Irreversible inhibitors of MENIN-MLL interaction

Abstract

The invention discloses a heterocyclic compound for inhibiting combination of menin and MLL or MLL fusion protein. The present invention also describes specific irreversible inhibitors of the menin-MLL interaction. The invention also discloses a pharmaceutical composition comprising the compound. The present invention discloses methods of using menin-MLL irreversible inhibitors, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or disorders, heteroimmune diseases or disorders, cancer, including lymphoma, leukemia, and other diseases or disorders that depend on menin-MLL interaction.

Description

This application is a divisional application of the invention application with the application date of December 31, 2019, the Chinese national application number 201980093262.8, and the invention name “Irreversible inhibitors of MENIN-MLL interaction”. Technical Field

[0001] The present invention describes compounds, methods for preparing such compounds, pharmaceutical compositions and agents containing such compounds, and methods of using such compounds and compositions to inhibit menin-MLL activity. (They may also act as anti-tumor agents through off-target activities by affecting other protein-protein interactions and kinases.) Background of the Invention

[0002] The histone-lysine N-methyltransferase 2 (KMT2) family of proteins currently consists of at least 5 members that methylate lysine 4 on the histone H3 tail at important regulatory regions in the genome, thereby conferring key functions by regulating chromatin structure and DNA accessibility (Morera, Lübbert, and Jung., Clin. Epigenetics 8, 57-(2016)). These enzymes are known to play an important role in regulating gene expression during early development and hematopoiesis (Rao & Dou., Nat. Rev. Cancer 15, 334-346 (2015)).

[0003] The human KMT2 family was initially named the mixed-lineage leukemia (MLL) family due to the role of the first member discovered in this disease; the member, KMT2A, is still commonly referred to as MLL1 or MLL in routine clinical practice.

[0004] KMT2A (MLL1) is often considered to be cytogenetically targeted in several types of leukemia (e.g., ALL and AML), and in those cases where balanced chromosomal translocations are found, these balanced chromosomal translocations often target KMT2A (MLL1) and one of the more than 80 translocation partner genes described to date (Winters and Bernt, Front. Pediatr. 5, 4 (2017)). These chromosomal abnormalities often result in the formation of fusion genes that encode fusion proteins that are believed to be causally related to the onset and / or progression of the disease. Inhibiting menin may be a promising strategy for treating MLL-related diseases, including leukemia.

[0005] M-525 is a highly potent, irreversible small molecule inhibitor of the menin-MLL protein-protein interaction. It forms a covalent bond with the Cys329 residue in menin. M-525 exhibits higher cell specificity than non-MLL leukemia cells and is more than 30 times more effective than corresponding reversible inhibitors. See S. Xu et al. Angewandte Chemie International Ed. 57(6), 1601-1605 (2017). Abstract

[0006] The present invention describes inhibitors of the menin-MLL interaction. The present invention also describes specific heterocyclic irreversible inhibitors of the menin-MLL or MLL fusion protein interaction.

[0007] The present invention also describes methods for synthesizing such inhibitors, methods for using such inhibitors in treating diseases, including diseases in which inhibition of the menin-MLL interaction provides a therapeutic benefit to patients suffering from the disease. The present invention further describes pharmaceutical compositions comprising inhibitors of the menin-MLL interaction. Specifically, the present invention describes compounds that inhibit the interaction of menin with MLL oncoproteins (e.g., MLL1, MLL2, MLL-fusion oncoproteins), and methods for using the same.

[0008] The present invention specifically describes irreversible inhibitors of the menin-MLL interaction that form a covalent bond with a cysteine ​​residue on menin. The present invention further describes irreversible inhibitors of the menin-MLL interaction that form a covalent bond with the Cys329 residue on menin. The present invention also describes pharmaceutical formulations comprising the irreversible inhibitors of menin.

[0009] Therefore, in some embodiments, the present invention provides a method for preventing, treating, or ameliorating a disease or condition in a mammal (which is causally related to the abnormal activity of menin-MLL interaction in vivo), comprising administering to the mammal an effective disease-treating or condition-treating amount of a compound represented by formula (I) having the following structure: or a pharmaceutically acceptable salt thereof, in: A is C or N; Cy is substituted or unsubstituted Q is N, -N(H)-, -O-, or -S-; Z is -CR 5a =, or -N=; X is -NR 3a -、-C(R 3b )2-, or -O-; Y is a single bond, -NR 3a -、-C(R 3b )2-, or -O-; W is -C(O)-, -S(O)-, or -S(O)2-; R 1 and R 2 One of them is Cy 2 -N(H)C(O)-C(R 6a )=C(R 6b )(R 6c ), or CH2-Cy 2 -N(H)C(O)-C(R 6a )=C(R 6b )(R 6c ); and the other is H, C 1-6 Alkyl, C 1-6 Haloalkyl, halogen, or CN;

[0010] Cy 2 is an optionally substituted group selected from the group consisting of phenyl, pyridyl, or a heterocycloalkyl ring of 4 to 7 atoms having 1 to 2 heteroatoms independently selected from N, O, or S; Each R 3a and R 3b are independently H or C 1-6 alkyl; Each R 4a and R 4b are independently H, halogen, CN, OR, -N(R)2, -C(O)N(R)2, -NRC(O)R, -SO2R, -C(O)R, -CO2R, or an optionally substituted group selected from the following: C 1-6 Alkyl, C 3-7 Cycloalkyl, heterocycloalkyl rings consisting of 4-7 atoms having 1-2 heteroatoms independently selected from N, O, or S, phenyl, bicyclic aryl rings consisting of 8-10 atoms, and heteroaryl rings consisting of 5-6 atoms having 1-4 heteroatoms independently selected from N, O, or S; Each R is independently H, or an optionally substituted group selected from the following: C 1-6 aliphatic, phenyl, a bicyclic aryl ring consisting of 8-10 atoms, a saturated or partially unsaturated heterocyclic ring consisting of 4-7 atoms having 1-2 heteroatoms independently selected from N, O or S, and a heteroaryl ring consisting of 5-6 atoms having 1-4 heteroatoms independently selected from N, O or S, or: Two R groups on the same nitrogen atom together with their intervening atoms form a heteroaryl ring of 4-7 atoms which is saturated, partially unsaturated, or has 0-3 heteroatoms independently selected from N, O or S in addition to the nitrogen atom; R 5a H, C 1-6 Alkyl, C 1-6 Haloalkyl, halogen, or CN; Each R 6a and R 6b are independently H or C 1-6 Alkyl; or R 6a and R 6b joined together to form a bond; R 6c is H, or substituted or unsubstituted C 1-6 alkyl; m is 1, 2, or 3; and n is 1, 2, 3, or 4.

[0011] In some embodiments, the present invention provides a compound represented by formula (I) having the following structure: or a pharmaceutically acceptable salt thereof, in: A is C or N; Cy is substituted or unsubstituted Q is N, -N(H)-, -O-, or -S-; Z is -CR 5a =, or -N=; X is -NR 3a -、-C(R 3b )2-, or -O-; Y is a single bond, -NR 3a -、-C(R 3b )2-, or -O-; W is -C(O)-, -S(O)-, or -S(O)2-; R 1 and R 2 One of them is Cy 2 -N(H)C(O)-C(R 6a )=C(R 6b )(R 6c ), or CH2-Cy 2 -N(H)C(O)-C(R 6a )=C(R 6b )(R 6c ); and the other is H, C 1-6 Alkyl, C1-6 Haloalkyl, halogen, or CN; Cy 2 is an optionally substituted group selected from the group consisting of phenyl, pyridyl, or a heterocycloalkyl ring of 4 to 7 atoms having 1 to 2 heteroatoms independently selected from N, O, or S; Each R 3a and R 3b are independently H or C 1-6 alkyl; Each R 4a and R 4b are independently H, halogen, CN, OR, -N(R)2, -C(O)N(R)2, -NRC(O)R, -SO2R, -C(O)R, -CO2R, or an optionally substituted group selected from the following: C 1-6 Alkyl, C 3-7 Cycloalkyl, heterocycloalkyl rings consisting of 4-7 atoms having 1-2 heteroatoms independently selected from N, O, or S, phenyl, bicyclic aryl rings consisting of 8-10 atoms, and heteroaryl rings consisting of 5-6 atoms having 1-4 heteroatoms independently selected from N, O, or S; Each R is independently H, or an optionally substituted group selected from the following: C 1-6 aliphatic, phenyl, a bicyclic aryl ring consisting of 8-10 atoms, a saturated or partially unsaturated heterocyclic ring consisting of 4-7 atoms having 1-2 heteroatoms independently selected from N, O or S, and a heteroaryl ring consisting of 5-6 atoms having 1-4 heteroatoms independently selected from N, O or S, or: Two R groups on the same nitrogen atom together with their intervening atoms form a heteroaryl ring of 4-7 atoms which is saturated, partially unsaturated, or has 0-3 heteroatoms independently selected from N, O or S in addition to the nitrogen atom; R 5a H, C 1-6 Alkyl, C 1-6 Haloalkyl, halogen, or CN; Each R 6a and R 6b are independently H or C 1-6 Alkyl; or R 6a and R 6b joined together to form a bond; R 6c is H, or substituted or unsubstituted C 1-6 alkyl; m is 1, 2, or 3; and n is 1, 2, 3, or 4.

[0012] In some embodiments, the present invention provides a compound represented by formula (XXI): or a pharmaceutically acceptable salt thereof, Among them, A, Cy, Cy 2 、R 4b 、R 6a 、R 6b 、R 6c , m and n have the definitions given for formula (I); and each R 8 and R 9 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, halogen, or CN.

[0013] In some embodiments, X is -N(H)-, and Y is -NH-, -C(H)2-, or O. In some embodiments, X and Y are each -N(H)-.

[0014] In some embodiments, W is -S(O)-, or -S(O)2-. In certain embodiments, W is -C(O)-.

[0015] In some embodiments, –XWY- is –N(H)-C(O)-N(H)-, –N(H)-C(O)-CH2-, –CH2-C(O)-N(H)-, –N(H)-S(O)-N(H)-, –N(H)-S(O)-CH2-, –CH2-S(O)-N(H)-, –N(H)-S(O)2-N(H)-, –N(H)-S(O)2-CH2-, –CH2-S(O)2-N(H)-, or –N(H)-C(O)-.

[0016] In some embodiments, the compound has a structure represented by Formula (IIa), (IIb), (IIc), or (IId): or a pharmaceutically acceptable salt thereof.

[0017] In some embodiments, R 2 is H, Me, Et, i-Pr, CF3, F, Cl, OMe, OEt, or CN.

[0018] In some embodiments, the compound has the structure shown in Formula (XV): or a pharmaceutically acceptable salt thereof.

[0019] In some embodiments, the compound has the structure shown in Formula (XVI): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has the structure shown in Formula (XVII): or a pharmaceutically acceptable salt thereof.

[0020] In some embodiments, the active site is a cavity wherein the compound or group moiety binds to the MLL site on the menin. In some embodiments, the active site is MEN1 at the MLL binding site.

[0021] In some embodiments, the disease or disorder is an autoimmune disease, a heteroimmune disease, cancer, mastocytosis, osteoporosis or a bone resorption disorder, or an inflammatory disease.

[0022] In some embodiments, the compounds of the present invention may also act as anti-tumor agents through off-target activities by affecting other protein-protein interactions and kinases.

[0023] In some embodiments, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound shown in formula (I) and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprising a compound shown in formula (I) is formulated for an administration route selected from oral administration, parenteral administration, buccal administration, nasal administration, topical administration, or rectal administration. In some embodiments, the present invention provides a method for treating an autoimmune disease or condition, comprising administering a therapeutically effective amount of a compound shown in formula (I) to a patient in need. In some embodiments, the autoimmune disease is selected from rheumatoid arthritis or lupus. In some embodiments, the present invention provides a method for treating a heteroimmune disease or condition, comprising administering a therapeutically effective amount of a compound shown in formula (I) to a patient in need. In some embodiments, the present invention provides a method for treating cancer, comprising administering a therapeutically effective amount of a compound shown in formula (I) to a patient in need. In some embodiments, the cancer is myeloid line of blood cell cancer. In some embodiments, the cancer is lymphoid line of blood cell cancer. In some embodiments, the cancer is a B cell proliferative disorder. In some embodiments, the cancer is a cancer of the lymphoid blood cells.

[0024] In some embodiments, the myeloid blood cell cancer is acute myeloid leukemia. In some embodiments, the lymphoid blood cell cancer is acute lymphoblastic leukemia. In some embodiments, the B cell proliferative disorder is diffuse large B cell lymphoma, follicular lymphoma, or chronic lymphocytic leukemia. In some embodiments, the cancer (soft tissue) is glioblastoma and pancreatic cancer. In some embodiments, the cancer is renal cell carcinoma.

[0025] In some embodiments, the present invention provides a method for treating mastocytosis, comprising administering a therapeutically effective amount of a compound of formula (I) to a patient in need thereof.

[0026] In some embodiments, the present invention provides a method for treating osteoporosis or bone resorption disorders, comprising administering a therapeutically effective amount of a compound of formula (I) to a patient in need thereof.

