Pharmaceutical Combinations of Amino-Pyrrolopyrimidinone Compounds and Methods of Use - Patent application

Abstract

The present application relates to a pharmaceutical combination or combination therapy comprising a therapeutically effective amount of a compound of formula (I), or a pharma- ceutical acceptable salt thereof, and at least one second agent, or a pharma- ceutical acceptable salt thereof, for use in the treatment of a BTK-mediated disease or disorder. TIFF2025513742000012.tif18158

Description

[Background technology]

[0001] BTK is a member of the Tec family of tyrosine kinases and plays a key role in the control of early B cell development as well as the activation and survival of mature B cells. By functioning downstream of multiple receptors, including growth factors, B cell antigens, chemokines and innate immune receptors, BTK initiates several cellular processes including cell proliferation, survival, differentiation, motility, angiogenesis, cytokine production and antigen presentation.

[0002] BTK-deficient mouse models have demonstrated the role that BTK plays in allergic and / or autoimmune and / or inflammatory disorders. For example, BTK deficiency in standard mouse preclinical models of systemic lupus erythematosus (SLE) has been shown to result in significant amelioration of disease progression. Furthermore, BTK-deficient mice may be resistant to developing collagen-induced arthritis and may be less susceptible to Staphylococcus aureus-induced arthritis. Due to the role of BTK in B cell activation, BTK inhibitors may also be useful as inhibitors of B cell-mediated pathogenic activity (such as autoantibody production). Expression of BTK in osteoclasts, mast cells and monocytes has been shown to be important for the function of these cells. For example, impaired IgE-mediated mast cell activation and reduced TNF-α production by activated monocytes have been associated with BTK deficiency in mice and humans. Thus, BTK inhibition may be useful in treating allergic disorders and / or autoimmune and / or inflammatory diseases, such as SLE, rheumatoid arthritis, polyangiitis, idiopathic thrombocytopenic purpura (ITP), myasthenia gravis, allergic rhinitis, multiple sclerosis, and asthma.

[0003] The role of BTK in apoptosis demonstrates the utility of inhibiting BTK activity for the treatment of cancer, B cell lymphoma, leukemia and other hematological malignancies. Furthermore, given the role of BTK in osteoclast function, inhibiting BTK activity may be useful in the treatment of bone disorders such as osteoporosis.

[0004] Many antagonists of B-cell receptor (BCR) signaling, especially inhibitors of BTK, have demonstrated clinical efficacy in the treatment of chronic lymphocytic leukemia (CLL). Although therapeutically effective, BTK inhibition alone is not sufficient to eliminate the disease, as evidenced by the fact that only a small proportion of patients treated with the BTK inhibitor (BTKi) ibrutinib achieve a complete response and very rarely achieve undetectable minimal residual disease (uMRD) (Ahn,ie,Farooqui MZH,Tian X,Valdez J,Sun C,Soto S,et al.Depth and durability of response to ibrutinib in CLL:5-year follow-up of a phase 2 study.Blood.2018;131(21):2357-66.). Previous studies have shown that long-term BTK inhibition increases dependency on B-cell lymphoma 2 (BCL2), an anti-apoptotic protein highly expressed in CLL (Deng J, et al., Leukemia. 2017; 31(10): 2075-84). In a phase 1 clinical trial, patients with relapsed / refractory (R / R) CLL treated with the BCL2 inhibitor venetoclax as monotherapy had an overall response rate of 79%, but only 5% of patients had uMRD in the bone marrow (Roberts AW, et al., N Engl J Med. 2016; 374(4): 311-22). Results from a phase 2 clinical trial investigating the combination of ibrutinib and venetoclax as a front-line treatment showed that after 18 cycles of combination therapy, 96% of patients achieved complete remission and 69% of patients had uMRD in the bone marrow, demonstrating the clinical efficacy of this combination (Jain N, et al., N Engl J Med. 2019;380(22):2095-103).

[0005] The compound of the present invention, nemtabrutinib (also known as MK1026 and ARQ531), is a potent, reversible BTK inhibitor that has demonstrated greater inhibition of downstream targets of BTK compared to ibrutinib, and efficacy in R / R disease (Reiff SD, Mantel R, Smith LL, Greene JT, Muhowski EM, Fabian CA, et al. The BTK Inhibitor ARQ 531 Targets Ibrutinib-Resistant CLL and Richter Transformation. Cancer Discovery. 2018;8(10):1300-15. Combinations of nemtabrutinib with other therapeutic agents, such as BCL2 inhibitors, are of particular interest in providing much-needed therapies to treat BTK-mediated disorders / diseases. One such combination therapy is nemtabrutinib in combination with venetoclax for treating patients with relapsed / refractory CLL / SLL after at least one line of prior therapy. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Ahn,ie,Farooqui MZH,Tian X,Valdez J,Sun C,Soto S,et al.Depth and durability of response to ibrutinib in CLL:5-year follow-up of a phase 2 study.Blood.2018;131(21):2357-66 [Non-Patent Document 2] Deng J,et al.,Leukemia.2017;31(10):2075-84 [Non-Patent Document 3] Roberts AW, et al.,N Engl J Med.2016;374(4):311-22 [Non-Patent Document 4] Jain N,et al.,N Engl J Med.2019;380(22):2095-103 [Non-Patent Document 5] Reiff SD,Mantel R,Smith LL,Greene JT,Muhowski EM,Fabian CA,et al.The BTK Inhibitor ARQ 531 Targets Ibrutinib-Resistant CLL and Richter Transformation.Cancer Discovery.2018;8(10):1300-15 Summary of the Invention

[0007] A first aspect of the application provides a therapeutically effective amount of a compound of formula (I): [ka]

[0008] or a pharmaceutically acceptable salt thereof. As used herein, the terms "compound of formula (I)", "compound (I)" or nemtabrutinib refer to the same compound and can be used interchangeably. [Brief description of the drawings]

[0009] [Figure 1A] 1 shows a chart comparing data for cells treated with venetoclax, compound 1, ibrutinib and the combination. [Figure 1B] Representative immunoblots are shown. [Figure 1C] Charts comparing data for cells treated with venetoclax, compound 1, ibrutinib and the combination are shown for various proteins (Figure 1C is pBTK). [Figure 1D]Charts comparing data for cells treated with venetoclax, compound 1, ibrutinib and the combination are shown for various proteins (Figure 1D is pERK). [Figure 1E] Charts comparing data for cells treated with venetoclax, compound 1, ibrutinib and the combination are shown for various proteins (Figure 1E is MCL-1). [Figure 1F] 1 shows a chart depicting data for cells co-cultured with NK Tert stromal cells performing BH3 profiling using BIM, BAD, MS-1 and Y4ek peptides. [Figure 2A] 1 depicts the study design for mice treated with vehicle, venetoclax, nemtabrutinib, ibrutinib, venetoclax and nemtabrutinib, or venetoclax and ibrutinib. [Figure 2B] 1 shows a chart showing survival data for mice treated with vehicle, venetoclax, nemtabrutinib, ibrutinib, venetoclax and nemtabrutinib, or venetoclax and ibrutinib. [Figure 2C] 1 shows a chart showing the probability of survival for treatment with vehicle, venetoclax, nemtabrutinib, ibrutinib, venetoclax and nemtabrutinib, or venetoclax and ibrutinib. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] A first aspect of the application provides a therapeutically effective amount of a compound of formula (I): [ka]

[0011] or a pharma- ceutically acceptable salt thereof.

[0012] Another aspect of the present application is a method of treating a BTK-mediated disease or disorder in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I) in combination with a therapeutically effective amount of at least one second agent, or a pharma- ceutical acceptable salt thereof. or a pharmaceutically acceptable salt thereof to said subject. A further aspect of the present invention is a method in which a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered simultaneously or concurrently with a therapeutically effective amount of at least one second drug or a pharmaceutically acceptable salt thereof. A further aspect of the present invention is a method in which a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered daily with a therapeutically effective amount of at least one second drug or a pharmaceutically acceptable salt thereof.

[0013] Another aspect of the application relates to the use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof in combination with at least one second agent or a pharma- ceutically acceptable salt thereof, in the treatment of a BTK-mediated disease or disorder.

[0014] Another aspect of the application relates to a compound of formula (I) or a pharma- ceutically acceptable salt thereof for use in combination therapy with at least one second agent, or a pharma- ceutically acceptable salt thereof, for the treatment of a BTK-mediated disease or disorder.

[0015] Another aspect of the present application relates to a method of treating cancer, such as a hematological cancer, including B-cell lymphoma or non-Hodgkin's lymphoma, wherein a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered with a therapeutically effective amount of at least one second agent or a pharmaceutically acceptable salt thereof.

[0016] Another aspect of the present application relates to a method of treating cancer, including chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL) or mantle cell lymphoma (MCL).Another aspect of the present application relates to a method of treating chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

[0017] Another aspect of the application relates to a method of modulating (e.g., inhibiting) BTK or a method of modulating (e.g., inhibiting) BTK by administering a compound of Formula (I) or a pharma- ceutically acceptable salt thereof in combination with at least one second agent or a pharma- ceutically acceptable salt thereof.

[0018] Another aspect of the application relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) or a pharma- ceutical acceptable salt thereof, in combination with a therapeutically effective amount of at least one second agent, or a pharma- ceutical acceptable salt thereof, for the manufacture of a medicament for the treatment of a BTK-mediated disease or disorder.

[0019] Another aspect of the application relates to the use of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof in combination with at least one second agent, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a BTK-mediated disease or disorder.

[0020] Another aspect of the application relates to a pharmaceutical composition of a compound of formula (I) or a pharma- ceutically acceptable salt thereof in combination with at least one second agent, wherein the second agent is selected from venetoclax, BI-97C1, sabutoclax, navitoclax, obatoclax, 4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl]-N-[4-[[(2R)-4-(dimethylamino)-1-phenylsulfanylbutan-2-yl]amino]-3-nitrophenyl]sulfonylbenzamide (ABT-737), N-[4-(2-tert-butylphenyl)sulfonylphenyl]-2,3,4-trihydroxy-5-[(2-propan-2-ylphenyl)methyl]benzamide (TW-37), APG-1252, APG-2575, or S55746. A further embodiment is a pharmaceutical composition of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, in combination with venetoclax, or a pharma- ceutically acceptable salt thereof.

[0021] In another embodiment, the pharmaceutical composition of the compound of formula (I) or a pharma- ceutically acceptable salt thereof in combination with venetoclax comprises about 30 mg to about 80 mg of the compound of formula (I) or a pharma- ceutically acceptable salt thereof. In a further embodiment, the pharmaceutical composition of the compound of formula (I) or a pharma- ceutically acceptable salt thereof in combination with venetoclax comprises about 45 mg of the compound of formula (I) or a pharma- ceutically acceptable salt thereof. In a further embodiment, the pharmaceutical composition of the compound of formula (I) or a pharma- ceutically acceptable salt thereof in combination with venetoclax comprises about 65 mg of the compound of formula (I) or a pharma- ceutically acceptable salt thereof. In a further embodiment, the pharmaceutical composition of the compound of formula (I) or a pharma- ceutically acceptable salt thereof in combination with venetoclax comprises about 80 mg of the compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0022] In a further embodiment, the pharmaceutical composition of the compound of formula (I) or a pharma- ceutically acceptable salt thereof in combination with venetoclax or a pharma- ceutically acceptable salt thereof comprises about 30 mg to about 80 mg of the compound of formula (I) or a pharma- ceutically acceptable salt thereof and about 400 mg of venetoclax or a pharma- ceutically acceptable salt thereof. In a further embodiment, the pharmaceutical composition of the compound of formula (I) or a pharma- ceutically acceptable salt thereof in combination with venetoclax comprises about 45 mg of the compound of formula (I) and about 400 mg of venetoclax. In a further embodiment, the pharmaceutical composition of the compound of formula (I) or a pharma- ceutically acceptable salt thereof in combination with venetoclax or a pharma- ceutically acceptable salt thereof comprises about 65 mg of the compound of formula (I) and about 400 mg of venetoclax. In a further aspect, the pharmaceutical composition of the compound of formula (I) or a pharma- ceutically acceptable salt thereof in combination with venetoclax or a pharma- ceutically acceptable salt thereof comprises about 80 mg of the compound of formula (I) or a pharma- ceutically acceptable salt thereof and about 400 mg of venetoclax or a pharma- ceutically acceptable salt thereof.

[0023] Another aspect of the present application is a method of treating a BTK-mediated disorder in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of Formula (I): [ka]

[0024] or a pharma- ceutically acceptable salt thereof to a subject in need of treating a BTK-mediated disorder, hi a further embodiment, the method comprises administering a compound of formula (I) after administering a second agent. In a further embodiment, the BTK-mediated disorder being treated is a cancer selected from CLL, SLL, or MLL. In a further embodiment, the method comprises administering a second agent selected from venetoclax, BI-97C1, sabutoclax, navitoclax, obatoclax, 4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl]-N-[4-[[(2R)-4-(dimethylamino)-1-phenylsulfanylbutan-2-yl]amino]-3-nitrophenyl]sulfonylbenzamide (ABT-737), N-[4-(2-tert-butylphenyl)sulfonylphenyl]-2,3,4-trihydroxy-5-[(2-propan-2-ylphenyl)methyl]benzamide (TW-37), APG-1252, APG-2575, or S55746. A further embodiment is a method wherein a compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered together with venetoclax or a pharma- ceutically acceptable salt thereof. A further embodiment is a method in which the compound of formula (I) or a pharma- ceutically acceptable salt thereof is co-administered with venetoclax or a pharma- ceutically acceptable salt thereof, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered after administration of venetoclax or a pharma- ceutically acceptable salt thereof. In a further embodiment, the compound of formula (I) is administered at least 10 hours after administration of venetoclax.

[0025] Another embodiment of the present application is a method of treating a BTK-mediated disorder in a subject in need thereof, wherein the BTK-mediated disorder is a cancer selected from CLL, SLL, or MLL, the method comprising co-administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of at least one second agent or a pharmaceutically acceptable salt thereof. A further embodiment of the present application is a method of treating a BTK-mediated disorder, wherein the second agent is venetoclax or a pharmaceutically acceptable salt thereof. A further embodiment of the method comprises administering about 20 to about 400 mg of venetoclax or a pharmaceutically acceptable salt thereof followed by about 30 mg to about 80 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In another embodiment, the method comprises administering about 400 mg of venetoclax or a pharmaceutically acceptable salt thereof followed by about 45 mg of the compound of Formula (I) or a pharmaceutically acceptable salt. In another embodiment, the method comprises administering about 400 mg of venetoclax or a pharmaceutically acceptable salt thereof followed by about 65 mg of the compound of Formula (I) or a pharmaceutically acceptable salt. In another embodiment, the method comprises administering about 400 mg of venetoclax or a pharmaceutically acceptable salt thereof followed by about 80 mg of the compound of Formula (I) or a pharmaceutically acceptable salt.

[0026] This application relates to pharmaceutical combinations or combination therapies that can modulate the activity of Bruton's tyrosine kinase (BTK). This application features a method of treating a disease or disorder in which BTK plays a role by administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof in combination with a therapeutically effective amount of a second agent, as described herein. The method of this application can be used in the treatment of various BTK-mediated diseases and disorders by inhibiting the activity of BTK kinase. Inhibition of BTK provides treatment, prevention or amelioration of diseases, including but not limited to immune disorders, cancer, cardiovascular diseases, viral infections, inflammation, metabolic / endocrine dysfunction and neurological disorders.

[0027] The compound of formula (I) or a pharma- ceutically acceptable salt thereof has the structure: [ka]

[0028] Compound (I) has the formula (I): ##STR00002## and is also known as nemtabrutinib, MK-1026, and formerly ARQ531, and is a reversible, non-covalent, adenosine triphosphate (ATP)-competitive inhibitor of Bruton's tyrosine kinase (BTK), designed to target both wild-type and BTK-C481S mutants. Methods for producing this compound are described in U.S. Pat. No. 9,630,968, which is incorporated herein by reference. The present invention encompasses compounds of formula (I) and salts thereof, as described in the '968 patent. Compound (I) (nemtabrutinib) has shown greater inhibition of downstream targets of BTK compared to another BTK inhibitor, ibrutinib. (Reiff SD, Mantel R, Smith LL, Greene JT, Muhowski EM, Fabian CA, et al.The BTK Inhibitor ARQ 531 Targets Ibrutinib-Resistant CLL and Richter Transformation.Cancer Discovery.2018;8(10):1300-15.

