, and wherein the ring is substituted with (R 3 )n and R 4 . and each of which is substituted with (R 3 ) n and one R 4 at any available carbon or nitrogen position.
  • substituted with (R 3 )n and one R 4 at any available carbon position each of which is substituted with (R 3 ) n and one R 4 at any available carbon or nitrogen position.
  • each occurrence of R 3 is independently hydrogen, halogen, or Ci- 4alkyl. In certain other embodiments, each occurrence of R 3 is independently Ci-4alkyl. In yet other embodiments, each occurrence of R 3 is independently methyl.
  • n is 0. In certain other embodiments, n is 1. In yet other embodiments, n is 2.
  • R 4 is independently hydrogen, Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, Ci- ealkoxy, (CH2)p-Ci-ealkoxy, phenyl, (CH2) P -phenyl, O(CH2) P -phenyl, CN, C3-7cycloalkyl, (CH2) P - C3-7cycloalkyl, C2-6alkenyl-C3-7cycloalkyl, C2-6alkynyl-C3-7cycloalkyl, O(CH2) P -C3-7cycloalkyl, in which each phenyl is independently optionally substituted with 1-3 of halogen, Ci-ealkyl, or Ci- ealkoxy.
  • R 4 is independently (CH2)q-5-6-membered heteroaryl ring substituted with 1-4 R 11 , or (CH2)q-5-7-membered heterocyclyl ring substituted with 1-4 R 11 .
  • R 4 is independently Ci-ealkyl, C2-ealkynyl, Ci-ealkoxy, (CH2)p-Ci-ealkoxy, C3-7cycloalkyl, (CH2) P -C3-7cycloalkyl, or C2-6alkenyl-C3-7cycloalkyl.
  • each occurrence of R 11 is independently hydrogen. In certain other embodiments, each occurrence of R 11 is independently Ci-ealkyl. In yet other embodiments, each occurrence of R 11 is independently Ci-ealkoxy. In yet other embodiments, each occurrence of R 11 is independently (CH2)p-Ci-6alkox. In yet other embodiments, each occurrence of R 11 is independently phenyl. In yet other embodiments, each occurrence of R 11 is independently (CH2)p- phenyl. In yet other embodiments, each occurrence of R 11 is independently C3-7cycloalkyl. In yet other embodiments, each occurrence of R 11 is independently (CH2) P -C3-7cycloalkyl.
  • each occurrence of R 11 is independently C2-6alkynyl-C3-7cycloalkyl. In yet other embodiments, each occurrence of R 11 is independently O(CH2) P -C3-7cycloalkyl. In any embodiments, each phenyl is independently optionally substituted with 1-3 of halogen, Ci-ealkyl, or Ci-ealkoxy.
  • each occurrence of R 12 is independently hydrogen. In certain other embodiments, each occurrence of R 12 is independently Ci-4alkyl. In yet other embodiments, each occurrence of R 12 is independently C3-7cycloalkyl. In yet other embodiments, R 12 andR 12 , together with the carbon atom to which they are attached, form a 3-6-membered cycloalkyl ring.
  • each occurrence of Ra and Rb is independently hydrogen. In certain other embodiments, each occurrence of Ra and Rb is independently Ci-ealkyl. In yet other embodiments, each occurrence of R 12 is independently C3-7cycloalkyl. In yet other embodiments, Ra and Rb, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of Cwalkyl, phenyl and benzyl.
  • R 13 is hydrogen. In certain other embodiments, R 13 is methyl. In yet other embodiments, R 13 is cyclopropyl. [0116] In any embodiments, the compound is selected from:
  • the compound is selected from:
  • the compound is selected from:
  • the compound is selected from:
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound disclosed herein, and a pharmaceutically acceptable carrier.
  • the present invention relates to a method for treating a disease associated with dysregulation of lysophosphatidic acid receptor 1 (LPAi) in a subject in need thereof, comprising administering an effective amount of a compound disclosed herein to the subject.
  • the disease is pathological fibrosis (e.g., pulmonary, liver, renal, cardiac, demal, ocular, or pancreatic fibrosis), idiopathic pulmonary fibrosis (IPF), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic kidney disease, or systemic sclerosis.
  • pathological fibrosis e.g., pulmonary, liver, renal, cardiac, demal, ocular, or pancreatic fibrosis
  • IPF idiopathic pulmonary fibrosis
  • NASH non-alcoholic steatohepatitis
  • NAFLD non-alcoholic fatty liver disease
  • chronic kidney disease diabetic kidney disease, or systemic
  • the present invention relates to a process of making a compound of Formulae (I), (II), (Ila), (Ilaa), (lib), (Hbb), (lie), (IIcc), (lid), (Ildd), (III), (Illa), (Illaa), (Illb), (Illbb), (IIIc), (IIIcc), (Illd), and (Illdd), including each exemplified compound and intermediates described herein.
  • the present invention relates to an intermediate selected from:
  • the compounds of the present invention can be synthesized using the methods describled herein, together with synthetic methods known in the art of synthetic organic chemistry, or by variations thereon as appreciated by those skilled in the art. Proffered methods include, but are not limited to, those exemplary schemes and working examples described below. All substituents are as defined hereinabove unless otherwise indicated.
  • the reactions are performed in a solvent or solvent mixture appropriate to the reagents and materials employed and suitable for the transformations proposed. This will sometimes require a judgment to modify the order of syntheitic steps or to select on particular process scheme over another in order to obtain a desired compound of the invention.
  • Scheme 1 describes the synthesis of carbonyl azine azole N-heteroaryl-azacyclohexyl acetic acids 8.
  • PGi and PG2 each represents a protecting group, and L 2 is (CR 7 R 7 ) P (e.g., CEE).
  • the halo azine derivative 1 is reacted with piperidine acetic ester 2 under Buckwald conditions with appropriate catalyst (e.g. Pd(OAc)2/BINAP) or nucleophilic aromatic substitution reaction or Ullmann reaction to give the corresponding carbonyl azine N-heteroaryl-piperidine acetic carboxylate 3.
  • appropriate catalyst e.g. Pd(OAc)2/BINAP
  • nucleophilic aromatic substitution reaction or Ullmann reaction to give the corresponding carbonyl azine N-heteroaryl-piperidine acetic carboxylate 3.
  • Deprotection of the protected hydroxylmethyl azole 3 provides the hydroxylmethyl azole 4, which is then reacted with MsCI (or PBn) to give the mesylate (or Br) 5.
  • MsCI or PBn
  • mesylate or Br
  • an appropriate base e.g. K2CO3, nucleophilic substitution reactions
  • Scheme 2 describes an alternative synthetic route to the carbonyl azine N-heteroaryl- azacyclohexyl acetic acids 8.