[0027] In some embodiments, the present invention provides a method for treating an inflammatory disease or condition, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I).

[0028] The present invention encompasses any combination of the groups described above for the various variables. It will be appreciated that one of ordinary skill in the art can select substituents and substitution patterns on the compounds provided herein to provide chemically stable compounds that can be synthesized by techniques known in the art as well as those described herein.

[0029] In some embodiments, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of any of the compounds of the present invention, or a pharmaceutically acceptable salt, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate. In certain embodiments, the compositions provided by the present invention further comprise a pharmaceutically acceptable diluent, excipient, and / or binder.

[0030] The present invention provides pharmaceutical compositions formulated for administration by appropriate routes and modes, containing effective concentrations of one or more of the compounds provided herein, or pharmaceutically effective derivatives thereof, that deliver an amount effective for treating, preventing, or ameliorating one or more symptoms of a disease, disorder, or condition that is regulated or otherwise affected by, or in which, Menin-MLL activity is implicated. The effective amounts and concentrations are effective to ameliorate any symptom of any of the diseases, disorders, or conditions disclosed herein.

[0031] In certain embodiments, the present invention provides pharmaceutical compositions comprising: i) a physiologically acceptable carrier, diluent, and / or excipient; and ii) one or more compounds provided herein.

[0032] In some embodiments, the present invention provides methods of treating a patient by administering a compound provided herein. In some embodiments, the present invention provides methods of inhibiting Menin-MLL activity in a patient or treating a disease, disorder, or condition that would benefit from inhibition of Menin-MLL activity, comprising administering to the patient a therapeutically effective amount of at least one of any of the compounds of the present invention, or a pharmaceutically acceptable salt, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate.

[0033] In some embodiments, the present invention provides the use of the compounds disclosed herein to inhibit Menin-MLL activity or to treat a disease, disorder, or condition that would benefit from inhibition of Menin-MLL activity.

[0034] In some embodiments, the compounds provided herein are administered to humans.

[0035] In some embodiments, the compounds provided herein are administered orally.

[0036] In some embodiments, the compounds provided herein are used to formulate a medicament for inhibiting Menin-MLL activity. In some embodiments, the compounds provided herein are used to formulate a medicament for inhibiting Menin-MLL activity.

[0037] Provided is an article of manufacture comprising a packaging material; a compound or composition provided herein, or a pharmaceutically acceptable derivative thereof, which effectively inhibits Menin-MLL activity within the packaging material; and a label indicating that the compound or composition, or a pharmaceutically acceptable salt, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, is used to inhibit Menin-MLL activity.

[0038] In some embodiments, the present invention provides a method of inhibiting Menin-MLL activity in an individual in need thereof by administering to the individual a composition comprising a therapeutically effective amount of at least one compound having the structure of Formula (I). In some embodiments, the individual in need thereof suffers from an autoimmune disease, such as inflammatory bowel disease, arthritis, lupus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, Sjögren's syndrome, syndrome), multiple sclerosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behçet's disease disease), chronic fatigue, dysautonomia, endometriosis, interstitial cystitis, neuromyotonia, scleroderma, or vulvodynia.

[0039] In some embodiments, the individual in need thereof suffers from a heteroimmune disease or disorder, such as graft-versus-host disease, transplantation, infusion, anaphylaxis, allergy, type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, or atopic dermatitis.

[0040] In certain embodiments, the individual in need thereof suffers from an inflammatory disease, such as asthma, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, Meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, or vulvitis.

[0041] In some embodiments, the individual in need thereof suffers from cancer. In some embodiments, the cancer is a B-cell proliferative disorder, such as diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenst macroglobulinemia ( macroglobulinemia), splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt lymphoma / leukemia, or lymphomatoid granulomatosis. In some embodiments, when the individual suffers from cancer, in addition to one of the above-mentioned compounds, an anti-cancer agent is administered to the individual.

[0042] In some embodiments, the individual in need thereof suffers from a thromboembolic disorder, such as myocardial infarction, angina pectoris, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after aortocoronary bypass grafting, restenosis after aortocoronary bypass grafting, stroke, transient ischemia, peripheral arterial occlusive disorder, pulmonary embolism, or deep vein thrombosis.

[0043] In some embodiments, the present invention provides a method for treating an autoimmune disease by administering to an individual in need thereof a composition containing a therapeutically effective amount of at least one compound of the structure shown in formula (I)-(XVII). In some embodiments, the autoimmune disease is arthritis. In some embodiments, the autoimmune disease is lupus. In some embodiments, the autoimmune disease is inflammatory bowel disease (including Crohn's disease and ulcerative colitis), rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, lupus, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Grave's disease, Sjögren's syndrome, multiple sclerosis, Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, Aplastic anemia, autoimmune hepatitis, celiac disease, Good-Bradford syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behçet's disease, chronic fatigue, dysautonomia, endometriosis, interstitial cystitis, neuromyotonia, scleroderma, or vulvodynia.

[0044] In some embodiments, the present invention provides a method for treating a heteroimmune disease or condition by administering to a subject in need thereof a composition comprising a therapeutically effective amount of at least one compound having a structure represented by Formula (I)-(XVII). In some embodiments, the heteroimmune disease or condition is graft-versus-host disease, transplantation, infusion, anaphylaxis, allergy, type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, or atopic dermatitis.

[0045] In some embodiments, the present invention provides a method for treating an inflammatory disease by administering to an individual in need thereof a composition comprising a therapeutically effective amount of at least one compound of formula (I)-(XVII). In some embodiments, the inflammatory disease is asthma, inflammatory bowel disease (including Crohn's disease and ulcerative colitis), appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis , mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, or vulvitis.

[0046] In some embodiments, the present invention provides a method for treating cancer by administering to an individual in need thereof a composition comprising a therapeutically effective amount of at least one compound having a structure shown in Formula (I)-(XVII). In some embodiments, the cancer is a B-cell proliferative disorder, such as diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenst macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, or lymphomatoid granulomatosis. In some embodiments, when the individual suffers from cancer, in addition to one of the compounds mentioned above, an anticancer agent is administered to the individual.

[0047] In some embodiments, the present invention provides a method for treating a thromboembolic disorder by administering to a subject in need thereof a composition comprising a therapeutically effective amount of at least one compound having a structure represented by Formula (I)-(XVII). In some embodiments, the thromboembolic disorder is myocardial infarction, angina pectoris, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after aortocoronary bypass, restenosis after aortocoronary bypass, stroke, transient ischemia, peripheral arterial occlusive disorder, pulmonary embolism, or deep vein thrombosis.

[0048] In some embodiments, the present invention provides a method of treating inflammation comprising administering to a mammal at least once an effective amount of at least one compound having a structure represented by Formula (I)-(XVII).

[0049] In some embodiments, the present invention provides a method for treating cancer, comprising administering to a mammal at least once an effective amount of at least one compound having a structure represented by Formula (I)-(XVII). Cancer types may include (but are not limited to) pancreatic cancer and other solid or hematological tumors.

[0050] In some embodiments, the present invention provides a method for treating a respiratory disease, comprising administering to a mammal an effective amount of at least one compound having a structure shown in Formula (I)-(XVII) at least once. In some embodiments, the respiratory disease is asthma. In some embodiments, the respiratory disease includes (but is not limited to) adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, isocapnic hyperventilation, childhood-onset asthma, adult-onset asthma, cough variant asthma, occupational asthma, steroid-resistant asthma, and seasonal asthma.

[0051] In some embodiments, the present invention provides a method for preventing rheumatoid arthritis and osteoarthritis, comprising administering to a mammal an effective amount of at least one compound having a structure represented by Formula (I)-(XVII) at least once.

[0052] In some embodiments, the present invention provides a method for treating an inflammatory reaction of the skin, comprising administering to a mammal at least once an effective amount of at least one compound having a structure as shown in Formula (I)-(XVII). Such inflammatory reactions of the skin include, for example, dermatitis, contact dermatitis, eczema, urticaria, rosacea, and scarring. In another embodiment, a method for reducing psoriatic lesions in the skin, joints, or other tissues or organs comprises administering to a mammal an effective amount of a first compound having a structure as shown in Formula (I)-(XVII).

[0053] In certain embodiments, the present invention discloses a method for treating the following disease or illness, comprising administering the compounds of this invention to a mammal. In some embodiments, the disease or illness is acute lymphoblastic lymphoma (ALL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), renal cell carcinoma (RCC), childhood medulloblastoma, glioblastoma, pancreatic tumor or cancer, liver cancer (hepatocellular carcinoma), prostate cancer (MYC), triple negative breast cancer (MYC), acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). In some embodiments, the disease or illness is early-onset dystonia. In some other embodiments, the disease or illness is Kabuki syndrome (Kabuki Syndrome).

[0054] In some embodiments, the disease or condition is a P53 driven tumor. P53 drives tumors and Menin / MLL1

[0055] The RUNX2 signaling pathway is a survival signal specific for p53-deficient cancer cells. RUNX2 recruits the Menin / MLL1 epigenetic complex to induce MYC expression. Targeting the RUNX2 / Menin / MLL1 / MYC axis using small molecule inhibitors of the Menin / MLL1 complex is a viable strategy for killing p53-deficient cancer cells (Shih et al., ARUNX2-Mediated Epigenetic Regulation of the Survival of p53 Defective Cancer Cells. PLOS Genetics, https: / / doi.org / 10.1371 / journal.pgen.1005884, 2016).

[0056] In some embodiments, the disease or disorder is a MYC-driven tumor. MYC-driven tumors and Menin / MLL1

[0057] MYC has been documented to be extensively involved in many cancers, with its expression estimated to be elevated or dysregulated in up to 70% of human cancers. High levels of MYC expression have been associated with aggressive human prostate cancer and triple-negative breast cancer (Gurel et al., Mod Pathol. 2008 Sep; 21(9): 1156-67; Palaskas et al., Cancer Res. 2011 Aug 1; 71(15): 5164-74). Experimental models of MYC-mediated tumor formation have shown that established tumors are addicted to Myc, and that dysregulated Myc expression leads to addiction not only to Myc but also to nutrients. These Myc-induced changes provide unique opportunities for novel therapeutic strategies. Despite the fact that normal proliferating cells (stem cell compartment and immune cells) also use Myc for renewal, many studies have focused on using Myc for cancer treatment. Strategies have emerged to inhibit MYC expression, disrupt Myc-Max dimerization, inhibit Myc-Max DNA binding, and interfere with key Myc target genes (Dang et al. Cell. 2012, 149(1):22-35).

[0058] Menin's role in tumor suppression is cell-specific; disruption of menin in the liver or hematopoietic system does not produce tumors. It is important to measure drug concentrations in endocrine tissues, liver tissue, bone marrow, and hematopoietic tissue.

[0059] In any of the foregoing embodiments, there are some embodiments in which the administration is enteral, parenteral, or both, and wherein (a) an effective amount of a provided compound is administered systemically to a mammal; (b) an effective amount of a provided compound is administered orally to a mammal; (c) an effective amount of a provided compound is administered intravenously to a mammal; (d) an effective amount of a provided compound is administered by inhalation; (e) an effective amount of a provided compound is administered by nasal administration; or (f) an effective amount of a provided compound is administered to a mammal by injection; (g) an effective amount of a provided compound is administered topically (dermally) to a mammal; (h) an effective amount of a provided compound is administered by ocular administration; or (i) an effective amount of a provided compound is administered rectally to a mammal.

[0060] In any of the foregoing embodiments, there are some embodiments comprising a single administration of an effective amount of a provided compound, including some embodiments wherein (i) the provided compound is administered once; (ii) the provided compound is administered to the mammal multiple times during a day; (iii) the administration is continuous; or (iv) the administration is ongoing.

[0061] In any of the foregoing embodiments, there are some embodiments comprising multiple administrations of an effective amount of a provided compound, including some embodiments wherein (i) the provided compound is administered as a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the provided compound is administered to the mammal every 8 hours. In some embodiments, the method comprises a drug holiday, wherein administration of the compound is suspended or the dose of the compound is temporarily reduced; at the end of the drug holiday, administration of the compound is resumed. The length of the drug holiday can vary from 2 days to 1 year.

[0062] In any of the above-mentioned embodiments directed to the treatment of a proliferative disorder, including cancer, there are some embodiments comprising administering at least one additional agent selected from the group consisting of alemtuzumab, arsenic trioxide, asparaginase (pegylated or non-pegylated), bevacizumab, cetuximab, a platinum compound (such as cisplatin), cladribine, daunorubicin / doxorubicin / idarubicin, irinotecan, fludarabine, 5-fluorouracil, gemtuzumab, methotrexate, paclitaxel TM , paclitaxel, temozolomide, thioguanine, or drug classes including hormones (antiestrogens, antiandrogens, or gonadotropin-releasing hormone analogs), interferons (such as interferon alpha), nitrogen mustards (such as busulfan or melphalan or dichloromethane), retinoids (such as tretinoin), irreversible topoisomerase inhibitors (such as irinotecan or topotecan), irreversible tyrosine kinase inhibitors (such as gefinitinib or imatinib), or drugs that treat signs or symptoms induced by such therapies (including allopurinol, filgrastim, granisetron / ondansetron / palonosetron, dronabinol).