[0029] This application provides the medical community with a novel pharmacological strategy for treating diseases and disorders associated with BTK kinase. Results of a phase 2 clinical trial investigating the combination of ibrutinib and venetoclax as a front-line treatment showed that after 18 cycles of combination therapy, 96% of patients achieved complete remission and 69% of patients had uMRD in bone marrow, demonstrating the clinical efficacy of this combination (Jain N, et al., N Engl J Med. 2019; 380(22): 2095-103).

[0030] The present application provides pharmaceutical combinations or combination therapies with additive or synergistic effects and safety profiles compared to known therapies using a compound of formula I or a pharma- ceutical acceptable salt thereof.One aspect of the present invention relates to a method of treating a BTK-mediated disease or disorder in a subject in need thereof, comprising co-administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharma- ceutical acceptable salt thereof in combination with a therapeutically effective amount of at least one second agent or a pharma- ceutical acceptable salt thereof, wherein the BTK-mediated disease state or disorder is cancer and the second agent is venetoclax or a pharma- ceutical acceptable salt thereof.

[0031] Details of the present application are described in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application, exemplary methods and materials are described herein. Other features, objects, and advantages of the present application will be apparent from the description and claims. In this specification and the appended claims, the singular form includes the plural form unless the context clearly dictates not to include the plural form. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. All patents and publications cited herein are incorporated herein by reference in their entirety.

[0032] definition The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0033] The term "and / or" is used in this application to mean either "and" or "or," unless otherwise stated.

[0034] The present application also includes a pharmaceutical composition comprising an effective amount of a compound of formula (I) and a pharma- ceutically acceptable carrier.

[0035] The term "carrier" as used in this application encompasses carriers, excipients and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, that is involved in carrying or transporting a pharmaceutical agent from one organ or part of the body to another organ or part of the body of a subject.

[0036] Compounds of formula (I) may be in the form of salts, esters, prodrugs, solvates, tautomers, isotopes, etc., which are also within the scope of this application and are taught in U.S. Pat. No. 9,630,968, which is incorporated herein by reference.

[0037] In this specification, the structural formulae of compounds may, in some instances, for convenience, represent certain isomers; however, this application includes all isomers, including geometric isomers, optical isomers based on asymmetric carbons, stereoisomers, tautomers, and the like, as set forth in U.S. Pat. No. 9,630,968, which is incorporated herein by reference.

[0038] The compounds of formula (I) may be more potent in inhibiting the activity of BTK containing one or more mutations described herein, e.g., C481S, than one or more known BTK inhibitors, including, but not limited to, ibrutinib, GDC-0834, RN486, CGI-560, CGI-1746, HM-71224, CC-292, ONO-4059, CNX-774, LFM-A13, GDC-0853, LOU684, PRN1008, acalabrutinib, zanubrutinib, and / or PRN2246. For example, the compounds may be more effective (e.g., IC) than ibrutinib, GDC-0834, RN486, CGI-560, CGI-1746, HM-71224, CC-292, ONO-4059, CNX-774, LFM-A13, GDC-0853, LOU684, PRN1008, acalabrutinib, zanubrutinib, and / or PRN2246 in inhibiting the activity of BTK containing one or more mutations described herein. 50 The drug-resistant BTK mutant can be at least about 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or about 100-fold more potent (as measured by β-actin, β-glucose ...

[0039] The terms "administer," "administering," or "administration" as used in this application refer to either administering to a subject a disclosed compound or a pharma- ceutically acceptable salt or composition of the disclosed compound directly, or administering to a subject a prodrug, derivative, or analog of the compound or a pharma- ceutically acceptable salt or composition of the compound that is capable of forming an equivalent amount of the active compound in the subject's body.

[0040] A "patient" or "subject" is a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or a non-human primate, such as a monkey, chimpanzee, baboon, or rhesus monkey.

[0041] An "effective amount" or "therapeutically effective amount" when used in connection with a compound or pharmaceutical composition is an amount effective to treat or prevent a disease in a subject as described herein.

[0042] The term "treating" with respect to a subject refers to improving at least one symptom of a disorder in a subject. Treating includes curing, improving, or at least partially ameliorating a disorder.

[0043] The compounds of the present application or pharma- ceutically acceptable salts thereof can also be used in combination with a second therapeutic agent to prevent a disease, condition, or disorder. As used herein, "preventing" or "prevent" describes reducing or eliminating the onset of symptoms or complications of a disease, condition, or disorder.

[0044] The term "disorder" is used in this application to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

[0045] As used herein, the term "BTK-mediated" disease or disorder refers to any disease or other deleterious condition in which BTK or a mutant thereof is known to play a role. Accordingly, another embodiment of the present application relates to treating or reducing the severity of one or more diseases in which BTK or a mutant thereof is known to play a role. Specifically, the present application relates to a method of treating or reducing the severity of a disease or condition selected from a proliferative disorder or an autoimmune disorder, comprising administering a compound of formula (I) or a pharmacologic acceptable salt thereof or a composition according to the present application to a patient / animal in need of treating or reducing the severity of a disease or condition selected from a proliferative disorder or an autoimmune disorder.

[0046] As used herein, the term "cell proliferative disorder" refers to a condition in which uncontrolled or abnormal proliferation of cells or both can lead to the development of an undesirable condition or disease, which may or may not be cancerous. Exemplary cell proliferative disorders of the present application encompass a variety of conditions in which cell division is deregulated. Exemplary cell proliferative disorders include, but are not limited to, neoplasms, benign tumors, malignant tumors, precancerous conditions, intraepithelial neoplasia, encapsulated tumors, metastatic tumors, liquid tumors, solid tumors, immune tumors, hematological tumors, cancers, carcinomas, leukemias, lymphomas, sarcomas, and rapidly dividing cells. As used herein, the term "rapidly dividing cells" is defined as any cell that divides at a rate that exceeds or is greater than that expected or observed between adjacent or juxtaposed cells in the same tissue.

[0047] Cell proliferation disorders include pre-cancer or pre-cancerous conditions. Cell proliferation disorders include cancer. Preferably, the methods provided herein are used to treat or alleviate the symptoms of cancer. The term "cancer" includes solid tumors as well as hematological tumors and / or malignant tumors. A "pre-cancer cell" or "pre-cancerous cell" is a cell that exhibits a cell proliferation disorder that is a pre-cancer or pre-cancerous condition. A "cancer cell" or "cancerous cell" is a cell that exhibits a cell proliferation disorder that is a cancer. Any reproducible means of measurement may be used to identify cancer or pre-cancerous cells. Cancer or pre-cancerous cells may be identified by histological classification or grading of tissue samples (e.g., biopsy samples). Cancer or pre-cancerous cells may be identified by the use of appropriate molecular markers.

[0048] Exemplary non-cancerous BTK-mediated conditions or disorders are referenced in U.S. Pat. No. 9,630,968, which is incorporated herein by reference.

[0049] Processes for preparing compounds of formula I Compounds of formula I can be made by a variety of methods, including standard chemistry. Compounds of formula (I) can be prepared by methods known in the art of organic synthesis, such as those described in U.S. Patent No. 9,630,968, which is incorporated herein by reference.

[0050] The compounds described herein can be made from commercially available starting materials or can be synthesized using known organic, inorganic and / or enzymatic processes.

[0051] The compounds of the present application can be prepared in a number of ways well known to those skilled in the art of organic synthesis.

[0052] How to Use the Compound Aspects of the present application relate to methods of treating, preventing, inhibiting, or eliminating a disease or disorder associated with the modulation of BTK (e.g., inhibition of BTK). The methods comprise administering to a patient in need of treatment for a disease or disorder associated with the modulation of BTK an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition of a compound of formula (I) in combination with a second agent as described herein. In one embodiment, the BTK-mediated disorder is selected from immune disorders, cancer, cardiovascular diseases, viral infections, inflammation, metabolic / endocrine dysfunction, and neurological disorders.

[0053] In embodiments, the BTK is a mutant BTK (e.g., the BTK C481S mutant).

[0054] Embodiments of the invention relate to methods that include administering at least one second agent selected from an anti-inflammatory agent, an immunomodulatory agent, a chemotherapeutic agent, a neurotropic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an antiviral agent, an agent for treating a blood disorder, an agent for treating diabetes, and an agent for treating an immunodeficiency disorder.

[0055] Another aspect of the present application relates to a method of modulating BTK comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula (I), in combination with a second agent as described herein. In one embodiment, modulating BTK is inhibiting BTK.

[0056] Another aspect of the present application relates to a compound of formula (I) or a pharma- ceutically acceptable salt thereof, in combination with a second agent as described herein, for use in a method of treating a BTK-mediated disorder. In one embodiment, the disease or disorder is selected from immune disorders, cancer, cardiovascular disease, viral infection, inflammation, metabolic / endocrine dysfunction, and neurological disorders.

[0057] In embodiments, the methods described herein include administering at least one second agent selected from an anti-inflammatory agent, an immunomodulatory agent, a chemotherapeutic agent, a neurotropic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an antiviral agent, an agent for treating a blood disorder, an agent for treating diabetes, and an agent for treating an immunodeficiency disorder.

[0058] In some embodiments, the BTK is wild-type BTK. In other embodiments, the BTK is a mutant BTK (e.g., the BTK C481S mutant).

[0059] In another aspect, the application relates to a pharmaceutical composition of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, in combination with a second agent, as described herein, for use in a method of treating a BTK-mediated disorder.

[0060] Another aspect of the present application relates to a compound of formula (I) or a pharma- ceutically acceptable salt thereof, in combination with a second agent as described herein, for use in a method for treating, preventing, inhibiting, or eliminating a cell proliferative disorder. In one embodiment, the cell proliferative disorder is cancer.

[0061] In another aspect, the present application relates to a pharmaceutical composition of a compound of formula (I) or a pharma- ceutically acceptable salt thereof in combination with a second agent as described herein for use in a method for treating, preventing, inhibiting, or eliminating a cell proliferative disorder. In one embodiment, the cell proliferative disorder is cancer.

[0062] In some embodiments of the methods and uses described herein, the cancer is selected from the group consisting of breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma (NSCLC), small cell carcinoma, lung adenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma and biliary tract, kidney carcinoma, pancreatic, myeloid disorders, lymphoma, hairy cell, oral cavity, nasopharynx, pharynx, lips, tongue, mouth, small intestine, colorectum, large intestine, rectum, brain and central nervous system, Hodgkin's leukemia, bronchus, thyroid, liver and and intrahepatic bile duct, hepatocellular, gastric, glioma / glioblastoma, endometrium, melanoma, kidney and renal pelvis, bladder, uterine corpus, cervix, multiple myeloma, acute myeloid leukemia, chronic myeloid leukemia, lymphocytic leukemia, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), B cell non-Hodgkin's lymphoma (e.g., diffuse large B cell lymphoma (DLBCL), follicular lymphoma, mantle cell lymphoma (MCL), CNS lymphoma (primary and secondary)), marginal zone lymphoma, myeloid leukemia, childhood sarcoma, childhood brain tumor, oral cavity and pharynx, non-Hodgkin's lymphoma, melanoma, villous colon adenoma, Richter's transformation, and Waldenstrom's macroglobulinemia. The terms "CLL" and "SLL" refer to the same disease located in different anatomical locations. CLL and SLL have the same treatment paradigm and expected clinical outcomes. CLL is sometimes used as an umbrella term for both CLL and SLL.

[0063] In any of the embodiments of the present application, the cancer may be any cancer in any organ, for example, the cancer is selected from the group consisting of glioma, thyroid carcinoma, breast carcinoma, small cell lung carcinoma, non-small cell carcinoma, gastric carcinoma, colon carcinoma, gastrointestinal stromal carcinoma, pancreatic carcinoma, bile duct carcinoma, CNS carcinoma, ovarian carcinoma, endometrial carcinoma, prostate carcinoma, renal carcinoma, anaplastic large cell lymphoma, leukemia, multiple myeloma, mesothelioma and melanoma, and combinations thereof.

[0064] In any of the embodiments of the present invention, the cancer is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL) or mantle cell lymphoma (MCL). In any of the embodiments, the cancer is chronic lymphocytic leukemia (CLL).

[0065] In some embodiments of the methods and uses described herein, the disease or disorder is an immune disorder. In one embodiment, the immune disorder is rheumatoid arthritis.

[0066] In some embodiments of the methods and uses described herein, the disease or disorder is systemic and local inflammation, arthritis, inflammation associated with immunosuppression, organ transplant rejection, allergy, ulcerative colitis, Crohn's disease, dermatitis, asthma, systemic lupus erythematosus, Sjogren's syndrome, multiple sclerosis, scleroderma / systemic sclerosis, idiopathic thrombocytopenic purpura (ITP), antineutrophil cytoplasmic antibody (ANCA) vasculitis, chronic obstructive pulmonary disease (COPD), psoriasis.

[0067] In one embodiment, a method for treating a disease or disorder associated with the regulation of BTK, including immune disorders, cancer, cardiovascular disease, viral infection, inflammation, metabolic / endocrine dysfunction, and neurological disorders, comprises administering a compound of Formula (I) in combination with at least one second agent to a patient suffering from at least one of said diseases or disorders.

[0068] The compound of formula (I) may be administered in a therapeutically effective amount in combination therapy with one or more therapeutic agents (pharmaceutical combinations) or therapeutic modalities, such as non-pharmaceutical therapies. For example, synergistic effects may occur with other antiproliferative, anticancer, immunomodulatory or anti-inflammatory substances. In some embodiments, the compound of formula (I) is administered in combination with at least one second drug selected from anti-inflammatory agents, immunomodulatory agents, chemotherapeutic agents, neurotropic factors, drugs for treating cardiovascular disease, drugs for treating liver disease, antiviral agents, drugs for treating blood disorders, drugs for treating diabetes, and drugs for treating immunodeficiency disorders. When the compound of formula (I) is administered in combination with other therapies, the dosage of the co-administered compound will of course vary depending on the type of co-drug used, the specific drug used, the condition being treated, and the like.

[0069] Combination therapy includes administration of Compound (I) in further combination with at least one second agent (biologically active component such as, but not limited to, anti-inflammatory agents, immunomodulatory agents, chemotherapeutic agents, neurotropic agents, agents for treating cardiovascular disease, agents for treating liver disease, antiviral agents, agents for treating blood disorders, agents for treating diabetes, and agents for treating immunodeficiency disorders.

[0070] In one embodiment, the compound of formula (I) is used in combination with at least one second agent, preferably a compound that can enhance the effect of the compound of formula (I). The compound of formula (I) can be administered simultaneously (as a single preparation or separate preparations) or sequentially with the second agent. In general, combination therapy contemplates the administration of two or more drugs during a single cycle or course of treatment. In an embodiment of the invention, the method includes administration of a therapeutically effective amount of the compound of formula (I) or a pharma- ceutically acceptable salt thereof prior to administration of a therapeutically effective amount of at least one second agent or a pharma- ceutically acceptable salt thereof. In an embodiment of the invention, the co-administration of the compound of formula (I) and the second agent is performed within 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours or 24 hours. In an embodiment of the invention, the co-administration of the compound of formula (I) and the second agent occurs within 1, 2, 3, 4, 5, 6 or 7 days. In an embodiment of the invention, the co-administration of the compound of formula (I) and the second agent occurs within 1, 2, 3 or 4 weeks.

[0071] The second agent may be an alkylating agent, an antibiotic, an antibiotic antineoplastic agent, an antimetabolite, an antimetabolite antineoplastic agent, an antidote, an interferon, a polyclonal or monoclonal antibody, a Bcl-2 inhibitor, a BTK inhibitor, an mTOR kinase inhibitor, an immunomodulatory drug (ImiD), a TOPK inhibitor, a sphingosine-1-phosphate receptor agonist, an anti-T cell immunoglobulin, an anti-IL-2 receptor antibody, an amide, an EGFR inhibitor, a HER2 inhibitor, a histone deacetylase inhibitor, a hormone or hormone analog, a mitotic inhibitor, a kinase inhibitor, a multikinase inhibitor, a serine / threonine kinase inhibitor, a tyrosine kinase inhibitor, a VEGF / VEGFR inhibitor, a taxane or a taxane derivative, an aromatase inhibitor, an anthracycline, a microtubule targeting drug, an antimicrotubule agent, an antimitotic agent, a mitotic inhibitor, a topoisomerase poison drug, inhibitors of molecular targets or enzymes (e.g., kinase inhibitors), cytidine analogs, phosphotidyl inositol-3 kinase (PI3K) inhibitors, antibody antagonists to receptor kinase ligand binding, anti-angiogenic therapeutics, SH2 / SH3 domain blockers, myo-inositol signaling inhibitors, Ras oncogene inhibitors, antineoplastic agents, antiproliferative agents, additional therapeutic agents, antiviral agents, antigens or adjuvants, cytotoxic agents, retinoids, chemotherapeutic agents, cell cycle signaling inhibitors, therapeutics used in pro-apoptotic regimes, PARP inhibitors, agents used in immunotherapy regimes, checkpoint inhibitors, PD-1 or PD-L1 inhibitors, anti-PD-L1 antibodies, PD-1 antagonists, PD-1 inhibitors, antibodies against ICOS, antibodies against OXO40, TLR agonists, TLR4 agonists, therapeutics useful in the prevention or treatment of bacterial and viral infections, TB infection (mycobacterium and the like, therapeutic agents useful in the treatment of Chlamydia, therapeutic agents useful in the treatment of Plasmodium infections, vaccines, immunogenic antigens, anti-inflammatory agents, or the like.The therapeutic agent may include, but is not limited to, any chemotherapeutic, antineoplastic or anti-proliferative agent listed at: org / docroot / cdg / cdg_0.asp.

