Bicyclic heteroaryl derivatives as ectonucleotide pyrophosphatase phosphodiesterase 1 inhibitors for the treatment of certain diseases

Abstract

The present disclosure provides certain bicyclic heteroaryl phosphonate and boronate compounds that inhibit ectonucleotide pyrophosphatase / phosphodiesterase 1 (ENPP1) enzymatic activity for the treatment of certain diseases mediated by upregulation of ENPP1 such as cancers, inflammatory diseases, and viral infections. Also provided are pharmaceutical compositions containing such compounds.

Description

BICYCLIC HETEROARYL DERIVATIVES AS ECTONUCLEOTIDE PYROPHOSPHATASE PHOSPHODIESTERASE 1 INHIBITORS FOR THE TREATMENT OF CERTAIN DISEASESCROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 63 / 665,760 filed June 28, 2024, the contents of which is herein incorporated by reference in its entirety for all purposes.STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

[0002] NOT APPLICABLEREFERENCE TO A "SEQUENCE LISTING," A TABLE, OR A COMPUTER PROGRAM LISTING APPENDIX SUBMITTED ON A COMPACT DISK

[0003] NOT APPLICABLEFIELD OF THE DISCLOSURE

[0004] The present disclosure provides certain bicyclic heteroaryl phosphonate and boronate compounds that inhibit ectonucleotide pyrophosphatase / phosphodiesterase 1 (ENPP1) enzymatic activity for the treatment of certain diseases mediated by upregulation of ENPP1 such as cancers, inflammatory diseases, and viral infections. Also provided are pharmaceutical compositions containing 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.

[0006] Cyclic GMP-AMP synthase (cGAS) is a patern 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 ty pe 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 also involved in host defense against RNA viruses and the immune control of tumor development (Aguirre S et al. 2012 PLoS Pathog 8: el002934; 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 atenuated 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 atractive 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 herein are methods of treating a disease selected from a cancer, an inflammatory disease, and a viral infection in a patient in need thereof, comprisingadministering to the patient a therapeutically effective amount of a compound of Formula (IA), (IB), or (IC) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (IA), (IB), or (IC) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, wherein(I) the compound of Formula (IA) has the formula:(alk)nwherein:X is N or CH;Z is NH, O, S, SO, or SO2; alk is alkydene optionally substituted with one, two, or three halo; m and n are independently 0 or 1 ;(i) -AHalk^m-Q is wherein Ar is aryl, heteroaryl, cycloalkyl, or heterocyclyl; alk1is alkylene wherein one carbon atom in the alkylene chain is optionally replaced by oxygen and further wherein alkylene is optionally substituted with one, two, or three halo; andQ is -B(OH)2or -P(O)(Ra)(Rb) wherein Raand Rbare independently selected from hydroxy, alkoxy, -Oaryl (where aryl is optionally substituted with one to three substituents independently selected from alkyl, alkenyl, alkoxy, halo, haloalkyl, amino, alkylamino, dialkylamino, cyano, or nitro), -O-(CH2)OCORC(where Rcis alkyl), -O-(alk2)ORd(where alk2is alkylene and Rdis alkyl), -S-(CH2)2SCORe(where Reis alkyl), or -NRg-(CHR)OCORf(where R is hydrogen, alkyl, hydroxymethyl, thiomethyl, methylthiomethyl, amidinopropyl, indol-3-ylmethyl. indol-4-ylmethyl, carboxymethy l, carboxyethyl, aminocarbonylmethyl, aminocarbonylethyl, phenyl or pheny lalky 1 (wherein pheny l either alone or as part of pheny lalky 1 is optionally substituted with one to three substituents independently selected from alkyl, alkoxy, halo, hydroxy, cyano or nitro), Rfis alkyl or benzyl, and Rgis hydrogen or Rgtogether with R forms -(CH2)3- ); or Raand Rbtogether with the phosphorus atom to which they are attached form a ring of formula (c):& O^.Ar1(c) wherein Ar1is phenyl or six membered heteroaryl optionally substituted with one to three halo; provided that, when Q is -P(O)(Ra)(Rb) or -B(0H)2, then at least one of n and m is 1; or(ii) -Ar- alk^m-Q is a ring of formula (a):R1is hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkylamino, alkoxyalkydamino, aminoalkyl, aminoalkoxy, aminoalkyl amino, diaminoalkyl, diaminoalkoxy, diaminoalkylamino or cyano;R2, R3, R9, and R10are independently hydrogen, alkyl, alkoxy, halo, haloalkyl, or haloalkoxy, or cyano;R7and R8are independently hydrogen or alkyl; and one of R4, R5, and R6is hydrogen, alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, cyano, amino, alkylamino, or dialkylamino; and the remaining two of R4, R5, and R6are independently hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, hydroxyalkyd, alkoxyalkyd, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkydamino, alkoxyalkylamino, aminoalkyd, aminoalkoxy, aminoalkylamino, heterocyclyl. heterocyclyloxy. heterocyclylamino (wherein heterocyclyl either alone or part of heterocyclyloxy and heterocyclylamino is optionally substituted with one, two, or three substituents 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 independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), cycloalkyloxy, phenyloxy, or heteroaryloxy (where phenyl in phenyloxy and heteroaryd in heteroarydoxy are optionally substituted with one or two substituents where two ofthe optional substituents are independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, and cyano);(II) the compound of Formula (IB) has the formula:wherein: a, b, d, and e are CH; or one or two of a, b, d, and e are N and remaining of a, b, d, and e are CH or C when attached to any one of R4, R5, and R6; one of y and z is N and the other y and z is CR7; or both y and z are CR7wherein each R7is independently hydrogen, alkyl, hydroxy, or halo; alk is alkylene optionally substituted with one, two, or three halo; alk1is alky lene wherein one carbon atom in the alkylene chain can be replaced by oxygen and the alkylene chain is optionally substituted with one, two, or three halo; m and n are independently 0 or 1; provided that at least one of m and n is 1;Ar is aryl or heteroaryl;Q is -P(O)(Ra)(Rb) or -B(RW)(RX), wherein Raand Rbare independently selected from hydroxy, alkoxy, -Oaryl (where aryl is optionally substituted with one to three substituents independently selected from alkyl, alkenyl, alkoxy, halo, haloalkyl. amino, alkylamino, dialkylamino, cyano, or nitro), -O-(CH2)OCORC(where Rcis alkyl), -O-(CH2)OCOORC(where Rcis alkyl), -O-(alk2)ORd(where alk2is alkydene and Rdis alkyl), -S-(CH2)2SCORe(where Reis alky 1), or -NRg-(CHR)OCORf(where R is hydrogen, alk l, hydroxymethyl, thiomethyl, methylthiomethyl, amidinopropyl. indol-3-ylmethyl, indol-4-ylmethyl, carboxymethyl, carboxyethyl, aminocarbonylmethyl, aminocarbonylethyl, phenyl or phenylalkyl (wherein phenyl either alone or as part of phenylalkyl is optionally7substituted with one to three substituents independently selected from alkyl, alkoxy, halo, hydroxy, cyano or nitro), Rfis al kyl or benzyl and Rgis hydrogen or together with R forms -(CH2)3- ); or Raand Rbtogether with the phosphorus atom to which they are attached form a ring of formula (a):wherein Ar2is phenyl or six membered heteroaryl optionally substituted with one to three halo; andRwand Rxare independently selected from hydroxy, alkoxy, -Oaryl (where aryl is optionally substituted with one to three substituents independently selected from alkyl, alkenyl, alkoxy, halo, haloalkyl, amino, alkylamino, dialkylamino, cyano, or nitro), -O-(CH2)OCORC(where Rcis alky l), -O-(alk2)ORd(where alk2is alkylene and Rdis alky l), -S-(CH2)2SCORe(where Reis alky l), or -NRg-(CHR)OCORf(where R is hydrogen, alkyl, hydroxymethyl, thiomethyl, methylthiomethyl, amidinopropyl. indol-3-ylmethyl, indol-4-ylmethyl, carboxymethyl, carboxyethyl, aminocarbonylmethyl, aminocarbonylethyl, phenyl or phenylalkyl (wherein phenyl either alone or as part of phenylalkyl is optionally substituted with one to three substituents independently selected from alkyl, alkoxy, halo, hydroxy, cyano or nitro), Rfis alk l or benzyd and Rgis hydrogen or together with R forms -(CH2)s- ); orR" and Rxtogether with the boron atom to which they are attached can form -0(CRR’)20- or -O(CRR’)3O- wherein each R and R’ is independently hydrogen or methyl;R2and R3are independently hydrogen, alkyd, alkoxy, halo, haloalkyl, haloalkoxy, or cyano;R4is hydrogen, alkyl, alkoxy, alkylthio, alkydsulfonyl, halo, haloalkyl, haloalkoxy, cyano, carboxy, alkoxy carbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, or dialkylaminosulfonyl; andR5and R6are independently hydrogen, alkyd, alkoxy, hydroxy, halo, haloalky 1, haloalkoxy, hydroxyalky 1, alkoxyalkyl, hydroxy alkoxy, alkoxyalkoxy, hydroxyalkylamino, alkoxyalkylamino, amino, aminoalkyl, aminoalkoxy, aminoalkylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino (wherein heterocyclyl either alone or part of heterocyclyloxy and heterocyclylamino is optionally substituted with Rh, R', or Rkindependently selected from alkyd, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalky 1), heterocyclylalky 1, heterocyclylalkyloxy, helerocyclylalkylamino (wherein the heterocyclyl ring in heterocyclylalky!, heterocyclylalkyloxy, and heterocyclylalkylamino is optionally substituted with one, two, or three substituents independently selected from alkyd, halo, hydroxy, alkoxy, hydroxy alkyl, alkoxyalkyd, and aminoalkyd), cycloalkyloxy, pheny doxy, or heteroaryloxy (where phenyl in pheny doxy andheteroaryl in heteroaryloxy are optionally substituted with one, two, or three substituents independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, and cyano); and(III) the compound of Formula (IC) has the formula:wherein:— dashed line is a bond between x and y or y and z; b. d, and e are CH or C when attached to R3or R4; or one or two of b. d, and e are N and remaining of b, d, and e are CH or C when attached to R3or R4: one of x and z is NH, O, or S and the other of x and z is CH or N; and y is CH, C when or C when attached to R5or R6, or N; provided that, at least one of y and the x or z that is CH or N. is CH or C when attached to R5or R6;G is a bond, NR (where R is hydrogen or alkyl), O, S, or SO2; alk is alkylene optionally substituted with one, two, or three halo or alkynylene, provided that when alk is alky nylene G is a bond and n is 1; alk1is alkylene optionally substituted with one, two, or three halo; m and n are independently 0 or 1; provided that at least one of m and n is 1 ;Ar is aryl or heteroaryl;Rwand Rxare independently selected from hydroxy, alkoxy, -Oaryl (where aryl is optionally substituted with one to three substituents independently selected from alkyd, alkenyl, alkoxy, halo, haloalkyl, ammo, alkylamino, dialkylamino, cyano, and nitro), -O-(CH2)OCORa(where Rais alky l), -O-(alk2)ORb(where alk2is alkylene and Rbis alky 1), -S-(CH2)2SCORC(where Rcis alky 1), or -NRe-(CHRd)OCORf(where Rdis hydrogen, alkyl, hydroxymethyl, thiomethyl, methylthiomethyl, amidinopropy 1, indol-3-ylmethyl, indol-4-ylmethyl, carboxymethyl, carboxyethyl, aminocarbonylmethyl, aminocarbonylethyl, phenyl or phenylalkyl (wherein phenyl either alone or as part of phenylalkyl is optionally substituted wdth one to three substituentsindependently selected from alkyl, alkoxy, halo, hydroxy, cyano and nitro), Rfis alky l or benzyl and Reis hydrogen or Retogether with Rdforms -(CH2)s-); orRwand Rxtogether with the boron atom to which they are attached can form a ring selected from:wherein each Rgand Rhis independently hydrogen or methyl;R1and R2are independently absent, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, or cyano;R3and R4are independently absent, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, alkylsulfonyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkylamino, alkoxyalkylamino, amino, aminoalkyl, aminoalkoxy, aminoalkylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino (wherein heterocyclyl, either alone or part of heterocyclyloxy, and heterocyclylamino is optionally substituted with R1, R'. or Rkindependently 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 independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), cycloalkyloxy, phenyl, heteroaryl, phenylalkenyl, heteroarylalkenyl, phenyloxy, or heteroaryloxy (where phenyl, by itself or as part of phenylalkenyl and phenyloxy and heteroaryl, by itself or as part of heteroarylalkenyl and heteroaryloxy, are optionally substituted with one or two substituents independently selected from alkyd, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, and cyano); provided that (i) when two of b, d. and e are N, then at least one of R3and R4is absent;R5is absent, alkyl, hydroxy, alkoxy, alkoxycarbonyl, halo, acylamino, hydroxyalkylamino, alkoxy alkylamino, cyano, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl; andR6is absent or alkyl; provided that one of R5and R6is absent when two of x, y. and z are other than CH; or a pharmaceutically acceptable salt thereof; and wherein the cancer is selected from one or more of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adenocarcinoma, adenoid cystic carcinoma, adolescent cancer, adrenal cancer, adrenocortical carcinoma, AIDS-related cancers (such as Kaposi Sarcoma), AIDS-related Lymphoma, primary CNS lymphoma, anal cancer, appendix cancer, astrocytomas, atypical teratoid / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer(including Ewing sarcoma and osteosarcoma, and / or malignant fibrous histiocytoma), brain cancer such as low grade glioma, large granular lymphocytic leukemia, T-cell prolymphocytic leukemia, prolymphocytic leukemia, colon adenocarcinoma, breast cancer, bronchial tumors, Burkitt lymphoma, carcinoma, central nervous system cancer, cervical cancer, childhood cancers, childhood cardiac tumors, cholangiocarcinoma, chordoma, chronic lymphocytic leukemia (CLL), colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma In Situ (DC1S), diffuse intnnsic pontine ghoma (DIPG), diffuse large B cell lymphoma, embryonal tumors, endometrial cancer, uterine cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fallopian tube cancer, gall bladder cancer, gastric (stomach) cancer, gastrointestinal tumors such as gastrointestinal neuroendocrine tumors and gastrointestinal stromal tumors (GIST), germ cell tumors, Gestational Trophoblastic Disease, Glioma, glioblastoma, hairy cell leukemia, head and neck cancer, heart tumors, histiocytosis, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, Kaposi sarcoma (soft tissue sarcoma), kidney (renal cell) cancer, Langerhans cell histiocytosis, laryngeal cancer, lip and oral cavity cancer, liver cancer, lung cancer (non-small cell lung cancer, small cell lung cancer, pleuropulmonary blastoma, pulmonary inflammatory myofibroblastic tumor, tracheobronchial tumor), lymphoma, medulloblastoma and other CNS embryonal tumors, uveal melanoma, Merkel cell carcinoma, mesothelioma, malignant metastatic cancer, metastatic squamous neck cancer with occult primary, midline tract carcinoma, mouth cancer, multiple endocrine neoplasia syndromes, mycosis fungoides (lymphoma), myelodysplastic syndromes, myelodysplastic / myeloproliferative neoplasms, myelogenous leukemia, chronic myeloid leukemia (CML), nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, neuroendocrine tumors, Non-Hodgkin lymphoma, oral cancer, oropharyngeal cancer, osteosarcoma, undifferentiated pleomorphic sarcoma of bone, ovarian cancer, ovarian germ cell tumors, pancreatic cancer, pancreatic neuroendocrine tumors, papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary' tumor, plasma cell neoplasms such as multiple myeloma, pleuropulmonary’ blastoma, primary Central Nervous System (CNS) lymphoma, peritoneal cancer, prostate cancer, pulmonary inflammatory myofibroblastic tumor, rectal cancer, rectum adenocarcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcomas, Sezary syndrome, skin cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma of the skin, squamous neck cancer, stomach cancer, T-Cell lymphoma, testicular cancer, throat cancer, thymoma and thy miccarcinoma, thyroid cancer, tracheobronchial tumors, urethral cancer, uterine sarcoma, vaginal cancer, vascular tumors, and vulvar cancer. the viral infection is selected from one or more of chronic virus infections, DNA virus infections, HBV, HIV, Herpes virus infections, Papilloma vims infections, and RNA virus infections; and the inflammatory disease is selected from one or more of arthritis, chronic inflammation, and sarcopenia.