[0063] In some embodiments, the compounds of formula (I)-(XLIIIc) are irreversible inhibitors of Menin-MLL activity. In certain embodiments, such irreversible inhibitors have an IC of less than 10 μM in an enzyme assay. 50 In some embodiments, the menin-MLL inhibitor has an IC of less than 1 μM. 50 , and in some embodiments, less than 0.25 μM.

[0064] Other objectives, features and advantages of the methods and compositions described herein will become apparent from the following embodiments. However, it should be understood that the embodiments and specific examples, although indicating specific embodiments, are given for illustration only, as it is obvious to those skilled in the art that various changes and modifications can be made within the spirit and scope of the invention according to this embodiment. The section headings used herein are for organizational purposes only and should not be understood as limiting the subject matter described. For any purpose, all documents or portions of documents cited in this application (including but not limited to patents, patent applications, articles, books, manuals and papers) are hereby expressly incorporated by reference in their entirety. BRIEF DESCRIPTION OF THE DRAWINGS

[0065] Figure 1 Shown are the effects of increasing concentrations of Compound 1 and MI-503 (0.027 μM-20 μM) on the proliferation of HL-60 cells after 4 days of treatment as detected by the CellTiterGlo cell viability assay. Each data point is the mean ± SEM of data from a single experiment performed in duplicate.

[0066] Figure 2 Shown are the effects of increasing concentrations of Compound 1 and MI-503 (0.027 μM-20 μM) on the proliferation of MV-4-11 cells after 4 days of treatment as detected by the CellTiterGlo cell viability assay. Each data point is the mean ± SEM of data from a single experiment performed in duplicate.

[0067] Figure 3 Shown is the effect of compound 1 and MI-503 (0.027 μM-20 μM) concentration increase on MOLM-13 cell proliferation after processing 4 days detected by CellTiterGlo cell viability assay.Each data point is the mean ± SEM of the data from the single experiment carried out in duplicate.

[0068] Figure 4Detected by CellTiterGlo cell viability assay, the concentration of compound 10 increases the impact of RS-411, HL-60, MOLM-13 and MV411 cell proliferation after processing 4, 7, 11 and 14 days (T4, T7, T11 and T14). Each data point is the mean ± SEM of the data from the single experiment carried out in duplicate.

[0069] Figure 5 Detected by CellTiterGlo cell viability assay, the concentration of compound 13 increases the impact of RS-411, HL-60, MOLM-13 and MV411 cell proliferation after processing 4, 7, 11 and 14 days (T4, T7, T11 and T14). Each data point is the mean ± SEM of the data from the single experiment carried out in duplicate.

[0070] Figure 6 Detected by CellTiterGlo cell viability assay, the concentration of compound 15 increases the impact of RS-411, HL-60, MOLM-13 and MV411 cell proliferation after processing 4, 7, 11 and 14 days (T4, T7, T11 and T14). Each data point is the mean ± SEM of the data from the single experiment carried out in duplicate.

[0071] Figure 7 The results of long-term proliferation assays of compound 10 are shown.

[0072] Figure 8 The results of long-term proliferation assays of Compound 13, Compound 15, and Compound 23 are shown. Detailed Description of the Invention Specific terms

[0073] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which the claimed subject matter pertains. Where multiple definitions exist for a term in the present invention, the definitions in this section shall prevail. Where reference is made to a URL or other such identifier or address, it should be understood that while such identifiers may change and specific information on the Internet may come and go, equivalent information can be found by searching the Internet. Reference hereto confirms the availability and public dissemination of such information.

[0074] It should be understood that the foregoing general description and the following detailed description are merely illustrative and explanatory and do not limit any claimed target. In this application, unless otherwise expressly provided, the use of the singular includes the plural. It must be noted that, unless the context clearly specifies otherwise, the singular forms "one / kind" and "said" as used in this specification and the appended claims include plural indicators. The use of the term "including" and other forms (such as "include," "includes," and "included") is not restrictive. Definitions of standard chemical terms can be found in reference works, including Carey and Sundberg "Advanced Organic Chemistry 4th Edition" Volume A (2000) and Volume B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology within the art are used. Unless specific definitions are provided, the nomenclature and laboratory procedures and techniques used in conjunction with analytical chemistry, synthetic organic chemistry, and medical and pharmaceutical chemistry described herein are those known in the art. Standard techniques can be used for chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and patient treatment. Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, liposome transfection). Reactions and purification techniques can be performed, for example, using a set of manufacturer's instructions or as commonly implemented in the art or as described herein. The aforementioned techniques and methods can generally be performed by conventional methods well known in the art and as described in each general and more specific reference cited and discussed throughout this specification.

[0075] It should be understood that the methods and compositions described herein are not limited to the specific methods, protocols, cell lines, constructs, and reagents described herein and may vary accordingly. It should also be understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to limit the scope of the methods and compositions described herein, which will be limited only by the scope of the appended claims.

[0076] All publications and patents mentioned herein are incorporated herein by reference in their entirety for the purpose of describing and disclosing, for example, the constructs and methodologies described in such publications, which can be used in conjunction with the methods, compositions, and compounds described herein. The publications discussed herein provide only their disclosures prior to the filing date of the patent applications. Nothing herein should be construed as an admission that the inventors described herein are not entitled to antedate such disclosures by reason of prior invention or for any other reason.

[0077] "Alkyl" refers to a group consisting of only carbon and hydrogen atoms, containing no unsaturation, and having one to fifteen carbon atoms (e.g., C1-C 15 In certain embodiments, the alkyl group contains one to thirteen carbon atoms (e.g., C1-C 13 In some embodiments, the alkyl group contains one to eight carbon atoms (e.g., C1-C8 alkyl). In some embodiments, the alkyl group contains five to fifteen carbon atoms (e.g., C5-C 15 Alkyl). In certain embodiments, the alkyl group contains five to eight carbon atoms (e.g., C5-C8 alkyl). The alkyl group is connected to the rest of the molecule by a single bond, such as methyl (ME), ethyl (ET), n-propyl (n-Pr), 1-methylethyl (isopropyl or i-Pr), n-butyl (n-Bu), n-pentyl, 1,1-dimethylethyl (tert-butyl or t-Bu), 3-methylhexyl, 2-methylhexyl, and the like. Unless otherwise specifically stated in this specification, an alkyl group is optionally substituted, as defined and described below and herein.

[0078] The alkyl group may also be a "lower alkyl" having 1 to 6 carbon atoms.

[0079] As used in the present invention, C1-C x Including C1-C2, C1-C3...C1-C x .

[0080] "Alkenyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one double bond, and having from 2 to 12 carbon atoms. In certain embodiments, an alkenyl group comprises from 2 to 8 carbon atoms. In some embodiments, an alkenyl group comprises from 2 to 4 carbon atoms. An alkenyl group is attached to the remainder of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, pent-1,4-dienyl, and the like. Unless specifically indicated otherwise in this specification, an alkenyl group is optionally substituted, as defined and described below and herein.

[0081] "Alkynyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one triple bond, and having from 2 to 12 carbon atoms. In certain embodiments, the alkynyl group comprises from 2 to 8 carbon atoms. In some embodiments, the alkynyl group has from 2 to 4 carbon atoms. The alkynyl group is connected to the remainder of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless otherwise specifically indicated in this specification, an alkynyl group is optionally substituted, as defined and described below and herein.

[0082] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain consisting solely of carbon and hydrogen, containing no unsaturation, and having from 1 to 12 carbon atoms, such as methylene, ethylene, propylene, n-butylene, and the like, which connects the rest of the molecule to a radical. The alkylene chain is connected to the rest of the molecule and to the radical through a single bond. The point of attachment of the alkylene chain to the rest of the molecule and to the radical can be through one carbon in the alkylene chain or through any two carbons within the chain. Unless otherwise specifically indicated in this specification, an alkylene chain is optionally substituted, as defined and described below and herein.

[0083] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain consisting solely of carbon and hydrogen, containing at least one double bond and having 2 to 12 carbon atoms, which connects the rest of the molecule to a radical, such as vinylene, propenylene, n-butenylene, and the like. The alkenylene chain is connected to the rest of the molecule and to the radical via a double bond or a single bond. The point of attachment of the alkylene chain to the rest of the molecule and the radical may be through one carbon or any two carbons within the chain. Unless otherwise specifically stated in this specification, the alkenylene chain is optionally substituted, as defined and described below and herein. "Aryl" refers to a radical derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing hydrogen atoms from ring carbon atoms. The aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon, with carbon being 6 to 18 carbon atoms, wherein at least one ring in the ring system is fully unsaturated, that is, according to Hückel theory, it contains a ring, a delocalized (4n+2)π electron system. Aryl includes, but is not limited to, groups such as phenyl (Ph), fluorenyl, and naphthyl. Unless otherwise specifically stated in this specification, the term "aryl" or the prefix "ar" (such as the "ar" in "aralkyl") means an aryl group that includes optional substitution, as defined and described below and herein.

[0084] "Aralkyl" refers to a group of the formula -R c -aryl groups, where R c is an alkylene chain as defined above, for example, benzyl, benzhydryl and the like. The alkylene chain portion of the aralkyl group is optionally substituted as described above for alkylene chains. The aryl portion of the aralkyl group is optionally substituted as described above for aryl groups.

[0085] "Aralkenyl" refers to a group of the formula -R d -aryl groups, where R d is an alkenylene chain as defined above. The aryl portion of the aralkenyl group is optionally substituted as described above for an aryl group. The alkenylene chain portion of the aralkenyl group is optionally substituted as defined above for an alkenylene group.

[0086] "Arylalkynyl" refers to a group of the formula -Re -aryl groups, where R e is an alkynylene chain as defined above. The aryl portion of the aralkynyl group is optionally substituted as described above for an aryl group. The alkynylene chain portion of the aralkynyl group is optionally substituted as defined above for an alkynylene chain.

[0087] "Carbocyclyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, including fused or bridged ring systems, with 3 to 15 carbon atoms. In certain embodiments, the carbocyclyl comprises 3 to 10 carbon atoms. In some embodiments, the carbocyclyl comprises 5 to 7 carbon atoms. The carbocyclyl is connected to the rest of the molecule via a single bond. The carbocyclyl is optionally saturated (i.e., containing only a single C-C bond) or unsaturated (i.e., containing one or more double or triple bonds). Fully saturated carbocyclyls are also referred to as "cycloalkyls." Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unsaturated carbocyclyls are also referred to as "cycloalkenyls." Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl groups include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, and the like. Unless otherwise specified herein, the term "carbocyclyl" includes optionally substituted carbocyclyl groups as defined and described below and herein. "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo substituents.

[0088] The terms "haloalkyl," "haloalkenyl," "haloalkynyl," and "haloalkoxy" include alkyl, alkenyl, alkynyl, and alkoxy structures in which at least one hydrogen atom is replaced by a halogen atom. In certain embodiments in which two or more hydrogen atoms are replaced by halogen atoms, the halogen atoms are all identical to one another. In some embodiments in which two or more hydrogen atoms are replaced by halogen atoms, the halogen atoms are not identical to one another.

[0089] "Fluoroalkyl" refers to an alkyl group as defined above substituted with one or more fluorine groups as defined above, for example, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl and the like. The alkyl portion of the fluoroalkyl group is optionally substituted as defined above for an alkyl group.

[0090] As used herein, the terms "non-aromatic heterocycle," "heterocycloalkyl," or "heteroalicyclic ring" refer to a non-aromatic ring in which one or more of the atoms forming the ring are heteroatoms. "Non-aromatic heterocycle" or "heterocycloalkyl" refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen, and sulfur. The group may be fused to an aryl or heteroaryl group. The heterocycloalkyl ring may be formed from 3 to 14 ring atoms, such as 3, 4, 5, 6, 7, 8, 9, or more than 9 ring atoms. The heterocycloalkyl ring is optionally substituted. In certain embodiments, the non-aromatic heterocycle contains one or more carbonyl or thiocarbonyl groups, such as oxo- and thio-containing groups. Examples of heterocycloalkyl groups include, but are not limited to, lactams, lactones, cyclic imides, cyclic sulfimides, cyclic carbamates, tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxine, 1,3-dioxane, 1,4-dioxine, 1,4-dioxane, piperazine, 1,3-oxathiinane, 1,4-oxathiinane, 1,4-oxathiinane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid,

[0014] Examples of heterocycloalkyl groups include 1,3-dioxolane, 1,3-dioxolane, 1,3-dithiole, 1,3-dithiole, 1,3-dithiole, 1,3-dithiole, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, and 1,3-oxathiolane. Illustrative examples of heterocycloalkyl groups, also known as non-aromatic heterocycles, include: and similar groups. The term heteroalicyclic also includes all rings forming carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. Depending on the structure, a heterocycloalkyl group can be a monovalent group or a divalent group (i.e., a heterocycloalkylene group).