[0072] B-cell lymphoma 2 protein (Bcl-2) is a key regulator of programmed cell death (apoptosis). Bcl-2 inhibitors can include, but are not limited to, venetoclax, BI-97C1, sabutoclax, navitoclax, obatoclax, 4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl]-N-[4-[[(2R)-4-(dimethylamino)-1-phenylsulfanylbutan-2-yl]amino]-3-nitrophenyl]sulfonylbenzamide (ABT-737), N-[4-(2-tert-butylphenyl)sulfonylphenyl]-2,3,4-trihydroxy-5-[(2-propan-2-ylphenyl)methyl]benzamide (TW-37), APG-1252 (Ascentage Pharma), APG-2575 (Ascentage Pharma) or S55746 (Servier). Bcl-2 inhibitors can also include, but are not limited to, other chemical entities such as antisense RNA, siRNA, peptidyl inhibitors and antibody inhibitors of Bcl-2.Bcl-2 inhibitors can also include, but are not limited to, inhibitors of other members of the Bcl-2-mediated signaling pathway that can be used instead of or in addition to Bcl-2 inhibitors.In one embodiment of the present invention, the second agent is a Bcl-2 inhibitor.In one embodiment of the present invention, the second agent is venetoclax.

[0073] Exemplary BTK inhibitors include ibrutinib, ACP-196 (acalabrutinib), BGB-3111 (zanubrutinib), spebrutinib, ONO-4059, HM71224, RN486, 4-(4-((4-((3-acrylamidophenyl)amino)-5-fluoropyrimidin-2-yl)amino)phenoxy)-N-methylpicolinamide (CNX-774), N-[3-[4,5-dihydro-4-methyl-6-[[4-(4-morpholinylcarbonyl)phenyl]amino]-5-oxopyrazinyl]-2-methylphenyl]-4-(1 ,1-dimethylethyl)-benzamide (CGI-1746), CGI-560, AVL-292 (CC-292), PRN1008, M7583, M2951, BIIB068, CT-1530, AC0058TA, GS-4059, REDX08608, RXC005, BMS-986142, TP-0158, SNS-062, BI-BTK-1, GDC-0834, GDC-0853, LFM-A13, LOU684, PRN1008, acalabrutinib, zanubrutinib and PRN2246. BTK inhibitors can include, but are not limited to, polyfluorinated compounds described in International Publication No. 2015 / 165279 and U.S. Patent Application No. 15 / 075,033, the disclosures of which are incorporated herein by reference in their entirety. BTK inhibitors can include, but are not limited to, other chemical entities such as antisense RNA, siRNA, peptidyl inhibitors, and antibody inhibitors of BTK. In some embodiments, the BTK inhibitor can bind irreversibly to BTK.

[0074] In some embodiments, the BTK inhibitor can bind to mutated BTK, such as BTK with a mutation at C481, e.g., a C481S mutation. In some embodiments, the BTK inhibitor can include, but is not limited to, inhibitors of other members of the BTK-mediated signaling pathway. Inhibitors of other members of the BTK-mediated signaling pathway can include, but are not limited to, inhibitors of protein kinase C (PKC) beta, such as enzastaurin and sotrastaurin. In some embodiments, the BTK inhibitor is ibrutinib, acalabrutinib, or zanubrutinib.

[0075] Immunomodulatory drugs (IMiDs) are useful for treating various inflammatory and autoimmune diseases.IMiDs are also useful for treating neoplastic diseases such as hematological neoplasms, such as multiple myeloma and myelodysplastic syndrome, and certain solid tumors.Exemplary immunomodulatory (IMiD) drugs can include, but are not limited to, lenalidomide, pomalidomide, thalidomide, revlimid, CC-112 and CC-220.

[0076] Mammalian target of rapamycin (mTOR) is a protein kinase that acts as a key regulator of cell growth, proliferation, metabolism and apoptosis. Exemplary mTOR kinase inhibitors include everolimus, rapamycin, [7-(6-amino-3-pyridinyl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl][3-fluoro-2-methyl-4-(methylsulfonyl)phenyl]-methanone (XL388), N-ethyl-N'-[4-[5,6,7,8-tetrahydro-4-[(3S)-3-methyl-4-morpholinyl]-7-(3-oxetanyl)pyrido[3,4-d]pyrimidin-2-yl]phenyl]-urea (GDC-0349 (Genentech)), 3-(2, 4-bis((S)-3-methylmorpholino)pyrido[2,3-d]pyrimidin-7-yl)-N-methylbenzamide (AZD2014 (AstraZeneca)), (5-(2,4-bis((S)-3-methylmorpholino)pyrido[2,3-d]pyrimidin-7-yl)-2-methoxyphenyl)methanol (AZD8055), GSK105965, 3-(2-aminobenzo[d]oxazol-5-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (TAK-228 or MLN0128 (Takeda)), Can include, but are not limited to, temsirolimus, ridaforolimus, PI-103, NVP-BEZ235, WJD008, XL765, SF-1126, torin1, PP242, PP30, Ku-0063794, WYE-354, WYE-687, WAY-600, INK128, OSI-027, gedatricib or PF-05212384 (Pfizer), CC-223 (Celgene), LY3023414 (Lilly), PQR309 (PIQUR Therapeutics), LXI-15029 (Luoxin Pharma) and SAR245409 (Sanofi). mTOR kinase inhibitor can also include, but are not limited to, other chemical entities such as antisense RNA, siRNA, peptidyl inhibitors and antibody inhibitors of mTOR. Exemplary mTOR kinase inhibitors can also include, but are not limited to, inhibitors of other members of mTOR-mediated signal transduction pathway.Inhibitors of other members of mTOR-mediated signal transduction pathway can include, but are not limited to, inhibitors of phosphoinositide 3-kinase (PI3K), such as BTG226, gedatrisib, apitolisib, omipalisib, dactolisib, duvelisib (COPIKTRA), idelalisib (Zydelig), temsirolimus (Torisel), rapamune, ridaforolimus and AP23573, and inhibitors of Akt (protein kinase B), such as 8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl-2H-[1,2,4]triazolo[3,4-f][1,6]naphthyridin-3-one; dihydrochloride (MK-2206).

[0077] Exemplary TOPK inhibitors include, but are not limited to, OTS964 ((R)-9-(4-(1-(dimethylamino)propan-2-yl)phenyl)-8-hydroxy-6-methylthieno[2,3-c]quinolin-4(5H)-one).

[0078] Exemplary sphingosine-1-phosphate receptor agonists can include, but are not limited to, fingolimod and KRP-203.

[0079] Exemplary anti-T cell immunoglobulins can include, but are not limited to, anti-thymocyte globulin (Atgam®).

[0080] Exemplary anti-IL-2 receptor antibodies can include, but are not limited to, daclizumab.

[0081] Exemplary amides can include, but are not limited to, CTX.

[0082] Exemplary second agents may also include, but are not limited to, ifosfamide (IFO), adriamycin (ADM), daunorubicin (DNR), vincristine (VCR), vinblastine (VBL), etoposide (VP16), vermeer (Vumon), carboplatin (CBP) and methotrexate (MTX), cyclosporine A, tacrolimus, sirolimus, everolimus, azathioprine, brequinar, leflunomide, LEA-29Y, anti-CD3 antibodies (e.g., OKT3), aspirin, B7-CD28 blocking molecules (e.g., belatacept, abatacept), CD40-CD154 blocking molecules (anti-CD40 antibodies), acetaminophen, ibuprofen, naproxen, piroxicam, and anti-inflammatory steroids (e.g., prednisolone or dexamethasone).

[0083] Alkylating agents are non-phase specific agents and strong electrophiles. Typically, alkylating agents form covalent bonds to DNA through nucleophilic moieties of the DNA molecule, such as phosphate, amino, sulfhydryl, hydroxyl, carboxyl and imidazole groups, by alkylation. Such alkylation disrupts nucleic acid function and leads to cell death. Examples of alkylating agents include, but are not limited to, nitrogen mustards, such as cyclophosphamide (e.g., CYTOXAN®), melphalan (e.g., ALKERAN®) and chlorambucil (e.g., LEUKERAN®); alkylsulfonates, such as busulfan (e.g., MYLERAN®); nitrosoureas, such as carmustine (e.g., BiCNU®); and triazenes, such as dacarbazine (e.g., DTIC-Dome®).

[0084] Exemplary alkylating agents include busulfan (Busulfex), lomustine (CeeNU), oxaliplatin (Eloxatin), carmustine (Gliadel), ifosfamide (Ifex), mechlorethamine (Mustargen), busulfan (Myleran), carboplatin (PARAPLATIN®), cisplatin (CDDP, PLATINOL®), temozolomide (Temodar), thiotepa (Thioplex), bendamustine (Treanda), streptozocin (Zanosar), 5-azacytidine (e.g., VIDAZA), decitabine (e.g., DECOGEN), temozolomide (e.g., T EMODAR and TEMODAL), dactinomycin (also known as actinomycin-D and sold under the trade name COSMEGEN), melphalan (also known as L-PAM, L-sarcolysin and phenylalanine mustard and sold under the trade name ALKERAN), altretamine (also known as hexamethylmelamine (HMM) and sold under the trade name HEXALEN), carmustine (e.g., BCNU, BiCNU), bendamustine (e.g., TREANDA), carboplatin (e.g., PARAPLATIN®), and lomustine (also known as CCNU and sold under the trade name CeeNU®).), cisplatin (also known as CDDP and sold under the trade names PLATINOL® and PLATINOL®-AQ), cyclophosphamide (sold under the trade names CYTOXAN® and NEOSAR®), dacarbazine (also known as DTIC, DIC and imidazole carboxamide and sold under the trade name DTIC-DOME®), altretamine (also known as hexamethylmelamine (HMM) and sold under the trade name HEXALEN®), ifosphatase (also known as hexamethylmelamine (HMM) and sold under the trade name HEXALEN®), and cyclophosphamide (also known as cyclophosphamide, ... Also included are, but are not limited to, bromine (e.g., IFEX®), procarbazine (e.g., MATULANE®), mechlorethamine (also known as nitrogen mustard, mustine, and mechloroethamine hydrochloride, sold under the trade name MUSTARGEN®), streptozocin (e.g., ZANOSAR®), and thiotepa (also known as thiophosphamide, TESPA, and TSPA, sold under the trade name THIOPLEX®).

[0085] Antibiotic antineoplastic agents are non-phase specific agents that bind to or intercalate with DNA. Typically, such action results in stable DNA complexes or strand breaks that disrupt the normal function of nucleic acids and cause cell death. Examples of antibiotic antineoplastic agents include, but are not limited to, actinomycins such as dactinomycin (e.g., COSMEGEN®), anthracyclines such as daunorubicin (e.g., in liposomal injectable form as DAUNOXOME® or injectable as CERUBIDINE®) and doxorubicin (e.g., RUBEX® or ADRIAMYCIN RDF®), and bleomycin (e.g., BLENOXANE®). Exemplary anthracyclines include, but are not limited to, daunorubicin, doxorubicin (Adriamycin), epirubicin, idarubicin, and valrubicin.

[0086] Exemplary antibiotics include doxorubicin (Adriamycin), doxorubicin liposomal (Doxil), mitoxantrone (Novantrone), bleomycin (Blenoxane), daunorubicin (Cerubidine), daunorubicin liposomal (DaunoXome), dactinomycin (Cosmegen), epirubicin (Ellence), idarubicin (Idamycin), plicamycin (Mithracin), mitomycin (Mutamycin), pentostatin (Nipent), valrubicin (Valstar), doxorubicin (e.g., ADRIAMYCIN ( Also included are, but are not limited to, bleomycin (e.g., LENOXANE®), daunorubicin (also known as dauorubicin hydrochloride, daunomycin and rubidomycin hydrochloride, sold under the trade name CERUBIDINE®), daunorubicin liposomal (daunorubicin citrate liposomal, sold under the trade name DAUNOXOME), mitoxantrone (also known as DHAD, sold under the trade name NOVANTRONE®), epirubicin (e.g., ELLENCE™), idarubicin (e.g., IDAMYCIN®, IDAMYCIN PFS®), and mitomycin C (e.g., MUTAMYCIN®).

[0087] Antimetabolites antineoplastic agents are phase-specific drugs that act at the S phase of the cell cycle (DNA synthesis) by inhibiting DNA synthesis or by inhibiting purine or pyrimidine base synthesis, thereby limiting DNA synthesis, so that progression through the S phase does not occur and cell death follows. Examples of antimetabolite antineoplastic agents include, but are not limited to, fluorouracil and its analogs (e.g., 5-fluorodeoxyuridine (floxuridine), 5-fluorodeoxyuridine monophosphate methotrexate), cytarabine (commonly known as Ara-C and available as CYTOSAR-U®) and its analogs (e.g., azacitidine, 2',2'-difluorodeoxycytidine (gemcitabine)), mercaptopurine (e.g., PURINETHOL®) and its analogs (e.g., azathioprine), thioguanine (e.g., TABLOID®) and its analogs (e.g., pentostatin, erythrohydroxynonyladenine (EHNA), fludarabine phosphate, and cladribine), gemcitabine (e.g., GEMZAR®), and methotrexate.

[0088] Exemplary antimetabolites include fluorouracil (Adrucil), capecitabine (Xeloda), hydroxyurea (Hydrea), mercaptopurine (Purinethol), pemetrexed (Alimta), fludarabine (Fludara), nelarabine (Arranon), cladribine (Cladribine), and the like. Novaplus), clofarabine (Clolar), cytarabine (Cytosar-U), decitabine (Dacogen), cytarabine liposomal (DepoCyt), hydroxyurea (Droxia), pralatrexate (Folotyn), floxuridine (FUDR), gemcitabine (Gemzar), cladribine (Leustatin), fludarabine (Oforta), methotrexate (MTX, Rheumatrex), methotrexate (Trexall), thioguanine (Tabloid), TS-1 or cytarabine (Tarabine PFS), claribine (2-chlorodeoxyadenosine, sold under the brand name LEUSTATIN®), 5-fluorouracil (sold under the brand name ADRUCIL®), 6-thioguanine (sold under the brand name PURINETHOL®), pemetrexed (sold under the brand name ALIMTA®), cytarabine (also known as arabinosylcytosine (Ara-C) and sold under the brand name CYTOSAR-U®), and cytarabine liposomal.Also included are, but are not limited to, Ara-C (sold under the trade name DEPOCYT™), decitabine (sold under the trade name DACOGEN®), hydroxyurea (sold under the trade names HYDREA®, DROXIA®, and MYLOCEL®), fludarabine (sold under the trade name FLUDARA®), floxuridine (sold under the trade name FUDR®), cladribine (sold under the trade name 2-chlorodeoxyadenosine (2-CdA) and LEUSTATIN®), methotrexate (sold under the trade names amethopterin, methotrexate sodium (MTX) and RHEUMATREX® and TREXALL®), and pentostatin (sold under the trade name NIPENT®).

[0089] Exemplary antidotes include, but are not limited to, amifostine (Ethyol) and mesna (Mesnex).

[0090] Exemplary interferons include, but are not limited to, interferon alpha-2b (Intron A) and interferon alpha-2a (Roferon-A).