  • PGi and PG2 each represents a protecting group, and L 2 is (CR 7 R 7 ) P (e.g., CH2).
  • L 2 is (CR 7 R 7 ) P (e.g., CH2).
  • Deprotection of the protected hydroxylmethyl azole derivative 1 gives hydroxylmethyl azole 9, which is then reacted with MsCl (or PBn) to give the mesylate (or Br) 10.
  • MsCl or PBn
  • mesylate or Br
  • Treatment of mesylate (or Br) 10 with 2-hydroxy azine in the presence of an appropriate base e.g. K2CO3, nucleophilic substitution reactions
  • the halo azine derivative 11 is reacted with piperidine acetic carboxylate under Buckwald conditions with appropriately catalyst (e.g. Pd(OAc)2/BINAP) or nucleophilic aromatic substitution reaction or Ullmann reaction to give the corresponding piperidine acetic carboxylate 7, which then undergoes ester deprotection to give the desired carbonyl azine L 2 -azole N-heteroaryl- azacyclohexyl acetic acids 8.
  • appropriately catalyst e.g. Pd(OAc)2/BINAP
  • Scheme 3 describes the synthesis of N-substituted aza-heterocyclopentyl ketone N- heteroaryl-azacyclohexyl acetic acids 13.
  • an appropriate base e.g. t-BuOK, nucleophilic substitution reactions
  • Scheme 4 describes the synthesis of oxy-Q ring N-heteroaryl-azacyclohexyl acetic acid 16, wherein Q represents a 5-membered heteroaryl or heterocyclyl or 6-membered heteroaryl or heterocyclyl.
  • Scheme 5 describes an alternative synthesis of oxy-Q ring N-heteroaryl-azacyclohexyl acetic acid 16, wherein Q represents a 5-membered heteroaryl or heterocyclyl or 6-membered heteroaryl or heterocyclyl.
  • Base-mediated SNAT reaction of hydroxylmethyl azole 9 with an appropriate halo- or methylsulfonyl-substitued Q ring 14 (X is halo or methyl sulfonyl) provides the oxy-Q ring 17, which is reacted with piperidine ethyl ester derivative under Buckwald conditions with appropriately catalyst (e.g.
  • Scheme 6 describes the synthesis of amino-Q ring N-heteroaryl-azacyclohexyl acetic acids 21.
  • the hydroxylmethyl azole 4 is reacted with MsCl with appropriately base (e.g. TEA) to give the corresponding mesylate 17.
  • MsCl with appropriately base (e.g. TEA)
  • TEA e.g. TEA
  • azide 18 e.g. Staudinger reduction with PPhV water
  • Amine 19 is then reacted with halo- or methylsulfonyl-substitued Q ring 14 (X is halo or methyl sulfonyl) in the presence of an appropriate base or via Pd catalyzed amination to give amino-azine piepridine acetic ester 20, which then undergoes ester deprotection to give the desired amino-Q ring N-heteroaryl-azacyclohexyl acetic acids 21.
  • Scheme 7 describes the synthesis of oxy-azole N-heteroaryl-azacyclohexyl acetic acids 24.
  • the hydroxylmethyl azole 4 is reacted with an appropriate haloazole or methyl sulfonyl azole 22 (which is a 5-membered heteroaryl ring that contains at least one nitrogen and may contain additional 1-3 heteroatoms selected from N, O and S) in the presence of an appropriate base (nucleophilic aromatic substitution reaction) to give oxy-azole N-heteroaryl piepridine acetic ester 23, which then undergoes ester deprotection to give the desired oxy-azole N-heteroaryl- azacyclohexyl acetic acids 24.
  • Scheme 8 describes the synthesis of amino-azole N-heteroaryl-azacyclohexyl acetic acids 28.
  • the hydroxylmethyl azole 4a is oxidized to the corresponding aldehyde 25 (e.g. with Dess- Martin periodinane or Swern Oxidation).
  • the aldehyde 25 can then undergo reductive amination with an appropriate amino-azole 26 (which is a 5-membered heteroaryl ring that contains at least one nitrogen and may contain additional 1-3 heteroatoms selected from N, O and S) to give amino- azole N-heteroaryl piepridine ecetic ester 27.
  • Subsequent deprotection of ester 27 provides the amino-azole N-heteroaryl-azacyclohexyl acetic acids 28.
  • Scheme 9 describes the synthesis of alkylated-triazole N-heteroaryl-azacyclohexyl acetic acids 32.
  • the halo-azine 30 is then reacted with piperidine acetic ester 2 under Buckwald conditions with appropriately catalyst (e.g.
  • Scheme 10 describes the synthesis of alkylated-tetrazoleN-heteroaryl-azacyclohexyl acetic acids 36 and 37.
  • the hydroxylmethyl azole 4 is reacted with tetrazole 33 under Mitsunobu conditions to provide the regioisomeric tetrazoles 34 and 35.
  • Deprotection piepridine acetic ester 34 and 35 provides the regioisomeric alkylated-tetrazole N-heteroaryl-azacyclohexyl acetic acids 36 and 37.
  • Scheme 11 describes the synthesis of carbamoyloxymethyl azole N-heteroaryl- azacyclohexyl acetic acids 41.
  • the hydroxylmethyl azole 4 is reacted with 4-nitrophenyl chloroformate in the presence of an appropriate base to give the corresponding 4-nitrophenyl carbonate 38, which is then reacted with an amine 39 in the presence of an appropriate base to give the carbomate 40.
  • Subsequent deprotection of ester 40 provides the carbamoyloxymethyl azole N- heteroaryl-azacyclohexyl acetic acids 41.
  • Scheme 12 describes the synthesis of l-azinemethyl-piperidine-3 -carboxylic acids 48, 49 and 50.
  • Carbonyl insertion of azine halide 1 in the presence of CO gas and appropriate catalyst in methanol gives azine carboxylate 42, which is then reduced with appropriate reductant to give azine methyl alcohol 43.
  • Treatment of azine methyl alcohol 43 with MsCl in the presence of appropriate base gives the corresponding mesylate 44.
  • Alkylation piperidine carboxylate 45 with mesylate 44 in the presence appropriate base affords azine methyl-piperidine-3 -carboxylate 46.
  • Deprotection of azine methyl-piperidine-3 -carboxylate 46 gives hydroxylmethyl azole 47, which is then converted to corresponding acids 48, 49 and 50 using similar methods as described herein over several steps.
  • compositions may be formulated together with a pharmaceutically acceptable carrier or adjuvant into pharmaceutically acceptable compositions prior to be administered to a subject.
  • pharmaceutically acceptable compositions further comprise additional therapeutic agents in amounts effective for achieving a modulation of disease or disease symptoms, including those described herein.