[0010] In one embodiment of the first aspect, the disease is cancer and the cancer is selected from the group consisting of 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, bladder cancer, colorectal cancer, gastric and gastrointestinal cancer, esophageal cancer, adenocarcinoma, anal cancer, cancer of the appendix, kidney cancer, skin cancer, ovarian cancer, uterine cancer, brain cancer, lung cancer, adrenal cancer, bile duct cancer, bone cancer, cervical cancer, fallopian tube cancer, sarcomas, germ cell tumors, testicular cancer, head and neck cancer, neuroblastoma, pheochromocytoma and paraganglioma, cholangiocarcinoma, peritoneal cancer, retinoblastoma, breast cancer, liver cancer, thymoma, thyroid cancer, urethral cancer, prostate cancer, uveal melanoma, adenoid cystic carcinoma, rectum adenocarcinoma, colon adenocarcinoma, and vaginal and vulvar cancer.

[0011] In another embodiment of the first aspect, the disease is cancer and the cancer is selected from the group consisting of 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, bladder cancer, colorectal cancer, gastric and gastrointestinal cancer, esophageal cancer, adenocarcinoma, anal cancer, cancer of the appendix, kidney cancer, skin cancer other than melanoma, ovarian cancer, uterine cancer, brain cancer other than glioblastoma, lung cancer, adrenal cancer, bile duct cancer, bone cancer, cervical cancer, fallopian tube cancer, sarcomas, germ cell tumors, head and neck cancer, neuroblastoma, pheochromocytoma and paraganglioma, cholangiocarcinoma, peritoneal cancer, retinoblastoma, liver cancer other than hepatocellularcarcinoma, thymoma, urethral cancer, prostate cancer, uveal melanoma, adenoid cystic carcinoma, rectum adenocarcinoma, colon adenocarcinoma, and vaginal and vulvar cancer.

[0012] In some embodiments of the first aspect, the cancer is multiple myeloma. In some embodiments of the first aspect, the cancer is acute lymphocytic leukemia. In some embodiments of the first aspect, the cancer is acute myeloid leukemia. In some embodiments of the first aspect, the cancer is Hodgkin lymphoma. In some embodiments of the first aspect, the cancer is nonHodgkin lymphoma. In some embodiments of the first aspect, the cancer is head and neck cancer. In some embodiments of the first aspect, the cancer is liver cancer. In some embodiments of the first aspect, the cancer is liver cancer other than hepatocellular carcinoma. In some embodiments of the first aspect, the cancer is prostate cancer. In some embodiments of the first aspect, the cancer is colon adenocarcinoma.

[0013] In some embodiments of the first aspect, the disease is a viral infection and is selected from the group consisting of one or more of chronic virus infections, DNA virus infections, HBV. HIV, Herpes virus infections, Papilloma virus infections, and RNA virus infections. In some embodiments of the first aspect, the disease is a viral infection and is chronic virus infections. In some embodiments of the first aspect, the disease is a viral infection and is DNA virus infections. In some embodiments of the first aspect, the disease is a viral infection and is HBV. In some embodiments of the first aspect, the disease is a viral infection and is HIV. In some embodiments of the first aspect, the disease is a viral infection and is Herpes virus infections. In some embodiments of the first aspect, the disease is a viral infection and is Papilloma virus infections. In some embodiments of the first aspect, the disease is a viral infection and is RNA vims infections.

[0014] In some embodiments of the first aspect, the disease is an inflammatory disease and is selected from the group consisting of arthritis, chronic inflammation, and sarcopenia. In some embodiments of the first aspect, the disease is an inflammatory disease and is arthritis. In some embodiments of the first aspect, the disease is an inflammatory disease and is chronic inflammation. In some embodiments of the first aspect, the disease is an inflammatory disease and is sarcopenia.

[0015] In some embodiments of the first aspect, the disease is an inflammatory disease and is arthritis. In some embodiments of the first aspect, the arthritis is one or more of osteoarthritis and calcium pyrophosphate deposition disease (CPPD). In some embodiments of the first aspect, thearthritis is osteoarthritis. In some embodiments of the first aspect, the arthritis is calcium pyrophosphate deposition disease (CPPD).

[0016] In a second aspect, provided is a compound of Formula (IA), (IB), or (IC) (or any embodiments thereof described herein) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (IA), (IB), or (IC) and a pharmaceutically acceptable excipient for use as a medicament for the treatment of a disease of the first aspect.

[0017] In a third aspect, provided is a compound of Formula (IA), (IB), or (IC) (or any embodiments thereof described herein) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (IA), (IB), or (IC) and a pharmaceutically acceptable excipient for use in the treatment of a disease of the first aspect.

[0018] In some embodiments of the first through the third aspect, a compound of Formula (IA) or a pharmaceutically acceptable salt thereof is used.

[0019] In some embodiments of the first through the third aspect, a compound of Formula (IB) or a pharmaceutically acceptable salt thereof is used.

[0020] In some embodiments of the first through the third aspect, a compound of Formula (IC) or a pharmaceutically acceptable salt thereof is used.

[0021] In some embodiments of the first through the third aspect, pharmaceutical composition comprising a compound of Formula (IA) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient is used.

[0022] In some embodiments of the first through the third aspect, pharmaceutical composition comprising a compound of Formula (IB) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient is used.

[0023] In some embodiments of the first through the third aspect, pharmaceutical composition comprising a compound of Formula (IC) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient is used.

[0024] In some embodiments of the first through the third aspect, the compound of Formula (IA) is selected from the group consisting of:

[0025] In some embodiments of the first through the third aspect, the compound of Formula (IB) is selected from the group consisting of:

[0026] In some embodiments of the first through the third aspect, the compound of Formula (IC) is selected from the group consisting of

[0027] In any of the aforementioned aspects involving the treatment of cancer, are further embodiments comprising administering the compound of Formula (IA), (IB), or (IC) or a pharmaceutically acceptable salt thereof (or any embodiments thereof disclosed herein) in combination with at least one additional anti-cancer agent. When combination therapy is used, the agents can be administered simultaneously or sequentially.BRIEF DESCRIPTION OF THE DRAWINGS

[0028] FIG. 1 depicts in vivo antitumor efficacy of RBS2418, alone or in combination with Radiation therapy, in the Pan02 syngeneic pancreatic cancer mouse model. FIG. 1A depicts treatment of Pan02 tumor-bearing C57BL / 6 mice with RBS2418 (10 mg / kg, p.o., BID for 5 days), radiation (5 Gy, once), or RBS2418 in combination with radiation (n=8) and tumor grow th kinetics of the mice after each treatment. Data are represented as mean ± SEM. FIG. IB depicts tumor volume (mm3) comparisons in Vehicle and treatment groups on Day 9 after tumor implantation. Data were analyzed using Dunnetf s T3 multiple comparisons test for Vehicle vs. treatment groups, and Welch’s t-test was used for the comparison between RT vs. RBS2418+RT. All tests were two-tailed, and p-values of < 0.05 were defined as statistically significant. *: represents p < 0.05, **: p < 0.01, ***: p < 0.001. FIGs. 1C-1E depict individual tumor growth kinetic of mice treated with RBS2418 (FIG. IC), Radiation (FIG. ID), and RBS2418 incombination with RT (FIG.. IE) along with mice treated with Vehicle. RT: radiation therapy; p.o.: orally; BID: twice a day. Statistical analyses were performed with GraphPad Prism 9 Software.

[0029] FIG. 2 depicts in vivo antitumor efficacy of RBS2418 in the Hepal-6 syngeneic liver cancer mouse model. FIG. 2A depicts treatment of Hepal-6 tumor-bearing C57BL / 6J mice with Vehicle or RBS2418 (30 mg / kg, i.m., QD for 10 days) and tumor growth kinetics of the mice (n = 8) after treated with Vehicle or RBS2418 (30 mg / kg, i.m., QD for 10 days). Data are represented as mean ± SEM. FIG. 2B depicts individual tumor growth kinetic of mice (n = 8) after treated with RBS2418 (30 mg / kg, i.m., QD for 10 days) along with the mice treated with Vehicle. FIG. 2C depicts survival curve of mice treated with Vehicle, RBS2418 (30 mg / kg, i.m., QD) for 10 days or 2 days. FIG. 2D depicts survival curve of cured mice after RBS2418 monotherapy (n=7) rechallenge with Hepal-6 cancer cells, i.m.: intramuscular; QD: once a day. Statistical analyses were performed with GraphPad Prism 9 Software. All tests were two-tailed, and p-values of < 0.05 were defined as statistically significant. *: represents p < 0.05, **: p < 0.01, ***: p < 0.001.

[0030] FIG. 3 depicts in vivo antitumor efficacy of RBS2418 in orthotopic GL261-luc syngeneic glioblastoma cancer mouse model. FIG. 3A depicts treatment of orthotopic GL261-luc tumorbearing C57BL / 6 mice with Vehicle, RBS2418 (200 pg / mouse, intraventricular injection, Q5D for 2 injections), anti-mPDl (10 mg / kg, i.p., BIW for 2 weeks), or RBS2418 in combination with anti-mPDl (n=8) and bioluminescence imaging (BLI) signal (p / s) kinetics. Data are represented as mean ± SEM. FIG. 3B-3C depicts quantification of BLI signals in regions of interest (ROIs) drawn around tumors. The BLI images of one of the mice treated w ith vehicle (FIG. 3B) and one treated with RBS2418 (FIG. 3C) on days 0, 7, 14, 21, and 28 and days 0, 7, 14, 21, 28, 42, and 55, respectively, are show n. FIG. 3D depicts survival curve of mice treated with Vehicle, RBS2418, and-mPDl, or RBS2418 in combination with anti-mPDl. FIG. 3E depicts survival curve of cured mice after RBS2418 or anti-mPDl monotherapy or RBS2418 in combination with anti-mPDl (n=5) treatments after rechallenge with GL261-luc tumor cells. Q5D: once every 5 days. Statistical analyses were performed with GraphPad Prism 9 Software. All tests were two-tailed, and p-values of < 0.05 were defined as statistically significant. *: represents p < 0.05, **: p < 0.01.

[0031] FIG. 4 depicts in vivo antitumor efficacy of RBS2418 in MC38 syngeneic colon cancer mouse model. FIG. 4A depicts treatment of MC38 tumor-bearing C57BL / 6 mice were treated with Vehicle or RBS2418 (10 mg / kg, p.o., BID for 5 days) and tumor growth kinetics of the mice after treatment (n = 8). Data were represented as mean ± SEM. FIG. 4B depicts individual tumor growth kinetic of mice treated with Vehicle or RBS2418 (10 mg / kg, p.o.. BID for 5 days). FIG. 4C depicts tumor volume (mm3) comparisons in Vehicle and treatment group on Day 10 after tumor implantation. FIG. 4D depicts tumor volume (mm3) comparisons in Vehicle and treatmentgroup on Day 14 after tumor implantation. Data were analyzed using Welch's t-test. All tests were two-tailed, and p-values of < 0.05 were defined as statistically significant. *: represents p < 0.05. p.o.: orally; BID: twice a day.

[0032] FIG. 5 depicts antitumor efficacy of RBS2418 in B16F10 syngeneic melanoma cancer mouse model. FIG. 5A depicts treatment of Bl 6F 10 tumor-bearing C57BL / 6 mice with Vehicle, RBS2418 (10 mg / kg, p.o., BID for 5 days), or Anti-PDl (10 mg / kg, i.p., BIW for 2 weeks) and tumor growth kinetics of the mice after treatment (n = 8). Data are represented as mean ± SEM. FIG. 5B depicts tumor volume (mm3) comparisons in Vehicle and treatment groups on Day 20 after tumor implantation. Data were analyzed using Dunn’s multiple comparisons test for Vehicle vs. treatment groups. All tests were two-tailed, and p-values of < 0.05 were defined as statistically significant. *: represents p < 0.05. FIGs. 5C-5D depict individual tumor growth kinetic of mice treated with Vehicle and RBS2418 (FIG. 5C) and Vehicle and Anti-PDl (FIG. 5D) along with mice treated with Vehicle, p.o.: orally; BID: twice a day. i.p.: intraperitoneally; BIW: twice a week. Statistical analyses were performed with GraphPad Prism 9 Software.DETAILED DESCRIPTIONDefinitions:

[0033] 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:

[0034] “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.

[0035] “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.

[0036] “Alkenyl” means a linear or branched monovalent hydrocarbon radical of two to six carbon atoms containing a double bond, e.g., ethenyl, propenyl, 2-propenyl, and the like.

[0037] “Alkynylene” means a linear or branched divalent hydrocarbon radical of two to six carbon atoms containing a triple bond e.g., ethynylene, propynylene, and the like.

[0038] “Alkylthio'’ means -SR radical where R is alky l as defined above, e.g., methylthio, ethylthio, and the like.

[0039] “Alkylsulfonyl” means -SO2R radical where R is alkyl as defined above, e.g., methylsulfonyl, ethylsulfonyl, and the like.

[0040] “Amino” means a -NH2.

[0041] “Aminocarbonyl” means -CONH2.

[0042] “Alkydaminocarbonyl” means -CONHR radical where R is alkyl as defined above, e.g., methylaminocarbonyl, ethylaminocarbonyl, and the like.

[0043] “Aminosulfonyl” means -SO2NH2.

[0044] “Alky laminosulfonyl” means - SO2NHR radical where R is alkyl as defined above, e.g., methylaminosulfonyl, ethylaminosulfonyl, and the like.

[0045] “Alkylamino” means a -NHR radical where R is alkyl as defined above, e.g., methylamino, ethylamino, propylamino, or 2-propylamino, and the like.

[0046] “Aminoalky 1” 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 independently hydrogen or alkyl as defined above, e.g., aminomethyl. aminoethyl, methylaminomethyl, and the like.

[0047] ‘ ‘Aminoalkylamino” means a -NRaRbradical where Rais hydrogen or alkyl and Rbis aminoalkyl as defined above, e.g., aminoethylamino, dimethylaminoethylamino, diethylaminoethylamino, dimethylaminopropylamino, diethylaminopropylamino, and the like.

[0048] “Aminoalkyloxy” means a -ORaradical where Rais aminoalkyl as defined above, e.g.. aminoethyloxy, dimethylaminoethyloxy, diethylaminoethyloxy, dimethylaminopropyloxy, di ethylaminopropyloxy, and the like.

[0049] “Acylamino” means -NHCOR radical where R is alkyl as defined above, e.g., methylcarbonylamino, and the like.

[0050] “Alkoxy” means a -OR radical where R is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, n-. iso-, or to7-butoxy, and the like.

[0051] “Alkoxycarbonyl” means a -C(O)OR radical where R is alkyl as defined above, e.g.. methoxy carbonyl, ethoxy carbonyl, and the like.

[0052] ” Alkoxy alkyl ” 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-methoxy ethyl, 1-, 2-, or 3-methoxypropyl, 2-ethoxy ethyl, and the like.

[0053] “Alkoxyalkylamino’' means a -NRR’ radical where R is hydrogen or alkyl and R’ is alkoxy alkyl as defined above, e.g., methoxy ethylamino, ethoxy ethylamino, propoxypropylamino, ethoxypropylamino, and the like.

[0054] “Alkoxyalkyloxy” or “alkoxyalkoxy” means a -(O)R radical where R is alkoxyalkyl as defined above, e.g., methoxyethoxy, ethoxy ethoxy, and the like.

[0055] The term “amidinopropyl” means -(CH2)3NHC(=NH)NH2.

[0056] “Aryl” means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms e.g.. phenyl or naphthyl.

[0057] “Phenyloxy” means a -OR radical where R is phenyl.

[0058] “Cycloalkyl” means a cyclic saturated monovalent hydrocarbon radical of three to ten carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, 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] “Dialkylaminocarbonyl” means -CONHRR’ where R and R’ are independently alkyl as defined above, e.g., dimethylaminocarbonyl, methylethylaminocarbonyl, and the like.

