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WO2025207514A1 - Bicyclic heteroaryl sulfanediimine derivatives as ectonucleotide pyrophosphatase phosphodiesterase 1 inhibitors - Google Patents

Bicyclic heteroaryl sulfanediimine derivatives as ectonucleotide pyrophosphatase phosphodiesterase 1 inhibitors

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Publication number
WO2025207514A1
WO2025207514A1 PCT/US2025/021136 US2025021136W WO2025207514A1 WO 2025207514 A1 WO2025207514 A1 WO 2025207514A1 US 2025021136 W US2025021136 W US 2025021136W WO 2025207514 A1 WO2025207514 A1 WO 2025207514A1
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WIPO (PCT)
Prior art keywords
compound
pharmaceutically acceptable
acceptable salt
fused
methyl
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French (fr)
Inventor
Ronald Hawley
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Riboscience LLC
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Riboscience LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B33—ADDITIVE MANUFACTURING TECHNOLOGY
    • B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
    • B33Y70/00—Materials specially adapted for additive manufacturing
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
    • C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
    • C08F220/52—Amides or imides
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F265/00—Macromolecular compounds obtained by polymerising monomers on to polymers of unsaturated monocarboxylic acids or derivatives thereof as defined in group C08F20/00
    • C08F265/04—Macromolecular compounds obtained by polymerising monomers on to polymers of unsaturated monocarboxylic acids or derivatives thereof as defined in group C08F20/00 on to polymers of esters

Definitions

  • ENPP1 enzyme is present in a wide range of tissues and cell types, such as lymphocytes, macrophages, liver, brain, heart, kidney, vascular smooth muscle cells, and chondrocytes.
  • ENPP1 hydrolyzes ATP and other nucleoside triphosphates and releases AMP or other nucleoside monophosphates as well as pyrophosphate (PPi) (Kato K et al.2012 PNAS 109:16876-16881; Hessle L et al.2002 PNAS 99:9445-9449).
  • ENPP1 has been identified as the dominant 2’-3’-cGAMP hydrolase in cultured cells, tissue extracts and blood (Li L et al.2014 Nat Chem Biol 10:1043-1048). Tissues and blood from ENPP1 knockout mice lack 2’-3’-cGAMP hydrolase activity.
  • Elevated levels of ENPP1 have been associated with calcific aortic valve disease (CAVD) and calcium pyrophosphate deposition disease (CPPD), an inflammatory disease resulting from CPPD crystal deposits in the joint and surrounding tissues (Cote N et al.2012 Eur J Pharmacol 689:139-146; Johnson K et al.2001 Arthritis Rheum 44:1071).
  • CAVD calcific aortic valve disease
  • CPPD calcium pyrophosphate deposition disease
  • ENPP1 expression is upregulated in certain hepatocellular carcinomas, glioblastomas, melanomas, testicular, pancreatic and thyroid and breast cancers and has been associated with resistance to chemotherapy (see Lau WM et al.2013 PLoS One 8:5; Bageritz J et al.2014 Mol Cell Oncology 1:3; Bageritz J et al.2014 Cell Death, Differentiation 21:929-940; Umar A et al. 2009 Mol Cell Proteomics 8:1278-1294).
  • ENPP1 upregulation and variants of ENPP1 are also associated with insulin resistance and type 2 diabetes (Meyre D et al.2005 Nat Genet 37:863-867; Maddux BA et al.1995 Nature 373:448-451; Rey D et al.2012 Mol Biol Rep 39:7687-7693) and enzyme activity of ENPP1 was reported to be required for the inhibition of insulin receptor signaling (Chin CN et al.2009 Eur J Pharmacol 606:17-24).
  • a pharmaceutical composition comprising a compound of Formula (I) (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • methods of treating a disease mediated by ENPP1 in a patient comprising administering to the patient a compound of Formula (I) (or any of the embodiments thereof described herein) or a pharmaceutically acceptable salt thereof in a therapeutically effective amount.
  • the disease is cancer.
  • the disease is cancer selected from hepatocellular carcinomas, glioblastomas, melanomas, testicular cancer, pancreatic cancer, thyroid cancer, cervical cancer, ovarian cancer, bladder cancer, colon cancer, and lung cancer.
  • the disease is cancer such as hepatocellular carcinomas, glioblastomas, melanomas, testicular, pancreatic, thyroid and breast cancer.
  • the disease is an inflammatory disease e.g., calcific aortic valve disease, osteoarthritis, and calcium pyrophosphate dihydrate disease.
  • the disease metabolic disease e.g., type 2 diabetes, or a viral infection such as DNA virus infections, HIV, Herpes virus infections, Papilloma virus infections, RNA virus infections, and HBV.
  • the disease is an inflammatory disease e.g., calcific aortic valve disease and calcium pyrophosphate deposition disease (CPPD).
  • CPPD calcium pyrophosphate deposition disease
  • the disease metabolic disease e.g., type 2 diabetes or a viral infection.
  • the disease is cancer selected from hepatocellular carcinomas, glioblastomas, melanomas, testicular cancer, pancreatic cancer, thyroid cancer, cervical cancer, ovarian cancer, bladder cancer, colon cancer, lung cancer, breast cancer, multiple myeloma, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, large granular lymphocytic leukemia, T-cell prolymphocytic leukemia, prolymphocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, diffuse large B cell lymphoma, low grade glioma, colorectal cancer, gastric and gastrointestinal cancer, esophageal cancer, anal cancer, cancer of the appendix, kidney cancer, skin cancer, uterine cancer, brain cancer, adrenal cancer, bile duct cancer, bone cancer, fallopian tube cancer,
  • the disease is cancer selected from hepatocellular carcinomas, glioblastomas, melanomas, testicular cancer, pancreatic cancer, thyroid cancer, cervical cancer, ovarian cancer, bladder cancer, colon cancer, and lung cancer.
  • the disease is an inflammatory disease e.g., calcific aortic valve disease, osteoarthritis, and calcium pyrophosphate dihydrate disease.
  • the disease metabolic disease e.g., type 2 diabetes, or a viral infection such as DNA virus infections, HIV, Herpes virus infections, Papilloma virus infections, RNA virus infections, and HBV.
  • the medicament is for use in the treatment of cancer such as hepatocellular carcinomas, glioblastomas, melanomas, testicular, pancreatic, thyroid and breast cancer.
  • the medicament is for use in the treatment of an inflammatory disease e.g., calcific aortic valve disease and calcium pyrophosphate deposition disease (CPPD).
  • CPPD calcium pyrophosphate deposition disease
  • the medicament is for use in the treatment of a metabolic disease e.g., type 2 diabetes or a viral infection.
  • the disease is cancer selected from hepatocellular carcinomas, glioblastomas, melanomas, testicular cancer, pancreatic cancer, thyroid cancer, cervical cancer, ovarian cancer, bladder cancer, colon cancer, lung cancer, breast cancer, multiple myeloma, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, large granular lymphocytic leukemia, T-cell prolymphocytic leukemia, prolymphocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, diffuse large B cell lymphoma, low grade glioma, colorectal cancer, gastric and gastrointestinal cancer, esophageal cancer, anal cancer, cancer of the appendix, kidney cancer, skin cancer, uterine cancer, brain cancer, adrenal cancer, bile duct cancer, bone cancer, fallopian
  • the disease is cancer selected from hepatocellular carcinomas, glioblastomas, melanomas, testicular cancer, pancreatic, thyroid cancer, cervical cancer, ovarian cancer, bladder cancer, colon cancer, and lung cancer.
  • the disease is an inflammatory disease e.g., calcific aortic valve disease, osteoarthritis, and calcium pyrophosphate dihydrate disease.
  • the disease metabolic disease e.g., type 2 diabetes, or a viral infection such as DNA virus infections, HIV, Herpes virus infections, Papilloma virus infections, RNA virus infections, and HBV.
  • the disease is cancer such as hepatocellular carcinomas, glioblastomas, melanomas, testicular, pancreatic, thyroid and breast cancer.
  • the disease is an inflammatory disease e.g., calcific aortic valve disease and calcium pyrophosphate deposition disease (CPPD).
  • the disease is a metabolic disease e.g., type 2 diabetes or a viral disease.
  • a compound of Formula (I) or any embodiments thereof described herein
  • a pharmaceutically acceptable salt thereof for use in the treatment of cancer, a metabolic disease, viral infection, or an inflammatory disease.
  • the disease is cancer.
  • the disease is cancer selected from hepatocellular carcinomas, glioblastomas, melanomas, testicular cancer, pancreatic cancer, thyroid cancer, cervical cancer, ovarian cancer, bladder cancer, colon cancer, lung cancer, breast cancer, multiple myeloma, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, large granular lymphocytic leukemia, T-cell prolymphocytic leukemia, prolymphocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, diffuse large B cell lymphoma, low grade glioma, colorectal cancer, gastric and gastrointestinal cancer, esophageal cancer, anal cancer, cancer of the appendix, kidney cancer, skin cancer, uterine cancer, brain cancer, adrenal cancer, bile duct cancer, bone cancer, fallopian
  • the disease is cancer selected from hepatocellular carcinomas, glioblastomas, melanomas, testicular cancer, pancreatic cancer, thyroid cancer, cervical cancer, ovarian cancer, bladder cancer, colon cancer, lung cancer, breast cancer, multiple myeloma, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, large granular lymphocytic leukemia, T-cell prolymphocytic leukemia, prolymphocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, diffuse large B cell lymphoma, low grade glioma, colorectal cancer, gastric and gastrointestinal cancer, esophageal cancer, anal cancer, cancer of the appendix, kidney cancer, skin cancer, uterine cancer, brain cancer, adrenal cancer, bile duct cancer, bone cancer, fallopian tube cancer,
  • the treatment is for cancer e.g., hepatocellular carcinomas, glioblastomas, melanomas, testicular, pancreatic, thyroid and breast cancer.
  • the use is for the treatment of an inflammatory disease e.g., calcific aortic valve disease and calcium pyrophosphate deposition disease (CPPD).
  • the medicament is for use in the treatment of a metabolic disease e.g., type 2 diabetes or a viral infection.
  • a metabolic disease e.g., type 2 diabetes or a viral infection.
  • Alkylcarbonyl means a -COR radical where R is alkyl as defined above, e.g., methylcarbonyl, ethylcarbonyl, propylcarbonyl, and the like.
  • Amino means a –NH2.
  • Aminocarbonyl means -CONH2.
  • Alkylaminocarbonyl means -CONHR radical where R is alkyl as defined above, e.g., methylaminocarbonyl, ethylaminocarbonyl, and the like.
  • Aminocarbonylalkyl means —(alkylene)-CONRR’ radical where R is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl and R’ is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, optionally substituted phenyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl; or R and R’ together with the nitrogen atom to which they are attached from optionally substituted cyclylaminyl, each term as defined herein, e.g., methylaminocarbonyl-ethyl, ethylaminocarbonylethyl, 2-[(HOCH2CH2)2NC(O)]ethyl, and the like.
  • Alkylamino means a -NHR radical where R is alkyl as defined above, e.g., methylamino, ethylamino, propylamino, or 2-propylamino, and the like.
  • Aminoalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with –NR’R” where R’and R” are each independently hydrogen or alkyl as defined above, e.g., aminomethyl, aminoethyl, methylaminomethyl, aminopropyl, methylaminopropyl, and the like.
  • Aminoalkylamino means a –NR a R b radical where R a is hydrogen or alkyl and R b is aminoalkyl as defined above, e.g., aminoethylamino, dimethylaminoethylamino, diethylaminoethylamino, dimethylaminopropylamino, diethylaminopropylamino, and the like.
  • aminoalkyloxy or “aminoalkoxy” means a –OR a radical where R a is aminoalkyl as defined above, e.g., aminoethyloxy, dimethylaminoethyloxy, diethylaminoethyloxy, dimethylaminopropyloxy, diethylaminopropyloxy, and the like.
  • Alkoxy means a -OR radical where R is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert-butoxy, and the like.
  • Alkoxycarbonyl a -C(O)OR radical where R is alkyl as defined above, e.g., methoxycarbonyl, ethoxycarbonyl, and the like.
  • Alkoxyalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one alkoxy group, such as one or two alkoxy groups, as defined above, e.g., 2- methoxyethyl, 1-, 2-, or 3-methoxypropyl, 2-ethoxyethyl, and the like.
  • Alkoxyalkylamino means a –NRR’ radical where R is hydrogen or alkyl and R’ is alkoxyalkyl as defined above, e.g., methoxyethylamino, ethoxyethylamino, propoxypropylamino, ethoxypropylamino, and the like.
  • Alkoxyalkyloxy or “alkoxyalkoxy” means a –(O)R radical where R is alkoxyalkyl as defined above, e.g., methoxyethoxy, ethoxyethoxy, and the like.
  • Aryl means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms e.g., phenyl or naphthyl.
  • Arylalkyl or “aralkyl” means a –(alkylene)-R where R is aryl as defined above e.g., benzyl.
  • Arylene means a divalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms e.g., phenylene or naphthylene.
  • Aryloxy means a -OR radical where R is aryl as defined above e.g., phenyloxy or naphthyloxy. When aryl is phenyl, the group is also referred to herein as phenyloxy or phenoxy.
  • Aryloxyalkyl means a –alkylene-OR radical where R is aryl as defined above, e.g., phenyloxymethyl, phenyloxyethyl, phenyloxypropyl, and the like.
  • “Bridged cyclylaminylene” means a saturated divalent bicyclic ring having 5 to 7 ring carbon ring atoms in which two non-adjacent ring atoms are linked by a (CR z R z ’) n group where n is an integer selected from 1 to 3, and R z and R z ’ are each independently H or methyl (also may be referred to herein as “bridging” group), and further wherein one of the ring carbon atoms is N and an additional ring carbon atom is replaced by a heteroatom selected from N, O, and S(O) n , where n is an integer selected from 0 to 2 inclusive.
  • the N, O, and S(O)n can be present in the bridging group. Examples include, but are not limited to, 3,8- diazabicyclo[3.2.1]octa-3,8-diyl, and the like.
  • Cycloalkyl means a cyclic saturated monovalent hydrocarbon radical of three to ten carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and the like.
  • Cycloalkylene means a cyclic saturated divalent hydrocarbon radical of three to ten carbon atoms, e.g., 1,3-cyclobutylene, 1,3-cyclopentylene, or 1,3- or 1,4-cyclohexylene, and the like.
  • Cycloalkylalkyl means an -(alkylene)-R radical where R is cycloalkyl as defined above, e.g., cyclopropylmethyl, cyclobutylethyl, and the like.
  • Cycloalkyloxy means a -OR radical where R is cycloalkyl (including specific heterocyclyl rings) as defined above e.g., cyclopropyloxy, and the like.
  • Carboxy means –COOH.
  • Cyclylaminylene means a saturated divalent monocyclic ring of 4 to 8 ring atoms in which one ring atom is nitrogen, an additional ring atom can be nitrogen, O, or S(O)n (where n is 0, 1 or 2), and the remaining ring atoms are C.
  • cyclylaminylene include, but is not limited to, 1,3- or 1,4-piperidindiyl, 1,4-piperazindiyl, 1,3-azetidindiyl, 1,3-morpholindiyl, and the like.
  • Carbonylaminoalkyl means —(alkylene)-NRCOR’ radical where R is hydrogen or alkyl and R’ is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, optionally substituted phenyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl; each term as defined herein, e.g., methylcarbonylaminomethyl, ethylcarbonylaminoethyl, 2- (HOCH 2 C(O)amino)ethyl, and the like.
  • “Fused cyclylaminylene” means a fused divalent bicyclic ring in which a first ring is a saturated ring having 4 to 8 ring atoms in which one ring atom is nitrogen, an additional ring atom can be nitrogen, O, or S(O)n (where n is 0, 1 or 2), and the remaining ring atoms are C. Two adjacent ring atoms of the first ring are fused to two adjacent ring atoms of a phenyl or a five or six membered heteroaryl, each as defined herein . Any two suitable ring atoms of the fused cyclcylaminylene can be points of attachment.
  • Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxy-ethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1- (hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3- dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4- dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3- dihydroxypropyl, and 1-(hydroxymethyl)-2-hydroxyethyl.
  • “Hydroxyalkylamino” means a –NR a R b radical where R a is hydrogen or alkyl and R b is hydroxyalkyl as defined above, e.g., hydroxyethylamino, hydroxypropylamino, and the like.
  • “Hydroxyalkyloxy” means a –OR a radical where R a is hydroxyalkyl as defined above, e.g., hydroxyethyloxy, hydroxypropyloxy, and the like.
  • Heterocyclyl means a saturated or unsaturated monovalent monocyclic group of 4 to 8 ring atoms in which one or two ring atoms are heteroatom selected from N, O, or S(O)n, where n is an integer from 0 to 2, the remaining ring atoms being C. Additionally, one or two ring carbon atoms in the heterocyclyl ring can optionally be replaced by a –CO- group.
  • heterocyclyl includes, but is not limited to, pyrrolidinyl, piperidinyl, homopiperidinoyl, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholinyl, piperazinyl, tetrahydro- pyranyl, thiomorpholinoyl, and the like.
  • heterocyclyl ring is unsaturated it can contain one or two ring double bonds provided that the ring is not aromatic.
  • heterocyclyl group contains at least one nitrogen atom, it is also referred to herein as heterocyclylaminyl andnd is a subset of the heterocyclyl group.
  • Heterocyclylalkylamino means a -NRR’ radical where R is hydrogen or alkyl and R' is heterocyclylalkyl ring (including specific heterocyclyl rings) as defined above e.g., tetraydrofuranylmethylamino, piperazinylethylamino, morpholinylethylamino, piperidinylmethylamino, and the like.
  • Heterocyclyloxy means a -OR radical where R is heterocyclyl (including specific heterocyclyl rings) as defined above.
  • Heterocyclylalkyloxy means a -OR radical where R is heterocyclylalkyl ring (including specific heterocyclyl rings) as defined above e.g., tetraydrofuranylmethyloxy, piperazinylethyloxy, morpholinylethyloxy, piperidinylmethyloxy, and the like.
  • Heteroaryl means a monovalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms, unless otherwise stated, where one or more, (in one embodiment, one, two, or three), ring atoms are heteroatom selected from N, O, or S, the remaining ring atoms being carbon.
  • Representative examples include, but are not limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, and the like.
  • the terms “heteroaryl” and “aryl” are mutually exclusive.
  • heteroaryl ring contains 5- or 6 ring atoms it is also referred to herein as 5-or 6- membered heteroaryl.
  • heteroaryl means a –alkylene-R radical where R is heteroaryl as defined above, e.g., pyridylmethyl, pyridylethyl, thiazolylpropyl, and the like.
  • Heteroaryloxy means a -OR radical where R is heteroaryl (including specific heteroaryl rings) as defined above.
  • Heteroaryloxyalkyl means a –alkylene-OR radical where R is heteroaryl as defined above, e.g., pyridyloxymethyl, pyridyloxyethyl, thiazolyloxypropyl, and the like.
  • Heteroarylene means a divalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms, unless otherwise stated, where one or more, (in one embodiment, one, two, or three), ring atoms are heteroatom selected from N, O, or S, the remaining ring atoms being carbon.
  • Representative examples include, but are not limited to, pyrroldiyl, thiazoldiyl, imidazoldiyl, furandiyl, indoldiyl, isoindoldiyl, oxazoldiyl, isoxazoldiyl, benzothiazoldiyl, benzoxazoldiyl, quinolindiyl, isoquinolindiyl, pyridindiyl, pyrimidindiyl, triazoldiyl, tetrazoldiyl, and the like.
  • Optionally substituted aryl means aryl as defined above, that is substituted with one, two, or three substituents each independently selected from alkyl, hydroxy, alkoxy, halo, cyano, haloalkyl, haloalkoxyl, amino, alkylamino, dialkylamino, carboxy, or alkoxycarbonyl, each as defined herein.
  • Optionally substituted heteroaryl means heteroaryl as defined above, that is substituted with one, two, or three substituents each independently selected from alkyl, hydroxy, alkoxy, halo, cyano, haloalkyl, haloalkoxyl, amino, alkylamino, dialkylamino, carboxy, or alkoxycarbonyl, each as defined herein.
  • Optionally substituted heterocyclyl means heterocyclyl as defined above, that is substituted with one, two, or three substituents each independently selected from alkyl, hydroxy, alkoxy, cyano, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, -COR (where R is alkyl), alkoxycarbonyl, each as defined herein.
  • “Spiro cyclylaminylene” means a saturated bicyclic divalent ring having 6 to 10 ring atoms in which one ring atom is N and an additional ring atom can be a heteroatom selected from N, O, and S(O)n, where n is an integer selected from 0 to 2, the remaining ring atoms being C and the rings are connected through only one atom, the connecting atom is also called the spiroatom, most often a quaternary carbon (“spiro carbon”).
  • Spiro cyclylaminylene is optionally substituted with one or two substituents each independently selected from alkyl, halo, alkoxy, hydroxy, and cyano, unless stated otherwise.
  • the present disclosure also includes protected derivatives of compounds of Formula (I).
  • compounds of Formula (I) when compounds of Formula (I) contain groups such as hydroxy, carboxy, thiol or any group containing a nitrogen atom(s), these groups can be protected with a suitable protecting groups.
  • a comprehensive list of suitable protective groups can be found in T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. (1999) , the disclosure of which is incorporated herein by reference in its entirety.
  • the protected derivatives of compounds of the present disclosure can be prepared by methods well known in the art.
  • the present disclosure also includes polymorphic forms and deuterated forms of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • a “pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • Such salts include: acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as formic acid, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4- hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzene
  • the compounds of Formula (I) may have asymmetric centers.
  • Compounds of Formula (I) containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of materials. All chiral, diastereomeric, all mixtures of chiral or diasteromeric forms, and racemic forms are within the scope of this disclosure, unless the specific stereochemistry or isomeric form is specifically indicated.
  • the R 4 floating substituent can replace any hydrogen on the six membered aromatic ring portion of the bicyclic ring system that is not substituted with R 5 or R 6 i.e., when any of a b, d, and e is CH and is not substituted with R 5 or R 6 .
  • the compounds of Formula (I) may also contain unnatural amounts of isotopes at one or more of the atoms that constitute such compounds. Unnatural amounts of an isotope may be defined as ranging from the amount found in nature to an amount 100% of the atom in question. that differ only in the presence of one or more isotopically enriched atoms.
  • Exemplary isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I, and 125 1, respectively.
  • Isotopically-labeled compounds e.g., those labeled with .sup.3H and .sup.14C
  • Tritiated (i.e., .sup.3H) and carbon-14 (i.e., .sup.14C) isotopes can be useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements).
  • substituents such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements).
  • one or more hydrogen atoms are replaced by 2 H or 3 H, or one or more carbon atoms are replaced by 13 C- or 14 C- enriched carbon.
  • Positron emitting isotopes such as 15 O, 13 N, 11 C, and 15 F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy.
  • Isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the Schemes or in the Examples herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • “Optional” or “optionally” means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
  • heterocyclyl group optionally substituted with an alkyl group means that the alkyl may but need not be present, and the description includes situations where the heterocyclyl group is substituted with an alkyl group and situations where the heterocyclyl group is not substituted with alkyl.
  • a “pharmaceutically acceptable carrier or excipient” means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • a pharmaceutically acceptable carrier/excipient as used in the specification and claims includes both one and more than one such excipient.
  • the terms “inhibiting” and “reducing,” or any variation of these terms in relation of EPPI, includes any measurable decrease or complete inhibition to achieve a desired result. For example, there may be a decrease of about, at most about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range derivable therein, reduction of EPPI activity compared to normal.
  • “Treating” or “treatment” of a disease includes: (1) preventing the disease, i.e.
  • a “therapeutically effective amount” means the amount of a compound of the present disclosure and/or a pharmaceutically acceptable salt thereof that, when administered to a patient for treating a disease, is sufficient to effect such treatment for the disease.
  • Embodiment A the compounds of Formula (I) or a pharmaceutically acceptable salt thereof as defined in the Summary above.
  • Embodiment B [0116] In embodiment B, the compounds of Formula (I) of embodiment A or a pharmaceutically acceptable salt thereof Z is bond.
  • Embodiment C [0117] In embodiment C, the compounds of Formula (I) of embodiment A or a pharmaceutically acceptable salt thereof Z is NH, O, S, or SO2.
  • Embodiment D the compounds of Formula (I) of any one of embodiments A, B, and C or a pharmaceutically acceptable salt thereof has a structure of formula (Ia), (Ib), (Ic), (Id), (If), (Ig), or (Ih): or SO 2 in the compounds of formulae (Ie) to (Ih) .
  • compound of Formulae (Ia), (Ib), (Ic), and (Id) will be selected with reference to embodiment B and (If), (Ig), and (Ih) will be selected with reference to C. [0119] (Di).
  • the compound of Formula (I) of embodiment A, B, or D, or a pharmaceutically acceptable salt thereof has structure (Ia). [0120] (Dii). In subembodiment (Dii), the compound of Formula (I) of embodiment A, B, or D, or a pharmaceutically acceptable salt thereof has structure (Ib). [0121] (Diii) . In subembodiment (Diii), the compound of Formula (I) of embodiment A, B, or D, or a pharmaceutically acceptable salt thereof has structure (Ic). [0122] (Div).
  • the compound of Formula (I) of embodiment A, B, or D, or a pharmaceutically acceptable salt thereof has structure (Id). [0123] (Dv). In subembodiment (Dv), the compound of Formula (I) of embodiment A, C, or D, or a pharmaceutically acceptable salt thereof has structure (Ie). [0124] (Dvi). In subembodiment (Dvi), the compound of Formula (I) of embodiment A, C, or D, or a pharmaceutically acceptable salt thereof has structure (If). [0125] (Dvii). In subembodiment (Dvii), the compound of Formula (I) of embodiment A, C, or D, or a pharmaceutically acceptable salt thereof has structure (Ig).
  • the compound of Formula (I) of embodiment A, C, or D, or a pharmaceutically acceptable salt thereof has structure (Ih).
  • Embodiment E [0127] In embodiment E, the compound of any one of embodiments A, C, and D, and subembodiments (Dv) to (Dviii), or a pharmaceutically acceptable salt thereof is wherein Z is NH.
  • Embodiment F [0128] In embodiment F, the compound of any one of embodiments A, C, and D, and subemodiments (Dv) to (Dviii), or a pharmaceutically acceptable salt thereof is wherein Z is O. [0129] (Fi).
  • the compound of any one of embodiments A, C, and D, and subemodiments (Dv) to (Dviii), or a pharmaceutically acceptable salt thereof is wherein Z is bond or O.
  • Embodiment G [0130] In embodiment G, the compound of any one of embodiments A, C, and D, and subembodiments (Dv) to (Dviii), or a pharmaceutically acceptable salt thereof is wherein Z is SO 2 .
  • Embodiment H [0131] In embodiment H, the compound of any one of embodiments A to D and E to G and subembodiments (Di) to (Dviii), or a pharmaceutically acceptable salt thereof is wherein X is N.
  • Embodiment I the compound of any one of embodiments A to D and E to G and subembodiments (Di) to (Dviii), or a pharmaceutically acceptable salt thereof is wherein X is CH or C when attached to R 1 . [0133] (Ii). In embodiment Ii, the compound of any one of embodiments A to E to G, and subembodiments (Di) to (Dviii), or a pharmaceutically acceptable salt thereof is wherein X is N or CH.
  • Embodiment J the compound of any one of embodiments A to D and E to Ii and subembodiments (Di) to (Dviii), or a pharmaceutically acceptable salt thereof is wherein R 1 is attached to carbon that is in between N and X.
  • Embodiment K the compound of any one of embodiments A to D and E to J and subembodiments (Di) to (Dviii), or a pharmaceutically acceptable salt thereof, are wherein a, b, d, and e are each independently CH or C when attached to any one of R 4 , R 5 , and R 6 .
  • Embodiment M the compound of any one of embodiments A to D and E to J and subembodiments (Di) to (Dviii), or a pharmaceutically acceptable salt thereof, are wherein a and d are N and b, and e are each indepdnently CH or C when attached to any one of R 4 , R 5 , and R 6 .
  • Embodiment N the compound of any one of embodiments A to D and E to J and subembodiments (Di) to (Dviii), or a pharmaceutically acceptable salt thereof, are wherein b is N and a, c, and e are each independently CH or C when attached to any one of R 4 , R 5 , and R 6 .
  • Embodiment O the compounds of any one of embodiments A to D and E to J and subembodiments (Di) to (Dviii), or a pharmaceutically acceptable salt thereof, are wherein b and e are N and a and d are each independently CH or C when attached to any one of R 4 , R 5 , and R 6 .
  • the compound of any one of embodiments A to D and E to J and subembodiments (Di) to (Dviii), or a pharmaceutically acceptable salt thereof is wherein a is CH; b is CH or C when attached to any one of R 4 , R 5 , or R 6 ; d is N or C when attached to any one of R 4 , R 5 , or R 6 ; and e is N, CH or C when attached to any one of R 4 , R 5 , or R 6 .
  • Embodiment R [0143]
  • the compound of any one of embodiments A to C and E to Q, or a pharmaceutically acceptable salt thereof are wherein n and m are 0.
  • Embodiment S the compound of any one of embodiments A to C and E to Qi, or a pharmaceutically acceptable salt thereof, are wherein n is 1 and m is 0.
  • Embodiment T the compound of any one of embodiments A to C and E to Qi, or a pharmaceutically acceptable salt thereof, are wherein n is 0 and m is 1.
  • Embodiment U the compound of any one of embodiments A to C and E to Qi, or a pharmaceutically acceptable salt thereof, are wherein each n and m is 1.
  • Embodiment V [0147] (V).
  • the compound of any one of embodiments A to D, E to Qi and S to V, and subembodiments D(i) to D(viii), or a pharmaceutically acceptable salt thereof are wherein alk 1 and/or alk, when present, are methylene.
  • the compound of any one of embodiments A to D, E to Qi and S to U, and subembodiments D(i) to D(viii), or a pharmaceutically acceptable salt thereof is wherein alk 1 and/or alk, when present, are alkylene.
  • the compound of any one of embodiments A to D, E to Qi, S to V and Vii, and subembodiments D(i) to D(viii), or a pharmaceutically acceptable salt thereof is wherein alk, when present, is methylene.
  • the compound of any one of embodiments A to D, E to Qi, S to V and Vii, and subembodiments D(i) to D(viii), or a pharmaceutically acceptable salt thereof is wherein alk 1 , when present, is methylene or ethylene.
  • Embodiment W the compounds of any one of embodiments A to D and E to V and Vii to Viv, and subembodiments D(i) to D(viii) and Vi , or a pharmaceutically acceptable salt thereof, are wherein Ar is phenylene or 5- or 6-membered heteroarylene, each ring substituted with R 2 and R 3 .
  • Ar is phenylene substituted with R 2 and R 3 .
  • the compound of any one of embodiments A to D, E to to V, Vii to Viv, and W, and subembodiments D(i) to D(viii) and Vi, or a pharmaceutically acceptable salt thereof is wherein Ar is a 5- or 6-membered heteroarylene e.g., divalent pyridine, pyrimidine, pyridazine, thiene, furan, thiazole, oxazole, isoxazole, pyrazole, triazole, oxadiazole, or imidazole, each ring substituted with with R 2 and R 3 .
  • Ar is a 5- or 6-membered heteroarylene e.g., divalent pyridine, pyrimidine, pyridazine, thiene, furan, thiazole, oxazole, isoxazole, pyrazole, triazole, oxadiazole, or imidazole, each ring substituted with with R 2 and R 3
  • the compound of any one of embodiments A to D, E to V, and Vii to Viv , and subembodiments D(i) to D(viii) and Vi, or a pharmaceutically acceptable salt thereof is wherein Ar is bicyclic heteroarylene e,.g., divalent benzofuran, quinoline, quinazoline, benzimidazole, indazole, benzotriazole, or benzoxazole.
  • Ar is bicyclic heteroarylene e,.g., divalent benzofuran, quinoline, quinazoline, benzimidazole, indazole, benzotriazole, or benzoxazole.
  • Embodiment X the compound of any one of embodiments A to D, E to V, and Vii to Viv Viv, and subembodiments D(i) to D(viii) and Vi, or a pharmaceutically acceptable salt thereof, are wherein Ar is cyclylaminylene, spiro cyclylaminylene, or bridged cyclylaminylene, each ring substituted with R 2 and R 3 . [0157] (Xi).
  • subembodiment Xi the compound of any one of embodiments A to D, E to V, V(ii) toViv, and X, and subembodiments D(i) to D(viii) and Vi, or a pharmaceutically acceptable salt thereof is wherein Ar is cyclylaminylene selected from divalent pyrrolidine, piperidine, or homopiperidine, each ring substituted with with R 2 and R 3 . [0158] (Xii). In subembodiment Xii, the compound of any one of embodiments A to D, E to V.
  • V(ii) to Viv and X, and subembodiments D(i) to D(viii) and Vi, or a pharmaceutically acceptable salt thereof is wherein Ar is spiro cyclylaminylene or bridged cyclylaminyl, each ring substituted with R 2 and R 3 . [0159] (Xiii).
  • the compound of any one of embodiments A to D, E to V, and Vii to Viv, and subembodiments D(i) to D(viii) and Vi, or a pharmaceutically acceptable salt thereof are wherein Ar is arylene, cyclylaminylene, or spiro cyclylaminylene, and each ring substituted with R 2 and R 3 . [0161] (Xv).
  • the compound of any one of embodiments A to D, E to V, Vii to Viv, and Xiv, and subembodiments D(i) to D(viii) and Vi, or a pharmaceutically acceptable salt thereof are wherein Ar is phenylene, piperidinylene, or 2- azaspiro[3.3]heptanylene, and each ring substituted with R 2 and R 3 . It is understood that phenylene, piperidinylene, and 2-azaspiro[3.3]heptanylene, refers to divalent phenyl, piperidinyl, and 2-azaspiro[3.3]heptanyl radicals, respectively. [0162] (Xvi).
  • the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, and Xvi to Xvi and subembodiments D(i) to D(viii), Wi to Wiii, Vi, and Xi to Xiii, and subembodiments contained therein or a pharmaceutically acceptable thereof is wherein R 1 is absent, alkyl, alkoxy, halo,
  • the compound of any one of embodiments A to D,E to V, Vii to Viv, W, X, Xvi to Xvi and Y and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Wi to Wiii, Xi to Xiii and Yi, or a pharmaceutically acceptable thereof are wherein R 1 is absent, methyl, ethyl or isopropyl. [0166] (Yiii).
  • the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi and Y and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii, Yi, and Yii, or a pharmaceutically acceptable thereof is wherein R 1 is absent. [0167] (Yiv).
  • the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, and Z, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii and Yi to Yvi, or a pharmaceutically acceptable thereof are wherein wherein R 2 and R 3 are absent. [0172] (Zii).
  • Embodiment A1 the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z and Zii, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii, Yi to Yvi, and Zi, or a pharmaceutically acceptable thereof, is wherein R 4 is absent, alkyl, alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cyano, carboxy, alkoxycarbonyl, hydroxy, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl.
  • subembodiment A1ii the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, Zii, and A1, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii, Yi to Yvi, Zi and A1i, or a pharmaceutically acceptable thereof, is wherein R 4 is absent, methoxy or ethoxy. [0176] (A1iii).
  • subembodiment A1iii the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, Zii, and A1, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii, Yi to Yvi, and Zi, or a pharmaceutically acceptable thereof, is wherein R 4 is cyano, carboxy, alkoxycarbonyl, alkylsulfonyl, hydroxy, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl. [0177] (A1iv).
  • subembodiment A1iv the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, Zii, and A1, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii, Yi to Yvi, Zi, A1i and A1iii, or a pharmaceutically acceptable thereof, is wherein R 4 is cyano, carboxy, methoxycarbonyl, methylsulfonyl, aminocarbonyl, hydroxy, methylaminocarbonyl, dimethylaminocarbonyl, or. [0178] (A1v).
  • subembodiment A1v the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, Zii, and o A1, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii, Yi to Yvi, Zi, A1iii, and A1iv, or a pharmaceutically acceptable thereof, is wherein R 4 is cyano, hydroxy, aminocarbonyl, methylsulfonyl, methylaminocarbonyl, or dimethylaminocarbonyl. [0179] (A1vi).
  • the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, Zii, and A1 and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii, Yi to Yvi, Zi, or a pharmaceutically acceptable thereof, is wherein R 4 is alkoxy or haloalkoxy. [0182] (A1ix).
  • the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, Zii, A1, and A1viii, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii, Yi to Yvi, and Zi, or a pharmaceutically acceptable thereof, is wherein R 4 is methoxy or fluoromethoxy.
  • subembodiment B1i the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, Zii, A1, A1viii and A1ix, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii, Yi to Yvi, Zi, and A1i to A1vi, or a pharmaceutically acceptable thereof, is wherein R 5 and R 6 are each independently absent, alkyl, alkoxy, hydroxy, amino, halo, haloalkyl, or haloalkoxy. [0185] (B1ii).
  • subembodiment B1v the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, Zii, A1, A1viii and A1ix, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii, Yi to Yvi, Zi, A1i to A1vi and B1i to B1iv, or a pharmaceutically acceptable thereof, is wherein R 5 and R 6 are are attached to to the six membered ring comprising a, b, d, and e of Formula I to (Ih) as shown below below wherein the wavy line denotes the the remainder of the molecule.
  • the compound of embodiment C1, or a pharmaceutically acceptable thereof is wherein R 5 is absent, methoxy, ethoxy, or hydroxy, preferably R 5 is methoxy or ethoxy; and R 6 is 2-hydroxyethyloxy, 3-hydroxypropyloxy, 2- methoxyethyloxy, 2-ethoxyethyloxy, 3-methoxypropyloxy, 3-ethoxypropyloxy, 2- aminoethyloxy, 2-methylaminoethyloxy, 2-dimethylaminoethyloxy, 2-diethylaminoethyloxy, 3-aminopropyloxy, 3-methylaminopropyloxy, 3-dimethylaminopropyloxy, 3- diethylaminopropyloxy, pyrrolidinyloxy, piperidinyloxy, pyrrolidinylmethyloxy, piperidinylmethyloxy, pyrrolidinyle
  • the compound of any one of embodiments C1 and C1i, or a pharmaceutically acceptable thereof is wherein R 5 and R 6 are are attached to to the six membered ring comprising a, b, d, and e of Formula I to (Ih) as shown below below: wherein the wavy line of the molecule.
  • R 5 and R 6 are each independently 2- hydroxyethyloxy, 3-hydroxypropyloxy, 2-methoxyethyloxy, 2-ethoxyethyloxy, 3- methoxypropyloxy, 3-ethoxypropyloxy, 2-aminoethyloxy, 2-methylaminoethyloxy, 2- dimethylaminoethyloxy, 2-diethylaminoethyloxy, 3-aminopropyloxy, 3- methylaminopropyloxy, 3-dimethylaminopropyloxy, 3-diethylaminopropyloxy, pyrrolidinyloxy, piperidinyloxy, pyrrolidinylmethyloxy, piperidinylmethyloxy, pyrrolidinylethyloxy, piperidinylethyloxy, 2-hydroxyethylamino, 3-hydroxypropyla
  • Embodiment E1 the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, Zii, A1, A1viii, A1ix, B1, B1vi, B1vii, C1, and D1 to D1ii, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii, Yi to Yvi, Zi, A1i to A1vii, B1i to B1v, C1i, and C1ii, or a pharmaceutically acceptable salt thereof,
  • R 7 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, carbonylaminoalkyl, carboxyaminoalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, aryl, fused
  • the compound any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, Zii, A1, A1viii, A1ix, B1, B1vi, B1vii, C1, D1 to D1ii, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, Zii, A1, A1viii, A1ix, B1, B1vi, B1vii, C1 and D1 to D1ii, andE1, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii, Yi to Yvi, Zi, A1i to A1vii, B1i to B1v, C1i, C1iii, and E1i to E1x, or a pharmaceutically acceptable salt thereof is wherein R 7 , R 8 , and R 9 are each independently
  • E1xii the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, Zii, A1, A1viii, A1ix, B1, B1vi, B1vii, C1, D1 to D1ii, and E1, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii, Yi to Yvi, Zi, A1i to A1vii, B1i to B1v, C1i, C1ii, and E1i to E1iv or a pharmaceutically acceptable salt thereof, wherein R 7 is alkyl or cycloalkyl.
  • E1xiii the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, Zii, A1, A1viii, A1ix, B1, B1vi, B1vii, C1, D1 to D1ii, E1, and E1xii, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii, Yi to Yvi, Zi, A1i to A1vii, B1i to B1v, C1i, C1ii, and and E1i to E1iv or a pharmaceutically acceptable salt thereof, wherein R 7 is methyl or cyclopropyl.
  • E1xiv the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, Zii, A1, A1viii, A1ix, B1, B1vi, B1vii, C1, and D1 to D1ii, E1, and E1xii and E1xiii, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii, Yi to Yvi, Zi, A1i to A1vii, B1i to B1v, C1i, and C1ii, or a pharmaceutically acceptable salt thereof, wherein R 8 and R 9 is hydrogen or alkyl.
  • E1xv the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, Zii, A1, A1viii, A1ix, B1, B1vi, B1vii, C1, and D1 to D1ii, , and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii, Yi to Yvi, Zi, A1i to A1vii, B1i to B1v, C1i, and C1ii, or a pharmaceutically acceptable salt thereof, wherein R 8 and R 9 is hydrogen, methyl, ethyl, or isopropyl.
  • Embodiment F1 the compound of any one of embodiments A to E1xv, and subembodiments contained therein, or a pharmaceutically acceptable salt thereof, wherein X is N or CH; a is CH; b is CH or C when attached to any one of R 4 , R 5 , or R 6 ; d is N or C when attached to any one of R 4 , R 5 , or R 6 ; e is N, CH or C when attached to any one of R 4 , R 5 , or R 6 ; Z is a bond or O; m and n are each independently 0 or 1; alk is alkylene; alk 1 is alkylene; Ar is arylene, cyclylaminylene, or spiro cyclylaminylene, and each ring substituted with R 2 and R 3 ; R 1 is absent; R 2 and R 3 are each independently absent or fluoro; one of R 4 , R 5 , and R 6 is alkoxy or
  • the starting materials and the intermediates, and the final products of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.
  • the reactions described herein take place at atmospheric pressure over a temperature range from about –78 o C to about 150 o C, such as from about 0 o C to about 125 o C and further such as at about room (or ambient) temperature, e.g., about 20 o C.
  • Compounds of Formula (I) as defined in the Summary can be prepared as illustrated and described in Scheme 1 below.
  • Compounds of formula 1 may also be obtained by treating a hydroxy compound such as 8-methoxy-1,7-naphthyridin-4-ol with a chlorinating agent such as P(O)Cl 3 in aprotic solvents with an organic aprotic base either with heating or room temperature.
  • a chlorinating agent such as P(O)Cl 3
  • Compound of formula 3 is converted into a compound of Formula (I) by treatment with aqueous ammonia and tert-butyl hypochlorite as described in working examples below.
  • the ENPP1 inhibitory activity of the compounds of the present disclosure can be tested using the in vitro assays described in Biological Examples 1 and 2 below.
  • the compounds of this disclosure will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities.
  • Therapeutically effective amounts of compounds this disclosure may range from about 0.01 to about 500 mg per kg patient body weight per day, which can be administered in single or multiple doses.
  • a suitable dosage level may be from about 0.1 to about 250 mg/kg per day; about 0.5 to about 100 mg/kg per day.
  • a suitable dosage level may be about 0.01 to about 250 mg/kg per day, about 0.05 to about 100 mg/kg per day, or about 0.1 to about 50 mg/kg per day. Within this range the dosage can be about 0.05 to about 0.5, about 0.5 to about 5 or about 5 to about 50 mg/kg per day.
  • compositions can be provided in the form of tablets containing about 1.0 to about 1000 milligrams of the active ingredient, particularly about 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient.
  • the actual amount of the compound of this disclosure, i.e., the active ingredient will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the patient, the potency of the compound being utilized, the route and form of administration, and other factors.
  • compositions will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration.
  • routes e.g., oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration.
  • parenteral e.g., intramuscular, intravenous or subcutaneous
  • compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.
  • formulations depend on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules, including enteric coated or delayed release tablets, pills or capsules are preferred) and the bioavailability of the drug substance.
  • pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size.
  • U.S. Pat. No.4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a cross-linked matrix of macromolecules.
  • compositions are comprised of in general, a compound of this disclosure in combination with at least one pharmaceutically acceptable excipient.
  • Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of this disclosure.
  • excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
  • Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like.
  • Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.
  • Preferred liquid carriers, particularly for injectable solutions include water, saline, aqueous dextrose, and glycols.
  • Compressed gases may be used to disperse a compound of this disclosure in aerosol form.
  • Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
  • Other suitable pharmaceutical excipients and their formulations are described in Remington’s Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 20th ed., 2000).
  • the level of the compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt. %) basis, from about 0.01-99.99 wt. % of a compound of this disclosure based on the total formulation, with the balance being one or more suitable pharmaceutical excipients.
  • the compound is present at a level of about 1-80 wt. %.
  • the compounds of this disclosure may be used in combination with one or more other drugs in the treatment of diseases or conditions for which compounds of this disclosure or the other drugs may have utility. Such other drug(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present disclosure.
  • a pharmaceutical composition in unit dosage form containing such other drugs and the compound of the present disclosure is preferred.
  • the combination therapy may also include therapies in which the compound of this disclosure and one or more other drugs are administered on different overlapping schedules.
  • Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present disclosure.
  • a pharmaceutical composition containing such other drugs in addition to the compound of this disclosure can be used.
  • the pharmaceutical compositions of the present disclosure also include those that also contain one or more other active ingredients, in addition to a compound of this disclosure.
  • the weight ratio of the compound of this disclosure to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used.
  • the subject in need is suffering from or at risk of suffering from cancer
  • the subject can be treated with a compound of this disclosure in any combination with one or more other anti-cancer agents.
  • one or more of the anti-cancer agents are proapoptotic agents.
  • anti-cancer agents include, but are not limited to, any of the following: gossyphol, genasense, polyphenol E, Chlorofusin, all trans-retinoic acid (ATRA), bryostatin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), 5-aza- 2’-deoxycytidine, all trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (Gleevec TM ), geldanamycin, 17-N-Allylamino-17-Demethoxygeldanamycin (17- AAG), flavopiridol, LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, or PD184352, Taxol TM , also referred to as “paclitaxel”, which is a well-known anti-cancer drug which acts by enhancing and stabilizing
  • anti-cancer agents for use in combination with a compound of this disclosure include inhibitors of mitogen-activated protein kinase signaling, e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002; Syk inhibitors; antibodies (e.g., rituxan); MET inhibitor such as foretinib, carbozantinib, or crizotinib; VEGFR inhibitor such as sunitinib, sorafenib, regorafinib, lenvatinib, vandetanib, carbozantinib
  • BEX235 (dactolisib), CAL101 (idelalisib), GSK2636771, TG100-115; MTOR inhibitor such as rapamycin (sirolimus), temsirolimus, everolimus, XL388, XL765, AZD2013, PF04691502, PKI-587, BEZ235, GDC0349; MEK inhibitor such as AZD6244, trametinib, PD184352, pimasertinib, GDC-0973, AZD8330; and proteasome inhibitor such as carfilzomib, MLN9708, delanzomib, or bortezomib.