[0091] "Heteroaryl" refers to a radical derived from an aromatic ring radical consisting of 3 to 18 atoms, comprising 2 to 17 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, a heteroaryl group is a monocyclic, bicyclic, tricyclic or tetracyclic ring system in which at least one ring in the ring system is fully unsaturated, i.e., it contains a ring, a delocalized (4n+2)π electron system according to the Huckel theory. Heteroaryls include fused or bridged ring systems. In some embodiments, the heteroaryl ring has five, six, seven, eight, nine or more ring atoms. The heteroatoms in the heteroaryl group are optionally oxidized. If one or more nitrogen atoms are present, they are optionally quaternized. The heteroaryl group is attached to the rest of the molecule via any ring atom. Examples of heteroaryls include, but are not limited to, aza benzo[b][1,4]dioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxolyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyrone, benzofuranyl, benzofuranone, benzothiophenyl (benzophenylthio), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h] Cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furano[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocyclooctano[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocyclooctano[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocyclooctano[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, dihydroindolinyl, isoindolyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-dihydroquinazolinyl, Pyridyl, 1,6- Pyridone, oxadiazolyl, 2-oxoazepine yl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenolazinyl, phenothiazinyl, phenoloxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5, 6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and phenylthio (i.e., thienyl). Unless otherwise specifically stated in the specification, the term "heteroaryl" is intended to include heteroaryl groups as defined above, which are optionally substituted as defined and described below and in the present invention.

[0092] "N-heteroaryl" refers to a heteroaryl group as defined above that contains at least one nitrogen atom and wherein the point of attachment of the heteroaryl group to the rest of the molecule is through the nitrogen atom in the heteroaryl group. N-heteroaryl groups are optionally substituted as described above for heteroaryl groups.

[0093] "C-heteroaryl" refers to a heteroaryl group as defined above, and wherein the point of attachment of the heteroaryl group to the rest of the molecule is through a carbon atom in the heteroaryl group. A C-heteroaryl group is optionally substituted as described above for a heteroaryl group.

[0094] "Heteroarylalkyl" refers to a group of the formula -R C -heteroaryl groups, wherein R C is an alkylene chain as defined above. If the heteroaryl group is a nitrogen-containing heteroaryl group, the heteroaryl group is optionally attached to the alkyl group at the nitrogen atom. The alkylene chain of the heteroarylalkyl group is optionally substituted as defined above for the alkylene chain. The heteroaryl portion of the heteroarylalkyl group is optionally substituted as defined above for the heteroaryl group.

[0095] "Thio" refers to an -S- group.

[0096] "Sulfinyl" refers to a -S(=O)- group.

[0097] "Sulfonyl" refers to a -S(=O)2- group.

[0098] "Amino" refers to a -NH2 group.

[0099] "Cyano" refers to a -CN group.

[0100] "Nitro" refers to a -NO2 group.

[0101] "Oxa" refers to an -O- group.

[0102] "Oxo" refers to a =0 group.

[0103] "Imino" refers to a =NH group.

[0104] "Thioketo" refers to a =S group.

[0105] An "alkoxy" group refers to an (alkyl)O- group where alkyl is as defined herein.

[0106] An "aryloxy" group refers to an (aryl)O- group in which aryl is as defined herein.

[0107] "Carbocyclylalkyl" refers to an alkyl group, as defined herein, substituted with a carbocyclyl group. "Cycloalkylalkyl" refers to an alkyl group, as defined herein, substituted with a cycloalkyl group. Non-limiting cycloalkylalkyl groups include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and the like.

[0108] As used herein, the terms "heteroalkyl," "heteroalkenyl," and "heteroalkynyl" include optionally substituted alkyl, alkenyl, and alkynyl groups in which one or more backbone chain atoms are heteroatoms, such as oxygen, nitrogen, sulfur, silicon, phosphorus, or combinations thereof. The heteroatom(s) may be placed at any interior position of the heteroalkyl group or at the position at which the heteroalkyl group is attached to the remainder of the molecule. Examples include, but are not limited to, -CH2-O-CH3, -CH2-CH2-O-CH3, -CH2-NH-CH3, -CH2-CH2-NH-CH3, -CH2-N(CH3)-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. In addition, up to two heteroatoms may be consecutively attached, such as -CH2-NH-OCH3 and -CH2-O-Si(CH3)3.

[0109] The term "heteroatom" refers to an atom other than carbon or hydrogen. Heteroatoms are typically independently selected from oxygen, sulfur, nitrogen, silicon, and phosphorus, but are not limited to such atoms. In embodiments where two or more heteroatoms are present, the two or more heteroatoms may be the same as one another, or some or all of the two or more heteroatoms may each be different from the other heteroatoms.

[0110] The terms "bond," "direct bond," or "single bond" refer to a chemical bond between two atoms or moieties of a group when the atoms connected by the bond are considered part of a larger substructure.

[0111] "Isocyanato" refers to an -NCO group.

[0112] "Isothiocyanato" refers to a -NCS group.

[0113] The term "moiety / molecular moiety" refers to a specific segment or functional group of a molecule. A chemical moiety is a generally recognized chemical entity embedded in or attached to a molecule.

[0114] "Thioalkoxy" or "alkylthio" refers to an -S-alkyl group.

[0115] "Alkylsulfanyl" refers to an alkyl group substituted with an -S-alkyl group.

[0116] As used herein, the term "acyloxy" refers to a group of formula RC(=O)O-.

[0117] "Carboxyl" refers to a -C(O)OH group.

[0118] As used herein, the term "acetyl" refers to a group of formula -C(=O)CH3.

[0119] "Acyl" refers to the group -C(O)R.

[0120] As used herein, the term "trihalomethanesulfonyl" refers to a group of formula X3CS(=O)2-, wherein X is a halogen.

[0121] "Cyanoalkyl" refers to an alkyl group, as defined herein, substituted with at least one cyano group.

[0122] As used herein, the term "N-sulfonamido" or "sulfonylamino" refers to a group of formula RS(=O)2NH-.

[0123] As used herein, the term "O-carbamoyl" refers to a group of formula -OC(=O)NR2.

[0124] As used herein, the term "N-carbamyl" refers to a group of formula ROC(=O)NH-.

[0125] As used herein, the term "O-thiocarbamoyl" refers to a group of formula -OC(=S)NR2.

[0126] As used herein, the term "N-thiocarbamyl" refers to a group of formula ROC(=S)NH-.

[0127] As used herein, the term "C-amido" refers to a group of formula -C(=O)NR2.

[0128] "Aminocarbonyl" refers to a -CONH2 group.

[0129] As used herein, the term "N-amido" refers to a group of formula RC(=O)NH-.

[0130] "Hydroxyalkyl" refers to an alkyl group, as defined herein, substituted with at least one hydroxy group. Non-limiting examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl, and 2-(hydroxymethyl)-3-hydroxypropyl.

[0131] "Alkoxyalkyl" refers to an alkyl group, as defined herein, substituted with an alkoxy group, as defined herein.

[0132] An "alkenyloxy" group refers to an (alkenyl)O- group where alkenyl is as defined herein.

[0133] The term "alkylamino" refers to -N(alkyl) x H y wherein x and y are selected from x = 1, y = 1 and x = 2, y = 0. When x = 2, the alkyl group together with the nitrogen atom to which it is attached may optionally form a cyclic ring system.

[0134] "Alkylaminoalkyl" refers to an alkyl group, as defined herein, substituted with an alkylamino group, as defined herein.

[0135] "Amide" is a chemical group moiety with the formula -C(O)NHR or -NHC(O)R, wherein R is selected from alkyl, cycloalkyl, aryl, heteroaryl (connected via a ring carbon atom) and heteroalicyclic (connected via a ring carbon atom). The amide group moiety can form a bond between an amino acid or a peptide molecule and the compound described in the present invention, thereby forming a prodrug. Any amine or carboxyl side chain on the compounds described in the present invention can be amidated. The method for preparing such amides and specific groups are known to those skilled in the art and can be easily learned in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York, Ny, 1999 (incorporated herein by reference in its entirety).

[0136] The term "ester" refers to a chemical group moiety having the formula -COOR, wherein R is selected from alkyl, cycloalkyl, aryl, heteroaryl (attached via a ring carbon atom), and heteroalicyclic (attached via a ring carbon atom). Any hydroxyl or carboxyl side chain on the compounds of the present invention may be esterified. Methods and specific groups for preparing such esters are known to those skilled in the art and can be readily found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, New York, Ny, 1999 (incorporated herein by reference in its entirety).

[0137] As used herein, the term "ring" refers to any covalently closed structure. Rings include, for example, carbocyclic rings (e.g., aryl and cycloalkyl), heterocyclic rings (e.g., heteroaryl and non-aromatic heterocycles), aromatic rings (e.g., aryl and heteroaryl), and non-aromatic rings (e.g., cycloalkyl and non-aromatic heterocycles). Rings may be optionally substituted. Rings may be monocyclic or polycyclic.

[0138] As used herein, the term "ring system" refers to one or more than one ring.

[0139] The term "ring of..." includes any cyclic structure. The term "ring of..." refers to the number of skeletal atoms that form the ring. Thus, for example, cyclohexyl, pyridine, pyran, and thiopyran are rings of 6 atoms, and cyclopentyl, pyrrole, furan, and thiophene are rings of 5 atoms.

[0140] The term "fused" refers to structures in which two or more rings share one or more bonds.

[0141] As described herein, the compounds of the present invention may be "optionally substituted" or may be "optionally substituted". In general, the term "substituted", whether or not preceded by the term "optionally", means that one or more hydrogens of the indicated group portion are replaced by a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted by more than one substituent selected from a specified group, the substituents at each position may be the same or different. The combinations of substituents envisioned by the present invention are preferably those that result in the formation of stable or chemically feasible compounds. As used herein, the term "stable" refers to a compound that does not substantially change when subjected to conditions that allow its production, detection, and (in certain embodiments) its recovery, purification, and use for one or more of the purposes disclosed herein.

[0142] Suitable monovalent substituents on the substitutable carbon atoms of an "optionally substituted" group are each independently halogen; -(CH2) 0-4 R°; -(CH2) 0-4 OR°; -O(CH2) 0-4 R o 、-O-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 CH(OR°)2;-(CH2) 0- 4SR°; -(CH2) 0-4 Ph, which may be substituted by R°; -(CH2) 0-4 O(CH2) 0-1 Ph, which may be substituted by R°; -CH=CHPH, which may be substituted by R°; -(CH2) 0-4 O(CH2) 0-1 -pyridyl, which may be substituted by R°; -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R°)2;-(CH2) 0-4 N(R°)C(O)R°;-N(R°)C(S)R°;-(CH2) 0-4 N(R°)C(O)NR°2;-N(R°)C(S)NR°2;-(CH2) 0-4 N(R°)C(O)OR°; -N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; -(CH2) 0-4 C(O)R°;-C(S)R°;-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 C(O)SR°;-(CH2) 0-4C(O)OSiR°3;-(CH2) 0-4 OC(O)R°; -OC(O)(CH2) 0-4 SR-, -SC(S)SR°; -(CH2) 0-4 SC(O)R°;-(CH2) 0-4 C(O)NR°2;-C(S)NR°2;-C(S)SR°;-(CH2) 0-4 OC(O)NR°2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -C(NOR°)R°; -(CH2) 0-4 SSR°; -(CH2) 0-4 S(O)2R°;-(CH2) 0-4 S(O)2OR°;-(CH2) 0-4 OS(O)2R°;-S(O)2NR°2;-(CH2) 0-4 S(O)R°; -N(R°)S(O)2NR°2; -N(R°)S(O)2R°; -N(OR°)R°; -C(NH)NR°2; -P(O)2R°; -P(O)R°2; -OP(O)R°2; -OP(O)(OR°)2; SiR°3; -(C 1-4 linear or branched alkylene)ON(R°)2; or -(C 1-4 linear or branched alkylene) C(O)ON(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH2- (heteroaryl ring of 5-6 atoms), or an aryl ring of 5-6 atoms that is saturated, partially unsaturated, or has 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, regardless of the above definition, has two independent occurrences of R°, which, together with their intervening atom(s), form an aryl monocyclic or bicyclic ring of 3-12 atoms that is saturated, partially unsaturated, or has 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted as defined below.

[0143] Suitable monovalent substituents on R° (or the ring formed by two independent occurrences of R° together with their intervening atoms) are independently halogen, -(CH2) 0-2 R ● 、-(halogenated R ● ), -(CH2) 0-2 OH, -(CH2) 0-2 OR ● 、-(CH2) 0-2 CH(OR● )2;-O(halogenated R ● )、-CN、-N3、-(CH2) 0-2 C(O)R ● 、-(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● 、-(CH2) 0-2 SR ● 、-(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR ● 、-(CH2) 0-2 NR ● 2. -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● 、-(C 1-4 linear or branched alkylene)C(O)OR ● , or -SSR ● , where each R ● is unsubstituted or, in the case of "halo" in front, is substituted only with one or more halogens, and is independently selected from C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a saturated, partially unsaturated, or aromatic ring of 5-6 atoms having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =O and =S.