[0062] “Dialkylaminosulfonyl” means -SO2NHRR’ where R and R’ are independently alkyl as defined above, e.g., dimethylaminosulfonyl, methylethylaminosulfonyl, and the like.

[0063] “Dialkylamino” means a -NRR’ radical where R and R’ are alkyd as defined above, e.g., dimethylamino, methylethylamino, and the like.

[0064] “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 independently hydrogen or alkyl as defined above, e.g., diaminoethyl, 1,3-diaminopropyl, 2-amino-3-methylaminopropyl, and the like.

[0065] “Diaminoalkylamino” means a -NRaRbradical where Rais hydrogen or alkyl and Rbis diaminoalkyl as defined above, e g., diaminoethylamino, 1,3-diaminopropylamino, 2-amino-3- methylaminopropylamino, and the like.

[0066] "Diaminoalkyloxy” means a-ORaradical where Rais diaminoalkyl as defined above, e g., 2-diaminoethyloxy, 1,3 -diaminopropyloxy, 2-amino-3-methylaminopropyloxy, and the like.

[0067] “Halo” means fluoro, chloro, bromo, or iodo, preferably fluoro or chloro.

[0068] "Halo alkyl” 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., -CH2CI, -CF3, -CHF2, -CH2CF3, -CF2CF3, -CF(CHs)2, and the like. When the alkyl is substituted with only fluoro, it can be referred to in this Application as fluoroalkyl.

[0069] “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.

[0070] “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, l-(hydroxymethyl)-2-methylpropyl, 2- hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl. 2,3 -dihydroxy propyl, l-(hydroxymethyl)-2- hydroxy ethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl, and l-(hydroxymethyl)-2-hydroxyethyl.

[0071] “Hydroxyalkylamino” means a -NRaRbradical where Rais hydrogen or alkyl and Rbis hydroxyalkyl as defined above, e.g., hydroxy ethylamino, hydroxypropylamino, and the like.

[0072] “Hydroxyalkyloxy” means a -ORaradical where Rais aminhydroxyoalkyl as defined above, e.g., hydroxyethyloxy, hydroxypropyloxy, and the like.

[0073] “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 nis 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, pyrrolidino, piperidine, homopiperidino, 2- oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino, tetrahydro-pyranyl, thiomorpholino, 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 heterocycloamino and is a subset of the heterocyclyl group.

[0074] “Heterocyclylalkyl” or “heterocycloalky 1” 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.

[0075] “Heterocyclylamino” means a -NRR’ radical where R is hydrogen or alkyl and R’ is heterocyclyl (including specific heterocyclyl rings) as defined above.

[0076] “Heterocyclylalkylamino” or “heterocycloalkyl amino’’ 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.

[0077] “Heterocyclyloxy” means a -OR radical where R is heterocyclyl (including specific heterocyclyl rings) as defined above.

[0078] “Heterocyclylalkyloxy” or “heterocycloalkyloxy” 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.

[0079] “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 heteroary l.

[0080] “Heteroaryloxy” means a -OR radical where R is heteroaryl (including specific heteroaryl rings) as defined above.

[0081] The term “methylthiomethyl” means -CH2SCH3.

[0082] The present disclosure also includes protected derivatives of compounds of the present disclosure. For example, when compounds of the present disclosure 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.

[0083] The present disclosure also includes polymorphic forms and deuterated forms of the compound of the present disclosure and / or a pharmaceutically acceptable salt thereof.

[0084] 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-hydroxy ethanesulfonic acid, benzenesulfonic acid, 4- chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-l-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 nontoxic. 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.

[0085] The compounds of the present disclosure may have asymmetric centers. Compounds of the present disclosure 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.

[0086] Certain compounds of the present disclosure 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 (IB) can exist as a tautomer as shown below:

[0087] Additionally, as used herein the term alkyl includes all the 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.

[0088] 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 structure:, the R4substituent can replace any hydrogen on the six membered aromatic ring portion of the bicyclic ring system, including the hydrogen of CH when a is CH.

[0089] The compounds of the present disclosure 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 (IA), (IB), and (IC) (and any embodiment thereof disclosed herein including specific compounds) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as2H,3H,nC,13C,14C,13N,15N,15O,170,180,32P,33P,35S,18F,36C1,123I, and1251, 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 1 below one or more hydrogen atoms are replaced by2H or3H, or one or more carbon atoms are replaced by13C- or14C-enriched carbon. Positron emitting isotopes such as15O,13N,nC, and15F 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.

[0090] '‘Oxo’’ or '‘carbonyl” means =(O) group.

[0091] “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.

[0092] 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 acceptablecarrier / excipient” as used in the specification and claims includes both one and more than one such excipient.

[0093] The term “thiomethyl” means -CH2SH.

[0094] 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.

[0095] 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.

[0096] 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.

[0097] 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.

[0098] “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 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.

[0099] 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 patientfor 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.

[0100] Dosage form or unit dosage form. Those skilled in the art will appreciate that the term “dosage form” may be used to refer to a physically discrete unit of an active agent (e.g., a therapeutic or diagnostic agent) for administration to a patient. Typically, each such unit contains a predetermined quantity of active agent. In some embodiments, such quantity is a unit dosage amount (or a whole fraction thereof) appropriate for administration in accordance with a dosing regimen that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population (i.e., with a therapeutic dosing regimen). Those of ordinary' skill in the art appreciate that the total amount of a therapeutic composition or agent administered to a particular patient is determined by one or more attending physicians and may involve administration of multiple dosage forms.

[0101] Dosing regimen or therapeutic regimen: Those skilled in the art will appreciate that the terms “dosing regimen” and “therapeutic regimen” may be used to refer to a set of unit doses (typically more than one) that are administered individually to a patient, typically separated by periods of time. In some embodiments, a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses. In some embodiments, a dosing regimen comprises a plurality' of doses each of which is separated in time from other doses. In some embodiments, individual doses are separated from one another by a time period of the same length; in some embodiments, a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses. In some embodiments, all doses within a dosing regimen are of the same unit dose amount. In some embodiments, different doses within a dosing regimen are of different amounts. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount different from the first dose amount. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by7one or more additional doses in a second dose amount same as the first dose amount. In some embodiments, a dosing regimen is correlated with a desired or beneficial outcome when administered across a relevant population (i.e., is a therapeutic dosing regimen).

[0102] In some embodiments, the compounds of the disclosure, such as RBS2418, are administered to the patient in an amount that is from about 100 mg / day7to about 800 mg / day. Insome embodiments, the patient is administered about 100 mg / day of a compound of the disclosure, such as RBS2418. In some embodiments, the patient is administered about 200 mg / day of a compound of the disclosure, such as RBS2418. In some embodiments, the patient is administered about 300 mg / day of a compound of the disclosure, such as RBS2418. In some embodiments, the patient is administered about 400 mg / day of a compound of the disclosure, such as RBS2418. In some embodiments, the patient is administered about 500 mg / day of a compound of the disclosure, such as RBS2418. In some embodiments, the patient is administered about 600 mg / day of a compound of the disclosure, such as RBS2418. In some embodiments, the patient is administered about 700 mg / day of a compound of the disclosure, such as RBS2418. In some embodiments, the patient is administered about 800 mg / day of a compound of the disclosure, such as RBS2418.

[0103] Representative compounds of Formula (IA) are disclosed in Table 1 below:Table 1

[0104] Representative compounds of Formula (IB) are disclosed in Table 2 below:Table 2

[0105] Representative compounds of Formula (IC) are disclosed in Table 3 below:Table 3

[0106] Compounds of Formula (IA), including those disclosed in compound Table 1 above, can be prepared and their ENPP1 activity can be determined as disclosed in PCT application publication No. W02020 / 140001, the contents of which is incorporated herein by reference for all purposes.

[0107] Compounds of Formula (IB), including those disclosed in compound Table 2 above, can be prepared and their ENPP1 activity can be determined as disclosed in PCT application publication No. WO 2020 / 210649, the contents of which is incorporated herein by reference for all purposes.

[0108] Compounds of Formula (IC), including those disclosed in compound Table 3 above, can be prepared and their ENPP1 activity can be determined as disclosed in PCT application publication No. WO2022 / 197734. the contents of which is incorporated herein by reference for all purposes.Embodiments:L Embodiments of compounds of Formula (IA);Embodiment Al

[0109] In embodiment Al, provided is a method of treating a cancer, an inflammatory7disease, and / or a viral infection with a compound of Formula (IA) or a pharmaceutically acceptable salt thereof as defined in the Summary above.

[0110] In a first subembodiment of embodiment A. the method is for treating cancer (such as multiple myeloma).[OHl] In a second subembodiment of embodiment A, the method is for treating an inflammatory7disease.

[0112] In a third subembodiment of embodiment A, the method is for treating a viral infection.Embodiment Bl

[0113] In embodiment B 1 , the method of embodiment Al, is wherein the compound of Formula (IA) or a pharmaceutically acceptable salt thereof has a structure of formula (Ibl) or (Icl):wherein Z is NH or O.

[0114] (Bli) In subembodiment (Bi) of embodiment Bl, the method is wherein the compound or a pharmaceutically acceptable salt thereof has structure (Ibl).

[0115] (Blii) In subembodiment (Bii) of embodiment Bl , the method is wherein the compound or a pharmaceutically acceptable salt thereof has structure (Icl).

[0116] (Bliii) In subembodiment (Bliii) the method of embodiments Al, Bl, (Bli) and (Blii) is wherein the compound or a pharmaceutically acceptable salt thereof is wherein Z is NH.

[0117] (Bliv) In subembodiment (Bliv), the method compounds of embodiments Al, Bl. (Bli) and (Blii) is wherein the compound or a pharmaceutically acceptable salt thereof is wherein Z is O.Embodiment C

[0118] In embodiment C, the method of any one of Embodiments Al and Bl, and subembodiments contained within embodiment Bl, is wherein the compound or a pharmaceutically acceptable salt thereof, is wherein Ar is aryl or heteroaryl.

[0119] (Ci). In subembodiment Ci of embodiment C, the method of embodiment C is wherein the compound or a pharmaceutically acceptable salt thereof are those wherein Ar is phenyl. In one subembodiment of subembodiment Ci, the method is wherein the compound of subembodiment Ci or a pharmaceutically acceptable salt thereof is wherein Q is attached to carbon of the phenyl ring that is meta to the carbon attaching the phenyl nng to the remainder of the compound of Formula (IA). In another subembodiment of subembodiment Ci, method is wherein the compound of subembodiment Ci or a pharmaceutically acceptable salt thereof is wherein Q is attached to carbon on the phenyl ring that is para to the carbon attaching the phenyl ring to the remainder of the compound of Formula (IA), (Ibl). or (Icl).

[0120] (Cii). In subembodiment Cii of embodiment C, the method of embodiment C is wherein the compound is wherein Ar is heteroaryl. In one subembodiment of subemebodiment Cii, the method is wherein the compound of subembodiment Cii or a pharmaceutically acceptable salt thereof is wherein Ar is pyridinyl, pyrimidinyl, pyridazinyl, thienyl, furanyl, thiazolyl, oxazolyl, isoxazolyl. pyrazolyl, triazolyl, oxadiazolyl. or imidazolyl. In another subembodiment of embodiment Cii, the method is wherein the compound of subembodiment Cii or a pharmaceutically acceptable salt thereof is wherein Ar is a six-membered ring such as pyridinyl, pyrimidinyl, or pyridazinyl wherein Q is attached to carbon on the pyridinyl, pyrimidinyl, orpyridazinyl ring that is meta to the carbon attaching the pyridinyl, pyrimidinyl, or pyridazinyl ring to remaining compound of Formula (IA), (Ibl), or (Icl).

[0121] Within subembodiment Cii, the method is wherein the compound is wherein Ar is benzofuranyl, quinolinyl, quinazolinyl, benzimidazolyl, indazolyl, benzotriazolyl, or benzoxazolyl.Embodiment D

[0122] In embodiment D, the method of Embodiments Al, and Bl. and subembodiments contained within embodiment Bl. is wherein the compound is wherein Ar is heterocyclyl.

[0123] (Di). In subembodiment Di of embodiment D, the method is wherein the compound of subembodiment Di or a pharmaceutically acceptable salt thereof is wherein Ar is pyrrolidinyl, piperidinyl, homopiperidinyl, or piperazinyl, preferably Ar is piperidinyl.

[0124] (Dii).In subembodiment Dii of embodiment D, the method is wherein the compound of subembodiment Di or a pharmaceutically acceptable salt thereof is wherein Ar is piperidinyl, homopiperidinyl, or piperazinyl wherein Q is attached to the ring atom of piperidinyl, homopiperidinyl, or piperazinyl that is meta or para, preferably para, to the ring atom attaching the aforementioned rings to the remaining compound of Formula (IA), (Ibl), or (Icl).Embodiment E

[0125] In embodiment E, the method of anyone of Embodiments Al. and formula (Ibl) and formula (Icl) in embodiments Bli, Blii, Bliii, and Bliv is wherein the compound is wherein (a) - Ar-Q in (Ibl) and Ar-alk^Q in (Icl) is a ring of formula (a) :

[0126] (Ei) In subembodiment Ei of embodiment E, the method is wherein the compounds of embodiment E or a pharmaceutically acceptable salt thereof are those wherein -Ar-Q in (Ibl) and Ar-alk'-Q in (Icl) is a ring of formula (a) wherein R7and R8are independently hydrogen or methyl.

[0127] (Eii) In subembodiment Eii of embodiment E, the method is wherein the compounds of embodiment E or a pharmaceutically acceptable salt thereof are those wherein -Ar-Q in (Ibl) and - Ar-alk'-Q in (Icl) is a ring of formula (a) wherein R7and R8are hydrogen.

[0128] (Eiii) In subembodiment Eiii of embodiment E, the method is wherein the compounds of embodiment E or a pharmaceutically acceptable salt thereof are those wherein -Ar-Q in (Ibl) and - Ar-alk'-Q in (Icl)is a ring of formula (a) wherein one of R7and R8is hydrogen and other methyl, or both R7and R8are methyl.Embodiment F

[0129] In embodiment F, the method of any one of embodiments Al , Bl , C, and D and subembodiments contained therein is wherein the compounds or a pharmaceutically acceptable salt thereof are those wherein Q is -P(O)(OH)2 or -B(OH)2.

[0130] (Fi). In subembodiment Fi of embodiment F, the method is wherein the compounds in embodiment F or a pharmaceutically acceptable salt thereof are those wherein Q is -P(O)(OH)2

[0131] (Fii). In subembodiment Fii, the method is wherein the compounds in embodiment F or a pharmaceutically acceptable salt thereof those wherein Q is -B(OH)2.

[0132] (Fiii). In subembodiment Fiii, the method of embodiments Al, Bl, C, and D and subembodiments contained therein is method is wherein the compounds or a pharmaceutically acceptable salt thereof are wherein Q is -P(O)(Ra)(Rb). Within subembodiment (Fiii), in a first group, the method is wherein the compounds are wherein Raand Rbare independently selected from hydroxy, alkoxy, -Oaryl (where aryl is optionally substituted with one to three substituents independently selected from alkyl, halo, haloalkyl, cyano, or nitro), -O-(CH2)OCORC(where Rcis alkyl), -O-(alk2)ORd(where alk2is alkylene and Rdis alkyl), and -S-(CH2)2SCORe(where Reis alkyl). Preferably. Raand Rbare independently selected from alkoxy, -Oaryl (where aryl is optionally substituted with one to three substituents independently selected from alkyl, halo, haloalkyl, cyano, or nitro), -O-(CH2)OCORC(where Rcis alkyd), and -O-(alk2)ORd(where alk2is alky dene and Rdis alkyd, such as methyl, isopropyl, n-propyl, isobutyl, n-butyl). Preferably, Raand Rbare independently hydroxy, alkoxy, -Ophenyl (where phenyl is optionally substituted with one to three substituents independently selected from alkoxy, halo, haloalkyl, cyano, or nitro), -O- (CH2)OCORC(where Rcis alkyl), or -NH-(CHR)OCORf(where R is alkyl, Rfis alkyl such as methyl, isopropyl, n-propyl, isobutyl, n-butyl or benzyl), preferably hy droxy or alkoxy .