  • MTOR inhibitor such as rapamycin (sirolimus), temsirolimus, everolimus, XL388, XL765, AZD2013, PF04691502, PKI-587, BEZ235, GDC0349
  • MEK inhibitor such as AZD6244
  • anti-cancer agents that can be employed in combination with a compound of this disclosure include Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carbop
  • antimetabolites include but are not limited to folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin).
  • folic acid analog e.g., methotrexate
  • pyrimidine analogs e.g., cytarabine
  • purine analogs e.g., mercaptopurine, thioguanine, pentostatin.
  • Examples of natural products useful in combination with a compound of this disclosure include but are not limited to vinca alkaloids (e.g., vincristine), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), or biological response modifiers (e.g., interferon alpha).
  • vinca alkaloids e.g., vincristine
  • epipodophyllotoxins e.g., etoposide
  • antibiotics e.g., daunorubicin, doxorubicin, bleomycin
  • enzymes e.g., L-asparaginase
  • biological response modifiers e.g., interferon alpha
  • alkylating agents examples include, but are not limited to, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, melphalan, etc.), ethylenimine and methylmelamines (e.g., hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin, etc.), or triazenes (decarbazine, etc.).
  • nitrogen mustards e.g., mechloroethamine, cyclophosphamide, chlorambucil, melphalan, etc.
  • ethylenimine and methylmelamines e.g., hexamethlymelamine, thiotepa
  • alkyl sulfonates e.g
  • antimetabolites include, but are not limited to folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxuridine, cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin.
  • folic acid analog e.g., methotrexate
  • pyrimidine analogs e.g., fluorouracil, floxuridine, cytarabine
  • purine analogs e.g., mercaptopurine, thioguanine, pentostatin.
  • hormones and antagonists useful in combination a compound of this disclosure include, but are not limited to, adrenocorticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethylstilbestrol, ethinyl estradiol), antiestrogen (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogen (e.g., flutamide), gonadotropin releasing hormone analog (e.g., leuprolide).
  • adrenocorticosteroids e.g., prednisone
  • progestins e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate
  • estrogens e
  • platinum coordination complexes e.g., cisplatin, carboblatin
  • anthracenedione e.g., mitoxantrone
  • substituted urea e.g., hydroxyurea
  • methyl hydrazine derivative e.g., procarbazine
  • adrenocortical suppressant e.g., mitotane, aminoglutethimide
  • the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody.
  • the anti- PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, or AMP-224.
  • the anti-PD-1 monoclonal antibody is nivolumab, or pembrolizumab or PDR001.
  • the anti-PD1 antibody is pembrolizumab.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody.
  • the anti- PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C.
  • the anti-PD-L1 monoclonal antibody is MPDL3280A (atezolizumab) or MEDI4736 (durvalumab).
  • the inhibitor of an immune checkpoint molecule is an inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody.
  • the anti-CTLA-4 antibody is ipilimumab or tremelimumab.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of LAG3, e.g., an anti-LAG3 antibody.
  • the anti-LAG3 antibody is BMS-986016 or LAG525.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of GITR, e.g., an anti-GITR antibody.
  • the anti-GITR antibody is TRX518 or, MK-4166, INCAGN01876 or MK-1248.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of OX40, e.g., an anti-OX40 antibody or OX40L fusion protein.
  • the anti-OX40 antibody is MEDI0562 or, INCAGN01949, GSK2831781, GSK-3174998, MOXR-0916, PF-04518600 or LAG525.
  • the OX40L fusion protein is MEDI6383 EXAMPLES [0246] The following preparations of compounds of Formula (I) are given to enable those skilled in the art to more clearly understand and to practice the present disclosure. They should not be considered as limiting the scope of the disclosure, but merely as being illustrative and representative thereof.
  • the TLC plate was developed with iodine (generated by adding approximately 1 g of I2 to 10 g silica gel and thoroughly mixing), ninhydrin (available commercially from Aldrich), or Magic Stain (generated by thoroughly mixing 25 g (NH4)6Mo7O24.4H2O, 5 g (NH4)2Ce(IV)(NO3)6 in 450 mL water and 50 mL concentrated H 2 SO 4 ) to visualize the compound. Flash chromatography was performed using 40-63 ⁇ m (230-400 mesh) silica gel from Silicycle following analogous techniques to those disclosed in Still, W.C.; Kahn, M.; and Mitra, M. Journal of Organic Chemistry, 1978, 43, 2923.
  • Step 2 8-Methoxy-1,7-naphthyridin-4-ol
  • Step 3 4-Chloro-8-methoxy-1,7-naphthyridine [0254] To a stirred solution of 8- 4-ol (1.60 g, 9.08 mmol, 1 equiv) in toluene (32 mL) was added g, 18.16 mmol, 2 equiv) and POCl 3 (1.67 g, 10.89 mmol, 1.2 equiv) at room temperature. After stirring overnight at 70 °C, the resulting mixture was concentrated under reduce pressure. Then crude product was purified by reversed phase flash eluted with ACN/H 2 O (35:65) to give the title compound (1.11 g, 62%) as a yellow solid.
  • Step 5 (3-(((8-methoxy-1,7-naphthyridin-4-yl)oxy)methyl)phenyl)(methyl)-lambda6- sulfanediimine [0256] To a solution of 8-methoxy- lfanyl)phenyl)methoxy)-1,7- naphthyridine (100 mg, 0.32 mmol, 1 equiv) in ACN (3 mL) was added NH3-H2O (897 mg , 20 equiv, 25%v/v) at -15 o C under nitrogen atmosphere.
  • Step 2 3-(Cyclopropylsulfanyl)phenyl]methanol
  • the title compound was proceeding analogously as described in Example 5, Step 1, except 3-(cyclopropylsulfanyl)benzoic acid (24.00 g, 117.37 mmol) was used.
  • [3-(cyclopropylsulfanyl)phenyl]methanol (20.00 g, 86%) was obtained as a yellow oil.
  • Step 3 4-((3-(Cyclopropylthio)benzyl)oxy)-8-methoxy-1,7-naphthyridine [0259]
  • the title compound was analogously as described in Example 1, Step 4, except (3-(cyclopropylthio)phenyl)methanol (511 mg, 2.84 mmol) was used.
  • the title compound (169 mg, 35%) was obtained as a yellow solid.
  • Step 4 Cyclopropyl(3-(((8-methoxy-1,7-naphthyridin-4-yl)oxy)methyl)phenyl)- lambda6-sulfanediimine [0260]
  • the title compound was analogously as described in Example 1, Step 5 except 4-((3- methoxy)-8-methoxy-1,7- naphthyridine (210 mg, 0.62 mmol) was used.
  • the crude product was purified by prep-HPLC with the following conditions: (UV 254 nm / 220 nm, Xbridge Prep OBD C18 Column, 30*150 mm, 5 ⁇ m Water (10mmol/L NH 4 HCO 3 ) ACN 60 mL/min 3% B to 33 % B in 10 min 8.68). The fractions containing the desired product were combined and lyophilized to afford the title compound (3.2 mg, 1%) as a yellow solid. MS (ESI, pos. ion) m/z: 369.1 (M+1).
  • Step 2 (4-(((8-methoxy-1,7-naphthyridin-4-yl)oxy)methyl)phenyl)(methyl)-lambda6- sulfanediimine
  • the title compound was analogously as described in Example 1, Step 5, except 8-methoxy-4-((4-(methylsulfanyl)phenyl)methoxy)-1,7- naphthyridine (430 mg, 1.37 mmol) was used.
  • the crude product was purified by prep-HPLC with the following conditions: (Column: XBridge Prep RP OBD C18 Column, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 2% B to 28% B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 9.3). The fractions containing the desired product were combined and lyophilized to give the title compound (6.6 mg, 11%) as a white solid. MS (ESI, pos. ion) m/z: 343.1 (M+1).
  • the crude product was purified by prep-HPLC with the following conditions: (Column: XBridge Prep RP OBD C18 Column, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water (10mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 2% B to 22% B in 10min; Wave Length: 254 nm / 220 nm; RT1(min): 9.2) The fractions containing the desired product were combined and lyophilized to afford the title compound (21 mg, 9.4%) as a white solid. MS (ESI, pos. ion) m/z: 334.2 (M+1).
  • Step 2 7-methoxy-4-((3-(methylsulfanyl)phenyl)methoxy)quinoline S [0268] To a stirred solution of methanol (500 mg, 3.24 mmol, 1 equiv) in DMF (10 mL) was added NaH (233 mg, 9.72 mmol, 3 equiv) at 0 o C. After stirring for 10 min, 4-chloro-7-methoxyquinoline (941 mg, 4.86 mmol, 1.5 equiv) was added.
  • Step 3 (3-(((7-methoxyquinolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda6- sulfanediimine
  • the title compound was analogously as described in Example 1, Step 5, except 7-methoxy-4-((3-(methylsulfanyl)phenyl)methoxy)quinoline (650 mg, 2.08 mmol) was used.
  • the crude product was purified by prep-HPLC with the following conditions: (Column: XBridge Prep RP OBD C18 Column, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 6% B to 36% B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 9.4). The fractions containing the desired product were combined and lyophilized to give the title compound (35.9 mg, 5%) as a white solid. MS (ESI, pos. ion) m/z: 342.1 (M+1).
  • Example 6 Synthesis of (3-(((6,7-dimethoxyquinolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda6- sulfanediimine Step 1: 6,7-dimethoxy-4-((3- methoxy)quinoline [0270]
  • the title compound was synthesized by proceeding analogously as described in Example 1, Step 4, except 4-chloro-6,7-dimethoxyquinoline (800 mg, 3.57 mmol) was used.
  • the title compound (1.00 g, 81%) was obtained as a brown solid.
  • the crude product was purified by prep-HPLC with the following conditions: (Column: XBridge Prep RP OBD C18 Column, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 6% B to 36% B in 10min; Wave Length: 254 nm / 220 nm; RT1(min): 9.4). The fractions containing the desired product were combined and lyophilized to the title compound (16.8 mg, 1.7%) as an off-white solid. MS (ESI, pos. ion) m/z: 372.1 (M+1).
  • the crude product was purified by prep-HPLC with the following conditions: (Column:( Welch Ultimate XB-Phenyl, 30*250 mm, 10 ⁇ m; Mobile Phase A: Water (10mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 11% B to 41% B in 10min; Wave Length: 254 nm / 220 nm; RT1(min): 9.9). The fractions containing the desired product were combined and lyophilized to afford the title compound (2 mg, 1%) as an off-white solid. MS (ESI, pos. ion) m/z: 373.1 (M+1).
  • Example 8 Synthesis of cyclopropyl(3-(((6,7-dimethoxyquinolin-4-yl)oxy)methyl)phenyl)-lambda6- sulfanediimine Step 1: 4-((3- dimethoxyquinoline [0274]
  • the title compound was analogously as described in Example 2, Step 3, except 4-chloro-6,7-dimethoxyquinoline (500 mg, 2.23 mmol) and (3- (cyclopropylsulfanyl)phenyl)methanol (806 mg, 4.47 mmol) were used.
  • the title compound (560 mg, 68%) was obtained as a yellow solid.
  • Step 2 cyclopropyl(3-(((6,7-dimethoxyquinolin-4-yl)oxy)methyl)phenyl)-lambda6- sulfanediimine
  • the title compound was analogously as described in Example 1, Step 5, except 4-((3-(cyclopropylsulfanyl)phenyl)methoxy)-6,7- dimethoxyquinoline (460 mg, 1.25 mmol) was used.
  • the crude product was purified by prep- HPLC with the following conditions: (Column: Xbridge Prep OBD C18 Column, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 6% B to36 % B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 8.68). The fractions containing the desired product were combined and lyophilized to give the title compound (22.5 mg, 4%) as a white solid. MS (ESI, pos. ion) m/z: 398.1 (M+1).
  • Example 9 Synthesis of cyclopropyl(3-(((6,7-dimethoxyquinazolin-4-yl)oxy)methyl)phenyl)-lambda6- sulfanediimine Step 1: 4-((3-(cyclopropylthio) [0276]
  • the title compound was analogously as described in Example 1, Step 4, except 4-chloro-6,7-dimethoxyquinazoline (1.00 g, 4.45 mmol) and (3- (cyclopropylsulfanyl)phenyl)methanol (960 mg, 5.3 mmol) were used.
  • the title compound (1.20 g, 68%) was obtained as a brown solid.
  • Step 2 cyclopropyl(3-(((6,7-dimethoxyquinazolin-4-yl)oxy)methyl)phenyl)-lambda6- sulfanediimine
  • 4-((3- oxy)-6,7-dimethoxyquinazoline (1.00 g, 2.71 mmol, 1.0 equiv) in ACN (20 mL) was added NH 3 -H 2 O (7.61 g, 54.28 mmol, 20.0 equiv, 25% v/v) under N 2 atmosphere at room temperature and the mixture was stirred at room temperature for 1 h.
  • Step 2 (3-(((6-fluoro-7-methoxyquinolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda6- sulfanediimine
  • the title compound was s eding analogously as described in Example 1, Step 5, except 6-fluoro-7-methoxy-4-((3- (methylsulfanyl)phenyl)methoxy)quinoline (340 mg, 1.032 mmol) was used.
  • Step 2 (4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)(methyl)-lambda6-sulfanediimine [0281]
  • the title compound was analogously as described in Example 1, Step 5, except 6,7- phenoxy)quinoline (1.30 g, 3.97 mmol) was used.
  • the crude product was purified by prep-HPLC with the following conditions: (Column: XBridge Prep RP OBD C18 Column, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 2% B to 32% B in 10min; Wave Length: 254 nm / 220 nm; RT1(min): 9.5 ). The fractions containing the desired product were combined and lyophilized to afford the title compound (30 mg, 2%) as an off-white solid. MS (ESI, pos. ion) m/z: 358.1 (M+1).
  • Step 3 6-[(Methylsulfanyl)methyl]-2-azaspiro[3.3]heptane [0284] To a solution of tert-butyl methyl]-2-azaspiro[3.3]heptane-2- carboxylate (300 mg, 1.16 mmol, 1 equiv) in DCM ( 10 mL) was added 2,6-lutidine (0.12 g, 1.16 mmol, 1 equiv) and TMSOTf (0.78 g, 3.498 mmol, 3 equiv) at room temperature. After stirring for 2 h, the reaction mixture was concentrated under reduced pressure to give the title compound (380 mg, crude) as a light yellow oil, which was used for next Step directly without further purification.
  • Step 2 ((2-(6,7-dimethoxyquinolin-4-yl)-2-azaspiro(3.3)heptan-6-yl)methyl)(methyl)- lambda6-sulfanediimine [0286]
  • the title compound was analogously as described in Example 1, Step 5, except 6,7-dimethoxy-4-(6-((methylsulfanyl)methyl)-2- azaspiro(3.3)heptan-2-yl)quinoline (440 mg, 1.27 mmol) was used.
  • Step 3 5-chloro-2-methoxy-1,8-naphthyridine [0303] To a stirred solution of 7-met hthyridin-4-ol (5.00 g, 28.38 mmol, 1 equiv) in toluene (100 mL) were added DIEA (7.34 g, 56.76 mmol, 2 equiv) and POCl 3 (5.22 g, 34.05 mmol, 1.2 equiv) at room temperature.
  • DIEA 7.34 g, 56.76 mmol, 2 equiv
  • POCl 3 5.22 g, 34.05 mmol, 1.2 equiv
  • Step 3 6-fluoro-7-methoxy-4-((3-(methylsulfanyl)phenyl)methoxy)quinazoline [0311] To a stirred solution of 4- (500 mg, 2.35 mmol, 1 equiv) in DMF (10 mL) were added Cs 2 CO 3 (2.30 g, 7.05 mmol, 3 equiv) and (3- (methylsulfanyl)phenyl)methanol (544 mg, 3.52 mmol, 1.5 equiv) at room temperature. After stirring at 80 o C for 2 h, the resulting mixture was concentrated under reduced pressure and diluted H2O and extracted with EtOAc .
  • Step 4 ((3-(((6-fluoro-7-methoxyquinazolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda4- sulfanylidene)azanium 2,4,6-trimethylbenzenesulfonate [0312] To a stirred solution of ((3- (methylsulfanyl)phenyl)methoxy)-quinazoline (400 mg, 1.21 mmol, 1 equiv) in DCM (8 mL) was added amino 2,4,6-trimethylbenzenesulfonate (781 mg, 3.63 mmol, 3 equiv) at room temperature.
  • the crude product was purified by reverse phase flash, eluted with ACN/H2O (20:80) and then re-purified by prep-HPLC with the following conditions (Column: XBridge Prep Shield RP18 OBD C18 Column, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 35 % B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 9.42) to afford (2-(1-(6-fluoro-7-methoxyquinolin-4-yl)piperidin-4-yl)ethyl)(methyl)- lambda6-sulfanediimine (51.9 mg, 13%) as an off-white solid.
  • Step 3 4-(2-(methylthio)ethyl)piperidine hydrochloride
  • a solution of tert-butyl 4-(2-(m anyl)ethyl)piperidine-1-carboxylate (851 mg, 3.28 mmol) in HCl (10 mL, gas, 4 M in 4-dioxane) was stirred at room temperature for 1 h.
  • the resulting mixture was concentrated under reduced pressure to afford 4-(2- (methylthio)ethyl)piperidine hydrochloride (716 mg, crude) as a white solid.
  • the crude product was purified by prep-HPLC with the following conditions (Column: XBridge Prep Shield RP18 OBD C18 Column, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 2% B to25 % B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 9.02) to afford (2-(1-(8-methoxy-1,7-naphthyridin-4-yl)piperidin-4- yl)ethyl)(methyl)-lambda6-sulfanediimine (59.8 mg, 12%) as a yellow solid.
  • the crude product was purified by reverse phase flash, eluted with ACN/H2O (29:61) and then re-purified by prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water (10 mmol /L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 12% B to27 % B in 18 min; Wave Length: 254 nm / 220 nm; RT1(min): 17.5) to afford cyclopropyl(3-((7- methoxyquinolin-4-yl)oxy)phenyl)-lambda6-sulfanediimine (4 mg, 2%) as an off-white solid.
  • Step 2 4-(3-(cyclopropylthio)phenoxy)-7-methoxyquinazoline [0333] To a stirred mixture (580 mg, 3.48 mmol, 1.5 equiv) and 4-chloro-7-methoxyquinazoline (450 mg, 2.31 mmol, 1.0 equiv) in DMSO (7 mL) was added Cs 2 CO 3 (1.50 g, 4.60 mmol, 2.0 equiv). After stirring at 80 °C for 2 h, the mixture was allowed to cool down to room temperature. The reaction mixture was diluted with water and then extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Step 4 cyclopropyl(3-((7-methoxyquinazolin-4-yl)oxy)phenyl)-lambda6-sulfanediimine
  • the crude product was purified by reverse phase flash, eluted with ACN/H 2 O (25:75) and then re-purified by prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 10% B to 40% B in 7 min; Wave Length: 254 nm / 220 nm; RT1(min): 6.82) to afford cyclopropyl(3-((7- methoxyquinazolin-4-yl)oxy)phenyl)-lambda6-sulfanediimine (12.2 mg, 2%) as an off-white solid.
  • Step 2 cyclopropyl(4-((6,7-dimethoxyquinazolin-4-yl)oxy)phenyl)-lambda4- sulfaniminium 2,4,6-trimethylbenzenesulfonate
  • 4-(4- xy)-6,7-dimethoxyquinazoline 400 mg, 1.12 mmol, 1.0 equiv
  • DCM 10 mL
  • amino 2,4,6- trimethylbenzenesulfonate 728 mg, 3.38 mmol, 3.0 equiv
  • Step 3 cyclopropyl(4-((6,7-dimethoxyquinazolin-4-yl)oxy)phenyl)-lambda6- sulfanediimine
  • the crude product was purified by reverse phase flash, eluted with ACN/H 2 O (45:55) to afford a crude product, which was re-purified by prep-HPLC with the following conditions ( Xbridge Prep OBD C18 Column, 30*150 mm, 5 ⁇ m Water (10 mmol/L NH 4 HCO 3 ); ACN; 60 mL/min; 11% B to 41 % B in 10 min Wave Length: 254 nm / 220 nm, RT1(min): 8.68) to afford cyclopropyl(4-((6,7-dimethoxyquinazolin-4- yl)oxy)phenyl)-lambda6-sulfanediimine (29.5 mg, 6%) as an off-white solid.
  • Step 2 cyclopropyl(3-(((7-methoxyquinazolin-4-yl)oxy)methyl)phenyl)-lambda4- sulfaniminium 2,4,6-trimethylbenzenesulfonate
  • 4-((3- yl)methoxy)-7-methoxyquinazoline 565 mg, 1.85 mmol, 1 equiv
  • DCM 6 mL
  • amino 2,4,6- trimethylbenzenesulfonate (1.20 g, 5.55 mmol, 3 equiv) at 0 o C.
  • the reaction mixture was stirred at room temperature for 1 h.
  • Half of DCM was concentrated and Et 2 O was added.
  • Step 3 cyclopropyl(3-(((7-methoxyquinazolin-4-yl)oxy)methyl)phenyl)-lambda6- sulfanediimine
  • the crude product was purified by reverse phase flash, eluted with ACN/H 2 O to afford 100 mg of crude ((2-(7- methoxyquinazolin-4-yl)-2-azaspiro[3.3]heptan-6-yl)methyl)(methyl)-lambda6- sulfanediimine and 50 mg of crude imino((2-(7-methoxyquinazolin-4-yl)-2- azaspiro[3.3]heptan-6-yl)methyl)(methyl)-lambda6-sulfanone.
  • Step 2 8-methoxy-1,7-naphthyridin-4-ol
  • a mixture of 5-(((2- amino)methylene)-2,2-dimethyl-1,3- dioxane-4,6-dione (1.50 g, 5.4 mmol, 1 equiv) in phenoxybenzene (38 mL) was stirred at 225 o C for 1.5 h. After cooling down to room temperature, PE was added to the reaction mixture.
  • the precipitated solid was collected by filtration, washed with PE (30 ml x 3) and then purified by reverse phase flash, eluted with ACN/H 2 O (26:74) to afford 8-methoxy-1,7- naphthyridin-4-ol (600 mg, 63%) as a white solid.
  • Step 3 8-methoxy-4-((4-(methylsulfanyl)phenyl)methoxy)-1,7-naphthyridine
  • Step 4 ((4-(((8-methoxy-1,7-naphthyridin-4-yl)oxy)methyl)phenyl)(methyl)-lambda4- sulfanylidene)azanium 2,4,6-trimethylbenzenesulfonate [0349] To a stirred solution of 8- phenyl)methoxy)-1,7- naphthyridine (300 mg, 0.96 mmol, 1 equiv) in DCM (6 mL) was added amino 2,4,6- trimethylbenzenesulfonate (620 mg, 2.88 mmol, 3 equiv) at room temperature. The resulting mixture was stirred at room temperature for 1 h.
  • Step 5 1-(4-(((8-methoxy-1,7-naphthyridin-4-yl)oxy)methyl)phenyl)-N,1-dimethyl- lambda6-sulfanediimine [0350] To a stirred solution of ((4- naphthyridin-4- yl)oxy)methyl)phenyl)-(methyl)- azanium 2,4,6- trimethylbenzenesulfonate (300 mg, 0.56 mmol, 1 equiv) in DMF (6 mL) were added Na2CO3 (72 mg, 0.68 mmol, 1.2 equiv) and NCS (108 mg, 0.68 mmol, 1.2 equiv) at 0 o C.
  • the crude product was re-purified by prep-HPLC (Column: Welch Ultimate PFP 30*250, 10 ⁇ m; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 6% B to36 % B in 10 min; Wave Length: 254 nm/220 nm; RT1(min): 7.5).
  • Step 2 2-(1-(7-methoxyquinazolin-4-yl)piperidin-4-yl)ethyl methanesulfonate
  • 2-(1-(7- 4-yl)piperidin-4-yl)ethan-1-ol (1.12 g, 3.89 mmol, 1.0 equiv) in DCM (10 mL)
  • TEA 788 mg, 7.79 mmol, 2.0 equiv
  • DMAP 47 mg, 0.39 mmol, 0.1 equiv
  • Step 3 7-methoxy-4-(4-(2-(methylsulfanyl)ethyl)piperidin-1-yl)quinazoline
  • 2-(1-(7- 4-yl)piperidin-4-yl)ethyl methanesulfonate (1.57 g, 4.29 mmol, 1.0 equiv) in EtOH (20 mL)
  • sodiummethanethiolate (3.01 g, 42.96 mmol, 10.0 equiv, 20% aq).
  • the resulting mixture was stirred at room temperature for 2 h.
  • the solution was concentrated under reduced pressure.
  • the residue was diluted with waterand extracted with EtOAc .
  • Step 4 (2-(1-(7-methoxyquinazolin-4-yl)piperidin-4-yl)ethyl)(methyl)-lambda6- sulfanediimine [0354]
  • the title compound was as described in Example 41, Step 3, except 7-methoxy-4-(4-(2-(methylsulfanyl)ethyl)piperidin-1-yl)quinazoline (500 mg, 1.57 mmol) was used.
  • the crude product was purified by prep-HPLC with the following conditions: (Column: XBridge Prep RP OBD C18 Column, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 15% B to 26% B in 7min; Wave Length: 254 nm / 220 nm; RT1(min): 6.5) to afford (2-(1-(7- methoxyquinazolin-4-yl)piperidin-4-yl)ethyl)(methyl)-lambda6-sulfanediimine (11.8 mg, 2%) as a white solid.
  • Step 2 (4-(((7-methoxyquinazolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda4- sulfaniminium 2,4,6-trimethylbenzenesulfonate
  • 7- oxy)quinazoline (272 mg, 0.87 mmol, 1.0 equiv)
  • DCM 3 mL
  • amino 2,4,6-trimethylbenzenesulfonate 562 mg, 2.61 mmol, 3.0 equiv
  • the resulting mixture was stirred at room temperature for 1 h.
  • the reaction mixture was concentrated under reduced pressure and filtered, and the filter cake was washed with Et 2 O.
  • Step 3 (4-(((7-methoxyquinazolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda6- sulfanediimine [0357]
  • the title compound was analogously as described in Example 40, Step 3, except (4-(((7-methoxyquinazolin-4-yl)oxy)methyl)phenyl)(methyl)- lambda4-sulfaniminium 2,4,6-trimethylbenzenesulfonate (520 mg, crude) was used instead of (4-(((7-methoxyquinolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda4-sulfaniminium 2,4,6- trimethylbenzenesulfonate.
  • the crude product was purified by reverse phase flash, eluted with ACN/H2O (35:65) to afford crude product, which was re-purified by prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 6% B to36 % B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 9.1) to afford (4-(((7-methoxyquinazolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda6- sulfanediimine (15.1 mg, 3%) as a white solid.
  • Step 3 except cyclopropyl(4-((7-methoxyquinazolin-4-yl)oxy)phenyl)-lambda4- sulfaniminium 2,4,6-trimethylbenzenesulfonate (500 g, crude) was used instead of (4-(((7- methoxyquinolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda4-sulfaniminium 2,4,6- trimethylbenzenesulfonate.
  • the crude product was purified by reverse phase flash, eluted with ACN/H 2 O (28:72) to afford 50 mg of crude cyclopropyl(4-((7-methoxyquinazolin-4- yl)oxy)phenyl)-lambda6-sulfanediimine and 50 mg of crude cyclopropyl(imino)(4-((7- methoxyquinazolin-4-yl)oxy)phenyl)-lambda6-sulfanone.
  • reaction mixture was stirred at 80 °C for 2 h. After cooling down to room temperature, the reaction mixture was quenched with water (and extracted with dichloromethane . The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc /PE (30:70) to 4-((3-fluoro-5- (methylsulfanyl)phenyl)methoxy)-7-methoxyquinazoline (800 mg, 78%) as a light yellow solid.
  • Step 2 (3-fluoro-5-(((7-methoxyquinazolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda4- sulfaniminium 2,4,6-trimethylbenzenesulfonate
  • 4-((3- phenyl)methoxy)-7- methoxyquinazoline 600 mg, 1.81 mmol, 1.0 equiv
  • amino 2,4,6- trimethylbenzenesulfonate (1.17 g, 5.44 mmol, 3.0 equiv) at 0 °C.
  • the reaction mixture was stirred at room temperature for 1 h.
  • Step 3 (3-fluoro-5-(((7-methoxyquinazolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda6- sulfanediimine
  • the crude product was purified by reverse phase flash, eluted with ACN/H2O (30:70) and then re-purified by prep-HPLC with the following conditions (Column: XselectCSH Prep OBD C18 Column, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 2% B to24 % B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 8.68) to afford (3-fluoro-5-(((7-methoxyquinazolin-4- yl)oxy)methyl)phenyl)(methyl)-lambda6-sulfanediimine (17.6 mg, 5%) as an off-white solid.
  • Step 2 7-methoxy-4-((3-(methylsulfanyl)phenyl)methoxy)quinazoline
  • 3-(methylsulfanyl)phenyl)methanol 713 mg, 4.62 mmol, 1.5 equiv
  • NaH 221 mg, 9.24 mmol, 3 equiv
  • 4-chloro-7-methoxyquinazoline 600 mg, 3.08 mmol, 1 equiv
  • the resulting mixture was quenched with water (100 mL) and extracted with EtOAc .
  • Step 3 (3-(((7-methoxyquinazolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda6- sulfanediimine [0367]
  • the title compound was as described in Example 41, Step 3, except 7-methoxy-4-((3-(methylsulfanyl)phenyl)methoxy)quinazoline (600 mg, 1.92 mmol) was used.
  • the crude product was purified by prep-HPLC with the following conditions: (Column: Welch Ultimate XB-C1850*250, 10 ⁇ m; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 17% B to 47 % B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 18.38).
  • Step 1 8-methoxy-4-((3-(methyls thoxy)-1,7-naphthyridine [0368] To a solution of 8- 4-ol (4.50 g, 25.54 mmol, 1 equiv) in toluene (5 mL) were added (3-(methylsulfanyl)phenyl)methanol (5.91 g, 38.31 mmol, 1.5 equiv) and 2-(tributyl-$l ⁇ (5)-phosphanylidene)acetonitrile (12.33 g, 51.08 mmol, 2 equiv) under nitrogen atmosphere. After cooling down to room temperature, the resulting mixture was concentrated under reduced pressure.
  • Step 2 ((3-(((8-methoxy-1,7-naphthyridin-4-yl)oxy)methyl)phenyl)(methyl)-lambda4- sulfanylidene)azanium 2,4,6-trimethylbenzenesulfonate
  • Step 2 (3-(((7-Methoxyquinazolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda6- sulfanediimine [0370] To a stirred solution of ( 4- yl)oxy)methyl)phenyl)-(methyl)-lambda4-sulfanylidene)azanium 2,4,6- trimethylbenzenesulfonate (157 mg, 0.34 mmol, 1 equiv) in DMF (3 mL) were added Na 2 CO 3 (158 mg, 1.49 mmol, 5 equiv) and NCS (57 mg, 0.35 mmol, 1.2 equiv) at 0 o C.
  • the crude product was re-purified by prep-HPLC (Column: XBridge Prep Shield RP18 OBD C18 Column, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water (10 mmol/LNH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 7% B to37 % B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 9.23).
  • Step 2 ((2-(7-methoxyquinolin-4-yl)-2-azaspiro[3.3]heptan-6-yl)methyl)(methyl)- lambda6-sulfanediimine [0372]
  • the title compounds were as described in Example 41, Step 3, except 7-methoxy-4-(6-((methylsulfanyl)methyl)-2-azaspiro[3.3]heptan-2- yl)quinoline (1.00 g, crude) was used.
  • Step 2 (4-(((7-methoxyquinolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda4- sulfaniminium 2,4,6-trimethylbenzenesulfonate [0375] To a solution of 7-methoxy-4-((4-(methylsulfanyl)phenyl)methoxy)quinoline (400 mg, 1.34 mmol, 1.0 equiv) in DCM (10 mL) was added amino 2,4,6- trimethylbenzenesulfonate (868 mg, 4.03 mmol, 3.0 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 1 h.
  • Step 3 (4-(((7-methoxyquinolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda6- sulfanediimine [0376] To a solution of (4-(((7- oxy)methyl)phenyl)(methyl)- lambda4-sulfaniminium 2,4,6-trimethylbenzenesulfonate (400 mg, crude) in DMF (10 mL) were added Na 2 CO 3 (109 mg, 1.03 mmol, 1.2 equiv) and NCS (165 mg, 1.03 mmol, 1.2 equiv) at 0 °C under nitrogen atmosphere.
  • Step 2 4-((3-fluoro-5-(methylthio)benzyl)oxy)-7-methoxyquinoline [0378] To a solution of (3- methanol (800 mg, 4.64 mmol, 1.0 equiv) in DMF (10 mL) was added NaH (371 mg, 9.29 mmol, 2.0 equiv, 60%) at 0°C. After stirring for 15 min, 4-chloro-7-methoxyquinoline (1.35 g, 6.96 mmol, 1.5 equiv) was added at the same temperature. The resulting mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was quenched with water and extracted with EtOAc.
  • Step 3 (3-fluoro-5-(((7-methoxyquinolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda6- sulfanediimine [0379] To a solution of 4-((3- oxy)-7-methoxyquinoline (600 mg, 1.82 mmol, 1.0 equiv) in ACN (20 mL) was added NH3-H2O (2.48 g, 25% (v/v)) at -15 °C under nitrogen atmosphere. The reaction mixture was stirred for 1 h at the same temperature.
  • iodomethane (21 mg, 0.15 mmol, 1.5 equiv) was added and the reaction mixture was stirred at room temperature for 2 h. The resulting mixture was quenched with water (2 mL) at 0 o C and concentrated under reduced pressure.
  • Examples 43 and 44 Synthesis of diethyl-1-(3-(((8-methoxy-1,7-naphthyridin-4-yl)oxy)methyl)phenyl)-1-methyl- lambda6-sulfanediimine and N-ethyl-1-(3-(((8-methoxy-1,7-naphthyridin-4- yl)oxy)methyl)phenyl)-1-methyl-lambda6-sulfanediimine.
  • the crude product was re-purified by prep-HPLC (Column: XBridge Prep RP OBD C18 Column, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 4% B to 34% B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 9.1, 9.4).
  • Step 2 2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)ethyl methanesulfonate
  • 2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)ethanol 970 mg, 3.10 mmol, 1 equiv
  • DCM 15 mL
  • methanesulfonic anhydride (1.60 g, 9.50 mmol, 3 equiv)
  • TEA 637 mg, 6.3 mmol, 2.00 equiv
  • DMAP 50 mg, 0.5 mmol, 0.15 equiv
  • Step 3 6,7-dimethoxy-4-(4-(2-(methylsulfanyl)ethyl)piperidin-1-yl)quinazoline
  • 2- 4-yl)piperidin-4-yl)ethyl methanesulfonate (1.60 g, crude) in EtOH (15 mL) was added sodiummethanethiolate (16.13 g, 46.10 mmol, 10 eq, 20% aq) at room temperature. After stirring for 2 h, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water,and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered.
  • Step 4 (2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)ethyl)(methyl)-lambda6- sulfanediimine [0389]
  • the title compound was syn ceeding as described in Example 41, Step 3, except 6,7-dimethoxy-4-(4-(2-(methylsulfanyl)ethyl)piperidin-1-yl)quinazoline (762 mg, 2.20 mmol,) was used.
  • the crude product was purified by prep-HPLC with the following conditions: purified by silica gel column chromatography, eluted with EtOAc / PE (1:1) to afford 150 mg of crude (2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)ethyl)(methyl)- lambda6-sulfanediimine and 150 mg of crude (2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin- 4-yl)ethyl)(imino)(methyl)-lambda6-sulfanone.
  • Step 2 2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)ethyl methanesulfonate
  • 2-(1-(6,7- 4-yl)piperidin-4-yl)ethanol 900 mg, 4.45 mmol, 1 equiv
  • DCM 15 mL
  • methanesulfonic anhydride 2.50 g, 13.10 mmol, 3 equiv
  • TEA 895 mg, 8.85 mmol, 2.00 equiv
  • DMAP 55 mg, 0.50 mmol, 0.10 equiv
  • Step 3 6,7-dimethoxy-4-(4-(2-(methylsulfanyl)ethyl)piperidin-1-yl)quinoline
  • 2-(1-(6,7- 4-yl)piperidin-4-yl)ethyl methanesulfonate (1.30 g, crude) in EtOH (15 mL) was added sodiummethanethiolate (13.15 g, 37.57 mmol, 10 equiv, 20% aq)at room temperature. After stirring for 2 h, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered.
  • Step 4 (2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)ethyl)(methyl)- lambda6- sulfanediimine [0394]
  • the title compound was as described in Example 41, Step 3, except 6,7-dimethoxy-4-(4-(2-(methylsulfanyl)ethyl)piperidin-1-yl)quinoline (250 mg, 0.72 mmol) was used.
  • the crude product was purified by prep-HPLC with the following conditions: purified by silica gel column chromatography, eluted with EtOAc / PE to afford 100 mg of crude (2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)ethyl)(methyl)- lambda6- sulfanediimine and 80 mg of crude (2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4- yl)ethyl)(imino)(methyl)-lambda6-sulfanone.
  • Step 2 2-(1-(7-methoxyquinolin-4-yl)piperidin-4-yl)ethyl methanesulfonate
  • TEA 763 mg, 7.54 mmol, 2 equiv
  • DMAP 46 mg, 0.37 mmol, 0.1 equiv
  • Step 3 7-methoxy-4-(4-(2-(methylsulfanyl)ethyl)piperidin-1-yl)quinoline
  • 2-(1-(7- yl)piperidin-4-yl)ethyl methanesulfonate (1.42 g, 3.89 mmol, 1 equiv) in EtOH (10 mL)
  • sodiummethanethiolate 13.65 g, 38.96 mmol, 10 equiv, 20% aq.
  • the resulting mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with EtOAc.
  • Step 4 (2-(1-(7-methoxyquinolin-4-yl)piperidin-4-yl)ethyl)(methyl)-lambda6- sulfanediimine [0399]
  • the title compound was as described in Example 41, Step 3, except 7-methoxy-4-(4-(2-(methylsulfanyl)ethyl)piperidin-1-yl)quinoline (400 mg, 1.26 mmol) was used.
  • the crude product was purified by prep-HPLC with the following conditions: (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 2% B to31 % B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 9.2).
  • Step 2 4-(cyclopropylthio)phenol [0401] To a solution of sulfane (5.40 g, 29.95 mmol, 1.0 equiv) in DCM (50 mL) was added BBr3 (50 mL, 50.00 mmol, 1 M in DCM) at 0 o C. After stirring at room temperature for 24 h, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc/PE (1:1) to afford 4-(cyclopropylthio)phenol (4.00 g, 80%) as a light yellow oil.
  • Step 3 4-(4-(cyclopropylsulfanyl)phenoxy)-7-methoxyquinoline [0402] To a mixture of 4-chl mg, 3.61 mmol, 1 equiv) in DMSO (15 mL) were added Cs2CO3 (3.53 g, 10.84 mmol, 3 equiv) and 4- (cyclopropylthio)phenol (901 mg, 5.42 mmol, 1.5 equiv). After stirring at 120 o C for 3 h, the resulting mixture was cooled to room temperature, diluted with water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure.
  • the crude product was purified by prep-HPLC with the following conditions: (Column: Xbridge Prep OBD C18 Column, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 11% B to 38 % B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 8.68 ).
  • Step 2 (3-(cyclopropylsulfanyl)phenyl)methanol [0405] To a solution of 3- acid (24.0 g, 117.37 mmol, 1 equiv) in THF (250 mL) was added lithium aluminum hydride (110 mL, 2 equiv, 2 M in THF) at 0 o C. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction mixture was quenched with saturated ammonium bicarbonate solution at 0 o C and extracted with EtOAc . The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure.
  • Step 3 4-((3-(cyclopropylsulfanyl)phenyl)methoxy)-7-methoxyquinoline [0406] To a solution of (3- (837 mg, 4.64 mmol, 1.5 equiv) in DMF (12 mL) was added NaH (223 mg, 9.29 mmol, 3 equiv) at 0 o C.
  • Step 4 cyclopropyl(3-(((7-methoxyquinolin-4-yl)oxy)methyl)phenyl)- lambda6- sulfanediimine [0407]
  • the crude product was purified by prep-HPLC with the following conditions: (Column: Xbridge Prep OBD C18 Column, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 11% B to 41 % B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 8.68).
  • iodomethane (104 mg, 0.73 mmol, 3.2 equiv) was added.
  • the reaction mixture was stirred at room temperature for 1 h, quenched with water and extracted with dichloromethane. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and filtered.
  • pNP-TMP p-Nitrophenyl thymidine 5'-monophosphate
  • the ENPP1 enzyme activity assay with pNP-TMP substrate was conducted as follows: [0410] First, in a 60 ⁇ l reaction, 7.5 ng purified ENPP1 was mixed with compounds of Formula (I) (test compound) ranging from 13.7 pM to 10 ⁇ M. Incubation of ENPP1 with compounds was set at 25 °C for 10 min. Reactions with DMSO only (with ENPP1 but no compound) gave the fastest reaction (MAX Activity).
  • Adjusted Vmax V0 X (Km + (S))/(S).
  • Km 232 ⁇ M
  • (S) 500 ⁇ M.
  • Adjusted Vmax 1.464 X V 0 .
  • V 0 (OD405nm with ENPP1 - OD405 nm ENPP1 blank)/minutes.
  • OD405 nm was plotted, with blank subtracted, against time (minutes), the initial linear rate is V0. blank subtracted, against time (minutes), the initial linear rate is V 0 .
  • the conversion factor (pmol/OD405nm), was determined by plotting the amount of standard, 4-Nitrophenol (Sigma-Aldrich, Catalog # 241326), against absorbance at 405nm. The slope is the conversion factor.
  • Ki for a representative compound of Formula (I) disclosed in Compound Table 1A and 1B above is provided in Table 2 below: Ki ( NP-TMP) o a p e Measurement of 2’3’-cGAMP hydrolysis by ENPP1 [0419] ENPP1 catalyzes the hydrolysis of 2’3’-cGAMP into 5’-AMP and 5’-GMP, and hence the ENPP1 enzyme activity with 2’3’-cGAMP as substrate is monitored by measurement of the product 5’-AMP.
  • the AMP-Glo assay kit from Promega (catalog number V5012) is used for measurement of 5’-AMP production.
  • an ENPP1 and test compound incubation is set up in assay buffer (50mM Tris- HCl, pH8.8, 250mM NaCl, 0.1mg/ml BSA, 1% DMSO) with following conditions: ENPP1 concentration: 1.25nM; test compound concentration ranging from 68 pM to 20 ⁇ M. This incubation is carried out at 25°C for 10 min.
  • % inhibition (MAX RLU - sample RLU)/MAX RLU X 100%.
  • Ingredient Quantity per tablet mg compound of this disclosure 400 cornstarch 50 croscarmellose sodium 25 lactose 120 magnesium stearate 5 Capsule Formulation [0428] The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule. Ingredient Quantity per capsule mg compound of this disclosure 200 lactose spray dried 148 magnesium stearate 2 Injectable Formulation [0429] Compound of the disclosure (e.g., compound 1) in 2% HPMC, 1% Tween 80 in DI water, pH 2.2 with MSA, q.s. to at least 20 mg/mL.
  • Inhalation Composition To prepare a pharmaceutical composition for inhalation delivery, 20 mg of a compound disclosed herein is mixed with 50 mg of anhydrous citric acid and 100 mL of 0.9% sodium chloride solution. The mixture is incorporated into an inhalation delivery unit, such as a nebulizer, which is suitable for inhalation administration.
  • Topical Gel Composition To prepare a pharmaceutical topical gel composition, 100 mg of a compound disclosed herein is mixed with 1.75 g of hydroxypropyl cellulose, 10 mL of propylene glycol, 10 mL of isopropyl myristate and 100 mL of purified alcohol USP. The resulting gel mixture is then incorporated into containers, such as tubes, which are suitable for topical administration.
  • Ophthalmic Solution Composition To prepare a pharmaceutical ophthalmic solution composition, 100 mg of a compound disclosed herein is mixed with 0.9 g of NaCl in 100 mL of purified water and filtered using a 0.2 micron filter. The resulting isotonic solution is then incorporated into ophthalmic delivery units, such as eye drop containers, which are suitable for ophthalmic administration.
  • Nasal spray solution To prepare a pharmaceutical nasal spray solution, 10 g of a compound disclosed herein is mixed with 30 mL of a 0.05M phosphate buffer solution (pH 4.4). The solution is placed in a nasal administrator designed to deliver 100 ul of spray for each application.

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Abstract

The present disclosure provides certain bicyclic heteroaryl sulfanediimine compounds that inhibit ectonucleotide pyrophosphatase/ phosphodiesterase 1 (ENPP1) enzymatic activity and are therefore useful for the treatment of diseases treatable by inhibition of ENPP1. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.