[0091] Exemplary polyclonal or monoclonal antibodies include trastuzumab (Herceptin), ofatumumab (Arzerra), bevacizumab (Avastin), rituximab (Rituxan), cetuximab (Erbitux), panitumumab (Vectibix), tositumomab / iodine 131These include, but are not limited to, tositumomab (Bexxar), alemtuzumab (Campath), ibritumomab (Zevalin, In-111, Y-90 Zevalin), gemtuzumab (Mylotarg), eculizumab (Soliris), ordenosumab, denosumab, and anti-CD20 antibodies (e.g., rituximab (Rituxan), obinutuzumab (Gazyva), ofatumumab (Arzerra), and ublituximab).

[0092] Exemplary EGFR inhibitors include, but are not limited to, gefitinib (Iressa), lapatinib (Tykerb), cetuximab (Erbitux), erlotinib (Tarceva), panitumumab (Vectibix), PKI-166, canertinib (CI-1033), matuzumab (Emd7200), and EKB-569.

[0093] Exemplary HER2 inhibitors include, but are not limited to, trastuzumab (Herceptin); lapatinib (Tykerb) and AC-480.

[0094] Exemplary histone deacetylase inhibitors include, but are not limited to, vorinostat (Zolinza).

[0095] Hormones and hormone analogues are useful compounds for treating cancers where there is a relationship between hormone(s) and the growth and / or lack of growth of the cancer.Examples of hormones and hormone analogues useful in cancer treatment include corticosteroids such as prednisone and prednisolone; aminoglutethimide and other aromatase inhibitors, such as, but not limited to, anastrozole, letrozole, vorozole and exemestane; progestins such as megestrol acetate; estrogens and antiestrogens such as fulvestrant, flutamide, nilutamide, bicalutamide, cyproterone acetate and 5-reductase inhibitors such as finasteride and dutasteride. antiestrogens such as tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene, and selective estrogen receptor modulators (SERMS) such as those described in U.S. Pat. Nos. 5,681,835, 5,877,219, and 6,207,716; and gonadotropin releasing hormone (GnRH) and its analogs; and LHRH agonists and antagonists, such as goserelin acetate and luprolide.

[0096] Exemplary aromatase inhibitors include, but are not limited to, aminoglutethimide, testolactone (Teslac), anastrozole (Arimidex), letrozole (Femara), exemestane (Aromasin), vorozole (Rivizor), formestane (Lentaron), fadrozole (Afema), 4-androstene-3,6,17trione (6-OXO), 1,4,6-androstatriene-3,17-dione (ATD), and 4-hydroxyandrostenedione.

[0097] Exemplary hormones include tamoxifen (Soltamox, Nolvadex), raloxifene (Evista), megestrol (Megace), leuprolide (Lupron, Lupron Depot, Eligard, Viadur), fulvestrant (Faslodex), letrozole (Femara), triptorelin (Trelstar LA, Trelstar Also include, but are not limited to, fluoxymesterone (Androxy, Halotestin), medroxyprogesterone (Provera, Depo-Provera), estramustine (Emcyt), flutamide (Eulexin), toremifene (Fareston), degarelix (Firmagon), nilutamide (Nilandron), abarelix (Plenaxis) or testolactone (Teslac).

[0098] Microtubule inhibitors or antimitotic agents or mitotic inhibitors are phase-specific agents that have activity against the microtubules of tumor cells during the M or mitosis phase of the cell cycle. Examples of microtubule inhibitors include, but are not limited to, diterpenoids and vinca alkaloids. Examples of diterpenoids include, but are not limited to, paclitaxel (e.g., TAXOL®) and its analog docetaxel (e.g., TAXOTERE®). Examples of vinca alkaloids include, but are not limited to, vinblastine (e.g., VELBAN®), vincristine (e.g., ONCOVIN®) and vinorelbine (e.g., NAVELBINE®).

[0099] Exemplary mitotic inhibitors also include, but are not limited to, paclitaxel (Taxol, Onxol, Abraxane), docetaxel (Taxotere), vincristine (Oncovin, Vincasar PFS), vinblastine (Velban), etoposide (Toposar, Etopophos, VePesid), teniposide (Vumon), ixabepilone (Ixempra), nocodazole, epothilones, vinorelbine (Navelbine), camptothecin (CPT), irinotecan (Camptosar), topotecan (Hycamtin), amsacrine, and lamellarin D (LAM-D).

[0100] Exemplary multikinase inhibitors include, but are not limited to, sorafenib (Nexavar), sunitinib (Sutent), BIBW 2992, E7080, Zd6474, PKC-412, motesanib, and AP24534.

[0101] Exemplary serine / threonine kinase inhibitors include, but are not limited to, ruboxistaurin, eril / easudil hydrochloride, flavopiridol, seliciclib (CYC202, Roscovitrine), SNS-032 (BMS-387032), Pkc412, bryostatin, KAI-9803, SF1126, VX-680, Azd1152, Arry-142886 (AZD-6244), SCIO-469, GW681323, CC-401, CEP-1347, and PD 332991.

[0102] Exemplary serine / threonine kinase inhibitors include rapamune (targets mTOR / FRAP1); deforolimus (targets mTOR); certican / everolimus (targets mTOR / FRAP1); AP23573 (targets mTOR / FRAP1); eril / fasudil hydrochloride (targets RHO); flavopiridol (targets CDK); seliciclib / CYC202 / roscovitrine (targets CDK); SNS-032 / BMS-387032 (targets CDK); ruboxistaurin (targets PKC); Pkc412 (targets PKC) These include, but are not limited to, bryostatin (targets PKC); KAI-9803 (targets PKC); SF1126 (targets PI3K); VX-680 (targets Aurora kinase); Azd1152 (targets Aurora kinase); Arry-142886 / AZD-6244 (targets MAP / MEK); SCIO-469 (targets MAP / MEK); GW681323 (targets MAP / MEK); CC-401 (targets JNK); CEP-1347 (targets JNK); and PD332991 (targets CDK).

[0103] Inhibitors of serine / threonine kinases also include MAP kinase cascade blockers, including blockers of Raf kinase (rafk), mitogen or extracellular regulated kinase (MEK) and extracellular regulated kinase (ERK); protein kinase C family member blockers, including blockers of PKC (alpha, beta, gamma, epsilon, mu, lambda, iota, zeta), IkB kinase family (IKKa, IKKb), PKB family kinases, AKT kinase family members and TGF beta receptor kinases. Inhibitors of serine / threonine kinases have also been described in J. Biochem. 126, 799 (1999), Biochem. Pharmacol. 60, 1101 (2000); Cancer Surveys 27, 41 (1996); Cancer Treatment Res. 78, 3 (1995); Bioorg. Med. Chem. Letters 10, 223 (2000); U.S. Patent No. 6,268,391; and Int. J. Cancer 88, 44 (2000).

[0104] Tyrosine kinase (also non-receptor tyrosine kinase) includes, but is not limited to, cSrc, Lck, Fyn, Yes, Jak, cAbl, FAK (focal adhesion kinase), Brutons tyrosine kinase and Bcr-Abl. Inhibitors of non-receptor tyrosine kinase are described in J.Hematotherapy Stem Cell Res.8,465(1999) and Annual Rev.Immunol.15,371(1997).

[0105] Exemplary tyrosine kinase inhibitors include erlotinib (Tarceva), gefitinib (Iressa), imatinib (Gleevec), sorafenib (Nexavar), sunitinib (Sutent), trastuzumab (Herceptin), bevacizumab (Avastin), rituximab (Rituxan), lapatinib (Tykerb), cetuximab (Erbitux), panitumumab (Vectibix), everolim. Also include, but are not limited to, temsirolimus (Afinitor), alemtuzumab (Campath), gemtuzumab (Mylotarg), temsirolimus (Torisel), pazopanib (Votrient), dasatinib (Sprycel), nilotinib (Tasigna), vatalanib (Ptk787, ZK222584), icotinib, CEP-701, SU5614, MLN518, XL999, VX-322, Azd0530, BMS-354825, SKI-606 CP-690, AG-490, WHI-P154, WHI-P131, AC-220 and AMG888.

[0106] Exemplary VEGF / VEGFR inhibitors include bevacizumab (Avastin), sorafenib (Nexavar), sunitinib (Sutent), ranibizumab, pegaptanib, and vandetinib, axitinib, brivanib alaninate ((S)-((R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]toluidinediaminetetraacetate). These include, but are not limited to, riazin-6-yloxy)propan-2-yl)2-aminopropanoate, also known as BMS-582664), motesanib (TST-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide), and pasireotide (also known as SO230).

[0107] Inhibitors of phosphotidyl inositol-3 kinase family members, including blockers of Pekinese, ATM, DNA-PK and Ku, may also be combined with the compounds of the present application. Such inhibitors are discussed in Curr. Opinion Immunol. 8, 412 (1996); Oncogene 17, 3301 (1998); Int. J. Biochem. Cell Biol. 29, 935 (1997); and Cancer Res. 60, 1541 (2000).

[0108] Exemplary kinase inhibitors include bevacizumab (targets VEGF), BIBW 2992 (targets EGFR and Erb2), cetuximab / Erbitux (targets Erb1), imatinib / Gleevic (targets Bcr-Abl, PDGFR and c-Kit), trastuzumab (targets Erb2), gefitinib / Iressa (targets EGFR), ranibizumab (targets VEGF), pegaptanib (targets VEGF), erlotinib / Tarceva (targets Erb1), nilotinib (targets Bcr-Abl), lapatinib (targets E rb1 and Erb2 / Her2), GW-572016 / lapatinib ditosylate (targets HER2 / Erb2), panitumumab / Vectibix (targets EGFR), vandetinib (targets RET / VEGFR), E7080 (multiple targets including RET and VEGFR), Herceptin (targets HER2 / Erb2), PKI-166 (targets EGFR), canertinib / CI-1033 (targets EGFR), sunitinib / SU-11 464 / Sutent (targets EGFR and FLT3), Matuzumab / Emd7200 (targets EGFR), EKB-569 (targets EGFR), Zd6474 (targets EGFR and VEGFR), PKC-412 (targets VEGR and FLT3), Vatalanib / Ptk787 / ZK222584 (targets VEGR), CEP-701 (targets FLT3), SU5614 (targets FLT3), MLN518 (targets FLT3), XL999 (targets FLT3) (targets FLT3), VX-322 (targets FLT3), Azd0530 (targets SRC), BMS-354825 (targets SRC), SKI-606 (targets SRC), CP-690 (targets JAK), AG-490 (targets JAK), WHI-P154 (targets JAK), WHI-P131 (targets JAK), sorafenib / nexavar (targets RAF kinase, VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-β, KIT, FLT-3 and RET),Also included are, but are not limited to, dasatinib / Sprycel (BCR / ABL and Src), AC-220 (targets Flt3), AC-480 (targets all HER proteins, "pan-HER"), motesanib diphosphate (targets VEGF1-3, PDGFR and c-kit), denosumab (targets RANKL and inhibits SRC), AMG888 (targets HER3) and AP24534 (multiple targets including Flt3).

[0109] Exemplary microtubule-targeting drugs include, but are not limited to, paclitaxel, docetaxel, vincristine, vinblastine, nocodazole, epothilones, and navelbine.

[0110] Exemplary topoisomerase poisons include, but are not limited to, teniposide, etoposide, adriamycin, camptothecin, daunorubicin, dactinomycin, mitoxantrone, amsacrine, epirubicin, and idarubicin.

[0111] Further topoisomerase toxic agents include topoisomerase II inhibitors, such as epipodophyllotoxins. Examples of epipodophyllotoxins include, but are not limited to, etoposide (VP-16, VePESID®) and teniposide (VM-26, VUMON®).

[0112] Exemplary taxanes or taxane derivatives include, but are not limited to, paclitaxel and docetaxol.

[0113] Antibody antagonists against receptor kinase ligand binding can also serve as inhibitors.Examples include Imclone C225 EGFR-specific antibody (see Cancer Treat.Rev.26,269(2000)), Herceptin(R)erbB2 antibody (see Breast Cancer Res.2,176(2000)) and 2CB VEGFR2-specific antibody (see Cancer Res.60,5117(2000)).

[0114] Antiangiogenic therapeutic agents, including non-receptor MEK angiogenesis inhibitors, may also be combined with the compounds of the present application, such as compounds of formula (I). Antiangiogenic agents such as those that inhibit the effects of vascular endothelial growth factor (e.g., bevacizumab [Avastin™]) and compounds that act by other mechanisms (e.g., linomide, an inhibitor of integrin ανβ3 function, endostatin and angiostatin).

[0115] SH2 / SH3 domain blockers can disrupt SH2 or SH3 domain binding in various enzymes or adaptor proteins, including PI3-Kp85 subunit, Src family kinases, adaptor molecules (She, Crk, Nek, Grb2) and Ras-GAP.SH2 / SH3 domain blockers as anticancer drugs are discussed in J.Pharm.Toxicol.Methods 34,125(1995).

[0116] Myo-inositol signaling inhibitors include, but are not limited to, phospholipase C blockers and myo-inositol analogues. Such signaling inhibitors are described in New Molecular Targets for Cancer Chemotherapy ed., Paul Workman and David Kerr, CRC press 1994, London. The inhibitor of Ras oncogene can include, but is not limited to, the inhibitor of farnesyltransferase, geranyl-geranyltransferase and CAAX protease, as well as antisense oligonucleotide, ribozyme and immunotherapy.Such inhibitors are discussed in J.Biomed.Sci.7,292(2000);Curr.Opin.Lipidology 9,99(1998);and BioChim.Biophys.Acta,1423,19(1989).

[0117] Additional exemplary common chemotherapeutic, antineoplastic or anti-proliferative agents include altretamine (Hexalen), isotretinoin (Accutane, Amnesteem, Claravis, Sotret), tretinoin (Vesanoid), azacitidine (Vidaza), bortezomib (Velcade), selinexor, asparaginase (Elspar), levamisole (Ergamisol), mitotane (Lysodren), procarbazine (Matula), and the like. ne), pegaspargase (Oncaspar), denileukin diftitox (Ontak), porfimer (Photofrin), aldesleukin (Proleukin), lenalidomide (Revlimid), bexarotene (Targretin), thalidomide (Thalomid), temsirolimus (Torisel), arsenic trioxide (Trisenox), verteporfin (Visudyne), mimosine (Leucenol), (1M tegafur-0.4M 5-chloro-2,4-dihydroxypyrimidine-1M potassium oxonate) and statins (e.g., lovastatin, atorvastatin, cerivastatin, fluvastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin).

[0118] Antiviral agents can include, but are not limited to, hepatitis B virus (HBV) inhibitors, hepatitis C virus (HCV) protease inhibitors, HCV polymerase inhibitors, HCV NS4A inhibitors, HCV NS5 A inhibitors, HCV NS5b inhibitors, and human immunodeficiency virus (HIV) inhibitors.

[0119] Antigens or adjuvants may include, but are not limited to, B7 costimulatory molecules, interleukin-2, interferon-y, GM-CSF, CTLA-4 antagonist, OX-40 / OX-40 ligand, CD40 / CD40 ligand, sargramostim, levamisole, vaccinia virus, Bacillus Calmette-Guerin (BCG), liposomes, alum, Freund's complete or incomplete adjuvant, detoxified endotoxin, mineral oil, surfactants such as lipolecithin, pluronic polyols, polyanions, peptides, and oil or hydrocarbon emulsions. In one embodiment, adjuvants such as aluminum hydroxide or aluminum phosphate may be added to increase the ability of the vaccine to elicit, enhance, or prolong an immune response. In one embodiment, additional materials such as cytokines, chemokines, and bacterial nucleic acid sequences such as CpGs, toll-like receptor (TLR) 9 agonists as well as further agonists for TLR2, TLR4, TLR5, TLR7, TLR8, TLR9 including lipoproteins, LPS, monophosphoryl lipid A, lipoteichoic acid, imiquimod, resiquimod, and even retinoic acid-inducible gene I (RIG-I) agonists such as poly I:C may also be used.

[0120] Cytotoxic agents may include, but are not limited to, arsenic trioxide (TRISENOX®), asparaginase (also known as L-asparaginase and Erwinia L-asparaginase, sold under the trade names ELSPAR® and KIDROLASE®).

[0121] Retinoids can include, but are not limited to, alitretinoin (sold under the trade name PANRETIN®), tretinoin (also known as all-trans retinoic acid, ATRA, sold under the trade name VESANOID®), isotretinoin (13-c / s-retinoic acid, sold under the trade names ACCUTANE®, AMNESTEEM®, CLARAVIS®, CLARUS®, DECUTAN®, ISOTANE®, IZOTECH®, ORATANE®, ISOTRET®, and SOTRET®), and bexarotene (sold under the trade name TARGRETIN®).