  • pharmaceutically acceptable carrier or adjuvant refers to a carrier or adjuvant that may be administered to a subject, together with a compound of this invention, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.
  • compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d- a-tocopherol polyethyleneglycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes
  • SEDDS self-emulsifying drug delivery systems
  • Cyclodextrins such as a-, 0- , and y-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-0-cyclodextrins, or other solubilized derivatives may also be advantageously used to enhance delivery of compounds of the formulae described herein.
  • compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection.
  • the pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles.
  • the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form.
  • parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • the pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3 -butanediol.
  • suitable vehicles and solvents that may be employed are mannitol, water, Ringer’s solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions.
  • surfactants such as Tweens or Spans and/or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
  • compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions.
  • carriers which are commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried corn starch.
  • aqueous suspensions and/or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oily phase is combined with emulsifying and/or suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.
  • compositions of this invention may also be administered in the form of suppositories for rectal administration.
  • These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components.
  • suitable non-irritating excipient include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
  • Topical administration of the pharmaceutical compositions of this invention is useful when the desired treatment involves areas or organs readily accessible by topical application.
  • the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier.
  • Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.
  • the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier with suitable emulsifying agents.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2- octyl dodecanol, benzyl alcohol and water.
  • the pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches are also included in this invention.
  • compositions of this invention may be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
  • compositions of this invention comprise a combination of a compound of the formulae described herein and one or more additional therapeutic or prophylactic agents
  • both the compound and the additional agent should be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen.
  • the additional agents may be administered separately, as part of a multiple dose regimen, from the compounds of this invention. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition.
  • the compounds described herein can, for example, be administered by injection, intravenously, intraarterially, subdermally, intraperitoneally, intramuscularly, or subcutaneously; or orally, buccally, nasally, transmucosally, topically, in an ophthalmic preparation, or by inhalation, with a dosage ranging from about 0.5 to about 100 mg/kg of body weight, alternatively dosages between 1 mg and 1000 mg/dose, every 4 to 120 hours, or according to the requirements of the drug.
  • the methods herein contemplate administration of an effective amount of compound or compound composition to achieve the desired or stated effect.
  • the pharmaceutical compositions of this invention will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion.
  • Such administration can be used as a chronic or acute therapy.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the mode of administration.
  • a typical preparation will contain from about 5% to about 95% active compound (w/w).
  • such preparations contain from about 20% to about 80% active compound.
  • a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level. Subjects may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
  • compositions described above comprising a compound of Formula (I) may further comprise another therapeutic agent useful for treating a disease associated with dysregulation of lysophosphatidic acid receptor 1 (LPAi).
  • LPAi lysophosphatidic acid receptor 1
  • such combination may be useful for treating pathological fibrosis (e.g., pulmonary, liver, renal, cardiac, dernal, ocular, or pancreatic fibrosis), idiopathic pulmonary fibrosis (IPF), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic kidney disease, or systemic sclerosis.
  • pathological fibrosis e.g., pulmonary, liver, renal, cardiac, dernal, ocular, or pancreatic fibrosis
  • IPF idiopathic pulmonary fibrosis
  • NASH non-alcoholic steatohepatitis
  • NAFLD non-alcoholic fatty liver disease
  • chronic kidney disease diabetic
  • the examples herein are provided to illustrate advantages of the present technology and to further assist a person of ordinary skill in the art with preparing or using the compounds of the present technology or salts, pharmaceutical compositions, derivatives, solvates, metabolites, prodrugs, racemic mixtures or tautomeric forms thereof.
  • the examples herein are also presented in order to more fully illustrate the preferred aspects of the present technology. The examples should in no way be construed as limiting the scope of the present technology, as defined by the appended claims.
  • the examples can include or incorporate any of the variations, aspects or aspects of the present technology described above.
  • the variations, aspects or aspects described above may also further each include or incorporate the variations of any or all other variations, aspects or aspects of the present technology.
  • the chemical reagents were purchased from commercial sources (such as Alfa, Acros, Sigma Aldrich, TCI and Shanghai Chemical Reagent Company), and used without further purification.
  • THF was continuously refluxed and freshly distilled from sodium and benzophenone under nitrogen
  • dichloromethane was continuously refluxed and freshly distilled from CaHz under nitrogen.
  • Flash chromatography was performed on an Ez Purifier III via column with silica gel particles of 200-300 mesh.
  • Analytical and preparative thin layer chromatography plates were HSGF 254 (0.15-0.2mm thickness, Shanghai Anbang Company, China).
  • Nuclear magnetic resonance (NMR) spectra were recorded using Brucker AMX-300 or AMX-400 NMR (Brucker, Switzerland) at around 20 - 30 °C unless otherwise specified.
  • Preparative HPLC unless otherwise described, the compounds were purified using a WATERS Fractionlynx system equipped with a YMC Pack Pro ds Column (5 pm, 120A, 50 x 20 mm) and the following solvent system: H2O, AcCN, and 2% TFA in H2O. Specific elution gradients were based on the retention times obtained with an analytical LC-MS, however, in general all elution gradients of H2O and MeCN were run over a 7 minute run time with a flow rate of 35 mL/min. An autoblend method was used to ensure a concentration of 0.1 % TFA throughout each run. Specific elution gradients were based on the retention times obtained with an analytical LC-MS, however, in general, all elution gradients of H2O and MeCN were run over at 8 minute run time with a flow rate of 50 mL/min.