Description

Mintz Ref. No.055577-526001WO Client Ref. No.2024-001PCT BICYCLIC HETEROARYL SULFANEDIIMINE DERIVATIVES AS ECTONUCLEOTIDE PYROPHOSPHATASE PHOSPHODIESTERASE 1 INHIBITORS CROSS-REFERENCES TO RELATED APPLICATIONS [0001] This application claims priority to U.S. Provisional Application No.63/569,614, filed March 25, 2024, which is hereby incorporated by reference in its entirety for all purposes. STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT [0002] NOT APPLICABLE REFERENCE TO A "SEQUENCE LISTING," A TABLE, OR A COMPUTER PROGRAM LISTING APPENDIX SUBMITTED ON A COMPACT DISK [0003] NOT APPLICABLE FIELD OF THE DISCLOSURE [0004] The present disclosure provides certain bicyclic heteroaryl sulfanediimine compounds that inhibit ectonucleotide pyrophosphatase/ phosphodiesterase 1 (ENPP1) enzymatic activity and are therefore useful for the treatment of diseases treatable by inhibition of ENPP1. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds. BACKGROUND [0005] ENPP1 enzyme is present in a wide range of tissues and cell types, such as lymphocytes, macrophages, liver, brain, heart, kidney, vascular smooth muscle cells, and chondrocytes. ENPP1 hydrolyzes ATP and other nucleoside triphosphates and releases AMP or other nucleoside monophosphates as well as pyrophosphate (PPi) (Kato K et al.2012 PNAS 109:16876-16881; Hessle L et al.2002 PNAS 99:9445-9449). The enzyme can also hydrolyze other nucleoside monophosphate esters (Kato K et al.2012 PNAS 109:16876- 16881). ENPP1 has been identified as the dominant 2’-3’-cGAMP hydrolase in cultured cells, tissue extracts and blood (Li L et al.2014 Nat Chem Biol 10:1043-1048). Tissues and blood from ENPP1 knockout mice lack 2’-3’-cGAMP hydrolase activity. Elevated levels of ENPP1 have been associated with calcific aortic valve disease (CAVD) and calcium pyrophosphate deposition disease (CPPD), an inflammatory disease resulting from CPPD crystal deposits in the joint and surrounding tissues (Cote N et al.2012 Eur J Pharmacol 689:139-146; Johnson K et al.2001 Arthritis Rheum 44:1071). ENPP1 expression is upregulated in certain hepatocellular carcinomas, glioblastomas, melanomas, testicular, pancreatic and thyroid and breast cancers and has been associated with resistance to chemotherapy (see Lau WM et al.2013 PLoS One 8:5; Bageritz J et al.2014 Mol Cell Oncology 1:3; Bageritz J et al.2014 Cell Death, Differentiation 21:929-940; Umar A et al. 2009 Mol Cell Proteomics 8:1278-1294). ENPP1 upregulation and variants of ENPP1 are also associated with insulin resistance and type 2 diabetes (Meyre D et al.2005 Nat Genet 37:863-867; Maddux BA et al.1995 Nature 373:448-451; Rey D et al.2012 Mol Biol Rep 39:7687-7693) and enzyme activity of ENPP1 was reported to be required for the inhibition of insulin receptor signaling (Chin CN et al.2009 Eur J Pharmacol 606:17-24). [0006] Cyclic GMP-AMP synthase (cGAS) is a pattern recognition receptor that synthesizes the endogenous messenger molecule cGAMP from ATP and GTP in response to the presence of DNA derived from viruses, bacteria, damaged mitochondria or cancer cells. The cGAMP molecule then binds to the stimulator of interferon genes (STING) protein, which initiates a signaling response that activates innate immunity and results in the production of type I interferon, antiviral and immune-stimulatory cytokines (Sun L et al. 2013 Science 339:786-791; Wu J et al.2013 Science 339:826-830; Gao D et al.2013 Science 341:903-906; Li X et al.2013 Science 341:1390-1394; Schoggins JW et al.2014 Nature 505:691-695; Wassermann R et al.2015 Cell Host Microbe 17:799-810; Watson RO et al. 2015 Cell Host Microbe 17:811-819; Collins A et al.2015 Cell Host Microbe 17:820-828; West A et al.2015 Nature 520:533-557; Woo SR et al.2014 Immunity 41:830-842; Deng L et al.2014 Immunity 41:843-852; Chen Q et al.2016 Nat Immunol 17:1142-1148). The cGAS enzyme, cGAMP messenger and STING are is also involved in host defense against RNA viruses and the immune control of tumor development (Aguirre S et al.2012 PLoS Pathog 8: e1002934; Barber GN 2015 Nat Rev Immunol 15:760-770). ENPP1 has been identified as the enzyme that naturally hydrolyzes cGAMP and therefore counteracts the innate immune response against infectious agents, damaged cells and cancer cells (Li L et al. 2014 Nat Chem Biol 10:1043-1048). The efficacy of non-hydrolyzable cGAMP analogs in inducing functional immune responses is higher than that of natural, hydrolysable cGAMP (Li L et al.2014 Nat Chem Biol 10:1043-1048; Corrales L et al.2015 Cell Rep 11:1018- 1030). Virus infection has been demonstrated to be facilitated by ENPP1 overexpression and is attenuated by silencing of ENPP1 (Wang J et al.2018 Mol Immunol 95:56-63). [0007] Inhibitors of cGAMP hydrolysis may therefore be used to increase the effectiveness of immune responses against cancer cells and tumors and against infections by RNA or DNA viruses or bacteria. Inhibitors of ENPP1 and of cGAMP or nucleoside triphosphate hydrolysis may also be used for the treatment of inflammatory diseases that are associated with elevated nucleotidase levels, reduced nucleoside triphosphate, reduced cGAMP or reduced nucleoside monophosphate ester levels or diseases associated with elevated nucleoside or nucleoside monophosphate levels. For these reasons, ENPP1 is an attractive therapeutic target for the treatment of diseases. [0008] The present disclosure addresses these needs and provides related advantages as well. SUMMARY [0009] In a first aspect, provided is a compound of Formula (I): wherein: X is N, CH, or C when attached to R1; a, b, d, and e are each independently CH or C when attached to any one of R4, R5, or R6; or one or two of a, b, d, and e are N and the remaining of a, b, d, and e are each independently CH or C when attached to any one of R4, R5, or R6; Z is a bond, NH, O, S, SO, or SO2; m and n are each independently 0 or 1; alk is alkylene substituted with 0 to 3 halo; alk1 is alkylene, wherein one carbon atom in the alkylene chain is optionally replaced by oxyen and further wherein alkylene is substituted with 0 to 3 halo; Ar is arylene, heteroarylene, cycloalkylene, cyclylaminylene, fused cyclylaminylene, bridged cyclylaminylene, or spiro cyclylaminylene; R1 is absent, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkylamino, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, diaminoalkyl, diaminoalkoxy, diaminoalkylamino or cyano; R2 and R3 are each independently absent, methyl, ethyl, methoxy, fluoro, trifluoromethyl, trifluoromethoxy, or cyano; one of R4, R5, and R6 is absent, alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, cyano, amino, alkylamino, dialkylamino, alkylsulfonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, carboxy, or alkoxycarbonyl; and the remaining two of R4, R5, and R6 are each independently absent, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkylamino, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino (wherein heterocyclyl either alone or part of heterocyclyloxy and heterocyclylamino is substituted with 0 to 3 substituents, each independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), heterocyclylalkyl, heterocyclylalkyloxy, heterocyclylalkylamino (wherein the heterocyclyl ring in heterocyclylalkyl, heterocyclylalkyloxy, and heterocyclylalkylamino is substituted with 0 to 3 substituents, each independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), cycloalkyloxy, phenyloxy, or heteroaryloxy (where phenyl in phenyloxy and heteroaryl in heteroaryloxy are substituted with 0 to 3 substituents, each independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, and cyano); R7 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, carbonylaminoalkyl, carboxyaminoalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, aryl, fused aryl, heteroaryl, fused heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, aryloxyalkyl, heteroaryloxyalkyl, fused aralkyl, fused heteroaryalkyl, or heterocyclylalkyl wherein cycloalkyl, aryl, fused aryl, heteroaryl, fused heteroaryl, heterocyclyl and the ring portion of cycloalkylalkyl, arylalkyl, heteroaralkyl, aryloxyalkyl, heteroaryloxyalkyl, fused aralkyl, fused heteroaryalkyl, or heterocyclylalkyl are substituted with one, two or three substituents each independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, cyano, alkylcarbonyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl; R8 and R9 are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, carbonylaminoalkyl, carboxyaminoalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, aryl, fused aryl, heteroaryl, fused heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, aryloxyalkyl, heteroaryloxyalkyl, fused aralkyl, fused heteroaryalkyl, or heterocyclylalkyl wherein cycloalkyl, aryl, fused aryl, heteroaryl, fused heteroaryl, heterocyclyl and the ring portion of cycloalkylalkyl, arylalkyl, heteroaralkyl, aryloxyalkyl, heteroaryloxyalkyl, fused aralkyl, fused heteroaryalkyl, or heterocyclylalkyl are substituted with one, two or three substituents each independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, cyano, alkylcarbonyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl; or a pharmaceutically acceptable salt thereof. [0010] In a second aspect, provided is a pharmaceutical composition comprising a compound of Formula (I) (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. [0011] In a third aspect, provided are methods of treating a disease mediated by ENPP1 in a patient, preferably in a patient recognized as needing such a treatment, comprising administering to the patient a compound of Formula (I) (or any of the embodiments thereof described herein) or a pharmaceutically acceptable salt thereof in a therapeutically effective amount. In one embodiment, the disease is cancer. In a second embodiment, the disease is cancer selected from hepatocellular carcinomas, glioblastomas, melanomas, testicular cancer, pancreatic cancer, thyroid cancer, cervical cancer, ovarian cancer, bladder cancer, colon cancer, lung cancer, breast cancer, multiple myeloma, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, large granular lymphocytic leukemia, T-cell prolymphocytic leukemia, prolymphocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, diffuse large B cell lymphoma, low grade glioma, colorectal cancer, gastric and gastrointestinal cancer, esophageal cancer, anal cancer, cancer of the appendix, kidney cancer, skin cancer, uterine cancer, brain cancer, adrenal cancer, bile duct cancer, bone cancer, fallopian tube cancer, sarcomas, germ cell tumors, head and neck cancer, neuroblastoma, pheochromocytoma and paraganglioma, cholangiocarcinoma, peritoneal cancer, retinoblastoma, liver cancer, thymoma, urethral cancer, prostate cancer, uveal melanoma, adenoid cystic carcinoma, and vaginal and vulvar cancer. In a third embodiment, the disease is cancer selected from hepatocellular carcinomas, glioblastomas, melanomas, testicular cancer, pancreatic cancer, thyroid cancer, cervical cancer, ovarian cancer, bladder cancer, colon cancer, and lung cancer. [0012] In a fourth embodiment, the disease is cancer such as hepatocellular carcinomas, glioblastomas, melanomas, testicular, pancreatic, thyroid and breast cancer. In another embodiment, the disease is an inflammatory disease e.g., calcific aortic valve disease, osteoarthritis, and calcium pyrophosphate dihydrate disease. In yet another embodiment the disease metabolic disease e.g., type 2 diabetes, or a viral infection such as DNA virus infections, HIV, Herpes virus infections, Papilloma virus infections, RNA virus infections, and HBV. In another embodiment, the disease is an inflammatory disease e.g., calcific aortic valve disease and calcium pyrophosphate deposition disease (CPPD). In yet another embodiment the disease metabolic disease e.g., type 2 diabetes or a viral infection. [0013] In a fourth aspect, provided is a compound of Formula (I) (or any embodiments thereof described herein) or a pharmaceutically acceptable salt thereof for use as a medicament. In a second embodiment, the disease is cancer selected from hepatocellular carcinomas, glioblastomas, melanomas, testicular cancer, pancreatic cancer, thyroid cancer, cervical cancer, ovarian cancer, bladder cancer, colon cancer, lung cancer, breast cancer, multiple myeloma, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, large granular lymphocytic leukemia, T-cell prolymphocytic leukemia, prolymphocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, diffuse large B cell lymphoma, low grade glioma, colorectal cancer, gastric and gastrointestinal cancer, esophageal cancer, anal cancer, cancer of the appendix, kidney cancer, skin cancer, uterine cancer, brain cancer, adrenal cancer, bile duct cancer, bone cancer, fallopian tube cancer, sarcomas, germ cell tumors, head and neck cancer, neuroblastoma, pheochromocytoma and paraganglioma, cholangiocarcinoma, peritoneal cancer, retinoblastoma, liver cancer, thymoma, urethral cancer, prostate cancer, uveal melanoma, adenoid cystic carcinoma, and vaginal and vulvar cancer. In a third embodiment, the disease is cancer selected from hepatocellular carcinomas, glioblastomas, melanomas, testicular cancer, pancreatic cancer, thyroid cancer, cervical cancer, ovarian cancer, bladder cancer, colon cancer, and lung cancer. [0014] In another embodiment, the disease is an inflammatory disease e.g., calcific aortic valve disease, osteoarthritis, and calcium pyrophosphate dihydrate disease. In yet another embodiment the disease metabolic disease e.g., type 2 diabetes, or a viral infection such as DNA virus infections, HIV, Herpes virus infections, Papilloma virus infections, RNA virus infections, and HBV. [0015] In one embodiment, the medicament is for use in the treatment of cancer such as hepatocellular carcinomas, glioblastomas, melanomas, testicular, pancreatic, thyroid and breast cancer. In another embodiment, the medicament is for use in the treatment of an inflammatory disease e.g., calcific aortic valve disease and calcium pyrophosphate deposition disease (CPPD). In yet another embodiment, the medicament is for use in the treatment of a metabolic disease e.g., type 2 diabetes or a viral infection. [0016] In a fifth aspect provided is the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (and any embodiments thereof disclosed herein) in the manufacture of a medicament for treating a disease in a patient in which the activity of ENPP1 contributes to the pathology and/or symptoms of the disease. In one embodiment, the disease is cancer. [0017] In a second embodiment, the disease is cancer selected from hepatocellular carcinomas, glioblastomas, melanomas, testicular cancer, pancreatic cancer, thyroid cancer, cervical cancer, ovarian cancer, bladder cancer, colon cancer, lung cancer, breast cancer, multiple myeloma, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, large granular lymphocytic leukemia, T-cell prolymphocytic leukemia, prolymphocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, diffuse large B cell lymphoma, low grade glioma, colorectal cancer, gastric and gastrointestinal cancer, esophageal cancer, anal cancer, cancer of the appendix, kidney cancer, skin cancer, uterine cancer, brain cancer, adrenal cancer, bile duct cancer, bone cancer, fallopian tube cancer, sarcomas, germ cell tumors, head and neck cancer, neuroblastoma, pheochromocytoma and paraganglioma, cholangiocarcinoma, peritoneal cancer, retinoblastoma, liver cancer, thymoma, urethral cancer, prostate cancer, uveal melanoma, adenoid cystic carcinoma, and vaginal and vulvar cancer. In a third embodiment, the disease is cancer selected from hepatocellular carcinomas, glioblastomas, melanomas, testicular cancer, pancreatic, thyroid cancer, cervical cancer, ovarian cancer, bladder cancer, colon cancer, and lung cancer. [0018] In another embodiment, the disease is an inflammatory disease e.g., calcific aortic valve disease, osteoarthritis, and calcium pyrophosphate dihydrate disease. In yet another embodiment the disease metabolic disease e.g., type 2 diabetes, or a viral infection such as DNA virus infections, HIV, Herpes virus infections, Papilloma virus infections, RNA virus infections, and HBV. [0019] In one embodiment, the disease is cancer such as hepatocellular carcinomas, glioblastomas, melanomas, testicular, pancreatic, thyroid and breast cancer. In another embodiment, the disease is an inflammatory disease e.g., calcific aortic valve disease and calcium pyrophosphate deposition disease (CPPD). In yet another embodiment, the disease is a metabolic disease e.g., type 2 diabetes or a viral disease. [0020] In a sixth aspect, provided is a compound of Formula (I) (or any embodiments thereof described herein) or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, a metabolic disease, viral infection, or an inflammatory disease. In one embodiment, the disease is cancer. [0021] In a second embodiment, the disease is cancer selected from hepatocellular carcinomas, glioblastomas, melanomas, testicular cancer, pancreatic cancer, thyroid cancer, cervical cancer, ovarian cancer, bladder cancer, colon cancer, lung cancer, breast cancer, multiple myeloma, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, large granular lymphocytic leukemia, T-cell prolymphocytic leukemia, prolymphocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, diffuse large B cell lymphoma, low grade glioma, colorectal cancer, gastric and gastrointestinal cancer, esophageal cancer, anal cancer, cancer of the appendix, kidney cancer, skin cancer, uterine cancer, brain cancer, adrenal cancer, bile duct cancer, bone cancer, fallopian tube cancer, sarcomas, germ cell tumors, head and neck cancer, neuroblastoma, pheochromocytoma and paraganglioma, cholangiocarcinoma, peritoneal cancer, retinoblastoma, liver cancer, thymoma, urethral cancer, prostate cancer, uveal melanoma, adenoid cystic carcinoma, and vaginal and vulvar cancer. In a third embodiment, the disease is cancer selected from hepatocellular carcinomas, glioblastomas, melanomas, testicular cancer, pancreatic, thyroid cancer, cervical cancer, ovarian cancer, bladder cancer, colon cancer, and lung cancer. [0022] In another embodiment, the disease is an inflammatory disease e.g., calcific aortic valve disease, osteoarthritis, and calcium pyrophosphate dihydrate disease. In yet another embodiment the disease metabolic disease e.g., type 2 diabetes, or a viral infection such as DNA virus infections, HIV, Herpes virus infections, Papilloma virus infections, RNA virus infections, and HBV. [0023] In a seventh aspect, provided is a method of increasing the activity of an immune cell comprising contacting the immune cell with a compound of Formula (I) or a pharmaceutically acceptable salt thereof (and any embodiments thereof disclosed herein). [0024] In an eighth aspect, provided is a method of increasing the activity of an immune cell in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (and any embodiments thereof disclosed herein). In one embodiment of the seventh aspect, the activity of the immune cell is increased in a subject suffering from cancer or a viral disease. [0025] In a second embodiment, the disease is cancer selected from hepatocellular carcinomas, glioblastomas, melanomas, testicular cancer, pancreatic cancer, thyroid cancer, cervical cancer, ovarian cancer, bladder cancer, colon cancer, lung cancer, breast cancer, multiple myeloma, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, large granular lymphocytic leukemia, T-cell prolymphocytic leukemia, prolymphocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, diffuse large B cell lymphoma, low grade glioma, colorectal cancer, gastric and gastrointestinal cancer, esophageal cancer, anal cancer, cancer of the appendix, kidney cancer, skin cancer, uterine cancer, brain cancer, adrenal cancer, bile duct cancer, bone cancer, fallopian tube cancer, sarcomas, germ cell tumors, head and neck cancer, neuroblastoma, pheochromocytoma and paraganglioma, cholangiocarcinoma, peritoneal cancer, retinoblastoma, liver cancer, thymoma, urethral cancer, prostate cancer, uveal melanoma, adenoid cystic carcinoma, and vaginal and vulvar cancer. In a third embodiment, the disease is cancer selected from hepatocellular carcinomas, glioblastomas, melanomas, testicular cancer, pancreatic cancer, thyroid cancer, cervical cancer, ovarian cancer, bladder cancer, colon cancer, and lung cancer. [0026] In yet another embodiment the disease is a viral infection such as DNA virus infections, HIV, Herpes virus infections, Papilloma virus infections, RNA virus infections, and HBV. [0027] In a ninth aspect, provided is a compound of Formula (I) or a pharmaceutically acceptable salt thereof (and any embodiments thereof disclosed herein) for use in the treatment of: 1. cancer; 2. an inflammatory disease; 3. a metabolic disease; or 4. a viral disease. [0028] In a first embodiment, the disease is cancer. In a second embodiment, the disease is cancer selected from hepatocellular carcinomas, glioblastomas, melanomas, testicular cancer, pancreatic cancer, thyroid cancer, cervical cancer, ovarian cancer, bladder cancer, colon cancer, lung cancer, breast cancer, multiple myeloma, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, large granular lymphocytic leukemia, T-cell prolymphocytic leukemia, prolymphocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, diffuse large B cell lymphoma, low grade glioma, colorectal cancer, gastric and gastrointestinal cancer, esophageal cancer, anal cancer, cancer of the appendix, kidney cancer, skin cancer, uterine cancer, brain cancer, adrenal cancer, bile duct cancer, bone cancer, fallopian tube cancer, sarcomas, germ cell tumors, head and neck cancer, neuroblastoma, pheochromocytoma and paraganglioma, cholangiocarcinoma, peritoneal cancer, retinoblastoma, liver cancer, thymoma, urethral cancer, prostate cancer, uveal melanoma, adenoid cystic carcinoma, and vaginal and vulvar cancer. In a third embodiment, the disease is cancer selected from hepatocellular carcinomas, glioblastomas, melanomas, testicular cancer, pancreatic cancer, thyroid cancer, cervical cancer, ovarian cancer, bladder cancer, colon cancer, and lung cancer. [0029] In another embodiment, the disease is an inflammatory disease e.g., calcific aortic valve disease, osteoarthritis, and calcium pyrophosphate dihydrate disease. In yet another embodiment the disease metabolic disease e.g., type 2 diabetes, or a viral infection such as DNA virus infections, HIV, Herpes virus infections, Papilloma virus infections, RNA virus infections, and HBV. [0030] In one embodiment, the treatment is for cancer e.g., hepatocellular carcinomas, glioblastomas, melanomas, testicular, pancreatic, thyroid and breast cancer. In another embodiment, the use is for the treatment of an inflammatory disease e.g., calcific aortic valve disease and calcium pyrophosphate deposition disease (CPPD). In yet another embodiment, the medicament is for use in the treatment of a metabolic disease e.g., type 2 diabetes or a viral infection. [0031] In any of the aforementioned aspects involving the treatment of cancer, are further embodiments comprising administering the compound of Formula (I) or a pharmaceutically acceptable salt thereof (or any embodiments thereof disclosed herein) in combination with at least one additional anticancer. When combination therapy is used, the agents can be administered simultaneously or sequentially. DETAILED DESCRIPTION Definitions: [0032] Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this Application and have the following meaning: [0033] “Alkyl” means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl, pentyl, and the like. When alkyl has 1 to 3 carbon atoms it is also referred to herein as C1-3alkyl. [0034] “Alkylene” means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms unless otherwise stated e.g., methylene, ethylene, propylene, 1-methylpropylene, 2- methylpropylene, butylene, pentylene, and the like. [0035] “Alkylsulfonyl” means -SO2R radical where R is alkyl as defined above, e.g., methylsulfonyl, ethylsulfonyl, and the like. [0036] “Alkylcarbonyl” means a -COR radical where R is alkyl as defined above, e.g., methylcarbonyl, ethylcarbonyl, propylcarbonyl, and the like. [0037] “Amino” means a –NH2. [0038] “Aminocarbonyl” means -CONH2. [0039] “Alkylaminocarbonyl” means -CONHR radical where R is alkyl as defined above, e.g., methylaminocarbonyl, ethylaminocarbonyl, and the like. [0040] “Aminocarbonylalkyl” means –(alkylene)-CONRR’ radical where R is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl and R’ is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, optionally substituted phenyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl; or R and R’ together with the nitrogen atom to which they are attached from optionally substituted cyclylaminyl, each term as defined herein, e.g., methylaminocarbonyl-ethyl, ethylaminocarbonylethyl, 2-[(HOCH2CH2)2NC(O)]ethyl, and the like. [0041] “Alkylamino” means a -NHR radical where R is alkyl as defined above, e.g., methylamino, ethylamino, propylamino, or 2-propylamino, and the like. [0042] “Aminoalkyl” means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with –NR’R” where R’and R” are each independently hydrogen or alkyl as defined above, e.g., aminomethyl, aminoethyl, methylaminomethyl, aminopropyl, methylaminopropyl, and the like. [0043] “Aminoalkylamino” means a –NRaRb radical where Ra is hydrogen or alkyl and Rb is aminoalkyl as defined above, e.g., aminoethylamino, dimethylaminoethylamino, diethylaminoethylamino, dimethylaminopropylamino, diethylaminopropylamino, and the like. [0044] “Aminoalkyloxy” or “aminoalkoxy” means a –ORa radical where Ra is aminoalkyl as defined above, e.g., aminoethyloxy, dimethylaminoethyloxy, diethylaminoethyloxy, dimethylaminopropyloxy, diethylaminopropyloxy, and the like. [0045] “Alkoxy” means a -OR radical where R is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert-butoxy, and the like. [0046] “Alkoxycarbonyl” a -C(O)OR radical where R is alkyl as defined above, e.g., methoxycarbonyl, ethoxycarbonyl, and the like. [0047] “Alkoxyalkyl” means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one alkoxy group, such as one or two alkoxy groups, as defined above, e.g., 2- methoxyethyl, 1-, 2-, or 3-methoxypropyl, 2-ethoxyethyl, and the like. [0048] “Alkoxyalkylamino” means a –NRR’ radical where R is hydrogen or alkyl and R’ is alkoxyalkyl as defined above, e.g., methoxyethylamino, ethoxyethylamino, propoxypropylamino, ethoxypropylamino, and the like. [0049] “Alkoxyalkyloxy” or “alkoxyalkoxy” means a –(O)R radical where R is alkoxyalkyl as defined above, e.g., methoxyethoxy, ethoxyethoxy, and the like. [0050] “Aryl” means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms e.g., phenyl or naphthyl. [0051] “Arylalkyl” or “aralkyl” means a –(alkylene)-R where R is aryl as defined above e.g., benzyl. [0052] “Arylene” means a divalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms e.g., phenylene or naphthylene. [0053] “Aryloxy” means a -OR radical where R is aryl as defined above e.g., phenyloxy or naphthyloxy. When aryl is phenyl, the group is also referred to herein as phenyloxy or phenoxy. [0054] “Aryloxyalkyl” means a –alkylene-OR radical where R is aryl as defined above, e.g., phenyloxymethyl, phenyloxyethyl, phenyloxypropyl, and the like. [0055] “Bridged cyclylaminylene” means a saturated divalent bicyclic ring having 5 to 7 ring carbon ring atoms in which two non-adjacent ring atoms are linked by a (CRzRz’)n group where n is an integer selected from 1 to 3, and Rz and Rz’ are each independently H or methyl (also may be referred to herein as “bridging” group), and further wherein one of the ring carbon atoms is N and an additional ring carbon atom is replaced by a heteroatom selected from N, O, and S(O)n, where n is an integer selected from 0 to 2 inclusive. The N, O, and S(O)n can be present in the bridging group. Examples include, but are not limited to, 3,8- diazabicyclo[3.2.1]octa-3,8-diyl, and the like. [0056] “Cycloalkyl” means a cyclic saturated monovalent hydrocarbon radical of three to ten carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and the like. [0057] “Cycloalkylene” means a cyclic saturated divalent hydrocarbon radical of three to ten carbon atoms, e.g., 1,3-cyclobutylene, 1,3-cyclopentylene, or 1,3- or 1,4-cyclohexylene, and the like. [0058] “Cycloalkylalkyl” means an -(alkylene)-R radical where R is cycloalkyl as defined above, e.g., cyclopropylmethyl, cyclobutylethyl, and the like. [0059] “Cycloalkyloxy” means a -OR radical where R is cycloalkyl (including specific heterocyclyl rings) as defined above e.g., cyclopropyloxy, and the like. [0060] “Carboxy” means –COOH. [0061] “Cyclylaminylene” means a saturated divalent monocyclic ring of 4 to 8 ring atoms in which one ring atom is nitrogen, an additional ring atom can be nitrogen, O, or S(O)n (where n is 0, 1 or 2), and the remaining ring atoms are C. Representative examples of cyclylaminylene include, but is not limited to, 1,3- or 1,4-piperidindiyl, 1,4-piperazindiyl, 1,3-azetidindiyl, 1,3-morpholindiyl, and the like. [0062] “Carbonylaminoalkyl” means –(alkylene)-NRCOR’ radical where R is hydrogen or alkyl and R’ is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, optionally substituted phenyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl; each term as defined herein, e.g., methylcarbonylaminomethyl, ethylcarbonylaminoethyl, 2- (HOCH2C(O)amino)ethyl, and the like. [0063] “Carboxyaminoalkyl” means –(alkylene)-NRC(O)OR’ radical where R’ is hydrogen, alkyl, optionally substituted phenyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl; each term as defined herein, e.g., methoxycarbonylaminomethyl, ethyloxycarbonylaminoethyl, phenyoxycarbonylethyl, and the like. [0064] “Cyanoalkyl” means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with cyano, e.g., cyanomethyl, cyanoethyl, cyanopropyl, and the like. [0065] “Dialkylaminocarbonyl” means -CONRR’ where R and R’ are each independently alkyl as defined above, e.g., dimethylaminocarbonyl, methylethylaminocarbonyl, and the like. [0066] “Dialkylamino” means a -NRR’ radical where R and R’ are alkyl as defined above, e.g., dimethylamino, methylethylamino, and the like. [0067] “Diaminoalkyl” means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with two –NR’R” where R’and R” are each independently hydrogen or alkyl as defined above, e.g., diaminoethyl, 1,3-diaminopropyl, 2-amino-3-methylaminopropyl, and the like. [0068] “Diaminoalkylamino” means a –NRaRb radical where Ra is hydrogen or alkyl and Rb is diaminoalkyl as defined above, e.g., diaminoethylamino, 1,3-diaminopropylamino, 2- amino-3-methylaminopropylamino, and the like. [0069] “Diaminoalkyloxy” or “diaminoalkoxy” means a –ORa radical where Ra is diaminoalkyl as defined above, e.g., 2-diaminoethyloxy, 1,3-diaminopropyloxy, 2-amino-3- methylaminopropyloxy, and the like. [0070] “Fused cyclylaminylene” means a fused divalent bicyclic ring in which a first ring is a saturated ring having 4 to 8 ring atoms in which one ring atom is nitrogen, an additional ring atom can be nitrogen, O, or S(O)n (where n is 0, 1 or 2), and the remaining ring atoms are C. Two adjacent ring atoms of the first ring are fused to two adjacent ring atoms of a phenyl or a five or six membered heteroaryl, each as defined herein . Any two suitable ring atoms of the fused cyclcylaminylene can be points of attachment. Non limiting examples of the fused cyclylaminylene include indolin-2-one-1-yl, indolinyl, isoindolinyl, and the like. [0071] “Fused aryl” means a fused monovalent bicyclic ring in which two adjacent ring atoms of phenyl are fused to two adjacent ring atoms of a cycloalkyl or heterocyclyl, each as defined herein. Any two suitable ring atoms of the fused aryl can be points of attachment. Non limiting examples of the fused aryl include indanyl, 2,3-dihydrobenzofuranyl, 2- oxoindolinyl, indolinyl, isoindolinyl, and the like. [0072] “Fused arylalkyl” or “fused aralkyl” means a –(alkylene)-R where R is fused aryl as defined above e.g., indolymethyl, indanylmethyl, indolylethyl, indolylpropyl, and the like. [0073] “Fused heteroaryl” means a fused monovalent bicyclic ring in which two adjacent ring atoms of a five or six-membered heteroaryl as defined herein are fused to two adjacent ring atoms of a cycloalkyl or heterocyclyl, each as defined herein. Any two suitable ring atoms of the fused aryl can be points of attachment. Non limiting examples of the fused heteroaryl include 2,3-dihydro-1H-pyrrolo[2,3-c]pyridine, 6,7-dihydro-5H- cyclopenta[c]pyridine, and the like. [0074] “Fused heteroaralkyl” means a –(alkylene)-R where R is aryl as defined above e.g., 2,3-dihydro-1H-pyrrolo[2,3-c]pyridine, 6,7-dihydro-5H-cyclopenta[c]pyridine, and the like attached via methyl, ethyl, or propyl. [0075] “Halo” means fluoro, chloro, bromo, or iodo, preferably fluoro or chloro. [0076] “Haloalkyl” means alkyl radical as defined above, which is substituted with one or more halogen atoms, such as one to five halogen atoms, such as fluorine or chlorine, including those substituted with different halogens, e.g., -CH2Cl, -CF3, -CHF2, -CH2CF3, - CF2CF3, -CF(CH3)2, and the like. When the alkyl is substituted with only fluoro, it can be referred to in this Application as fluoroalkyl. [0077] “Haloalkoxy” means a –OR radical where R is haloalkyl as defined above e.g., - OCF3, -OCHF2, and the like. When R is haloalkyl where the alkyl is substituted with only fluoro, it is referred to in this Application as fluoroalkoxy. [0078] “Hydroxyalkyl” means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one or two hydroxy groups, provided that if two hydroxy groups are present they are not both on the same carbon atom. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxy-ethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1- (hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3- dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4- dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3- dihydroxypropyl, and 1-(hydroxymethyl)-2-hydroxyethyl. [0079] “Hydroxyalkylamino” means a –NRaRb radical where Ra is hydrogen or alkyl and Rb is hydroxyalkyl as defined above, e.g., hydroxyethylamino, hydroxypropylamino, and the like. [0080] “Hydroxyalkyloxy” means a –ORa radical where Ra is hydroxyalkyl as defined above, e.g., hydroxyethyloxy, hydroxypropyloxy, and the like. [0081] “Heterocyclyl” means a saturated or unsaturated monovalent monocyclic group of 4 to 8 ring atoms in which one or two ring atoms are heteroatom selected from N, O, or S(O)n, where n is an integer from 0 to 2, the remaining ring atoms being C. Additionally, one or two ring carbon atoms in the heterocyclyl ring can optionally be replaced by a –CO- group. More specifically the term heterocyclyl includes, but is not limited to, pyrrolidinyl, piperidinyl, homopiperidinoyl, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholinyl, piperazinyl, tetrahydro- pyranyl, thiomorpholinoyl, and the like. When the heterocyclyl ring is unsaturated it can contain one or two ring double bonds provided that the ring is not aromatic. When the heterocyclyl group contains at least one nitrogen atom, it is also referred to herein as heterocyclylaminyl andnd is a subset of the heterocyclyl group. [0082] “Heterocyclylalkyl” means a –(alkylene)-R radical where R is heterocyclyl ring (including specific heterocyclyl rings) as defined above e.g., tetraydrofuranylmethyl, piperazinylmethyl, morpholinylethyl, and the like. [0083] “Heterocyclylamino” means a -NRR’ radical where R is hydrogen or alkyl and R’ is heterocyclyl (including specific heterocyclyl rings) as defined above. [0084] “Heterocyclylalkylamino” means a -NRR’ radical where R is hydrogen or alkyl and R' is heterocyclylalkyl ring (including specific heterocyclyl rings) as defined above e.g., tetraydrofuranylmethylamino, piperazinylethylamino, morpholinylethylamino, piperidinylmethylamino, and the like. [0085] “Heterocyclyloxy” means a -OR radical where R is heterocyclyl (including specific heterocyclyl rings) as defined above. [0086] “Heterocyclylalkyloxy” means a -OR radical where R is heterocyclylalkyl ring (including specific heterocyclyl rings) as defined above e.g., tetraydrofuranylmethyloxy, piperazinylethyloxy, morpholinylethyloxy, piperidinylmethyloxy, and the like. [0087] “Heteroaryl” means a monovalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms, unless otherwise stated, where one or more, (in one embodiment, one, two, or three), ring atoms are heteroatom selected from N, O, or S, the remaining ring atoms being carbon. Representative examples include, but are not limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, and the like. As defined herein, the terms “heteroaryl” and “aryl” are mutually exclusive. When the heteroaryl ring contains 5- or 6 ring atoms it is also referred to herein as 5-or 6- membered heteroaryl. [0088] “Heteroaralkyl” means a –alkylene-R radical where R is heteroaryl as defined above, e.g., pyridylmethyl, pyridylethyl, thiazolylpropyl, and the like. [0089] “Heteroaryloxy” means a -OR radical where R is heteroaryl (including specific heteroaryl rings) as defined above. [0090] “Heteroaryloxyalkyl” means a –alkylene-OR radical where R is heteroaryl as defined above, e.g., pyridyloxymethyl, pyridyloxyethyl, thiazolyloxypropyl, and the like. [0091] “Heteroarylene” means a divalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms, unless otherwise stated, where one or more, (in one embodiment, one, two, or three), ring atoms are heteroatom selected from N, O, or S, the remaining ring atoms being carbon. Representative examples include, but are not limited to, pyrroldiyl, thiazoldiyl, imidazoldiyl, furandiyl, indoldiyl, isoindoldiyl, oxazoldiyl, isoxazoldiyl, benzothiazoldiyl, benzoxazoldiyl, quinolindiyl, isoquinolindiyl, pyridindiyl, pyrimidindiyl, triazoldiyl, tetrazoldiyl, and the like. [0092] “Optionally substituted aryl” means aryl as defined above, that is substituted with one, two, or three substituents each independently selected from alkyl, hydroxy, alkoxy, halo, cyano, haloalkyl, haloalkoxyl, amino, alkylamino, dialkylamino, carboxy, or alkoxycarbonyl, each as defined herein. [0093] “Optionally substituted heteroaryl” means heteroaryl as defined above, that is substituted with one, two, or three substituents each independently selected from alkyl, hydroxy, alkoxy, halo, cyano, haloalkyl, haloalkoxyl, amino, alkylamino, dialkylamino, carboxy, or alkoxycarbonyl,, each as defined herein. [0094] “Optionally substituted heterocyclyl” means heterocyclyl as defined above, that is substituted with one, two, or three substituents each independently selected from alkyl, hydroxy, alkoxy, cyano, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, -COR (where R is alkyl), alkoxycarbonyl, each as defined herein. [0095] “Spiro cyclylaminylene" means a saturated bicyclic divalent ring having 6 to 10 ring atoms in which one ring atom is N and an additional ring atom can be a heteroatom selected from N, O, and S(O)n, where n is an integer selected from 0 to 2, the remaining ring atoms being C and the rings are connected through only one atom, the connecting atom is also called the spiroatom, most often a quaternary carbon (“spiro carbon”). Spiro cyclylaminylene is optionally substituted with one or two substituents each independently selected from alkyl, halo, alkoxy, hydroxy, and cyano, unless stated otherwise. Representative examples include, the [0096] The present disclosure also includes protected derivatives of compounds of Formula (I). For example, when compounds of Formula (I) contain groups such as hydroxy, carboxy, thiol or any group containing a nitrogen atom(s), these groups can be protected with a suitable protecting groups. A comprehensive list of suitable protective groups can be found in T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. (1999) , the disclosure of which is incorporated herein by reference in its entirety. The protected derivatives of compounds of the present disclosure can be prepared by methods well known in the art. [0097] The present disclosure also includes polymorphic forms and deuterated forms of the compound of Formula (I) or a pharmaceutically acceptable salt thereof. [0098] A “pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include: acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as formic acid, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4- hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4- toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4’-methylenebis-(3- hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference in its entirety. [0099] The compounds of Formula (I) may have asymmetric centers. Compounds of Formula (I) containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of materials. All chiral, diastereomeric, all mixtures of chiral or diasteromeric forms, and racemic forms are within the scope of this disclosure, unless the specific stereochemistry or isomeric form is specifically indicated. It will also be understood by a person of ordinary skill in the art that when a compound is denoted as (R) stereoisomer, it may contain the corresponding (S) stereoisomer as an impurity i.e., the (S) stereoisomer in less than about 5%, preferably 2% by wt and then it is denoted as a mixture of R and S isomers, the amounts of R or S isomer in the mixture is greater than about 5%, preferably 2% w/w. [0100] Certain compounds of Formula (I) can exist as tautomers and/or geometric isomers. All possible tautomers and cis and trans isomers, as individual forms and mixtures thereof are within the scope of this disclosure. For example, hydroxy substituted compound of Formula (I) can exist as a tautomer as shown below: [0101] Additionally, possible isomeric forms of said alkyl group. Furthermore, when the cyclic groups such as aryl, heteroaryl, heterocyclyl are substituted, they include all the positional isomers. Furthermore, all hydrates of a compound of the present disclosure are within the scope of this disclosure. [0102] Certain structures provided herein are drawn with one or more floating substituents. Unless provided otherwise or otherwise clear from the context, the substituent(s) may be present on any atom of the ring through which the substituent is drawn, where chemically feasible and valency rules permitting. For example, in the , the R4 floating substituent can replace any hydrogen on the six membered aromatic ring portion of the bicyclic ring system that is not substituted with R5 or R6 i.e., when any of a b, d, and e is CH and is not substituted with R5 or R6. [0103] The compounds of Formula (I) may also contain unnatural amounts of isotopes at one or more of the atoms that constitute such compounds. Unnatural amounts of an isotope may be defined as ranging from the amount found in nature to an amount 100% of the atom in question. that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into compounds of the present invention, such as a compound of Formula (I) (and any embodiemtn thereof disclosed herein including specific compounds) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 32P, 33P, 35S, 18F, 36Cl, 123I, and 1251, respectively. Isotopically-labeled compounds (e.g., those labeled with .sup.3H and .sup.14C) can be useful in compound or substrate tissue distribution