[0122] Chemotherapeutic agents include abiraterone acetate, altretamine, anhydrovinblastine, auristatin, bexarotene, bicalutamide, BMS 184476, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzenesulfonamide, bleomycin, N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-1-proline-t-butylamide, cachectin, cemadotin, chlorambucil, cyclophosphamide, 3',4'-didehydro-4'deoxy-8'-norvincaleukoblastine, docetaxol, doxetaxel, cyclophosphatase, amide, carboplatin, carmustine, cisplatin, cryptophycin, cyclophosphamide, cytarabine, dacarbazine (DTIC, DITC-Dome), dactinomycin, daunorubicin, decitabine dolastatin, doxorubicin (adriamycin), etoposide, 5-fluorouracil, finasteride, flutamide, hydroxyurea and hydroxyurea and taxanes, ifosfamide, liarozole, lonidamine, lomustine (CCNU), MDV3100, mechlorethamine (nitrogen mustard), melphalan, mibobroline isethionate, rhizoxin, sertenef, streptozocin, mitomycin, methotrexate, taxanes, nilutamide, nivolumab, onapristone, paclitaxel, pembrolizumab, prednimustine, procarbazine, RPR109881, stramstine phosphate, tamoxifen, tasonermin, taxol, tretinoin, vinblastine, vincristine, vindesine sulfate, vinflunine, CHOP (i.e., cyclophosphamide, doxorubicin, These include, but are not limited to, EPOH (i.e., a combination of etoposide, prednisolone, Oncovin and hydroxydaunorubicin), EPOCH (i.e., a combination of etoposide, prednisolone, Oncovin, cyclophosphamide and hydroxydaunorubicin) and R-EPOCH (i.e., a combination of rituximab, etoposide, prednisolone, Oncovin, cyclophosphamide and hydroxydaunorubicin).

[0123] Exemplary cytidine analogs include, but are not limited to, gemcitabine, azacytidine (eg, 5-azacytidine), and cytosine arabinoside (cytarabine, araC, Cytosar).

[0124] Additional therapeutic agents can include, but are not limited to, inhibitors of cell cycle signaling, pro-apoptotic agents, PARP inhibitors, checkpoint therapeutic agents, and immunomodulatory agents.

[0125] Cell cycle signaling inhibitors inhibit molecules involved in the control of cell cycle. A family of protein kinases called cyclin-dependent kinases (CDKs) and their interaction with a family of proteins called cyclins control progression through the eukaryotic cell cycle. Several inhibitors of cell cycle signaling are under development. For example, examples of cyclin-dependent kinases and inhibitors thereof, including CDK2, CDK4 and CDK6, are described in Exp.Opin.Ther.Patents 10,215(2000).

[0126] Therapeutic agents used in pro-apoptotic regimens (e.g., bcl-2 antisense oligonucleotides) may also be used in combination with the compounds of the present application, e.g., compounds of Formula (I).

[0127] As used herein, PARP inhibitors refer to a group of pharmacological inhibitors of the enzyme poly ADP ribose polymerase (PARP). Exemplary PARP inhibitors include, but are not limited to, olaparib (AZD-2281 by Astra Zeneca, Lynparza®), rucaparib (PF-01367338, Rubraca® by Clovis Oncology), niraparib (MK-4827, Zejula® by Tesaro), talazoparib (BMN-673), veliparib (ABT-888), olaparib (AZD-2281), olaparib TOPARP-A, rucaparib (PF-01367338, AG014699), CEP9722, E7016 (developed by Eisai), BGB-2901, iniparib (BSI201), 3-aminobezamide, and pamiparib.

[0128] Agents used in immunotherapy regimens may also be useful in combination with the compounds of the present application, such as compounds of formula (I). Immunotherapeutic approaches include ex vivo and in vivo approaches to increase the immunogenicity of patient / animal tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony-stimulating factor, approaches to decrease T cell energy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumor cell lines, and approaches using anti-idiotypic antibodies.

[0129] As used herein, checkpoint inhibitor therapy refers to a form of cancer treatment immunotherapy that targets immune checkpoints, which are key regulators of the immune system that stimulate or inhibit the action of the immune system and may allow tumors to protect themselves from attack by the immune system. Checkpoint therapy can block inhibitory checkpoints and restore immune system function.

[0130] As used herein, "immune-modulators" or "immunomodulators" refers to any substance, including monoclonal antibodies, that affects the immune system. Immunomodulators and immunomodulators can include, but are not limited to, checkpoint inhibitors. Immunomodulators can be used as antineoplastic agents for the treatment of cancer. For example, immunomodulators include, but are not limited to, anti-CTLA-4 antibodies, such as ipilimumab (YERVOY), and anti-PD-1 antibodies (Opdivo / nivolumab and Keytruda / pembrolizumab). Other immunomodulators include, but are not limited to, ICOS antibodies, OX-40 antibodies, PD-L1 antibodies, LAG3 antibodies, TIM-3 antibodies, 41BB antibodies, and GITR antibodies.

[0131] CTLA-4 and PD-1 pathways are important negative regulators of immune response. Activated T cells bind to antigen-presenting cells and upregulate CTLA-4, which inhibits T cell stimulation, IL-2 gene expression and T cell proliferation. PD-1 binds to activated T cells and suppresses T cell activation. PD-1 antagonists have demonstrated antitumor effects. CTLA-4 and PD-1 pathway antagonists that can be used in combination with the compounds of the present application include ipilimumab, tremelimumab, nivolumab, pembrolizumab, CT-011, AMP-224 and MDX-1106.

[0132] As used herein, PD-1 inhibitors and PD-L1 inhibitors refer to a group of checkpoint inhibitors or immune checkpoint inhibitors that are useful in the treatment of cancer. Both PD1 and PD-L1 are proteins present on the surface of cells. PD-1 and PD-L1 inhibitors act to inhibit the association of programmed death ligand (PD-L1) with its receptor, programmed cell death protein 1 (PD-1). Exemplary PD-1 and / or PD-L1 inhibitors include, but are not limited to, nivolumab (Opdivo), pembrolizumab (MK-3475 or lambrolizumab, Keytruda), atezolizumab (Tecentriq), avelumab (Bavencio), durvalumab (Imfinzi), tislelizumab, pidilizumab, AMP-224, AMP-514, PDR001, cemiplimab, BMS-936559 and CK-301.

[0133] In some embodiments, the PD-1 or PD-L1 inhibitor is nivolumab (Opdivo), pembrolizumab (MK-3475 or lambrolizumab, Keytruda), atezolizumab (Tecentriq), avelumab (Bavencio), durvalumab (Imfinzi), or tislelizumab.

[0134] Anti-PD-L1 antibodies and methods for making them are known in the art. Such antibodies to PD-L1 can be polyclonal or monoclonal, and / or recombinant, and / or humanized. Exemplary PD-L1 antibodies are disclosed in U.S. Patent Nos. 8,217,149, 8,383,796, 8,552,154, 9,212,224 and 8,779,108, and U.S. Patent Application Publication Nos. 20110280877, 20140341902 and 20130045201. Further exemplary antibodies to PD-L1 (also known as CD274 or B7-H1) and methods of use are disclosed in U.S. Patent Nos. 7,943,743, 8,168,179, and 7,595,048; WO 2014055897, WO 2016007235; and U.S. Patent Application Publication Nos. 20130034559 and 20150274835. In one embodiment, the anti-PD-L1 antibody is BMS-936559 (MDX-1105), MPDL3280A (RG7446), MEDI4736, TECENTRIQ™ (atezolizumab), YW243.55.S70, MPDL3280A, BMS-936559, MEDI4736 or MSB0010718C, or any of the V-cells described in WO2013019906. H and V L (e.g. SEQ ID NOs: 21 and 24 therein). Examples of anti-PD-L1 antibodies and methods for making them are also described in WO2010077634, WO2007005874, WO2011066389, WO2013019906, WO2010077634, U.S. Patent Nos. 8,217,149 and 8,383,796, and U.S. Patent Application Publication No. 2013034559.

[0135] PD-1 antagonist or PD-1 inhibitor refers to any chemical compound or biological molecule that blocks the binding of PD-L1 expressed on cancer cells to PD-1 expressed on immune cells (T cells, B cells or NKT cells), and preferably also blocks the binding of PD-L2 expressed on cancer cells to PD-1 expressed by immune cells. Alternative names or synonyms for PD-1 and its ligands include PDCD1, PD1, CD279 and SLEB2 for PD-1, PDCD1L1, PDL1, B7H1, B7-4, CD274 and B7-H for PD-L1; and PDCD1L2, PDL2, B7-DC, Btdc and CD273 for PD-L2. Human PD-1 amino acid sequence can be found in NCBI Locus No.: NP_005009. The human PD-L1 and PD-L2 amino acid sequences can be found at NCBI Locus No.: NP_054862 and NP_079515, respectively.

[0136] The PD-1 antagonist may include, but is not limited to, a monoclonal antibody (mAb) or an antigen-binding fragment thereof that specifically binds to PD-1 or PD-L1, preferably specifically binds to human PD-1 or human PD-L1. The mAb may be a human antibody, a humanized antibody, or a chimeric antibody and may include a human constant region. In some embodiments, the human constant region is selected from the group consisting of IgG1, IgG2, IgG3, and IgG4 constant regions, and in some embodiments, the human constant region is an IgG1 or IgG4 constant region. In some embodiments, the antigen-binding fragment is selected from the group consisting of Fab, Fab'-SH, F(ab')2, scFv, and Fv fragments.

[0137] Examples of mAbs that bind human PD-1 are described in U.S. Patent Nos. 7,488,802, 7,521,051, 8,008,449, 8,354,509, and 8,168,757, WO 2004004771, WO 2004072286, WO 2004056875, and U.S. Patent Publication No. 20110271358. In one embodiment, anti-human PD-1 mAbs useful as PD-1 antagonists include MK-3475, nivolumab, the humanized antibodies h409All, h409A16, and h409A17 described in WO 2008156712, and AMP-514.

[0138] Other PD-1 antagonists useful in any of the aspects and embodiments herein include immunoadhesins that specifically bind to PD-1, preferably human PD-1, such as fusion proteins that contain the extracellular or PD-1-binding portion of PD-L1 or PD-L2 fused to a constant region, such as the Fc region, of an immunoglobulin molecule. Examples of immunoadhesion molecules that specifically bind to PD-1 are described in WO2010027827 and WO2011066342. In one embodiment, the PD-1 antagonist includes AMP-224 (also known as B7-DCIg), which is a PD-L2-FC fusion protein and binds to human PD-1.

[0139] In one embodiment, the anti-PD-1 antibody is KEYTRUDA / pembrolizumab, disclosed in U.S. Pat. No. 8,168,757, or Opdivo / nivolumab (also known as BMS-936558, MDX-1106, and ONO-4538), disclosed in U.S. Pat. No. 8,008,449.

[0140] In one embodiment, the CTLA-4 antagonist is Yervoy (ipilimumab), which is described in US Pat. Nos. 6,984,720 and 7,605,238.

[0141] Further examples of other therapeutic agents (anti-cancer agents) for use in combination or simultaneous administration with the compounds of the present application, such as compounds of formula (I), include antibodies against ICOS. Agonist antibodies against ICOS or ICOS binding proteins are disclosed in WO 2012013004, WO 2014033327, WO 2016120789, US Patent Application Publication Nos. 20160215059 and 20160304610, and include, for example, SEQ ID NOs: 1-6 or their direct equivalents disclosed in WO 2016120789, V comprising an amino acid sequence at least 90% identical to SEQ ID NO: 7 disclosed in WO 2016120789, and V comprising an amino acid sequence at least 90% identical to SEQ ID NO: 7 disclosed in WO 2016120789. H domain, and / or V comprising an amino acid sequence that is at least 90% identical to SEQ ID NO:8 disclosed in WO2016120789. L It is a domain.

[0142] Further examples of other therapeutic agents (anti-neoplastic agents) for use in combination or co-administration with the compounds of the present application, e.g., compounds of formula (I), include antibodies against OXO40. Such antibodies are described in WO2012027328, WO2013028231 (e.g., V having a sequence at least 90% identical to SEQ ID NO: 10). L and / or V having a sequence at least 90% identical to SEQ ID NO:4 therein H (Antibodies including

[0143] Further examples of other therapeutic agents for use in combination or co-administration with the compounds of the present application, for example, compounds of formula (I), include immunostimulants.As used herein, immunostimulants refer to any agent that can stimulate the immune system.As used herein, immunostimulants include, but are not limited to, vaccine adjuvants such as Toll-like receptor agonists, T-cell checkpoint blockers such as mAbs against PD-1 and CTL4, and T-cell checkpoint agonists such as agonist mAbs against OX-40 and ICOS.

[0144] In one embodiment, the TLR agonists include Pam3Cys, a TLR 1 / 2 agonist; CFA, a TLR2 agonist; MALP2, a TLR2 agonist; Pam2Cys, a TLR2 agonist; FSL-I, a TLR-2 agonist; Hib-OMPC, a TLR-2 agonist; polyinosinic:polycytidylic acid (Poly I:C), a TLR3 agonist; polyadenosinic-polyuridylic acid (Poly AU), a TLR3 agonist; poly-L-lysine and carboxymethylcellulose stabilized polyinosinic-polycytidylic acid (Hilt Additional TLR agonists include, but are not limited to, aminoalkyl glucosaminide phosphate (AGP). An example of a naturally occurring TLR4 agonist is bacterial LPS. An example of a semi-synthetic TLR4 agonist is monophosphoryl lipid A (MPL). Additional AGP derivatives are disclosed in U.S. Patent Nos. 7,129,219, 6,525,028 and 6,911,434.

[0145] In one embodiment, the immunostimulant for use in combination with the compounds of the present application, for example, the compounds of formula (I), is a TLR4 agonist. In one embodiment, the TLR4 agonist is CRX-601, CRX-527 or CRX 547. Other embodiments include AGPs such as CRX 602 or CRX 526.

[0146] Furthermore, the compounds of the present application, for example compounds of formula (I), may be combined with other therapeutic agents that act to stimulate the immune system to respond to cancer antigens present on inactivated tumor cell(s) due to their adjuvant properties. Such adjuvants include, but are not limited to, lipids, liposomes, inactivated bacteria that induce innate immunity (e.g., inactivated or attenuated Listeria monocytogenes), compositions that mediate innate immune activation via (NOD)-like receptors (NLRs), retinoic acid-inducible gene-based (RIG)-I-like receptors (RLRs), and / or C-type lectin receptors (CLRs). Examples of PAMPs include lipoproteins, lipopolypeptides, peptidoglycans, zymosan, lipopolysaccharides, Neisserial porins, flagellins, profilins, galactoceramides, and muramyl dipeptides. Peptidoglycans, lipoproteins, and lipoteichoic acid are gram-positive cell wall components. Lipopolysaccharide is expressed by most bacteria, MPL being one example. Flagellin refers to a structural component of the bacterial flagellum secreted by pathogenic and commensal bacteria, and rt-galactosylceramide (rt.-GalCer) is an activator of natural killer T (NKT) cells. Muramyl dipeptide is a peptidoglycan motif with biological activity common to all bacteria.

[0147] Further examples of other therapeutic agents for use in combination or co-administration with the compounds of the present application, e.g., the compounds of Formula (I), include IDO inhibitors (e.g., epacadostat as disclosed in U.S. Pat. No. 8,034,953), CD73 inhibitors, and A2a and A2b adenosine antagonists.

[0148] In one embodiment, the compound may be administered in combination with one or more separate pharmaceutical agents, for example, a chemotherapeutic, immunotherapeutic or adjunctive therapeutic agent.