[0133] Within subembodiment (Fiii), in a second group, the method is wherein the compounds are wherein Rais selected from hydroxy, alkoxy, -Oaryl (where aryl is optionally substituted with one to three substituents independently selected from alkyl, alkenyl, alkoxy, halo, haloalkyl, amino, alkylamino, dialkylamino, cyano, or nitro), -O-(CH2)OCORC(where Rcis alkyl), -O- (alk2)ORd(where alk2is alkylene and Rdis alkyl), and -S-(CH2)2SCORe(where Reis alkyl), and Rbis selected from -NR8-(CHR)OCORf(where R is hydrogen, alkyl, hydroxymethyl, thiomethyl, methylthiomethyl, amidinopropyl. indol-3-ylmethyl, indol-4-ylmethyl. carboxy methyl, carboxyethyl, aminocarbonylmethyl, aminocarbonylethyl, phenyl or phenylalkyl (wherein phenyl either alone or as part of phenylalkyd is optionally substituted with one to three substituents independently selected from alkyl, alkoxy, halo, hydroxy, cyano or nitro), Rfis alkyl or benzyl, and Rsis hydrogen or together with R forms -(CH2)s- ). Preferably’, Rais selected from alkoxy and -Oaryl (where aryl is optionally substituted with one to three substituents independently selected from halo, cyano, or nitro) and Rbis selected from -NRg-(CHR)OCORf(where R is alkyl such as methyl, isopropy l, n-propyl, isobuty l, n-butyl).

[0134] Within subembodiment (Fiii), in a third group, the compounds are wherein Raand Rbtogether with the phosphorus atom to which they are attached form a ring of formula (i):(i) wherein Ar1is phenyl or six membered heteroaryl optionally substituted with one to three halo. Preferably, Ar1is phenyl substituted one to three halo or pyridinyl.Embodiment Gl

[0135] In embodiment Gl, the method of any one of embodiments Al. Bl, C, D, and F and subembodiments contained therein is wherein the compounds or a pharmaceutically acceptable salt thereof are those wherein one of n and m is 1 and the other of n and m is 0. In a first subembodiment of embodiment Gl, the compounds are where alk or alkl is independently methyl, ethyl, or propyl, preferably methyl when Ar is a six membered ring. In a second subembodiment of embodiment Gl. the compounds are wherein n is 0. m is 1, and alkl is -O- CH2- or -O-(CH2)2- when Ar is a six membered ring wherein O in -O-CH2- and -O-(CH2)2- is attached to Ar.Embodiment Hl

[0136] (i) In embodiment (i) of embodiment Hl, the method of any one of embodiments Al, Bl. C, D, E, F. and Gl, is wherein the compounds and subembodiments contained therein or apharmaceutically acceptable thereof are those wherein R1is hydrogen or alkyl, preferably hydrogen or methyl, more preferably hydrogen.

[0137] (ii) In embodiment (ii) of embodiment Hl, the method of any one of embodiments Al. Bl , C, D, E, F, and G1 and subembodiments contained therein is wherein the compounds or a pharmaceutically acceptable thereof are those wherein R1is halo, haloalkyl, or haloalkoxy.

[0138] (iii) In embodiment (iii) of embodiment Hl, the method of any one of embodiments Al, Bl. C, D, E, F, and G1 and subembodiments contained therein is wherein the compounds or a pharmaceutically acceptable thereof are wherein R1is amino, alkylamino, or dialkylamino, preferably amino, methylamino or dimethylamino.

[0139] (iv) In embodiment (iv) of embodiment Hl, the method of any one of embodiments Al, Bl, C, D, E, F, and G1 and subembodiments contained therein is wherein the compounds or a pharmaceutically acceptable thereof are wherein R1is hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkylamino, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, diaminoalkyl, diaminoalkoxy, diaminoalkylamino, or cyano.Embodiment I

[0140] In embodiment I, the method of any one of embodiments Al, Bl, C, D, E, F, Gl, Hl, and I and subembodiments contained therein is wherein the compounds or a pharmaceutically acceptable thereof are wherein R2. R3. R9. R10, R11and R12are independently hydrogen, methyl, ethyl, methoxy, fluoro, trifluoromethyl, trifluoromethoxy, or cyano, preferably hydrogen.Embodiment J

[0141] In embodiment J, the method of any one of embodiments Al, Bl, C, D, E, F, Gl, Hl , and I and subembodiments contained therein is wherein the compounds or a pharmaceutically acceptable thereof are those wherein R4is hydrogen, alkyl, hydroxy, alkoxy, halo, haloalkyl. haloalkoxy, or cyano.

[0142] (Li) In subembodiment Li of embodiment L, R4is hydrogen, methyl, hydroxy, methoxy, ethoxy , fluoro, chloro, trifluoromethyl, cyano, or trifluoromethyl; preferably R4is hydrogen, methoxy or ethoxy, more preferably R4is hydrogen.Embodiment K

[0143] (Ki) In embodiment Ki, the method of any one of embodiments Al, Bl, C, D, E, F, GL Hl, I, and J and subembodiments contained therein is wherein the compounds or a pharmaceutically acceptable thereof are those wherein R5and R6are independently hydrogen,alky l, alkoxy, hydroxy, halo, haloalkyl, or haloalkoxy; preferably R5and R6are independently hydrogen, alkoxy, or hydroxy, more preferably R5and R6are independently alkoxy such as methoxy, ethoxy, or propoxy and are attached to C6 and C7 carbons of the bicyclic ring. It is understood that the nitrogen atom para to ring carbon attached to -Z-(alk)n-Ar-(alk1)m-Q group of the bicyclic ring is position 1. Certain ring numberings for the bicyclic ring are also shown in subformulea (Ibl) and (Icl).

[0144] (Kii) In embodiment Kii, the method of any one of embodiments Al. Bl. C, D, E, F. Gl, Hl, I, and J and subembodiments contained therein is wherein the compounds or a pharmaceutically acceptable thereof are those whereinR5is hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl. or haloalkoxy; andR6is hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkylamino, alkoxyalkylamino, aminoalkyl. aminoalkoxy, aminoalkyl amino, heterocyclyl, heterocyclyloxy, heterocyclylamino (wherein heterocyclyl either alone or part of heterocyclyloxy and heterocyclylamino is optionally substituted with one, two, or three substituents independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), heterocyclylalkyl, heterocyclylalkyloxy, heterocyclylalkylamino (wherein the heterocyclyl ring in heterocyclylalkyl, heterocyclylalky loxy, and heterocyclylalkylamino is optionally substituted with one, two, or three substituents independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), cycloalkyloxy, phenyloxy, or heteroaryloxy (where phenyl in phenyloxy and heteroaryl in heteroaryloxy are optionally substituted with one or two substituents w here two of the optional substituents are independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, and cyano).

[0145] In a first subembodiment of embodiment Kii, R5is hydrogen, methoxy, ethoxy, or hydroxy, preferably R5is methoxy or ethoxy; and R6is 2-hydroxyethyloxy, 3-hydroxypropyloxy, 2-methoxyethyloxy, 2-ethoxy ethyloxy, 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 optionally substituted with one or two substituents independently selected from methyl, fluoro, hydroxy, or methoxy) and one of R ' and R6is attached to C6 and the other of R5and R6is attached to C7 carbons of the bicyclic ring.

[0146] (Kiii)In embodiment Ki, the method of any one of embodiments Al, Bl, C, D, E, F, Gl, Hl, I, and J and subembodiments contained therein is wherein the compounds or a pharmaceutically acceptable thereof are those wherein R5and R6are independently hydroxyalkyl, alkoxyalky l, 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 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 or two substituents independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), cycloalkyloxy, phenyloxy, or heteroaryloxy (where phenyl of phenyloxy and heteroaryl of heteroaryl oxy are optionally substituted with one, two, or three substituents where two of the optional substituents are independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, and cyano).

[0147] In a first subembodiment of embodiment Kiii. R5and R6are independently 2- hydroxy ethyloxy, 3-hydroxypropyloxy, 2 -methoxy ethyloxy, 2-ethoxyethyloxy, 3- methoxypropyloxy, 3-ethoxypropyloxy, 2-aminoethyloxy, 2-methylaminoethyloxy, 2- dimethylaminoethyloxy, 2-diethylaminoethyloxy, 3 -aminopropyloxy, 3-methylaminopropyloxy. 3-dimethylaminopropyloxy, 3-diethylaminopropyloxy, pyrrolidinyloxy, piperidinyloxy, pyrrohdinylmethyloxy, piperidinylmethyloxy, pyrrolidinylethyloxy, piperidinylethyloxy, 2- hydroxyethylamino, 3 -hydroxy propyl amino, 2-methoxy ethyl amino, 2-ethoxy ethylamino, 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 optionally substituted with one or twosubstituents independently selected from methyl, fluoro, hydroxy, or methoxy) and R5and R6are attached to C6 and C7 carbons of the bicyclic ring.

[0148] (Kiv)In embodiment Kiv, the method of any one of embodiments Al, Bl, C. D, E. F, Gl , Hl, I, and J and subembodiments contained therein is wherein the compounds or a pharmaceutically acceptable thereof are those wherein R5is hydrogen and R6is hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, or haloalkoxy; preferably R6is hydrogen, alkoxy, or hydroxy, more preferably R6is independently alkoxy such as methoxy, ethoxy, or propoxy and is attached to C7 carbons of the bicyclic ring.Embodiment L

[0149] In embodiment L, the method of embodiment Al is wherein the compounds or a pharmaceutically acceptable thereof are those wherein X is CH. With embodiment L, the compounds or a pharmaceutically acceptable thereof are those wherein Z, alk, n, m, R1, R2, R3, R4, R5, R6, R7, R8R9, R10, R11and R12are as defined in embodiment B 1 K above, and subembodiments contained therein.II. Embodiments of compounds of Formula (IB);Embodiment A

[0150] In embodiment A, provided is a method of treating a cancer, an inflammatory disease, and / or a viral infection with a compound of Formula (IB) or a pharmaceutically acceptable salt thereof as defined in the Summary above.

[0151] In a first subembodiment of embodiment A. the method is for treating cancer (such as multiple myeloma).

[0152] In a second subembodiment of embodiment A, the method is for treating an inflammatory disease.

[0153] In a third subembodiment of embodiment A, the method is for treating a viral infection.Embodiment B

[0154] In embodiment B, the method of embodiment A and subembodiments contained therein, is wherein the compound of Formula (IB), or a pharmaceutically acceptable salt thereof has a structure of formula (IBa) or (IBb):

[0155] (Bi) In subembodiment (Bi), the method of embodiment B is wherein the compound of Formula (IB), or a pharmaceutically acceptable salt thereof, has structure of formula (IBa).

[0156] (Bii) In subembodiment (Bii), the method of embodiment B is wherein the compound of Formula (IB), or a pharmaceutically acceptable salt thereof, has structure of formula (IBb).

[0157] (Biii)In subembodiment (Biii), the method of embodiment B is wherein the compounds of formulae (IBa) and (IBb) or a pharmaceutically acceptable salt thereof, are wherein y is N and z is CR7Embodiment C

[0158] In embodiment C, the method of any one of embodiment A and subembodiments contained therein, is wherein the compound of Formula (IB), or a pharmaceutically acceptable salt thereof, has a structure of formula (IBc) or (IBd):

[0159] (Ci) In subembodiment (Ci), the method of embodiment C is wherein the compound of Formula (IB), or a pharmaceutically acceptable salt thereof, has structure of formula (IBc).

[0160] (Cii) In subembodiment (Cii), the method of embodiment C is wherein the compound of Formula (IB), or a pharmaceutically acceptable salt thereof, has structure of formula (IBd).Embodiment D

[0161] In embodiment D, the method of any one of embodiment A and subembodiments contained therein, is wherein the compound of Formula (IB), or a pharmaceutically acceptable salt thereof, has a structure of formula (IBe) or (IBf):

[0162] (Di) In subembodiment (Di), the method of embodiment D is wherein the compound ofFormula (IB), or a pharmaceutically acceptable salt thereof, has structure of formula (IBe).

[0163] (Dii) In subembodiment (Dii), the method of embodiment D is wherein the compound of Formula (IB), or a pharmaceutically acceptable salt thereof, has structure of formula (IBf).Embodiment DI

[0164] In embodiment DI, the method of any one of embodiment A and subembodiments contained therein, is wherein the compound of Formula (IB), or a pharmaceutically acceptable salt thereof, has a structure of formula (IBg) or (IBh):where R7is alkyl, halo, or hydroxy.

[0165] (Dii) In subembodiment (Dii), the method of embodiment D is wherein the compound of Formula (IB), or a pharmaceutically acceptable salt thereof, has structure of formula (IBg).

[0166] (Dlii) In subembodiment (Dii), the method of embodiment D is wherein the compound of Formula (IB), or a pharmaceutically acceptable salt thereof, has structure of formula (IBh).

[0167] (Dliii) In subembodiment (Dii), the method of embodiment D is wherein the compound of structures (IBg) and (IBh), or a pharmaceutically acceptable salt, are those wherein R7is alkyl.Embodiment E

[0168] In embodiment E, the method of any one of embodiments A, B. C, D, and DI and subembodiments contained therein, is wherein the compounds of formulae (IB) and (IBa) to (IBh), or a pharmaceutically acceptable salt thereof, are wherein a, b, d, and e are CH or C when attached to any one of R4, R5, and R6.Embodiment F

[0169] In embodiment F, the method of any one of embodiments A, B, C, D. and DI and subembodiments contained therein, is wherein the compounds of formulae (IB) and (IBa) to (IBh), or a pharmaceutically acceptable salt thereof, are wherein a is N and b, d, and e are CH or C when attached to any one of R4, R5, and R6.Embodiment G

[0170] In embodiment G, the method of any one of embodiments A, B, C, D, and DI and subembodiment contained therein, is wherein the compounds of formulae (IB) and (IBa) to (IBh), or a pharmaceutically acceptable salt thereof, are wherein a and d are N and b. and e are CH or C when attached to any one of R4, R3, and R6.Embodiment H

[0171] In embodiment H, the method of any one of embodiments A, B, C, D, and DI and subembodiments contained therein, is wherein the compounds of formulae (IB) and (IBa) to (IBh), or a pharmaceutically acceptable salt thereof, are wherein b is N and a, c. and e are CH or C when attached to any one of R4, R5, and R6.Embodiment I

[0172] In embodiment I, the method of any one of embodiments A, B, C, D, and DI and subembodiments contained therein, is wherein the compounds of formulae (IB) and (IBa) to(IBh),or a pharmaceutically acceptable salt thereof, are wherein b and e are N and a and d are CH or C when attached to any one of R4, R5, and R6.

[0173] In subembodiment li, the method of any one of embodiments A, B. C, D. and D I and subembodiments contained therein, is wherein the compounds of formulae (IB) and (IBa) to (IBh), or a pharmaceutically acceptable salt thereof, are wherein b and e are N, a is C-R5and d is C-R6, and R5is hydroxyl. As described above, subembodiment li, where R5is hydroxyl, can exist in the tautomeric forms shown below:Embodiment J

[0174] In embodiment J, the method of any one of embodiments A, B, C, D, and DI and subembodiment contained therein, is wherein the compounds of formulae (IB) and (IBa) to (IBh), or a pharmaceutically acceptable salt thereof, are wherein b and e are N and a and d are CH or C when attached to any one of R4, R3, and R6.Embodiment K

[0175] In embodiment K, the method of any one of embodiments A, B, C, D, and DI and subembodiments contained therein, is wherein the compounds of formulae (IB) and (IBa) to (IBh), or a pharmaceutically acceptable salt thereof, are wherein d is N and a, b and e are CH or C when attached to any one of R4, R5, and R6.Embodiment L

[0176] (Li). In subembodiment Li, the method of any one of embodiments A, B. C, D, DI, E, F, G, H. I, J, and K. and subembodiment contained therein, is wherein the compounds of formulae (IB) and (IBa) to (IBh), or a pharmaceutically acceptable salt thereof, are wherein Q is - P(O)(OH)2

[0177] (Lii). Within subembodiment Lii, the method of any one of embodiments A, B, C, D, DI, E, F, G, H, I, J, and K, and subembodiment contained therein, is wherein the compounds of formulae (IB) and (IBa) to (IBh), or a pharmaceutically acceptable salt thereof, are wherein Q is - B(OH)2.