  • Analytical LC-MS analytical LC-MS was performed on a WATERS Acquity UPLC-MS instrument equipped with a ACQUITY UPLC BEH Cig Column (2.1 x 50 mm, 1 .7 pu
  • Step 3 (4-(5-bromo-6-ethylpyridin-2-yl)-l-((trimethylsilyl)methyl)-lH-l,2,3-triazol-5- yl)methanol
  • Step 4 (4-(5-bromo-6-ethylpyridin-2-yl)-l-methyl-lH-l,2,3-triazol-5-yl)methanol
  • Step 5 3-bromo-2-ethyl-6-(l-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-lH-l,2,3- triazol-4-yl)pyridine
  • Step 1 2-ethyl-3-iodo-6-(l-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-lH-l,2,3- triazol-4-yl)pyridine
  • Step 2 (4-(6-ethyl-5-iodopyridin-2-yl)-l-methyl-lH-l,2,3-triazol-5-yl) methanol (6)
  • Step 3 5-bromo-4-ethyl-2-(l-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-lH- pyrazol-4-yl)pyrimidine
  • Step 1 benzyl 5-(2-diazoacetyl)-3,3-difluoropiperidine-l-carboxylate
  • Step 2 benzyl (S)-3,3-difluoro-5-(2-methoxy-2-oxoethyl)piperidine-l-carboxylate (3A) and benzyl (R)-3,3-difluoro-5-(2-methoxy-2-oxoethyl)piperidine-l-carboxylate (3B)
  • Step 1 2-((3S)-5,5-difluoro-l-(2-methyl-6-(l-methyl-5-(((tetrahydro-2H-pyran-2- yl)oxy)methyl)-lH-l,2,3-triazol-4-yl)pyridin-3-yl)piperidin-3-yl)acetic acid
  • Step 2 methyl (S)-2-(5,5-difluoro-l-(6-(5-(hydroxymethyl)-l-methyl-lH-l,2,3-triazol-4-yl)- 2-methylpyridin-3-yl)piperidin-3-yl)acetate
  • Step 1 methyl 2-((3S)-5,5-difluoro-l-(4-methyl-2-(l-methyl-5-(((tetrahydro-2H-pyran-2- yl)oxy)methyl)-lH-pyrazol-4-yl)pyrimidin-5-yl)piperidin-3-yl)acetate
  • Step 2 methyl (S)-2-(l-(4-ethyl-2-(5-(hydroxymethyl)-l-methyl-lH-pyrazol-4-yl)pyrimidin- 5-yl)-5,5-difluoropiperidin-3-yl)acetate
  • Intermediate 9 was synthesized according the same sequence as was used for the synthesis of intermediate 5.
  • LC/MS (ESI) m/z: 410 (M+H) + .
  • Step 1 Methyl 2-methyl-6-(l-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-lH-l,2,3- triazol-4-yl)nicotinate
  • Step 2 (2-methyl-6-(l-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-lH-l,2,3-triazol- 4-yl)pyridin-3-yl)methanol
  • Step 3 3-(chloromethyl)-2-methyl-6-(l-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)- lH-l,2,3-triazol-4-yl)pyridine
  • Step 4 Methyl 5,5-difluoro-l-((2-methyl-6-(l-methyl-5-(((tetrahydro-2H-pyran-2- yl)oxy)methyl)-lH-l,2,3-triazol-4-yl)pyridin-3-yl)methyl)piperidine-3-carboxylate
  • Step 5 Methyl 5,5-difluoro-l-((6-(5-(hydroxymethyl)-l-methyl-lH-l,2,3-triazol-4-yl)-2- methylpyridin-3-yl)methyl)piperidine-3-carboxylate
  • Step 1 cyclopropyl(2-fluoro-3-methylpyridin-4-yl)methanol
  • Step 1 N'-[(lE)-cyclopropylmethylidene]-4-methylbenzene-l-sulfonohydrazide
  • Step 2 5-(cyclopropylmethyl)-2-methoxypyridine [0196] To mixture of N'-[(lE)-cyclopropylmethylidene]-4-methylbenzene-l-sulfonohydrazide (1 g, 4.2 mmol) and (6-methoxypyri din-3 -yl)boronic acid (0.64 g, 4.2 mmol) in 1,4-dioxane (10 mL) was added K2CO3 (580 mg, 4.2 mmol) and the mixture was stirred at 110 °C for 16 hrs. The mixture was diluted with EtOAc (15 mL), washed with brine, dried over Na2SO4, filtered and concentrated to dryness.
  • Step 1 2-methoxy-5-(prop-l-en-2-yl)pyridine [0200] To a solution of 5-bromo-2-methoxypyridine (1.0 g, 5.32 mmol) and 4,4,5,5-tetramethyl- 2-(prop-l-en-2-yl)-l,3,2-dioxaborolane (1.34 g, 7.98 mmol) in 1,4-dioxane (10 ml) and water (2 mL) were added K2CO3 (1.47 g, 10.64 mmol), Pd(PPh3)4 (0.61 g, 0.53 mmol) under N2 atmosphere, after addition, the mixture was degassed under N2 atmosphere for three times and stirred at 100 °C for 16 hrs.
  • Step 1 l-(6-methoxypyridin-3-yl)cyclobutan-l-ol [0203] To a stirred solution of 5-bromo-2-methoxypyridine (1.38 mL, 10.6 mmol) in dry THF (25 mL) was added n-BuLi (5.5 mL, 13.8 mmol) drop-wisely at -78 °C. After stirring at this temperature for 30 mins, cyclobutanone (1.2 mL, 15.9 mmol) was added and the resulting mixture was stirred at -78 °C for 30 mins and r.t. for 30 mins. The mixture was quenched with ice-water and extracted with EtOAc (2 x 10 mL).
  • Step 2 4-propylpyridazin-3(2H)-one
  • TEA 0.05 mL, 0.360 mmol
  • Pd/C 60 mg, 10% wt
  • the reaction was filtered and the filtrate was concentrated to dryness.
  • Step 3 6-propylpyridazin-3-ol
  • Pd/C 20 mg, 10% wt
  • the mixture was degassed under N2 atmosphere for three times and stirred under a H2 balloon at room temperature for 2 hrs.
  • the mixture was filtered and the filtrate was concentrated to dryness to give the title compound (32 mg, 51.2% yield) as yellow solid.
  • Step 2 ethyl (2Z)-5-cyclopropyl-4-oxopent-2-enoate
  • Step 1 (R)-2-((tert-butoxycarbonyl)amino)-3-cyclopropylpropanoic acid
  • Step 2 (R)-tert-butyl (l-cyclopropyl-3-hydroxypropan-2-yl)carbamate
  • Step 3 (R)-2-((tert-butoxycarbonyl)amino)-3-cyclopropylpropyl methanesulfonate
  • Step 4 (R)-tert-butyl (l-azido-3-cyclopropylpropan-2-yl)carbamate
  • Step 5 (R)-tert-butyl (l-azido-3-cyclopropylpropan-2-yl)(methyl)carbamate
  • Step 6 (R)-tert-butyl (l-amino-3-cyclopropylpropan-2-yl)(methyl)carbamate
  • Step 8 (S)-5-(cyclopropylmethyl)-l-methylimidazolidin-2-one
  • Step 1 6-propyl-3,4-dihydropyrimidin-4-one [0251] To a solution of methyl 3-cyclobutyl-3-oxopropanoate (2 g, 12.81 mmol) and formamidine acetate salt (1.33 g, 19.98 mmol) in MeOH (30 mL) was added 5N MeONa/MeOH solution (7.7 mL, 38.5 mmol) drop-wisely at 0 °C. After the addition, the mixture was stirred at 70 °C for 4 hrs.
  • Step 2 5-cyclopropyl-l,2,4-oxadiazol-3-amine
  • N-cyanocyclopropanecarboxamide 525 mg, 4.77 mmol
  • hydroxylamine hydrochloride 497.0 mg, 7.15 mmol
  • EtOH 6 mL
  • pyridine 1.51 g, 19.07 mmol
  • the mixture was diluted with water (10 mL) and extracted with DCM (3 x 5 mL).