[0149] The compounds of the present application, such as compounds of formula (I), may be used in combination with at least one other therapeutic agent useful in the prevention or treatment of bacterial and viral infections.Examples of such agents include, but are not limited to, polymerase inhibitors such as those disclosed in WO2004037818 and WO2006045613; JTK-003, JTK-019, NM-283, HCV-796, R-803, R1728, R1626, and those disclosed in WO2006018725, WO2004074270, WO2003095441, U.S. Patent Application Publication No. 20050176701, WO2006020082, WO2005080388, those disclosed in WO 2004064925, WO 2004065367, WO 2003007945, WO 2002004425, WO 2005014543, WO 2003000254, EP 1065213, WO 2001047883, WO 2002057287, WO 2002057245; replication inhibitors such as acyclovir, famciclovir, ganciclovir, cidofovir, lamivudine and similar agents; HIV protease inhibitors protease inhibitors such as the HCV protease inhibitors BILN2061, VX-950, SCH503034 and similar agents; zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavudine, adefovir, adefovir dipivoxil, fozivudine, todoxil, emtricitabine, alovudine, amdoxovir, espiravir, serovar ... Nucleoside and nucleotide reverse transcriptase inhibitors such as rubucitabine, tenofovir disproxil fumarate, tenofovir alafenamide fumarate / hemifumarate and similar agents; non-nucleoside reverse transcriptase inhibitors such as nevirapine, delavirdine, efavirenz, loviride, immunocal, oltipraz, capravirine, TMC-278, TMC-125, etravirine, rilpivirine and similar agents (including agents with antioxidant activity such as immunocal, oltipraz).); entry inhibitors such as enfuvirtide (T-20), T-1249, PRO-542, PRO-140, TNX-355, BMS-806, 5-Helix, and similar agents; integrase inhibitors such as dolutegravir, elvitegravir, raltegravir L-870, 180, and similar agents; budding inhibitors such as PA-344 and PA-457, and similar agents; vicriviroc (Sch-C), Sch-D, TAK779, maraviroc (UK-4 27, 857), TAK449, and those disclosed in WO 2002074769, WO 20040054974, WO 2004055012, WO 2004055010, WO 2004055016, WO 2004055011, and WO 2004054581, and similar agents; pharmacokinetic enhancers such as cobicistat enhancer); neuraminidase inhibitors such as CS-8958, zanamivir, oseltamivir, peramivir and similar agents; ion channel blockers such as amantadine or rimantadine and similar agents; interfering RNA and antisense oligonucleotides, such as ISIS-14803 and similar agents; and antiviral agents with unknown mechanism of action, such as those disclosed in WO2005105761, WO2003085375, WO2006122011, ribavirin, and similar agents.

[0150] The compounds of the present application, e.g., compounds of formula (I), may be used in combination with at least one other therapeutic agent that may be useful in the treatment of Kaposi's sarcoma-associated herpesvirus infections (KSHV and KSHV-associated), including, but not limited to, chemotherapeutic agents such as bleomycin, vinblastine, vincristine, cyclophosphamide, prednisone, alitretinoin, and the like, and immunotherapeutic agents such as liposomal anthracyclines such as doxorubicin, daunorubicin, rituximab, tocilizumab, siltuximab, and others such as paclitaxel and rapamycin.

[0151] The compounds of the present application, e.g., compounds of formula (I), may be administered in combination with at least one other therapeutic agent that may be useful in the treatment of TB infection (Mycobacterium tuberculosis) and tularemia (Franciseiia tularensis), including, but not limited to, first-line oral agents isoniazid, rifampicin, pyrazinamide, ethambutol, streptomycin, rifabutin; injectables including kanamycin, amikacin, capreomycin, streptomycin; fluoroquinolones including levofloxacin, moxifloxacin, ofloxacin; oral bacteriostatic agents para-aminosalicylic acid, cycloserine, terizidone, thionamide, prothionamide; SQ-109, PNU-100480, rifapentine, linezolid, PA-824, AZD5847, gatifloxacin. It may be used in combination with drugs of unknown mechanism of action in the treatment of drug-resistant TB, including moxifloxacin, Sirturo (bedaquiline) delamanid (OPC-67683) and clofazimine, linezolid, amoxicillin / clavulanate thioacetazone imipenem / cilastatin high-dose isoniazid clarithromycin and ciprofloxacin.

[0152] The compounds of the present application, e.g., compounds of formula (I), may be administered in combination with at least one antimycobacterial agent (such as isoniazid (INH), ehambutol (Myambutol®), rifampin (Rifadin®) and pyrazinamide (PZA)), bactericidal antibiotics (such as rifabutin (Mycobutin®) or rifapentin (Priftin®)), aminoglycosides (Capreomycin®), fluoroquinolones (levofloxacin, moxifloxicin, ofloxacin, sirolimustine ... In some embodiments, the medicaments may be used in combination with cyclosporine (Sandimmune®), thioamides (ehionamide), cyclosporine (Sandimmune®), para-aminosalicylic acid (Paser®), cycloserine (Seromycin®), kanamycin (Kantrex®), streptomycin, viomycin, capreomycin (Capastat®), bedaquiline fumarate (Sirturo®), oxazolidinones (Sutezolid®), PN-100480 or delamanid (OPC-67683).

[0153] The compounds of the present application, such as compounds of formula (I), may be used in combination with at least one other therapeutic agent that may be useful in the treatment of chlamydia, including, but not limited to, azithromycin, doxycycline, erythromycin, levofloxacin, and ofloxacin.

[0154] The compounds of the present application, e.g., compounds of formula (I), may be used in combination with at least one other therapeutic agent that may be useful in the treatment of Plasmodium infection, including, but not limited to, chloroquine, atovaquone-proguanil, artemether-lumefantrine, mefloquine, quinine, quinidine, doxocycline, sindamycin, artesunate, and primaquine.

[0155] The compounds of the present application, e.g., compounds of formula (I), may be used in the treatment of amyotrophic lateral sclerosis (ALS), for example, in combination with glutamate blockers (Riluzole (Rilutek®)), quinidine (Nuedexta®), anticholinergics (amitriptyline®, Artane®, scopolamine patch (Transderm Scop®)), sympathomimetics (pseudoephedrine), mucolytics (guaifenesin) or analgesics (tramadol (Ultram®); ketorolac (Toradol®); morphine; or fentanyl patch (Duragesic®)).

[0156] The compounds of the present application, e.g., compounds of formula (I), can be used in combination with other agents such as corticosteroids (prednisone, methylprednisolone), interferon beta 1-A (Avonex®, Extavia®, Rebif®, Betaseron®), pegylated interferon beta-1A (Plegridy®), glatiramer acetate (Copaxone®); glatiramer acetate (Glatopa® - the generic equivalent of Copaxone) ; dimethyl fumarate (Tecfidera®); fingolimod (Gilenya®); teriflunomide (Aubagio®); dalfampridine (Ampyra®); daclizumab (Zinbryta); alemtuzumab (Lemtrada®); natalizumab (Tysabri®); or mitoxantrone hydrochloride (Novantrone®) may be used in the treatment of multiple sclerosis.

[0157] The compounds of the present application, such as compounds of formula (I), may be used in combination with one or more vaccines or immunogenic antigens useful in the prevention or treatment of viral infections. Such vaccines or immunogenic antigens include, but are not limited to, pathogen-derived proteins or particles, such as attenuated viruses, viral particles and viral proteins that are typically used as immunogenic agents. Examples of viruses and viral antigens include, but are not limited to, poliovirus, coronaviruses and coronaviruses, rhinoviruses (all subtypes), adenoviruses (all subtypes), hepatitis A, hepatitis B, hepatitis C, hepatitis D, human papillomaviruses (including all subtypes), rabies virus, human T-cell lymphotropic virus (including all subtypes), rubella virus, mumps virus, coxsackievirus A (all subtypes), Cosackievirus B (including all subtypes), human enteroviruses, herpes viruses including cytomegalovirus, Epstein-Barr virus, human herepes virus (all subtypes), herpes simplex virus, varicella zoster virus, human immunodeficiency virus (HIV) (all subtypes), Epstein-Barr virus, reovirus ( all subtypes), Filoviruses (all strains) including Marburg virus and Ebola virus, Lymphocytic choriomeningitis virus, Arenaviruses including Lassa virus, Junin virus and Machupo virus, Arboviruses including West Nile virus, Dengue virus (all serotypes), Zika virus, Colorado tick fever virus, Sindbis virus, Togaviridae, Flaviviridae, Bunyaviridae, Reoviridae, Rhabdoviridae, Orthomyxoviridae, Poxviruses including Orthopoxviruses (Volavirus, Monkeypox virus, Vaccinia virus, Cowpox virus), Yatapoxviruses (Tanapox virus, Yabasa monkey tumor virus), Parapoxvirus, Morsipoxvirus, Yellow fever, Hantaviruses including Hantan, Seoul, Dobrava, Sin Nombre, Puumala and Dobrava-like Saaremaa,These include human parainfluenza viruses and influenza viruses (all types), HlN1 influenza and swine influenza viruses, respiratory syncytial viruses (all subgroups), rotaviruses including human rotaviruses A-E, bovine rotavirus, rhesus rotavirus, polyomaviruses including simian virus 40, JC virus, BK virus, coltivirus, eyak virus, calci virus, and parvoviridae including dependovirus, parvovirus, and erythrovirus.

[0158] The compounds of the present application, e.g., compounds of formula (I), may be used in combination with at least one other therapeutic agent that may be useful in the prevention or treatment of viral infections, e.g., immunotherapy (e.g., interferons or other cytokines / chemokines, cytokine / chemokine receptor modulators, cytokine agonists or antagonists and similar agents); and anti-inflammatory agents, such as therapeutic vaccines, anti-fibrotic agents, corticosteroids or NSAIDs (non-steroidal anti-inflammatory drugs) and similar agents.

[0159] The compounds of the present application, e.g., compounds of formula (I), may be used in combination with other anti-inflammatory agents, including oral or topical corticosteroids, anti-TNF agents, 5-aminosalicyclic acid and mesalamine preparations, hydroxychloroquine, thiopurines, methotrexate, cyclophosphamide, cyclosporine, calcineurin inhibitors, mycophenolic acid, mTOR inhibitors, JAK inhibitors, Syk inhibitors, anti-IL6 biological agents, anti-IL1 agents, anti-IL17 biological agents, anti-CD22, anti-integrin agents, anti-IFNa, anti-CD20 or CD4 biological agents, and other cytokine inhibitors or biological agents against T cell or B cell receptors or interleukins.

[0160] The compounds of the present application, e.g., compounds of formula (I), may be used as an adjunct to corticosteroids (prednisolone (Delatsone®), Orapred, Millipred, Omnipred, Econopred, Flo-Pred, etc.), immunosuppressants (methotrexate (Rhuematrex®, Trexall®), dexamethasone (Decadron®, Solurex®), mycophenolate mofetil (Cellcept®), Tacrolimus®, Sirolimus®), B-cell therapy (belimumab (Benlysta®), B-cell inhibitors (Atacicept®, Apratuzumab®), etc.), in the treatment of systemic lupus erythematosus and related lupus disorders. (R) (anti-CD22), SBI-087 (anti-CD20), anti-BAFF antibodies (LY2127399, A623), Velcade(R)), azathioprine (Azasan(R), Imuran(R)), triamcinolone (Clinacort(R), Kenalog-10(R)), hydroxychloroquine (Plaquenil(R)), thalidomide (Immunoprin(R), Contergan(R)), immunoglobulin therapy (HyQiva(R), Flebogamma(R), Gamunex(R), Privigen(R), Gammagard(R)), anti-interferon-alpha therapy (Rontalizumab(R), Sifalimumab(R), AGS-009(R), IFN Kinoid), TLR7 and TLR9 blockers (IMO-3100), anti-cytokine therapy (anti-IL6 (CNTO-136), anti-interferon-gamma (AMG811), immunomodulatory therapy (Lupuzor™, Abatacept, Orencia®, AMG557, Laquinimod, Paquinimod, Leflunomide, anti-ICOS (Medi-570), anti-CD40 ligand antibody (CDP7657)), and / or platelet aggregation inhibitors (aspirin).

[0161] The compounds of the present application, e.g., compounds of formula (I), may be used in combination with alkylating agents (cyclophosphamide, Cytoxan®), anti-rheumatic anti-CD20 antibodies (Rituxan®, Rituximab®) and anti-TNF inhibitors (Etanrcept®), for example, in the treatment of vasculitis and diseases involving inflammation of small or medium sized blood vessels.

[0162] Compounds of the present application, such as compounds of formula (I), may be used in combination with ixekizumab, tildrakizumab (MK-3222) or secukinumab (AIN457), for example, in the treatment of psoriasis.

[0163] The second agent may be selected from an inhaled corticosteroid, a long-acting beta agonist, a combination of an inhaled corticosteroid and a long-acting beta agonist, a short-acting beta agonist, a leukotriene modifier, an anti-IgE, a methylxanthine bronchodilator, a mast cell inhibitor, and a long-acting muscarinic antagonist. The compounds of the present application may be used, for example, in the treatment of asthma in combination with inhaled corticosteroids (ICS), such as fluticasone proprionate (Flovent®), beclomethasone dipropionate (QVAR®), budesonide (Pulmicort®), trimcinolone acetonide (Azmacort®), flunisolide (Aerobid®), mometasone furoate (Asmanex®, Twisthaler®), or ciclesonide (Alvesco®)), long-acting beta agonists (LABA), such as formoterol fumarate (Foradil®), salmeterol xinafoate (Serevent®), combinations of ICS and LABA (fluticasone furoate and vilanterol (Breo®)), short-acting beta agonists (SABAs) such as Ellipta®), formoterol / budesonide inhalation (Symbicort®), beclomethasone dipropionate / formoterol (Inuvair®) and fluticasone propionate / salmeterol (Advair®); albuterol sulfate (ProAir®, Proventil HFA®, Ventolin HFA®, AccuNeb® Inhalation Solution); levalbuterol tartrate (Xopenex®);HFA), ipratropium bromide / albuterol (Combivent®Respimat®), ipratropium bromide (Atrovent®HFA), leukotriene modifiers (such as montelukast sodium (Singulair®), zafirlukast (Accolate®) or zileuton (Zyflo®)), and anti-IgE (such as omalizumab (Xolair®)), methylxanthine bronchodilators (theophylline (Accurbron®, Aerolate®, Aquaphyllin®, Asbron®, Bronkodyl®, Duraphyl®, Elixicon®, Elixomin®, Elixophyllin®, Labid®, Lanophyllin®, Quibron-T®) , So-Bid®, So-Phyllin®, Somophyllin®, Sustaire®, Synophylate®, T-Phyll®, Theo-24®, Theo-Dur®, Theobid®, Theochron®, Theoclear®, Theolair®, Theolixir®, Theophyl®, Theovent®, Uni-dur®, Uniphyl®, etc.), mast cell inhibitors (such as cromulyn sodium (Nasalcrom®) and nedocromil sodium (Tilade®)), long-acting muscarinic antagonists (LAMAs, such as mometasone furoate / formoterol fumarate dihydrate (Dulera®)).

[0164] Secondary agents include protein tyrosine kinase inhibitors (masitinib), CRTH2 / D-prostanoid receptor antagonists (AMG 853), indacaterol (Arcapta® Neohaler®), epinephrine inhalation aerosol (E004), fluticasone furoate / fluticasone propionate, binanterol inhalation / fluticasone furoate powder (Relovair®), fluticasone propionate / eformoterol fumarate anhydrous (Flutiform®), reslizumab, and salbutamol dry. Also included may be, but are not limited to, powder inhalation, tiotropium bromide (Spiriva® HandiHaler®), formoterol / budesonide (Symbicort® SMART®), fluticasone furoate (Veramyst®), Vectura's VR506, lebrikizumab (RG3637), combined phosphodiesterase (PDE)-3 and (PDE)-4 inhibitors (RPL554).

[0165] The second agent may also include, but is not limited to, a combination of a long-acting beta agonist, a long-acting inhaled anticholinergic or muscarinic antagonist, a phosphodiesterase inhibitor, an inhaled corticosteroid, a long-acting beta agonist, a short-acting beta agonist, and an inhaled corticosteroid. For example, in the treatment of COPD, the compounds of the present application are used in combination with LABAs (salmeterol xinafoate (Serevent), umeclidinium / vilanterol (Anoro Ellipta®), umeclidinium (Incruse®), ketamine (Ezetamine ... Ellipta®), aformoterol tartrate (Brovana®), formoterol fumarate inhalation powder (Foradil®), indacterol maleate (Arcapta®, Neohaler®) or fluticasone propionate / eformoterol fumarate dehydrate (Flutiform®), long-acting inhaled anticholinergic or muscarinic antagonists such as tiotropium bromide (Spiriva®), and aclidinium bromide (Tudorza®, Pressair®), phosphodiesterase (PDE-r) inhibitors (such as roflumilast, Daliresp®), ICS / LABA combinations (fluticasone furoate and vilanterol (Breo Ellipta®), fluticasone propionate / salmeterol (Advair®), budesonide / formoterol (Symbicort®), mometasone / formoterol (Dulera®), ipratropium bromide / albuterol sulfate (Duoneb®, Atrovent®), albuterol / ipratropium (Combivent Respimat®)), SABAs (ipratropium bromide (Atrovent®) and albuterol sulfate (ProAir®, Proventil®)), and ICS (such as budesonide (Pulmicort®) and fluticasone propionate (Flovent®)), beclomethasone dipropionate (QVAR®).