assays. Tritiated (i.e., .sup.3H) and carbon-14 (i.e., .sup.14C) isotopes can be useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In some embodiments, in compounds disclosed herein, including in Table 1A and 1B below one or more hydrogen atoms are replaced by 2H or 3H, or one or more carbon atoms are replaced by 13C- or 14C- enriched carbon. Positron emitting isotopes such as 15O, 13N, 11C, and 15F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the Schemes or in the Examples herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. [0104] “Oxo” or “carbonyl” means =(O) group. [0105] “Optional” or “optionally” means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “heterocyclyl group optionally substituted with an alkyl group” means that the alkyl may but need not be present, and the description includes situations where the heterocyclyl group is substituted with an alkyl group and situations where the heterocyclyl group is not substituted with alkyl. [0106] A “pharmaceutically acceptable carrier or excipient” means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use. “A pharmaceutically acceptable carrier/excipient” as used in the specification and claims includes both one and more than one such excipient. [0107] The term “about,” as used herein, is intended to qualify the numerical values which it modifies, denoting such a value as variable within a margin of error. When no particular margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the term “about” should be understood to mean that range which would encompass ± 10%, preferably ± 5%, the recited value and the range is included. [0108] The term “disease” as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder,” “syndrome,” and “condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life. [0109] The term “patient” is generally synonymous with the term “subject” and includes all mammals including humans. Examples of patients include humans, livestock such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, and horses. Preferably, the patient is a human. [0110] The terms "inhibiting" and "reducing," or any variation of these terms in relation of EPPI, includes any measurable decrease or complete inhibition to achieve a desired result. For example, there may be a decrease of about, at most about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range derivable therein, reduction of EPPI activity compared to normal. [0111] “Treating” or “treatment” of a disease includes: (1) preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease; (2) inhibiting the disease, i.e., arresting (i.e., stabilizing) or reducing the development of the disease or its clinical symptoms; or (3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms. [0112] A “therapeutically effective amount” means the amount of a compound of the present disclosure and/or a pharmaceutically acceptable salt thereof that, when administered to a patient for treating a disease, is sufficient to effect such treatment for the disease. The “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated. [0113] Representative compounds of Formula (I) are disclosed in Table 1A below: Cpd Structure Name No. Cpd Structure Name No. 5 2 67Di th i li 4 l 2 - Cpd Structure Name No. 11 4 8M th 17 hth idi 4 l th l)- )- - Cpd Structure Name No. 16 2 67Di th i li 4 l 2 - )- Cpd Structure Name No. 21 3 6Fl 7 th i li 4 4- Cpd Structure Name No. 2 21 Mth 17 hth ii 4 l i ii 4- Cpd Structure Name No. 31 2 7M th i li 4 l 2 - Cpd Structure Name No. 36 3Fl 5 7 th i li 4 - - Cpd Structure Name No. 41 3Fl 5 7 th i li 4 Cpd Structure Name No. 46 2 1 67Di th i li 4 l i idi 4 Cpd Structure Name No. 51 1C l l1 3 8 th 17 hth idin- [0114] Additional representative compounds of Formula (I) are disclosed in Table 1B below: Cpd Structure Name No. Cpd Structure Name No. 55 C l l3fl 5 7 fl th 6 6- - Cpd Structure Name No. 60 C l l3fl 5 8 th 17 Embodiments: Embodiment A [0115] In embodiment A, the compounds of Formula (I) or a pharmaceutically acceptable salt thereof as defined in the Summary above. Embodiment B [0116] In embodiment B, the compounds of Formula (I) of embodiment A or a pharmaceutically acceptable salt thereof Z is bond. Embodiment C [0117] In embodiment C, the compounds of Formula (I) of embodiment A or a pharmaceutically acceptable salt thereof Z is NH, O, S, or SO2. Embodiment D [0118] In embodiment D, the compounds of Formula (I) of any one of embodiments A, B, and C or a pharmaceutically acceptable salt thereof has a structure of formula (Ia), (Ib), (Ic), (Id), (If), (Ig), or (Ih): or SO2 in the compounds of formulae (Ie) to (Ih). For sake of clarity, in embodiment D, compound of Formulae (Ia), (Ib), (Ic), and (Id) will be selected with reference to embodiment B and (If), (Ig), and (Ih) will be selected with reference to C. [0119] (Di). In subembodiment (Di), the compound of Formula (I) of embodiment A, B, or D, or a pharmaceutically acceptable salt thereof has structure (Ia). [0120] (Dii). In subembodiment (Dii), the compound of Formula (I) of embodiment A, B, or D, or a pharmaceutically acceptable salt thereof has structure (Ib). [0121] (Diii) . In subembodiment (Diii), the compound of Formula (I) of embodiment A, B, or D, or a pharmaceutically acceptable salt thereof has structure (Ic). [0122] (Div). In subembodiment (Div), the compound of Formula (I) of embodiment A, B, or D, or a pharmaceutically acceptable salt thereof has structure (Id). [0123] (Dv). In subembodiment (Dv), the compound of Formula (I) of embodiment A, C, or D, or a pharmaceutically acceptable salt thereof has structure (Ie). [0124] (Dvi). In subembodiment (Dvi), the compound of Formula (I) of embodiment A, C, or D, or a pharmaceutically acceptable salt thereof has structure (If). [0125] (Dvii). In subembodiment (Dvii), the compound of Formula (I) of embodiment A, C, or D, or a pharmaceutically acceptable salt thereof has structure (Ig). [0126] (Dviii). In subembodiment (Dviii), the compound of Formula (I) of embodiment A, C, or D, or a pharmaceutically acceptable salt thereof has structure (Ih). Embodiment E [0127] In embodiment E, the compound of any one of embodiments A, C, and D, and subembodiments (Dv) to (Dviii), or a pharmaceutically acceptable salt thereof is wherein Z is NH. Embodiment F [0128] In embodiment F, the compound of any one of embodiments A, C, and D, and subemodiments (Dv) to (Dviii), or a pharmaceutically acceptable salt thereof is wherein Z is O. [0129] (Fi). In embodiment Fi, the compound of any one of embodiments A, C, and D, and subemodiments (Dv) to (Dviii), or a pharmaceutically acceptable salt thereof is wherein Z is bond or O. Embodiment G [0130] In embodiment G, the compound of any one of embodiments A, C, and D, and subembodiments (Dv) to (Dviii), or a pharmaceutically acceptable salt thereof is wherein Z is SO2. Embodiment H [0131] In embodiment H, the compound of any one of embodiments A to D and E to G and subembodiments (Di) to (Dviii), or a pharmaceutically acceptable salt thereof is wherein X is N. Embodiment I [0132] In embodiment I, the compound of any one of embodiments A to D and E to G and subembodiments (Di) to (Dviii), or a pharmaceutically acceptable salt thereof is wherein X is CH or C when attached to R1. [0133] (Ii). In embodiment Ii, the compound of any one of embodiments A to E to G, and subembodiments (Di) to (Dviii), or a pharmaceutically acceptable salt thereof is wherein X is N or CH. Embodiment J [0134] In embodiment J, the compound of any one of embodiments A to D and E to Ii and subembodiments (Di) to (Dviii), or a pharmaceutically acceptable salt thereof is wherein R1 is attached to carbon that is in between N and X. Embodiment K [0135] In embodiment K, the compound of any one of embodiments A to D and E to J and subembodiments (Di) to (Dviii), or a pharmaceutically acceptable salt thereof, are wherein a, b, d, and e are each independently CH or C when attached to any one of R4, R5, and R6. Embodiment L [0136] In embodiment L, the compound of any one of embodiments A to D and E to J and subembodiments (Di) to (Dviii), or a pharmaceutically acceptable salt thereof, are wherein a is N and b, d, and e are each independently CH or C when attached to any one of R4, R5, and R6. Embodiment M [0137] In embodiment M, the compound of any one of embodiments A to D and E to J and subembodiments (Di) to (Dviii), or a pharmaceutically acceptable salt thereof, are wherein a and d are N and b, and e are each indepdnently CH or C when attached to any one of R4, R5, and R6. Embodiment N [0138] In embodiment N, the compound of any one of embodiments A to D and E to J and subembodiments (Di) to (Dviii), or a pharmaceutically acceptable salt thereof, are wherein b is N and a, c, and e are each independently CH or C when attached to any one of R4, R5, and R6. Embodiment O [0139] In embodiment O, the compounds of any one of embodiments A to D and E to J and subembodiments (Di) to (Dviii), or a pharmaceutically acceptable salt thereof, are wherein b and e are N and a and d are each independently CH or C when attached to any one of R4, R5, and R6. Embodiment P [0140] In embodiment P, the compound of any one of embodiments A to D and E to J and subembodiments (Di) to (Dviii), or a pharmaceutically acceptable salt thereof, are wherein d is N and a, b, and e are each independently CH or C when attached to any one of R4, R5, and R6. Embodiment Q [0141] In embodiment Q, the compound of any one of embodiments A to D and E to J and subembodiments (Di) to (Dviii), or a pharmaceutically acceptable salt thereof, are wherein e is N and a, b and d are each independently CH or C when attached to any one of R4, R5, and R6. [0142] (Qi). In embodiment Qi, the compound of any one of embodiments A to D and E to J and subembodiments (Di) to (Dviii), or a pharmaceutically acceptable salt thereof, is wherein a is CH; b is CH or C when attached to any one of R4, R5, or R6; d is N or C when attached to any one of R4, R5, or R6; and e is N, CH or C when attached to any one of R4, R5, or R6. Embodiment R [0143] In embodiment R, the compound of any one of embodiments A to C and E to Q, or a pharmaceutically acceptable salt thereof, are wherein n and m are 0. Embodiment S [0144] In embodiment S, the compound of any one of embodiments A to C and E to Qi, or a pharmaceutically acceptable salt thereof, are wherein n is 1 and m is 0. Embodiment T [0145] In embodiment T, the compound of any one of embodiments A to C and E to Qi, or a pharmaceutically acceptable salt thereof, are wherein n is 0 and m is 1. Embodiment U [0146] In embodiment U, the compound of any one of embodiments A to C and E to Qi, or a pharmaceutically acceptable salt thereof, are wherein each n and m is 1. Embodiment V [0147] (V). In embodiment (V), the compound of any one of embodiments A to D, E to Qi, and S to U, and subembodiments D(i) to D(viii), or a pharmaceutically acceptable salt thereof, are wherein alk1 and/or alk, when present, are each independently selected from methylene, ethylene, or propylene, preferably alk1 and/or alk, when present, are each independently selected from methylene or ethylene. [0148] (Vi). In subembodiment (Vi), the compound of any one of embodiments A to D, E to Qi and S to V, and subembodiments D(i) to D(viii), or a pharmaceutically acceptable salt thereof, are wherein alk1 and/or alk, when present, are methylene. [0149] (Vii). In embodiment Vii, the compound of any one of embodiments A to D, E to Qi and S to U, and subembodiments D(i) to D(viii), or a pharmaceutically acceptable salt thereof, is wherein alk1 and/or alk, when present, are alkylene. [0150] (Viii). In embodiment Viii, the compound of any one of embodiments A to D, E to Qi, S to V and Vii, and subembodiments D(i) to D(viii), or a pharmaceutically acceptable salt thereof, is wherein alk, when present, is methylene. [0151] (Viv). In embodiment Viv, the compound of any one of embodiments A to D, E to Qi, S to V and Vii, and subembodiments D(i) to D(viii), or a pharmaceutically acceptable salt thereof, is wherein alk1, when present, is methylene or ethylene. Embodiment W [0152] In embodiment W, the compounds of any one of embodiments A to D and E to V and Vii to Viv, and subembodiments D(i) to D(viii) and Vi , or a pharmaceutically acceptable salt thereof, are wherein Ar is phenylene or 5- or 6-membered heteroarylene, each ring substituted with R2 and R3. [0153] (Wi). In subembodiment Wi, the compound of any one of embodiments A to D, E to V, Vii to Viv, and W, and subembodiments D(i) to D(viii) and Vi, or a pharmaceutically acceptable salt thereof is wherein Ar is phenylene substituted with R2 and R3. In one subembodiment of subembodiment Wi, the compound of any one of embodiments A to W (including subembodiments therein), or a pharmaceutically acceptable salt thereof is wherein –(alk1)m-S(=NR8)(=NR9)R7 is attached to carbon of the phenylene ring that is meta to the carbon attaching the phenylene ring to the remainder of the compound of Formulae (I) and (Ia) to (Ih). In another subembodiment of subembodiment Wi, the compound of any one of embodiments A to W (including subembodiments therein), or a pharmaceutically acceptable salt thereof is wherein –(alk1)m-S(=NR8)(=NR9)R7 is attached to carbon of the phenylene ring that is para to the carbon attaching the phenylene ring to the remainder of the compound of Formula (I) and (Ia) to (Ih), respectively. [0154] (Wii). In subembodiment Wii, the compound of any one of embodiments A to D, E to to V, Vii to Viv, and W, and subembodiments D(i) to D(viii) and Vi, or a pharmaceutically acceptable salt thereof is wherein Ar is a 5- or 6-membered heteroarylene e.g., divalent pyridine, pyrimidine, pyridazine, thiene, furan, thiazole, oxazole, isoxazole, pyrazole, triazole, oxadiazole, or imidazole, each ring substituted with with R2 and R3. In one subembodiment of embodiment Wii, Ar is a six-membered heteroarylene such as divalent pyridine, pyrimidine, or pyridazine wherein –(alk1)m-S(=NR8)(=NR9)R7 is attached to carbon on the pyridine, pyrimidine, or pyridazine ring that is meta to the carbon attaching the pyridine, pyrimidine, or pyridazine ring to remaining compound of Formula (I) and (Ia) to (Ih), respectively. [0155] (Wiii). With subembodiment Wiii, the compound of any one of embodiments A to D, E to V, and Vii to Viv , and subembodiments D(i) to D(viii) and Vi, or a pharmaceutically acceptable salt thereof is wherein Ar is bicyclic heteroarylene e,.g., divalent benzofuran, quinoline, quinazoline, benzimidazole, indazole, benzotriazole, or benzoxazole. Embodiment X [0156] In embodiment X, the compound of any one of embodiments A to D, E to V, and Vii to Viv Viv, and subembodiments D(i) to D(viii) and Vi, or a pharmaceutically acceptable salt thereof, are wherein Ar is cyclylaminylene, spiro cyclylaminylene, or bridged cyclylaminylene, each ring substituted with R2 and R3. [0157] (Xi). In subembodiment Xi, the compound of any one of embodiments A to D, E to V, V(ii) toViv, and X, and subembodiments D(i) to D(viii) and Vi, or a pharmaceutically acceptable salt thereof is wherein Ar is cyclylaminylene selected from divalent pyrrolidine, piperidine, or homopiperidine, each ring substituted with with R2 and R3. [0158] (Xii). In subembodiment Xii, the compound of any one of embodiments A to D, E to V. V(ii) to Viv and X, and subembodiments D(i) to D(viii) and Vi, or a pharmaceutically acceptable salt thereof is wherein Ar is spiro cyclylaminylene or bridged cyclylaminyl, each ring substituted with R2 and R3. [0159] (Xiii). In subembodiment Xiii, the compound of any one of embodiments A to D, E to V, Vii to Viv and X and subembodiments D(i) to D(viii), Vi, Xi, and Xii, or a pharmaceutically acceptable salt thereof is wherein the cyclylaminylene, spiro cyclylaminylene and bridged cyclylaminyl are selected from: 1 m 8 9 7 –(alk ) -S(=NR )(=NR )R and is of attachment to remainder of the compound of Formula (I) to (Ih). [0160] (Xiv). In embodiment Xiv, the compound of any one of embodiments A to D, E to V, and Vii to Viv, and subembodiments D(i) to D(viii) and Vi, or a pharmaceutically acceptable salt thereof, are wherein Ar is arylene, cyclylaminylene, or spiro cyclylaminylene, and each ring substituted with R2 and R3. [0161] (Xv). In embodiment Xv, the compound of any one of embodiments A to D, E to V, Vii to Viv, and Xiv, and subembodiments D(i) to D(viii) and Vi, or a pharmaceutically acceptable salt thereof, are wherein Ar is phenylene, piperidinylene, or 2- azaspiro[3.3]heptanylene, and each ring substituted with R2 and R3. It is understood that phenylene, piperidinylene, and 2-azaspiro[3.3]heptanylene, refers to divalent phenyl, piperidinyl, and 2-azaspiro[3.3]heptanyl radicals, respectively. [0162] (Xvi). In embodiment Xvi, the compound of any one of embodiments A to D, E to V, Vii to Viv, Xiv and Xv, and subembodiments D(i) to D(viii) and Vi, or a pharmaceutically acceptable salt thereof, are wherein Ar is , each ring is substituted with R2 and R3, and to –(alk1)m-S(=NR8)(=NR9)R7 and is the point of attachment to the remainder of the compound of Formula (I) to Embodiment Y [0163] In embodiment Y, the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, and Xvi to Xvi and subembodiments D(i) to D(viii), Wi to Wiii, Vi, and Xi to Xiii, and subembodiments contained therein or a pharmaceutically acceptable thereof is wherein R1 is absent, alkyl, alkoxy, halo, haloalkyl, or haloalkoxy. [0164] (Yi). In subembodiment Yi, the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi and Y, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, and Xi to Xiii, or a pharmaceutically acceptable thereof is wherein R1 is absent, alkyl, or halo, preferably R1 is absent, methyl, ethyl, isopropyl, or fluoro. [0165] (Yii). In subembodiment Yii, the compound of any one of embodiments A to D,E to V, Vii to Viv, W, X, Xvi to Xvi and Y and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Wi to Wiii, Xi to Xiii and Yi, or a pharmaceutically acceptable thereof are wherein R1 is absent, methyl, ethyl or isopropyl. [0166] (Yiii). In subembodiment Yii, the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi and Y and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii, Yi, and Yii, or a pharmaceutically acceptable thereof is wherein R1 is absent. [0167] (Yiv). In subembodiment Yiv, the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi and Y, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, and Xi to Xiii, or a pharmaceutically acceptable thereof is wherein R1 is halo, haloalkyl, or haloalkoxy. [0168] (Yv). In subembodiment Yv, the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, and Xvi to Xvi, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, and Xi to Xiii, or a pharmaceutically acceptable thereof is wherein R1 is amino, alkylamino, or dialkylamino, preferably amino, methylamino or dimethylamino. [0169] (Yvi). In subembodiment Yvi, the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, and Xvi to Xvi, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, and Xi to Xiii, or a pharmaceutically acceptable thereof is R1 is hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkylamino, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, diaminoalkyl, diaminoalkoxy, diaminoalkylamino, or cyano, preferably hydroxymethyl, methoxymethyl, or ethoxymethyl. Embodiment Z [0170] In embodiment Z, the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi and Y, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii and Yi to Yvi, or a pharmaceutically acceptable thereof, are wherein R2 and R3 are each independently absent, methyl, ethyl, methoxy, fluoro, trifluoromethyl, trifluoromethoxy, or cyano. [0171] (Zi). In subembodiment Zi, the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, and Z, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii and Yi to Yvi, or a pharmaceutically acceptable thereof are wherein wherein R2 and R3 are absent. [0172] (Zii). In embodiment Zii, the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, and Z, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii and Yi to Yvi, or a pharmaceutically acceptable thereof, are wherein R2 and R3 are each independently absent or fluoro. Embodiment A1 [0173] In embodiment A1, the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z and Zii, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii, Yi to Yvi, and Zi, or a pharmaceutically acceptable thereof, is wherein R4 is absent, alkyl, alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cyano, carboxy, alkoxycarbonyl, hydroxy, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl. [0174] (A1i). In subembodiment A1i, the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, Zii, and A1, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii, Yi to Yvi, and Zi, or a pharmaceutically acceptable thereof, is wherein R4 is absent, methyl, methoxy, ethoxy, fluoro, chloro, trifluoromethyl, hydroxy, cyano, or trifluoromethyloxy. [0175] (A1ii). In subembodiment A1ii, the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, Zii, and A1, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii, Yi to Yvi, Zi and A1i, or a pharmaceutically acceptable thereof, is wherein R4 is absent, methoxy or ethoxy. [0176] (A1iii). In subembodiment A1iii, the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, Zii, and A1, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii, Yi to Yvi, and Zi, or a pharmaceutically acceptable thereof, is wherein R4 is cyano, carboxy, alkoxycarbonyl, alkylsulfonyl, hydroxy, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl. [0177] (A1iv). In subembodiment A1iv, the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, Zii, and A1, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii, Yi to Yvi, Zi, A1i and A1iii, or a pharmaceutically acceptable thereof, is wherein R4 is cyano, carboxy, methoxycarbonyl, methylsulfonyl, aminocarbonyl, hydroxy, methylaminocarbonyl, dimethylaminocarbonyl, or. [0178] (A1v). In subembodiment A1v, the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, Zii, and o A1, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii, Yi to Yvi, Zi, A1iii, and A1iv, or a pharmaceutically acceptable thereof, is wherein R4 is cyano, hydroxy, aminocarbonyl, methylsulfonyl, methylaminocarbonyl, or dimethylaminocarbonyl. [0179] (A1vi). In subembodiment A1vi, the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, Zii, and A1, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii, Yi to Yvi, Zi, and A1iii to A1v, or a pharmaceutically acceptable thereof, is wherein R4 is aminocarbonyl, methylaminocarbonyl, or dimethylaminocarbonyl. [0180] (A1vii). In subembodiment A1vii, the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, Zii, and A1, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii, Yi to Yvi, Zi, and A1i to A1vi, or a pharmaceutically acceptable thereof, is wherein R4 is attached to the six membered ring comprising a, b, d, and e of Formula (I) to (Ih) in any one of carbons shown in formula (a) to (c) below: wherein the [0181] (A1viii). In embodiment A1viii, the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, Zii, and A1 and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii, Yi to Yvi, Zi, or a pharmaceutically acceptable thereof, is wherein R4 is alkoxy or haloalkoxy. [0182] (A1ix). In embodiment A1ix, the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, Zii, A1, and A1viii, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii, Yi to Yvi, and Zi, or a pharmaceutically acceptable thereof, is wherein R4 is methoxy or fluoromethoxy. Embodiment B1 [0183] In embodiment B1, the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, Zii, A1, A1viii andto A1ix, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii, Yi to Yvi, Zi, and A1i to A1vii, or a pharmaceutically acceptable thereof, is wherein wherein R5 and R6 are absent. [0184] (B1i). In subembodiment B1i, the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, Zii, A1, A1viii and A1ix, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii, Yi to Yvi, Zi, and A1i to A1vi, or a pharmaceutically acceptable thereof, is wherein R5 and R6 are each independently absent, alkyl, alkoxy, hydroxy, amino, halo, haloalkyl, or haloalkoxy. [0185] (B1ii). In subembodiment B1ii, the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, Zii, A1, A1viii and A1ix, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii, Yi to Yvi, Zi, A1i to A1vi and B1i, or a pharmaceutically acceptable thereof, is wherein R5 and R6 are each independently absent, methyl, methoxy, ethoxy, propoxy, hydroxy, fluoro, difluoromethyl, trifluoromethyl, difluoromethoxy, or trifluoromethoxy. [0186] (B1iii). In subembodiment B1iii, the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, Zii, A1, A1viii and A1ix, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii, Yi to Yvi, Zi, A1i to A1vi, B1i, and B1ii, or a pharmaceutically acceptable thereof, is wherein R5 and R6 are each independently absent, methyl, methoxy, ethoxy, hydroxy, fluoro, difluoromethoxy, or trifluoromethoxy. [0187] (B1iv). In subembodiment B1iv, the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, Zii, A1, A1viii and A1ix, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii, Yi to Yvi, Zi, A1i to A1vi, and B1i to B1iii, or a pharmaceutically acceptable thereof, is wherein R5 and R6 are each independently absent, methoxy, ethoxy, propoxy, or fluoro. [0188] (B1v). In subembodiment B1v, the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, Zii, A1, A1viii and A1ix, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii, Yi to Yvi, Zi, A1i to A1vi and B1i to B1iv, or a pharmaceutically acceptable thereof, is wherein R5 and R6 are are attached to to the six membered ring comprising a, b, d, and e of Formula I to (Ih) as shown below below wherein the wavy line denotes the the remainder of the molecule. In one embodiment R4 is absent. [0189] (B1vi). In embodiment B1vi, the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, Zii, and A1, , and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii, Yi to Yvi, Zi, A1i, A1ii, B1i, and B1v, or a pharmaceutically acceptable thereof, is wherein wherein R5 and R6 are each independently absent, alkoxy, halo, or haloalkoxy. [0190] (B1vii). In embodiment B1vii, the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, Zii, A1, and B1vi, and subembodiments D(i) to D(viii), Xi to Xiii, Vi, Wi to Wiii, Yi to Yvi, Zi, A1i, A1ii, B1i and B1v, or a pharmaceutically acceptable thereof, is wherein wherein R5 and R6 are each independently absent, methoxy, fluoro, or fluoromethoxy. [0191] (B1viii). In embodiment B1viii, the compound of embodiment B1vii, or a pharmaceutically acceptable thereof, is wherein wherein R4 is absent. Embodiment C1 [0192] In embodiment C1, the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, andZii, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii, Yi to Yvi, and Zi, or a pharmaceutically acceptable thereof, is wherein: R4 is absent; R5 is absent, alkyl, alkoxy, hydroxy, halo, haloalkyl, or haloalkoxy; and R6 is hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkylamino, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino (wherein heterocyclyl either alone or part of heterocyclyloxy and heterocyclylamino is optionally substituted with one, two, or three substituents each independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), heterocyclylalkyl, heterocyclylalkyloxy, heterocyclylalkylamino (wherein the heterocyclyl ring in heterocyclylalkyl, heterocyclylalkyloxy, and heterocyclylalkylamino is substituted with 0 to 3 substituents each independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), cycloalkyloxy, phenyloxy, or heteroaryloxy (where phenyl in phenyloxy and heteroaryl in heteroaryloxy are substituted with 0 to 3 substituents each independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, and cyano). [0193] (C1i). In subembodiment C1i, the compound of embodiment C1, or a pharmaceutically acceptable thereof, is wherein R5 is absent, methoxy, ethoxy, or hydroxy, preferably R5 is methoxy or ethoxy; and R6 is 2-hydroxyethyloxy, 3-hydroxypropyloxy, 2- methoxyethyloxy, 2-ethoxyethyloxy, 3-methoxypropyloxy, 3-ethoxypropyloxy, 2- aminoethyloxy, 2-methylaminoethyloxy, 2-dimethylaminoethyloxy, 2-diethylaminoethyloxy, 3-aminopropyloxy, 3-methylaminopropyloxy, 3-dimethylaminopropyloxy, 3- diethylaminopropyloxy, pyrrolidinyloxy, piperidinyloxy, pyrrolidinylmethyloxy, piperidinylmethyloxy, pyrrolidinylethyloxy, piperidinylethyloxy, 2-hydroxyethylamino, 3- hydroxypropylamino, 2-methoxyethylamino, 2-ethoxyethylamino, 3-methoxypropylamino, 3- ethoxypropylamino, 2-aminoethylamino, 2-methylaminoethylamino, 2- dimethylaminoethylamino, 2-diethylaminoethylamino, 3-aminopropylamino, 3- methylaminopropylamino, 3-dimethylaminopropylamino, 3-diethylaminopropylamino, pyrrolidinylamino, piperidinylamino, pyrrolidinylmethylamino, piperidinylmethylamino, pyrrolidinylethylamino, or piperidinylethylamino (wherein pyrrolidinyl and piperidinyl in each of aforementioned groups, alone or part of another group is substituted with 0 to 2 substituents each independently selected from methyl, fluoro, hydroxy, or methoxy). [0194] (C1ii). In embodiment C1ii, the compound of any one of embodiments C1 and C1i, or a pharmaceutically acceptable thereof, is wherein R5 and R6 are are attached to to the six membered ring comprising a, b, d, and e of Formula I to (Ih) as shown below below: wherein the wavy line of the molecule. Embodiment D1 [0195] In embodiment D1, the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, andZii, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii, Yi to Yvi, and Zi, or a pharmaceutically acceptable thereof, is wherein R4 is absent R5 and R6 are each independently hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkylamino, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino (wherein heterocyclyl either alone or part of heterocyclyloxy and heterocyclylamino is substituted with 0 to 3 substituents each independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), heterocyclylalkyl, heterocyclylalkyloxy, heterocyclylalkylamino (wherein the heterocyclyl ring in heterocyclylalkyl, heterocyclylalkyloxy, and heterocyclylalkylamino is optionally substituted with one, two, or three substituents each independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), cycloalkyloxy, phenyloxy, or heteroaryloxy (where phenyl of phenyloxy and heteroaryl of heteroaryloxy are substituted with 0 to 3 substituents each independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, and cyano). [0196] (D1i). In embodiment D1i, the compound of embodiments D1, or a pharmaceutically acceptable thereof, is wherein R5 and R6 are each independently 2- hydroxyethyloxy, 3-hydroxypropyloxy, 2-methoxyethyloxy, 2-ethoxyethyloxy, 3- methoxypropyloxy, 3-ethoxypropyloxy, 2-aminoethyloxy, 2-methylaminoethyloxy, 2- dimethylaminoethyloxy, 2-diethylaminoethyloxy, 3-aminopropyloxy, 3- methylaminopropyloxy, 3-dimethylaminopropyloxy, 3-diethylaminopropyloxy, pyrrolidinyloxy, piperidinyloxy, pyrrolidinylmethyloxy, piperidinylmethyloxy, pyrrolidinylethyloxy, piperidinylethyloxy, 2-hydroxyethylamino, 3-hydroxypropylamino, 2- methoxyethylamino, 2-ethoxyethylamino, 3-methoxypropylamino, 3-ethoxypropylamino, 2- aminoethylamino, 2-methylaminoethylamino, 2-dimethylaminoethylamino, 2- diethylaminoethylamino, 3-aminopropylamino, 3-methylaminopropylamino, 3- dimethylaminopropylamino, 3-diethylaminopropylamino, pyrrolidinylamino, piperidinylamino, pyrrolidinylmethylamino, piperidinylmethylamino, pyrrolidinylethylamino, or piperidinylethylamino (wherein pyrrolidinyl and piperidinyl in each of aforementioned groups, alone or part of another group is substituted with 0 to 2 substituents each independently selected from methyl, fluoro, hydroxy, or methoxy). [0197] (D1ii). In embodiment D1ii, the compound of any one of embodiments D1 and D1i, or a pharmaceutically acceptable thereof, is wherein R5 and R6 are are attached to to the six membered ring comprising a, b, d, and e of Formula I to (Ih) as shown below below: wherein the wavy line denotes the the remainder of the molecule. Embodiment E1 [0198] In embodiment E1, the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, Zii, A1, A1viii, A1ix, B1, B1vi, B1vii, C1, and D1 to D1ii, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii, Yi to Yvi, Zi, A1i to A1vii, B1i to B1v, C1i, and C1ii, or a pharmaceutically acceptable salt thereof, R7 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, carbonylaminoalkyl, carboxyaminoalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, aryl, fused aryl, heteroaryl, fused heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, aryloxyalkyl, heteroaryloxyalkyl, fused aralkyl, fused heteroaryalkyl, or heterocyclylalkyl wherein cycloalkyl, aryl, fused aryl, heteroaryl, fused heteroaryl, heterocyclyl and the ring portion of cycloalkylalkyl, arylalkyl, heteroaralkyl, aryloxyalkyl, heteroaryloxyalkyl, fused aralkyl, fused heteroaryalkyl, or heterocyclylalkyl are substituted with one, two or three substituents each independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, cyano, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl and R8, and R9 are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, carbonylaminoalkyl, carboxyaminoalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, aryl, fused aryl, heteroaryl, fused heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, aryloxyalkyl, heteroaryloxyalkyl, fused aralkyl, fused heteroaryalkyl, or heterocyclylalkyl wherein cycloalkyl, aryl, fused aryl, heteroaryl, fused heteroaryl, heterocyclyl and the ring portion of cycloalkylalkyl, arylalkyl, heteroaralkyl, aryloxyalkyl, heteroaryloxyalkyl, fused aralkyl, fused heteroaryalkyl, or heterocyclylalkyl are substituted with one, two or three substituents each independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, cyano, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl. [0199] (E1i). In subembodiment (E1i), the compound any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, Zii, A1, A1viii, A1ix, B1, B1vi, B1vii, C1, and D1 to D1ii, and E1, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii, Yi to Yvi, Zi, A1i to A1vii, B1i to B1v, C1i, and C1ii, or a pharmaceutically acceptable salt thereof is wherein R7 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, carbonylaminoalkyl, carboxyaminoalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, aryl, fused aryl, heteroaryl, fused heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, aryloxyalkyl, heteroaryloxyalkyl, fused aralkyl, fused heteroaryalkyl, or heterocyclylalkyl wherein cycloalkyl, aryl, fused aryl, heteroaryl, fused heteroaryl, heterocyclyl and the ring portion of cycloalkylalkyl, arylalkyl, heteroaralkyl, aryloxyalkyl, heteroaryloxyalkyl, fused aralkyl, fused heteroaryalkyl, or heterocyclylalkyl are substituted with one, two or three substituents each independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, cyano, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl and R8 and R9 are hydrogen. [0200] (E1ii). In subembodiment (E1ii), the compound any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, Zii, A1, A1viii, A1ix, B1, B1vi, B1vii, C1, D1 to D1ii, andE1, and subembodiments D(i) to D(viii), Vi, Wi to Wii, Xi to Xiii, Yi to Yvi, Zi, A1i to A1vii, B1i to B1v, C1i, and C1ii, or a pharmaceutically acceptable salt thereof is wherein R7 and R8 are each independently alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, carbonylaminoalkyl, carboxyaminoalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, aryl, fused aryl, heteroaryl, fused heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, aryloxyalkyl, heteroaryloxyalkyl, fused aralkyl, fused heteroaryalkyl, or heterocyclylalkyl wherein cycloalkyl, aryl, fused aryl, heteroaryl, fused heteroaryl, heterocyclyl and the ring portion of cycloalkylalkyl, arylalkyl, heteroaralkyl, aryloxyalkyl, heteroaryloxyalkyl, fused aralkyl, fused heteroaryalkyl, or heterocyclylalkyl are substituted with one, two or three substituents each independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, cyano, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl and R9 is hydrogen. [0201] (E1iii). In subembodiment (E1iii), the compound any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, Zii, A1, A1viii, A1ix, B1, B1vi, B1vii, C1, D1 to D1ii, and E1, and subembodiments D(i) to D(viii), Vi, Wi to Wii, Xi to Xiii, Yi to Yvi, Zi, A1i to A1vii, B1i to B1v, C1i, and C1ii, or a pharmaceutically acceptable salt thereof is wherein R7, R8, and and R9 are each independently alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, carbonylaminoalkyl, carboxyaminoalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, aryl, fused aryl, heteroaryl, fused heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, aryloxyalkyl, heteroaryloxyalkyl, fused aralkyl, fused heteroaryalkyl, or heterocyclylalkyl wherein cycloalkyl, aryl, fused aryl, heteroaryl, fused heteroaryl, heterocyclyl and the ring portion of cycloalkylalkyl, arylalkyl, heteroaralkyl, aryloxyalkyl, heteroaryloxyalkyl, fused aralkyl, fused heteroaryalkyl, or heterocyclylalkyl are substituted with one, two or three substituents each independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, cyano, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl. [0202] (E1iv). In subembodiment (E1iv), the compound any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, Zii, A1, A1viii, A1ix, B1, B1vi, B1vii, C1, D1 to D1ii, and E1, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii, Yi to Yvi, Zi, A1i to A1vii, B1i to B1v, C1i, C1ii, and E1i to E1iii, or a pharmaceutically acceptable salt thereof wherein R7 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, or heterocyclyl wherein cycloalkyl and heterocyclyl are substituted with one, two or three substituents each independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, cyano, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl. [0203] (E1v). In subembodiment (E1v), the compound any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, Zii, A1, A1viii, A1ix, B1, B1vi, B1vii, C1, D1 to D1ii,and E1, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii, Yi to Yvi, Zi, A1i to A1vii, B1i to B1v, C1i, C1ii, and E1i to E1iv, or a pharmaceutically acceptable salt thereof is wherein R7 is alkyl. [0204] (E1vi). In subembodiment (E1vi), the compound any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, Zii, A1, A1viii, A1ix, B1, B1vi, B1vii, C1, D1 to D1ii, and E1, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii, Yi to Yvi, Zi, A1i to A1vii, B1i to B1v, C1i, C1ii, and E1i to E1iv, or a pharmaceutically acceptable salt thereof is wherein R7 is hydroxyalkyl, aminoalkyl, or alkoxyalkyl. [0205] (E1vii). In subembodiment (E1vii), the compound any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, Zii, A1, A1viii, A1ix, B1, B1vi, B1vii, C1, D1 to D1ii, and E1, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii, Yi to Yvi, Zi, A1i to A1vii, B1i to B1v, C1i, C1ii, and E1i to E1iv, or a pharmaceutically acceptable salt thereof is wherein R7 is haloalkyl [0206] (E1viii). In subembodiment (E1viii), the compound any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, Zii, A1, A1viii, A1ix, B1, B1vi, B1vii, C1, D1 to D1ii, andE1, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii, Yi to Yvi, Zi, A1i to A1vii, B1i to B1v, C1i, C1ii, and E1i to E1iv, or a pharmaceutically acceptable salt thereof is wherein R7 is cycloalkyl or cycloalkylalkyl. [0207] (E1ix). In subembodiment (E1ix), the compound any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, Zii, A1, A1viii, A1ix, B1, B1vi, B1vii, C1, D1 to D1ii, andE1, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii, Yi to Yvi, Zi, A1i to A1vii, B1i to B1v, C1i, C1ii, and E1i to E1iv, or a pharmaceutically acceptable salt thereof is wherein R7 is heterocyclyl substituted as described therein. [0208] (E1x). In subembodiment (E1x), the compound any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, Zii, A1, A1viii, A1ix, B1, B1vi, B1vii, C1, D1 to D1ii, andE1, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii, Yi to Yvi, Zi, A1i to A1vii, B1i to B1v, C1i, C1ii, and E1ii to E1ix, or a pharmaceutically acceptable salt thereof is wherein R8, and R9 are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, aryloxyalkyl, heteroaryloxyalkyl, or heterocyclylalkyl wherein cycloalkyl, aryl, heteroaryl, heterocyclyl and the ring portion of cycloalkylalkyl, arylalkyl, heteroaralkyl, aryloxyalkyl, heteroaryloxyalkyl, or heterocyclylalkyl are substituted with one, two or three substituents each independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, cyano, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl. For sake of clarity, R8 and R9 are both hydrogen with reference to subsembodiment (E1i) and other than hydrogen with reference to subembodiment (E1iii); and R8, is other than hydrogen with reference to subembodiment (E1ii). [0209] (E1xi). In subembodiment (E1xi), the compound any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, Zii, A1, A1viii, A1ix, B1, B1vi, B1vii, C1, D1 to D1ii, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, Zii, A1, A1viii, A1ix, B1, B1vi, B1vii, C1 and D1 to D1ii, andE1, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii, Yi to Yvi, Zi, A1i to A1vii, B1i to B1v, C1i, C1ii, and E1i to E1x, or a pharmaceutically acceptable salt thereof is wherein R7, R8, and R9 are each independently methyl, ethyl, cyclopropyl, cyclopropylmethyl, 1-cyclopropylethyl, 1-hydroxycyclprop-1- ylmethyl, 3,3-difluorobutylmethyl, cyclobutylmethyl, -CH2CH2NH2, -CH2CH2NH(COCH3), - CH2CH2NH(COphenyl), 2,2,2-trifluoroethyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl, 2,3-dihydroxypropyl, 1-hydroxymethylethyl, 2-hydroxymethyl, 2-hydroxypropyl, carboxymethyl, morpholin-4-yl, pyrrolidinyl-1-methyl, phenyl, phenylmethyl, 2-phenylethyl, 1-phenylethyl, 2-phenoxyethyl, 4-pyridin-4-ylphenylmethyl, 4-pyridin-4-ylphenyl, 2-oxazol- 2-ylmethyl, 2-thiazol-2-ylmethyl, 1-methylimidazol-2-ylmethyl, pyridine-2-ylmethyl, pyridine-3-ylmethyl, pyridin-4-ylmethyl, 2-pyridin-2-yloxyethyl, 2-pyridin-3-yloxyethyl, or 2-pyridin-4-yloxyethyl unless stated otherwise. [0210] (E1xii). In embodiment E1xii, the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, Zii, A1, A1viii, A1ix, B1, B1vi, B1vii, C1, D1 to D1ii, and E1, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii, Yi to Yvi, Zi, A1i to A1vii, B1i to B1v, C1i, C1ii, and E1i to E1iv or a pharmaceutically acceptable salt thereof, wherein R7 is alkyl or cycloalkyl. [0211] (E1xiii). In embodiment E1xiii, the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, Zii, A1, A1viii, A1ix, B1, B1vi, B1vii, C1, D1 to D1ii, E1, and E1xii, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii, Yi to Yvi, Zi, A1i to A1vii, B1i to B1v, C1i, C1ii, and and E1i to E1iv or a pharmaceutically acceptable salt thereof, wherein R7 is methyl or cyclopropyl. [0212] (E1xiv). In embodiment E1xiv, the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, Zii, A1, A1viii, A1ix, B1, B1vi, B1vii, C1, and D1 to D1ii, E1, and E1xii and E1xiii, and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii, Yi to Yvi, Zi, A1i to A1vii, B1i to B1v, C1i, and C1ii, or a pharmaceutically acceptable salt thereof, wherein R8 and R9 is hydrogen or alkyl. [0213] (E1xv). In embodiment E1xv, the compound of any one of embodiments A to D, E to V, Vii to Viv, W, X, Xvi to Xvi, Y, Z, Zii, A1, A1viii, A1ix, B1, B1vi, B1vii, C1, and D1 to D1ii, , and subembodiments D(i) to D(viii), Vi, Wi to Wiii, Xi to Xiii, Yi to Yvi, Zi, A1i to A1vii, B1i to B1v, C1i, and C1ii, or a pharmaceutically acceptable salt thereof, wherein R8 and R9 is hydrogen, methyl, ethyl, or isopropyl. Embodiment F1 [0214] In embodiment F1, the compound of any one of embodiments A to E1xv, and subembodiments contained therein, or a pharmaceutically acceptable salt thereof, wherein X is N or CH; a is CH; b is CH or C when attached to any one of R4, R5, or R6; d is N or C when attached to any one of R4, R5, or R6; e is N, CH or C when attached to any one of R4, R5, or R6; Z is a bond or O; m and n are each independently 0 or 1; alk is alkylene; alk1 is alkylene; Ar is arylene, cyclylaminylene, or spiro cyclylaminylene, and each ring substituted with R2 and R3; R1 is absent; R2 and R3 are each independently absent or fluoro; one of R4, R5, and R6 is alkoxy or haloalkoxy; and the remaining two of R4, R5, and R6 are each independently absent, alkoxy, halo, or haloalkoxy; R7 is alkyl or cycloalkyl; and R8 and R9 are each independently hydrogen or alkyl. [0215] (F1i). In embodiment F1i, the compound of any one of embodiments A to E1xv, and subembodiments contained therein, or a pharmaceutically acceptable salt thereof, wherein X is N or CH; a is CH; b is CH or C when attached to any one of R4, R5, or R6; d is N or C when attached to any one of R4, R5, or R6; e is N, CH or C when attached to any one of R4, R5, or R6; Z is a bond or O; m and n are each independently 0 or 1; alk is methylene; alk1 is methylene or ethylene; Ar is R7 of attachment to the remainder of the compound of (I); R1 is absent; R2 and R3 are each independently absent or fluoro; one of R4, R5, and R6 is methoxy or fluoromethoxy; and the remaining two of R4, R5, and R6 are each independently absent, methoxy, fluoro, or fluoromethoxy; R7 is methyl or cyclopropyl; and R8 and R9 are each independently hydrogen, methyl, ethyl, or isopropyl. [0216] (F1ii). In embodiment F1ii, the compound or a pharmaceutically acceptable salt thereof is selected from Table 1A and Table 1B. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is selected from Table 1A. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is selected from Table 1B. GENERAL SYNTHETIC SCHEME [0217] Compounds of this disclosure can be made by the methods depicted in the reaction schemes shown below. [0218] The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Bachem (Torrance, Calif.), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March’s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition) and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some methods by which the compounds of this disclosure can be synthesized, and various modifications to these schemes can be made and will be suggested to one skilled in the art reading this disclosure. The starting materials and the intermediates, and the final products of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and the like. Such materials may be characterized using conventional means, including physical constants and spectral data. [0219] Unless specified to the contrary, the reactions described herein take place at atmospheric pressure over a temperature range from about –78 oC to about 150 oC, such as from about 0 oC to about 125 oC and further such as at about room (or ambient) temperature, e.g., about 20 oC. [0220] Compounds of Formula (I) as defined in the Summarycan be prepared as illustrated and described in Scheme 1 below. Scheme 1