  • Example 1 (S)-2-(5,5-difluoro-l-(2-methyl-6-(l-methyl-5-((3-methyl-2-oxo-5-propylpyridin- l(2H)-yl)methyl)-lH-l,2,3-triazol-4-yl)pyridin-3-yl)piperidin-3-yl)acetic acid
  • Step 1 methyl (S)-2-(5,5-difluoro-l-(2-methyl-6-(l-methyl-5-(((methylsulfonyl)oxy)methyl)- lH-l,2,3-triazol-4-yl)pyridin-3-yl)piperidin-3-yl)acetate
  • Step 2 methyl (S)-2-(5,5-difluoro-l-(2-methyl-6-(l-methyl-5-((3-methyl-2-oxo-5- propylpyridin-l(2H)-yl)methyl)-lH-l,2,3-triazol-4-yl)pyridin-3-yl)piperidin-3-yl)acetate
  • Step 3 (S)-2-(5,5-difluoro-l-(2-methyl-6-(l-methyl-5-((3-methyl-2-oxo-5-propylpyridin- l(2H)-yl)methyl)-lH-l,2,3-triazol-4-yl)pyridin-3-yl)piperidin-3-yl)acetic acid
  • Step 1 3-bromo-6-(5-(bromomethyl)-l-methyl-lH-l,2,3-triazol-4-yl)-2-methylpyridine
  • Step 2 l-((4-(5-bromo-6-methylpyridin-2-yl)-l-methyl-lH-l,2,3-triazol-5-yl)methyl)-4- (cyclopropylmethyl)-3-methylpyridin-2(lH)-one
  • Step 3 methyl (S)-2-(l-(6-(5-((4-(cyclopropylmethyl)-3-methyl-2-oxopyridin-l(2H)- yl)methyl)-l-methyl-lH-l,2,3-triazol-4-yl)-2-methylpyridin-3-yl)-5,5-difluoropiperidin-3- yl)acetate
  • Step 4 (S)-2-(l-(6-(5-((4-(cyclopropylmethyl)-3-methyl-2-oxopyridin-l(2H)-yl)methyl)-l- methyl-lH-l,2,3-triazol-4-yl)-2-methylpyridin-3-yl)-5,5-difluoropiperidin-3-yl)acetic acid
  • Step 4 methyl (R)-2-(5,5-difluoro-l-(2-methyl-6-(l-methyl-5-((4-oxo-3-propylpyridin- l(4H)-yl)methyl)-lH-l,2,3-triazol-4-yl)pyridin-3-yl)piperidin-3-yl)acetate
  • Step 5 (R)-2-(5,5-difluoro-l-(2-methyl-6-(l-methyl-5-((4-oxo-3-propylpyridin-l(4H)- yl)methyl)-lH-l,2,3-triazol-4-yl)pyridin-3-yl)piperidin-3-yl)acetic acid
  • Step 1 2-[4-(5-bromo-6-methylpyridin-2-yl)-l-methyl-lH-l,2,3-triazol-5-yl]acetonitrile
  • Step 3 2-[4-(5-bromo-6-methylpyridin-2-yl)-l-methyl-lH-l,2,3-triazol-5-yl]ethan-l-ol
  • Step 4 2-[4-(5-bromo-6-methylpyridin-2-yl)-l-methyl-lH-l,2,3-triazol-5-yl]ethyl methanesulfonate
  • Step 5 2- ⁇ 2-[4-(5-bromo-6-methylpyridin-2-yl)-l-methyl-lH-l,2,3-triazol-5-yl]ethyl ⁇ -4- propyl-2,3-dihydropyridazin-3-one
  • Step 6 methyl 2-[(3R)-5,5-difluoro-l-(2-methyl-6- ⁇ l-methyl-5-[2-(6-oxo-5-propyl-l,6- dihydropyridazin-l-yl)ethyl]-lH-l,2,3-triazol-4-yl ⁇ pyridin-3-yl)piperidin-3-yl]acetate
  • Step 7 2-[5,5-difluoro-l-(2-methyl-6- ⁇ l-methyl-5-[2-(6-oxo-5-propyl-l,6-dihydropyridazin-
  • Example 45 and 46 2-((3R,5R) or (3S,5S)-l-(2-ethyl-6-(l-methyl-5-((2-oxo-5-propylpyridin- l(2H)-yl)methyl)-lH-l,2,3-triazol-4-yl)pyridin-3-yl)-5-fluoropiperidin-3-yl)acetic acid and
  • Step 9 Trans-methyl 2-(l-(2-ethyl-6-(l-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)- lH-l,2,3-triazol-4-yl)pyridin-3-yl)-5-fluoropiperidin-3-yl)acetate
  • Step 10 Methyl 2-((3S,5S) or (3R,5R)-l-(2-ethyl-6-(5-(hydroxymethyl)-l-methyl-lH-l,2,3- triazol-4-yl)pyridin-3-yl)-5-fluoropiperidin-3-yl)acetate (14-P1) & methyl 2-((3R,5R) or (3S,5S)-l-(2-ethyl-6-(5-(hydroxymethyl)-l-methyl-lH-l,2,3-triazol-4- yl)pyridin-3-yl)-5-fluoropiperidin-3-yl)acetate (14-P2)
  • Step 12 methyl 2-((3S,5S) or (3R,5R)-l-(2-ethyl-6-(l-methyl-5-((2-oxo-5-propylpyridin- l(2H)-yl)methyl)-lH-l,2,3-triazol-4-yl)pyridin-3-yl)-5-fluoropiperidin-3-yl)acetate
  • Step 13 2-((3S,5S) or (3R,5R)-l-(2-ethyl-6-(l-methyl-5-((2-oxo-5-propylpyridin-l(2H)- yl)methyl)-lH-l,2,3-triazol-4-yl)pyridin-3-yl)-5-fluoropiperidin-3-yl)acetic acid
  • Example 46 2-((3R,5R) or (33,5S)-l-(2-ethyl-6-(l-methyl-5-((2-oxo-5-propylpyridin-l(2H)- yl)methyl)-lH-l,2,3-triazol-4-yl)pyridin-3-yl)-5-fluoropiperidin-3-yl)acetic acid