[0166] Other agents that may be suitable for use in combination therapy with the compounds of the present disclosure, e.g., compounds of Formula (I), e.g., in the treatment of COPD, include, but are not limited to, SCH527123 (CXCR2 antagonist), glycopronium bromide ((NVA237) Seebri® Breezhaler®), glycopyrronium bromide and indacaterol maleate ((QVA149) Ultibro® Breezhaler®), glycopyrrolate and formoterol fumarate (PT003), indacaterol maleate (QVA149), olodaterol (Striverdi® Respimat®), tiotropium (Spiriva®) / olodaterol (Striverdi® Respimat®), and aclidinium / formoterol inhalation.

[0167] The second agent can include, but is not limited to, oral corticosteroids, antithymocyte globulin, thalidomide, chlorambucil, calcium channel blockers, topical emollients, ACE inhibitors, serotonin reuptake inhibitors, endothelin-1 receptor inhibitors, antifibrotic agents, proton pump inhibitors or imatinib, ARG201, and tocilizumab.

[0168] The compounds of the present application, e.g., compounds of formula (I), can be used as an alternative to oral corticosteroids (prednisolone (Delatsone®), Orapred, Millipred, Omnipred, Econopred, Flo-Pred, etc.), immunosuppressants (methotrexate (Rhuematrex®, Trexall®), cyclosporine (Sandimmune®), antithymocyte globulin (Atgam®), mycophenolate mofetil (CellCept®), cyclophosphamide (Cytoxan®), cyclosporine (Cyclosporin ... R)), FK506 (tacrolimus), thalidomide (Thalomid(R)), chlorambucil (Leukeran(R)), azathioprine (Imuran(R), Azasan(R)), etc.), calcium channel blockers (nifedipine (Procardia(R), Adalat(R)) or nicardipine (Cardene(R)), topical emollients (nitroglycerin ointment), ACE inhibitors (lisinopril (Zestril(R), Prinivil(R)), diltaizem (Cardizem(R), Cardizem SR(R), Cardizem CD(R), Cardia(R), Dilacor(R), Tiazac(R)), serotonin reuptake inhibitors (such as fluoxetine (Prozac(R))), endothelin-1 receptor inhibitors (such as bosentan (Tracleer(R)) or epoprostenol (Flolan(R), Veletri(R), Prostacyclin(R))), antifibrotic agents (such as colchicine (Colcrys(R)), para-aminobenzoic acid (PABA), dimethyl sulfoxide (DMSO) and D-penicillamine ( Cuprimine(R), Depen(R), interferon alpha and interferon gamma (INF-g), proton pump inhibitors (omeprazole (Prilosec(R)), metoclopramide (Reglan(R)), lansoprazole (Prevacid(R)), esomeprazole (Nexium(R)), pantoprazole (Protonix(R)), rabeprazole (Aciphex(R)), etc.) or imatinib (Gleevec(R)) ARG201 (arGentisIt may be used in combination with rituximab (Benlysta®), belimumab (Benlysta®), and tocilizumab (Actema®).

[0169] The compounds of the present application, e.g., compounds of formula (I), may be used in combination with anti-rheumatic agents (hydroxychloroquine and Plaquenil®, Ridaura®, Kineret®), cholinergic agonists (Salagen®, Evoxac®), JAK inhibitors (Xelijanz®) and anti-TNF treatments (Remicade®, Humira®, Enbrel®, Cimzia®, Simponi®), e.g., in the treatment of Sjogren's syndrome.

[0170] The second agent can include, but is not limited to, ciliary neurotrophic growth factor or gene transfer agent.For example, in the treatment of retinitis pigmentosa, the compound of the present application can be used in combination with ciliary neurotrophic growth factor (NT-501-CNTF) or gene transfer agent UshStat (R).

[0171] The second agent can include, but is not limited to, a trivalent (IIV3) inactivated influenza vaccine, a quadrivalent (IIV4) inactivated influenza vaccine, a trivalent recombinant influenza vaccine, a quadrivalent live attenuated influenza vaccine, an antiviral agent, or an inactivated influenza vaccine. For example, in treating influenza, the compounds of the present application, e.g., compounds of formula (I), can be used in combination with trivalent (IIV3) inactivated influenza vaccines (Afluria®, Fluarix®, Flucelvax®, FluLaval®, Fluvirin®, Fluzone®, etc.), quadrivalent (IIV4) inactivated influenza vaccines (Fluarix® Quadrivalent, Flulaval® Quadrivalent, Fluzone® Quadrivalent, etc.), tri ... In some embodiments, the vaccine may be used in combination with a tetravalent recombinant influenza vaccine (such as FluBlok®), a tetravalent live attenuated influenza vaccine (such as FluMist® Quadrivalent), an antiviral (such as oseltamivir (Tamiflu®), zanamivir (Relenza®), rimantadine (Flumadine®) or amantadine (Symmetrel®)) or Fluad®, Fludase, FluNhance®, Preflucel or VaxiGrip®.

[0172] The compounds of the present application, e.g., compounds of formula (I), may be used in combination with antibiotics, such as β-lactam cephalosporins (Duricef®, Kefzol®, Ancef®, Biocef®, etc.), nafcillin (Unipen®), sulfonamides (sulfamethoxazole and trimethoprim (Bacrim®, Septra®, etc.), sulfasalazine (Azulfidine®), acetylsulfisoxazole (Gantrisin®), or vancomycin (Vancocin®), for example, in the treatment of staphylococcal infections.

[0173] The second agent can include, but is not limited to, a topical immunomodulator or calcineurin inhibitor, a topical corticosteroid, an oral corticosteroid, interferon gamma, an antihistamine, or an antibiotic. The compounds of the present application, e.g., compounds of formula (I), can be used in combination with topical immunomodulators or calcineurin inhibitors, such as pimecrolimus (Elidel®) or tacrolimus ointment (Protopic®), topical corticosteroids (hydrocortisone (Synacort®, Westcort®), betamethasone (Diprolene®), flurandrenolide (Cordan®), fluticasone (Cutiva®), cyclosporine (Cucurbit ... te(R)), triamcinolone (Kenalog(R)), fluocinonide (Lidex(R)) and clobetasol (Temovate(R))), oral corticosteroids (hydrocortisone (Cortef(R)), methylprednisolone (Medrol(R)) or prednisolone (Pediapred(R), Prelone(R)), immunosuppressants (cyclosporine (Neoral(R)) or interferon gamma (Alferon(R)) N(R), Infergen(R), Intron A, Roferon-A(R) etc.), antihistamines (for itching, Atarax(R), Vistaril(R), Benadryl(R) etc.), antibiotics (such as the penicillin derivatives flucloxacillin (Floxapen(R)) or dicloxacillin (Dynapen(R)), erythromycin (Eryc(R), T-Stat(R), Erythra-Derm(R) etc.), non-steroidal immunosuppressants (such as azathioprine (Imuran(R), Azasan(R)), methotrexate (Rhuematrex(R), Trexall(R)), cyclosporine (Sandimmune(R)) or mycophenolate mofetil (CellCept(R))).

[0174] In another embodiment, the second agent can include, but is not limited to, a cytokine, such as G-CSF (granulocyte colony stimulating factor). In another embodiment, the compounds of the present invention, e.g., compounds of formula (I), or a pharmaceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof, can be administered in combination with radiation therapy. Radiation therapy can also be administered in combination with the compounds of the present invention, e.g., compounds of formula (I), and another chemotherapeutic agent described herein as part of a multi-drug therapy. In yet another embodiment, the compounds of the present invention, e.g., compounds of formula (I), or a pharmaceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof, can be administered in combination with CMF (cyclophosphamide, methotrexate, and 5-fluorouracil), CAF (cyclophosphamide, adriamycin, and 5-fluorouracil), AC (adriamycin, and cyclophosphamide), FEC (5-fluorouracil, epirubicin, and cyclophosphamide), ACT, or ATC (adriamycin, cyclophosphamide, methotrexate, and 5-fluorouracil), or other chemotherapeutic agents. The drug may be administered in combination with standard chemotherapy combinations such as, but not limited to, rituximab, Xeloda (capecitabine), cisplatin (CDDP), carboplatin, TS-1 (tegafur, gimestat and otastat potassium in a 1:0.4:1 molar ratio), camptothecin-11 (CPT-11, Irinotecan or Camptosar™) or CMFP (cyclophosphamide, methotrexate, 5-fluorouracil and prednisone).

[0175] In some embodiments, the compound of the present invention, for example the compound of formula (I), or its pharma- ceutically acceptable salt, prodrug, metabolite, polymorph or solvate, can be administered with an inhibitor of enzymes such as receptor or non-receptor kinases.The receptor kinase and non-receptor kinase of the present invention is, for example, tyrosine kinase or serine / threonine kinase.The kinase inhibitor of the present invention is a small molecule, polynucleic acid, polypeptide or antibody.

[0176] Pharmaceutical Compositions The application also provides a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof, in combination with at least one pharma- ceutically acceptable excipient or carrier.

[0177] A "pharmaceutical composition" is a formulation containing a compound of the present application in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or unit dosage form. The unit dosage form can be in any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler, or a vial. The amount of active ingredient (e.g., a formulation of the disclosed compound or its pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative) in a unit dose of the composition is an effective amount and varies according to the particular treatment involved. Those skilled in the art will understand that it is sometimes necessary to make routine modifications to the dosage depending on the age and condition of the patient / animal. The dosage also depends on the route of administration.

[0178] A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, intranasal, etc. Dosage forms for topical or transdermal administration of the compounds of the present application include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharma- ceutically acceptable carrier and any required preservatives, buffers, or propellants.

[0179] As used herein, the phrase "pharmacologically acceptable" refers to compounds, materials, compositions, carriers, and / or dosage forms that are suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, within the scope of sound medical judgment, commensurate with a reasonable benefit / risk ratio.

[0180] "Pharmaceutically acceptable excipient" means an excipient that is generally safe, non-toxic, and not biologically or otherwise undesirable, and is useful in preparing pharmaceutical compositions, and includes excipients that are acceptable for human pharmaceutical use as well as veterinary use. As used in the specification and claims, "pharmaceutically acceptable excipient" includes both one and more than one such excipient.

[0181] The pharmaceutical composition of the present application is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical) and transmucosal administration. Solutions or suspensions used for parenteral, intradermal or subcutaneous application can contain the following components: a sterile diluent such as water for injection, saline, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for adjusting isotonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases such as hydrochloric acid or sodium hydroxide. Parenteral preparations can be enclosed in glass or plastic ampoules, disposable syringes or multiple dose vials.

[0182] The compounds or pharmaceutical compositions of the present application can be administered to a subject by many well-known methods currently used for chemotherapy treatment.For example, for the treatment of cancer, the compounds of the present application can be directly injected into a tumor, injected into the bloodstream or body cavity, taken orally, or applied through the skin using a patch.The dose selected should be sufficient to constitute an effective treatment, but not so high as to cause unacceptable side effects.The disease state (e.g., cancer, pre-cancer, etc.) and the health condition of the patient / animal should preferably be closely monitored during and for a reasonable period after treatment.

[0183] The term "therapeutically effective amount" as used herein refers to the amount of pharmaceutical agent to treat, improve or prevent a specified disease or condition, or to show a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The exact effective amount for a subject depends on the subject's weight, size and health; the nature and extent of the condition; and the therapeutic agent or combination of therapeutic agents selected for administration. The therapeutically effective amount for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.

[0184] For any compound, the therapeutically effective amount can be estimated first in cell culture assays, for example in neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. Animal models can also be used to determine appropriate concentration ranges and routes of administration. Such information can then be used to determine useful doses and routes of administration in humans. Therapeutic / prophylactic efficacy and toxicity can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, ED 50 (the dose that is therapeutically effective in 50% of the population) and LD 50 (the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD 50 / ED 50 Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage can vary within this range depending on the dosage form used, the sensitivity of the patient / animal, and the route of administration.

[0185] Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors that may be considered include the severity of the disease state, the general health of the subject, the age, weight and sex of the subject, diet, time and frequency of administration, drug(s) combination, reaction sensitivities, and tolerance / response to treatment. Long-acting pharmaceutical compositions may be administered once every 3-4 days, once a week, or once every two weeks, depending on the half-life and clearance rate of the particular formulation.

[0186] Pharmaceutical compositions containing the active compounds of the present application (i.e., compounds of formula (I)) can be manufactured in a generally known manner, for example, by conventional mixing, dissolving, levigating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. Pharmaceutical compositions can be formulated in a conventional manner using one or more pharma- ceutically acceptable carriers that contain excipients and / or auxiliaries that facilitate the processing of the active compounds into pharma- ceutically usable preparations. Of course, the appropriate formulation depends on the selected route of administration.

[0187] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringability exists. The composition must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, liquid polyethylene glycol, and the like), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it is preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

[0188] Sterile injectable solution can be prepared by incorporating the active compound in the required amount in suitable solvent with one or combination of the above-listed components as required, followed by sterilization by filtration.Generally, dispersion is prepared by incorporating active compound in sterile vehicle that contains basic dispersion medium and other components required from above-listed.In the case of sterile powder for preparing sterile injectable solution, the preparation method is vacuum drying and freeze-drying, which produces powder of active ingredient plus any additional desired components from their solution that has been previously sterilized and filtered.

[0189] Oral compositions generally contain an inert diluent or edible pharma- ceutically acceptable carrier. Oral compositions can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, active compounds can be incorporated with excipients and used in the form of tablets, troches or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, in which the compound in the fluid carrier is applied orally, swished in the cheek, and expectorated or swallowed. Pharmaceutically compatible binding agents and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring such as peppermint, methyl salicylate or orange flavoring.

[0190] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

[0191] Systemic administration can also be by transmucosal or transdermal means.For transmucosal or transdermal administration, a penetrant suitable for the barrier to be permeated is used in the formulation.Such penetrants are generally known in the art, and for example, for transmucosal administration, include surfactants, bile salts and fusidic acid derivatives.Transmucosal administration can be achieved by using nasal sprays or suppositories.For transdermal administration, active compound is formulated into ointments, salves, gels or creams generally known in the art.

[0192] The active compound may be prepared with a pharma- ceutically acceptable carrier that protects the compound from rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable biocompatible polymers, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid, may be used. Methods for preparing such formulations will be clear to those skilled in the art. Materials may also be commercially available from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions, including liposomes targeted to infected cells with monoclonal antibodies against viral antigens, may also be used as pharma-ceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

[0193] For ease of administration and uniformity of dosage, it is particularly advantageous to formulate oral or parenteral compositions in dosage unit form.Dosage unit form as used herein refers to a physically separate unit suitable as a unitary dosage for the subject to be treated, each unit containing a predetermined amount of active compound calculated to produce desired therapeutic effect in association with required pharmaceutical carrier.The specification of dosage unit form of this application is determined and directly depends on the unique characteristics of active compound and the specific therapeutic effect to be achieved.

[0194] In therapeutic applications, the dosage of the pharmaceutical composition used according to the application will vary depending on the agent, the age, weight and clinical condition of the recipient patient / animal, and the experience and judgment of the clinician or practitioner administering the treatment, among other factors influencing the selected dosage. In general, the dosage should be sufficient to slow, and preferably regress, the growth of the tumor, and also preferably cause complete regression of the cancer. The dosage may range from about 0.01 mg / kg / day to about 5000 mg / kg / day. An effective amount of a pharmaceutical agent is an amount that provides an objectively identifiable improvement as noted by a clinician or other qualified observer. For example, tumor regression in a patient / animal may be measured with reference to the diameter of the tumor. A decrease in the diameter of the tumor indicates regression. Regression may also be indicated by failure of the tumor to recur after treatment has been stopped. As used herein, the term "dosage effective manner" refers to an amount of an active compound that produces a desired biological effect in a subject or cell.

[0195] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0196] It should be understood that all references to pharma- ceutically acceptable salts include the solvent addition forms (solvates) or crystal forms (polymorphs), as defined herein, of the same salt.

[0197] The compounds of the present application can also be prepared as esters, such as pharma- ceutically acceptable esters. For example, a carboxylic acid function in a compound can be converted to its corresponding ester, such as methyl, ethyl, or other ester. Also, an alcohol group in a compound can be converted to its corresponding ester, such as acetate, propionate, or other ester.

[0198] The compound or its pharmaceutically acceptable salt is administered orally, nasally, transdermally, pulmonary, inhalation, buccal, sublingual, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally.In one embodiment, the compound or its pharmaceutically acceptable salt is administered orally.Those skilled in the art will recognize the advantages of certain administration routes.