[0221] Reaction of a compound of formula 1 where hal is halo such as chloro, X is CH, N, R1, R4, R5, and R6 as defined in the Summary, with a compound of the formula 2 where Z, n, m, Ar, R2, R3 and R7 are as defined in the Summary provides a sulfide of compound of formula 3. The reaction is carried out under using an organic base such as DIEA, TEA, and the like, or an inorganic base, in aprotic organic solvents such as NMP, 1,3-dioxolane, TOU ((2,5,7,10-tetraoxaundecane), DMSO, DMPU, HMA, 1,4- dioxane, tetrahydrofuran (THF), dimethylformamide (DMF) and the like, either at room temperature or heating. Compounds of formula 1 such as 4-chloro-1,7-naphthyridine or 4-chloro-8-methoxypyrido[3,4- d]pyrimidine are commercially available. Compounds of formula 1 may also be obtained by treating a hydroxy compound such as 8-methoxy-1,7-naphthyridin-4-ol with a chlorinating agent such as P(O)Cl3 in aprotic solvents with an organic aprotic base either with heating or room temperature. Compound of formula 3 is converted into a compound of Formula (I) by treatment with aqueous ammonia and tert-butyl hypochlorite as described in working examples below. Testing [0222] The ENPP1 inhibitory activity of the compounds of the present disclosure can be tested using the in vitro assays described in Biological Examples 1 and 2 below. Administration and Pharmaceutical Composition [0223] In general, the compounds of this disclosure will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. Therapeutically effective amounts of compounds this disclosure may range from about 0.01 to about 500 mg per kg patient body weight per day, which can be administered in single or multiple doses. A suitable dosage level may be from about 0.1 to about 250 mg/kg per day; about 0.5 to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to about 250 mg/kg per day, about 0.05 to about 100 mg/kg per day, or about 0.1 to about 50 mg/kg per day. Within this range the dosage can be about 0.05 to about 0.5, about 0.5 to about 5 or about 5 to about 50 mg/kg per day. For oral administration, the compositions can be provided in the form of tablets containing about 1.0 to about 1000 milligrams of the active ingredient, particularly about 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient. The actual amount of the compound of this disclosure, i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the patient, the potency of the compound being utilized, the route and form of administration, and other factors. [0224] In general, compounds of this disclosure will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration. The preferred manner of administration is oral using a convenient daily dosage regimen, which can be adjusted according to the degree of affliction. Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions. [0225] The choice of formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules, including enteric coated or delayed release tablets, pills or capsules are preferred) and the bioavailability of the drug substance. Recently, pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size. For example, U.S. Pat. No.4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a cross-linked matrix of macromolecules. U.S. Pat. No.5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability. [0226] The compositions are comprised of in general, a compound of this disclosure in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of this disclosure. Such excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art. [0227] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols. [0228] Compressed gases may be used to disperse a compound of this disclosure in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc. [0229] Other suitable pharmaceutical excipients and their formulations are described in Remington’s Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 20th ed., 2000). [0230] The level of the compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt. %) basis, from about 0.01-99.99 wt. % of a compound of this disclosure based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. For example, the compound is present at a level of about 1-80 wt. %. [0231] The compounds of this disclosure may be used in combination with one or more other drugs in the treatment of diseases or conditions for which compounds of this disclosure or the other drugs may have utility. Such other drug(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present disclosure. When a compound of this disclosure is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of the present disclosure is preferred. However, the combination therapy may also include therapies in which the compound of this disclosure and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present disclosure and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present disclosure also include those that contain one or more other drugs, in addition to a compound of the present disclosure. [0232] The above combinations include combinations of a compound of this disclosure not only with one other drug, but also with two or more other active drugs. Likewise, a compound of this disclosure may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which a compound of this disclosure is useful. Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present disclosure. When a compound of this disclosure is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of this disclosure can be used. Accordingly, the pharmaceutical compositions of the present disclosure also include those that also contain one or more other active ingredients, in addition to a compound of this disclosure. The weight ratio of the compound of this disclosure to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. [0233] Where the subject in need is suffering from or at risk of suffering from cancer, the subject can be treated with a compound of this disclosure in any combination with one or more other anti-cancer agents. In some embodiments, one or more of the anti-cancer agents are proapoptotic agents. Examples of anti-cancer agents include, but are not limited to, any of the following: gossyphol, genasense, polyphenol E, Chlorofusin, all trans-retinoic acid (ATRA), bryostatin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), 5-aza- 2’-deoxycytidine, all trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (GleevecTM), geldanamycin, 17-N-Allylamino-17-Demethoxygeldanamycin (17- AAG), flavopiridol, LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, or PD184352, TaxolTM, also referred to as “paclitaxel”, which is a well-known anti-cancer drug which acts by enhancing and stabilizing microtubule formation, and analogs of TaxolTM., such as TaxotereTM. Compounds that have the basic taxane skeleton as a common structure feature, have also been shown to have the ability to arrest cells in the G2-M phases due to stabilized microtubules and may be useful for treating cancer in combination with the compounds described herein. [0234] Further examples of anti-cancer agents for use in combination with a compound of this disclosure include inhibitors of mitogen-activated protein kinase signaling, e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002; Syk inhibitors; antibodies (e.g., rituxan); MET inhibitor such as foretinib, carbozantinib, or crizotinib; VEGFR inhibitor such as sunitinib, sorafenib, regorafinib, lenvatinib, vandetanib, carbozantinib, axitinib; EGFR inhibitor such as afatinib, brivanib, carbozatinib, erlotinib, gefitinib, neratinib, lapatinib; PI3K inhibitor such as XL147, XL765, BKM120 (buparlisib), GDC-0941, BYL719, IPI145, BAY80-6946. BEX235 (dactolisib), CAL101 (idelalisib), GSK2636771, TG100-115; MTOR inhibitor such as rapamycin (sirolimus), temsirolimus, everolimus, XL388, XL765, AZD2013, PF04691502, PKI-587, BEZ235, GDC0349; MEK inhibitor such as AZD6244, trametinib, PD184352, pimasertinib, GDC-0973, AZD8330; and proteasome inhibitor such as carfilzomib, MLN9708, delanzomib, or bortezomib. [0235] Other anti-cancer agents that can be employed in combination with a compound of this disclosure include Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; interleukin II (including recombinant interleukin II, or Ril2), interferon alfa-2a; interferon alfa-2b; interferon alfa-n1; interferon alfa-n3; interferon beta-1a; interferon gamma-1 b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride. [0236] Other anti-cancer agents that can be employed in combination with a compound of the disclosure such as 8-(3-(4-acryloylpiperazin-1-yl)propyl)-6-(2,6-dichloro-3,5- dimethoxyphenyl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one, dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; Bfgf inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; 9-dioxamycin; diphenyl spiromustine; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflomithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; fmasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor-1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin; monophosphoryl lipid A; diethylstilbesterol; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1-based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylerie conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; R.sub.11 retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen-binding protein; sizofuran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer. [0237] Yet other anticancer agents that can be employed in combination with a compound of this disclosure include alkylating agents, antimetabolites, natural products, or hormones, e.g., nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, etc.), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, etc.), or triazenes (decarbazine, etc.). Examples of antimetabolites include but are not limited to folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin). [0238] Examples of natural products useful in combination with a compound of this disclosure include but are not limited to vinca alkaloids (e.g., vincristine), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), or biological response modifiers (e.g., interferon alpha). [0239] Examples of alkylating agents that can be employed in combination a compound of this disclosure) include, but are not limited to, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, melphalan, etc.), ethylenimine and methylmelamines (e.g., hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin, etc.), or triazenes (decarbazine, etc.). Examples of antimetabolites include, but are not limited to folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxuridine, cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin. [0240] Examples of hormones and antagonists useful in combination a compound of this disclosure include, but are not limited to, adrenocorticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethylstilbestrol, ethinyl estradiol), antiestrogen (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogen (e.g., flutamide), gonadotropin releasing hormone analog (e.g., leuprolide). Other agents that can be used in the methods and compositions described herein for the treatment or prevention of cancer include platinum coordination complexes (e.g., cisplatin, carboblatin), anthracenedione (e.g., mitoxantrone), substituted urea (e.g., hydroxyurea), methyl hydrazine derivative (e.g., procarbazine), adrenocortical suppressant (e.g., mitotane, aminoglutethimide). [0241] Examples of anti-cancer agents which act by arresting cells in the G2-M phases due to stabilized microtubules and which can be used in combination with an irreversible Btk inhibitor compound include without limitation the following marketed drugs and drugs in development: Erbulozole (also known as R-55104), Dolastatin 10 (also known as DLS-10 and NSC-376128), Mivobulin isethionate (also known as CI-980), Vincristine, NSC-639829, Discodermolide (also known as NVP-XX-A-296), ABT-751 (Abbott, also known as E-7010), Altorhyrtins (such as Altorhyrtin A and Altorhyrtin C), Spongistatins (such as Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, and Spongistatin 9), Cemadotin hydrochloride (also known as LU-103793 and NSC-D-669356), Epothilones (such as Epothilone A, Epothilone B, Epothilone C (also known as desoxyepothilone A or dEpoA), Epothilone D (also referred to as KOS-862, dEpoB, and desoxyepothilone B), Epothilone E, Epothilone F, Epothilone B N-oxide, Epothilone A N-oxide, 16-aza-epothilone B, 21-aminoepothilone B (also known as BMS- 310705), 21-hydroxyepothilone D (also known as Desoxyepothilone F and dEpoF), 26- fluoroepothilone), Auristatin PE (also known as NSC-654663), Soblidotin (also known as TZT-1027), LS-4559-P (Pharmacia, also known as LS-4577), LS-4578 (Pharmacia, also known as LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis), Vincristine sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, also known as WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences), BSF-223651 (BASF, also known as ILX-651 and LU-223651), SAH-49960 (Lilly/Novartis), SDZ-268970 (Lilly/Novartis), AM-97 (Armad/Kyowa Hakko), AM-132 (Armad), AM-138 (Armad/Kyowa Hakko), IDN-5005 (Indena), Cryptophycin 52 (also known as LY-355703), AC-7739 (Ajinomoto, also known as AVE-8063A and CS-39.HCl), AC-7700 (Ajinomoto, also known as AVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and RPR-258062A), Vitilevuamide, Tubulysin A, Canadensol, Centaureidin (also known as NSC-106969), T- 138067 (Tularik, also known as T-67, TL-138067 and TI-138067), COBRA-1 (Parker Hughes Institute, also known as DDE-261 and WHI-261), H10 (Kansas State University), H16 (Kansas State University), Oncocidin A1 (also known as BTO-956 and DIME), DDE- 313 (Parker Hughes Institute), Fijianolide B. Laulimalide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute, also known as SPIKET-P), 3-IAABU (Cytoskeleton/Mt. Sinai School of Medicine, also known as MF-569), Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica), A-105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton/Mt. Sinai School of Medicine, also known as MF-191), TMPN (Arizona State University), Vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, Inanocine (also known as NSC-698666), 3-1AABE (Cytoskeleton/Mt. Sinai School of Medicine), A-204197 (Abbott), T-607 (Tuiarik, also known as T-900607), RPR-115781 (Aventis), Eleutherobins (such as Desmethyleleutherobin, Desaetyleleutherobin, Isoeleutherobin A, and Z- Eleutherobin), Caribaeoside, Caribaeolin, Halichondrin B, D-64131 (Asta Medica), D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), Taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott), Diozostatin, (-)-Phenylahistin (also known as NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta Medica), Myoseverin B, D-43411 (Zentaris, also known as D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286 (also known as SPA-110, trifluoroacetate salt) (Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC-12983 (NCI), Resverastatin phosphate sodium, BPR-OY-007 (National Health Research Institutes), and SSR-250411 (Sanofi). [0242] Further examples of anti-cancer agents for use in combination with a compound of this disclosure include immune checkpoint inhibitors. Exemplary immune checkpoint inhibitors include inhibitors (small molecules or biologics) against immune checkpoint molecules such as CD27, CD28, CD40, CD122, CD96, CD73, CD39, CD47, OX40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM kinase, arginase, CD137 (also known as 4- 1BB), ICOS, A2AR, A2BR, HIF-2α, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, CD96, TIGIT, PD-1, PD-L1 and PD-L2. In some embodiments, the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40, GITR, CD137 and STING. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint molecule selected from B7-H3, B7-H4, BTLA, CTLA- 4, IDO, TDO, Arginase, KIR, LAG3, PD-1, TIM3, CD96, TIGIT and VISTA. In some embodiments, the compounds provided herein can be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFR beta inhibitors. [0243] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In some embodiments, the anti- PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, or AMP-224. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, or pembrolizumab or PDR001. In some embodiments, the anti-PD1 antibody is pembrolizumab. [0244] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In some embodiments, the anti- PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments, the anti-PD-L1 monoclonal antibody is MPDL3280A (atezolizumab) or MEDI4736 (durvalumab). [0245] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab or tremelimumab. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016 or LAG525. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments, the anti-GITR antibody is TRX518 or, MK-4166, INCAGN01876 or MK-1248. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of OX40, e.g., an anti-OX40 antibody or OX40L fusion protein. In some embodiments, the anti-OX40 antibody is MEDI0562 or, INCAGN01949, GSK2831781, GSK-3174998, MOXR-0916, PF-04518600 or LAG525. In some embodiments, the OX40L fusion protein is MEDI6383 EXAMPLES [0246] The following preparations of compounds of Formula (I) are given to enable those skilled in the art to more clearly understand and to practice the present disclosure. They should not be considered as limiting the scope of the disclosure, but merely as being illustrative and representative thereof. [0247] All solvents used were commercially available and were used without further purification. Reactions were typically run using anhydrous solvents under an inert atmosphere of nitrogen. [0248] 1H spectra were recorded at 400 MHz or 300 MHz for proton on a Bruker 400 NMR Spectrometer equipped with a Bruker 400 BBO probe or Bruker BBFO ULTRASHIELD™300 AVANCE III, respectively. All deuterated solvents contained typically 0.03% to 0.05% v/v tetramethylsilane, which was used as the reference signal (set at d 0.00 for both 1H and 13C). [0249] LCMS analyses were performed on a SHIMADZU LCMS consisting of an UFLC 20-AD and LCMS 2020 MS detector. The Diode Array Detector was scanned from 190-400 nm. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in a positive or negative mode. The mass spectrometer was scanned between m/z 90-900 with a scan time from 0.5 to 3.0 s. [0250] HPLC analyses were performed on a SHIMADZU UFLC with two LC20 AD pump and a SPD-M20A Photodiiode Array Detector. The column used was an XBridge C18, 3.5 µm, 4.6 × 100 mm. A linear gradient was applied, starting at 90 % A (A: 0.05% TFA in water) and ending at 95% B (B: 0.05% TFA in MeCN) over 10 min with a total run time of 15 min. The column temperature was at 40 °C with the flow rate of 1.5 mL/min. The Diode Array Detector was scanned from 200-400 nm. [0251] Thin layer chromatography (TLC) was performed on Alugram® (Silica gel 60 F254) from Mancherey-Nagel and UV was typically used to visualize the spots. Additional visualization methods were also employed in some cases. In these cases, the TLC plate was developed with iodine (generated by adding approximately 1 g of I2 to 10 g silica gel and thoroughly mixing), ninhydrin (available commercially from Aldrich), or Magic Stain (generated by thoroughly mixing 25 g (NH4)6Mo7O24.4H2O, 5 g (NH4)2Ce(IV)(NO3)6 in 450 mL water and 50 mL concentrated H2SO4) to visualize the compound. Flash chromatography was performed using 40-63 µm (230-400 mesh) silica gel from Silicycle following analogous techniques to those disclosed in Still, W.C.; Kahn, M.; and Mitra, M. Journal of Organic Chemistry, 1978, 43, 2923. Typical solvents used for flash chromatography or thin layer chromatography were mixtures of chloroform/ methanol, dichloromethane/methanol, ethyl acetate/methanol and hexanes/ethyl acetate. Synthetic Examples Example 1 Synthesis of (3-(((8-methoxy-1,7-naphthyridin-4-yl)oxy)methyl)phenyl)(methyl)-lambda6- sulfanediimine Step 1: 5-(((2-Methoxypyridin-3- -2,2-dimethyl-1,3-dioxane-4,6- dione [0252] A solution of 2- g, 24.2 mmol, 1 equiv), 2,2- dimethyl-1,3-dioxane-4,6-dione (4.50 g, 31.46 mmol, 1.3 equiv) and trimethoxymethane (3.60 g, 33.8 mmol, 1.4 equiv) in acetonitrile (30 mL) was stirred at 80 oC for 2 h under nitrogen atmosphere. After cooling to room temperature, the resulting solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA/ PE (25:75). The fractions containing the desired product were combined and concentrated under reduced pressure to afford the title compound (6.50 g, 97% ) as a yellow solid. Step 2: 8-Methoxy-1,7-naphthyridin-4-ol [0253] A mixture of 5-(((2- amino)methylene)-2,2-dimethyl-1,3- dioxane-4,6-dione (1.50 g, 5.4 mmol) in diphenyl ether (38 mL) was stirred at 225 oC for 1.5 h. After cooling to room temperature, PE was poured into the reaction mixture, the precipitated solids were collected by filtration and washed with PE. The crude product was purified by reverse phase flash chromatography, eluted with ACN/H2O (23:77) to the title compound (600 mg, 63%) as a white solid. Step 3: 4-Chloro-8-methoxy-1,7-naphthyridine [0254] To a stirred solution of 8- 4-ol (1.60 g, 9.08 mmol, 1 equiv) in toluene (32 mL) was added g, 18.16 mmol, 2 equiv) and POCl3 (1.67 g, 10.89 mmol, 1.2 equiv) at room temperature. After stirring overnight at 70 °C, the resulting mixture was concentrated under reduce pressure. Then crude product was purified by reversed phase flash eluted with ACN/H2O (35:65) to give the title compound (1.11 g, 62%) as a yellow solid. Step 4: 8-methoxy-4-((3-(methylsulfanyl)phenyl)methoxy)-1,7-naphthyridine [0255] To a stirred solution of 3- methanol (237 mg, 1.54 mmol, 1.5 equiv) in DMF (4 mL) was added NaH (74 mg, 3.08 mmol, 3 equiv) at 0 °C. After stirring for 10 min, 4-chloro-8-methoxy-1,7-naphthyridine (200 mg, 1.02 mmol, 1 equiv) was added. The resulting mixture was stirred for 2 h at 80 °C. After cooling to room temperature, the reaction mixture was quenched with water and extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EA/PE (15:85) to afford the title compound (130 mg, 40%) as a yellow solid. Step 5: (3-(((8-methoxy-1,7-naphthyridin-4-yl)oxy)methyl)phenyl)(methyl)-lambda6- sulfanediimine [0256] To a solution of 8-methoxy- lfanyl)phenyl)methoxy)-1,7- naphthyridine (100 mg, 0.32 mmol, 1 equiv) in ACN (3 mL) was added NH3-H2O (897 mg , 20 equiv, 25%v/v) at -15 oC under nitrogen atmosphere. The resulting mixture was stirred for 1 h at the same temperature and tert-butyl hypochlorite (174 mg, 1.60 mmol, 5 equiv) was added. After stirring at -15 oC for 1 h, NH3-H2O (448 mg, 10 equiv, 25%v/v) was added. The reaction mixture was stirred overnight from -15 oC to room temperature. The resulting mixture was concentrated under reduced pressure and was purified by reverse phase flash chromatography, eluting with ACN/H2O (15:85) to afford the crude product, which was re- purified by reverse phase prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 nmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 2% B to 24% B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 9.07) to afford the title compound (7.4 mg, 6%) as a white solid. MS (ESI, pos. ion) m/z: 343.1 (M+1).1H NMR (400 MHz, DMSO-d6, ppm) δ 8.79 (d, J = 5.2 Hz, 1H), 8.25 (t, J = 1.8 Hz, 1H), 8.11 - 8.02 (m, 2H), 7.81 - 7.74 (m, 1H), 7.64 (t, J = 7.7 Hz, 1H), 7.56 (d, J = 5.9 Hz, 1H), 7.39 (d, J = 5.3 Hz, 1H), 5.51 (s, 2H), 4.05 (s, 3H), 3.04 (s, 3H), 2.98 (s, 2H). Example 2 Synthesis of cyclopropyl(3-(((8-methoxy-1,7-naphthyridin-4-yl)oxy)methyl)phenyl)- lambda6-sulfanediimine Step 1: 3-(Cyclopropylsulfanyl) [0257] To a mixture of 3-sulfanylbenz (5.00 g, 30.80 mmol, 1 equiv) in DMSO (50 mL) were added bromocyclopropane (5.88 g, 46.21 mmol, 1.5 equiv) and potassium tert- butoxide (9.10 g, 77.02 mmol, 2.5 equiv). The resulting mixture was stirred for 24 h at 80 oC. After cooling down to room temperature, the reaction mixture was diluted with water, adjusted the pH to 5 with 1 N HCl (aq) and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford the title compound (3.99 g, 61%) as a colorless oil. Step 2: 3-(Cyclopropylsulfanyl)phenyl]methanol [0258] The title compound was proceeding analogously as described in Example 5, Step 1, except 3-(cyclopropylsulfanyl)benzoic acid (24.00 g, 117.37 mmol) was used. [3-(cyclopropylsulfanyl)phenyl]methanol (20.00 g, 86%) was obtained as a yellow oil. Step 3: 4-((3-(Cyclopropylthio)benzyl)oxy)-8-methoxy-1,7-naphthyridine [0259] The title compound was analogously as described in Example 1, Step 4, except (3-(cyclopropylthio)phenyl)methanol (511 mg, 2.84 mmol) was used. The title compound (169 mg, 35%) was obtained as a yellow solid. Step 4: Cyclopropyl(3-(((8-methoxy-1,7-naphthyridin-4-yl)oxy)methyl)phenyl)- lambda6-sulfanediimine [0260] The title compound was analogously as described in Example 1, Step 5 except 4-((3- methoxy)-8-methoxy-1,7- naphthyridine (210 mg, 0.62 mmol) was used. The crude product was purified by prep-HPLC with the following conditions: (UV 254 nm / 220 nm, Xbridge Prep OBD C18 Column, 30*150 mm, 5μm Water (10mmol/L NH4HCO3) ACN 60 mL/min 3% B to 33 % B in 10 min 8.68). The fractions containing the desired product were combined and lyophilized to afford the title compound (3.2 mg, 1%) as a yellow solid. MS (ESI, pos. ion) m/z: 369.1 (M+1).1H NMR (400 MHz, DMSO-d6, ppm) δ 8.78 (d, J = 5.2 Hz, 1H), 8.18 (d, J = 1.8 Hz, 1H), 8.08 (d, J = 5.8 Hz, 1H), 8.01 (dt, J = 7.9, 1.6 Hz, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.63 (t, J = 7.7 Hz, 1H), 7.56 - 7.50 (m, 1H), 7.37 (d, J = 5.3 Hz, 1H), 5.51 (s, 2H), 4.05 (s, 3H), 2.84 (s, 2H), 2.76 - 2.68 (m, 1H), 0.99 - 0.92 (m, 2H), 0.85 - 0.74 (m, 2H). Example 3 Synthesis of (4-(((8-methoxy-1,7-naphthyridin-4-yl)oxy)methyl)phenyl)(methyl)-lambda6- sulfanediimine Step 1: 8-methoxy-4-((4- -1,7-naphthyridine [0261] The title compound was synth roceeding analogously as described in Example 1, Step 4 except (4-(methylsulfanyl)phenyl)methanol (435 mg, 2.82 mmol) was used. The title compound (480 mg, 49%) was obtained as an off-white solid. Step 2: (4-(((8-methoxy-1,7-naphthyridin-4-yl)oxy)methyl)phenyl)(methyl)-lambda6- sulfanediimine [0262] The title compound was analogously as described in Example 1, Step 5, except 8-methoxy-4-((4-(methylsulfanyl)phenyl)methoxy)-1,7- naphthyridine (430 mg, 1.37 mmol) was used. The crude product was purified by prep-HPLC with the following conditions: (Column: XBridge Prep RP OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 2% B to 28% B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 9.3). The fractions containing the desired product were combined and lyophilized to give the title compound (6.6 mg, 11%) as a white solid. MS (ESI, pos. ion) m/z: 343.1 (M+1).1H NMR (400 MHz, DMSO-d6, ppm) δ 8.78 (d, J = 5.2 Hz, 1H), 8.14 - 8.05 (m, 3H), 7.77 - 7.70 (m, 2H), 7.58 (d, J = 5.9 Hz, 1H), 7.36 (d, J = 5.3 Hz, 1H), 5.51 (s, 2H), 4.05 (s, 3H), 3.03 (s, 3H), 2.96 (s, 2H). Example 4 Synthesis of ((1-(8-methoxy-1,7-naphthyridin-4-yl)piperidin-4-yl)methyl)(methyl)-lambda6- sulfanediimine Step 1: (1-(8-methoxy-1,7-naphthyrid eridin-4-yl)methanol [0263] To a solution of 4-chloro-8- (500 mg, 2.56 mmol, 1.0 equiv) in NMP (6 mL) were added DIEA (996 mg, 7.70 mmol, 3.0 equiv) and piperidin-4- ylmethanol (739 mg, 6.42 mmol, 2.5 equiv). The resulting mixture was stirred at 100 oC for 2 h. After cooling to room temperature, the solution was concentrated under reduced pressure and purified by reverse phase flash chromatography, eluting with ACN/H2O (37/63) to afford (1-(8-methoxy-1,7-naphthyridin-4-yl)piperidin-4-yl)methanol (577 mg, 80%) as a brown solid. Step 2: (1-(8-methoxy-1,7-naphthyridin-4-yl)piperidin-4-yl)methyl methanesulfonate [0264] To a solution of (1-(8- 4-yl)piperidin-4-yl)methanol (557 mg, 2.03 mmol, 1 equiv) in DCM (6 mL) were added TEA (412 mg, 4.07 mmol, 2 equiv), DMAP (24 mg, 0.20 mmol, 0.1 equiv) and methanesulfonic anhydride (532 mg, 3.05 mmol, 1.5 equiv) at 0 oC. The resulting mixture was stirred at room temperature for 2 h. The solution was quenched with H2O and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to afford the title compound (750 mg, 99%) as a brown oil. Step 3: 8-methoxy-4-(4-((methylsulfanyl)methyl)piperidin-1-yl)-1,7-naphthyridine [0265] To a solution of 8-methoxy-4- methyl)piperidin-1-yl)-1,7- naphthyridine (715 mg, 2.35 mmol, 1 (8 mL) was added sodiummethanethiolate (7.13 g, 20.35 mmol, 10 equiv, 20%). The resulting mixture was stirred at 35 oC for 2 h. Then the solution was concentrated under reduced pressure and purified by silica gel column chromatography, eluting with MeOH/DCM (6/94) to afford the title compound (543 mg, 82%) as a yellow oil. Step 4: ((1-(8-methoxy-1,7-naphthyridin-4-yl)piperidin-4-yl)methyl)(methyl)-lambda6- sulfanediimine [0266] The title compound was analogously as described in Example 1, Step 5, except 8-methoxy-4-(4-((methylsulfanyl)methyl)piperidin-1-yl)-1,7- naphthyridine (200 mg, 0.65 mmol) was used. The crude product was purified by prep-HPLC with the following conditions: (Column: XBridge Prep RP OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 2% B to 22% B in 10min; Wave Length: 254 nm / 220 nm; RT1(min): 9.2) The fractions containing the desired product were combined and lyophilized to afford the title compound (21 mg, 9.4%) as a white solid. MS (ESI, pos. ion) m/z: 334.2 (M+1).1H NMR (400 MHz, DMSO-d6, ppm) δ 8.67 (d, J = 5.0 Hz, 1H), 8.02 (d, J = 5.9 Hz, 1H), 7.32 (d, J = 6.0 Hz, 1H), 7.15 (d, J = 5.1 Hz, 1H), 4.03 (s, 3H), 3.51 (d, J = 12.4 Hz, 2H), 3.07 (d, J = 6.0 Hz, 2H), 2.93 - 2.81 (m, 5H), 2.38 (s, 2H), 2.30 - 2.17 (m, 1H), 2.11 (d, J = 12.8 Hz, 2H), 1.71 - 1.57 (m, 2H). Example 5 Synthesis of (3-(((7-methoxyquinolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda6- sulfanediimine Step 1: 3-(Methylsulfanyl) [0267] To a solution of 3- acid (4.00 g, 23.78 mmol, 1 equiv) in THF (40 mL) was slowly added LiAlH4 (14.2 mL, 2 M in THF) at 0 oC under nitrogen atmosphere. After stirring at room temperature for 2 h, the mixture was quenched by addition of saturated ammonium chloride solution and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc / PE (43:57) to afford the title compound (3.08 g, 84%) as a colorless oil. Step 2: 7-methoxy-4-((3-(methylsulfanyl)phenyl)methoxy)quinoline S [0268] To a stirred solution of methanol (500 mg, 3.24 mmol, 1 equiv) in DMF (10 mL) was added NaH (233 mg, 9.72 mmol, 3 equiv) at 0 oC. After stirring for 10 min, 4-chloro-7-methoxyquinoline (941 mg, 4.86 mmol, 1.5 equiv) was added. The mixture was stirred at 80 oC for 2 h. The resulting mixture was quenched with H2O, then extracted with EtOAc and washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (750 mg, 74%) as a yellow oil. MS (ESI, pos. ion) m/z: 312.0 (M+1). Step 3: (3-(((7-methoxyquinolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda6- sulfanediimine [0269] The title compound was analogously as described in Example 1, Step 5, except 7-methoxy-4-((3-(methylsulfanyl)phenyl)methoxy)quinoline (650 mg, 2.08 mmol) was used. The crude product was purified by prep-HPLC with the following conditions: (Column: XBridge Prep RP OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 6% B to 36% B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 9.4). The fractions containing the desired product were combined and lyophilized to give the title compound (35.9 mg, 5%) as a white solid. MS (ESI, pos. ion) m/z: 342.1 (M+1).1H NMR (400 MHz, DMSO-d6, ppm) δ 8.68 (d, J = 5.2 Hz, 1H), 8.25 (t, J = 1.8 Hz, 1H), 8.13 - 8.02 (m, 2H), 7.78 (dt, J = 7.6, 1.4 Hz, 1H), 7.64 (t, J = 7.7 Hz, 1H), 7.35 (d, J = 2.5 Hz, 1H), 7.21 (dd, J = 9.1, 2.6 Hz, 1H), 7.03 (d, J = 5.3 Hz, 1H), 5.48 (s, 2H), 3.91 (s, 3H), 3.04 (s, 3H), 2.97 (s, 2H). Example 6 Synthesis of (3-(((6,7-dimethoxyquinolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda6- sulfanediimine Step 1: 6,7-dimethoxy-4-((3- methoxy)quinoline [0270] The title compound was synthesized by proceeding analogously as described in Example 1, Step 4, except 4-chloro-6,7-dimethoxyquinoline (800 mg, 3.57 mmol) was used. The title compound (1.00 g, 81%) was obtained as a brown solid. Step 2: (3-(((6,7-dimethoxyquinolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda6- sulfanediimine [0271] The title compound was analogously as described in Example 1, Step 5, except 6,7-dimethoxy-4-((3-(methylsulfanyl)phenyl)methoxy)quinoline (900 mg, 2.63 mmol) was used. The crude product was purified by prep-HPLC with the following conditions: (Column: XBridge Prep RP OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 6% B to 36% B in 10min; Wave Length: 254 nm / 220 nm; RT1(min): 9.4). The fractions containing the desired product were combined and lyophilized to the title compound (16.8 mg, 1.7%) as an off-white solid. MS (ESI, pos. ion) m/z: 372.1 (M+1).1H NMR (400 MHz, DMSO-d6, ppm) δ 8.54 (d, J = 5.2 Hz, 1H), 8.31 (s, 1H), 8.03 (d, J Hz, 1H ), 7.75 (d, J = 7.6 Hz, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.44 (s, 1H), 7.34 (s, 1H), 7.00 (d, J = 5.2 Hz, 1H), 5.49 (s, 2H), 3.91 (d, J = 7.2 Hz, 6H), 3.03 (s, 3H), 2.95 (s, 2H). Example 7 Synthesis of (3-(((6,7-dimethoxyquinazolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda6- sulfanediimine Step 1: 6,7-dimethoxy-4-((3- methoxy)quinazoline [0272] To a stirred mixture of 4-c yquinazoline (500 mg, 2.22 mmol, 1 equiv) in DMF (10 mL) were added Cs2CO3 (1.45 g, 4.45 mmol, 2 equiv) and (3- (methylsulfanyl)-phenyl)methanol (514 mg, 3.33 mmol, 1.5 equiv). The resulting mixture was stirred at 80 oC for 2 h. After cooling to room temperature, the resulting mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous sodium sulfate. After filtration the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EtOAc / PE (45:55) to afford the title compound (719 mg, 92%) as a white solid. Step 2: (3-(((6,7-dimethoxyquinazolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda6- sulfanediimine [0273] The title compound was analogously as described in Example , 1, Step 5, except 6,7-dimethoxy-4-((3- (methylsulfanyl)phenyl)methoxy)quinazoline (500 mg, 1.46 mmol) and Chloramine-T (1.66 g, 7.30 mmol ) were used. The crude product was purified by prep-HPLC with the following conditions: (Column:( Welch Ultimate XB-Phenyl, 30*250 mm, 10 μm; Mobile Phase A: Water (10mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 11% B to 41% B in 10min; Wave Length: 254 nm / 220 nm; RT1(min): 9.9). The fractions containing the desired product were combined and lyophilized to afford the title compound (2 mg, 1%) as an off-white solid. MS (ESI, pos. ion) m/z: 373.1 (M+1).1H NMR (400 MHz, DMSO-d6, ppm) δ 8.66 (s, 1H), 8.26 (s, 1H), 8.03 (d, J = 8.0, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.61 (t, J = 8 Hz, 1H), 7.40 (s, 1H), 7.34 (s, 1H), 5.74 (s, 2H), 3.96 (s, 3H), 3.92 (s, 3H), 3.03 (s, 3H). Example 8 Synthesis of cyclopropyl(3-(((6,7-dimethoxyquinolin-4-yl)oxy)methyl)phenyl)-lambda6- sulfanediimine Step 1: 4-((3- dimethoxyquinoline [0274] The title compound was analogously as described in Example 2, Step 3, except 4-chloro-6,7-dimethoxyquinoline (500 mg, 2.23 mmol) and (3- (cyclopropylsulfanyl)phenyl)methanol (806 mg, 4.47 mmol) were used. The title compound (560 mg, 68%) was obtained as a yellow solid. Step 2: cyclopropyl(3-(((6,7-dimethoxyquinolin-4-yl)oxy)methyl)phenyl)-lambda6- sulfanediimine [0275] The title compound was analogously as described in Example 1, Step 5, except 4-((3-(cyclopropylsulfanyl)phenyl)methoxy)-6,7- dimethoxyquinoline (460 mg, 1.25 mmol) was used. The crude product was purified by prep- HPLC with the following conditions: (Column: Xbridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 6% B to36 % B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 8.68). The fractions containing the desired product were combined and lyophilized to give the title compound (22.5 mg, 4%) as a white solid. MS (ESI, pos. ion) m/z: 398.1 (M+1).1H NMR (400 MHz, DMSO-d6, ppm) δ 8.54 (d, J = 5.3 Hz, 1H), 8.25 (t, J = 1.9 Hz, 1H), 7.99 (d, J = 8.0 Hz 1H), 7.74 (d, J = 7.8, 1.3 Hz, 1H), 7.62 (t, J = 7.7 Hz, 1H), 7.44 (s, 1H), 7.34 (s, 1H), 7.00 (d, J = 5.3 Hz, 1H), 5.50 (s, 2H), 3.92 (d, J = 7.2 Hz, 6H), 2.80 (s, 2H), 2.73 - 2.65 (s, 1H), 0.97 - 0.88 (s, 2H), 0.83 - 0.71 (s, 2H). Example 9 Synthesis of cyclopropyl(3-(((6,7-dimethoxyquinazolin-4-yl)oxy)methyl)phenyl)-lambda6- sulfanediimine Step 1: 4-((3-(cyclopropylthio) [0276] The title compound was analogously as described in Example 1, Step 4, except 4-chloro-6,7-dimethoxyquinazoline (1.00 g, 4.45 mmol) and (3- (cyclopropylsulfanyl)phenyl)methanol (960 mg, 5.3 mmol) were used. The title compound (1.20 g, 68%) was obtained as a brown solid. Step 2: cyclopropyl(3-(((6,7-dimethoxyquinazolin-4-yl)oxy)methyl)phenyl)-lambda6- sulfanediimine [0277] To a solution of 4-((3- oxy)-6,7-dimethoxyquinazoline (1.00 g, 2.71 mmol, 1.0 equiv) in ACN (20 mL) was added NH3-H2O (7.61 g, 54.28 mmol, 20.0 equiv, 25% v/v) under N2 atmosphere at room temperature and the mixture was stirred at room temperature for 1 h. Tert-butyl hypochlorite (1.47 g, 13.54 mmol, 5.0 equiv) was added at 0 oC and the mixture was stirred at room temperature for 1 h. NH3▪H2O (7.61 g, 54.28 mmol, 20.0 equiv, 25%) was added and the mixture was stirred overnight at room temperature. Then the reaction was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography, eluting with ACN/H2O (36/64) to give crude product which was re-purified by prep-HPLC with the following conditions (Column: YMC-Actus Triart C18ExRs, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 9% B to 39% B in 10min; Wave Length: 254 nm / 220 nm; RT1(min): 9.5) to afford the title compound (11.4 mg, 1%) as a white solid. MS (ESI, pos. ion) m/z: 399.1 (M+1).1H NMR (400 MHz, DMSO- d6, ppm) δ 8.66 (s, 1H), 8.19 (t, J = 1.8 Hz, 1H), 7.97 (dt, J = 7.8, 1.4 Hz, 1H), 7.73 (dt, J = 7.9, 1.3 Hz, 1H), 7.59 (t, J = 7.7 Hz, 1H), 7.39 (s, 1H), 7.34 (s, 1H), 5.73 (s, 2H), 3.96 (s, 3H), 3.92 (s, 3H), 2.79 (s, 2H), 2.74 - 2.63 (m, 1H), 0.97 - 0.88 (m, 2H), 0.83 - 0.71 (m, 2H). Example 10 Synthesis of (3-(((6-fluoro-7-methoxyquinolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda6- sulfanediimine Step 1: 6-fluoro-7-methoxy-4-( methoxy)quinoline [0278] The title compound was analogously as described in Example 5, Step 2, except 4-chloro-6-fluoro-7-methoxyquinoline (1.00 g, 4.725 mmol) was used. The title compound (440 mg, 28%) was obtained as a light yellow solid . Step 2: (3-(((6-fluoro-7-methoxyquinolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda6- sulfanediimine [0279] The title compound was s eding analogously as described in Example 1, Step 5, except 6-fluoro-7-methoxy-4-((3- (methylsulfanyl)phenyl)methoxy)quinoline (340 mg, 1.032 mmol) was used. The crude product was purified by prep-HPLC with the following conditions: (Column: XBridge Prep RP OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 10% B to 40% B in 10min; Wave Length: 254 nm / 220 nm; RT1(min): 9.4) to afford the title compound (13.1 mg, 3.5%) as an off-white solid. MS (ESI, pos. ion) m/z: 360.0 (M+1).1H NMR (400 MHz, DMSO-d6, ppm) δ 8.68 (d, J = 5.3 Hz, 1H), 8.24 (t, J = 1.8 Hz, 1H), 8.05 (d, J = 7.9 Hz, 1H), 7.86 - 7.76 (m, 2H), 7.64 (t, J = 7.7 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.09 (d, J = 5.3 Hz, 1H), 5.49 (s, 2H), 4.00 (s, 3H), 3.04 (s, 3H), 2.96 (s, 2 H) Example 11 Synthesis of (4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)(methyl)-lambda6-sulfanediimine Step 1: 6,7-dimethoxy-4-(4- quinoline [0280] To a stirred mixture of (500 mg, 2.23 mmol, 1 equiv) in DMSO (10 mL) were added Cs2CO3 (1.09 g, 3.35 mmol, 1.5 equiv) and 4- (methylthio)-phenol (1.25 g, 8.94 mmol, 4 equiv). The resulting mixture was stirred overnight at 120 oC. After cooling to room temperature, the resulting mixture was diluted with water (100 mL), extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EtOAc / PE (40:60) to afford the title compound (630 mg, 83%) as an off white solid. Step 2: (4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)(methyl)-lambda6-sulfanediimine [0281] The title compound was analogously as described in Example 1, Step 5, except 6,7- phenoxy)quinoline (1.30 g, 3.97 mmol) was used. The crude product was purified by prep-HPLC with the following conditions: (Column: XBridge Prep RP OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 2% B to 32% B in 10min; Wave Length: 254 nm / 220 nm; RT1(min): 9.5 ). The fractions containing the desired product were combined and lyophilized to afford the title compound (30 mg, 2%) as an off-white solid. MS (ESI, pos. ion) m/z: 358.1 (M+1).1H NMR (400 MHz, DMSO-d6, ppm) δ 8.55 (d, J = 5.2 Hz, 1H), 8.16 - 8.14 (m, 2H), 7.44 (d, J = 4.4 Hz, 2H), 7.42 - 7.40 (m, 2H), 6.66 (d, J = 5.2 Hz, 1H), 3.96 (s, 3H), 3.91 (s, 3H), 3.06 (s, 3H), 2.97 (s, 2H). Example 12 Synthesis of ((2-(6,7-dimethoxyquinolin-4-yl)-2-azaspiro[3.3]heptan-6-yl)methyl)(methyl)- lambda6-sulfanediimine) Step 1: tert-Butyl 6-[ -2-azaspiro[3.3]heptane-2-carboxylate [0282] To a stirred solution of tert-butyl 6-(hydroxymethyl)-2-azaspiro[3.3]heptane-2- carboxylate (1.00 g, 4.39 mmol, 1 equiv) in DCM (12 mL) was added TEA (890 mg, 8.79 mmol, 2 equiv) and MsCl (604 mg, 5.27 mmol, 1.2 equiv) at 0 °C. After stirring at room temperature for 2 h, the resulting mixture was diluted with DCM (100 mL) and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (1.34 g, 99%) as a yellow solid. Step 2: tert-Butyl 6-[(methylsulfanyl)methyl]-2-azaspiro[3.3]heptane-2-carboxylate [0283] To a stirred solution of methyl]-2- azaspiro[3.3]heptane-2-carboxylate (1.34 g, 4.38 mmol, 1 equiv) in EtOH (10 mL) was added sodiummethanethiolate (6.68 mL, 20% in H2O) at room temperature. After stirring for 2 h, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with EA/PE (18:82) to afford the title compound (894 mg, 79%) as a yellow solid. Step 3: 6-[(Methylsulfanyl)methyl]-2-azaspiro[3.3]heptane [0284] To a solution of tert-butyl methyl]-2-azaspiro[3.3]heptane-2- carboxylate (300 mg, 1.16 mmol, 1 equiv) in DCM ( 10 mL) was added 2,6-lutidine (0.12 g, 1.16 mmol, 1 equiv) and TMSOTf (0.78 g, 3.498 mmol, 3 equiv) at room temperature. After stirring for 2 h, the reaction mixture was concentrated under reduced pressure to give the title compound (380 mg, crude) as a light yellow oil, which was used for next Step directly without further purification. Step 4: 6,7-dimethoxy-4-(6-((methylsulfanyl)methyl)-2-azaspiro(3.3)heptan-2- yl)quinoline [0285] To a solution of 6-((methylsulfanyl)methyl)-2-azaspiro[3.3]heptane (2.10 g, crude) in NMP (8 mL) and DIEA (3 mL) was added 4-chloro-6,7-dimethoxyquinoline (350 mg, 1.57 mmol, 1.0 equiv) at room temperature. The resulting mixture was stirred at 130 oC for 2 h. After cooled to room temperature, the crude product was purified by reverse phase flash chromatography, eluting with ACN/H2O (85:15) to afford the title compou d (440 mg, 81%) as a brown solid. Step 2: ((2-(6,7-dimethoxyquinolin-4-yl)-2-azaspiro(3.3)heptan-6-yl)methyl)(methyl)- lambda6-sulfanediimine [0286] The title compound was analogously as described in Example 1, Step 5, except 6,7-dimethoxy-4-(6-((methylsulfanyl)methyl)-2- azaspiro(3.3)heptan-2-yl)quinoline (440 mg, 1.27 mmol) was used. The crude product was purified by prep-HPLC with the following conditions: (XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 nmol/LNH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 2% B to25 % B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 8.5). The fractions containing the desired product were combined and lyophilized to afford the title compound (36.9 mg, 7%) as a white solid. MS (ESI, pos. ion) m/z: 375.2 (M+1).1H NMR (400 MHz, DMSO-d6, ppm) δ 8.24 (d, J = 5.2 Hz, 1H), 7.20 (s, 1H), 7.17 (s, 1H), 6.17 (d, J = 5.3 Hz, 1H), 4.39 (s, 2H), 4.20 (s, 2H), 3.88 (d, J = 4.7 Hz, 6H), 3.13 (d, J = 7.0 Hz, 2H), 2.80 (s, 3H), 2.77 - 2.66 (m, 1H), 2.49 - 2.45 (m, 2H), 2.23 (s, 2H), 2.20 - 2.10 (m, 2H). Example 13 Synthesis of (4-(((6,7-dimethoxyquinolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda6- sulfanediimine Step 1: 6,7-dimethoxy-4-((4-(meth l)methoxy)quinoline [0287] The title compound was analogously as described in Example 5, Step, 2 except 4-chloro-6,7-dimethoxyquinoline (600 mg, 2.68 mmol) and (4- (methylsulfanyl)phenyl)methanol (1.03 g, 6.70 mmol) were used. The title compound (629 mg, 89%) was obtained as an orange solid. Step 2: (4-(((6,7-dimethoxyquinolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda6- sulfanediimine [0288] The title compound was analogously as described in Example 1, Step 5, except 6,7-dimethoxy-4-((4-(methylsulfanyl)phenyl)methoxy)quinoline (400 mg, 1.17 mmol) was used. The crude product was purified by prep-HPLC with the following conditions: (Column: XBridge Prep Shield RP18 OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 nmol/LNH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 2% B to32 % B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 9.92). The fractions containing the desired product were combined and lyophilized to give the title compound (6.6 mg, 1%) as a white solid. MS (ESI, pos. ion) m/z: 372.1 (M+1).1H NMR (400 MHz, DMSO-d6, ppm) δ 8.53 (d, J = 5.3 Hz, 1H), 8.14 - 8.06 (m, 2H), 7.77 - 7.70 (m, 2H), 7.43 (s, 1H), 7.34 (s, 1H), 6.97 (d, J = 5.4 Hz, 1H), 5.50 (s, 2H), 3.92 (d, J = 4.6 Hz, 6H), 3.03 (s, 3H), 2.93 (s, 2H). Example 14 Synthesis of cyclopropyl(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-lambda6- sulfanediimine 2,2,2-trifluoroacetate HN S NH F Step 1: 4-(4- [0289] To a stirred mixture of (400 mg, 1.788 mmol, 1 equiv) and 4-(cyclopropylsulfanyl)phenol (450 mg, 2.707 mmol, 1.51 equiv) in DMSO (8 mL) was added Cs2CO3 (1.20 g, 3.683 mmol, 2.06 equiv) in portions at room temperature. The resulting mixture was stirred overnight at 120 °C. After cooling down to room temperature, the reaction mixture was diluted with water and then extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by purified by reverse phase flash, eluted with ACN/H2O (52:48) to afford 4-(4-(cyclopropylsulfanyl)phenoxy)-6,7- dimethoxyquinoline (450 mg, 70%) as a light yellow solid. Step 2: cyclopropyl(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-lambda4- sulfaniminium 2,4,6-trimethylbenzenesulfonate [0290] A mixture of 4-(4- -6,7-dimethoxyquinoline (200 mg, 0.566 mmol, 1 equiv) and amino 2,4,6-trimethylbenzenesulfonate (365 mg, 1.696 mmol, 3.00 equiv) in DCM (4 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure to afford cyclopropyl(4-((6,7-dimethoxyquinolin-4- yl)oxy)phenyl)-lambda4-sulfaniminium 2,4,6-trimethylbenzenesulfonate (340 mg, crude) as a brown solid. The resulting mixture was used in the next step directly without further purification. Step 3: cyclopropyl(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-lambda6- sulfanediimine 2,2,2-trifluoroacetate [0291] The title compound was synthesized by proceeding analogously as described in Example 40, Step 3, except cyclopropyl(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)- lambda4-sulfaniminium 2,4,6-trimethylbenzenesulfonate (340 mg, crude) was used instead of (4-(((7-methoxyquinolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda4-sulfaniminium 2,4,6- trimethylbenzenesulfonate. The crude product was purified by reverse phase flash, eluted with ACN/H2O (31:69) and then re-purified by prep-HPLC with the following conditions (Column: Xselect CSH Prep C18 Column, 30*250 mm, 10μm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 2% B to 27 % B in 10 min; Wave Length: 254 nm / 220nm; RT1(min): 8.5) to afford cyclopropyl(4-((6,7- dimethoxyquinolin-4-yl)oxy)phenyl)-lambda6-sulfanediimine 2,2,2-trifluoroacetate (4.4 mg, 1%) as a white solid. MS (ESI, pos. ion) m/z: 384.2 (M+1-114).1H NMR (400 MHz, DMSO- d6) δ 8.76 (d, J = 5.8 Hz, 1H), 8.27 (d, J = 8.5 Hz, 2H), 7.74 (d, J = 8.6 Hz, 2H), 7.65 (s, 1H), 7.52 (s, 1H), 7.00 (d, J = 6.1 Hz, 1H), 3.99 (d, J = 20.5 Hz, 6H), 3.51 - 3.44 (m, 1H), 1.36 - 1.24 (m, 4H). 19F NMR (377 MHz, DMSO) δ -73.95 (s, 3 F). Example 15 Synthesis of ((2-(8-methoxy-1,7-naphthyridin-4-yl)-2-azaspiro[3.3]heptan-6- yl)methyl)(methyl)-lambda6-sulfanediimine Step 1: 8-methoxy-4-(6-((methylsulfa -2-azaspiro[3.3]heptan-2-yl)-1,7- naphthyridine [0292] To a solution of 6-( -2-azaspiro[3.3]heptane (750 mg, crude) in NMP (10 mL) were added DIEA (664 mg, 5.13 mmol, 5.00 equiv) and 4-chloro-8- methoxy-1,7-naphthyridine (200 mg, 1.02 mmol, 1.00 equiv). The reaction mixture was stirred at 130°C for 3 h. After cooling down to room temperature, the reaction mixture was purified by reverse phase flash, eluted with ACN/H2O (35:65) to afford 8-methoxy-4-(6- ((methylsulfanyl)methyl)-2-azaspiro[3.3]heptan-2-yl)-1,7-naphthyridine (250 mg, 77%) as a brown solid. Step 2: ((2-(8-methoxy-1,7-naphthyridin-4-yl)-2-azaspiro[3.3]heptan-6- yl)methyl)(methyl)-lambda6-sulfanediimine [0293] The title compound was analogously as described in Example 41, Step 3, except 8-methoxy-4-(6-((methylsulfanyl)methyl)-2-azaspiro[3.3]heptan- 2-yl)-1,7-naphthyridine (250 mg, 0.79 mmol) was used. The crude product was purified by reverse phase flash, eluted with ACN/H2O (45:55) and then re-purified by prep-HPLC with the following conditions (Column: Xbridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 2% B to 16 % B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 8.68) to afford ((2-(8-methoxy-1,7-naphthyridin-4-yl)-2-azaspiro[3.3]heptan-6- yl)methyl)(methyl)-lambda6-sulfanediimine (8.2 mg, 2%) as an off-white solid. MS (ESI, pos. ion) m/z: 346.1 (M+1). 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.41 (d, J = 5.2 Hz, 1H), 7.87 (d, J = 6.0 Hz, 1H), 7.36 (d, J = 6.4 Hz, 1H), 6.42 (d, J = 5.2 Hz, 1H), 4.40 (s, 2H), 4.24 (s, 2H), 3.98 (s, 3H), 3.13 (d, J = 7.2 Hz, 2H), 2.81 (s, 3H), 2.78 - 2.66 (m, 1H), 2.51 - 2.43 (m, 2H), 2.28 (s, 2H), 2.20 - 2.10 (m, 2H). Example 16 Synthesis of ((2-(6,7-dimethoxyquinazolin-4-yl)-2-azaspiro[3.3]heptan-6-yl)methyl)(methyl)- lambda6-sulfanediimine Step 1: 6,7-dimethoxy-4-(6-( -2-azaspiro[3.3]heptan-2- yl)quinazoline [0294] To a stirred solution of 4- (270 mg, 1.20 mmol, 1 equiv) in NMP (5 mL) were added DIEA (310 mg, 2.40 mmol, 2 equiv) and 6- ((methylsulfanyl)methyl)-2-azaspiro[3.3]heptane (226 mg, 1.44 mmol, 1.2 equiv) at room temperature. The resulting mixture was stirred at 130 oC for 2 h. After cooling down to room temperature, the crude product was purified by reverse phase flash, eluted with ACN/H2O (60:40) to afford 6,7-dimethoxy-4-(6-((methylsulfanyl)methyl)-2-azaspiro[3.3]heptan-2- yl)quinazoline (230 mg, 55%) as a yellow solid. Step 2: ((2-(6,7-dimethoxyquinazolin-4-yl)-2-azaspiro[3.3]heptan-6-yl)methyl)(methyl)- lambda6-sulfanediimine [0295] The title compound was analogously as described in Example 41, Step 3, except 6,7- methyl)-2- azaspiro[3.3]heptan-2-yl)quinazoline (170 mg, 0.49 mmol) was used. The crude product was purified by reverse phase flash, eluted with ACN/H2O (25:75) and then re-purified by prep- HPLC with the following conditions (Column: XBridge Prep Shield RP18 OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 2% B to 25 % B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 9.13). The fractions containing the desired product were combined and lyophilized to give ((2-(6,7-dimethoxyquinazolin-4-yl)-2-azaspiro[3.3]heptan-6- yl)methyl)(methyl)-lambda6-sulfanediimine (17.6 mg, 9%) as a white solid. MS (ESI, pos. ion) m/z: 376.1 (M+1).1H NMR (400 MHz, DMSO-d6, ppm) δ 8.33 (s, 1H), 7.15 (d, J = 24.0 Hz, 2H), 4.56 (s, 2H), 4.38 (s, 2H), 3.89 (s, 6H), 3.13 (d, J = 7.0 Hz, 2H), 2.82 - 2.66 (m, 4H), 2.52 (s, 1H), 2.50 - 2.43 (m, 1H), 2.24 (s, 2H), 2.20 - 2.10 (m, 2H). Example 17 Synthesis of cyclopropyl(3-(((6-fluoro-7-methoxyquinazolin-4-yl)oxy)methyl)phenyl)- lambda6-sulfanediimine Step 1: 4-((3-(cyclopropylsulfanyl)phenyl)methoxy)-6-fluoro-7-methoxyquinazoline S [0296] To a stirred solution of (500 mg, 2.35 mmol, 1 equiv) in DMF (10 mL) g, 7.05 mmol, 3 equiv) and (3- (cyclopropyllsulfanyl)phenyl)methanol (635 mg, 3.52 mmol, 1.5 equiv) at room temperature. After stirring at 80 oC for 2 h, the resulting mixture was cooling down to room temperature. Then reaction mixture was diluted H2O and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with EtOAc/PE (34:66) to give 4-((3- (cyclopropylsulfanyl)phenyl)methoxy)-6-fluoro-7-methoxyquinazoline (507 mg, 60%) as a yellow solid. Step 2: (cyclopropyl(3-(((6-fluoro-7-methoxyquinazolin-4-yl)oxy)methyl)phenyl)- lambda4-sulfanylidene)azanium 2,4,6-trimethylbenzenesulfonate [0297] To a stirred solution of phenyl)methoxy)-6-fluoro-7- methoxyquinazoline (400 mg, 1.12 mmol, 1 equiv) in DCM (8 mL) was added amino 2,4,6- trimethylbenzenesulfonate (724 mg, 3.36 mmol, 3 equiv) at room temperature. After stirring for 1 h, the resulting mixture was concentrated under reduced pressure to give (cyclopropyl(3-(((6-fluoro-7-methoxyquinazolin-4-yl)oxy)methyl)phenyl)-lambda4- sulfanylidene)azanium 2,4,6-trimethylbenzenesulfonate (450 mg, crude) as a white solid. MS (ESI, pos. ion) m/z: 372.0 (M+1-200). Step 3: cyclopropyl(3-(((6-fluoro-7-methoxyquinazolin-4-yl)oxy)methyl)phenyl)- lambda6-sulfanediimine [0298] The title compound was ding analogously as described in Example 40, Step 3, except (cyclopropyl(3-(((6-fluoro-7-methoxyquinazolin-4- yl)oxy)methyl)phenyl)-lambda4-sulfanylidene)azanium 2,4,6-trimethylbenzenesulfonate (400 mg, crude) was used instead of (4-(((7-methoxyquinolin-4-yl)oxy)methyl)phenyl)(methyl)- lambda4-sulfaniminium 2,4,6-trimethylbenzenesulfonate. The crude product was purified by reverse phase flash, eluted with ACN/H2O (34:66) and then re-purified by prep-HPLC with the following conditions (Column: XBridge Prep Shield RP18 OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 12% B to 42 % B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 9.62). The fractions containing the desired product were combined and lyophilized to give cyclopropyl(3-(((6-fluoro-7-methoxyquinazolin-4-yl)oxy)methyl)phenyl)- lambda6-sulfanediimine (26.2 mg, 9%) as a white solid. MS (ESI, pos. ion) m/z: 387.1 (M+1).1H NMR (400 MHz, DMSO-d6, ppm) δ 8.77 (s, 1H), 8.16 (t, J = 1.8 Hz, 1H), 8.01 - 7.94 (m, 1H), 7.87 (d, J = 11.0 Hz, 1H), 7.78 - 7.74 (m, 1H), 7.65 - 7.49 (m, 2H), 5.72 (s, 2H), 4.04 (s, 3H), 2.80 (s, 2H), 2.76 - 2.68 (m, 1H), 0.97 - 0.86 (m, 2H), 0.82 - 0.75 (m, 2H). 19F NMR (376 MHz, DMSO-d6) δ -130.56 (s, 1 F). Example 18 Synthesis of (3-(((7-methoxy-1,8-naphthyridin-4-yl)oxy)methyl)phenyl)(methyl)-lambda6- sulfanediimine Step 1: 2-methoxy-5-((3- -1,8-naphthyridine [0299] To a solution of 5-chloro- hthyridine (600 mg, 3.08 mmol, 1.0 equiv) and KF (17 mg, 0.30 mmol, 0.1 equiv) in DMF (10 mL) were added Cs2CO3 (2.00 g, 6.16 mmol, 2.0 equiv) and (3-(methylsulfanyl)phenyl)methanol (713 mg, 4.62 mmol, 1.5 equiv). The reaction mixture was stirred at 100°C for 3 h. After cooling down to room temperature, the resulting mixture was diluted with EtOAc and washed with H2O. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc / PE (78:22) to afford 2-methoxy-5-((3- (methylsulfanyl)phenyl)methoxy)-1,8-naphthyridine (900 mg, 74%) as a light yellow oil. Step 2: (3-(((7-methoxy-1,8-naphthyridin-4-yl)oxy)methyl)phenyl)(methyl)-lambda6- sulfanediimine [0300] The title compound was analogously as described in Example 41, Step 3, except 2-methoxy-5-((3-(methylsulfanyl)phenyl)methoxy)-1,8- naphthyridine (600 mg, 1.92 mmol) was used. The crude product was purified by reverse phase flash, eluted with ACN/H2O (35:65) and then re-purified by prep-HPLC with the following conditions (Column: Xselect CSH Prep C18 Column, 30*250 mm, 10μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 8% B to38 % B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 8.5) to afford (3-(((7-methoxy-1,8-naphthyridin-4-yl)oxy)methyl)phenyl)(methyl)-lambda6- sulfanediimine (38.1 mg, 5%) as an off-white solid. MS (ESI, pos. ion) m/z: 343.0 (M+1).1H NMR (400 MHz, DMSO-d6, ppm) δ 8.77 (d, J = 5.6 Hz, 1H), 8.46 (d, J = 8.8 Hz, 1H), 8.23 (d, J = 2.0 Hz, 1H), 8.09 - 8.02 (m, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.15 (d, J = 5.6 Hz, 1H), 7.07 (d, J = 8.8 Hz, 1H), 5.50 (s, 2H), 4.01 (s, 3H), 3.03 - 2.97 (m, 5H). Example 19 Synthesis of cyclopropyl(3-(((7-methoxy-1,8-naphthyridin-4-yl)oxy)methyl)phenyl)- lambda6-sulfanediimine Step 1: 5-(((6-methoxypyridin-2-yl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6- dione [0301] A mixture of 2,2- (5.20 g, 36.08 mmol, 2.2 equiv) in trimethoxymethane (22 mL) was refluxed for 2 h. The solution was allowed to cool to room temperature, 6-methoxypyridin-2-amine (2.00 g, 16.11 mmol, 1 equiv) was added and the resulting solution was stirred overnight at 105 oC. The mixture was cooled to room temperature and the resulting precipitate was filtered, washed with EtOH and dried in vacuo to afford 5-(((6-methoxypyridin-2-yl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (4.01 g, 88%) as an orange solid. Step 2: 7-methoxy-1,8-naphthyridin-4-ol [0302] A mixture of 5-(((6- methylene)-2,2-dimethyl-1,3- dioxane-4,6-dione (4.00 g, 14.37 mmol, 1.0 equiv) in phenoxybenzene (40 mL) was stirred at 225 oC for 1.5 h. After cooling down to room temperature, the mixture was diluted with Et2O. The resulting precipitate was filtered, washed with Et2O and dried to afford 7-methoxy-1,8- naphthyridin-4-ol (968 mg, 30%) as a grey solid. Step 3: 5-chloro-2-methoxy-1,8-naphthyridine [0303] To a stirred solution of 7-met hthyridin-4-ol (5.00 g, 28.38 mmol, 1 equiv) in toluene (100 mL) were added DIEA (7.34 g, 56.76 mmol, 2 equiv) and POCl3 (5.22 g, 34.05 mmol, 1.2 equiv) at room temperature. After stirring at 70 °C for 2 h, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with EtOAc/PE (46:54) to afford 5-chloro-2-methoxy-1,8- naphthyridine (2.30 g, 37%) as a yellow solid. Step 4: 5-((3-(cyclopropylsulfanyl)phenyl)methoxy)-2-methoxy-1,8-naphthyridine [0304] A solution of (3- (1.10 g, 6.10 mmol, 1.48 equiv) in DMF (15 mL) was treated with NaH (500 mg, 12.50 mmol, 3.0 equiv, 60%) at 0 oC for 10 min under nitrogen atmosphere followed by the addition of 5-chloro-2- methoxy-1,8-naphthyridine (800 mg, 4.11 mmol, 1 equiv) dropwise at 0 oC. The resulting mixture was stirred at room temperature for 2 h under nitrogen atmosphere. The reaction was quenched by the addition of water at 0 oC and extracted with EtOAc . The combined organic layers were washed with brine , dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash, eluted with ACN/H2O (28:72) to afford 5-((3-(cyclopropylsulfanyl)phenyl)methoxy)-2-methoxy- 1,8-naphthyridine (580 mg, 41%) as a yellow solid. Step 5: cyclopropyl(3-(((7-methoxy-1,8-naphthyridin-4-yl)oxy)methyl)phenyl)-lambda6- sulfanediimine [0305] The title compound was synthesized by proceeding analogously as described in Example 41, Step 3, except 5-((3-(cyclopropylsulfanyl)phenyl)methoxy)-2-methoxy-1,8- naphthyridine (440 mg, 1.30 mmol) was used. The crude product was purified by reverse phase flash, eluted with ACN/H2O (28:72) and then re-purified by prep-HPLC with the following conditions (Column: Xbridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 9% B to 39 % B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 8.68). The fractions containing the desired product were combined and lyophilized to give cyclopropyl(3-(((7-methoxy-1,8-naphthyridin-4-yl)oxy)methyl)phenyl)-lambda6- sulfanediimine (4.5 mg, 0.9%) as a white solid. MS (ESI, pos. ion) m/z: 369.1 (M+1).1H NMR (400 MHz, DMSO-d6, ppm) δ 8.77 (d, J = 5.4 Hz, 1H), 8.45 (d, J = 8.9 Hz, 1H), 8.15 (d, J = 2.2 Hz, 1H), 7.96 (d, J = 7.9 Hz, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.58 (t, J = 7.7 Hz, 1H), 7.14 (d, J = 8.9 Hz, 1H), 7.04 (d, J = 5.5 Hz, 1H), 5.62 (s, 2H), 4.05 (s, 3H), 2.77 (s, 2H), 2.73 - 2.64 (m, 1H), 0.96 - 0.85 (m, 2H), 0.82 - 0.72 (m, 2H). Example 20 Synthesis of (3-fluoro-5-(((6-fluoro-7-methoxyquinazolin-4-yl)oxy)methyl)phenyl)(methyl)- lambda6-sulfanediimine Step 1: 6-fluoro-4-((3-fluoro-5- methoxy)-7-methoxyquinazoline [0306] To a solution of 4-chloro- (600 mg, 2.82 mmol, 1.0 equiv) and KF (16 mg, 0.28 mmol, 0.1 equiv) in DMF (10 mL) were added (3-fluoro-5- (methylsulfanyl)phenyl)methanol (729 mg, 4.23 mmol, 1.5 equiv) and Cs2CO3 (1.84 g, 5.64 mmol, 2.0 equiv). The reaction mixture was stirred at 100 °C for 3 h. After cooling to room temperature, the resulting mixture was diluted H2O and extracted with DCM. The organic layer was washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced. The residue was purified by silica gel column chromatography, eluted with EtOAc / PE (38:62) to afford 6-fluoro-4-((3-fluoro-5- (methylsulfanyl)phenyl)methoxy)-7-methoxyquinazoline (900 mg, 74%) as an off-white solid. Step 2: (3-fluoro-5-(((6-fluoro-7-methoxyquinazolin-4-yl)oxy)methyl)phenyl)(methyl)- lambda4-sulfaniminium 2,4,6-trimethylbenzenesulfonate [0307] To a solution of 6- phenyl)methoxy)-7- methoxyquinazoline (500 mg, 1.43 mmol, 1.0 equiv) in DCM (5 mL) was added amino 2,4,6- trimethylbenzenesulfonate (926 mg, 4.30 mmol, 3.0 equiv) under 0 °C. The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure to afford (3-fluoro-5-(((6-fluoro-7-methoxyquinazolin-4- yl)oxy)methyl)phenyl)(methyl)-lambda4-sulfaniminium 2,4,6-trimethylbenzenesulfonate (800 mg, crude) as an off-white solid. The crude product was used in the next step directly without further purification. Step 3: (3-fluoro-5-(((6-fluoro-7-methoxyquinazolin-4-yl)oxy)methyl)phenyl)(methyl)- lambda6-sulfanediimine [0308] The title compound was analogously as described in Example 40, Step 3, except (3-fluoro-5-(((6-fluoro-7-methoxyquinazolin-4- yl)oxy)methyl)phenyl)(methyl)-lambda4-sulfaniminium 2,4,6-trimethylbenzenesulfonate (500 mg, crude) was used instead of (4-(((7-methoxyquinolin-4- yl)oxy)methyl)phenyl)(methyl)-lambda4-sulfaniminium 2,4,6-trimethylbenzenesulfonate. The crude product was purified by reverse phase flash, eluted with ACN/H2O (35:65) and then re-purified by prep-HPLC with the following conditions (Column: Xbridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 11% B to 41 % B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 8.68) to afford (3-fluoro-5-(((6-fluoro-7-methoxyquinazolin-4- yl)oxy)methyl)phenyl)(methyl)-lambda6-sulfanediimine (30.3 mg, 7%) as an off-white solid. MS (ESI, pos. ion) m/z: 379.1 (M+1). 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.79 (s, 1H), 8.06 (d, J = 1.6 Hz, 1H), 7.97 (d, J = 11.2 Hz, 1H), 7.81 (d, J = 8.4, 1H), 7.69 (d, J = 9.2, 1H), 7.56 (d, J = 8.0 Hz, 1H), 5.72 (s, 2H), 4.05 (s, 3H), 3.15 (s, 2H), 3.07 (s, 3H). 19F NMR (376 MHz, DMSO-d6) δ -111.40 (s, 1 F), δ -130.53 (s, 1 F). Example 21 (3-(((6-fluoro-7-methoxyquinazolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda6- sulfanediimine Step 1: 6-fluoro-7-methoxy-3H-quinazolin-4-one [0309] To a stirred solution of 2- methoxybenzoic acid (4.90 g, 26.46 mmol, 1 equiv) in 2-methoxyethanol (100 mL) was added formamidine acetate (5.51 g, 52.92 mmol, 2 equiv) at room temperature. After stirring at 120 oC for 2 h, the resulting mixture was cooling down to room temperature and dissolved in water (200 mL). The precipitated solids were collected by filtration, washed with water (150 mL) and dried under reduced pressure to give 6-fluoro-7-methoxy-3H-quinazolin-4-one (4.67 g, 91%) as a yellow solid. Step 2: 4-chloro-6-fluoro-7-methoxyquinazoline [0310] To a stirred solution of 6-fluoro-7-methoxy-3H-quinazolin-4-one (4.50 g, 23.17 mmol, 1 equiv) in toluene (90 mL) were added DIEA (5.99 g, 46.35 mmol, 2 equiv) and phosphoroyl trichloride (17.77 g, 115.88 mmol, 5 equiv) at room temperature. After stirring at 90 oC for 2 h, the resulting mixture was concentrated under reduced pressure and diluted with H2O ( and extracted with EtOAc The organic layer was washed with brine dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-chloro-6-fluoro-7-methoxyquinazoline (4.80 g, 97%) as a yellow solid. Step 3: 6-fluoro-7-methoxy-4-((3-(methylsulfanyl)phenyl)methoxy)quinazoline [0311] To a stirred solution of 4- (500 mg, 2.35 mmol, 1 equiv) in DMF (10 mL) were added Cs2CO3 (2.30 g, 7.05 mmol, 3 equiv) and (3- (methylsulfanyl)phenyl)methanol (544 mg, 3.52 mmol, 1.5 equiv) at room temperature. After stirring at 80 oC for 2 h, the resulting mixture was concentrated under reduced pressure and diluted H2O and extracted with EtOAc . The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with EtOAc/PE (33:67) to give 6-fluoro-7-methoxy-4-((3- (methylsulfanyl)phenyl)methoxy)quinazoline (610 mg, 70%) as a yellow solid. Step 4: ((3-(((6-fluoro-7-methoxyquinazolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda4- sulfanylidene)azanium 2,4,6-trimethylbenzenesulfonate [0312] To a stirred solution of ((3- (methylsulfanyl)phenyl)methoxy)-quinazoline (400 mg, 1.21 mmol, 1 equiv) in DCM (8 mL) was added amino 2,4,6-trimethylbenzenesulfonate (781 mg, 3.63 mmol, 3 equiv) at room temperature. After stirring for 1 h, the resulting mixture was concentrated under reduced pressure to give ((3-(((6-fluoro-7-methoxyquinazolin-4- yl)oxy)methyl)phenyl)(methyl)-lambda4-sulfanylidene)azanium 2,4,6- trimethylbenzenesulfonate (560 mg, crude) as a white solid. Step 5: (3-(((6-fluoro-7-methoxyquinazolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda6- sulfanediimine [0313] The title compound was analogously as described in Example 40, Step 3, except ((3-(( 4- yl)oxy)methyl)phenyl)(methyl)-lambda4-sulfanylidene)azanium 2,4,6- trimethylbenzenesulfonate (400 mg, crude) was used instead of (4-(((7-methoxyquinolin-4- yl)oxy)methyl)phenyl)(methyl)-lambda4-sulfaniminium 2,4,6-trimethylbenzenesulfonate. The crude product was purified by reverse phase flash, eluted with ACN/H2O (22:78) and then re-purified by prep-HPLC with the following conditions (Column: Xselect CSH Prep C18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 3% B to 25% B in 8 min; Wave Length: 254 nm / 220 nm; RT1(min): 7.17). The fractions containing the desired product were combined and lyophilized to give (3-(((6-fluoro-7-methoxyquinazolin-4-yl)oxy)methyl)phenyl)(methyl)- lambda6-sulfanediimine (32.5 mg, 11%) as a white solid. MS (ESI, pos. ion) m/z: 361.1 (M+1).1H NMR (400 MHz, DMSO-d6, ppm) δ 8.78 (s, 1H), 8.22 (t, J = 1.9 Hz, 1H), 8.03 (d, J = 7.8 Hz, 1H), 7.89 (d, J = 11.0 Hz, 1H), 7.78 (d, J = 7.7 Hz, 1H), 7.61 (t, J = 7.7 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 5.72 (s, 2H), 4.04 (s, 3H), 3.03 (s, 3H). 19F NMR (376 MHz, DMSO-d6) δ -130.57 (s, 1 F). Example 22 Synthesis of cyclopropyl(4-(((7-methoxy-1,8-naphthyridin-4-yl)oxy)methyl)phenyl)- lambda6-sulfanediimine Step 1: 4-(cyclopropylsulfanyl)ben [0314] To a stirred solution of 4-mercaptobenzoic acid (2.00 g, 12.97 mmol, 1 equiv) in DMSO (20 mL) were added potassium tert-butoxide (3.64 g, 32.43 mmol, 2.5 equiv) and bromocyclopropane (1.6 mL) at room temperature. The resulting mixture was stirred overnight at 120 oC. After cooling down to room temperature, the mixture was dissolved in water (200 mL) and acidified to pH = 5 with 1 M HCl (aq). The precipitated solid was collected by filtration, washed with water (150 mL) and dried under vacuum to give 4- (cyclopropylsulfanyl)benzoic acid (1.69 g, 67%) as a white solid. Step 2: (4-(cyclopropylsulfanyl)phenyl)methanol [0315] To a stirred solution of 4- benzoic acid (500 mg, 2.57 mmol, 1 equiv) in THF (10 mL) was added LiAlH4 (2.8 mL, 5.60 mmol, 2.18 equiv) at 0 oC. After stirring for 2 h at room temperature, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with MeOH/DCM (9:91) to afford (4-(cyclopropylsulfanyl)phenyl)methanol (292 mg, 62%) as a colorless oil. Step 3: 5-((4-(cyclopropylsulfanyl)phenyl)methoxy)-2-methoxy-1,8-naphthyridine [0316] To a stirred solution of 5-ch -1,8-naphthyridine (400 mg, 2.05 mmol, 1 equiv) in DMF (8 mL) were added Cs2CO3 (2.00 g, 6.16 mmol, 3 equiv), (4- (cyclopropylsulfanyl)phenyl)methanol and KF (11 mg, 0.20 mmol, 0.1 equiv) at room temperature. The resulting mixture was stirred at 100 oC for 2 h. After cooling down to room temperature, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with EA/PE (61:39) to afford 5-((4- (cyclopropylsulfanyl)phenyl)methoxy)-2-methoxy-1,8-naphthyridine (390 mg, 55%) as a yellow solid. Step 4: cyclopropyl(4-(((7-methoxy-1,8-naphthyridin-4-yl)oxy)methyl)phenyl)-lambda6- sulfanediimine [0317] The title compound was analogously as described in Example 41, Step 3, except 5-((4-(cyclopropylsulfanyl)phenyl)methoxy)-2-methoxy-1,8- naphthyridine (400 mg, 1.18 mmol) was used. The crude product was purified by reverse phase flash, eluted with ACN/H2O (30:70) and then re-purified by prep-HPLC with the following conditions (Column: Xbridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to35 % B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 8.68). The fractions containing the desired product were combined and lyophilized to give cyclopropyl(4-(((7-methoxy-1,8-naphthyridin-4-yl)oxy)methyl)phenyl)-lambda6- sulfanediimine (19.6 mg, 4%) as a white solid. MS (ESI, pos. ion) m/z: 369.1 (M+1).1H NMR (400 MHz, DMSO-d6, ppm) δ 8.77 (d, J = 5.4 Hz, 1H), 8.50 (d, J = 8.9 Hz, 1H), 8.08 - 8.01 (m, 2H), 7.72 (d, J = 8.2 Hz, 2H), 7.13 (d, J = 5.5 Hz, 1H), 7.07 (d, J = 8.9 Hz, 1H), 5.49 (s, 2H), 4.01 (s, 3H), 2.79 (s, 2H), 2.76 - 2.68 (m, 1H), 0.97 - 0.92 (m, 2H), 0.86 - 0.75 (m, 2H). Example 23 Synthesis of (2-(1-(6-fluoro-7-methoxyquinazolin-4-yl)piperidin-4-yl)ethyl)(methyl)- lambda6-sulfanediimine Step 1: 6-fluoro-7-methoxy-4-(4- ethyl)piperidin-1-yl)quinazoline [0318] To a solution of 4-chloro-6- (300 mg, 1.41 mmol, 1 equiv) in NMP (6 mL) were added DIEA (910 mg, 7.041 mmol, 5 equiv) and 4-(2- (methylsulfanyl)ethyl)piperidine hydrochloride (420 mg, 2.14 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred at 100 oC for 3 h. After cooling down to room temperature, the reaction mixture was purified by reversed phase flash, eluted with ACN/H2O (68:32) to afford 6-fluoro-7-methoxy-4-(4-(2-(methylsulfanyl)ethyl)piperidin-1- yl)quinazoline (400 mg, 84%) as a brown solid. Step 2: (2-(1-(6-fluoro-7-methoxyquinazolin-4-yl)piperidin-4-yl)ethyl)(methyl)-lambda6- sulfanediimine [0319] The title compound was syn ceeding analogously as described in Example 41, Step 3, except 6-fluoro-7-methoxy-4-(4-(2-(methylsulfanyl)ethyl)piperidin-1- yl)quinazoline (350 mg, 1.04 mmol) was used. The crude product was purified by reverse phase flash, eluted with ACN/H2O (28:72) and then re-purified by prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 30% B in 8min; Wave Length: 254 nm / 220 nm; RT1(min): 7.63) to afford (2-(1-(6-fluoro-7-methoxyquinazolin-4-yl)piperidin-4-yl)ethyl)(methyl)-lambda6- sulfanediimine (27.5 mg, 7%) as a white solid. MS (ESI, pos. ion) m/z: 366.1 (M+1).1H NMR (400 MHz, DMSO-d6, ppm) δ 8.56 (s, 1H), 7.66 (d, J = 12.2 Hz, 1H), 7.39 (d, J = 8.5 Hz, 1H), 4.19 (d, J = 13.0 Hz, 2H), 4.00 (s, 3H), 3.16 - 2.98 (m, 4H), 2.86 (s, 3H), 2.27 (s, 2H), 1.87 - 1.78 (m, 2H), 1.77 - 1.67 (m, 3H), 1.44 - 1.33 (m, 2H). 19F NMR (377 MHz, DMSO-d6) δ -132.81 (s, 1 F). Example 24 Synthesis of (2-(1-(6-fluoro-7-methoxyquinolin-4-yl)piperidin-4-yl)ethyl)(methyl)-lambda6- sulfanediimine Step 1: 6-fluoro-7-methoxy-4-(4- ethyl)piperidin-1-yl)quinoline [0320] To a solution of 4-chloro-6- xyquinoline (500 mg, 2.36 mmol, 1.0 equiv) in NMP were added DIEA (1526 mg, 11.81 mmol, 5.0 equiv) and 4-(2- (methylsulfanyl)ethyl)-piperidine hydrochloride (693 mg, 3.54 mmol, 1.5 equiv). The reaction mixture was stirred at 130 °C for 3 h. The mixture was allowed to cool down to room temperature. The crude product was purified by reverse phase flash, eluted with ACN/H2O (65:35) to afford 6-fluoro-7-methoxy-4-(4-(2-(methylsulfanyl)ethyl)piperidin-1- yl)quinoline (450 mg, 56%) as an off-white solid. Step 2: (2-(1-(6-fluoro-7-methoxyquinolin-4-yl)piperidin-4-yl)ethyl)(methyl)-lambda6- sulfanediimine [0321] The title compound was analogously as described in Example 41, Step 3, except 6-fluoro-7-methoxy-4-(4-(2-(methylsulfanyl)ethyl)piperidin-1- yl)quinoline (350 mg, 1.04 mmol) was used. The crude product was purified by reverse phase flash, eluted with ACN/H2O (20:80) and then re-purified by prep-HPLC with the following conditions (Column: XBridge Prep Shield RP18 OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 35 % B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 9.42) to afford (2-(1-(6-fluoro-7-methoxyquinolin-4-yl)piperidin-4-yl)ethyl)(methyl)- lambda6-sulfanediimine (51.9 mg, 13%) as an off-white solid. MS (ESI, pos. ion) m/z: 365.1 (M+1). 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.60 (d, J = 5.2 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 6.92 (d, J = 5.2 Hz, 1H), 3.99 (s, 3H), 3.46 (d, J = 9.2 Hz, 2H), 3.10 - 3.01 (m, 2H), 2.87 (s, 3H), 2.83 - 2.73 (m, 2H), 2.36 - 2.30 (m, 2H), 1.90 - 1.82 (m, 2H), 1.82 - 1.72 (m, 2H), 1.67 - 1.45 (m, 3H). 19F NMR (376 MHz, DMSO-d6) δ -133.51 (s, 1 F). Example 25 Synthesis of (2-(1-(8-methoxypyrido[3,4-d]pyrimidin-4-yl)piperidin-4-yl)ethyl)(methyl)- lambda6-sulfanediimine HN S NH Step 1: 1-(8-methoxypyrido[3,4-d] -4-(2-(methylsulfanyl)ethyl)piperidine [0322] To a solution of 4-chloro-8- [3,4-d]pyrimidine (300 mg, 1.53 mmol, 1 equiv) in NMP (6 mL) were added DIEA (991 mg, 7.67 mmol, 5 equiv) and 4-(2- (methylsulfanyl)ethyl)piperidine hydrochloride (450 mg, 2.30 mmol, 1.5 equiv). The resulting mixture was stirred at 100 oC for 2 h. After cooled to room temperature, the crude product was purified by reverse phase flash, eluted with ACN/H2O (60:40) to afford 1-(8- methoxypyrido[3,4-d]pyrimidin-4-yl)-4-(2-(methylsulfanyl)ethyl)piperidine (330 mg, 67%) as a yellow solid. Step 2: (2-(1-(8-methoxypyrido[3,4-d]pyrimidin-4-yl)piperidin-4-yl)ethyl)(methyl)- lambda6-sulfanediimine
[0323] The title compound was sy ceeding analogously as described in Example 41, Step 3, except 1-(8-methoxypyrido[3,4-d]pyrimidin-4-yl)-4-(2- (methylsulfanyl)ethyl)piperidine (280 mg, 0.87 mmol) was used. The crude product was purified by reverse phase flash, eluted with ACN/H2O (23:77) and then re-purified by prep- HPLC (Column: Xbridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 2% B to 29 % B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 8.68). The fractions containing the desired product were combined and lyophilized to give (2-(1-(8-methoxypyrido[3,4- d]pyrimidin-4-yl)piperidin-4-yl)ethyl)(methyl)-lambda6-sulfanediimine (27.4 mg, 8%) as yellow solid. MS (ESI, pos. ion) m/z: 349.1 (M+1).1H NMR (400 MHz, DMSO-d6, ppm) δ 8.64 (s, 1H), 8.04 (d, J = 5.9 Hz, 1H), 7.30 (d, J = 5.9 Hz, 1H), 4.33 (d, J = 13.0 Hz, 2H), 4.01 (s, 3H), 3.19 - 3.08 (m, 2H), 3.05 - 2.99 (m, 2H), 2.85 (s, 3H), 2.28 (s, 2H), 1.83 (d, J = 13.0 Hz, 2H), 1.75 - 1.66 (m, 3H), 1.41 - 1.27 (m, 2H). Example 26 Synthesis of (2-(1-(8-methoxy-1,7-naphthyridin-4-yl)piperidin-4-yl)ethyl)(methyl)-lambda6- sulfanediimine Step 1: tert-butyl 4-(2-( 1-carboxylate [0324] To a solution of tert-butyl 4-(2- ethyl)piperidine-1-carboxylate (9.00 g, 39.24 mmol, 1 equiv) in DCM (150 mL) were added TEA (11.91 g, 117.73 mmol, 3 equiv), DMAP (0.48 g, 3.925 mmol, 0.1 equiv) and methanesulfonic anhydride (20.51 g, 117.74 mmol, 3 equiv) at 0 oC. After stirring at room temperature for 2 h, the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford tert-butyl 4-(2-(methanesulfonyloxy)ethyl)piperidine-1- carboxylate (10.00 g, crude) as a light yellow oil, which was used for next step directly without further purification. Step 2: tert-butyl 4-(2-(methylsulfanyl)ethyl)piperidine-1-carboxylate [0325] To a solution of tert-butyl 4-(2- ethyl)piperidine-1-carboxylate (10.00 g, 32.53 mmol, 1 equiv) in EtOH (150 mL) was added sodium methanethiolate (113.98 g, 325.30 mmol, 10 equiv, 20% aq). After stirring at room temperature for 2 h, the resulting mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with EtOAc.The combined organic layers were washed with brine , dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with EA/PE (20:80) to afford tert-butyl 4-(2-(methylsulfanyl)ethyl)piperidine-1-carboxylate (7.00 g, 69% for two steps) as a colorless oil. Step 3: 4-(2-(methylthio)ethyl)piperidine hydrochloride [0326] A solution of tert-butyl 4-(2-(m anyl)ethyl)piperidine-1-carboxylate (851 mg, 3.28 mmol) in HCl (10 mL, gas, 4 M in 4-dioxane) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure to afford 4-(2- (methylthio)ethyl)piperidine hydrochloride (716 mg, crude) as a white solid. Step 4: 8-methoxy-4-(4-(2-(methylsulfanyl)ethyl)piperidin-1-yl)-1,7-naphthyridine [0327] To a stirred mixture of 4-(2- piperidine hydrochloride (400 mg, crude) and 4-chloro-8-methoxy-1,7-naphthyridine (600 mg, 3.08 mmol) in NMP (8 mL) was added DIEA (1.34 g, 10.36 mmol, 2.5 equiv) at room temperature. The resulting mixture was stirred at 130 °C for 3 h. After cooling down to room temperature, the crude product was purified by reverse phase flash chromatography with the following conditions ACN/water (56:44) to afford 8-methoxy-4-(4-(2-(methylsulfanyl)ethyl)piperidin-1-yl)-1,7-naphthyridine (480 mg, 64%) as a brown solid. Step 5: (2-(1-(8-methoxy-1,7-naphthyridin-4-yl)piperidin-4-yl)ethyl)(methyl)-lambda6- sulfanediimine