[0178] (Liii). In subembodiment Liii, the method of any one of embodiments A, B, C, D, DI, E, F, G, H, I, J, and K, and subembodiments contained therein, is wherein the compounds of formulae (IB) and (IBa) to (IBh), or a pharmaceutically acceptable salt thereof, are wherein Q is - P(O)(Ra)(Rb).

[0179] Within subembodiment (Liii), in a first group of compounds, Q is Raand Rbare independently selected from hydroxy, alkoxy, -Oaryl (where aryl is optionally substituted with one to three substituents independently selected from alkyl, halo, haloalkyl, cyano, or nitro), -O- (CH2)OCORC(where Rcis alkyl), -O-(CH2)OCOORC(where Rcis alkyl). -O-(alk2)ORd(where alk2is alkylene and Rdis alkyl), and -S-(CH2)2SCORe(where Reis alkyl). Preferably, Raand Rbare independently selected from alkoxy, -Oaryl (where aryl is optionally substituted with one to three substituents independently selected from alkyl, halo, haloalkyl, cyano, or nitro), -O- (CH2)OCORC(where Rcis alkyl), and -O-(alk2)ORd(where alk2is alkylene and Rdis alkyl, such as methyl, isopropyl, n-propyl, isobutyl, or n-butyl). Preferably, Raand Rbare independently hydroxy, alkoxy. -Ophenyl (where phenyl is optionally substituted with one to three substituents independently selected from alkoxy, halo, haloalkyl, cyano, or nitro), -O-(CH2)OCORC(where Rcis alkyl), or -NH-(CHR)OCORf(where R is alky l, Rfis alkyl such as methyl, isopropyl, n-propyl, isobutyl, n-butyl or benzyl), preferably hydroxy or alkoxy.

[0180] Within subembodiment (Liii), in a second group of compounds, Q is Rais selected from hydroxy, alkoxy. -Oaryl (where aryl is optionally substituted with one to three substituents independently selected from alkyl, alkenyl, alkoxy, halo, haloalkyl, amino, alkylamino, dialkylamino, cyano, or nitro), -O-(CH2)OCORC(where Rcis alkyl), -O-(alk2)ORd(where alk2is alkylene and Rdis alkyl), and -S-(CH2)2SCORe(where Reis alkyl), and Rbis selected from -NR8- (CHR)OCORf(where R is hydrogen, alkyl, hydroxymethyl, thiomethyl, methylthiomethyl, amidinopropyl, indol-3-ylmethyl, indol-4-ylmethyl, carboxymethyl, carboxyethyl,aminocarbonylmethyl, aminocarbonylethyl, phenyl or phenylalkyl (wherein phenyl either alone or as part of phenylalkyl is optionally substituted with one to three substituents independently selected from alkyl, alkoxy, halo, hydroxy, cyano or nitro), Rfis alkyl or benzyl, and Rsis hydrogen or together with R forms -(CH2)3- ). Preferably, Rais selected from alkoxy and -Oaryl (where aryl is optionally substituted with one to three substituents independently selected from halo, cyano, or nitro) and Rbis selected from -NRs-(CHR)OCORf(where R is alkyl such as methyl, isopropyl, n-propyL isobutyl, n-butyl).

[0181] Within subembodiment (Liii), in a third group of compounds, Q is where Raand Rbtogether with the phosphorus atom to which they are attached form a ring of formula (a):wherein Ar1is phenyl or six membered heteroaryl optionally substituted with one to three halo. Preferably, Ar1is phenyl substituted one to three halo or pyridinyl.

[0182] (Liv). In subembodiment Liv, the method of any one of embodiments A, B, C, D, DI, E, F, G. H, I, J, and K, and subembodiments contained therein, is wherein the compounds of formulae (IB) and (IBa) to (IBh), or a pharmaceutically acceptable salt thereof, are wherein Q is - B(RW)(RX).

[0183] Within subembodiment (Liv), in a first group of compounds, Rwand Rxare independently selected from hydroxy, alkoxy. -Oaryl (where aryl is optionally substituted with one to three substituents independently selected from alkyl, halo, haloalkyl, cyano, or nitro). -O- (CH2)OCORC(where Rcis alkyl), or -O-(alk2)ORd(where alk2is alkylene and Rdis alkyl). Preferably, Rwand Rxare independently selected from alkoxy, -Oary l (where ary 1 is optionally substituted with one to three substituents independently selected from alkyl, halo, haloalkyl, cyano, or nitro), -O-(CH2)OCORC(where Rcis alkyl), and -O-(alk2)ORd(where alk2is alkylene and Rdis alkyl, such as methyl, isopropyl, n-propyl, isobutyl, or n-butyl). Preferably, Rwand Rxare independently hydroxy, alkoxy, or -Ophenyl (where phenyl is optionally substituted with one to three substituents independently selected from alkoxy, halo, haloalkyl, cyano, or nitro).

[0184] Within subembodiment (Liv), in a second group of compounds. Rwand Rxare independently selected from hydroxy and alkoxy, preferably hydroxy.

[0185] Within subembodiment (Liv), in a third group of compounds, Rwand Rxtogether with the boron atom to which they are attached form a ring of formula (b) or (c):Embodiment M

[0186] In embodiment M, the method of any one of embodiments A, B, C. D, DI, E, F, G. H, I, J, K, and L, and subembodiments contained therein, is wherein the compounds of formulae (IB) and (IBa) to (IBh), or a pharmaceutically acceptable salt thereof, are wherein Ar is aryl.

[0187] (Mi). In subembodiment Mi of embodiment M, the method of embodiment M, is wherein the compounds of formulae (IB) and (IBa) to (IBh), or a pharmaceutically acceptable salt thereof, are wherein Ar is phenyl. In one subembodiment of subembodiment Mi. the method of subembodiment Mi, is wherein the compounds of formulae (IB) and (IBa) to (IBh), or a pharmaceutically acceptable salt thereof, are wherein Q is attached to carbon of the phenyl ring that is meta to the carbon attaching the phenyl ring to remaining compound of Formulae (IB) and (IBa) to (IBh). In another subembodiment of subembodiment Mi, the method of subembodiment Mi. is wherein the compounds of formulae (IB) and (IBa) to (IBh). or a pharmaceutically acceptable salt thereof, are wherein Q is attached to carbon on the phenyl ring that is para to the carbon attaching the phenyl ring to remaining compound of Formulae (IB) and (IBa) to (IBh), respectively.Embodiment N:

[0188] In embodiment N, the method of any one of embodiments A, B, C, D, DI, E. F, G, H, I, J, K, and L, and subembodiments contained therein, is wherein the compounds of formulae (IB) and (IBa) to (IBh), or a pharmaceutically acceptable salt thereof, are wherein Ar is heteroaryl. In one subembodiment of embodiment N, the method of embodiment N, is wherein the compounds of formulae (IB) and (IBa) to (IBh), or a pharmaceutically acceptable salt thereof, is wherein Ar is pyridinyl, pyrimidinyl, pyridazinyl. thienyl, furanyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, oxadiazolyl, or imidazolyl. In another subembodiment of embodiment N, the method of embodiment Mii, is wherein the compounds of formulae (IB) and (IBa) to (IBh), or a pharmaceutically acceptable salt thereof is wherein Ar is a six-membered ring such as pyridinyl.pyrimidinyl, or pyridazinyl wherein Q is atached to carbon on the pyridinyl, pyrimidinyl, or pyridazinyl ring that is meta to the carbon ataching the pyridinyl, pyrimidinyl. or pyridazinyl ring to remaining compound of Formula (IB) and (IBa) to (IBh), respectively.

[0189] With embodiment N in yet another group, the method of subembodiment N, is wherein the compounds of formulae (IB) and (IBa) to (IBh), or a pharmaceutically acceptable salt thereof is wherein Ar is benzofuranyl, quinolinyl, quinazolinyl, benzimidazolyl, indazolyl, benzotriazolyl. or benzoxazolyl.Embodiment O

[0190] In embodiment O, the method of any one of embodiments A, B, C, D, DI , E, F, G, H, I, J, K, L, M and N, and subembodiments contained therein, is wherein the compounds of formulae (IB) and (IBa) to (IBh), or a pharmaceutically acceptable salt thereof, are wherein alk and alk1are independently methylene, ethylene, or propylene. In a first subembodiment of embodiment O, alk and alk1are methylene, preferably alk and alk1are methylene when Ar is a six membered ring. In a second subembodiment of embodiment O, alk is methylene and alk1is absent (i.e., m is 0).Embodiment P

[0191] In embodiment P, the method of any one of embodiments A, B, D, DI, E, F, G, H, J, K, L, M, and O. and subembodiments contained therein, is wherein the compounds of formulae (IB) and (IBa) to (IBh), or a pharmaceutically acceptable thereof are wherein R7is hydrogen, methyl, isopropyl, or fluoro. In a first subembodiment of embodiment P, the compounds are those wherein R7is hydrogen, methyl, or fluoro. In a second subembodiment of embodiment P, the compounds are those wherein R7is hydrogen. In a second subembodiment of embodiment P, the compounds are those wherein R7is methyl or isopropyl. In a third subembodiment of embodiment P, the compounds are those wherein R7is isopropyl. In a fourth subembodiment of embodiment P, the compounds are those wherein R7is methyl.Embodiment Q

[0192] In embodiment Q, the method of any one of embodiments A, B, C, D, DI, E, F, G, H, I, J. K, L. M. N, O. and P, and subembodiments contained therein, is wherein the compounds of formulae (IB) and (IBa) to (IBh), or a pharmaceutically acceptable thereof, are wherein R2and R3are independently hydrogen, methyl, ethyl, methoxy, fluoro, trifluoromethyl, trifluoromethoxy, or cyano. In a first subembodiment of embodiment Q, the compounds are those wherein R2and R3are hydrogen.Embodiment R

[0193] In embodiment R, the method of any one of embodiments A, B, C, D, DI, E, F, G, H, I, J. K, L, M, N, O. P, and Q, and subembodiments contained therein, is wherein the compounds of formulae (IB) and (IBa) to (IBh), or a pharmaceutically acceptable thereof, are wherein R4is hydrogen, alkyd, alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, or dialkylaminosulfonyl.

[0194] (Ri) In subembodiment (Ri) of embodiment R, R4is hydrogen, methyl, methoxy, ethoxy, fluoro, chloro, trifluoromethyl, cyano, or tri fluoromethyl oxy. In a first subembodiment of (Ri), the compounds are wherein R4is hydrogen, methoxy or ethoxy. In a second subembodiment of (Ri), the compounds are whereinR4is hydrogen.

[0195] (Rii) In subembodiment (Rii) of embodiment R. R4is cyano, carboxy, alkoxy carbonyl, alkylsulfonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, or dialkylaminosulfonyl. Within (Rii), in one group of compounds, R4is cyano, carboxy, methoxy carbonyl, methylsulfonyl, aminocarbonyl, methyl aminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl, or dimethylaminosulfonyl. Within (Rii). in another group of compounds, R4is cyano, carboxy, methoxy carbonyl, aminocarbonyl, methylsulfonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl, or dimethylaminosulfonyl. Within (Rii), in yet another group of compounds, R4is aminocarbonyl, methylaminocarbonyl, or dimethylaminocarbonyl. Within R(ii) and groups contained therein, in another group of compounds, R4is attached to the six membered ring comprising a, b. d, and e of Formulae (IB) and (IBa) to (IBh) as shown belowwherein the wavy line denotes the attachment point to the remainder of the molecule (for sake of clarity, the six membered ring comprising a, b, d, and e of Formulae (IB) and (IBa) to (IBh), has been shown as an example. It will be apparent to a person skilled in the art, that in embodiments covering one or more of compounds of formulae (IBa) to (IBh), R4will be attached to the same carbon of the six membered ring comprising a, b, d. and e as depicited above).

[0196] (Riii) In subembodiment (Riii) of embodiment R, the compounds are wherein R4is alkylsulfonyl, preferably methylsulfonyl and R4is attached to the six membered ring comprising a, b, d, and e of Formula I as shown belowwherein the wavy line denotes the attachment point to the remainder of the molecule.Embodiment S

[0197] (Si) In embodiment Si, the method of any one of embodiments A, B, C, D, DI, E, F, G, H, I, J, K, L, M, N, O, P. Q and R. and subembodiments (or groups) contained therein, is wherein the compounds of formulae (IB) and (IBa) to (IBh). or a pharmaceutically acceptable thereof, are wherein R5and R6are independently hydrogen, alkyl, alkoxy, hydroxy, amino, halo, haloalkyl, or haloalkoxy. In a first subembodiment of embodiment (Si) the compounds are wherein R5and R6are independently hydrogen, alkoxy, amino, or hydroxy. In a second subembodiment of embodiment (Si) the compounds are wherein R5and R6are independently alkoxy such as methoxy, ethoxy, or propoxy and are attached to to the six membered ring comprising a, b, d, and e of Formulae (IB) and (IBa) to (IBh), as shown belowwherein the wavy line denotes the attachment point to the remainder of the molecule. In a third subembodiment of embodiment (Si) the compounds are wherein R5and R6are independently hydrogen. In a fourth subembodiment of embodiment (Si) the compounds are wherein R5is attached to the six membered ring comprising a, b, d, and e of Formulae (IB) and (IBa) to (IBh), as shown belowwherein the wavy line denotes the attachment point to the remainder of the molecule. Within the fourth subembodiment, in one group of compounds R5is hydroxy and R4and R6are hydrogen.III. Embodiments of compounds of Formula (IC):Embodiment A

[0198] In embodiment A, provided is a method of treating a cancer, an inflammatory disease, and / or a viral infection with a compound of Formula (IC) or a pharmaceutically acceptable salt thereof.

[0199] In a first subembodiment of embodiment A, the method is for treating cancer (such as multiple myeloma).

[0200] In a second subembodiment of embodiment A, the method is for treating an inflammatory disease.

[0201] In a third subembodiment of embodiment A, the method is for treating a viral infection.Embodiment B

[0202] In embodiment B, the method of embodiment A is where the compound of Formula (IC), or a pharmaceutically acceptable salt thereof, have a structure of formula (ICa) or (ICb):

[0203] (Bi) In subembodiment (Bi) of embodiment B, the method is wherein the compounds of embodiment B, or a pharmaceutically acceptable salt thereof, have a structure of formula (ICa).Embodiment C

[0204] In embodiment C, the method of embodiment A is wherein the compound of Formula (IC), or a pharmaceutically acceptable salt thereof, has a structure of formula (ICc) or (ICd):wherein x is NH. O, or S.

[0205] (Ci) In subembodiment (Ci) of embodiment C, the method of embodiment C, is wherein the compound or a pharmaceutically acceptable salt thereof, has a structure of formula (ICc).

[0206] (Cii) In subembodiment (Cii) of embodiment C, the method of embodiment C, is wherein the compound or a pharmaceutically acceptable salt thereof, has a structure of formula (ICd).

[0207] (Ciii) In subembodiment (Ciii) of embodiment C, the method of any one of embodiment C and subembodiments (Ci), and (Cii) contained therein, is wherein the compound or a pharmaceutically acceptable salt thereof, is wherein x is NH.

[0208] (Civ) In subembodiment (Civ) of embodiment C, the method of any one of embodiment C and subembodiments (Ci), and (Cii) contained therein, is wherein the compound or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, is wherein x is O.

[0209] (Cv) In subembodiment (Cv) of embodiment C, the method of any one of embodiment C and subembodiments (Ci), and (Cii) contained therein, is wherein the compound or a pharmaceutically acceptable salt thereof, is wherein x is S.

[0210] (Cvi)In subembodiment (Cvi) of embodiment C, the method of any one of embodiment C and subembodiments (Ci) to (Ciii) contained therein, is wherein the compound or a pharmaceutically acceptable salt thereof, is where, when x is NH, then R6is either attached to the nitrogen of NH or the carbon of the 5-membering ring that is adjacent to x, and R5is attached to carbon of the 5-membered ring that is adjacent to a bridgehead carbon, i.e.