[0144] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following: =0, =S, =NNR * 2. =NNHC(O)R * 、=NNHC(O)OR * 、=NNHS(O)2R * 、=NR * 、=NOR * 、-O(C(R * 2)) 2-3 O- or -S(C(R * 2)) 2-3 S-, where each independent occurrence of R * are respectively selected from hydrogen, C 1-6An aliphatic group which may be substituted as defined below; or an unsubstituted 5-6 atom saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents attached to an adjacent substitutable carbon of an "optionally substituted" group include: -O(CR * 2) 2- 3O-, where each independent occurrence of R * are independently selected from hydrogen, C which may be substituted as defined below 1-6 an aliphatic group, or an unsubstituted aromatic ring consisting of 5-6 atoms, which is saturated, partially unsaturated, or has 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0145] R * Suitable substituents on the aliphatic group include halogen, -R ● 、-(halogenated R ● ), -OH, -OR ● 、-O(halogenated R ● )、-CN、-C(O)OH、-C(O)OR ● 、-NH2、-NHR ● 、-NR ● 2 or -NO2, where each R ● is unsubstituted or, when preceded by "halo", is substituted only by one or more halogens, and is independently C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or an aryl ring consisting of 5-6 atoms which is saturated, partially unsaturated, or has 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0146] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include Among them are independently hydrogen, C 1-6 an aliphatic group which may be substituted as defined below: unsubstituted -OPh, or an unsubstituted aromatic ring of 5-6 atoms consisting of a saturated, partially unsaturated, or unsubstituted aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definitions, two independent occurrences of Together with its (one or more) intervening atoms, it forms an unsubstituted aryl monocyclic or bicyclic ring consisting of 3-12 atoms, which is saturated, partially unsaturated, or has 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0147] Suitable substituents on the aliphatic group are independently halogen, -R ● 、-(halogenated R ● ), -OH, -OR ●、-O(halogenated R ● )、-CN、-C(O)OH、-C(O)OR ● 、-NH2、-NHR ● 、-NR ● 2 or -NO2, where each R ● is unsubstituted or, when preceded by "halo", is substituted only by one or more halogens, and is independently C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or an aryl ring consisting of 5-6 atoms which is saturated, partially unsaturated, or has 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0148] The term "nucleophile" or "nucleophile" refers to an electron-rich compound or a radical thereof.

[0149] The term "electrophile" or "electrophile" refers to a molecule or moiety that lacks electrons or is electron-deficient. Examples of electrophiles include, but are not limited to, Michael acceptor moieties.

[0150] As used herein with respect to a formulation, composition or ingredient, the term "acceptable" or "pharmaceutically acceptable" means having no persistent adverse effect on the general health of the subject being treated, does not abrogate the biological activity or properties of the compound, and is relatively non-toxic.

[0151] As used herein, "amelioration" of the symptoms of a particular disease, disorder, or condition by the administration of a particular compound or pharmaceutical composition refers to any lessening of severity, delay in onset, slowing of progression, or shortening of duration, whether permanent or temporary, sustained or transient, attributable to or associated with the administration of the compound or composition.

[0152] "Bioavailability" refers to the percentage by weight of a compound disclosed herein, such as any one of Formulas (I)-(XLIIIc), that is delivered to the general circulation of the animal or human being studied. When administered intravenously, the total exposure (AUC (0-∞) ) is generally defined as 100% bioavailable (F%). "Oral bioavailability" refers to the extent to which a disclosed compound (such as a compound of Formula (I)-(XLIIIc)) is absorbed into the systemic circulation when the pharmaceutical composition is taken orally, as compared to intravenous injection.

[0153] "Plasma concentration" refers to the concentration of a compound disclosed herein, such as a compound of any of Formulas (I)-(XLIIIc), in the plasma fraction of the blood of an individual. It is understood that the plasma concentration of a compound of any of Formulas (I)-(XLIIIc) may vary significantly between individuals due to variability associated with metabolism and / or possible interactions with other therapeutic agents. According to some embodiments disclosed herein, the plasma concentration of a compound of any of Formulas (I)-(XLIIIc) may vary between individuals. Similarly, between different individuals, such as the maximum plasma concentration (C max ) or time to maximum plasma concentration (T max ) or the total area under the plasma concentration-time curve (AUC (0-∞) Because of this variability, the amount required to constitute a "therapeutically effective amount" of a compound of any one of Formulas (I)-(XLIIIc) may vary between individuals.

[0154] As used herein, the term "co-administration" or its analogous forms is meant to encompass the administration of selected therapeutic agents to a single patient and is intended to include treatment regimens in which the agents are administered by the same or different routes of administration, or at the same time or at different times.

[0155] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of an administered agent or compound sufficient to alleviate to some extent one or more symptoms of the disease or condition being treated. The result can be a reduction and / or alleviation of the signs, symptoms, or cause of the disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound as disclosed herein required to provide a clinically significant reduction in disease symptoms without undue adverse side effects. Techniques such as dose escalation studies can be used to determine the appropriate "effective amount" in any individual case. The term "therapeutically effective amount" includes, for example, a prophylactic effective amount. An "effective amount" of a compound disclosed herein is an amount effective to achieve the desired pharmacological effect or therapeutic improvement without undue adverse side effects. It should be understood that the "effective amount" or "therapeutically effective amount" may vary between individuals due to differences in the metabolism of any compound of Formula (I)-(XVII), the individual's age, weight, general condition, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician. By way of example only, a therapeutically effective amount can be determined by routine experimentation including, but not limited to, dose escalation clinical trials.

[0156] The terms "enhance" or "enhancing" refer to increasing or prolonging the potency or duration of a desired effect. As an example, "enhancing" the effect of a therapeutic agent refers to the ability to increase or prolong, in potency or duration, the effect of a therapeutic agent during the treatment of a disease, disorder, or condition. As used herein, an "enhancing-effective amount" refers to an amount sufficient to enhance the effect of a therapeutic agent in treating a disease, disorder, or condition. When used in a patient, the effective amount for this use will depend on the severity and course of the disease, disorder, or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.

[0157] As used in the present invention, the term "identity" refers to that two or more sequences or subsequences are identical. In addition, as used in the present invention, the term "substantial identity" refers to that two or more sequences are compared and compared according to maximum identity (such as measured by using a comparison algorithm or by manual comparison and visual inspection) on a comparison window or a specified region, and the same sequence unit reaches a certain percentage. For example only, if the sequence unit has about 60% identity, about 65% identity, about 70% identity, about 75% identity, about 80% identity, about 85% identity, about 90% identity or about 95% identity on a specified region, then two or more sequences can be "substantially identical". Such percentages are used to describe the "percentage identity" of two or more sequences. Sequence identity can exist in a region of at least about 75-100 continuous units in length, a region of about 50 continuous units in length, or exist in the entire sequence when not specified. This definition also refers to the complementary sequence of a test sequence. By way of example only, two or more polypeptide sequences are identical when the amino acid residues are identical, and are “substantially identical” if the amino acid residues are about 60% identical, 65% identical, 70% identical, 75% identical, 80% identical, 85% identical, 90% identical, or about 95% identical over a specified region. Identity can exist over a region that is at least about 75-100 amino acids in length, over a region that is about 50 amino acids in length, or, when not specified, over the entire sequence of the polypeptide sequence. Furthermore, by way of example only, two or more polynucleotide sequences are identical when the nucleic acid residues are identical, and are “substantially identical” if the nucleic acid residues are about 60% identical, about 65% identical, about 70% identical, about 75% identical, about 80% identical, about 85% identical, about 90% identical, or about 95% identical over a specified region. The identity can exist over a region that is at least about 75-100 nucleotides in length, over a region that is about 50 nucleotides in length, or, where not specified, across the entire sequence of a polynucleotide sequence.

[0158] As used herein, the term "isolation" refers to separating and removing a component of interest from non-target components. The isolated material may be in a dry or semi-dry state, or in the form of a solution, including but not limited to an aqueous solution. The isolated component may be in a homogenous state, or the isolated component may be part of a pharmaceutical composition comprising additional pharmaceutically acceptable carriers and / or excipients. By way of example only, a nucleic acid or protein is "isolated" when it is free of at least some of the cellular components with which it is associated in its native state, or when the nucleic acid or protein has been concentrated to a level greater than the concentration at which it is produced in vivo or in vitro. Additionally, for example, a gene is isolated when it is separated from open reading frames that flank the gene and encode proteins other than the gene of interest.

[0159] "Metabolites" of the compounds disclosed herein are derivatives of the compounds formed when the compounds are metabolized. The term "active metabolite" refers to biologically active derivatives of the compounds formed when the compounds are metabolized. As used herein, the term "metabolism" refers to the sum of processes by which a particular substance is altered by an organism (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes, such as oxidation reactions). Thus, enzymes can cause specific structural changes in a compound. For example, cytochrome P450 catalyzes a variety of oxidation and reduction reactions, while UDP-glucuronosyltransferase catalyzes the conversion of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups. Further information on metabolism can be obtained from The Pharmacological Basis of Therapeutics, 9th ed., Mcgraw-Hill (1996). Metabolites of the compounds disclosed herein can be identified by administering the compounds to a host and analyzing tissue samples from the host; or by incubating the compounds in hepatocytes in vitro and analyzing the resulting compounds. Both methods are well known in the art. In some embodiments, a metabolite of a compound is formed by an oxidative process and corresponds to the corresponding hydroxyl-containing compound. In some embodiments, a compound is metabolized to a pharmacologically active metabolite.

[0160] As used herein, the term "modulate" refers to interacting directly or indirectly with a target to change the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or extending the activity of the target.

[0161] As used herein, the term "modulator" refers to a compound that alters the activity of a molecule. For example, a modulator can cause the magnitude of a certain activity of a molecule to increase or decrease compared to the magnitude of the activity in the absence of the modulator. In certain embodiments, a modulator is an inhibitor that decreases the magnitude of one or more activities of a molecule. In certain embodiments, an inhibitor completely blocks one or more activities of a molecule. In certain embodiments, a modulator is an activator that increases the magnitude of at least one activity of a molecule. In certain embodiments, the presence of a modulator produces an activity that does not occur in the absence of the modulator.

[0162] As used herein, the term "irreversible inhibitor" refers to a compound that, upon contact with a target protein (e.g., menin), results in the formation of new covalent bonds with or within the protein, and one or more biological activities of the target protein (e.g., phosphotransferase activity) are reduced or abolished, regardless of the subsequent presence of the irreversible inhibitor. In contrast, a reversible inhibitor compound, upon contact with a target protein, does not result in the formation of new covalent bonds with or within the protein and, therefore, can associate with and dissociate from the target protein.

[0163] As used herein, the term "irreversible inhibitor of menin-MLL protein-protein interaction" refers to a menin inhibitor that can form a covalent bond with an amino acid residue of menin. In one embodiment, the irreversible inhibitor of menin can form a covalent bond with a Cys residue of menin; in a specific embodiment, the irreversible inhibitor can form a covalent bond with Cys 329 residue of menin (or a homolog thereof).

[0164] As used herein, the term "prophylactically effective amount" refers to an amount of the composition that, when administered to a patient, will alleviate to some extent one or more symptoms of the disease, condition, or disorder being treated. In such prophylactic applications, such amount may depend on the patient's health status, weight, etc. It is considered well within the skill of those skilled in the art to determine such a prophylactically effective amount by routine experimentation (including, but not limited to, a dose escalation clinical trial).

[0165] As used herein, the term "selective binding compound" refers to a compound that selectively binds to any portion of one or more target proteins.

[0166] As used herein, the term "selective binding" refers to the ability of a selective binding compound to bind to a target protein (such as menin) with greater affinity than when it binds to a non-target protein. In certain embodiments, specific binding refers to binding to a target with an affinity that is at least 10, 50, 100, 250, 500, 1000, or more times greater than the affinity for a non-target.

[0167] As used herein, the term "selective modulator" refers to a compound that selectively modulates a target activity relative to a non-target activity. In certain embodiments, a specific modulator modulates a target activity at least 10, 50, 100, 250, 500, 1000-fold more than a non-target activity.

[0168] As used herein, the term "substantially purified" refers to a component of interest that is substantially or essentially free of other components that normally accompany or interact with the component of interest prior to purification. By way of example only, a component of interest may be "substantially purified" when its preparation contains less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% (by dry weight) of a contaminating component. Thus, a "substantially purified" component of interest may have a purity level of about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99% or more.

[0169] As used herein, the term "subject" or "patient" refers to an animal that is the subject of treatment, observation, or experiment. By way of example only, the subject may be, but is not limited to, a mammal, including, but not limited to, a human.

[0170] As used herein, the term "target activity" refers to a biological activity that can be modulated by a selective modulator. Certain exemplary target activities include, but are not limited to, binding affinity, signal transduction, enzyme activity, tumor growth, inflammation or inflammation-related processes, and improvement of one or more symptoms associated with a disease or condition.

[0171] As used herein, the term "target protein" refers to a molecule or portion of a protein that can be bound by a selective binding compound. In certain embodiments, the target protein is menin.