  • Step 3 6-bromo-3-(3-(2-ethoxy-2-oxoethyl)piperidin-l-yl)-2-methyl-4-nitropyridine 1-oxide
  • TEA 0.7 mL, 5.04 mmol
  • ethyl 2-(piperi din-3 -yl)acetate 0.9 g, 5.26 mmol
  • Step 4 ethyl 2-(l-(6-bromo-2-methyl-4-nitropyridin-3-yl)piperidin-3-yl)acetate
  • Step 5 ethyl 2-(l-(6-bromo-4-fluoro-2-methylpyridin-3-yl)piperidin-3-yl)acetate
  • Step 6 ethyl 2-(l-(4-fluoro-6-(3-hydroxyprop-l-yn-l-yl)-2-methylpyridin-3-yl)piperidin-3- yl)acetate
  • Step 7 ethyl 2-(l-(4-fluoro-6-(5-(hydroxymethyl)-l-methyl-lH-l,2,3-triazol-4-yl)-2- methylpyridin-3-yl)piperidin-3-yl)acetate
  • Step 8 ethyl 2-(l-(4-fluoro-2-methyl-6-(l-methyl-5-(((methylsulfonyl)oxy)methyl)-lH-l,2,3- triazol-4-yl)pyridin-3-yl)piperidin-3-yl)acetate
  • Step 9 ethyl 2-(l-(4-fluoro-2-methyl-6-(l-methyl-5-((2-oxo-5-propylpyridin-l(2H)- yl)methyl)-lH-l,2,3-triazol-4-yl)pyridin-3-yl)piperidin-3-yl)acetate
  • Step 10 2-(l-(4-fluoro-2-methyl-6-(l-methyl-5-((2-oxo-5-propylpyridin-l(2H)-yl)methyl)- lH-l,2,3-triazol-4-yl)pyridin-3-yl)piperidin-3-yl)acetic acid
  • Example 48 2-(l-(2-ethyl-4-fluoro-6-(l-methyl-5-((2-oxo-5-propylpyridin-l(2H)-yl)methyl)- lH-l,2,3-triazol-4-yl)pyridin-3-yl)piperidin-3-yl)acetic acid
  • Step 1 6-bromo-2-ethyl-3-fluoropyridine
  • Step 4 6-bromo-3-(3-(2-ethoxy-2-oxoethyl)piperidin-l-yl)-2-ethyl-4-nitropyridine 1-oxide
  • Step 5 ethyl 2-(l-(6-bromo-2-ethyl-4-nitropyridin-3-yl)piperidin-3-yl)acetate
  • 6-bromo-3-(3-(2-ethoxy-2-oxoethyl)piperidin-l-yl)-2-ethyl-4- nitropyridine 1 -oxide (480 mg, 1.15 mmol) in DCM (5 mL) was added a solution of PBrs (0.11 mL, 1.15 mmol) in DCM (1 mL) at 0 °C under N2 atmosphere and the mixture was stirred at r.t. for 5 hrs.
  • Step 6 ethyl 2-(l-(6-bromo-2-ethyl-4-fluoropyridin-3-yl)piperidin-3-yl)acetate
  • Step 7 ethyl 2-(l-(2-ethyl-4-fluoro-6-(3-hydroxyprop-l-yn-l-yl)pyridin-3-yl)piperidin-3- yl)acetate
  • Step 8 ethyl 2-(l-(2-ethyl-4-fluoro-6-(5-(hydroxymethyl)-l-methyl-lH-l,2,3-triazol-4- yl)pyridin-3-yl)piperidin-3-yl)acetate
  • Step 9 ethyl 2-(l-(2-ethyl-4-fluoro-6-(l-methyl-5-(((methylsulfonyl)oxy)methyl)-lH-l,2,3- triazol-4-yl)pyridin-3-yl)piperidin-3-yl)acetate
  • Step 10 2-(l-(2-ethyl-4-fluoro-6-(l-methyl-5-((2-oxo-5-propylpyridin-l(2H)-yl)methyl)-lH-
  • Step 3 3-bromo-6-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-l-yn-l-yl)picolinonitrile
  • Step 4 3-bromo-6-(l-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-lH-l,2,3-triazol-4- yl)picolinonitrile
  • Step 6 methyl 2-((3S)-l-(2-cyano-6-(l-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)- lH-l,2,3-triazol-4-yl)pyridin-3-yl)-5,5-difluoropiperidin-3-yl)acetate
  • Step 7 methyl (S)-2-(l-(2-cyano-6-(5-(hydroxymethyl)-l-methyl-lH-l,2,3-triazol-4- yl)pyridin-3-yl)-5,5-difluoropiperidin-3-yl)acetate
  • Step 8 methyl (S)-2-(l-(2-cyano-6-(l-methyl-5-(((methylsulfonyl)oxy)methyl)-lH-l,2,3- triazol-4-yl)pyridin-3-yl)-5,5-difluoropiperidin-3-yl)acetate
  • Step 9 methyl (S)-2-(l-(2-cyano-6-(l-methyl-5-((2-oxo-5-propylpyridin-l(2H)-yl)methyl)- lH-l,2,3-triazol-4-yl)pyridin-3-yl)-5,5-difluoropiperidin-3-yl)acetate
  • Step 10 (S)-2-(l-(2-cyano-6-(l-methyl-5-((2-oxo-5-propylpyridin-l(2H)-yl)methyl)-lH-
  • reaction mixture was acidified with IM aq.HCl and extracted with EtOAc (3 x 3 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by prep-HPLC to give the title compound (20 mg, 58.7% yield) as white solid.