[0211] (Cvii) In subembodiment (Cvii) of embodiment C, the method of any one of embodiment C and subembodiments (Ci), (Cii), (Civ) and (Cv) contained therein, is wherein the compound or a pharmaceutically acceptable salt thereof, is where, when, x is O or S, R6is attached to the carbon of the 5-membered ring that is adjacent to x and R5when present is attached to carbon of the 5-membered ring that is adjacent to a bridgehead carbon, i.e.Embodiment D

[0212] In embodiment D, the method of any one of embodiment A, is wherein the compound or a pharmaceutically acceptable salt thereof, has a structure of formula (ICe) or (ICf):wherein x is NH. O, or S.

[0213] (Di) In subembodiment (Di) of embodiment D, the method of embodiment D, is wherein the compound or a pharmaceutically acceptable salt thereof, has a structure of formula (ICe).

[0214] (Dii) In subembodiment (Dii) of embodiment D, the method of embodiment D, is wherein the compound or a pharmaceutically acceptable salt thereof, has a structure of formula (ICQ.

[0215] (Diii) In subembodiment (Diii) of embodiment D, the method of any one of embodiment D and subembodiments (Di), and (Dii) contained therein, is wherein the compound or a pharmaceutically acceptable salt thereof, is wherein x is NH.

[0216] (Div)In subembodiment (Div) of embodiment D, the method of any one of embodiment D and subembodiments (Di), and (Dii) contained therein, or a pharmaceutically acceptable salt thereof, is wherein x is O.

[0217] (Dv) In subembodiment (Dv) of embodiment D, the method of any one of embodiment D and subembodiments (Di), and (Dii) contained therein, is wherein the compound or a pharmaceutically acceptable salt thereof, is wherein x is S.

[0218] (Dvi)In subembodiment (Dvi) of embodiment D, the method of any one of embodiment D and subembodiments (Di) to (Diii) contained therein, is wherein the compound or a pharmaceutically acceptable salt thereof, is where, when x is NH, then R6is attached to the nitrogen of NH and R5is attached to carbon of the 5 -membered ring that is adjacent to x, i.e.

[0219] (Dvii) In subembodiment (Dvii) of embodiment D, the method of any one of embodiment D and subembodiments (Di). (Dii), (Div) and (Dv) contained therein, is wherein the compound or a pharmaceutically acceptable salt thereof, is where, when, x is O or S, R6is absent and R5is attached to carbon of the 5-membered ring that is adjacent to x, i.e.Embodiment E

[0220] In embodiment E, the method of embodiment A, is wherein the compound or a pharmaceutically acceptable salt thereof, has a structure of formula (ICg) or (ICh):wherein x is NH, O, or S.

[0221] (Ei) In subembodiment (Ei) of embodiment E, the method of embodiment E, is wherein the compound or a pharmaceutically acceptable salt thereof, have a structure of formula (ICg).

[0222] (Eii) In subembodiment (Eii) of embodiment E. the method of embodiment E, is wherein the compound or a pharmaceutically acceptable salt thereof, has as structure of formula (ICh).

[0223] (Eiii) In subembodiment (Eiii) of embodiment E, the method of any one of embodiment E and subembodiments (Ei), and (Eii) contained therein, is wherein the compound or a pharmaceutically acceptable salt thereof, has wherein x is NH.

[0224] (Eiv) In subembodiment (Eiv) of embodiment E, the method of any one of embodiment E and subembodiments (Ei) and (Eii) contained therein, is wherein the compound or a pharmaceutically acceptable salt thereof, is wherein x is O.

[0225] (Ev) In subembodiment (Ev) of embodiment E, the compounds of any one of embodiment E and subembodiments (Ei) and (Eii) contained therein, or a pharmaceutically acceptable salt thereof, are wherein x is S.

[0226] (Evi) In subembodiment (Evi) of embodiment E, the method of any one of embodiment E and subembodiments (Ei) to (Eiii) contained therein, is wherein the compound or a pharmaceutically acceptable salt thereof, is where, when x is NH, then R6, when present, isattached to the nitrogen of NH and R5is attached to carbon of the 5-membered ring that is adjacent to a bridgehead carbon, i.e.

[0227] (Evii) In subembodiment (Evii) of embodiment E, the method of any one of embodiment E and subembodiments (Ei), (Eii), (Eiv) and (Ev) contained therein, is wherein the compound or a pharmaceutically acceptable salt thereof, is where, when, x is O or S, R6is absent and R5is attached to carbon of the 5-membered ring that is adjacent to a bridgehead carbon, i.e.Embodiment El

[0228] In embodiment El. the method of any one of embodiments A, B, C, D. and E and subembodiments contained therein, is wherein the compound or a pharmaceutically acceptable salt thereof, is wherein G is NR, preferably NH.Embodiment E2

[0229] In embodiment E2, the method of any one of embodiments A, B, C, D, and E and subembodiments contained therein, is wherein the compound or a pharmaceutically acceptable salt thereof, is wherein G is O.Embodiment E3

[0230] In embodiment E3, the method of any one of embodiments A, B, C, D, and E and subembodiments contained therein, is wherein the compound or a pharmaceutically acceptable salt thereof, is wherein G is bond.Embodiment F

[0231] In embodiment F, the method of any one of embodiments A, B, C, D. E, El, E2, and E3 and subembodiments contained therein, is wherein the compound or a pharmaceutically acceptable salt thereof is wherein b, d, and e are CH or C when attached to any one of R3and R4.Embodiment G

[0232] In embodiment G, the method of any one of embodiments A, B, C, D, E, El, E2, and E3 and subembodiments contained therein, is wherein the compound or a pharmaceutically acceptable salt thereof, is wherein b is N and d, and e are CH or C when attached to any one of R3and R4.Embodiment H

[0233] In embodiment H, the method of any one of embodiments A, B, C, D, E, El E2, and E3 and subembodiments contained therein, is wherein the compound or a pharmaceutically acceptable salt thereof, is wherein d is N and b and e are CH or C when attached to any one of R3and R4.Embodiment I

[0234] In embodiment I, the method of any one of embodiments A, B, C, D, E, El, E2, and E3 and subembodiments contained therein, is wherein the compound or a pharmaceutically acceptable salt thereof, is wherein e is N and b and d are CH or C when attached to any one of R3and R4Embodiment J

[0235] In embodiment J, the method of any one of embodiments A, B, C, D. E, El, E2, and E3 and subembodiments contained therein, is wherein the compound or a pharmaceutically acceptable salt thereof, is wherein b and e are N and d is CH or C when attached to any one of R3and R4.Embodiment K

[0236] In embodiment K, the method of any one of embodiments A, B, C, D, E, El, E2, E3. F, G, H, I, and J and subembodiment contained therein, is wherein the compound or a pharmaceutically acceptable salt thereof, is wherein -B(RX)(RW) is -B(OH)2.Embodiment L

[0237] In embodiment L, the method of any one of embodiments A, B. C, D, E, El, E2, E3, F, G, H. I, and J and subembodiment contained therein, is wherein the compound or a pharmaceutically acceptable salt thereof, is wherein R" and Rxare independently selected from hydroxy, alkoxy, -Oaryl (where ar l is optionally substituted with one to three substituents independently selected from alkyl, halo, haloalkyl, cyano, and nitro), -O-(CH2)OCORa(where Rais alkyl), or -O-(alk2)ORb(where alk2is alkylene and Rbis alkyl). Preferably, Rwand Rxare independently selected from alkoxy, -Oaryl (where aryl is optionally substituted with one to three substituents independently selected from alkyl, halo, haloalkyl, cyano, and nitro), -O- (CH2)OCORa(where Rais alkyl), and -O-(alk2)ORb(where alk2is alkylene and Rbis alkyl, such as methyl, isopropyl, n-propyl, isobutyl, or n-butyl). Preferably, Rwand Rxare independently hydroxy, alkoxy, or -Ophenyl (where phenyl is optionally substituted with one to three substituents independently selected from alkoxy, halo, haloalkyl, cyano, and nitro); or Rwand Rxtogether wi th the boron atom to which they are attached form a ring of formula (a) or (b):

[0238] (Li) In subembodiment (Li) of embodiment L, the method of embodiment L, is wherein the compound or a pharmaceutically acceptable salt thereof, is wherein Rwand Rxare independently selected from hydroxy and alkoxy.

[0239] (Lii) In subembodiment (Lii) of embodiment L, the method of embodiment L, is wherein the compound or a pharmaceutically acceptable salt thereof, is wherein R'¥and Rxtogether with the boron atom to which they are attached form a ring of formula (a) or (b):(a) (b)Embodiment M

[0240] In embodiment M, the method of any one of embodiments A, B, C, D, E, El, E2, E3, F, G, H. I, J, K, and L, and subembodiments contained therein is wherein the compound or a pharmaceutically acceptable salt thereof, is wherein Ar is aryl or heteroaryl.

[0241] (Mi). In subembodiment (Mi) of embodiment M, the method of embodiment M, is wherein the compound or a pharmaceutically acceptable salt thereof, is wherein Ar is phenyl.

[0242] (Mii). In subembodiment (Mii) of embodiment M, the method of embodiment M, is wherein the compound or a pharmaceutically acceptable salt thereof, is wherein Ar is phenyl and -B(RW)(RX) is attached to carbon of the phenyl ring that is meta to the carbon attaching the phenyl ring to remaining compound of Formula (IC) and (ICa) to (ICh).

[0243] (Miii). In subembodiment (Miii) of embodiment M, the method of embodiment M, is wherein the compound or a pharmaceutically acceptable salt thereof, is wherein Ar is phenyl and -B(RW)(RX) is attached to carbon on the phenyl ring that is para to the carbon attaching the phenyl ring to remaining compound of Formula (IC), and (ICa) to (ICh), respectively.

[0244] (Miv). In subembodiment (Miv) of embodiment M. the method of embodiment M. is wherein the compound or a pharmaceutically acceptable salt thereof, is wherein Ar is heteroaryl.

[0245] (Mv). In subembodiment (Mv) of embodiment M, the method of embodiment M, is wherein the compound or a pharmaceutically acceptable salt thereof, is wherein Ar is pyridinyl, pyrimidinyl, pyridazinyl, thienyl, furanyl. thiazolyl, oxazolyl. isoxazolyl. pyrazolyl, triazolyl, oxadiazolyl, or imidazolyl.

[0246] (Mvi). In subembodiment (Mvi) of embodiment M, the method of embodiment M, is wherein the compound or a pharmaceutically acceptable salt thereof, is wherein Ar is a sixmembered ring such as pyridinyl, pyrimidinyl, or pyridazinyl wherein Q is attached to carbon on the pyridinyl, pyrimidinyl. or pyridazinyl ring that is meta to the carbon attaching the pyridinyl,pyrimidinyl, or pyridazinyl ring to remaining compound of Formula (IC), and (ICa) to (ICh), respectively.

[0247] (Mvii). In subembodiment (Mvii) of embodiment M, the method of embodiment M, is wherein the compound or a pharmaceutically acceptable salt thereof, is wherein Ar is benzofuranyl, quinolinyl, quinazolinyl, benzimidazolyl, indazolyl, benzotriazolyl, or benzoxazolyl.Embodiment N[024S] In embodiment N, the method of any one of embodiments A, B, C, D, E, El. E2. E3. F,G, H, I, J, K, L, and M, and subembodiments contained therein, is wherein the compound or a pharmaceutically acceptable salt thereof, is wherein alk and alk1are independently methylene, ethylene, or propylene.

[0249] (Ni) In subembodiment (Ni) of embodiment N, the method of embodiment N, is wherein the compound or a pharmaceutically acceptable salt thereof, is wherein alk and alk1are methylene.Embodiment O

[0250] In embodiment O, the method of any one of embodiments A, B, D, E, El, E2, E3, F, G,H, J, K, L, M, and N and subembodiments contained therein, is wherein the compound or a pharmaceutically acceptable thereof, is wherein R6is absent, methyl, or isopropyl.

[0251] (Oi). In subembodiment (Oi) of embodiment O, the method of embodiment O, is wherein the compound or a pharmaceutically acceptable salt thereof, is wherein R6is absent.

[0252] (Oii).In subembodiment (Oii) of embodiment O, the method of embodiment O, is wherein the compound or a pharmaceutically acceptable salt thereof, is wherein R6is methyl or isopropyl.Embodiment P

[0253] In embodiment P, the method of any one of embodiments A, B, D, E, El, E2, E3, F, G, H, J, K, L, M, N, and O, and subembodiments contained therein, is wherein the compound or a pharmaceutically acceptable thereof, is wherein R5is absent, alkyl, hydroxy, halo, acylamino, alkoxyalkylamino, cyano, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl.

[0254] (Pi). In subembodiment (Pi) of embodiment P, the method of embodiment P. is wherein the compound or a pharmaceutically acceptable salt thereof, is wherein R5is absent or alky .

[0255] (Pii). In subembodiment (Pii) of embodiment P, the method of embodiment P, is wherein the compound or a pharmaceutically acceptable salt thereof, is wherein R5is cyano, acylamino, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl. Preferably R5is acylamino, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, dimethylaminocarbonyl, or isopropylcarbonyl.Embodiment Q

[0256] In embodiment Q, the method of any one of embodiments A, B, C, D, E, El, E2, E3. F, G, H, I, J, K, L, M, N, O, and P, and subembodiments contained therein, is wherein the compound or a pharmaceutically acceptable thereof, is wherein R1and R2are independently absent, methyl, ethyl, methoxy, fluoro, trifluoromethyl, trifluoromethoxy, or cyano.

[0257] (Qi). In subembodiment (Qi) of embodiment, Q, the method of embodiment Q, is wherein the compound or a pharmaceutically acceptable salt thereof, is wherein R1and R2are absent.Embodiment R

[0258] (Ri) In embodiment Ri, the method of any one of embodiments A, B, C, D, E, El, E2, E3, F, G, H, I, J, K, L, M, N, O, P. an Q and subembodiments contained therein, is wherein the compound or a pharmaceutically acceptable thereof, is wherein R3and R4are independently absent, alkyl, alkoxy, hydroxy, amino, halo, haloalkyl, or haloalkoxy.

[0259] (Ril). In subembodiment (Ril) of embodiment (Ri), the method of embodiment (Ri), is wherein the compound or a pharmaceutically acceptable thereof, is wherein R3and R4are independently absent, alkoxy, amino, or hydroxy.

[0260] (Ri2). In subembodiment (Ri2) of embodiment (Ri), the method of embodiment (Ri), is wherein the compound or pharmaceutically acceptable thereof, is wherein R3and R4are independently alkoxy such as methoxy, ethoxy, or propoxy and are attached to to the six membered ring comprising b, d, and e of Formula (IC) and (ICa) to (ICh) as show n below7wherein the wavy line denotes the attachment point to the remainder of the molecule.

[0261] (Ri3). In subembodiment (Ri3) of embodiment (Ri), the method of embodiment (Ri), is wherein the compound or pharmaceutically acceptable thereof, is wherein R3and R4are absent.

[0262] (Ri4). In subembodiment (Ri4) of embodiment (Ri), the method of embodiment (Ri), is wherein the compound or pharmaceutically acceptable thereof, is wherein when R4is present, R4is attached to the six membered ring comprising b, d, and e of Fonnula (IC) and (ICa) to (ICh) as shown below:wherein the wavy line denotes the attachment point to the remainder of the molecule.

[0263] (Rii). In embodiment (Rii), the method of any one of embodiments A, B, C, D, E, El, E2, E3, F, G, H, I, J, K, L, M, N, O, P. an Q and subembodiments contained therein, is wherein the compound or a pharmaceutically acceptable thereof, is wherein:R3is absent, alkyl, alkoxy, hydroxy, halo, haloalkyl, or haloalkoxy; andR4is hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkylamino, alkoxyalkylamino, aminoalkyd, aminoalkoxy, aminoalkylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino (wherein heterocyclyl either alone or part of heterocyclyloxy and heterocyclylamino is optionally substituted with one, two, or three substituents independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), heterocyclylalkyl, heterocyclylalkyloxy, heterocyclylalkylamino (wherein the heterocyclyl ring in heterocyclylalkyl, heterocycly lalkyloxy . and heterocyclylalkylamino is optionally substituted with one, two, or three substituents independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalky 1), cycloalkyloxy, phenyloxy, or heteroaryloxy (where phenyl in phenyloxy and heteroaryl in heteroaryloxy are optionally substituted with one, two, or three substituents, preferably one or two optional substituents, where two of the optional substituents are independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, and cyano).