[0172] As used herein, the terms "treat," "treating," or "treatment" include alleviating, alleviating, or ameliorating symptoms of a disease or condition; preventing other symptoms; ameliorating or preventing the underlying metabolic causes of symptoms; inhibiting the disease or condition, such as arresting the progression of the disease or condition; relieving the disease or condition; causing regression of the disease or condition; alleviating symptoms caused by the disease or condition; or halting symptoms of the disease or condition. The terms "treat," "treating," or "treatment" include, but are not limited to, prophylactic and / or therapeutic treatment.

[0173] As used in the present invention, IC 50It refers to the amount, concentration, or dose of a particular test compound that achieves 50% inhibition of a maximal response (such as inhibition of menin-MLL) in an assay measuring such a response.

[0174] As used in the present invention, EC 50 It refers to the dose, concentration or amount at which a particular test compound elicits a dose-dependent response that is 50% of the maximal expression of a particular response induced, provoked or enhanced by the particular test compound.

[0175] The methods described herein comprise administering to a subject in need thereof a composition comprising a therapeutically effective amount of one or more menin-MLL inhibitor compounds described herein.

[0176] In some embodiments, the methods of the present invention can be used to treat autoimmune diseases including, but not limited to, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, lupus, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Odd's thyroiditis, Grave's disease, Sjögren's syndrome, multiple sclerosis, Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitis, Antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Good-Burster's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behçet's disease, chronic fatigue, dysautonomia, endometriosis, interstitial cystitis, neuromyotonia, scleroderma, or vulvodynia.

[0177] In some embodiments, the methods described herein can be used to treat heteroimmune diseases or disorders, including but not limited to graft-versus-host disease, transplantation, infusion, anaphylaxis, allergies (e.g., to plant pollens, latex, drugs, foods, insect poisons, animal hair, animal dander, dust mites, or cockroach calyx), type I hypersensitivity reactions, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis.

[0178] In some embodiments, the methods of the present invention can be used to treat inflammatory diseases, including but not limited to asthma, inflammatory bowel disease, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitis suppurativa, Laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, or vulvitis.

[0179] In some embodiments, the methods described herein can be used to treat cancer, such as B-cell proliferative disorders including, but not limited to, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenstrom's macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, and lymphomatoid granulomatosis.

[0180] In some embodiments, the methods described herein can be used to treat thromboembolic disorders, including but not limited to myocardial infarction, angina (including unstable angina), reocclusion or restenosis after angioplasty or aortocoronary bypass, stroke, transient ischemia, peripheral arterial occlusive disorders, pulmonary embolism, or deep vein thrombosis.

[0181] Symptom diagnostic tests and prognostic tests for the various conditions mentioned above are known in the art. See, for example, Harrison's Principles of Internal Medicine. 16th ed., 2004, The McGraw-Hill Companies, Inc.; Dey et al. (2006), Cytojournal 3(24), and the "Revised European American Lymphoma" (REAL) classification system (see, for example, the website maintained by the National Cancer Institute).

[0182] A variety of animal models are useful for establishing therapeutically effective dosage ranges of Menin-MLL inhibitor compounds for treating any of the aforementioned diseases.

[0183] For example, the dosage of a Menin-MLL inhibitor compound for treating autoimmune diseases can be evaluated in a mouse model of rheumatoid arthritis. In this model, anti-collagen antibodies and lipopolysaccharide are administered to induce arthritis in Balb / c mice. See Nandakumar et al. (2003), Am. J. Pathol 163:1827-1837.

[0184] In another example, doses of Menin-MLL inhibitors for treating B-cell proliferative disorders can be tested, for example, in a human-to-mouse xenograft model in which human B-cell lymphoma cells (e.g., Ramos cells) are implanted into immunodeficient mice (e.g., "nude" mice), as described, for example, in Pagel et al. (2005), Clin Cancer Res 11(13):4857-4866.

[0185] Animal models for treating thromboembolic disorders are also known.

[0186] The therapeutic efficacy of a provided compound for one of the aforementioned diseases can be optimized during the course of treatment. For example, a treated individual can undergo a diagnostic evaluation to correlate the alleviation of disease symptoms or pathology with the inhibition of Menin-MLL activity in vivo achieved by administering a given dose of a Menin-MLL inhibitor. Compound

[0187] In the following description of Menin-MLL inhibitor compounds suitable for use in the methods of the present invention, definitions of standard chemical terms are found in the referenced works (unless otherwise defined herein), including Carey and Sundberg's "Advanced Organic Chemistry, 4th Edition," Volumes A (2000) and B (2001), Plenum Press, New York. Conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology, within the ordinary skill of those skilled in the art, are employed unless otherwise indicated. Unless specific definitions are provided, the nomenclature employed in connection with analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein, and the laboratory procedures and techniques thereof, are those known in the art. Standard techniques may be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients.

[0188] Menin-MLL inhibitor compounds can be used in the preparation of a medicament for treating any of the aforementioned disorders (eg, autoimmune diseases, inflammatory diseases, allergic disorders, B-cell proliferative disorders, myeloproliferative disorders, lymphoproliferative disorders, or thromboembolic disorders).

[0189] In some embodiments, the Menin-MLL inhibitor compounds used in the methods of the present invention inhibit Menin-MLL activity with an in vitro IC 50 less than about 10 μM (e.g., less than about 1 μM, less than about 0.5 μM, less than about 0.4 μM, less than about 0.3 μM, less than about 0.1 μM, less than about 0.08 μM, less than about 0.06 μM, less than about 0.05 μM, less than about 0.04 μM, less than about 0.03 μM, less than about 0.02 μM, less than about 0.01 μM, less than about 0.008 μM, less than about 0.006 μM, less than about 0.005 μM, less than less than about 0.004 μM, less than about 0.003 μM, less than about 0.002 μM, less than about 0.001 μM, less than about 0.00099 μM, less than about 0.00098 μM, less than about 0.00097 μM, less than about 0.00096 μM, less than about 0.00095 μM, less than about 0.00094 μM, less than about 0.00093 μM, less than about 0.00092 μM or less than about 0.00090 μM).

[0190] In some embodiments, Menin-MLL inhibitor compounds selectively inhibit the activated form of its target, menin.

[0191] The present invention also describes methods for synthesizing such irreversible inhibitors, methods of using such irreversible inhibitors to treat diseases, including diseases in which inhibition of the menin-MLL interaction provides a therapeutic benefit to patients suffering from the disease. The present invention further describes pharmaceutical compositions comprising inhibitors of the menin-MLL interaction. Specifically, the present invention describes compounds and methods of using the same to inhibit the interaction of menin with MLL oncoproteins (e.g., MLL1, MLL2, MLL fusion oncoproteins).

[0192] The present invention specifically describes irreversible inhibitors of the menin-MLL interaction that form a covalent bond with a cysteine ​​residue on menin. The present invention further describes irreversible inhibitors of the menin-MLL interaction that form a covalent bond with the Cys329 residue on menin. The present invention also describes pharmaceutical formulations comprising the irreversible menin inhibitors.

[0193] The menin inhibitor compounds of the present invention are selective for menin having a cysteine ​​residue at an amino acid sequence position in the menin protein that is homologous to the amino acid sequence position of cysteine ​​329 in menin. The irreversible inhibitor compounds of the present invention include a Michael acceptor group portion.

[0194] Generally, the reversible or irreversible menin inhibitor compounds used in the methods of the present invention are identified or characterized in in vitro assays, such as cell-free biochemical assays or cell-based functional assays. Such assays can be used to determine the in vitro IC values ​​of reversible or irreversible menin inhibitor compounds. 50 .

[0195] In addition, the formation of a covalent complex between menin and a candidate irreversible menin inhibitor is a useful indicator of irreversible menin inhibition, which can be readily determined by various methods known in the art (e.g., mass spectrometry). For example, some irreversible menin inhibitor compounds can form a covalent bond with Cys 329 of menin (e.g., via a Michael reaction). See S. Xu et al. Angewandte Chemie International Ed. 57 (6), 1601-1605 (2017) (incorporated herein by reference in its entirety).

[0196] The present invention describes compounds of any of Formulas (I)-(XIVc). The present invention also describes pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable metabolites, and pharmaceutically acceptable prodrugs of such compounds. The present invention provides pharmaceutical compositions comprising at least one such compound or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically active metabolite, or pharmaceutically acceptable prodrug of such a compound. In some embodiments, when the compounds disclosed herein contain an oxidizable nitrogen atom, the nitrogen atom can be converted to an N-oxide by methods known in the art. In certain embodiments, the present invention also provides isomers and chemically protected forms of compounds having a structure represented by any of Formulas (I)-(XLIIIc).

[0197] In some embodiments, the present invention provides irreversible inhibitors of menin-MLL according to the compound represented by formula (I).

[0198] In some embodiments, the present invention provides a compound represented by formula (I) having the following structure: or a pharmaceutically acceptable salt thereof, in: A is C or N; Cy is substituted or unsubstituted Q is N, -N(H)-, -O-, or -S-; Z is -CR 5a =, or -N=; X is -NR 3a -、-C(R 3b )2-, or -O-; Y is a single bond, -NR 3a -、-C(R 3b )2-, or -O-; W is -C(O)-, -S(O)-, or -S(O)2-; R 1 and R 2 One of them is Cy 2 -N(H)C(O)-C(R 6a )=C(R 6b )(R 6c ), or CH2-Cy 2 -N(H)C(O)-C(R 6a )=C(R 6b )(R 6c ); and the other is H, C 1-6 Alkyl, C 1-6 Haloalkyl, halogen, or CN; Cy 2 is an optionally substituted group selected from the group consisting of phenyl, pyridyl, or a heterocycloalkyl ring of 4 to 7 atoms having 1 to 2 heteroatoms independently selected from N, O, or S; Each R 3a and R 3b are independently H or C 1-6 alkyl; Each R 4a and R 4b are independently H, halogen, CN, OR, -N(R)2, -C(O)N(R)2, -NRC(O)R, -SO2R, -C(O)R, -CO2R, or an optionally substituted group selected from the following: C 1-6 Alkyl, C 3-7 Cycloalkyl, heterocycloalkyl rings consisting of 4-7 atoms having 1-2 heteroatoms independently selected from N, O, or S, phenyl, bicyclic aryl rings consisting of 8-10 atoms, and heteroaryl rings consisting of 5-6 atoms having 1-4 heteroatoms independently selected from N, O, or S; Each R is independently H, or an optionally substituted group selected from the following: C 1-6aliphatic, phenyl, a bicyclic aryl ring consisting of 8-10 atoms, a saturated or partially unsaturated heterocyclic ring consisting of 4-7 atoms having 1-2 heteroatoms independently selected from N, O or S, and a heteroaryl ring consisting of 5-6 atoms having 1-4 heteroatoms independently selected from N, O or S, or: Two R groups on the same nitrogen atom together with their intervening atoms form a heteroaryl ring of 4-7 atoms which is saturated, partially unsaturated, or has 0-3 heteroatoms independently selected from N, O or S in addition to the nitrogen atom; R 5a H, C 1-6 Alkyl, C 1-6 Haloalkyl, halogen, or CN; Each R 6a and R 6b are independently H or C 1-6 Alkyl; or R 6a and R 6b joined together to form a bond; R 6c is H, or substituted or unsubstituted C 1-6 alkyl; m is 1, 2, or 3; and n is 1, 2, 3, or 4.

[0199] In some embodiments, W is -S(O)-, or -S(O)2-.

[0200] In some embodiments, W is -C(O)-.

[0201] In some embodiments, X is -NR 3a -; and Y is -C(R 3b )2-、-NR 3b -, or -O-.

[0202] In some embodiments, Y is a single bond, or -NR 3a -; and X is –C(R 3b )2-、-NR 3b -, or –O-.

[0203] In some embodiments, each X and Y is independently -NR 3a -.

[0204] In some embodiments, R 3a For H.

[0205] In some embodiments, R 3b It is H or Me.

[0206] In some embodiments, X and Y are each -N(H)-.

[0207] In some embodiments, –XWY- is –N(H)-C(O)-N(H)-, –N(H)-C(O)-CH2-, –CH2-C(O)-N(H)-, –N(H)-S(O)-N(H)-, –N(H)-S(O)-CH2-, –CH2-S(O)-N(H)-, –N(H)-S(O)2-N(H)-, –N(H)-S(O)2-CH2-, –CH2-S(O)2-N(H)-, or –N(H)-C(O)-.

[0208] In some embodiments, R 1 Cy 2 -N(H)C(O)-C(R 6a )=C(R 6b )(R 6c ), or CH2-Cy 2 -N(H)C(O)-C(R 6a )=C(R 6b )(R 6c ); and R 2 is H, halogen, hydroxy, CN, substituted or unsubstituted C 1-6 an alkyl group, a substituted or unsubstituted amino group, or a substituted or unsubstituted alkoxy group.

[0209] In some embodiments, R 1 Cy 2 -N(H)C(O)-C(R 6a )=C(R 6b )(R 6c ), or CH2-Cy 2 -N(H)C(O)-C(R 6a )=C(R 6b )(R 6c ); and R 2 is H, Me, Et, i-Pr, CF3, F, Cl, OMe, OEt, or CN.