[0328] The title compound was synt oceeding analogously as described in Example 41, Step 3, except 8-methoxy-4-(4-(2-(methylsulfanyl)ethyl)piperidin-1-yl)-1,7- naphthyridine (430 mg, 1.35 mmol) was used. The crude product was purified by prep-HPLC with the following conditions (Column: XBridge Prep Shield RP18 OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 2% B to25 % B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 9.02) to afford (2-(1-(8-methoxy-1,7-naphthyridin-4-yl)piperidin-4- yl)ethyl)(methyl)-lambda6-sulfanediimine (59.8 mg, 12%) as a yellow solid. MS (ESI, pos. ion) m/z: 348.1 (M+1).1H NMR (400 MHz, DMSO-d6) δ 8.67 (d, J = 5.0 Hz, 1H), 8.02 (d, J = 5.9 Hz, 1H), 7.33 (d, J = 6.0 Hz, 1H), 7.15 (d, J = 5.1 Hz, 1H), 4.03 (s, 3H), 3.55 (d, J = 12.3 Hz, 2H), 3.09 - 3.02 (m, 2H), 2.88 (s, 3H), 2.85 - 2.76 (m, 2H), 2.46 - 2.13 (m, 2H), 1.92 - 1.84 (m, 2H), 1.81 - 1.73 (m, 2H), 1.68 - 1.57 (m, 1H), 1.55 - 1.43 (m, 2H). Example 27 Synthesis of cyclopropyl(3-((7-methoxyquinolin-4-yl)oxy)phenyl)-lambda6-sulfanediimine Step 1: 4-(3- [0329] To a stirred mixture (650 mg, 3.91 mmol, 1.5 equiv) and 4-chloro-7-methoxyquinoline (500 mg, 2.58 mmol, 100 equiv) in DMF (10 mL) was added Cs2CO3 (1.70 g, 5.22 mmol, 2.0 equiv). After stirring at 120 °C for 2 h, the mixture was allowed to cool down to room temperature. The reaction mixture was diluted with waterand then extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase flash with the following conditions ACN/water (22:78) to afford 4-(3-(cyclopropylsulfanyl)phenoxy)-7-methoxyquinoline (700 mg, 82%) as brown oil Step 2: cyclopropyl(3-((7-methoxyquinolin-4-yl)oxy)phenyl)-lambda4-sulfaniminium 2,4,6-trimethylbenzenesulfonate [0330] A mixture of 4-(3- 7-methoxyquinoline (400 mg, 1.237 mmol, 1 equiv) and amino 2,4,6-trimethylbenzenesulfonate (800 mg, 3.716 mmol, 3.00 equiv) in DCM (8 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure to afford cyclopropyl(3-((7-methoxyquinolin-4- yl)oxy)phenyl)-lambda4-sulfaniminium 2,4,6-trimethylbenzenesulfonate (680 mg, crude) as a brown solid witch was used in the next step directly without further purification. Step 3: cyclopropyl(3-((7-methoxyquinolin-4-yl)oxy)phenyl)-lambda6-sulfanediimine [0331] The title compound analogously as described in Example 40, Step 3, except cyclopropyl(3-((7-methoxyquinolin-4-yl)oxy)phenyl)-lambda4- sulfaniminium 2,4,6-trimethylbenzenesulfonate (680 mg, crude) was used instead of (4-(((7- methoxyquinolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda4-sulfaniminium 2,4,6- trimethylbenzenesulfonate. The crude product was purified by reverse phase flash, eluted with ACN/H2O (29:61) and then re-purified by prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol /L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 12% B to27 % B in 18 min; Wave Length: 254 nm / 220 nm; RT1(min): 17.5) to afford cyclopropyl(3-((7- methoxyquinolin-4-yl)oxy)phenyl)-lambda6-sulfanediimine (4 mg, 2%) as an off-white solid. MS (ESI, pos. ion) m/z: 354.1 (M+1).1H NMR (400 MHz, DMSO-d6) δ 8.67 (d, J = 5.1 Hz, 1H), 8.20 (d, J = 9.1 Hz, 1H), 7.93 (d, J = 7.9 Hz, 1H), 7.83 - 7.78 (m, 1H), 7.70 (t, J = 7.9 Hz, 1H), 7.53 - 7.42 (m, 2H), 7.35 - (m, 1H), 6.57 (d, J = 5.1 Hz, 1H), 3.95 (s, 3H), 2.91 (s, 2H), 2.82 - 2.73 (m, 1H), 0.97 - 0.90 (m, 2H), 0.86 - 0.79 (m,2H). Example 28 Synthesis of cyclopropyl(3-((7-methoxyquinazolin-4-yl)oxy)phenyl)-lambda6-sulfanediimine Step 1: 3- [0332] To a stirred solution of 3- (5.00 g, 39.62 mmol, 1 equiv) in DMSO (70 mL) was added potassium tert-butoxide (8.00 g, 71.29 mmol, 1.80 equiv) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 30 min. To the above mixture was added bromocyclopropane (5.72 mL, 71.39 mmol, 1.80 equiv) dropwise at room temperature. After stirring overnight at 90 °C, the resulting mixture was allowed to cool down to room temperature. The reaction mixture was diluted with water (500 mL) and then extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by purified by reverse phase flash, eluted with EtOAc/PE (5:95) to afford 3-(cyclopropylsulfanyl)phenol (5.00 g, 74%) as yellow oil. Step 2: 4-(3-(cyclopropylthio)phenoxy)-7-methoxyquinazoline [0333] To a stirred mixture (580 mg, 3.48 mmol, 1.5 equiv) and 4-chloro-7-methoxyquinazoline (450 mg, 2.31 mmol, 1.0 equiv) in DMSO (7 mL) was added Cs2CO3 (1.50 g, 4.60 mmol, 2.0 equiv). After stirring at 80 °C for 2 h, the mixture was allowed to cool down to room temperature. The reaction mixture was diluted with water and then extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase flash with the following conditions ACN/water (61:39) to afford 4- (3-(cyclopropylsulfanyl)phenoxy)-7-methoxyquinazoline (680 mg, 87%) as yellow oil. Step 3: cyclopropyl(3-((7-methoxyquinazolin-4-yl)oxy)phenyl)-lambda4-sulfaniminium 2,4,6-trimethylbenzenesulfonate [0334] A mixture of 4-(3- 7-methoxyquinazoline (250 mg, 0.771 mmol, 1 equiv) and amino 2,4,6-trimethylbenzenesulfonate (500 mg, 2.323 mmol, 3.01 equiv) in DCM (5 mL) was stirred at RT for 1 h. The resulting mixture was concentrated under reduced pressure to afford cyclopropyl(3-((7-methoxyquinazolin-4-yl)oxy)phenyl)- lambda4-sulfaniminium 2,4,6-trimethylbenzenesulfonate (530 mg, crude) as a brown solid. The crude product was used in the next step directly without further purification. Step 4: cyclopropyl(3-((7-methoxyquinazolin-4-yl)oxy)phenyl)-lambda6-sulfanediimine [0335] The title compound analogously as described in Example 40, Step 3, except cyclopropyl(3-((7-methoxyquinazolin-4-yl)oxy)phenyl)- lambda4-sulfaniminium 2,4,6-trimethylbenzenesulfonate (530 mg, crude) was used instead of (4-(((7-methoxyquinolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda4-sulfaniminium 2,4,6- trimethylbenzenesulfonate. The crude product was purified by reverse phase flash, eluted with ACN/H2O (25:75) and then re-purified by prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 10% B to 40% B in 7 min; Wave Length: 254 nm / 220 nm; RT1(min): 6.82) to afford cyclopropyl(3-((7- methoxyquinazolin-4-yl)oxy)phenyl)-lambda6-sulfanediimine (12.2 mg, 2%) as an off-white solid. MS (ESI, pos. ion) m/z: 355.2 (M+1).1H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.30 (d, J = 9.8 Hz, 1H), 7.97 - 7.87 (m, 2H), 7.67 (t, J = 8.0 Hz, 1H), 7.60 - 7.54 (m, 1H), 7.44 - 7.37 (m, 2H), 3.99 (s, 3H), 2.90 (s, 2H), 2.81 - 2.72 (m, 1H), 0.99 - 0.93 (m, 2H), 0.86 - 0.79 (m, 2H). Example 29 Synthesis of cyclopropyl(4-((6,7-dimethoxyquinazolin-4-yl)oxy)phenyl)-lambda6- sulfanediimine Step 1: 4-(4- [0336] To a solution of 4- (500 mg, 2.22 mmol, 1.0 equiv) in DMSO (10 mL) were added 4-(cyclopropylsulfanyl)phenol (555 mg, 3.33 mmol, 1.5 equiv) and Cs2CO3 (1450 mg, 4.45 mmol, 2.0 equiv). The reaction mixture was stirred at 100 °C for 3 h. After cooling down to room temperature, the resulting mixture was diluted EtOAc and washed with H2O. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc / PE (60:40) to afford 4-(4- (cyclopropylsulfanyl)phenoxy)-6,7-dimethoxyquinazoline (700 mg, 88%) as an off-white solid. Step 2: cyclopropyl(4-((6,7-dimethoxyquinazolin-4-yl)oxy)phenyl)-lambda4- sulfaniminium 2,4,6-trimethylbenzenesulfonate [0337] To a solution of 4-(4- xy)-6,7-dimethoxyquinazoline (400 mg, 1.12 mmol, 1.0 equiv) in DCM (10 mL) was added amino 2,4,6- trimethylbenzenesulfonate (728 mg, 3.38 mmol, 3.0 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure to afford cyclopropyl(4-((6,7-dimethoxyquinazolin-4-yl)oxy)phenyl)-lambda4- sulfaniminium 2,4,6-trimethylbenzenesulfonate (600 mg, crude). The crude product was used in the next step directly without further purification. Step 3: cyclopropyl(4-((6,7-dimethoxyquinazolin-4-yl)oxy)phenyl)-lambda6- sulfanediimine [0338] The title compound analogously as described in Example 40, Step 3, except cyclopropyl(4-((6,7-dimethoxyquinazolin-4-yl)oxy)phenyl)- lambda4-sulfaniminium 2,4,6-trimethylbenzenesulfonate (600 mg, crude) was used instead of (4-(((7-methoxyquinolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda4-sulfaniminium 2,4,6- trimethylbenzenesulfonate. The crude product was purified by reverse phase flash, eluted with ACN/H2O (45:55) to afford a crude product, which was re-purified by prep-HPLC with the following conditions ( Xbridge Prep OBD C18 Column, 30*150 mm, 5μm Water (10 mmol/L NH4HCO3); ACN; 60 mL/min; 11% B to 41 % B in 10 min Wave Length: 254 nm / 220 nm, RT1(min): 8.68) to afford cyclopropyl(4-((6,7-dimethoxyquinazolin-4- yl)oxy)phenyl)-lambda6-sulfanediimine (29.5 mg, 6%) as an off-white solid. MS (ESI, pos. ion) m/z: 385.1 (M+1).1H NMR (400 MHz, DMSO-d6, ppm) δ 8.59 (s, 1H), 8.10 (s, 1H), 8.08 (s, 1H), 7.57 (s, 1H), 7.51 (s, 1H), 7.49 (s, 1H), 7.41 (s, 1H), 3.99 (d, J = 7.2 Hz, 6H), 2.84 (s, 2H), 2.83 - 2.72 (m, 1H), 1.02 - 0.94 (m, 2H), 0.90 - 0.79 (m, 2H). Example 30 Synthesis of cyclopropyl(3-(((7-methoxyquinazolin-4-yl)oxy)methyl)phenyl)-lambda6- sulfanediimine Step 1: 4-((3- [0339] To a solution of 4- (500 mg, 2.50 mmol, 1 equiv) in DMF (12 mL) were added Cs2CO3 (1.70 g, 5.20 mmol, 2.0 equiv) and (3- (cyclopropylsulfanyl)phenyl)-methanol (556 mg, 3.10 mmol, 1.2 equiv) at room temperature. The resulting mixture was stirred at 80 oC for 2 h. After cooling down to room temperature, water was added, then extracted with EtOAc . The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc / PE (87/13) to afford 4-((3-(cyclopropylsulfanyl)phenyl)methoxy)-7-methoxyquinazoline (566 mg, 65%) as an orange solid. Step 2: cyclopropyl(3-(((7-methoxyquinazolin-4-yl)oxy)methyl)phenyl)-lambda4- sulfaniminium 2,4,6-trimethylbenzenesulfonate [0340] To a solution of 4-((3- yl)methoxy)-7-methoxyquinazoline (565 mg, 1.85 mmol, 1 equiv) in DCM (6 mL) was added amino 2,4,6- trimethylbenzenesulfonate (1.20 g, 5.55 mmol, 3 equiv) at 0 oC. The reaction mixture was stirred at room temperature for 1 h. Half of DCM was concentrated and Et2O was added. The product crystallized upon storage at 4 oC 1 h and was collected by filtration and dried in high vacuum to afford cyclopropyl(3-(((7-methoxyquinazolin-4-yl)oxy)methyl)phenyl)-lambda4- sulfaniminium 2,4,6-trimethylbenzenesulfonate (1.00 g, crude) as an yellow solid. Step 3: cyclopropyl(3-(((7-methoxyquinazolin-4-yl)oxy)methyl)phenyl)-lambda6- sulfanediimine [0341] The title compound analogously as described in Example 40, Step 3, except cyclopropyl(3-(((7-methoxyquinazolin-4-yl)oxy)methyl)phenyl)- lambda4-sulfaniminium 2,4,6-trimethylbenzenesulfonate (1.00 g, crude) was used instead of (4-(((7-methoxyquinolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda4-sulfaniminium 2,4,6- trimethylbenzenesulfonate. The crude product was purified by reverse phase flash, eluted with ACN/H2O (28:72) to afford 100 mg of crude cyclopropyl(3-(((7-methoxyquinazolin-4- yl)oxy)methyl)phenyl)-lambda6-sulfanediimine and 150 mg of crude cyclopropyl(imino)(3- (((7-methoxyquinazolin-4-yl)oxy)methyl)phenyl)-lambda6-sulfanone. [0342] The 100 mg of crude cyclopropyl(3-(((7-methoxyquinazolin-4- yl)oxy)methyl)phenyl)-lambda6-sulfanediimine was re-purified by purified prep-HPLC with the following conditions Column: Xbridge Prep OBD C18 Column, 19*250 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: MeOH; Flow rate: 25 mL/min; Gradient: 45% B to 67 % B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 8.68. The fractions containing the desired product were combined and lyophilized to afford cyclopropyl(3-(((7-methoxyquinazolin-4-yl)oxy)methyl)phenyl)-lambda6-sulfanediimine (12.1 mg, 1%) as a white solid. MS (ESI, pos. ion) m/z: 369.1 (M+1).1H NMR (400 MHz, DMSO-d6, ppm) δ 8.75 (s, 1H), 8.16 (s, 1H), 8.10 (d, J = 9.0 Hz, 1H), 7.98 (d, J = 7.9, 1.5 Hz, 1H), 7.74 (d, J = 7.6, 1.4 Hz, 1H), 7.59 (t, J = 7.7 Hz, 1H), 7.33 (d, J = 2.5 Hz, 1H), 7.29 (q, J = 9.0, 2.5 Hz, 1H), 5.72 (s, 2H), 3.95 (s, 3H), 2.80 (s, 2H), 2.75 - 2.66 (m, 1H), 0.97 - 0.89 (m, 2H), 0.80 - 0.72 (m, 2H). Example 31 Synthesis of ((2-(7-methoxyquinazolin-4-yl)-2-azaspiro[3.3]heptan-6-yl)methyl)(methyl)- lambda6-sulfanediimine Step 1: 7-methoxy-4-(6-( azaspiro[3.3]heptan-2-yl)quinazoline [0343] To a solution of 4-chloro- (655 mg, 3.37 mmol) in NMP (10 mL) were added DIEA (3 mL) and 6-((methylsulfanyl)methyl)-2-azaspiro[3.3]heptane (1.90 g, crude). The resulting mixture was stirred at 100 oC for 2 h. After cooling down to room temperature, the crude product was purified by reverse phase flash, eluted with ACN/H2O (90:10) to afford 7-methoxy-4-(6-((methylsulfanyl)methyl)-2-azaspiro[3.3]heptan-2- yl)quinazoline (640 mg, 49%) as a brown yellow oil. Step 2: ((2-(7-methoxyquinazolin-4-yl)-2-azaspiro[3.3]heptan-6-yl)methyl)(methyl)- lambda6-sulfanediimine [0344] The title compound was analogously as described in Example 41, Step 3, except 7-methoxy-4-(6-((methylsulfanyl)methyl)-2- azaspiro[3.3]heptan-2-yl)quinazoline (640 mg, 1.75 mmol) was used. The crude product was purified by reverse phase flash, eluted with ACN/H2O to afford 100 mg of crude ((2-(7- methoxyquinazolin-4-yl)-2-azaspiro[3.3]heptan-6-yl)methyl)(methyl)-lambda6- sulfanediimine and 50 mg of crude imino((2-(7-methoxyquinazolin-4-yl)-2- azaspiro[3.3]heptan-6-yl)methyl)(methyl)-lambda6-sulfanone. [0345] The 100 mg of crude ((2-(7-methoxyquinazolin-4-yl)-2-azaspiro[3.3]heptan-6- yl)methyl)(methyl)-lambda6-sulfanediimine was re-purified by prep-HPLC with the following conditions Column: (XBridge Prep Shield RP18 OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/LNH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 2% B to 27 % B in 10 min; Wave Length: 254 nm / 220nm; RT1(min): 9.92). The fractions containing the desired product were combined and lyophilized to afford ((2-(7-methoxyquinazolin-4-yl)-2-azaspiro[3.3]heptan-6-yl)methyl)(methyl)-lambda6- sulfanediimine (36.9 mg, 7%) as a white solid. MS (ESI, pos. ion) m/z: 346.1 (M+1).1H NMR (400 MHz, DMSO-d6, ppm) δ 8.37 (s, 1H), 7.84 (d, J = 9.1 Hz, 1H), 7.09 (d, J = 2.6 Hz, 1H), 7.07 - 7.03 (m, 1H), 4.52 (s, 2H), 4.36 (s, 2H), 3.88 (s, 3H), 3.13 (d, J = 7.0 Hz, 2H), 2.80 (s, 3H), 2.72 (p, J = 7.4 Hz, 1H), 2.50 - 2.43 (m, 2H), 2.27 - 2.23 (m, 2H), 2.20 - 2.10 (m, 2H). Example 32 Synthesis of 1-(4-(((8-Methoxy-1,7-naphthyridin-4-yl)oxy)methyl)phenyl)-N,1-dimethyl- lambda6-sulfanediimine Step 1: 5-(((2-methoxypyridin-3-yl) ne)-2,2-dimethyl-1,3-dioxane-4,6- dione [0346] A solution of 2- g, 24.2 mmol, 1 equiv), 2,2- dimethyl-1,3-dioxane-4,6-dione (4.50 g, 31.46 mmol, 1.3 equiv) and trimethoxymethane (3.60 g, 33.8 mmol, 1.4 equiv) in acetonitrile (30 mL) was stirred at 80 oC for 2 h under nitrogen atmosphere. After cooling down to room temperature, the resulting solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA/ PE (25:75). The fractions containing the desired product were combined and concentrated under reduced pressure to afford 5-(((2-methoxypyridin-3- yl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (6.50 g, 97% ) as a yellow solid. Step 2: 8-methoxy-1,7-naphthyridin-4-ol [0347] A mixture of 5-(((2- amino)methylene)-2,2-dimethyl-1,3- dioxane-4,6-dione (1.50 g, 5.4 mmol, 1 equiv) in phenoxybenzene (38 mL) was stirred at 225 oC for 1.5 h. After cooling down to room temperature, PE was added to the reaction mixture. The precipitated solid was collected by filtration, washed with PE (30 ml x 3) and then purified by reverse phase flash, eluted with ACN/H2O (26:74) to afford 8-methoxy-1,7- naphthyridin-4-ol (600 mg, 63%) as a white solid. Step 3: 8-methoxy-4-((4-(methylsulfanyl)phenyl)methoxy)-1,7-naphthyridine [0348] To a mixture of 8-methoxy-1 in-4-ol (550 mg, 2.96 mmol, 1 equiv) in toluene (8 mL) were added (4-(methylthio)phenyl)methanol (912 mg, 5.92 mmol, 2 equiv) and 2-(tributyl-$l^(5)-phosphanylidene)acetonitrile (1.40 g, 5.92 mmol, 2 equiv). The resulting mixture was stirred at 130 oC for 2 h. After cooling down to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluted with MeOH/ DCM (9:91) to give 650 mg crude product, which was purified by reverse phase flash, eluted with ACN/H2O (45:55) to afford 8-methoxy-4- ((4-(methylsulfanyl)phenyl)methoxy)-1,7-naphthyridine (470 mg, 44%) as a white solid. Step 4: ((4-(((8-methoxy-1,7-naphthyridin-4-yl)oxy)methyl)phenyl)(methyl)-lambda4- sulfanylidene)azanium 2,4,6-trimethylbenzenesulfonate [0349] To a stirred solution of 8- phenyl)methoxy)-1,7- naphthyridine (300 mg, 0.96 mmol, 1 equiv) in DCM (6 mL) was added amino 2,4,6- trimethylbenzenesulfonate (620 mg, 2.88 mmol, 3 equiv) at room temperature. The resulting mixture was stirred at room temperature for 1 h. Half of the DCM was evaporated, and diethyl ether was added. The product crystallized upon storage at 0 oC for 10 min and was collected by filtration and dried under vacuum to give ((4-(((8-methoxy-1,7-naphthyridin-4- yl)oxy)methyl)phenyl)(methyl)-lambda4-sulfanylidene)azanium 2,4,6- trimethylbenzenesulfonate (320 mg, crude) as a yellow solid. Step 5: 1-(4-(((8-methoxy-1,7-naphthyridin-4-yl)oxy)methyl)phenyl)-N,1-dimethyl- lambda6-sulfanediimine [0350] To a stirred solution of ((4- naphthyridin-4- yl)oxy)methyl)phenyl)-(methyl)- azanium 2,4,6- trimethylbenzenesulfonate (300 mg, 0.56 mmol, 1 equiv) in DMF (6 mL) were added Na2CO3 (72 mg, 0.68 mmol, 1.2 equiv) and NCS (108 mg, 0.68 mmol, 1.2 equiv) at 0 oC. After stirring for 15 min, methanamine hydrochloride (191 mg, 2.84 mmol, 5 equiv) was added at 0 oC and the mixture was stirred overnight at room temperature. The resulting mixture was purified by reverse phase flash, eluted with ACN/H2O (28:72) and was concentrated under reduced pressure. The crude product was re-purified by prep-HPLC (Column: Welch Ultimate PFP 30*250, 10μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 6% B to36 % B in 10 min; Wave Length: 254 nm/220 nm; RT1(min): 7.5). The fractions containing the desired product were combined and lyophilized to give 1-(4-(((8-Methoxy-1,7-naphthyridin-4- yl)oxy)methyl)phenyl)-N,1-dimethyl-lambda6-sulfanediimine (9.8 mg, 4%) as a white solid. MS (ESI, pos. ion) m/z: 357.1 (M+1).1H NMR (400 MHz, DMSO-d6, ppm) δ 8.20 (d, J = 7.8 Hz, 1H), 7.99 (d, J = 5.4 Hz, 1H), 7.94 - 7.87 (m, 2H), 7.63 (d, J = 5.3 Hz, 1H), 7.29 (d, J = 8.2 Hz, 2H), 6.30 (d, J = 7.7 Hz, 1H), 5.82 (s, 2H), 3.82 (s, 3H), 2.97 (s, 3H), 2.57 (s, 1H), 2.45 (s, 3H). Example 33 Synthesis of (2-(1-(7-methoxyquinazolin-4-yl)piperidin-4-yl)ethyl)(methyl)-lambda6- sulfanediimine Step 1: 2-(1-(7-methoxyquinazolin- 4-yl)ethan-1-ol [0351] To a solution of 4-chloro- (800 mg, 4.11 mmol, 1.0 equiv) in NMP (8 mL) were added DIEA (1.59 g, 12.33 mmol, 3.0 equiv) and 4- piperidineethanol (1.33 g, 10.27 mmol, 2.5 equiv). The resulting mixture was stirred at 100 oC for 2 h. After cooling down to room temperature, the crude product was purified by reverse phase flash, eluted with ACN/H2O (44/56) to afford 2-(1-(7-methoxyquinazolin-4- yl)piperidin-4-yl)ethan-1-ol (1.15 g, 96%) as a yellow solid. Step 2: 2-(1-(7-methoxyquinazolin-4-yl)piperidin-4-yl)ethyl methanesulfonate [0352] To a solution of 2-(1-(7- 4-yl)piperidin-4-yl)ethan-1-ol (1.12 g, 3.89 mmol, 1.0 equiv) in DCM (10 mL) were added TEA (788 mg, 7.79 mmol, 2.0 equiv) and DMAP (47 mg, 0.39 mmol, 0.1 equiv) at room temperature. Then methanesulfonic anhydride (1.02 g, 5.84 mmol, 1.5 equiv) was added at 0 oC. The resulting mixture was stirred at room temperature for 2 h. Then the reaction mixture was diluted with water (200 mL) and extracted with DCM (3 x 200 mL). The combined organic layers were washed with brine (250 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 2-(1-(7-methoxyquinazolin-4- yl)piperidin-4-yl)ethyl methanesulfonate (1.60 g, 99%) as a yellow oil. Step 3: 7-methoxy-4-(4-(2-(methylsulfanyl)ethyl)piperidin-1-yl)quinazoline [0353] To a solution of 2-(1-(7- 4-yl)piperidin-4-yl)ethyl methanesulfonate (1.57 g, 4.29 mmol, 1.0 equiv) in EtOH (20 mL) was added sodiummethanethiolate (3.01 g, 42.96 mmol, 10.0 equiv, 20% aq). The resulting mixture was stirred at room temperature for 2 h. The solution was concentrated under reduced pressure. The residue was diluted with waterand extracted with EtOAc . The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with MeOH/DCM (7:93) to afford 7-methoxy-4-(4-(2- (methylsulfanyl)ethyl)piperidin-1-yl)quinazoline (1.26 g, 85%) as a yellow solid. Step 4: (2-(1-(7-methoxyquinazolin-4-yl)piperidin-4-yl)ethyl)(methyl)-lambda6- sulfanediimine [0354] The title compound was as described in Example 41, Step 3, except 7-methoxy-4-(4-(2-(methylsulfanyl)ethyl)piperidin-1-yl)quinazoline (500 mg, 1.57 mmol) was used. The crude product was purified by prep-HPLC with the following conditions: (Column: XBridge Prep RP OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 15% B to 26% B in 7min; Wave Length: 254 nm / 220 nm; RT1(min): 6.5) to afford (2-(1-(7- methoxyquinazolin-4-yl)piperidin-4-yl)ethyl)(methyl)-lambda6-sulfanediimine (11.8 mg, 2%) as a white solid. MS (ESI, pos. ion) m/z: 348.2 (M+1).1H NMR (400 MHz, DMSO-d6, ppm) δ 8.52 (s, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.17 (d, J = 2.8 Hz, 1H), 7.15 - 7.09 (m, 1H), 4.23 (d, J = 13.2 Hz, 2H), 3.90 (s, 3H), 3.15 - 3.09 (m, 2H), 3.07 - 2.97 (m, 2H), 2.85 (s, 3H), 2.26 (s, 2H), 1.87 - 1.78 (m, 2H), 1.77 - 1.67 (m, 3H), 1.44 - 1.26 (m, 2H). Example 34 Synthesis of (4-(((7-methoxyquinazolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda6- sulfanediimine Step 1: 7-methoxy-4-((4- [0355] To a solution of (4- (1.19 g, 7.70 mmol, 2.5 equiv) in DMF (6 mL) was added NaH (369 mg, 9.24 mmol, 3.0 equiv, 60%) at 0 oC. After stirring at 0 oC for 10 min, 4-chloro-7-methoxyquinazoline (600 mg, 3.083 mmol, 1 equiv) was added. The resulting mixture was stirred at 0 oC for 2 h, and then water was added. The mixture was extracted with EtOAc and the organic layer was washed with brine , dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc/PE (30:70) to afford 7-methoxy-4-((4-(methylthio)benzyl)oxy)quinazoline (472 mg, 47%) as a white solid. Step 2: (4-(((7-methoxyquinazolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda4- sulfaniminium 2,4,6-trimethylbenzenesulfonate [0356] To a solution of 7- oxy)quinazoline (272 mg, 0.87 mmol, 1.0 equiv) in DCM (3 mL). Then amino 2,4,6-trimethylbenzenesulfonate (562 mg, 2.61 mmol, 3.0 equiv) was added at 0 oC. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and filtered, and the filter cake was washed with Et2O. The filtrate was concentrated under reduced pressure to afford (4-(((7-methoxyquinazolin-4-yl)oxy)methyl)phenyl)(methyl)- lambda4-sulfaniminium 2,4,6-trimethylbenzenesulfonate (520 mg, crude) as a colorless oil. Step 3: (4-(((7-methoxyquinazolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda6- sulfanediimine [0357] The title compound was analogously as described in Example 40, Step 3, except (4-(((7-methoxyquinazolin-4-yl)oxy)methyl)phenyl)(methyl)- lambda4-sulfaniminium 2,4,6-trimethylbenzenesulfonate (520 mg, crude) was used instead of (4-(((7-methoxyquinolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda4-sulfaniminium 2,4,6- trimethylbenzenesulfonate. The crude product was purified by reverse phase flash, eluted with ACN/H2O (35:65) to afford crude product, which was re-purified by prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 6% B to36 % B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 9.1) to afford (4-(((7-methoxyquinazolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda6- sulfanediimine (15.1 mg, 3%) as a white solid. MS (ESI, pos. ion) m/z: 343.1 (M+1).1H NMR (400 MHz, DMSO-d6, ppm) δ 8.75 (s, 1H), 8.13 (d, J = 9.2 Hz, 1H), 8.10 - 8.04 (m, 2H), 7.72 (d, J = 8.4 Hz, 2H), 7.36 - 7.26 (m, 2H), 5.71 (s, 2H), 3.95 (s, 3H), 3.02 (s, 3H), 2.94 (s, 2H). Example 35 Synthesis of cyclopropyl(4-((7-methoxyquinazolin-4-yl)oxy)phenyl)-lambda6-sulfanediimine Step 1: 4-(4- [0358] To a stirred mixture (600 mg, 3.08 mmol, 1 equiv) in DMF (12 mL) were added Cs2CO3 (2.0 g, 6.20 mmol, 2 equiv) and 4- (cyclopropylsulfanyl)phenol (768 mg, 4.62 mmol, 1.5 equiv). The resulting mixture was stirred at 80 ℃ for 2 h. After cooling down to room temperature, the resulting mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine , dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc / PE (24:76) to afford 4-(4-(cyclopropylsulfanyl)phenoxy)-7-methoxyquinazoline (1.00 g, 83%) as an off- white solid. Step 2: cyclopropyl(4-((7-methoxyquinazolin-4-yl)oxy)phenyl)-lambda4-sulfaniminium 2,4,6-trimethylbenzenesulfonate [0359] To a solution of 4-(4- y)-7-methoxyquinazoline (300 mg, 0.93 mmol, 1 equiv) in DCM (6 mL) was added amino 2,4,6-trimethylbenzenesulfonate (540 mg, 2.50 mmol, 2.70 equiv) at 0 oC. The reaction mixture was stirred at room temperature for 1 h. Half of DCM was concentrated and Et2O (10 mL) was added. The product crystallized upon storage at 4 oC overnight and was collected by filtration and dried in high vacuum to afford cyclopropyl(4-((7-methoxyquinazolin-4-yl)oxy)phenyl)-lambda4- sulfaniminium 2,4,6-trimethylbenzenesulfonate (500 mg, crude) as an yellow solid. Step 3: cyclopropyl(4-((7-methoxyquinazolin-4-yl)oxy)phenyl)-lambda6-sulfanediimine [0360] The title compound as described in Example 40. Step 3, except cyclopropyl(4-((7-methoxyquinazolin-4-yl)oxy)phenyl)-lambda4- sulfaniminium 2,4,6-trimethylbenzenesulfonate (500 g, crude) was used instead of (4-(((7- methoxyquinolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda4-sulfaniminium 2,4,6- trimethylbenzenesulfonate. The crude product was purified by reverse phase flash, eluted with ACN/H2O (28:72) to afford 50 mg of crude cyclopropyl(4-((7-methoxyquinazolin-4- yl)oxy)phenyl)-lambda6-sulfanediimine and 50 mg of crude cyclopropyl(imino)(4-((7- methoxyquinazolin-4-yl)oxy)phenyl)-lambda6-sulfanone. [0361] The 50 mg of crude cyclopropyl(4-((7-methoxyquinazolin-4-yl)oxy)phenyl)- lambda6-sulfanediimine was re-purified by prep-HPLC with the following conditions: Column: Xbridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 11% B to 36 % B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 8.68. The fractions containing the desired product were combined and lyophilized to afford cyclopropyl(4-((7- methoxyquinazolin-4-yl)oxy)phenyl)-lambda6-sulfanediimine (11.1 mg, 3%) as a white solid. MS (ESI, pos. ion) m/z: 355.1 (M+1).1H NMR (400 MHz, DMSO-d6, ppm) δ 8.67 (s, 1H), 8.32 - 8.25 (m, 1H), 8.10 (d, J = 2.0 Hz, 1H), 8.08 (d, J = 2.0 Hz, 1H), 7.52 (d, J = 2.0 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.40 (d, J = 7.7 Hz, 2H), 3.99 (s, 3H), 2.85 (s, 2H), 2.81 - 2.74 (m, 1H), 1.02 - 0.94 (m, 2H), 0.90 - 0.79 (m, 2H). Example 36 Synthesis of (3-fluoro-5-(((7-methoxyquinazolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda6- sulfanediimine Step 1: 4-((3-fluoro-5- -7-methoxyquinazoline [0362] To a solution of 4- (600 mg, 3.08 mmol, 1.0 equiv) in DMF (10 mL) were added Cs2CO3 (2.08 g, 6.16 mmol, 2.0 equiv) and (3-fluoro-5- (methylsulfanyl)-phenyl)methanol (796 mg, 4.62 mmol, 1.5 equiv). The reaction mixture was stirred at 80 °C for 2 h. After cooling down to room temperature, the reaction mixture was quenched with water (and extracted with dichloromethane . The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc /PE (30:70) to 4-((3-fluoro-5- (methylsulfanyl)phenyl)methoxy)-7-methoxyquinazoline (800 mg, 78%) as a light yellow solid. Step 2: (3-fluoro-5-(((7-methoxyquinazolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda4- sulfaniminium 2,4,6-trimethylbenzenesulfonate [0363] To a solution of 4-((3- phenyl)methoxy)-7- methoxyquinazoline (600 mg, 1.81 mmol, 1.0 equiv) in DCM was added amino 2,4,6- trimethylbenzenesulfonate (1.17 g, 5.44 mmol, 3.0 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure to afford (3-fluoro-5-(((7-methoxyquinazolin-4-yl)oxy)methyl)phenyl)(methyl)- lambda4-sulfaniminium 2,4,6-trimethylbenzenesulfonate (850 mg, crude). The crude product was used in the next step directly without further purification. Step 3: (3-fluoro-5-(((7-methoxyquinazolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda6- sulfanediimine [0364] The title compound analogously as described in Example 40, Step 3, except (3-fluoro-5-(((7-methoxyquinazolin-4- yl)oxy)methyl)phenyl)(methyl)-lambda4-sulfaniminium 2,4,6-trimethylbenzenesulfonate (800 mg, crude) was used instead of (4-(((7-methoxyquinolin-4- yl)oxy)methyl)phenyl)(methyl)-lambda4-sulfaniminium 2,4,6-trimethylbenzenesulfonate. The crude product was purified by reverse phase flash, eluted with ACN/H2O (30:70) and then re-purified by prep-HPLC with the following conditions (Column: XselectCSH Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 2% B to24 % B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 8.68) to afford (3-fluoro-5-(((7-methoxyquinazolin-4- yl)oxy)methyl)phenyl)(methyl)-lambda6-sulfanediimine (17.6 mg, 5%) as an off-white solid. MS (ESI, pos. ion) m/z: 361.1 (M+1). 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.77 (s, 1H), 8.14 (d, J = 8.8 Hz, 1H), 8.07 (d, J = 1.2 Hz, 1H), 7.88 - 7.78 (m, 1H), 7.69 - 7.62 (m, 1H), 7.37 - 7.27 (m, 2H), 5.72 (s, 2H), 3.96 (s, 3H), 3.15 (s, 2H), 3.07 (s, 3H). 19F NMR (376 MHz, DMSO-d6) δ -111.43 (s, 1 F). Example 37 Synthesis of (3-(((7-methoxyquinazolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda6- sulfanediimine Step 1: 4-chloro-7- Cl N [0365] To a solution of 7- one (5.00 g, 28.38 mmol, 1 equiv) in SOCl2 (60 mL) was added DMF (0.5 mL) at room temperature. After stirred at 80 oC for 2 h, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in sodium bicarbonate saturated solution at 0 oC and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography, eluted with EtOAc/PE (26:74) to afford 4-chloro-7-methoxyquinazoline (4.90 g, 88%) as a yellow solid. Step 2: 7-methoxy-4-((3-(methylsulfanyl)phenyl)methoxy)quinazoline [0366] To a solution of (3-(methylsulfanyl)phenyl)methanol (713 mg, 4.62 mmol, 1.5 equiv) in DMF (12 mL) was added NaH (221 mg, 9.24 mmol, 3 equiv) at 0 oC. After stirred for 10 min, 4-chloro-7-methoxyquinazoline (600 mg, 3.08 mmol, 1 equiv) was added. After stirring at 0 oC for 2 h, the resulting mixture was quenched with water (100 mL) and extracted with EtOAc . The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with EtOAc/PE (30:70) to give 7-methoxy-4-((3- (methylsulfanyl)phenyl)methoxy)quinazoline (710 mg, 73%) as a yellow solid. Step 3: (3-(((7-methoxyquinazolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda6- sulfanediimine [0367] The title compound was as described in Example 41, Step 3, except 7-methoxy-4-((3-(methylsulfanyl)phenyl)methoxy)quinazoline (600 mg, 1.92 mmol) was used. The crude product was purified by prep-HPLC with the following conditions: (Column: Welch Ultimate XB-C1850*250, 10 μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 17% B to 47 % B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 18.38). The fractions containing the desired product were combined and lyophilized to give (3-(((7-methoxyquinazolin-4- yl)oxy)methyl)phenyl)(methyl)-lambda6-sulfanediimine (47.4 mg, 7%) as a white solid. MS (ESI, pos. ion) m/z: 343.1 (M+1).1H NMR (400 MHz, DMSO-d6, ppm) δ 8.76 (s, 1H), 8.23 (t, J = 1.8 Hz, 1H), 8.10 (d, J = 9.0 Hz, 1H), 8.07 - 8.01 (m, 1H), 7.80 - 7.73 (m, 1H), 7.61 (t, J = 7.7 Hz, 1H), 7.34 - 7.27 (m, 2H), 5.72 (s, 2H), 3.95 (s, 3H), 3.03 (s, 3H), 2.95 (s, 2H). Example 38 Synthesis of N-isopropyl-1-(3-(((8-methoxy-1,7-naphthyridin-4-yl)oxy)methyl)phenyl)-1- methyl-lambda6-sulfanediimine
Step 1: 8-methoxy-4-((3-(methyls thoxy)-1,7-naphthyridine [0368] To a solution of 8- 4-ol (4.50 g, 25.54 mmol, 1 equiv) in toluene (5 mL) were added (3-(methylsulfanyl)phenyl)methanol (5.91 g, 38.31 mmol, 1.5 equiv) and 2-(tributyl-$l^(5)-phosphanylidene)acetonitrile (12.33 g, 51.08 mmol, 2 equiv) under nitrogen atmosphere. After cooling down to room temperature, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA/PE (65:35) to afford crude product (7.0 g). The crude product was re-purified by reverse phase flash, eluted with ACN/Water (55:45) to afford 8- methoxy-4-((3-(methylsulfanyl)phenyl)methoxy)-1,7-naphthyridine (2.80 g, 34%) as a yellow solid. Step 2: ((3-(((8-methoxy-1,7-naphthyridin-4-yl)oxy)methyl)phenyl)(methyl)-lambda4- sulfanylidene)azanium 2,4,6-trimethylbenzenesulfonate
[0369] To a solution of 8-methox anyl)phenyl)methoxy)-1,7- naphthyridine (300 mg, 0.96 mmol, 1 equiv) in DCM (6 mL) was added amino 2,4,6- trimethylbenzenesulfonate (620 mg, 2.88 mmol, 3 equiv) at room temperature. The resulting mixture was stirred at room temperature for 1 h, then half of the DCM was evaporated and diethyl ether was added. The product crystallized upon storage at 0 oC for 10 min and was collected by filtration and dried under reduced pressure to give ((3-(((8-methoxy-1,7- naphthyridin-4-yl)oxy)methyl)phenyl)-(methyl)-lambda4-sulfanylidene)azanium 2,4,6- trimethylbenzenesulfonate (220 mg, crude) as a yellow solid. Step 2: (3-(((7-Methoxyquinazolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda6- sulfanediimine [0370] To a stirred solution of ( 4- yl)oxy)methyl)phenyl)-(methyl)-lambda4-sulfanylidene)azanium 2,4,6- trimethylbenzenesulfonate (157 mg, 0.34 mmol, 1 equiv) in DMF (3 mL) were added Na2CO3 (158 mg, 1.49 mmol, 5 equiv) and NCS (57 mg, 0.35 mmol, 1.2 equiv) at 0 oC. After stirring for 15 min, isopropylamine (21 mg, 0.35 mmol, 1.2 equiv) was added at 0 oC and the mixture was stirred overnight at room temperature. The resulting mixture was purified by reverse phase flash, eluted with ACN/H2O (28:72) and concentrated under reduced pressure. The crude product was re-purified by prep-HPLC (Column: XBridge Prep Shield RP18 OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 mmol/LNH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 7% B to37 % B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 9.23). The fractions containing the desired product were combined and lyophilized to give N-Isopropyl-1-(3-(((8-methoxy-1,7- naphthyridin-4-yl)oxy)methyl)phenyl)-1-methyl-lambda6-sulfanediimine (4.6 mg, 3.9%) as an off-white solid. MS (ESI, pos. ion) m/z: 385.1 (M+1).1H NMR (400 MHz, DMSO-d6, ppm) δ 8.78 (d, J = 5.2 Hz, 1H), 8.21 (t, J = 1.8 Hz, 1H), 8.07 (d, J = 5.8 Hz, 1H), 8.09 - 8.00 (m, 1H), 7.79 - 7.73 (m, 1H), 7.64 (t, J = 7.7 Hz, 1H), 7.55 (d, J = 5.8 Hz, 1H), 7.38 (d, J = 5.3 Hz, 1H), 5.52 (s, 2H), 4.05 (s, 3H), 3.33 -3.26 (m, 1H), 3.01 (s, 3H), 2.68 (s, 1H), 1.08 (d, J = 6.3 Hz, 3H), 0.88 (d, J = 6.3 Hz, 3H). Example 39 Synthesis of ((2-(7-methoxyquinolin-4-yl)-2-azaspiro[3.3]heptan-6-yl)methyl)(methyl)- lambda6-sulfanediimine Step 1: 7-methoxy-4-(6-( azaspiro[3.3]heptan-2-yl)quinoline [0371] To a solution of 4-chloro- (500 mg, 2.58 mmol, 1 equiv) in NMP (8 mL) were added DIEA (3 mL) and 6-((methylsulfanyl)methyl)-2- azaspiro[3.3]heptane (1.22 g, crude). The resulting mixture was stirred at 130 oC for 2 h. After cooled to room temperature, the crude product was purified by reverse phase flash, eluted with ACN/H2O (95:5) to afford 7-methoxy-4-(6-((methylsulfanyl)-methyl)-2- azaspiro[3.3]heptan-2-yl)quinoline (1.00 g, crude) as a brown yellow oil. Step 2: ((2-(7-methoxyquinolin-4-yl)-2-azaspiro[3.3]heptan-6-yl)methyl)(methyl)- lambda6-sulfanediimine [0372] The title compounds were as described in Example 41, Step 3, except 7-methoxy-4-(6-((methylsulfanyl)methyl)-2-azaspiro[3.3]heptan-2- yl)quinoline (1.00 g, crude) was used. The crude product was purified by silica gel column chromatography, eluted with MeOH / DCM (1:10) to afford 100 mg of crude ((2-(7- methoxyquinolin-4-yl)-2-azaspiro[3.3]heptan-6-yl)methyl)(methyl)-lambda6-sulfanediimine and 100 mg of crude imino((2-(7-methoxyquinolin-4-yl)-2-azaspiro[3.3]heptan-6- yl)methyl)(methyl)-lambda6-sulfanone. [0373] The 100 mg of crude ((2-(7-methoxyquinolin-4-yl)-2-azaspiro[3.3]heptan-6- yl)methyl)(methyl)-lambda6-sulfanediimine was re-purified by prep-HPLC with the following conditions: (Column: SHIMADZU Shim-pack Scepter C18-120, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 2% B to 23 % B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 7.92). The fractions containing the desired product were combined and lyophilized to afford ((2-(7-methoxyquinolin-4-yl)-2-azaspiro[3.3]heptan-6-yl)methyl)(methyl)-lambda6- sulfanediimine (28.4 mg, 2.3%) as a white solid. MS (ESI, pos. ion) m/z: 345.1 (M+1).1H NMR (400 MHz, DMSO-d6, ppm) δ 8.31 (d, J = 5.3 Hz, 1H), 7.86 (d, J = 9.3 Hz, 1H), 7.19 (d, J = 2.8 Hz, 1H), 7.00 (dd, J = 9.3, 2.7 Hz, 1H), 6.13 (d, J = 5.4 Hz, 1H), 4.37 (s, 2H), 4.22 (s, 2H), 3.86 (s, 3H), 3.13 (d, J = 7.0 Hz, 2H), 2.81 (s, 3H), 2.79 - 2.67 (m, 1H), 2.52 - 2.41 (m, 2H), 2.23 (s, 2H), 2.20 - 2.10 (m, 2H). Example 40 Synthesis of (4-(((7-methoxyquinolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda6- sulfanediimine Step 1: 7-methoxy-4-((4- quinoline [0374] To a solution of 4-chloro- (600 mg, 3.09 mmol, 1.0 equiv) in DMSO (10 mL) were added Cs2CO3 (2019 mg, 6.19 mmol, 2.0 equiv) and (4- (methylsulfanyl)-phenyl)methanol (716 mg, 4.64 mmol, 1.5 equiv). The reaction mixture was stirred at 100 °C for 3 h. After cooling down to room temperature, the resulting mixture was diluted with DCM (100 mL) and washed with H2O. The organic layer was washed with brine (, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc / PE (88:12) to afford 7-methoxy-4-((4-(methylsulfanyl)phenyl)methoxy)quinoline (600 mg, 62%) as a light yellow solid. Step 2: (4-(((7-methoxyquinolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda4- sulfaniminium 2,4,6-trimethylbenzenesulfonate [0375] To a solution of 7-methoxy-4-((4-(methylsulfanyl)phenyl)methoxy)quinoline (400 mg, 1.34 mmol, 1.0 equiv) in DCM (10 mL) was added amino 2,4,6- trimethylbenzenesulfonate (868 mg, 4.03 mmol, 3.0 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to afford (4-(((7-methoxyquinolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda4- sulfaniminium 2,4,6-trimethylbenzenesulfonate (650 mg, crude) as an off-white solid. The crude product was used in the next step directly without further purification. Step 3: (4-(((7-methoxyquinolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda6- sulfanediimine [0376] To a solution of (4-(((7- oxy)methyl)phenyl)(methyl)- lambda4-sulfaniminium 2,4,6-trimethylbenzenesulfonate (400 mg, crude) in DMF (10 mL) were added Na2CO3 (109 mg, 1.03 mmol, 1.2 equiv) and NCS (165 mg, 1.03 mmol, 1.2 equiv) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 15 min, NH3 (0.37 mL, 2.59 mmol, 3.0 equiv, 7 M in MeOH) was added. The resulting mixture was stirred at room temperature for 12 h. The mixture was purified by reverse phase flash, eluted with ACN/H2O (35:65) to afford a crude product, which was repurified by prep-HPLC with the following conditions (Column: XBridge Prep RP OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 6% B to 36% B in 10min; Wave Length: 254 nm / 220 nm; RT1(min): 9.2) to afford (4-(((7-methoxyquinolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda6- sulfanediimine (22.5 mg, 7%) as an off-white solid. MS (ESI, pos. ion) m/z: 342.1 (M+1).1H NMR (400 MHz, DMSO-d6, ppm) δ 8.66 (d, J = 5.2 Hz, 1H), 8.15 - 8.06 (m, 3H), 7.74 (s, 1H), 7.72 (s, 1H), 7.34 (d, J = 2.4 Hz, 1H), 7.21 (d, J = 9.2 Hz, 1H), 6.99 (d, J = 5.2 Hz, 1H), 5.48 (s, 2H), 3.91 (s, 3H), 3.03 (s, 3H), 2.92 (s, 2H). Example 41 Synthesis of (3-fluoro-5-(((7-methoxyquinolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda6- sulfanediimine Step 1: (3-fluoro-5- [0377] To a solution of (3,5- (5.00 g, 34.69 mmol, 1.0 equiv) in DMF (50 mL) was added sodiummethanethiolate (3.16 g, 45.10 mmol, 1.3 equiv). The reaction mixture was stirred at 110 °C for 2 h. After cooling down to room temperature, the resulting mixture was diluted with DCM and washed with H2O. The organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc / PE (18:82) to afford (3-fluoro-5-(methylsulfanyl)phenyl)methanol (4.50 g, 75%) as a colorless oil. Step 2: 4-((3-fluoro-5-(methylthio)benzyl)oxy)-7-methoxyquinoline [0378] To a solution of (3- methanol (800 mg, 4.64 mmol, 1.0 equiv) in DMF (10 mL) was added NaH (371 mg, 9.29 mmol, 2.0 equiv, 60%) at 0°C. After stirring for 15 min, 4-chloro-7-methoxyquinoline (1.35 g, 6.96 mmol, 1.5 equiv) was added at the same temperature. The resulting mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc / PE (87:13) to afford 4-((3-fluoro-5-(methylthio)benzyl)oxy)-7-methoxyquinoline (800 mg, 39%) as an off- white solid. Step 3: (3-fluoro-5-(((7-methoxyquinolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda6- sulfanediimine [0379] To a solution of 4-((3- oxy)-7-methoxyquinoline (600 mg, 1.82 mmol, 1.0 equiv) in ACN (20 mL) was added NH3-H2O (2.48 g, 25% (v/v)) at -15 °C under nitrogen atmosphere. The reaction mixture was stirred for 1 h at the same temperature. Tert-butyl hypochlorite (988 mg, 9.11 mmol, 5.0 equiv) was added, then the mixture was stirred at -15 °C for another1 h. NH3-H2O (2.48 g, 25%(v/v)) was added. After stirring overnight at room temperature, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH/DCM (8:92) to afford crude product, which was re-purified by prep-HPLC with following conditions (Column: XBridge Prep RP OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 10% B to 40% B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 9.2) to afford (3-fluoro-5-(((7-methoxyquinolin-4-yl)oxy)methyl)phenyl)(methyl)-lambda6- sulfanediimine (8.5 mg, 1%) as an off-white solid. MS (ESI, pos. ion) m/z: 360.1 (M+1).1H NMR (400 MHz, DMSO-d6, ppm) δ 8.68 (d, J = 5.2 Hz, 1H), 8.12 (d, J = 9.2 Hz, 1H), - 8.08 (m, 1H), 7.87 - 7.79 (m, 1H), 7.69 - 7.61 (m, 1H), 7.35 (d, J = 2.4 Hz, 1H), 7.26 - 7.18 (m, 1H), 7.01 (d, J = 5.2 Hz, 1H), 5.48 (s, 2H), 3.91 (s, 3H), 3.13 (s, 2H), 3.07 (s, 3H). 19F NMR (377 MHz, DMSO-d6) δ -111.26 (s, 1 F). Examples 45 and 42 Synthesis of 1-(3-(((8-methoxy-1,7-naphthyridin-4-yl)oxy)methyl)phenyl)-N,N,1-trimethyl- l6-sulfanediimine and 1-(3-(((8-methoxy-1,7-naphthyridin-4-yl)oxy)methyl)phenyl)-N,1- dimethyl-lambda6-sulfanediimine [0380] To a stirred -yl)oxy)methyl)phenyl)- (methyl)-lambda6-sulfanediimine7 (35 mg, 0.10 mmol, 1 equiv) in DMF (1 mL) was added NaH (4 mg, 0.20 mmol, 2 equiv) at 0 oC. After stirring for 10 min, iodomethane (21 mg, 0.15 mmol, 1.5 equiv) was added and the reaction mixture was stirred at room temperature for 2 h. The resulting mixture was quenched with water (2 mL) at 0 oC and concentrated under reduced pressure. The crude product was purified by prep-HPLC (Column: XBridge Prep RP OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 4% B to 34% B in 10min; Wave Length: 254 nm / 220 nm; RT1 (min): 8.7, 9.3 min) The fractions containing the desired product were combined and lyophilized to give [0381] Fraction 1: 1-(3-(((8-methoxy-1,7-naphthyridin-4-yl)oxy)methyl)phenyl)-N,N,1- trimethyl-l6-sulfanediimine (6.0 mg, 15%) as a white solid. MS (ESI, pos. ion) m/z: 371.1 (M+1).1H NMR (400 MHz, DMSO-d6, ppm) δ 8.79 (d, J = 5.2 Hz, 1H), 8.13 (d, J = 1.8 Hz, 1H), 8.09 (d, J = 5.8 Hz, 1H), 7.98 - 7.91(m, 1H), 7.84 - 7.79 (m, 1H), 7.67 (t, J = 7.7 Hz, 1H), 7.55 (d, J = 5.8 Hz, 1H), 7.38 (d, J = 5.3 Hz, 1H), 5.53 (s, 2H), 4.06 (s, 3H), 3.01 (s, 3H), 2.53 (s, 6H). [0382] Fraction 2: 1-(3-(((8-methoxy-1,7-naphthyridin-4-yl)oxy)methyl)phenyl)-N,1- dimethyl-lambda6-sulfanediimine (2.0 mg, 5%) as a yellow solid. MS (ESI, pos. ion) m/z: 357.1 (M+1).1H NMR (400 MHz, DMSO-d6, ppm) δ 8.79 (d, J = 5.2 Hz, 1H), 8.16 (t, J = 1.9 Hz, 1H), 8.11 - 8.05 (m, 1H), 8.00 - 7.93 (m, 1H), 7.82 - 7.77 (m, 1H), 7.66 (t, J = 7.7 Hz, 1H), 7.59 - 7.53 (m, 1H), 7.39 (d, J = 5.2 Hz, 1H), 5.52 (s, 2H), 4.06 (s, 3H), 3.04 (s, 3H), 2.70 (s, 1H), 2.50 (s, 3H). Examples 43 and 44 Synthesis of diethyl-1-(3-(((8-methoxy-1,7-naphthyridin-4-yl)oxy)methyl)phenyl)-1-methyl- lambda6-sulfanediimine and N-ethyl-1-(3-(((8-methoxy-1,7-naphthyridin-4- yl)oxy)methyl)phenyl)-1-methyl-lambda6-sulfanediimine. [0383] To a yl)oxy)methyl)phenyl)- (methyl)-lambda6- mg, (3 mL) was added NaH (21 mg, 0.87 mmol, 2 equiv) at 0 oC. After stirring for 10 min, iodoethane (102 mg, 0.65 mmol, 1.5 equiv) was added and the mixture was stirred at room temperature for 2 h. The resulting mixture was quenched with water (2 mL) at 0 oC and concentrated under reduced pressure. The residue was purified by reverse phase flash, eluted with ACN/H2O (26:74) and was concentrated under reduced pressure. The crude product was re-purified by prep-HPLC (Column: XBridge Prep RP OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 4% B to 34% B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 9.1, 9.4). The fractions containing the desired product were combined and lyophilized to give: [0384] Fraction 1: N-ethyl-1-(3-(((8-methoxy-1,7-naphthyridin-4-yl)oxy)methyl)phenyl)-1- methyl-lambda6-sulfanediimine (26.3 mg, 15%) as a yellow solid. MS (ESI, pos. ion) m/z: 371.1 (M+1).1H NMR (400 MHz, DMSO-d6, ppm) δ 8.79 (d, J = 5.2 Hz, 1H), 8.18 (t, J = 1.9 Hz, 1H), 8.08 (d, J = 5.8 Hz, 1H), 8.03 - 7.96 (m, 1H), 7.82 - 7.75 (m, 1H), 7.66 (t, J = 7.7 Hz, 1H), 7.56 (d, J = 5.8 Hz, 1H), 7.38 (d, J = 5.2 Hz, 1H), 5.53 (s, 2H), 4.06 (s, 3H), 3.04 (s, 3H), 2.98 - 2.86 (m, 1H), 2.79 - .67 (m, 2H), 1.02 (t, J = 7.2 Hz, 3H). [0385] Fraction 2: diethyl-1-(3-(((8-methoxy-1,7-naphthyridin-4-yl)oxy)methyl)phenyl)-1- methyl-lambda6-sulfanediimine(6.2 mg, 3%) as yellow solid. MS (ESI, pos. ion) m/z: 399.2 (M+1).1H NMR (400 MHz, DMSO-d6, ppm) δ 8.78 (d, J = 5.2 Hz, 1H), 8.17 (s, 1H), 8.07 (d, J = 5.8 Hz, 1H), 7.98 (d, J = 7.8 Hz, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.66 (t, J = 7.7 Hz, 1H), 7.54 (d, J = 5.8 Hz, 1H), 7.36 (d, J = 5.2 Hz, 1H), 5.53 (s, 2H), 4.05 (s, 3H), 3.01 (s, 3H), 2.97 - 2.87 (m, 2H), 2.86 - 2.76 (m, 2H), 1.06 (t, J = 7.2 Hz, 6H). Example 46 Synthesis of (2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)ethyl)(methyl)-lambda6- sulfanediimine Step 1: 2-(1-(6,7- 4-yl)ethanol [0386] To a solution of 4-chloro- (800 mg, 3.55 mmol, 1 equiv) in NMP (10 mL) were added DIEA (1.40 g, 10.70 mmol, 3 equiv) and 4-piperidineethanol (920 mg, 7.10 mmol, 2 equiv). The resulting mixture was stirred at 100 oC for 2 h. After cooling down to room temperature, the crude product was purified by reverse phase flash, eluted with ACN/H2O (58:42) to afford 2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4- yl)ethanol (970 mg, 85%) as a brown yellow oil. Step 2: 2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)ethyl methanesulfonate [0387] To a solution of 2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)ethanol (970 mg, 3.10 mmol, 1 equiv) in DCM (15 mL) were added methanesulfonic anhydride (1.60 g, 9.50 mmol, 3 equiv), TEA (637 mg, 6.3 mmol, 2.00 equiv) and DMAP (50 mg, 0.5 mmol, 0.15 equiv) at 0 oC. After stirring at room temperature for 2 h, the reaction mixture was diluted with water and extracted with DCM . The combined organic layers were washed with brine , dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)ethyl methanesulfonate (1.60 g, crude) as a light yellow oil, which was used for next step directly without further purification. Step 3: 6,7-dimethoxy-4-(4-(2-(methylsulfanyl)ethyl)piperidin-1-yl)quinazoline [0388] To a stirred solution of 2- 4-yl)piperidin-4-yl)ethyl methanesulfonate (1.60 g, crude) in EtOH (15 mL) was added sodiummethanethiolate (16.13 g, 46.10 mmol, 10 eq, 20% aq) at room temperature. After stirring for 2 h, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water,and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with EA/PE (56:44) to afford 6,7- dimethoxy-4-(4-(2-(methylsulfanyl)ethyl)piperidin-1-yl)quinazoline (762 mg, 55%) as a yellow solid. Step 4: (2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)ethyl)(methyl)-lambda6- sulfanediimine [0389] The title compound was syn ceeding as described in Example 41, Step 3, except 6,7-dimethoxy-4-(4-(2-(methylsulfanyl)ethyl)piperidin-1-yl)quinazoline (762 mg, 2.20 mmol,) was used. The crude product was purified by prep-HPLC with the following conditions: purified by silica gel column chromatography, eluted with EtOAc / PE (1:1) to afford 150 mg of crude (2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl)ethyl)(methyl)- lambda6-sulfanediimine and 150 mg of crude (2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin- 4-yl)ethyl)(imino)(methyl)-lambda6-sulfanone. [0390] The 150 mg of crude (2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4- yl)ethyl)(methyl)-lambda6-sulfanediimine was re-purified by prep-HPLC with the following conditions (Column: XBridge Prep RP OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 2% B to 28% B in 10min; Wave Length: 254 nm / 220 nm; RT1(min): 9.4). The fractions containing the desired product were combined and lyophilized to afford (2-(1-(6,7- dimethoxyquinazolin-4-yl)piperidin-4-yl)ethyl)(methyl)-lambda6-sulfanediimine (65.2 mg, 8%) as a white solid. MS (ESI, pos. ion) m/z: 378.1 (M+1).1H NMR (400 MHz, DMSO-d6, ppm) δ 8.52 (s, 1H), 7.20 (s, 1H), 7.11 (s, 1H), 4.15 (d, J = 13.1 Hz, 2H), 3.92 (d, J = 7.0 Hz, 6H), 3.09 - 2.98 (m, 4H), 2.86 (s, 3H), 2.26 (s, 2H), 1.84 (d, J = 12.4 Hz, 2H), 1.79 - 1.62 (m, 3H), 1.48 - 1.35 (m, 2H). Example 47 Synthesis of (2-(1-(6,7-Dimethoxyquinolin-4-yl)piperidin-4-yl)ethyl)(methyl)-lambda6- sulfanediimine Step 1: 2-(1-(6,7-dimethoxyquinolin n-4-yl)ethanol [0391] To a solution of 4-chloro- (800 mg, 3.50 mmol, 1 equiv) in NMP (15 mL) were added DIEA (1.40 g, 10.70 mmol, 3.00 equiv) and 4-piperidineethanol (1.40 g, 10.70 mmol, 3.00 equiv). The resulting mixture was stirred at 130 oC for 2 h. After cooling down to room temperature, the crude product was purified by reverse phase flash, eluted with ACN/H2O (86:14) to afford 2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4- yl)ethanol (900 mg, 80%) as a brown yellow oil. Step 2: 2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)ethyl methanesulfonate [0392] To a solution of 2-(1-(6,7- 4-yl)piperidin-4-yl)ethanol (900 mg, 4.45 mmol, 1 equiv) in DCM (15 mL) were added methanesulfonic anhydride (2.50 g, 13.10 mmol, 3 equiv), TEA (895 mg, 8.85 mmol, 2.00 equiv) and DMAP (55 mg, 0.50 mmol, 0.10 equiv) at 0 oC. After stirring at room temperature for 2 h, the resulting mixture was quenched with H2O