[0264] In a first subembodiment of embodiment (Rii), the method of embodiment (Rii), is wherein the compound or pharmaceutically acceptable thereof, is wherein R3is absent, methoxy,ethoxy, or hydroxy, preferably R3is methoxy or ethoxy; and R4is 2-hydroxyethyloxy, 3- hydroxypropyloxy, 2-methoxyethyloxy. 2-ethoxy ethyloxy, 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 optionally substituted with one or two substituents independently selected from methyl, fluoro, hydroxy, or methoxy). Preferably, when R3and R4are present, R3and R4are attached to the six membered ring comprising b. d, and e of Formula (IC) and (ICa) to (ICh) as shown belowwherein the wavy line denotes the attachment point to the remainder of the molecule.

[0265] (Riii). In embodiment (Riii), the method of any one of embodiments A, B, C, D, E, El, E2, E3, F, G, H, I, J, K, L, M, N, O, P, an Q and subembodiments contained therein, is wherein the compound or a pharmaceutically acceptable thereof, is wherein R3and R4is independently hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkylamino, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkyl amino, heterocyclyl, heterocyclyloxy, heterocyclylamino (wherein heterocyclyl either alone or part of heterocyclyloxy and heterocyclylamino is optionally substituted with one, two, or three substituents independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxy alkyl, and aminoalkyl), heterocyclylalkyl, heterocyclylalkyloxy, heterocyclylalkylamino (wherein the heterocyclyl ring in heterocyclylalkyl, heterocyclylalkyloxy, and heterocyclylalkylamino is optionally substituted with one, two, or three substituents independently selected from alkyd, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalky l), cycloalky loxy, phenyloxy, or heteroaryloxy (wherephenyl of phenyloxy and heteroaryl of heteroaryloxy are optionally substituted with one, two, or three substituents, preferably one or two optional substituents, where two of the optional substituents are independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyL haloalkoxy, and cyano).

[0266] In a first subembodiment of embodiment (Riii), the method of embodiment (Riii), is wherein the compound or pharmaceutically acceptable thereof, is wherein R3and R4are 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- hydroxy ethylamino, 3-hydroxypropylamino, 2-methoxy ethyl amino, 2-ethoxy ethylamino, 3- methoxypropylamino, 3-ethoxypropylamino, 2-aminoethylamino, 2-methylaminoethylamino, 2- dimethylaminoethylamino, 2-di ethylaminoethylamino, 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 optionally substituted with one or two substituents independently selected from methyl, fluoro, hydroxy, or methoxy). Preferably, R3and R4are attached to the six membered ring comprising b. d, and e of Formula (IC) and (ICa) to (ICh) as shown below:wherein the wavy line denotes the attachment point to the remainder of the molecule.Administration and Pharmaceutical Composition

[0267] 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 / kgper 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. In one embodiment, the dosage is 200 mg BID. In one embodiment, the dosage is 400 mg BID. In one embodiment, the dosage is 600 mg BID. In one embodiment, the dosage is 800 mg BID. 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.

[0268] 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.

[0269] 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 show7poor bioavailability7based upon the principle that bioavailability7can 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.

[0270] 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 compoundof 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.

[0271] 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.

[0272] 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.

[0273] 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).

[0274] 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. %.

[0275] 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.

[0276] 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.

[0277] 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’- deoxy cytidine, all trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (Gleevec™), geldanamycin, 17-N-Allylamino-17-Demethoxygeldanamycin (17-AAG), flavopiridol, LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, or PD184352, Taxol™, also referred to as “paclitaxel”, which is a well-known anti -cancer drug which acts by enhancing and stabilizing microtubule formation, and analogs of Taxol™ , such as Taxotere™. 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.

[0278] 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, wortmannm, 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, gelitinib, 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.

[0279] 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; eflomithine 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-nl; interferon alfa-n3; interferon beta- la; 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; procarbazinehydrochloride; 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.

[0280] Other anti-cancer agents that can be employed in combination with a compound of the disclosure such as 8-(3-(4-acryloylpiperazin-l-yl)propyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)- 2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one used to determine the anti-tumor activity in HGS and RT4 tumor models (Example 4 below: In HGS model, vehicle dosed group reached tumor size 645dosing at day 42 after inoculation whereas for animals treated with 20 / kg of compound, the tumor size was 55 mm3showing significant antitumor activity and induced tumor regression), include: 20-epi-l, 25 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 111 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; chlorins; 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; fdgrastim; finasteride; 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; 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-benzylguaninc; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosanpolysulfate 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; pyrazoloacndine; pyndoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras famesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozy mes; R.sub.ll retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone Bl; ruboxyl; safmgol; 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; thiocorahne; 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.

[0281] Yet other anti-cancer 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).

[0282] 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), enzy mes (e.g., L- asparaginase), or biological response modifiers (e.g., interferon alpha).

[0283] 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 methyl melamines (e.g., hexamethlymelamine, thiotepa), alkyd 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.

[0284] 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).

[0285] 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, andSpongistatin 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 -hydroxy epothilone 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), Cr ptophycin 52 (also known as LY-355703), AC- 7739 (Ajinomoto, also known as AVE-8063A and CS-39.HC1), 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 Al (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), NPL2350 (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).

[0286] 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 (smack molecules or biologies) against immune checkpoint molecules such as CD27, CD28, CD40, CD122, CD96, CD73, CD39, CD47, 0X40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM kinase, arginase, CD137 (also known as 4-1BB), ICOS, A2AR, A2BR, HIF-2a, 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, 0X40, 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, CD 160 inhibitors, 2B4 inhibitors and TGFR beta inhibitors.

[0287] 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-PDl antibody is pembrolizumab.

[0288] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, e.g., an anti-PD-Ll monoclonal antibody. In some embodiments, the anti-PD-Ll monoclonal antibody is BMS-935559. MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments, the anti-PD-Ll monoclonal antibody is MPDL3280A (atezolizumab) or MEDI4736 (durvalumab).

[0289] 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 0X40, e.g., an anti-OX40 antibody or OX40L fusion protein. In some embodiments, the anti-OX40 antibody isMEDI0562 or, INCAGN01949, GSK2831781, GSK-3174998, MOXR-0916, PF-04518600 or LAG525. In some embodiments, the OX40L fusion protein is MEDI6383.Biological ExamplesAnti-tumor effect of ENPP1 inhibitor RBS2418, in In Vivo Syngeneic Mouse Cancer Models

[0290] In vivo anti -tumor effect of ENPP1 inhibitor RBS2418, a compound disclosed herein, was determined in syngeneic mouse cancer models of pancreatic, liver, glioblastoma, colon cancer, melanoma. Summary of the studies are as disclosed in Table 4 below and detailed description of the studies are provided in Examples 1 to 5 below.Table 4 Summary of Evaluation of RBS2418 in Syngeneic Mouse Cancer ModelsExample 1Pan02 Syngeneic Pancreatic Cancer Mouse Model

[0291] The Pan02 syngeneic mouse model was derived from a pancreatic tumor. Each study arm had 8 tumor bearing C57BL / 6 mice. The treatment was conducted as shown in FIG. 1 A. On day 5 after implantation, the mice were treated with either vehicle (control group), RBS2418 and radiation with or without RBS2418. RBS2418 was dosed at 10 mg / kg twice a day (BID) by oral gavage for 5 days. 10% ethanol / 40% PEG400 / 50% water was used as vehicle control. RBS2418 dose formulation is 1 mg / mL in vehicle. The results of the study are shown in FIGs. 1A-1E.Results:

[0292] As seen in FIG. 1 A, RBS2418 showed a significant delay in tumor growth in this study. The nadir of response was observed at the end of the 5-day dosing period (day 9). The response w as similar to that observed by a single radiation treatment of 5 Gy (SARRP). There was a further significant improvement in the response in the group of animals that were treated with the combination of radiation and RBS2418. FIG. IB shows tumor volume (mm3) comparisons of mice across vehicle control and treatment groups on day 9 after tumor implantation. FIGs. 1C-1E show individual tumor growth curves of mice across vehicle control and treatment groups. As seen in FIG. IE, four out of eight animals showed complete tumor regression at the end of RBS2418 treatment in the combination treatment group.Example 2Hepal-6 Syngeneic Liver Cancer Mouse Model

[0293] The Hepal -6 syngeneic mouse model was derived from a liver tumor. Each study arm had 8 tumor bearing C57BL / 6J mice. The treatment was initiated after the average tumor size was 97 mm3. RBS2418 was dosed at 30 mg / kg once daily (QD) by intramuscular injection for 2 days or 10 days. 20 mM Tris-HCl, pH7.4 was used as vehicle control. RBS2418 dose formulation is 6 mg / mL in vehicle. The results of the study are shown in FIGs. 2A-2E.Results:

[0294] The results of the study are shown in FIGs. 2A-2E. RBS2418 dosed at 30 mg / kg once daily (QD) by intramuscular injection for 10 days showed a significant delay of tumor growth in the Hepal-6 syngeneic mouse model of liver cancer (FIG. 2A-2B). Mean tumor growth curves (FIG. 2A) and individual tumor growth curves (FIG. 2B) of mice in vehicle control and treatment group were plotted. Three mice in the group treated for 2 days and four mice in the group treated for 10 days showed complete tumor regression that was maintained after the end of treatment (see FIG. 2B). RBS2418 treatment was associated with increased survival compared with the vehicle- treated group (FIG. 2C). The seven animals that achieved complete tumor regression were resistant to a rechallenge with Hepal-6 cancer cells, while all control animals died within less than 60 days after cancer cell challenge (see FIG. 2D). These results are consistent with the induction of immune-mediated cure by RBS2418 monotherapy in the Hepal-6 liver cancer model and the establishment of immune memory sufficient to protect animals from cancer cell rechallenge.Example 3GL261-Luc Syngeneic Glioblastoma Cancer Mouse Model

[0295] The GL261-luc syngeneic mouse model was derived from a glioblastoma tumor. Each study arm had 8 tumor bearing C57BL / 6 mice. lxlOA5 GL261-luc cells suspended in 10 pL phosphate-buffered saline (PBS) were orthotopically inoculated at the striatal (anterior fontanelle right 2mm and 3mm, depth 1.5 mm) of each mouse. Three days after GL261-luc cell inoculation, all the mice were imaged by In Vivo Imaging System (IVIS) to verify the presence of tumor cells by Bioluminescence imaging (BLI) signals and the treatment was initiated and was denoted as day 0. RBS2418 was dosed at 200 pg / kg (10 mg / kg) on day 0 and day 5 by intraventricular injection either alone or in combination with an anti-m-PD-1 . Anti-m-PD-1 (In FzvoPlus anti-mouse PD-1 (CD279), clone # RMP1-14, catalog# BP0146, Bio X Cell) was administered at 10 mg / kg by intraperitoneal injection, twice a week for 2 weeks either alone or in combination with RBS2418. 20 mM Tris-HCl, pH7.4 was used as vehicle control. RBS2418 dose formulation is 20 mg / ml in vehicle. The results of the study are shown in FIGs. 3A -3E.Results:

[0296] RBS2418 dosed on Day 0 and Day 5 showed a significant inhibition of cancer cell grow th and increased survival in the GL261 -luc syngeneic mouse model of Glioblastoma (see FIGs. 3A, 3D and 3E). Significant differences in cancer cell numbers, as measured by bioluminescence imaging, were observed from Day 14 onwards between mice treated with RBS2418 compared with vehicle-treated mice (See FIG. 3A-3C). Mice showed a significant increase in median survival time when treated with RBS2418 alone or in combination with biweekly i.p. injection of anti-mouse-PDl -antibody (See FIG. 3D). One of eight (12.5%) mice treated with RBS2418 alone or with anti-mouse-PDl antibody alone, and three of eight (37.5%) mice treated with the combination of RBS2418 and anti-mouse-PDl antibody achieved full clearance of cancer cells and long-term survival. The long-term survivors (n=5) were rechallenged with the same number of GL261-luc cancer cells. Four of the five long-term survivors fully cleared the cancer cells after the re-challenge, consistent with the prior treatment having induced an effective cure and anti-GL261 -cancer immunity.Example 4MC38 Syngeneic Colon Cancer Mouse Model

[0297] The MC38 syngeneic mouse model was derived from a colon tumor. Each study arm had 8 tumor bearing C57BL / 6 mice. The treatment was initiated after the average tumor size was 66.6 mm3. RBS2418 was dosed at 10 mg / kg BID by oral gavage for 5 days. 10% ethanol / 40%PEG400 / 50% water was used as vehicle control. RBS2418 dose formulation is 1 mg / mL in vehicle. The results of the study are shown in FIGs. 4A-4D.Results:

[0298] FIG. 4A shows mean tumor grow th curves of mice across vehicle control and treatment group. FIG. 4B shows individual tumor growth curves of mice across vehicle control and treatment group. A significantly lower tumor volume was observed in the RBS2418 -treated animals as compared to vehicle-treated animals on day 11 and 14 of the study (see FIGs. 4C-4D). In contrast to Pan02, the MC38 tumor model responds well to treatment with checkpoint inhibitors, consistent with a lower deficit in the abi 1 i ty to activate antigen-presenting cells. The observed activity of RBS2418 suggests that inhibition of ENPP1 in this model has additional benefit.Example 5B16F10 Syngeneic Melanoma Cancer Mouse Model

[0299] The B16F10 syngeneic mouse model was derived from a melanoma tumor. Each study arm had 8 tumor bearing C57BL / 6 mice. The treatment was initiated after the average tumor size was 61 mm3. RBS2418 was dosed at 10 mg / kg BID by oral gavage for 5 days or with anti-mPDl antibody ( / nFzvoPlus anti-mouse PD-1 (CD279), clone # RMP1-14, catalog# BP0146, Bio X Cell) twice per w eek by intraperitoneal injection. 10% ethanol / 40% PEG400 / 50% water was used as vehicle control. RBS2418 dose formulation is 1 mg / mL in vehicle. The results of the study are shown in FIGs. 5A-5D.Results:

[0300] FIG. 5A shows mean tumor growth curves of mice across vehicle control and treatment groups. FIGs. 5C and 5D shows individual tumor growth curves of mice across vehicle control and treatment groups. A significantly lower tumor volume was observed in RBS2418-treated animals as compared to vehicle-treated animals on days 16 and 20 of the study. The treatment response to RBS2418 was similar to that with anti-mouse-PDl antibody (see FIGs. 5A-5B).Formulation Examples

[0301] The following are representative pharmaceutical formulations containing a compound of the present disclosure.Tablet Formulation

[0302] 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 5Capsule Formulation

[0303] 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 2Injectable Formulation

[0304] 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

[0305] To prepare a pharmaceutical composition for inhalation delivery7, 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

[0306] To prepare a pharmaceutical topical gel composition, 100 mg of a compound disclosed herein is mixed with 1.75 g of hydroxy propyl 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