[0210] In some embodiments, R 1 Cy 2 -N(H)C(O)-C(R 6a )=C(R 6b )(R 6c ), or CH2-Cy 2 -N(H)C(O)-C(R 6a )=C(R 6b )(R 6c ); and R 2 For H.

[0211] In some embodiments, R 2 Cy2 -N(H)C(O)-C(R 6a )=C(R 6b )(R 6c ), or CH2-Cy 2 -N(H)C(O)-C(R 6a )=C(R 6b )(R 6c ); and R 1 is H, halogen, hydroxy, CN, substituted or unsubstituted C 1-6 an alkyl group, a substituted or unsubstituted amino group, or a substituted or unsubstituted alkoxy group.

[0212] In some embodiments, R 2 Cy 2 -N(H)C(O)-C(R 6a )=C(R 6b )(R 6c ), or CH2-Cy 2 -N(H)C(O)-C(R 6a )=C(R 6b )(R 6c ); and R 1 is H, Me, Et, i-Pr, CF3, F, Cl, OMe, OEt, or CN.

[0213] In some embodiments, R 2 Cy 2 -N(H)C(O)-C(R 6a )=C(R 6b )(R 6c ), or CH2-Cy 2 -N(H)C(O)-C(R 6a )=C(R 6b )(R 6c ); and R 1 For H.

[0214] The compound according to claim 1, wherein -XWY- is -N(H)-C(O)-; R 1 -CH2-Cy 2 -N(H)C(O)-C(R 6a )=C(R 6b )(R 6c ); and R 2 For H.

[0215] In some embodiments, the compound has the structure shown in Formula (XXI): or a pharmaceutically acceptable salt thereof, Among them, A, Cy, Cy 2 、R 4b 、R 6a 、R 6b 、R 6c , m and n are all as defined above for formula (I); and each R 8 and R 9 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, halogen, or CN.

[0216] In some embodiments, R 8 and R 9 One of them is H, halogen, hydroxy, CN, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted amino, or substituted or unsubstituted alkoxy; and another is H.

[0217] In some embodiments, each R 8 and R 9 They are H, or Me respectively.

[0218] In some embodiments, each R 8 and R 9 They are H respectively.

[0219] In some embodiments, A is N.

[0220] In some embodiments, A is C.

[0221] In some embodiments, m is 1 or 2.

[0222] In some embodiments, n is 1 or 2.

[0223] In some embodiments, each R 4a are independently H, halogen, hydroxy, CN, substituted or unsubstituted C 1-6 an alkyl group, a substituted or unsubstituted amino group, or a substituted or unsubstituted alkoxy group.

[0224] In some embodiments, each R 4a are each independently H, Me, Et, i-Pr, CF3, F, Cl, OMe, OEt, or CN.

[0225] In some embodiments, each R 4a They are H respectively.

[0226] In some embodiments, each R 4b are independently H, halogen, hydroxy, CN, substituted or unsubstituted C 1-6 an alkyl group, a substituted or unsubstituted amino group, or a substituted or unsubstituted alkoxy group.

[0227] In some embodiments, each R 4b are each independently H, Me, Et, i-Pr, CF3, F, Cl, OMe, OEt, or CN.

[0228] In some embodiments, each R 4b They are H respectively.

[0229] In some embodiments, the compound has a structure represented by Formula (IIa), (IIb), (IIc), or (IId): or a pharmaceutically acceptable salt thereof.

[0230] In some embodiments, R 2 is H, Me, Et, i-Pr, CF3, F, Cl, OMe, OEt, or CN.

[0231] In some embodiments, R 2 For H.

[0232] In some embodiments, the compound has the structure shown in formula (XXIIa) or (XXIIb): or a pharmaceutically acceptable salt thereof; wherein Cy, Cy 2 、R 6a 、R 6b or R 6c All have the definitions given for formula (I).

[0233] In some embodiments, the compound has a structure represented by Formula (IIIa), (IIIb), (IIIc), or (IIId): or a pharmaceutically acceptable salt thereof.

[0234] In some embodiments, the compound of claim 1, wherein the compound has a structure represented by Formula (XXXIIa), (XXXIIb), (XXXIIc), (XXXIId), (XXXIIe), or (XXXIIf): or a pharmaceutically acceptable salt thereof.

[0235] In some embodiments, R 1 is H, Me, Et, i-Pr, CF3, F, Cl, OMe, OEt, or CN.

[0236] In some embodiments, R 1For H.

[0237] In some embodiments, the compound has a structure represented by Formula (XXXIIIa), (XXXIIIb), (XXXIIIc), (XXXIIId), (XXXIIIe), or (XXXIIIf): or a pharmaceutically acceptable salt thereof.

[0238] In some embodiments, Cy 2 is substituted or unsubstituted Ph, pyridyl, azetidinyl, pyrrolidinyl, piperidinyl, or azepine base.

[0239] In some embodiments, the compound has a structure shown in Formula (IVa) or (IVb): or a pharmaceutically acceptable salt thereof; and wherein p is 0, 1, 2, or 3.

[0240] In some embodiments, the compound has the structure shown in formula (XXIIIa) or (XXIIIb): or a pharmaceutically acceptable salt thereof; and wherein p is 0, 1, 2, or 3.

[0241] In some embodiments, Cy is substituted or unsubstituted

[0242] In some embodiments, Cy is substituted or unsubstituted

[0243] In some embodiments, Q is -N(H)-.

[0244] In some embodiments, Q is -O-.

[0245] In some embodiments, Q is -S-.

[0246] In some embodiments, Z is -N=.

[0247] In some embodiments, Z is -CR 5a =.

[0248] In some embodiments, R 5a is H, Me, Et, i-Pr, Cl, F, CF3, or CN.

[0249] In some embodiments, R 5a is H, Me, or F.

[0250] In some embodiments, R 5a For H.

[0251] In some embodiments, Z is -C(H)=.

[0252] In some embodiments, Cy is where R 7 is an optionally substituted group selected from a heterocycloalkyl ring consisting of 4 to 7 atoms having 1 to 2 heteroatoms independently selected from N, O or S, a phenyl group, a bicyclic aryl ring consisting of 8 to 10 atoms, and a heteroaryl ring consisting of 5 to 6 atoms having 1 to 4 heteroatoms independently selected from N, O or S.

[0253] In some embodiments, Cy is substituted or unsubstituted where R 7 is an optionally substituted group selected from a heterocycloalkyl ring consisting of 4 to 7 atoms having 1 to 2 heteroatoms independently selected from N, O or S, a phenyl group, a bicyclic aryl ring consisting of 8 to 10 atoms, and a heteroaryl ring consisting of 5 to 6 atoms having 1 to 4 heteroatoms independently selected from N, O or S.

[0254] In some embodiments, the compound has a structure shown in Formula (Va) or (Vb): or a pharmaceutically acceptable salt thereof; and wherein p is 0, 1, 2, or 3; and R 7 is an optionally substituted group selected from a heterocycloalkyl ring consisting of 4 to 7 atoms having 1 to 2 heteroatoms independently selected from N, O or S, a phenyl group, a bicyclic aryl ring consisting of 8 to 10 atoms, and a heteroaryl ring consisting of 5 to 6 atoms having 1 to 4 heteroatoms independently selected from N, O or S.

[0255] In some embodiments, the compound has the structure shown in Formula (XXIVa) or (XXIVb): or a pharmaceutically acceptable salt thereof; and wherein p is 0, 1, 2, or 3; and R 7 is an optionally substituted group selected from a heterocycloalkyl ring consisting of 4 to 7 atoms having 1 to 2 heteroatoms independently selected from N, O or S, a phenyl group, a bicyclic aryl ring consisting of 8 to 10 atoms, and a heteroaryl ring consisting of 5 to 6 atoms having 1 to 4 heteroatoms independently selected from N, O or S.

[0256] In some embodiments, the compound has a structure shown in Formula (XXXIVa) or (XXXIVb): or a pharmaceutically acceptable salt thereof.

[0257] In some embodiments, the compound has a structure shown in Formula (XXXVa) or (XXXVb): or a pharmaceutically acceptable salt thereof.

[0258] In some embodiments, the compound has a structure shown in Formula (XXXVIa) or (XXXVIb): or a pharmaceutically acceptable salt thereof.

[0259] In some embodiments, R 7 is a heterocycloalkyl ring composed of 4 to 7 atoms having 1 to 2 heteroatoms independently selected from N, O or S substituted by Me, Et or i-Pr.

[0260] In some embodiments, R 7 is pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl.

[0261] In some embodiments, R 7 It is a morpholinyl group.

[0262] In some embodiments, R 7 is a substituted or unsubstituted heteroaryl group.

[0263] In some embodiments, R 7 is a substituted or unsubstituted pyridyl or pyrimidinyl group.

[0264] In some embodiments, R 7 is an unsubstituted pyridyl group.

[0265] In some embodiments, R 7 is substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted amino, or substituted or unsubstituted alkoxy substituted pyridyl.

[0266] In some embodiments, R 7 is pyridyl substituted by Me, Et, i-Pr, OH, Cl, F, CF3, CN, or NH2.

[0267] In some embodiments, R 7 is pyridyl substituted by Me, Et, i-Pr, Cl, F, CF3, or CN.

[0268] In some embodiments, R 7 is substituted or unsubstituted pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, triazolyl, thiazolyl, oxadiazolyl, or thiadiazolyl.

[0269] In some embodiments, R 7 is a substituted or unsubstituted imidazolyl group.

[0270] In some embodiments, R 7 is an imidazolyl group substituted by Me, Et, i-Pr, Cl, F, CF3, or CN.

[0271] In some embodiments, R 7 is an imidazolyl group substituted by Me.

[0272] In some embodiments, the compound has a structure represented by formula (VIa) or (VIb): or a pharmaceutically acceptable salt thereof; and wherein p is 0, 1, 2, or 3.

[0273] In some embodiments, the compound has the structure shown in Formula (XXVa) or (XXVb): or a pharmaceutically acceptable salt thereof; and wherein p is 0, 1, 2, or 3.

[0274] In some embodiments, p is 0, 1, or 2.

[0275] In some embodiments, R 2 H or F.

[0276] In some embodiments, R 2 For H.

[0277] In some embodiments, the compound has a structure represented by Formula (VIIa), (VIIb), or (VIIc): or a pharmaceutically acceptable salt thereof.

[0278] In some embodiments, the compound has a structure represented by Formula (VIIIa), (VIIIb), or (VIIIc): or a pharmaceutically acceptable salt thereof.

[0279] In some embodiments, the compound has the structure shown in Formula (XXVIa), (XXVIb), or (XXVIc): or a pharmaceutically acceptable salt thereof.

[0280] In some embodiments, the compound has the structure shown in Formula (XXXVIIa) or (XXXVIIb): or a pharmaceutically acceptable salt thereof.

[0281] In some embodiments, the compound has the structure shown in Formula (XXXVIIIa) or (XXXVIIIb): or a pharmaceutically acceptable salt thereof.

[0282] In some embodiments, the compound has the structure shown in Formula (XXXIXa) or (XXXIXb): or a pharmaceutically acceptable salt thereof.

[0283] In some embodiments, R 6a 、R 6b and R 6c Each is H.

[0284] In some embodiments, R 6a and R 6b Each is H; and R 6c is a substituted or unsubstituted alkyl group.

[0285] In some embodiments, R 6a and R 6b Each is H; and R 6c is an unsubstituted alkyl group.

[0286] In some embodiments, R 6a and R 6b Each is H; and R 6c For Me or Et.

[0287] In some embodiments, R 6a and R 6b Each is H; and R 6c is an alkyl group substituted by an amino group, an alkylamino group or a dialkylamino group.

[0288] In some embodiments, R 6a and R 6b Each is H; and R 6c is an alkyl group substituted by a dimethylamino group.

[0289] In some embodiments, R 6aand R 6b Each is H; and R 6c is –CH2NMe2.

[0290] In some embodiments, R 6a and R 6b together to form a bond; and R 6c is H, or a substituted or unsubstituted alkyl group.

[0291] In some embodiments, R 6a and R 6b together to form a bond; and R 6c For Me.

[0292] In some embodiments, the compound has a structure represented by Formula (IXa), (IXb), or (IXc): or a pharmaceutically acceptable salt thereof.

[0293] In some embodiments, the compound has a structure represented by Formula (Xa), (Xb), or (Xc): or a pharmaceutically acceptable salt thereof.

[0294] In some embodiments, the compound has a structure represented by Formula (XIa), (XIb), or (XIc): or a pharmaceutically acceptable salt thereof.

[0295] In some embodiments, the compound has a structure represented by Formula (XIIa), (XIIb), or (XIIc): or a pharmaceutically acceptable salt thereof.

[0296] In some embodiments, the compound has a structure represented by Formula (XIIIa), (XIIIb), or (XIIIc): or a pharmaceutically acceptable salt thereof.

[0297] In some embodiments, the compound has a structure represented by Formula (XIVa), (XIVb), or (XIVc): or a pharmaceutically acceptable salt thereof.

[0298] In some embodiments, the compound has the structure shown in Formula (XV): or a pharmaceutically acceptable salt thereof.