and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)ethyl methanesulfonate (1.30 g, crude) as a light yellow oil, which was used for next step directly without further purification. Step 3: 6,7-dimethoxy-4-(4-(2-(methylsulfanyl)ethyl)piperidin-1-yl)quinoline [0393] To a solution of 2-(1-(6,7- 4-yl)piperidin-4-yl)ethyl methanesulfonate (1.30 g, crude) in EtOH (15 mL) was added sodiummethanethiolate (13.15 g, 37.57 mmol, 10 equiv, 20% aq)at room temperature. After stirring for 2 h, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with EA/PE (67:33) to afford 6,7- dimethoxy-4-(4-(2-(methylsulfanyl)ethyl)piperidin-1-yl)quinoline (250 mg, 25% for two steps) as a yellow solid. Step 4: (2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)ethyl)(methyl)- lambda6- sulfanediimine [0394] The title compound was as described in Example 41, Step 3, except 6,7-dimethoxy-4-(4-(2-(methylsulfanyl)ethyl)piperidin-1-yl)quinoline (250 mg, 0.72 mmol) was used. The crude product was purified by prep-HPLC with the following conditions: purified by silica gel column chromatography, eluted with EtOAc / PE to afford 100 mg of crude (2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4-yl)ethyl)(methyl)- lambda6- sulfanediimine and 80 mg of crude (2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4- yl)ethyl)(imino)(methyl)-lambda6-sulfanone. [0395] The 100 mg of crude (2-(1-(6,7-dimethoxyquinolin-4-yl)piperidin-4- yl)ethyl)(methyl)-lambda6-sulfanediimine was re-purified by prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 2% B to 9 % B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 9.2. The fractions containing the desired product were combined and lyophilized to afford (2-(1-(6,7- dimethoxyquinolin-4-yl)piperidin-4-yl)ethyl)(methyl)-lambda6-sulfanediimine (28.3 mg, 10%) as a white solid. MS (ESI, pos. ion) m/z: 377.1 (M+1).1H NMR (400 MHz, DMSO-d6, ppm) δ 8.48 (d, J = 5.0 Hz, 1H), 7.30 (s, 1H), 7.18 (s, 1H), 6.85 (d, J = 5.1 Hz, 1H), 3.91 (s, 6H), 3.49 (d, J = 11.8 Hz, 2H), 3.10 - 3.01 (m, 2H), 2.87 (s, 3H), 2.75 (t, J = 11.6 Hz, 2H), 2.28 (s, 2H), 1.89 (d, J = 12.1 Hz, 2H), 1.83 - 1.73 (m, 2H), 1.65 - 1.42 (m, 3H). Example 48 Synthesis of (2-(1-(7-methoxyquinolin-4-yl)piperidin-4-yl)ethyl)(methyl)-lambda6- sulfanediimine Step 1: 2-(1-(7-methoxyquinolin- ethanol [0396] To a solution of 4-chloro-7- (800 mg, 4.13 mmol, 1 equiv) in NMP (8 mL) were added DIEA (1.60 g, 12.39 mmol, 3 equiv) and 4-piperidineethanol (1.33 g, 10.33 mmol, 2.5 equiv). The resulting mixture was stirred at 130 oC for 2 h. After cooling down to room temperature, the mixture was diluted with H2O and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash, eluted with ACN/H2O (89:11) to afford 2-(1-(7-methoxyquinolin-4- yl)piperidin-4-yl)ethanol (1.11 g, 90%) as a yellow solid. Step 2: 2-(1-(7-methoxyquinolin-4-yl)piperidin-4-yl)ethyl methanesulfonate [0397] To a solution of 2-(1-(7- yl)piperidin-4-yl)ethanol (1.08 g, 3.77 mmol, 1 equiv) in DCM (15 mL) were added TEA (763 mg, 7.54 mmol, 2 equiv) and DMAP (46 mg, 0.37 mmol, 0.1 equiv) at room temperature. Then methanesulfonic anhydride (985 mg, 5.65 mmol, 1.5 equiv) was added at 0 oC. After stirring at room temperature for 2 h, the resulting mixture was quenched with H2O and extracted with DCM. The combined organic layers were washed with brine , dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was concentrated under reduced pressure to afford 2-(1-(7-methoxyquinolin-4-yl)piperidin-4-yl)ethyl methanesulfonate (1.45 g, 98%) as a yellow solid. Step 3: 7-methoxy-4-(4-(2-(methylsulfanyl)ethyl)piperidin-1-yl)quinoline [0398] To a solution of 2-(1-(7- yl)piperidin-4-yl)ethyl methanesulfonate (1.42 g, 3.89 mmol, 1 equiv) in EtOH (10 mL) was added sodiummethanethiolate (13.65 g, 38.96 mmol, 10 equiv, 20% aq). After stirred at room temperature for 2 h, the resulting mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with MeOH/DCM (6:94) to afford 7-methoxy-4-(4-(2-(methylsulfanyl)ethyl)piperidin- 1-yl)quinoline (1.03 g, 80%) as a yellow solid. Step 4: (2-(1-(7-methoxyquinolin-4-yl)piperidin-4-yl)ethyl)(methyl)-lambda6- sulfanediimine [0399] The title compound was as described in Example 41, Step 3, except 7-methoxy-4-(4-(2-(methylsulfanyl)ethyl)piperidin-1-yl)quinoline (400 mg, 1.26 mmol) was used. The crude product was purified by prep-HPLC with the following conditions: (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 2% B to31 % B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 9.2). The fractions containing the desired product were combined and lyophilized to afford (2-(1-(7- methoxyquinolin-4-yl)piperidin-4-yl)ethyl)(methyl)-lambda6-sulfanediimine (37.8 mg, 8 %) as a yellow solid. MS (ESI, pos. ion) m/z: 347.2 (M+1).1H NMR (400 MHz, DMSO-d6, ppm) δ 8.58 (d, J = 5.0 Hz, 1H), 7.88 (d, J = 9.2 Hz, 1H), 7.31 (d, J = 2.6 Hz, 1H), 7.18 (dd, J = 9.2, 2.7 Hz, 1H), 6.84 (d, J = 5.1 Hz, 1H), 3.90 (s, 3H), 3.51 (d, J = 12.0 Hz, 2H), 3.10 - 3.01 (m, 2H), 2.87 (s, 3H), 2.84 - 2.73 (m, 2H), 2.36 - 2.30 (m, 2H), 1.90 - 1.82 (m, 2H), 1.82 - 1.72 (m, 2H), 1.50 (m, 2H), 1.39 (s, 1H). Example 49 Synthesis of cyclopropyl(4-((7-methoxyquinolin-4-yl)oxy)phenyl)-lambda6-sulfanediimine Step 1: cyclopropyl(4-methox [0400] To a solution of 4-methoxythiophenol (5.00 g, 35.66 mmol, 1.0 equiv) in DMF (50 mL) were added K2CO3 (9.86 g, 71.32 mmol, 2.0 equiv) and bromocyclopropane (8.63 g, 71.32 mmol, 2.0 equiv) at room temperature. After stirring overnight at 120 oC, the reaction mixture was cooled to room temperature and quenched with water. The resulting mixture was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc/PE (1:4) to afford cyclopropyl(4-methoxyphenyl)sulfane (5.40 g, 83%) as a colorless oil. Step 2: 4-(cyclopropylthio)phenol [0401] To a solution of sulfane (5.40 g, 29.95 mmol, 1.0 equiv) in DCM (50 mL) was added BBr3 (50 mL, 50.00 mmol, 1 M in DCM) at 0 oC. After stirring at room temperature for 24 h, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc/PE (1:1) to afford 4-(cyclopropylthio)phenol (4.00 g, 80%) as a light yellow oil. Step 3: 4-(4-(cyclopropylsulfanyl)phenoxy)-7-methoxyquinoline [0402] To a mixture of 4-chl mg, 3.61 mmol, 1 equiv) in DMSO (15 mL) were added Cs2CO3 (3.53 g, 10.84 mmol, 3 equiv) and 4- (cyclopropylthio)phenol (901 mg, 5.42 mmol, 1.5 equiv). After stirring at 120 oC for 3 h, the resulting mixture was cooled to room temperature, diluted with water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash, eluted with ACN/H2O (92:8) to afford 4-(4- (cyclopropylsulfanyl)phenoxy)-7-methoxyquinoline (880 mg, 71%) as an off-white solid. Step 4: cyclopropyl(4-((7-methoxyquinolin-4-yl)oxy)phenyl)-lambda6-sulfanediimine [0403] The title compound as described in Example 41, Step 3, except 4-(4-(cyclopropylsulfanyl)phenoxy)-7-methoxyquinoline (750 mg, 2.31 mmol) was used. The crude product was purified by prep-HPLC with the following conditions: (Column: Xbridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 11% B to 38 % B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 8.68 ). The fractions containing the desired product were combined and lyophilized to afford cyclopropyl(4-((7-methoxyquinolin- 4-yl)oxy)phenyl)-lambda6-sulfanediimine (6.0 mg, 0.7%) as an off-white solid. MS (ESI, pos. ion) m/z: 354.1 (M+1).1H NMR (400 MHz, DMSO-d6, ppm) δ 8.70 (d, J = 5.2 Hz, 1H), 8.15 - 8.07 (m, 3H), 7.45 (d, J = 2.4 Hz, 1H), 7.41 - 7.38 (m, 2H), 7.32 - 7.29 (m, 1H), 6.66 (d, J = 5.2 Hz, 1H), 3.95 (s, 3H), 2.84 (s, 2H), 2.77 - 2.73 (m, 1H), 0.97 - 0.94 (m, 2H), 0.85 (d, J = 1.2 Hz, 2H). Example 50 Synthesis of cyclopropyl(3-(((7-methoxyquinolin-4-yl)oxy)methyl)phenyl)-lambda6- sulfanediimine Step 1: 3- [0404] To a mixture of 3- g, 129.72 mmol, 1.0 equiv) in DMSO (200 mL) were added and bromocyclopropane (23.54 g, 194.57 mmol, 1.5 equiv) and potassium tert-butoxide (36.39 g, 324.29 mmol, 2.5 equiv). The reaction mixture was stirred at 80 oC for 24 h. After cooling down to room temperature, the reaction mixture was diluted with water, adjusted the pH to 5 with 1 N HCl (aq) and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc / PE (40:60) to afford 3- (cyclopropylsulfanyl)benzoic acid (20.00 g, 69%) as a colorless oil. Step 2: (3-(cyclopropylsulfanyl)phenyl)methanol [0405] To a solution of 3- acid (24.0 g, 117.37 mmol, 1 equiv) in THF (250 mL) was added lithium aluminum hydride (110 mL, 2 equiv, 2 M in THF) at 0 oC. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction mixture was quenched with saturated ammonium bicarbonate solution at 0 oC and extracted with EtOAc . The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc / PE (10:90) to afford (3- (cyclopropylsulfanyl)phenyl)methanol (20.0 g, 86%) as a yellow oil. Step 3: 4-((3-(cyclopropylsulfanyl)phenyl)methoxy)-7-methoxyquinoline [0406] To a solution of (3- (837 mg, 4.64 mmol, 1.5 equiv) in DMF (12 mL) was added NaH (223 mg, 9.29 mmol, 3 equiv) at 0 oC. After stirring for 10 min, 4-chloro-7-methoxyquinoline (600 mg, 3.09 mmol, 1 equiv) was added at the same temperature. The reaction mixture was stirred at 80 oC for 2 h. Then the resulting mixture was quenched with water at 0 oC and extracted with EtOAc. The combined organic layers were washed with brine. and dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc/PE (62:38) to give 4-((3-(cyclopropylsulfanyl)phenyl)-methoxy)-7- methoxyquinoline (620 mg, 43%) as a yellow solid. Step 4: cyclopropyl(3-(((7-methoxyquinolin-4-yl)oxy)methyl)phenyl)- lambda6- sulfanediimine [0407] The title compound as described in Example 41, Step 3, except 4-((3-(cyclopropylsulfanyl)phenyl)methoxy)-7-methoxyquinoline (500 mg, 1.48 mmol) was used. The crude product was purified by prep-HPLC with the following conditions: (Column: Xbridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 11% B to 41 % B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 8.68). The fractions containing the desired product were combined and lyophilized to give cyclopropyl(3-(((7- methoxyquinolin-4-yl)oxy)methyl)phenyl)- lambda6-sulfanediimine (3.7 mg, 0.7%) as a white solid. MS (ESI, pos. ion) m/z: 368.1 (M+1).1H NMR (400 MHz, DMSO-d6, ppm) δ 8.67 (d, J = 5.3 Hz, 1H), 8.19 (s, 1H), 8.09 (d, J = 9.1 Hz, 1H), 8.00 (d, J = 7.8 Hz, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.62 (t, J = 7.7 Hz, 1H), 7.35 (d, J = 2.6 Hz, 1H), 7.26 - 7.16 (m, 1H), 7.01 (d, J = 5.3 Hz, 1H), 5.48 (s, 2H), 3.91 (s, 3H), 2.82 (s, 2H), 2.76 - 2.66 (m, 1H), 1.01 - 0.88 (m, 2H), 0.84 - 0.73 (m, 2H). Example 51 Synthesis of 1-cyclopropyl-1-(3-(((8-methoxy-1,7-naphthyridin-4-yl)oxy)methyl)phenyl)-N- methyl-lambda6-sulfanediimine [0408] To a solution of naphthyridin-4- yl)oxy)methyl)phenyl)-lambda6-sulfanediimine (85 mg, 0.23 mmol, 1.0 equiv) in DMF (3 mL) was added NaH (11 mg, 0.46 mmol, 2.0 equiv) at 0 °C. After stirring at 0 °C for 0.5 h, iodomethane (104 mg, 0.73 mmol, 3.2 equiv) was added. The reaction mixture was stirred at room temperature for 1 h, quenched with water and extracted with dichloromethane. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by prep-HPLC with the following conditions (Column: Welch Ultimate PFP-C1830*250, 10μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 2% B to32 % B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 7.47, 8.25 (min): ) to afford crude product, which was re-purified by the chiral SFC with the following conditions (Column: CHIRALPAKIG3; Mobile Phase A: Hex(0.1%DEA): (MeOH: DCM=1: 1)=40: 60; Flow rate: 1 mL/min; Gradient: isocratic; Injection Volume: 1μ mL) to afford 1-cyclopropyl-1-(3-(((8-methoxy-1,7-naphthyridin-4-yl)oxy)methyl)phenyl)- N-methyl-lambda6-sulfanediimine (6.3 mg, 7%) as an off-white solid. MS (ESI, pos. ion) m/z: 383.0 (M+1).1H NMR (400 MHz, DMSO-d6, ppm) δ 8.78 (d, J = 5.2 Hz, 1H), 8.13 - 8.05 (m, 2H), 7.94 - 7.87 (m, 1H), 7.81 - 7.73 (m, 1H), 7.68 - 7.60 (m, 1H), 7.54 (d, J = 5.6 Hz, 1H), 7.37 (d, J = 5.2 Hz, 1H), 5.52 (s, 2H), 4.05 (s, 3H), 2.77 - 2.67 (m, 1H), 2.47 (s, 3H), 2.37 (s, 1H), 1.26 - 1.14 (m, 1H), 0.96 - 0.83 (m, 1H), 0.73 - 0.60 (m, 2H). Biological Examples Example 1 Measurement of pNP-TMP hydrolysis by ENPP1 [0409] p-Nitrophenyl thymidine 5'-monophosphate (pNP-TMP) is a synthesized substrate for ENPP1. The ENPP1 enzyme activity assay with pNP-TMP substrate was conducted as follows: [0410] First, in a 60 μl reaction, 7.5 ng purified ENPP1 was mixed with compounds of Formula (I) (test compound) ranging from 13.7 pM to 10 μM. Incubation of ENPP1 with compounds was set at 25 ℃ for 10 min. Reactions with DMSO only (with ENPP1 but no compound) gave the fastest reaction (MAX Activity). For each compound dilution, wells with assay buffer (50 mM Tris-HCl, pH8.8, 250mM NaCl, 0.1mg/ml BSA, 1% DMSO) only but no ENPP1 were included as controls for subtraction of test compound derived absorbance at 405 nm. [0411] Second, after the 10 minutes ENPP1 and test compound incubation the assay was initiated by transferring 50 μl of the above mentioned ENPP1/test compound reaction into 50 μl of 1mM pNP-TMP in assay buffer results in a 100 μl total reaction in clear bottom 96 well plates. Absorbance at 405 nm was recorded immediately in kinetic mode by PerkinElmer 2300 Enspire multimode plate reader. [0412] For each inhibitor, the specific ENPP1 activity was calculated using the following equation: ENPP1 activity (pmol/min/μg) = Adjusted Vmax (OD405nm/min) X conversion factor (pmol/OD405nm)/amount of enzyme (μg) [0413] Adjusted Vmax = V0 X (Km + (S))/(S). In this assay, Km = 232 µM, (S) = 500 µM. Adjusted Vmax = 1.464 X V0. [0414] V0 = (OD405nm with ENPP1 - OD405 nm ENPP1 blank)/minutes. OD405 nm was plotted, with blank subtracted, against time (minutes), the initial linear rate is V0. blank subtracted, against time (minutes), the initial linear rate is V0. [0415] The conversion factor (pmol/OD405nm), was determined by plotting the amount of standard, 4-Nitrophenol (Sigma-Aldrich, Catalog # 241326), against absorbance at 405nm. The slope is the conversion factor. The percent ENPP1 activity for each sample was calculated using the following equation: % enzyme activity = sample enzyme activity/MAX Activity X 100%. [0416] To determine the IC50 for each compound, compound concentration values and percent enzyme activity values were inserted into GraphPad Prism (GraphPad Prism version 7.0 for Windows, GraphPad Software, La Jolla California USA, www.graphpad.com), and Prism's Transform analysis was used to convert the x-axis values (compound concentration) to logarithms. A sigmoidal variable slope nonlinear regression analysis was performed using the following equation: Y = Bottom + (Top-Bottom)/(1+10^((LogIC50-X)*HillSlope)). [0417] Ki values for each compound were calculated from the observed IC50 from GraphPad analysis using the Cheng-Prusoff equation: Ki = IC50/(1+(S)/KM). (S) here is 500 μM and KM is determined to be 232 μM. [0418] Ki for a representative compound of Formula (I) disclosed in Compound Table 1A and 1B above is provided in Table 2 below: Ki ( NP-TMP) o a p e Measurement of 2’3’-cGAMP hydrolysis by ENPP1 [0419] ENPP1 catalyzes the hydrolysis of 2’3’-cGAMP into 5’-AMP and 5’-GMP, and hence the ENPP1 enzyme activity with 2’3’-cGAMP as substrate is monitored by measurement of the product 5’-AMP. The AMP-Glo assay kit from Promega (catalog number V5012) is used for measurement of 5’-AMP production. [0420] First, an ENPP1 and test compound incubation is set up in assay buffer (50mM Tris- HCl, pH8.8, 250mM NaCl, 0.1mg/ml BSA, 1% DMSO) with following conditions: ENPP1 concentration: 1.25nM; test compound concentration ranging from 68 pM to 20 μM. This incubation is carried out at 25℃ for 10 min. [0421] Second, after the 10 minute ENPP1 and test compound incubation, prepare on a separate plate, 15 μl of the substrate 2’3’-cGAMP at 200 μM in assay buffer. Then, 15 μl of the ENPP1/Compound incubation is transferred to the 200 μM 2’3’-cGAMP solution to initiate the reaction. The 30 μl mixture is incubated for 30 min at 25℃. In all these assays a DMSO control without compound is included which gave the maximum 5’-AMP production (MAX RLU). After 30 min the reaction is stopped by heating at 90 ℃ for 3 min. [0422] Third, the Promega AMP-Glo kit is used to detect 5’-AMP production as a measurement of ENPP1 enzyme activity. To do this 10 μl of the above mentioned 30 μl total reaction per sample is transferred into 384 well white solid assay plate for measurement of 5’-AMP production. For each well, 10 μl of AMP-Glo Reagent I is added, mixed well, and incubated for 1 hour at 25℃. At this time AMP detection solution is prepared and 20 μl is added per well, and the resulting solution is incubated for 1 hr at 25℃. Duplicates are run for each inhibitor concentration. Luminescence signal (relative luminescence units, RLU) is recorded using a PerkinElmer 2300 Enspire multimode plate reader. [0423] The % inhibition is calculated using the following equation: % inhibition = (MAX RLU - sample RLU)/MAX RLU X 100%. [0424] IC50 values of compounds are determined by loading compound concentration data and percent inhibition values into GraphPad Prism (GraphPad Prism version 7.0 for Windows, GraphPad Software, La Jolla California USA, www.graphpad.com) and conducted a Sigmoidal variable slope nonlinear regression fitting. [0425] Ki values for each compound are calculated from the observed IC50 from GraphPad analysis using the Cheng-Prusoff equation: Ki = IC50/(1+(S)/KM). (S) here is 100 μM and KM is 32 μM. Formulation Examples [0426] The following are representative pharmaceutical formulations containing a compound of the present disclosure. Tablet Formulation [0427] The following ingredients are mixed intimately and pressed into single scored tablets. Ingredient Quantity per tablet mg compound of this disclosure 400 cornstarch 50 croscarmellose sodium 25 lactose 120 magnesium stearate 5 Capsule Formulation [0428] The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule. Ingredient Quantity per capsule mg compound of this disclosure 200 lactose spray dried 148 magnesium stearate 2 Injectable Formulation [0429] Compound of the disclosure (e.g., compound 1) in 2% HPMC, 1% Tween 80 in DI water, pH 2.2 with MSA, q.s. to at least 20 mg/mL. Inhalation Composition [0430] To prepare a pharmaceutical composition for inhalation delivery, 20 mg of a compound disclosed herein is mixed with 50 mg of anhydrous citric acid and 100 mL of 0.9% sodium chloride solution. The mixture is incorporated into an inhalation delivery unit, such as a nebulizer, which is suitable for inhalation administration. Topical Gel Composition [0431] To prepare a pharmaceutical topical gel composition, 100 mg of a compound disclosed herein is mixed with 1.75 g of hydroxypropyl cellulose, 10 mL of propylene glycol, 10 mL of isopropyl myristate and 100 mL of purified alcohol USP. The resulting gel mixture is then incorporated into containers, such as tubes, which are suitable for topical administration. Ophthalmic Solution Composition [0432] To prepare a pharmaceutical ophthalmic solution composition, 100 mg of a compound disclosed herein is mixed with 0.9 g of NaCl in 100 mL of purified water and filtered using a 0.2 micron filter. The resulting isotonic solution is then incorporated into ophthalmic delivery units, such as eye drop containers, which are suitable for ophthalmic administration. Nasal spray solution [0433] To prepare a pharmaceutical nasal spray solution, 10 g of a compound disclosed herein is mixed with 30 mL of a 0.05M phosphate buffer solution (pH 4.4). The solution is placed in a nasal administrator designed to deliver 100 ul of spray for each application.

Claims

What is Claimed: 1. A compound of Formula (I): wherein: X is N, CH, or C when attached to R1; a, b, d, and e are each independently CH or C when attached to any one of R4, R5, or R6; or one or two of a, b, d, and e are N and the remaining of a, b, d, and e are each independently CH or C when attached to any one of R4, R5, or R6; Z is a bond, NH, O, S, SO, or SO2; m and n are each independently 0 or 1; alk is alkylene substituted with 0 to 3 halo; alk1 is alkylene, wherein one carbon atom in the alkylene chain is optionally replaced by oxyen and further wherein alkylene is substituted with 0 to 3 halo; Ar is arylene, heteroarylene, cycloalkylene, cyclylaminylene, fused cyclylaminylene, bridged cyclylaminylene, or spiro cyclylaminylene; R1 is absent, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkylamino, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, diaminoalkyl, diaminoalkoxy, diaminoalkylamino, or cyano; R2 and R3 are each independently absent, methyl, ethyl, methoxy, fluoro, trifluoromethyl, trifluoromethoxy, or cyano; one of R4, R5, and R6 is absent, alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, cyano, amino, alkylamino, dialkylamino, alkylsulfonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, carboxy, or alkoxycarbonyl; and the remaining two of R4, R5, and R6 are each independently absent, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkylamino, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino (wherein heterocyclyl either alone or part of heterocyclyloxy and heterocyclylamino is substituted with 0 to 3 substituents, each independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), heterocyclylalkyl, heterocyclylalkyloxy, heterocyclylalkylamino (wherein the heterocyclyl ring in heterocyclylalkyl, heterocyclylalkyloxy, and heterocyclylalkylamino is substituted with 0 to 3 substituents, each independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), cycloalkyloxy, phenyloxy, or heteroaryloxy (where phenyl in phenyloxy and heteroaryl in heteroaryloxy are substituted with 0 to 3 substituents, each independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, and cyano); R7 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, carbonylaminoalkyl, carboxyaminoalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, aryl, fused aryl, heteroaryl, fused heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, aryloxyalkyl, heteroaryloxyalkyl, fused aralkyl, fused heteroaryalkyl, or heterocyclylalkyl, wherein cycloalkyl, aryl, fused aryl, heteroaryl, fused heteroaryl, heterocyclyl and the ring portion of cycloalkylalkyl, arylalkyl, heteroaralkyl, aryloxyalkyl, heteroaryloxyalkyl, fused aralkyl, fused heteroaryalkyl, or heterocyclylalkyl are substituted with one, two or three substituents each independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, cyano, alkylcarbonyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl; R8 and R9 are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, carbonylaminoalkyl, carboxyaminoalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, aryl, fused aryl, heteroaryl, fused heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, aryloxyalkyl, heteroaryloxyalkyl, fused aralkyl, fused heteroaryalkyl, or heterocyclylalkyl, wherein cycloalkyl, aryl, fused aryl, heteroaryl, fused heteroaryl, heterocyclyl and the ring portion of cycloalkylalkyl, arylalkyl, heteroaralkyl, aryloxyalkyl, heteroaryloxyalkyl, fused aralkyl, fused heteroaryalkyl, or heterocyclylalkyl are substituted with one, two or three substituents each independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, cyano, alkylcarbonyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl; or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Z is bond.
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Z is NH, O, S, or SO2.
4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is according to Formula (Ia), (Ib), (Ic), (Id), (If), (Ig), or (Ih): SO2. in the compounds of formulae (Ie) to (Ih).
5. The compound of any one of claims 1, 2, and 4, or a pharmaceutically acceptable salt thereof, having Formula (Ia).
6. The compound of any one of claims 1, 2, and 4, or a pharmaceutically acceptable salt thereof, having Formula (Ib).
7. The compound of any one of claims 1, 3, and 4, or a pharmaceutically acceptable salt thereof, having Formula (Ig).
8. The compound of any one of claims 1, 3, 4, and 7, or a pharmaceutically acceptable salt thereof, wherein Z is O.
9. The compound of any one of claims 1, 3, 4, and 7, or a pharmaceutically acceptable salt thereof, wherein Z is a bond or O.
10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein X is N.
11. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein X is CH or C when attached to R1.
12. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein X is N or CH.
13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein a, b, d, and e are each independently CH or C when attached to any one of R4, R5, and R6.
14. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein d is N and a, b, and e are each independently CH or C when attached to any one of R4, R5, and R6.
15. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein a is CH; b is CH or C when attached to any one of R4, R5, or R6; d is N or C when attached to any one of R4, R5, or R6; and e is N, CH or C when attached to any one of R4, R5, or R6.
16. The compound of any one of claims 1, 2, 3, and 8 to 15, or a pharmaceutically acceptable salt thereof, wherein n and m are 0.
17. The compound of any one of claims 1, 2, 3, and 8 to 15, or a pharmaceutically acceptable salt thereof, wherein n is 1 and m is 0.
18. The compound of any one of claims 1 to 15 and 17, or a pharmaceutically acceptable salt thereof, wherein alk and/or alk1, when present, are each independently selected from methylene, ethylene, or propylene.
19. The compound of any one of claims 1 to 15 and 17, or a pharmaceutically acceptable salt thereof, wherein alk and/or alk1, when present, are each independently selected from methylene.
20. The compound of any one of claims 1 to 15 and 17, or a pharmaceutically acceptable salt thereof, wherein alk and/or alk1, when present, are each independently alkylene.
21. The compound of any one of claims 1 to 15 and 17, or a pharmaceutically acceptable salt thereof, wherein alk, when present, is methylene.
22. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein alk1, when present, is methylene or ethylene.
23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein Ar is phenylene or 5- or 6-membered heteroarylene, each ring substituted with R2 and R3.
24. The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein Ar is phenylene substituted with R2 and R3.
25. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein –(alk1)m–S(=NR8)(=NR9)R7 is attached to carbon of the phenylene ring that is meta to the carbon attaching the phenylene ring to the remainder of the compound of Formulae (I) and (Ia) to (Ih).
26. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein –(alk1)m–S(=NR8)(=NR9)R7 is attached to carbon of the phenylene ring that is para to the carbon attaching the phenylene ring to the remainder of the compound of Formula (I) and (Ia) to (Ih).
27. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein Ar is cyclylaminylene, spiro cyclylaminylene, or bridged cyclylaminylene, each ring substituted with R2 and R3.
28. The compound of any one of claims 1 to 22 and 27, or a pharmaceutically acceptable salt thereof, wherein Ar is cyclylaminylene selected from divalent pyrrolidine, piperidine, or homopiperidine, each ring substituted with R2 and R3.
29. The compound of any one of claims 1 to 22 and 27, or a pharmaceutically acceptable salt thereof, wherein Ar is spiro cyclylaminylene or bridged cyclylaminyl, and each ring substituted with R2 and R3.
30. The compound of any one of claims 1 to 22 and 27 to 29, or a pharmaceutically acceptable salt thereof, wherein the cyclylaminylene, spiro cyclylaminylene and bridged cyclylaminyl are selected from: , each –(alk1)m-S(=NR8)(=NR9)R7 and is the of attachment to the remainder of the compound of Formula (I) to
31. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein Ar is arylene, cyclylaminylene, or spiro cyclylaminylene, and each ring substituted with R2 and R3.
32. The compound of any one of claims 1 to 22 and 32, or a pharmaceutically acceptable salt thereof, wherein Ar is – m- the point of attachment to the remainder of the compound of Formula (I) to
33. The compound of any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein R1 is absent, alkyl, alkoxy, halo, haloalkyl, or haloalkoxy.
34. The compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein R1 is absent.
35. The compound of any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 are each independently absent, methyl, methoxy, fluoro, trifluoromethyl, trifluoromethoxy, or cyano.
36. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 are absent.
37. The compound of any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 are each independently absent or fluoro.
38. The compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein R4 is absent, alkyl, alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cyano, carboxy, alkoxycarbonyl, hydroxy, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl.
39. The compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, wherein R4 is absent, methyl, methoxy, ethoxy, fluoro, chloro, trifluoromethyl, hydroxy, cyano, or trifluoromethyloxy.
40. The compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein R4 is absent, methoxy, or ethoxy.
41. The compound of any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein R4 is methoxy or ethoxy.
42. The compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, wherein R4 is alkoxy or haloalkoxy.
43. The compound of any one of claims 1 to 38 and 42, or a pharmaceutically acceptable salt thereof, wherein R4 is methoxy or fluoromethoxy.
44. The compound of any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, wherein R4 is attached to the six membered ring comprising a, b, d, and e of Formula (I) to (Ih) in any one of carbons shown in formula (a) to (c) below: wherein the olecule.
45. The compound of any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, wherein R5 and R6 are absent.
46. The compound of any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, wherein R5 and R6 are each independently absent, alkyl, alkoxy, hydroxy, amino, halo, haloalkyl, or haloalkoxy.
47. The compound of any one of claims 1 to 44 and 46, or a pharmaceutically acceptable salt thereof, wherein R5 and R6 are each independently absent, methyl, methoxy, ethoxy, propoxy, hydroxy, fluoro, difluoromethyl, trifluoromethyl, difluoromethoxy, or trifluoromethoxy.
48. The compound of any one of claims 1 to 44, 46, and 47, or a pharmaceutically acceptable salt thereof, wherein R5 and R6 are each independently absent, methyl, methoxy, ethoxy, hydroxy, fluoro, difluoromethoxy, or trifluoromethoxy.
49. The compound of any one of claims 1 to 44 and 46 to 48, or a pharmaceutically acceptable salt thereof, wherein R5 and R6 are each independently absent, methoxy, ethoxy, propoxy, or fluoro.
50. The compound of any one of claims 1 to 44 and 46 to 49, or a pharmaceutically acceptable salt thereof, wherein R5 and R6 are each independently absent, alkoxy, halo, or haloalkoxy.
51. The compound of any one of claims 1 to 44 and 46 to 50, or a pharmaceutically acceptable salt thereof, wherein R5 and R6 are each independently absent, methoxy, fluoro, or fluoromethoxy.
52. The compound of any one of claims 1 to 40, 50, and 51, or a pharmaceutically acceptable salt thereof, wherein R5 and R6 are attached to the six membered ring comprising a, b, d, and e of Formula I to (Ih) as shown below wherein the wavy line denotes the at the remainder of the molecule.
53. The compound of any one of claims 1 to 52, or a pharmaceutically acceptable salt thereof, wherein R7 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, carbonylaminoalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, aryl, fused aryl, heteroaryl, fused heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, aryloxyalkyl, heteroaryloxyalkyl, fused aralkyl, fused heteroaryalkyl, or heterocyclylalkyl wherein cycloalkyl, aryl, fused aryl, heteroaryl, fused heteroaryl, heterocyclyl and the ring portion of cycloalkylalkyl, arylalkyl, heteroaralkyl, aryloxyalkyl, heteroaryloxyalkyl, fused aralkyl, fused heteroaryalkyl, or heterocyclylalkyl are substituted with one, two or three substituents each independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, cyano, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl; and R8 and R9 are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, carbonylaminoalkyl, carboxyaminoalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, aryl, fused aryl, heteroaryl, fused heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, aryloxyalkyl, heteroaryloxyalkyl, fused aralkyl, fused heteroaryalkyl, or heterocyclylalkyl wherein cycloalkyl, aryl, fused aryl, heteroaryl, fused heteroaryl, heterocyclyl and the ring portion of cycloalkylalkyl, arylalkyl, heteroaralkyl, aryloxyalkyl, heteroaryloxyalkyl, fused aralkyl, fused heteroaryalkyl, or heterocyclylalkyl are substituted with one, two or three substituents each independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, cyano, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl.
54. The compound of any one of claims 1 to 52, or a pharmaceutically acceptable salt thereof, wherein R7 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, carbonylaminoalkyl, carboxyaminoalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, aryl, fused aryl, heteroaryl, fused heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, aryloxyalkyl, heteroaryloxyalkyl, fused aralkyl, fused heteroaryalkyl, or heterocyclylalkyl wherein cycloalkyl, aryl, fused aryl, heteroaryl, fused heteroaryl, heterocyclyl and the ring portion of cycloalkylalkyl, arylalkyl, heteroaralkyl, aryloxyalkyl, heteroaryloxyalkyl, fused aralkyl, fused heteroaryalkyl, or heterocyclylalkyl are substituted with one, two or three substituents each independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, cyano, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl and R8 and R9 are hydrogen.
55. The compound of any one of claims 1 to 52, or a pharmaceutically acceptable salt thereof, wherein R7 and R8 are each independently alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, carbonylaminoalkyl, carboxyaminoalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, aryl, fused aryl, heteroaryl, fused heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, aryloxyalkyl, heteroaryloxyalkyl, fused aralkyl, fused heteroaryalkyl, or heterocyclylalkyl wherein cycloalkyl, aryl, fused aryl, heteroaryl, fused heteroaryl, heterocyclyl and the ring portion of cycloalkylalkyl, arylalkyl, heteroaralkyl, aryloxyalkyl, heteroaryloxyalkyl, fused aralkyl, fused heteroaryalkyl, or heterocyclylalkyl are substituted with one, two or three substituents each independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, cyano, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl and R9 is hydrogen.
56. The compound of any one of claims 1 to 52, or a pharmaceutically acceptable salt thereof, wherein R7, R8, and R9 are each independently alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, carbonylaminoalkyl, carboxyaminoalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, aryl, fused aryl, heteroaryl, fused heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, aryloxyalkyl, heteroaryloxyalkyl, fused aralkyl, fused heteroaryalkyl, or heterocyclylalkyl wherein cycloalkyl, aryl, fused aryl, heteroaryl, fused heteroaryl, heterocyclyl and the ring portion of cycloalkylalkyl, arylalkyl, heteroaralkyl, aryloxyalkyl, heteroaryloxyalkyl, fused aralkyl, fused heteroaryalkyl, or heterocyclylalkyl are substituted with one, two or three substituents each independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, cyano, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl.
57. The compound of any one of claims 1 to 52, or a pharmaceutically acceptable salt thereof, wherein R7 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, or heterocyclyl wherein cycloalkyl and heterocyclyl are substituted with one, two or three substituents each independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, cyano, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl.
58. The compound of any one of claims 1 to 57, or a pharmaceutically acceptable salt thereof, wherein R8 and R9 are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, aryloxyalkyl, heteroaryloxyalkyl, or heterocyclylalkyl wherein cycloalkyl, aryl, heteroaryl, heterocyclyl and the ring portion of cycloalkylalkyl, arylalkyl, heteroaralkyl, aryloxyalkyl, heteroaryloxyalkyl, or heterocyclylalkyl are substituted with one, two or three substituents each independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, cyano, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl unless stated otherwise.
59. The compound of any one of claims 1 to 57, or a pharmaceutically acceptable salt thereof, wherein R7 is methyl, ethyl, cyclopropyl, cyclopropylmethyl, 1-cyclopropylethyl, 1-hydroxycyclprop-1-ylmethyl, 3,3-difluorobutylmethyl, cyclobutylmethyl, -CH2CH2NH2, - CH2CH2NH(COCH3), -CH2CH2NH(COphenyl), 2,2,2-trifluoroethyl, 2-hydroxyethyl, 2- hydroxy-2-methylpropyl, 2,3-dihydroxypropyl, 1-hydroxymethylethyl, 2-hydroxymethyl, 2- hydroxypropyl, carboxymethyl, morpholin-4-yl, pyrrolidinyl-1-methyl, phenyl, phenylmethyl, 2-phenylethyl, 1-phenylethyl, 2-phenoxyethyl, 4-pyridin-4-ylphenylmethyl, 4- pyridin-4-ylphenyl, 2-oxazol-2-ylmethyl, 2-thiazol-2-ylmethyl, 1-methylimidazol-2- ylmethyl, pyridine-2-ylmethyl, pyridine-3-ylmethyl, pyridin-4-ylmethyl, 2-pyridin-2- yloxyethyl, 2-pyridin-3-yloxyethyl, or 2-pyridin-4-yloxyethyl and R8 and R9 are each independently hydrogen, methyl, ethyl, cyclopropyl, cyclopropylmethyl, 1-cyclopropylethyl, 1-hydroxycyclprop-1-ylmethyl, 3,3-difluorobutylmethyl, cyclobutylmethyl, -CH2CH2NH2, - CH2CH2NH(COCH3), -CH2CH2NH(COphenyl), 2,22-trifluoroethyl, 2-hydroxyethyl, 2- hydroxy-2-methylpropyl, 2,3-dihydroxypropyl, 1-hydroxymethylethyl, 2-hydroxymethyl, 2- hydroxypropyl, carboxymethyl, morpholin-4-yl, pyrrolidinyl-1-methyl, phenyl, phenylmethyl, 2-phenylethyl, 1-phenylethyl, 2-phenoxyethyl, 4-pyridin-4-ylphenylmethyl, 4- pyridin-4-ylphenyl, 2-oxazol-2-ylmethyl, 2-thiazol-2-ylmethyl, 1-methylimidazol-2- ylmethyl, pyridine-2-ylmethyl, pyridine-3-ylmethyl, pyridin-4-ylmethyl, 2-pyridin-2- yloxyethyl, 2-pyridin-3-yloxyethyl, or 2-pyridin-4-yloxyethyl unless stated otherwise.
60. The compound of any one of claims 1 to 59, or a pharmaceutically acceptable salt thereof, wherein R7 is alkyl.
61. The compound of any one of claims 1 to 59, or a pharmaceutically acceptable salt thereof, wherein R7 is hydroxyalkyl, aminoalkyl, or alkoxyalkyl.
62. The compound of any one of claims 1 to 59, or a pharmaceutically acceptable salt thereof, wherein R7 is haloalkyl.
63. The compound of any one of claims 1 to 59, or a pharmaceutically acceptable salt thereof, wherein n R7 is cycloalkyl or cycloalkylalkyl.
64. The compound of any one of claims 1 to 59, or a pharmaceutically acceptable salt thereof, wherein R7 is heterocyclyl substituted substituted with 0 to 3 substituents.
65. The compound of any one of claims 1 to 59, or a pharmaceutically acceptable salt thereof, wherein R7 is alkyl or cycloalkyl.
66. The compound of any one of claims 1 to 59, or a pharmaceutically acceptable salt thereof, wherein R7 is methyl or cyclopropyl.
67. The compound of any one of claims 1 to 53, and 57 to 66, or a pharmaceutically acceptable salt thereof, wherein R8 and R9 are each independently hydrogen or alkyl.
68. The compound of any one of claims 1 to 53, 57, 58, and 60 to 67, or a pharmaceutically acceptable salt thereof, wherein R8 and R9 are each independently hydrogen, methyl, ethyl, or isopropyl.
69. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is N or CH; a is CH; b is CH or C when attached to any one of R4, R5, or R6; d is N or C when attached to any one of R4, R5, or R6; e is N, CH or C when attached to any one of R4, R5, or R6; Z is a bond or O; m and n are each independently 0 or 1; alk is alkylene; alk1 is alkylene; Ar is arylene, cyclylaminylene, or spiro cyclylaminylene, and each ring substituted with R2 and R3; R1 is absent; R2 and R3 are each independently absent or fluoro; one of R4, R5, and R6 is alkoxy or haloalkoxy; and the remaining two of R4, R5, and R6 are each independently absent, alkoxy, halo, or haloalkoxy; R7 is alkyl or cycloalkyl; and R8 and R9 are each independently hydrogen or alkyl.
70. The compound of claim 1 or 69, or a pharmaceutically acceptable salt thereof, wherein X is N or CH; a is CH; b is CH or C when attached to any one of R4, R5, or R6; d is N or C when attached to any one of R4, R5, or R6; e is N, CH or C when attached to any one of R4, R5, or R6; Z is a bond or O; m and n are each independently 0 or 1; alk is methylene; alk1 is methylene or ethylene; Ar is R7 (I); R1 is absent; R2 and R3 are each independently absent or fluoro; one of R4, R5, and R6 is methoxy or fluoromethoxy; and the remaining two of R4, R5, and R6 are each independently absent, methoxy, fluoro, or fluoromethoxy; R7 is methyl or cyclopropyl; and R8 and R9 are each independently hydrogen, methyl, ethyl, or isopropyl.
71. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from Table 1A and Table 1B.
72. A pharmaceutical composition comprising a compound any one of claims 1 to 71, and a pharmaceutically acceptable excipient.
73. A method of treating a disease or condition mediated by ENPP1 in a patient comprising administering to the patient a therapeutically effective amount of compound of any one of claims 1 to 71, or a pharmaceutical composition of claim 72, optionally with at least one other anticancer agent.
74. The method of claim 73, wherein the disease or condition is a cancer, an inflammatory disease, a metabolic disease, or a viral disease.
75. The method of claim 73 or 74, wherein the disease or condition is a cancer.
76. The method of claim 75, wherein the disease or condition is a cancer wherein the cancer is hepatocellular carcinomas, glioblastomas, melanomas, testicular, pancreatic, thyroid or breast cancer.
PCT/US2025/021136 2024-03-25 2025-03-24 Bicyclic heteroaryl sulfanediimine derivatives as ectonucleotide pyrophosphatase phosphodiesterase 1 inhibitors Pending WO2025207514A1 (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9790189B2 (en) * 2014-04-01 2017-10-17 Bayer Pharma Aktiengesellschaft Disubstituted 5-fluoro pyrimidine derivatives containing a sulfondiimine group
US20230002406A1 (en) * 2020-05-04 2023-01-05 Volastra Therapeutics, Inc. Imino sulfanone inhibitors of enpp1
US20230183239A1 (en) * 2017-08-31 2023-06-15 Abbvie Inc. Ectonucleotide pyrophosphatase-phosphodiesterase 1 (enpp-1) inhibitors and uses thereof
US11707471B2 (en) * 2017-09-08 2023-07-25 The Board Of Trustees Of The Leland Stanford Junior University ENPP1 inhibitors and their use for the treatment of cancer

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9790189B2 (en) * 2014-04-01 2017-10-17 Bayer Pharma Aktiengesellschaft Disubstituted 5-fluoro pyrimidine derivatives containing a sulfondiimine group
US20230183239A1 (en) * 2017-08-31 2023-06-15 Abbvie Inc. Ectonucleotide pyrophosphatase-phosphodiesterase 1 (enpp-1) inhibitors and uses thereof
US11707471B2 (en) * 2017-09-08 2023-07-25 The Board Of Trustees Of The Leland Stanford Junior University ENPP1 inhibitors and their use for the treatment of cancer
US20230002406A1 (en) * 2020-05-04 2023-01-05 Volastra Therapeutics, Inc. Imino sulfanone inhibitors of enpp1

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