[0307] 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

[0308] 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 method of treating a disease selected from a cancer, an inflammatory disease, and a viral infection in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (IA), (IB), or (IC) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (IA), (IB), or (IC) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, wherein(I) the compound of Formula (IA) has the formula:wherein:X is N or CH;Z is NH, O, S, SO, or SO2; alk is alkylene optionally substituted with one, two, or three halo; m and n are independently 0 or 1;(i) -Ar^alk^m-Q is wherein Ar is aryl, heteroaryl, cycloalkyl, or heterocyclyl; alk1is alkylene wherein one carbon atom in the alkylene chain is optionally replaced by oxygen and further wherein alkylene is optionally substituted with one, two, or three halo; andQ is -B(OH)2or -P(O)(Ra)(Rb) wherein Raand Rbare independently selected from hydroxy, alkoxy, -Oaryl (where aryl is optionally substituted with one to three substituents independently selected from alkyl, alkenyl, alkoxy, halo, haloalkyl, amino, alkylamino, dialkylamino, cyano, or nitro), -O-(CH2)OCORC(where Rcis alkyd), -O-(alk2)ORd(where alk2is alkylene and Rdis alkyl), -S-(CH2)2SCORe(where Reis alkyl), or -NRg- (CHR)OCORf(where R is hydrogen, alkyl, hydroxymethyl, thiomethyl, methylthiomethyl, amidinopropyl, indol-3-ylmethyl, indol-4-ylmethyl, carboxymethyl, carboxyethyl, aminocarbonylmethyl, aminocarbonylethyl, phenyl or phenylalkyl (wherein phenyl either alone oras part of pheny lalkyl is optionally substituted with one to three substituents independently selected from alkyl, alkoxy, halo, hydroxy, cyano or nitro), Rfis alkyl or benzy l, and R8is hydrogen or Rgtogether with R forms -(Cffch- ); or Raand Rbtogether with the phosphorus atom to which they are attached form a ring of formula (c):wherein Ar1is phenyl or six membered heteroaryl optionally substituted with one to three halo; provided that, when Q is -P(O)(Ra)(Rb) or -B(OH)2, then at least one of n and m is 1 ; or(ii) -Ar^alk^m-Q is a ring of formula (a):Rxis hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkylamino, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkyl amino, diaminoalkyl, diaminoalkoxy, diaminoalkylamino or cyano;R2, R'1, R9, and R10are independently hydrogen, alkyl, alkoxy, halo, haloalkyl, or haloalkoxy, or cyano;R7and R8are independently hydrogen or alkyl; and one of R4, R5, and R6is hydrogen, alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, cyano, amino, alkylamino, or dialkylamino; and the remaining two of R4, R5, and R6are independently hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, hydroxyalkyd, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkylamino, alkoxyalky lamino, 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 independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalky l), heterocyclylalkyl, heterocyclylalkyloxy, heterocyclylalkylamino (wherein theheterocyclyl ring in heterocyclylalkyl, heterocyclylalkyloxy, and heterocyclylalkylamino is optionally substituted with one. two. or three substituents independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyd), cycloalkyloxy, phenyloxy, or heteroaryloxy (where phenyl in phenyloxy and heteroaryl in heteroaryloxy are optionally substituted with one or two substituents where two of the optional substituents are independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, and cyano);(II) the compound of Formula (IB) has the formula:wherein: a, b, d, and e are CH; or one or two of a, b. d, and e are N and remaining of a, b, d, and e are CH or C when atached to any one of R4, R5, and R6; one of y and z is N and the other y and z is CR7; or both y and z are CR7wherein each R7is independently hydrogen, alkyl, hydroxy, or halo; alk is alky lene optionally substituted with one. two, or three halo; alk1is alkylene wherein one carbon atom in the alkylene chain can be replaced byoxygen and the alkylene chain is optionally substituted with one, two, or three halo; m and n are independently 0 or 1 ; provided that at least one of m and n is i;Ar is ary l or heteroaryl;Q is -P(O)(Ra)(Rb) or -B(RW)(RX), wherein Raand Rbare independently selected from hydroxy, alkoxy. -Oaryl (where aryl is optionally substituted with one to three substituents independently selected from alkyl, alkenyl, alkoxy, halo, haloalkyl, amino, alkylamino, dialkylamino, cyano, or nitro), -O-(CH2)OCORC(where Rcis alkyl), -0-(CH2)0C00Rc(where R‘ is alkyl), -O-(alk2)ORd(where alk2is alkylene and Rdis alkyl), -S-(CH2)2SCORe(where Reis alkyl), or -NRs-(CHR)OCORf(where R is hydrogen, alkyl, hydroxymethyl, thiomethyl, methylthiomethyl, amidinopropyl, indol-3-ylmethyl, indol-4-ylmethyl, carboxy methyl, carboxyethyl, aminocarbonylmethyl, aminocarbonylethyl, phenyl or phenyl alky I (wherein phenyleither alone or as part of phenylalkyl is optionally substituted with one to three substituents independently selected from alkyl, alkoxy, halo, hydroxy, cyano or nitro), Rfis alkyl or benzyl and Rgis hydrogen or together with R forms -(Chh)?- ); or Raand Rbtogether with the phosphorus atom to which they are attached form a ring of formula (a):wherein Ar2is phenyl or six membered heteroaryl optionally substituted with one to three halo; andRwand Rxare independently selected from hydroxy, alkoxy, -Oaryl (where aryl is optionally substituted with one to three substituents independently selected from alky l, alkenyl, alkoxy, halo, haloalkyl, amino, alkylamino, dialkylamino, cyano, or nitro), -O-(CH2)OCORC(where Rcis alky l), -O-(alk2)ORd(where alk2is alkylene and Rdis alkyd), -S-(CH2)2SCORe(where Reis alky 1), or -NRg-(CHR)OCORf(where R is hydrogen, alkyl, hydroxymethyl, thiomethyl, methy lthiomethyl, amidinopropy 1, indol-3-ylmethyl, indol-4-ylmethyl, carboxymethy l, carboxyethyl, aminocarbonylmethyl, aminocarbonylethyl, phenyl or phenylalkyl (wherein pheny l either alone or as part of phenylalkyl is optionally substituted with one to three substituents independently selected from alkyl, alkoxy, halo, hydroxy, cyano or nitro), R1is alkyl or benzyl and Rgis hydrogen or together with R forms -(CH2)s- ); orRwand Rxtogether with the boron atom to which they are attached can form - 0(CRR’)20- or -O(CRR?)sO- wherein each R and R’ is independently hydrogen or methyl;R2and R3are independently hydrogen, alkyl, alkoxy, halo, haloalky 1, haloalkoxy, or cyano;R4is hydrogen, alkyl, alkoxy, alkylthio, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cyano, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, or dialkylaminosulfony 1; andR ' and R6are independently hydrogen, alkyl, alkoxy, hydroxy', halo, haloalky 1, haloalkoxy , hy droxy alkyl, alkoxyalky l, hydroxyalkoxy, alkoxy alkoxy, hydroxyalky lamino, alkoxyalkylamino, amino, aminoalkyl, aminoalkoxy, aminoalkylamino, heterocyclyl, heterocyclyloxy. heterocyclylamino (wherein heterocyclyl either alone or part of heterocyclyloxy and heterocyclylamino is optionally substituted with Rh, R>, or Rkindependently selected from alkyd, halo, hydroxy, alkoxy, hydroxyalky l, alkoxyalkyl, and aminoalkyl), heterocyclylalkyl, heterocyclylalkyloxy, heterocyclylalky lamino (wherein the heterocyclyl ring in heterocyclylalkyl,heterocyclylalkyloxy, and heterocyclylalkylamino is optionally substituted with one, two, or three substituents independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), cycloalkyloxy, phenyloxy, or heteroaryloxy (where phenyl in phenyloxy and heteroaryl in heteroaryloxy are optionally substituted with one, two, or three substituents independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, and cyano); and(III) the compound of Formula (IC) has the formula:wherein:— dashed line is a bond between x and y or y and z; b, d, and e are CH or C when attached to R3or R4; or one or two of b, d, and e are N and remaining of b, d. and e are CH or C when attached to R3or R4; one of x and z is NH, O, or S and the other of x and z is CH or N; and y is CH, C when or C when attached to R3or R6, or N; provided that, at least one of y and the x or z that is CH or N, is CH or C when attached to R5or R6;G is a bond, NR (where R is hydrogen or alkyl), O, S, or SO2: alk is alkylene optionally substituted with one, two, or three halo or alkynylene, provided that when alk is alkynylene G is a bond and n is 1 ; alk1is alky lene optionally substituted with one, two, or three halo; m and n are independently 0 or 1; provided that at least one of m and n is 1:Ar is aryl or heteroaryl;Rwand Rxare independently selected from hydroxy, alkoxy, -Oaryl (where aryl is optionally substituted with one to three substituents independently selected from alkyd, alkenyl, alkoxy, halo, haloalkyl, amino, alkylamino, dialkylamino, cyano, and nitro), -0-(CH2)0C0Ra(where Rais alkyl), -O-(alk2)ORb(where alk2is alkylene and Rbis alkyl), -S-(CH2)2SCORC(where Rcis alky 1), or -NRe-(CHRd)OCORf(where Rdis hydrogen, alkyl, hydroxymethyl, thiomethyl.methylthiomethyl, amidinopropyl, indol-3-ylmethyl, indol-4-ylmethyl, carboxymethyl, carboxyethyl, aminocarbonylmethyl, aminocarbonylethyl, phenyl or phenylalkyl (wherein phenyl either alone or as part of phenylalkyl is optionally substituted with one to three substituents independently selected from alkyl, alkoxy, halo, hydroxy, cyano and nitro), Rfis alkyl or benzyl and Reis hydrogen or Retogether with Rdforms -(CHz)?-); orRwand Rxtogether with the boron atom to which they are attached can form a ring selected from:wherein each Rgand Rhis independently hydrogen or methyl;R1and R2are independently absent, alky l, alkoxy, halo, haloalkyl. haloalkoxy, or cyano;R3and R4are independently absent, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, alkyl sulfonyl, hydroxyalkyl, alkoxyalkyl, hydroxy alkoxy, alkoxyalkoxy, hydroxyalkylamino, alkoxyalkylamino, amino, aminoalkyl, aminoalkoxy, aminoalky lamino, heterocyclyl, heterocyclyloxy, heterocyclylamino (wherein heterocyclyl, either alone or part of heterocyclyloxy. and heterocyclylamino is optionally substituted with R1. R'. or Rkindependently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), heterocyclylalkyl, heterocyclylalkyloxy, heterocyclylalkylamino (wherein the heterocyclyl ring in heterocyclylalkyl, heterocyclylalky loxy, and heterocyclylalkylamino is optionally substituted with one, two, or three substituents independently selected from alkyl, halo, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), cycloalkyloxy, phenyl, heteroaryl, phenylalkenyl, heteroarylalkenyl, phenyloxy, or heteroaryloxy (where phenyl, by itself or as part of phenylalkenyl and phenyloxy and heteroaryl, by itself or as part of heteroarylalkenyl and heteroaryloxy, are optionally substituted with one or two substituents independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, and cyano); provided that (i) when two of b, d, and e are N, then at least one of R3and R4is absent;R3is absent, alky l, hydroxy, alkoxy, alkoxy carbonyl, halo, acylamino, hydroxyalkylamino, alkoxyalkylamino, cyano, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl; andR6is absent or alkyl; provided that one of R3and R6is absent when two of x, y, and z are other than CH; or a pharmaceutically acceptable salt thereof; and whereinthe cancer is selected from one or more of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adenocarcinoma, adenoid cystic carcinoma, adolescent cancer, adrenal cancer, adrenocortical carcinoma, AIDS-related cancers (such as Kaposi Sarcoma), AIDS- related Lymphoma, primary CNS lymphoma, anal cancer, appendix cancer, astrocytomas, atypical teratoid / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (including Ewing sarcoma and osteosarcoma, and / or malignant fibrous histiocytoma), brain cancer such as low grade glioma, large granular lymphocytic leukemia, T-cell prolymphocytic leukemia, prolymphocytic leukemia, colon adenocarcinoma, breast cancer, bronchial tumors, Burkitt lymphoma, carcinoma, central nervous system cancer, cervical cancer, childhood cancers, childhood cardiac tumors, cholangiocarcinoma, chordoma, chronic lymphocytic leukemia (CLL), colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma In Situ (DCIS), diffuse intrinsic pontine glioma (DIPG), diffuse large B cell lymphoma, embryonal tumors, endometrial cancer, uterine cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fallopian tube cancer, gall bladder cancer, gastric (stomach) cancer, gastrointestinal tumors such as gastrointestinal neuroendocrine tumors and gastrointestinal stromal tumors (GIST), germ cell tumors, Gestational Trophoblastic Disease, Glioma, glioblastoma, hairy cell leukemia, head and neck cancer, heart tumors, histiocytosis, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, Kaposi sarcoma (soft tissue sarcoma), kidney (renal cell) cancer. Langerhans cell histiocytosis, laryngeal cancer, lip and oral cavity cancer, liver cancer, lung cancer (non-small cell lung cancer, small cell lung cancer, pl europul monary blastoma, pulmonary inflammatory myofibroblastic tumor, tracheobronchial tumor), lymphoma, medulloblastoma and other CNS embryonal tumors, uveal melanoma, Merkel cell carcinoma, mesothelioma, malignant metastatic cancer, metastatic squamous neck cancer with occult primary, midline tract carcinoma, mouth cancer, multiple endocrine neoplasia syndromes, mycosis fungoides (lymphoma), myelodysplastic syndromes, myelodysplastic / myeloproliferative neoplasms, myelogenous leukemia, chronic myeloid leukemia (CML), nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, neuroendocrine tumors, Non-Hodgkin lymphoma, oral cancer, oropharyngeal cancer, osteosarcoma, undifferentiated pleomorphic sarcoma of bone, ovarian cancer, ovarian germ cell tumors, pancreatic cancer, pancreatic neuroendocrine tumors, papillomatosis, paraganglioma, paranasal sinus and nasal cavity7cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary tumor, plasma cell neoplasms such as multiple myeloma, pleuropulmonary blastoma, primary Central Nervous System (CNS) lymphoma, peritoneal cancer, prostate cancer, pulmonary inflammatory7myofibroblastic tumor, rectal cancer, rectum adenocarcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcomas, Sezary syndrome, skin cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma of the skin, squamous neck cancer, stomach cancer, T-Cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, tracheobronchial tumors, urethral cancer, uterine sarcoma, vaginal cancer, vascular tumors, and vulvar cancer; the viral infection is selected from one or more of chronic virus infections, DNA virus infections, HBV, HIV, Herpes virus infections, Papilloma virus infections, and RNA virus infections; and the inflammatory disease is selected from one or more of arthritis, chronic inflammation, and sarcopenia.

2. The method of claim 1, wherein the disease is cancer and the cancer is selected from one or more of 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, bladder cancer, colorectal cancer, gastric and gastrointestinal cancer, esophageal cancer, adenocarcinoma, anal cancer, cancer of the appendix, kidney cancer, skin cancer other than melanoma, ovarian cancer, uterine cancer, brain cancer other than glioblastoma, lung cancer, adrenal cancer, bile duct cancer, bone cancer, cervical cancer, fallopian tube cancer, sarcomas, germ cell tumors, head and neck cancer, neuroblastoma, pheochromocytoma and paraganglioma, cholangiocarcinoma. peritoneal cancer, retinoblastoma, liver cancer other than hepatocellular carcinoma, thymoma, urethral cancer, prostate cancer, uveal melanoma, adenoid cystic carcinoma, rectum adenocarcinoma, colon adenocarcinoma, and vaginal and vulvar cancer.

3. The method of claim 2, wherein the cancer is multiple myeloma.

4. The method of claim 2, wherein the cancer is acute lymphocytic leukemia.

5. The method of claim 2. wherein the cancer is acute myeloid leukemia.

6. The method of claim 2, wherein the cancer is Hodgkin lymphoma.

7. The method of claim 2. wherein the cancer is non-Hodgkin lymphoma.

8. The method of claim 2, wherein the cancer is head and neck cancer.

9. The method of claim 2, wherein the cancer is liver cancer other than hepatocellular carcinoma.

10. The method of claim 2. wherein the cancer is prostate cancer.

11. The method of claim 2, wherein the cancer is colon adenocarcinoma.

12. The method of claim 1. wherein the disease is osteoarthritis.

13. The method of any one of claims 1-12, comprising administering to the patient a therapeutically effective amount of a compound of Formula (IA) or a pharmaceutically acceptable salt thereof.

14. The method of any one of claims 1-12, comprising administering to the patient a therapeutically effective amount of a compound of Formula (IB) or a pharmaceutically acceptable salt thereof.

15. The method of any one of claims 1-12, comprising administering to the patient a therapeutically effective amount of a compound of Formula (IC) or a pharmaceutically acceptable salt thereof.

16. The method of any one of claims 1-12, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (IA) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

17. The method of any one of claims 1-12, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (IB) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient18. The method of any one of claims 1-12. comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (IC) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

19. The method of claim 13 or 16, wherein the compound of Fomiula (IA) is selected from the group consisting of:The method of claim 14 or 17, wherein the compound of Formula (IB) isset21. The method of claim 15 or 18, wherein the compound of Formula (IC) is selected from the group consisting of:

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