  • Example 52 and 53 (R) or (S)-2-(l-(2-ethyl-6-(l-methyl-5-((2-oxo-5-propylpyridin-l(2H)- yl)methyl)-lH-l,2,3-triazol-4-yl)pyridin-3-yl)-2-oxopiperidin-3-yl)acetic aci and (S) or (R)-2- (l-(2-ethyl-6-(l-methyl-5-((2-oxo-5-propylpyridin-l(2H)-yl)methyl)-lH-l,2,3-triazol-4- yl)pyridin-3-yl)-2-oxopiperidin-3-yl)acetic acid Step 1: (4-(6-ethyl-5-iodopyridin-2-yl)-l-methyl-lH-l,2,3-triazol-5-yl)methyl methanesulfonate
  • Step 2 l-((4-(6-ethyl-5-iodopyridin-2-yl)-l-methyl-lH-l,2,3-triazol-5-yl)methyl)-5- propylpyridin-2(lH)-one
  • Step 3 ethyl (R)-2-(l-(2-ethyl-6-(l-methyl-5-((2-oxo-5-propylpyridin-l(2H)-yl)methyl)-lH- l,2,3-triazol-4-yl)pyridin-3-yl)-2-oxopiperidin-3-yl)acetate and ethyl (S)-2-(l-(2-ethyl-6-(l- methyl-5-((2-oxo-5-propylpyridin-l(2H)-yl)methyl)-lH-l,2,3-triazol-4-yl)pyridin-3-yl)-2- oxopiperidin-3-yl)acetate
  • Step 4 (R) or (S)-2-(l-(2-ethyl-6-(l-methyl-5-((2-oxo-5-propylpyridin-l(2H)-yl)methyl)-lH- l,2,3-triazol-4-yl)pyridin-3-yl)-2-oxopiperidin-3-yl)acetic acid
  • Example 53 (S) or (R)-2-(l-(2-ethyl-6-(l-methyl-5-((2-oxo-5-propylpyridin-l(2H)- yl)methyl)-lH-l,2,3-triazol-4-yl)pyridin-3-yl)-2-oxopiperidin-3-yl)acetic acid
  • Example 54 and 55 (R) or (S)-2-(l-(2-ethyl-6-(l-methyl-5-((2-oxo-5-propylpyridin-l(2H)- yl)methyl)-lH-l,2,3-triazol-4-yl)pyridin-3-yl)-6-oxopiperidin-3-yl)acetic acid and (S) or (R)- 2-(l-(2-ethyl-6-(l-methyl-5-((2-oxo-5-propylpyridin-l(2H)-yl)methyl)-lH-l,2,3-triazol-4- yl)pyridin-3-yl)-6-oxopiperidin-3-yl)acetic acid
  • Step 1 tert-butyl 3-(2-ethoxy-2-oxoethyl)piperidine-l-carboxylate
  • Step 2 tert-butyl 5-(2-ethoxy-2-oxoethyl)-2-oxopiperidine-l-carboxylate
  • Step 5 (R) or (S)-2-(l-(2-ethyl-6-(l-methyl-5-((2-oxo-5-propylpyridin-l(2H)-yl)methyl)-lH-
  • Example 55 (S) or (R)-2-(l-(2-ethyl-6-(l-methyl-5-((2-oxo-5-propylpyridin-l(2H)- yl)methyl)-lH-l,2,3-triazol-4-yl)pyridin-3-yl)-6-oxopiperidin-3-yl)acetic acid
  • Step 3 (4-(5-bromopyrazin-2-yl)-l-methyl-lH-l,2,3-triazol-5-yl)methyl methanesulfonate
  • Step 4 l-((4-(5-bromopyrazin-2-yl)-l-methyl-lH-l,2,3-triazol-5-yl)methyl)-5- propylpyridin-2(lH)-one
  • Step 5 methyl (S)-2-(5,5-difluoro-l-(5-(l-methyl-5-((2-oxo-5-propylpyridin-l(2H)- yl)methyl)-lH-l,2,3-triazol-4-yl)pyrazin-2-yl)piperidin-3-yl)acetate
  • Step 6 (S)-2-(5,5-difluoro-l-(5-(l-methyl-5-((2-oxo-5-propylpyridin-l(2H)-yl)methyl)-lH- 1 ,2,3-tr iazol-4-yl)pyrazin-2-yl)piperidin-3-yl)acetic acid
  • Example 58 2-[(3R)-l-(6- ⁇ l-methyl-5-[(2-oxo-5-propyl-l,2-dihydropyridin-l-yl)methyl]- lH-l,2,3-triazol-4-yl ⁇ -2-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl]acetic acid
  • Step 2 3-bromo-6-[3-(oxan-2-yloxy)prop-l-yn-l-yl]-2-(trifluoromethyl)pyridine
  • Step 3 3-bromo-6-(l-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-lH-l,2,3-triazol-4- yl)-2-(trifluoromethyl)pyridine
  • Step 4 ethyl 2-((3R)-l-(6-(l-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-lH-l,2,3- triazol-4-yl)-2-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl)acetate
  • Step 5 ethyl (R)-2-(l-(6-(5-(hydroxymethyl)-l-methyl-lH-l,2,3-triazol-4-yl)-2- (trifluoromethyl)pyridin-3-yl)piperidin-3-yl)acetate
  • Step 6 ethyl (R)-2-(l-(6-(l-methyl-5-(((methylsulfonyl)oxy)methyl)-lH-l,2,3-triazol-4-yl)-2- (trifluoromethyl)pyridin-3-yl)piperidin-3-yl)acetate
  • Step 7 ethyl 2-[(3R)-l-(6- ⁇ l-methyl-5-[(2-oxo-5-propyl-l,2-dihydropyridin-l-yl)methyl]- lH-l,2,3-triazol-4-yl ⁇ -2-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl]acetate
  • Step 8 2-[(3R)-l-(6- ⁇ l-methyl-5-[(2-oxo-5-propyl-l,2-dihydropyridin-l-yl)methyl]-lH- l,2,3-triazol-4-yl ⁇ -2-(trifluoromethyl)pyridin-3-yl)piperidin-3-yl]acetic acid
  • Step 3 3-bromo-2-(difluoromethyl)-6-[3-(oxan-2 yloxy)prop-l-yn-l-yl]pyridine
  • Step 4 3-bromo-2-(difluoromethyl)-6- ⁇ l-methyl-5-[(oxan-2-yloxy)methyl]-lH-l,2,3-triazol- 4-yl ⁇ pyridine
  • Step 5 ethyl 2-[(3R)-l-[2-(difluoromethyl)-6- ⁇ l-methyl-5-[(oxan-2-yloxy)methyl]-lH-l,2,3- triazol-4-yl ⁇ pyridin-3-yl] piperidin-3-yl] acetate
  • Step 6 ethyl (S)-2-(l-(2-cyano-6-(l-methyl-5-(((methylsulfonyl)oxy)methyl)-lH-l,2,3- triazol-4-yl)pyridin-3-yl)piperidin-3-yl)acetate
  • Step 7 ethyl (S)-2-(l-(2-cyano-6-(l-methyl-5-(((methylsulfonyl)oxy)methyl)-lH-l,2,3- triazol-4-yl)pyridin-3-yl)piperidin-3-yl)acetate
  • Step 8 [(3R)-l-[2-(difluoromethyl)-6- ⁇ l-methyl-5-[(2-oxo-5-propyl-l,2-dihydropyridin-l- yl)methyl]-lH-l,2,3-triazol-4-yl ⁇ pyridin-3-yl]piperidin-3-yl]acetate [0359] To a mixture of 2- ⁇ 4-[6-(difluoromethyl)-5-[(3R)-3-(2-ethoxy-2-oxoethyl)piperidin-l- yl]pyridin-2-yl]-l-methyl-lH-l,2,3-triazol-5-yl ⁇ ethane-l-sulfonic acid (60 mg, 0.1 mmol) and 5- propylpyridin-2-ol (17 mg, 0.1 mmol) in toluene (5 mL) and water (1 mL) was added K2CO3 (51 mg, 0.3
  • Step 9 2-[(3R)-l-[2-(difluoromethyl)-6- ⁇ l-methyl-5-[(2-oxo-5-propyl-l,2-dihydropyridin-l- yl)methyl]-lH-l,2,3-triazol-4-yl ⁇ pyridin-3-yl]piperidin-3-yl]acetic acid