[0199] The dosage regimen utilizing the compound is selected according to a variety of factors, including the type, species, age, weight, sex, and condition of the patient / animal; the severity of the condition being treated; the route of administration; the renal and hepatic function of the patient / animal; and the particular compound being used, or a pharma- ceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog, or derivative thereof. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progression of the condition.

[0200] Techniques for formulation and administration of the compounds disclosed in this application are described in Remington: The Science and Practice of Pharmacy, 1999. th edition, Mack Publishing Co., Easton, PA (1995). In one embodiment, the compounds described herein and their pharma- ceutically acceptable salts are used in pharmaceutical preparations in combination with pharma- ceutically acceptable carriers or diluents. Suitable pharma-ceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compounds or their pharma-ceutically acceptable salts are present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage within the range described herein.

[0201] All percentages and ratios used herein are by weight unless otherwise specified. Other features and advantages of the present application are apparent from the different examples. The examples provided illustrate different components and methodologies useful in carrying out the present application. The examples do not limit the claimed application. Based on the present application, a person skilled in the art can identify and use other components and methodologies useful in carrying out the present application.

[0202] [Example] The present application is further illustrated by the following examples and synthetic schemes, which should not be construed as limiting the scope or spirit of the present application to the specific procedures described herein. It should be understood that the examples are provided to illustrate certain embodiments, and that no limitation to the scope of the present application is intended thereby. It should be further understood that the present application is entitled to various other embodiments, modifications thereof, and equivalents thereof that may occur to those skilled in the art without departing from the spirit of the present application and / or the scope of the appended claims.

[0203] Studies on the combination of compounds of formula I and venetoclax Studies in primary CLL cells demonstrated that there was a significantly decreased viability of cells treated with venetoclax compared to vehicle (p<0.0001), and the addition of ibrutinib or nemtabrutinib increased cytotoxicity by 6 and 10%, respectively, compared to venetoclax alone (Figure 1A). Primary CLL cells were treated with DMSO, venetoclax (5 nM), nemtabrutinib (1 μM), ibrutinib (1 μM) or the combination. Ibrutinib was washed out after 1 h, and the total incubation time was 24 h. Cell viability was assessed by flow cytometry after Annexin V / PI staining. Data are normalized to DMSO control. Raw data were analyzed using a linear mixed effects model and p values ​​were adjusted for multiple comparisons using Tukey's method (*, p ≤ 0.05, **, p ≤ 0.01, ***, p ≤ 0.001).

[0204] The effect of combining venetoclax with BTKi on BCR signaling can be seen in Figure 1B. Primary CLL cells were treated with DMSO, venetoclax (5 nM), nemtabrutinib (1 μM), ibrutinib (1 μM) or the combination. Ibrutinib was washed out after 1 h, and the total incubation time was 24 h. After stimulating cells with 10 μg of plate-bound anti-IgM for 15 min, total cell lysates were collected and analyzed using SDS-PAGE.

[0205] In Figures 1C-1E, all immunoblots of primary CLL patient samples were quantified using densitometry software (AlphaView). Protein levels normalized to GAPDH loading control (Figure 1C: pBTK, Figure 1D: pERK, Figure 1E: MCL-1) are reported as fold change relative to vehicle control. Raw data normalized to GAPDH loading control were analyzed using a linear mixed-effects model, with p-values ​​adjusted for multiple comparisons using Tukey's method (*, p ≤ 0.05, **, p ≤ 0.01, ***, p ≤ 0.001).

[0206] Both ibrutinib and nemtabrutinib are BTK inhibitors. Y223Nemtabrutinib significantly inhibited autophosphorylation of VENCLEXTA (ibrutinib vs stimulated vehicle p=0.0021, nemtabrutinib vs stimulated vehicle p=0.0024), and this inhibition was not affected by the addition of venetoclax (Figure 1C). ERK phosphorylation was inhibited to a more significant extent with nemtabrutinib than with ibrutinib (nemtabrutinib vs stimulated vehicle p<0.0001, nemtabrutinib vs ibrutinib p=0.0461), and this inhibition was not affected by the addition of venetoclax (Figure 1D). However, expression of MCL1, a BCL2 family protein, was significantly reduced by the BTKi+venetoclax combination (ibrutinib combination vs stimulated vehicle p=0.0001, nemtabrutinib combination vs stimulated vehicle p=0.0003). Furthermore, ibrutinib plus venetoclax significantly reduced MCL-1 expression compared to either single agent (combination vs. ibrutinib p=0.0171, combination vs. venetoclax p=0.0262) (Figure 1E).

[0207] In Figure 1F, primary CLL cells from patients treated with nemtabrutinib were co-cultured with NK Tert stromal cells followed by BH3 profiling using BIM, BAD, MS-1, Y4ek and PUMA2A peptides. Baseline cytochrome c release measured in DMSO-treated cells was subtracted from all test conditions and controls presented. Cytochrome c release in response to interaction with BIM, BAD and Y4ek peptides indicates the dependence of cells on BCL-2 and BCL-xL. Raw data were analyzed using a linear mixed-effects model and p-values ​​were adjusted for multiple comparisons using Tukey's method. All statistics shown are relative to DMSO-treated controls (*, p ≤ 0.05, **, p ≤ 0.01, ***, p ≤ 0.001). BH3 profiling of samples from three nemtabrutinib-treated patients showed cytochrome c release in response to interactions with BIM, BAD, and Y4ek, indicating that these CLL cells maintained their dependency on BCL2 and BCL-xL (Figure 1F) (Ryan J, et al., Biol Chem. 2016;397(7):671-8), demonstrating venetoclax sensitivity.

[0208] The Eμ-TCL1 adoptive transfer CLL mouse model was used to test the in vivo efficacy of venetoclax in combination with ibrutinib or nemtabrutinib. (Bichi R, et al. Proc Natl Acad Sci US A. 2002;99(10):6955-60). In FIG. 2A, 93 C57BL / 6NTac mice were transplanted with splenocytes from Eμ-TCL1 donor mice via tail vein injection. Recipient mice were randomly enrolled into treatment groups after developing CD5+CD19+ disease as assessed by flow cytometry of peripheral blood. Mice were treated daily via oral gavage with vehicle, venetoclax (100 mg / kg), nemtabrutinib (75 mg / kg), ibrutinib (25 mg / kg), venetoclax (100 mg / kg) and nemtabrutinib (75 mg / kg), or venetoclax (100 mg / kg) and ibrutinib (25 mg / kg). Due to the large study size, splenocytes from multiple Eμ-TCL1 donors were required for transplantation into C57BL / 6NTac mice. Groups of 48, 25, 17, and 3 recipient mice, respectively, were transplanted with splenocytes from four donors.

[0209] Peripheral blood disease progression was monitored weekly by flow cytometry and reported as %CD5+CD19+ of CD45+ cells (Figure 2B). High variability was observed between recipient groups, including those without BCR-dependent disease, evidenced by lack of response to ibrutinib. These groups were excluded from the analysis. Differences in survival were evaluated in 48 mice transplanted with splenocytes from a single donor with BCR-dependent disease. Mice treated with ibrutinib reached a median survival of 56.5 days, whereas mice treated with ibrutinib and venetoclax had a median survival of 66 days (ns, p=untested). Mice treated with nemtabrutinib reached a median survival of 81.5 days, whereas mice treated with nemtabrutinib and venetoclax reached a median survival of 92 days (preliminary p=0.03). Mice treated with vehicle and venetoclax had similar overall survival times (median 31 days and 34.5 days, respectively). Furthermore, the combination of nemtabrutinib and venetoclax extended survival compared to the combination of ibrutinib and venetoclax (preliminary p=0.003).

[0210] Figure 2C shows Kaplan-Meier estimated survival of mice with BCR-dependent disease treated with BTKi, venetoclax or the combination. Inhibition of BCR signaling by nemtabrutinib is unaffected by the addition of venetoclax, while the cytotoxicity of venetoclax is unaffected by the addition of nemtabrutinib. In vivo data showed that combined treatment with nemtabrutinib and venetoclax was superior to treatment with either drug alone.

[0211] Further Study of Nemtabrutinib + Venetoclax vs. Venetoclax + Rituximab Objectives and Endpoints In participants at least 18 years of age with relapsed or refractory CLL / SLL who have failed at least one prior therapy: [Table 1]

[0212] Part 1 (dose escalation and confirmation) design Part 1 will include an open-label, non-randomized, dose escalation and confirmatory design aimed at identifying the optimal dose of nemtabrutinib used in combination with venetoclax. Up to approximately 30 participants, 15 participants per dose level, will be enrolled in Part 1. Two predefined dose levels of nemtabrutinib will be evaluated in combination with venetoclax.

[0213] Dose 1: 45mg (starting dose level) Dose 2: 65mg The end of the dose-limiting toxicity (DLT) assessment window corresponds to approximately 12 weeks after participants received their first dose of nemtabrutinib.

[0214] Part 2 Design Part 2 is a randomized, standard-controlled, parallel-group, multicenter, open-label study of nemtabrutinib plus venetoclax in participants with relapsed / refractory CLL / SLL.

[0215] Approximately 690 eligible participants will be enrolled and randomly assigned to one of two groups.

[0216] Treatment arm: nemtabrutinib + venetoclax Comparison group: venetoclax + rituximab (VR) (or generic rituximab biologic) In the treatment arm, nemtabrutinib administration will continue for up to 2 years. Venetoclax administration will be escalated over 4 weeks until a dose of 400 mg is reached. In the comparison arm, venetoclax administration will be escalated over 4 weeks until a dose of 400 mg is reached. Rituximab administration will be 375 mg / m 2 and 500 mg / m for subsequent doses. 2 increases to.

[0217] PFS was the primary endpoint in part 2 and was defined as the time from randomization to first documented disease progression or death from any cause, whichever occurred first, as assessed by BICR (blinded independent central review) and by the 2018 iwCLL criteria.

[0218] Secondary endpoints include undetectable MRD in bone marrow at 14 months as assessed by a central laboratory, OS, OR, DOR, and safety. Exploratory efficacy endpoints include OR with response categories including PRL.

[0219] Study treatment will be administered for 2 years or until unacceptable toxicity, confirmed disease progression (radiographic or nonradiographic progression), or another discontinuation criterion is met. Part 2 will consist of: a. Nemtabrutinib + venetoclax is superior to VR in terms of PFS according to the 2018 iwCLL criteria as assessed by BICR.

[0220] b. Nemtabrutinib + venetoclax is superior to VR in terms of undetectable bone marrow MRD rate at 14 months as assessed by central laboratory c. Nemtabrutinib + venetoclax is superior to VR in terms of OS d. Nemtabrutinib + venetoclax is superior to VR in terms of ORR by 2018 iwCLL criteria as assessed by BICR Evaluate whether:

[0221] Scientific basis for study design This is a randomized, standard-controlled, parallel-group, open-label Phase 3 study designed to evaluate nemtabrutinib plus venetoclax, a reversible, non-covalent, ATP-competitive inhibitor of BTK, compared with VR in participants with CLL / SLL that is relapsed or refractory to at least one prior therapy.

[0222] treatment Treatment arm (nemtabrutinib + venetoclax; Part 1 and Part 2) Venetoclax will be administered as doses of 20 to 400 mg per day during a 5-week dose-escalation phase, then at 400 mg per day after the dose-escalation phase. Venetoclax dosing will continue until confirmed disease progression, unacceptable toxicity, discontinuation criteria are met, or for up to 2 years.

[0223] Nemtabrutinib will be administered as a daily dose of 45 mg or 65 mg taken orally at least 10 hours after the venetoclax dose. Each cycle consists of 4 weeks (28 days).

[0224] Comparison arm (venetoclax + rituximab; part 2) Venetoclax will be administered as doses of 20 to 400 mg per day during a 5-week dose-escalation phase, then at 400 mg per day after the dose-escalation phase. Venetoclax dosing will continue until confirmed disease progression, unacceptable toxicity, discontinuation criteria are met, or for up to 2 years.

[0225] Rituximab (or its biogeneric equivalent) is administered as an IV infusion. The initial dose is 375 mg / m 2 and 500 mg / m for subsequent injections. 2 It is.

[0226] Timing of Dose Administration Venetoclax Participants will be instructed to take the tablet in the morning with food and water. Venetoclax dosing will be titrated up over a 5-week period.

[0227] Nemtabrutinib Participants enrolled in Part 1 or randomly assigned to a treatment group in Part 2 will be instructed to take a tablet once daily under fasting conditions (either 1 hour before or 2 hours after a meal), preferably at the same time each day. Nemtabrutinib will be administered at least 10 hours after venetoclax administration.

[0228] Participants will be instructed to take their assigned dose of nemtabrutinib unless the dose has been reduced for management of AEs. Treatment will continue until unacceptable toxicity, documented disease progression, or another discontinuation criterion is met.

[0229] Rituximab Rituximab (or its biogeneric equivalent) is administered in the doctor's office.

[0230] First infusion: Begin the infusion at a rate of 50 mg / hour. In the absence of infusion toxicity, increase the infusion rate by 50 mg / hour every 30 minutes to a maximum of 400 mg / hour.

[0231] Subsequent infusions (standard infusion): Begin the infusion at a rate of 100 mg / hour. In the absence of infusion toxicity, increase the rate by 100 mg / hour at 30 minute intervals up to a maximum of 400 mg / hour.

[0232] Table 1 below details the arms / intervention groups of the study: [Table 2] TIFF2025513742000008.tif160153

[0233] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments specifically described herein which equivalents are intended to be encompassed by the following claims.

Claims

1. 2. For use in treating a BTK mediated disease or disorder, a therapeutically effective amount of a compound of formula (I): 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof.

2. 2. The pharmaceutical composition of claim 1, wherein the second agent is selected from venetoclax, BI-97C1, sabutoclax, navitoclax, obatoclax, 4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl]-N-[4-[[(2R)-4-(dimethylamino)-1-phenylsulfanylbutan-2-yl]amino]-3-nitrophenyl]sulfonylbenzamide (ABT-737), N-[4-(2-tert-butylphenyl)sulfonylphenyl]-2,3,4-trihydroxy-5-[(2-propan-2-ylphenyl)methyl]benzamide (TW-37), APG-1252, APG-2575, or S55746.

3. 3. The pharmaceutical composition of claim 2, wherein the second agent is venetoclax.

4. A method of treating a BTK-mediated disorder in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of formula (I): 【Chemistry 2】 or a pharma- ceutically acceptable salt thereof to a subject in need of treatment for a BTK-mediated disorder.

5. 5. The method of claim 4, wherein a therapeutically effective amount of the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to a patient / animal in need thereof after administering a therapeutically effective amount of at least one second agent or a pharma- ceutically acceptable salt thereof.

6. 6. The method of treating a BTK-mediated disorder according to claim 4 or 5, wherein the BTK-mediated disorder is a cancer selected from CLL, SLL, or MLL.

7. 7. The method of claim 6, wherein the at least one second agent is selected from the group consisting of a BCL-2 inhibitor selected from venetoclax, BI-97C1, sabutoclax, navitoclax, obatoclax, 4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl]-N-[4-[[(2R)-4-(dimethylamino)-1-phenylsulfanylbutan-2-yl]amino]-3-nitrophenyl]sulfonylbenzamide (ABT-737), N-[4-(2-tert-butylphenyl)sulfonylphenyl]-2,3,4-trihydroxy-5-[(2-propan-2-ylphenyl)methyl]benzamide (TW-37), APG-1252, APG-2575, or S55746.

8. 8. The method of claim 7, wherein the at least one second agent is venetoclax.

9. The method of claim 7, wherein about 30 to about 80 mg of the compound of formula (I) is administered.

10. 10. The method of claim 9, wherein about 45 mg of the compound of formula (I) is administered.

11. 10. The method of claim 9, wherein about 65 mg of the compound of formula (I) is administered.

12. 10. The method of claim 9, wherein about 80 mg of the compound of formula (I) is administered.

13. The method of claim 8, wherein about 20 to about 400 mg of venetoclax is administered.

14. The method of claim 8, wherein about 20 to about 400 mg of venetoclax is administered.

15. A method of treating cancer comprising administering to a subject in need of treating cancer a therapeutically effective amount of a compound of formula (I): 【Chemistry 3】 or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from CLL, SLL, or MLL, and about 30 mg to about 80 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered following about 20 to about 400 mg of venetoclax or a pharmaceutically acceptable salt thereof.

16. 16. The method of claim 15, wherein 65 mg of the compound of formula (I) or a pharma- ceutically acceptable salt is administered.

17. 16. The method of claim 15, wherein 400 mg of venetoclax or a pharma- ceutically acceptable salt is administered.

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