  • Example 61 2-((S)-l-(6-(5-(((S)-4-(cyclopropylmethyl)-3-methyl-2-oxoimidazolidin-l- yl)methyl)-l-methyl-lH-l,2,3-triazol-4-yl)-2-ethylpyridin-3-yl)-5,5-difluoropiperidin-3- yl)acetic acid
  • Step 1 (4S)-l- ⁇ [4-(5-bromo-6-ethylpyridin-2-yl)-l-methyl-lH-l,2,3-triazol-5-yl]methyl ⁇ -4- (cyclopropylmethyl)-3-methylimidazolidin-2-one
  • Step 2 methyl 2-[(3S)-l-[6-(5- ⁇ [(4S)-4-(cyclopropylmethyl)-3-methyl-2-oxoimidazolidin-l- yl]methyl ⁇ -l-methyl-lH-l,2,3-triazol-4-yl)-2-ethylpyridin-3-yl]-5,5-difluoropiperidin-3- yl] acetate
  • Step 3 2-[(3S)-l-[6-(5- ⁇ [(4S)-4-(cyclopropylmethyl)-3-methyl-2-oxoimidazolidin-l- yl]methyl ⁇ -l-methyl-lH-l,2,3-triazol-4-yl)-2-ethylpyridin-3-yl]-5,5-difluoropiperidin-3- yl] acetic acid
  • Example 65 2-((S)-l-(6-(5-(((S)-4-(cyclopropylmethyl)-2-oxoimidazolidin-l-yl)methyl)-l- methyl-lH-l,2,3-triazol-4-yl)-2-ethylpyridin-3-yl)-5,5-difluoropiperidin-3-yl)acetic acid
  • Step 1 tert-butyl (S)-(l-amino-3-cyclopropylpropan-2-yl)carbamate
  • Step 2 4-(6-ethyl-5-iodopyridin-2-yl)-l-methyl-lH-l,2,3-triazole-5-carbaldehyde
  • Step 3 tert-butyl (S)-(l-cyclopropyl-3-(((4-(6-ethyl-5-iodopyridin-2-yl)-l-methyl-lH-l,2,3- triazol-5-yl)methyl)amino)propan-2-yl)carbamate

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Abstract

Cette invention concerne des nouveaux composés d'acide azacyclohexyl acétique substitués, leur fabrication, des compositions pharmaceutiques les comprenant, ainsi que leur utilisation en tant que médicaments pour traiter une maladie associée à une dysrégulation des récepteurs de l'acide lysophosphatidique (LPA).
PCT/IB2021/059266 2020-08-11 2021-10-09 Composés d'acide azacyclohexyle acétique substitués par triazole-pyridinyle utilisés en tant qu'antagonistes du récepteur lpa Ceased WO2022034568A1 (fr)

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KR1020237008152A KR20240068583A (ko) 2020-08-11 2021-10-09 Lpa 수용체 길항제로서의 트리아졸-피리디닐 치환된 아자시클로헥실 아세트산 화합물
EP21791479.5A EP4196220A1 (fr) 2020-08-11 2021-10-09 Composés d'acide azacyclohexyle acétique substitués par triazole-pyridinyle utilisés en tant qu'antagonistes du récepteur lpa
AU2021323515A AU2021323515A1 (en) 2020-08-11 2021-10-09 Triazole-pyridinyl substituted azacyclohexyl acetic acid compounds as LPA receptor antagonists
MX2023001812A MX2023001812A (es) 2020-08-11 2021-10-09 Compuestos del acido azociclohexil acetico sustituidos por triazol-piridinilo como antagonistas del receptor lpa.
CN202180067597.XA CN116669727B (zh) 2020-08-11 2021-10-09 作为lpa受体拮抗剂的三唑-吡啶基取代的氮杂环己基乙酸化合物
JP2023510342A JP2023544476A (ja) 2020-08-11 2021-10-09 Ｌｐａ受容体アンタゴニストとしてのトリアゾール－ピリジニル置換アザシクロヘキシル酢酸化合物
CA3191452A CA3191452A1 (fr) 2020-08-11 2021-10-09 Composes d'acide azacyclohexyle acetique substitues par triazole-pyridinyle utilises en tant qu'antagonistes du recepteur lpa
IL300525A IL300525A (en) 2020-08-11 2021-10-09 Triazole-pyridinyl-substituted azacyclohexyl acetic acid compounds as LPA receptor antagonists

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US11548871B2 (en) 2019-11-15 2023-01-10 Gilead Sciences, Inc. Triazole carbamate pyridyl sulfonamides as LPA receptor antagonists and uses thereof
US11702407B2 (en) 2020-06-03 2023-07-18 Gilead Sciences, Inc. LPA receptor antagonists and uses thereof
US11912686B2 (en) 2020-06-03 2024-02-27 Gilead Sciences, Inc. LPA receptor antagonists and uses thereof
US11584738B2 (en) 2020-06-03 2023-02-21 Gilead Sciences, Inc. LPA receptor antagonists and uses thereof
US12139474B2 (en) 2020-06-03 2024-11-12 Gilead Sciences, Inc. LPA receptor antagonists and uses thereof
WO2022232459A1 (fr) * 2021-04-30 2022-11-03 Viva Star Biosciences (Suzhou) Co., Ltd. Nouveaux composés d'acide pyrrolidinyl et tétrahydro-2 h-pyranyl acétique à substitution par triazole-pyridine utilisés en tant qu'antagonistes de lpa
US11980609B2 (en) 2021-05-11 2024-05-14 Gilead Sciences, Inc. LPA receptor antagonists and uses thereof
US12503454B2 (en) 2021-05-13 2025-12-23 Gilead Sciences, Inc. LPA receptor antagonists and uses thereof
US11939318B2 (en) 2021-12-08 2024-03-26 Gilead Sciences, Inc. LPA receptor antagonists and uses thereof
US11884627B2 (en) 2022-02-25 2024-01-30 Lhotse Bio, Inc. Compounds and compositions for treating conditions associated with LPA receptor activity
US12428375B2 (en) 2022-02-25 2025-09-30 Lhotse Bio, Inc. Compounds and compositions for treating conditions associated with LPA receptor activity
WO2024022314A1 (fr) * 2022-07-25 2024-02-01 武汉人福创新药物研发中心有限公司 Composés triazoles et leur utilisation en tant qu'antagonistes de lpar1
WO2025051266A1 (fr) * 2023-09-08 2025-03-13 西藏海思科制药有限公司 Antagoniste de lpar1 dérivé d'un dérivé hétéroaromatique et son utilisation

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