[0299] In some embodiments, the compound has the structure shown in Formula (XVI): or a pharmaceutically acceptable salt thereof.

[0300] In some embodiments, the compound has the structure shown in Formula (XVII): or a pharmaceutically acceptable salt thereof.

[0301] In some embodiments, the compound has the structure shown in Formula (XXVIIa), (XXVIIb), or (XXVIIc): or a pharmaceutically acceptable salt thereof.

[0302] In some embodiments, the compound has the structure shown in Formula (XXVIIIa), (XXVIIIb), or (XXVIIIc): or a pharmaceutically acceptable salt thereof.

[0303] In some embodiments, the compound has the structure shown in Formula (XXIXa), (XXIXb), or (XXIXc): or a pharmaceutically acceptable salt thereof.

[0304] In some embodiments, the compound has a structure represented by Formula (XLa), (XLb), or (XLc): or a pharmaceutically acceptable salt thereof.

[0305] In some embodiments, the compound has a structure represented by Formula (XLIa), (XLIb), or (XLIc): or a pharmaceutically acceptable salt thereof.

[0306] In some embodiments, the compound has a structure represented by Formula (XLIa), (XLIb), or (XLIc): or a pharmaceutically acceptable salt thereof.

[0307] In some embodiments, the compound has the structure shown in Formula (XLIIa), (XLIIb), or (XLIIc): or a pharmaceutically acceptable salt thereof.

[0308] In some embodiments, the compound has the structure shown in Formula (XLIIIa), (XLIIIb), or (XLIIIc): or a pharmaceutically acceptable salt thereof.

[0309] In some embodiments, the compound has the structure shown in Formula (XLIIa).

[0310] In some embodiments, the compound has the structure shown in Formula (XLIIIa).

[0311] Embodiments of the compounds of formula (I) exhibit improved potency against menin-MLL, with IC values ​​of 0.001 when administered in vivo (e.g., in rats) at low doses of less than 5 mg / kg (e.g., equal to or less than 3 mg / kg). 50 Values ​​as low as less than 1 nM or less than 0.1 nM, and / or high occupancy of the menin active site (eg, greater than 50%, 70%, or 90% occupancy).

[0312] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound represented by formula (I).

[0313] In some embodiments, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compound shown in (I); and a pharmaceutically acceptable excipient.

[0314] In some embodiments, the pharmaceutical composition is formulated for a route of administration selected from oral, parenteral, buccal, nasal, topical, or rectal administration.

[0315] In some embodiments, the present invention provides a method of treating an autoimmune disease or disorder comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition of the present invention.

[0316] In some embodiments, the autoimmune disease is selected from rheumatoid arthritis or lupus.

[0317] In some embodiments, the present invention provides a method of treating a heteroimmune disease or disorder comprising administering a pharmaceutical composition of the present invention to a patient in need thereof.

[0318] In some embodiments, the present invention provides a method of treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition of the present invention.

[0319] In some embodiments, the cancer is a B-cell proliferative disorder.

[0320] In some embodiments, the B-cell proliferative disorder is diffuse large B-cell lymphoma, follicular lymphoma, or chronic lymphocytic leukemia. In some embodiments, the disorder is a myeloid leukemia. In some embodiments, the disorder is AML. In some embodiments, the B-cell proliferative disorder is a lymphoid leukemia. In some embodiments, the disorder is ALL. In some embodiments, the disorder is a soft tissue tumor. In some embodiments, the tumor is a glioblastoma. In some embodiments, the tumor is a pancreatic tumor. In some embodiments, the disorder is renal cell carcinoma.

[0321] In some embodiments, the present invention provides a method of treating mastocytosis comprising administering a pharmaceutical composition of the present invention to a patient in need thereof.

[0322] In some embodiments, the present invention provides a method of treating osteoporosis or a bone resorption disorder comprising administering a pharmaceutical composition of the present invention to a patient in need thereof.

[0323] In some embodiments, the present invention provides a method of treating an inflammatory disease or disorder comprising administering a pharmaceutical composition of the present invention to a patient in need thereof.

[0324] In some embodiments, the present invention provides a method for treating lupus, comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of a compound of formula (I), ie, an inhibitor of menin-MLL interaction.

[0325] In some embodiments, the present invention provides a method for treating a heteroimmune disease or disorder comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of a compound of formula (I), an inhibitor of menin-MLL interaction.

[0326] In some embodiments, the present invention provides a method for treating diffuse large B-cell lymphoma, follicular lymphoma, or chronic lymphocytic leukemia, comprising administering to an individual in need thereof a composition comprising a therapeutically effective amount of a compound of formula (I), i.e., an inhibitor of menin-MLL interaction.

[0327] In some embodiments, the present invention provides a method for treating mastocytosis, comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of a compound of formula (I), an inhibitor of menin-MLL interaction.

[0328] In some embodiments, the present invention provides a method for treating osteoporosis or bone resorption disorders, comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of a compound of formula (I), an inhibitor of menin-MLL interaction.

[0329] In some embodiments, the present invention provides a method for treating an inflammatory disease or condition comprising administering to a subject in need thereof a composition comprising a therapeutically effective amount of a compound of formula (I), which is an inhibitor of menin-MLL interaction.

[0330] In some embodiments, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound according to any one of the general formulas described herein. In some embodiments, the compound is any one of formulas (I)-(XVII).

[0331] In some embodiments, the pharmaceutical composition is formulated for a route of administration selected from oral, parenteral, buccal, nasal, topical, or rectal administration.

[0332] In some embodiments, the carrier is a parenteral carrier.

[0333] In some embodiments, the carrier is an oral carrier.

[0334] In some embodiments, the carrier is a topical carrier.

[0335] The present invention encompasses any combination of the groups described above for the various variables. It should be understood that one of ordinary skill in the art can select substituents and substitution patterns on the compounds provided by the present invention to provide chemically stable compounds that can be synthesized by techniques known in the art and the technology described herein.

[0336] Further representative embodiments of compounds of formula (I) include the compounds listed in Table 1, or solvates or pharmaceutically acceptable salts thereof.

[0337] Throughout the specification, groups and substituents thereof can be selected by one skilled in the art to provide stable moieties and compounds.

[0338] In some embodiments, the compounds of Formula (I)-(XLIIIc) inhibit menin-MLL. In some embodiments, the compounds of Formula (I)-(XLIIIc) are used to treat patients suffering from conditions or diseases that are dependent on menin-MLL or mediated by menin-MLL interactions, including but not limited to cancer, autoimmune and other inflammatory diseases.

[0339] In some embodiments, the compounds of Formula (I)-(XLIIIc) inhibit menin-MLL interaction. In some embodiments, the compounds of Formula (I)-(XLIIIc) are used to treat patients suffering from conditions or diseases dependent on or mediated by menin-MLL interaction, including but not limited to cancer, autoimmune and other inflammatory diseases. Preparation of compounds

[0340] Any of the compounds of formula (I)-(XLIIIc) can be synthesized using standard synthetic reactions known to those skilled in the art or using methods known in the art. The reactions can be employed in a linear sequence to obtain the compound, or they can be used to synthesize fragments which are then linked by methods known in the art.

[0341] The present invention describes compounds that inhibit menin-MLL activity and methods for their preparation. Also described are pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically active metabolites, and pharmaceutically acceptable prodrugs of such compounds. The present invention provides pharmaceutical compositions comprising at least one such compound or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically active metabolite, or pharmaceutically acceptable prodrug of such a compound.

[0342] The starting materials used to synthesize the compounds described herein can be obtained synthetically or from commercial sources such as, but not limited to, Aldrich Chemical Company (Milwaukee, Wisconsin), Bachem (Torrance, California), or Sigma Chemical Company (St. Louis, Mo.). The compounds described herein and other related compounds having various substituents can be synthesized using techniques and materials known to those skilled in the art, such as those described in: March, ADVANCED ORGANIC CHEMISTRY 4 th Ed., (Wiley 1992); Carey and Sundberg, ADVANCEDORGANIC CHEMISTRY 4 thEd., Vols. A and B (Plenum 2000, 2001); Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3 rd Ed., (Wiley 1999); Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). (All of which are incorporated herein by reference in their entirety). Additional methods for synthesizing the compounds described herein can be found in International Patent Publication No. WO 01 / 01982901, Arnold et al. Bioorganic & Medicinal Chemistry Letters 10 (2000) 2167-2170; Burchat et al. Bioorganic & Medicinal Chemistry Letters 12 (2002) 1687-1690. General methods for preparing the compounds disclosed herein can be derived from known reactions in the art, and the reactions can be modified using appropriate reagents and conditions as recognized by those skilled in the art to introduce various moieties found in the general formulas provided herein.

[0343] If necessary, the reaction products can be isolated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, etc. Such materials can be characterized using conventional means, including physical constants and spectral data.

[0344] The compounds of the present invention can be prepared as a single isomer or a mixture of isomers.

[0345] In some embodiments, representative compounds of Formula (I) are prepared according to the synthetic schemes depicted herein. Other forms of compounds

[0346] The compounds disclosed herein have the structures of Formulas (I)-(XLIIIc). It should be understood that, unless otherwise indicated, when referring to the compounds of the present invention, it is intended to include any compound represented by Formulas (I)-(XLIIIc) and all specific compounds falling within the scope of such general formulas.

[0347] The compounds of the present invention may have one or more stereogenic centers, and each center may exist in the R or S configuration. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms, as well as appropriate mixtures thereof. If desired, stereoisomers can be obtained by methods known in the art, such as separation of stereoisomers by chiral chromatography columns.

[0348] Diastereomeric mixtures can be separated into their individual diastereomers based on their physicochemical differences by known methods such as chromatography and / or fractional crystallization. In some embodiments, enantiomers can be separated by chiral chromatography columns. In some embodiments, enantiomers can be separated as follows: by reacting the enantiomeric mixture with an appropriate optically active compound (e.g., alcohol) to convert it into a diastereomeric mixture, separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. All such isomers, including diastereomers, enantiomers, and mixtures thereof, are considered to be part of the compositions described herein.

[0349] The methods and formulations described herein include the use of N-oxides, crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of the compounds of the present invention, as well as active metabolites of such compounds having the same type of activity. In some cases, the compounds may exist as tautomers. All tautomers are included within the scope of the compounds presented herein. Additionally, the compounds of the present invention may exist in unsolvated and solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0350] The compound of any one of formula (I)-(XLIIIc) in unoxidized form can be prepared from the N-oxide of the compound of any one of formula (I)-(XLIIIc) by treatment with a reducing agent (such as but not limited to sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide or the like) in a suitable inert organic solvent (such as but not limited to acetonitrile, ethanol, aqueous dioxane or the like) at 0 to 80°C.

[0351] In some embodiments, the compounds of the present invention are prepared in the form of prodrugs. A "prodrug" refers to an agent that is converted into the parent drug in vivo. Prodrugs are generally useful because, in some cases, they can be easier to administer than the parent drug. They can, for example, be bioavailable by oral administration, whereas the parent drug is not. Prodrugs can also have improved solubility in pharmaceutical compositions over that of the parent drug. An example of a prodrug is, but is not limited to, a compound of the present invention that is administered as an ester ("prodrug") to facilitate transport across cell membranes, where water solubility is detrimental to fluidity, but then metabolically hydrolyzes to a carboxylic acid (the active entity) once inside the cell, where water solubility is beneficial. Another example of a prodrug is a short peptide (polyamino acid) linked to an acid group, where the peptide undergoes metabolism to reveal the active group moiety. In certain embodiments, upon in vivo administration, the prodrug is chemically converted to the biologically, pharmaceutically, or therapeutically active form of the compound. In certain embodiments, the prodrug is enzymatically metabolized to the biologically, pharmaceutically, or therapeutically active form of the compound by one or more steps or processes. To generate a prodrug, a pharmaceutically active compound is modified so that the active compound will be regenerated when administered in vivo. Prodrugs can be designed to alter the metabolic stability or transport characteristics of a drug, mask side effects or toxicity, improve the flavor of a drug, or alter other characteristics or properties of a drug. With the knowledge of in vivo pharmacodynamic processes and drug metabolism, those skilled in the art can design prodrugs of a compound once a pharmaceutically active compound is known. (See, for example, Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392; Silverman (1992), The Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc., San Diego, pages 352-401, Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985).

[0352] Prodrug forms of the compounds of the present invention are included within the scope of the present invention, wherein the prodrug is metabolized in vivo to produce a derivative as described herein. In some cases, some compounds of the present invention may be a prodrug of another derivative or active compound.

[0353] Prodrugs are often useful because, in some cases, they can be easier to administer than the parent drug. They can, for example, be bioavailable via oral administration, whereas the parent drug is not. Prodrugs can also have improved solubility in pharmaceutical compositions compared to the parent drug. Prodrugs can be designed as reversible drug derivatives for use as modifiers to enhance drug delivery to site-specific tissues. In some embodiments, prodrugs are designed to increase effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen andH.Bundgaard,Int.J.Pharmaceutics,37,87(1987); J.Larsen et al.,Int.J.Pharmaceutics,47,103(1988); Systems, Vol.14 of the ACSSymposium Series; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all of which are incorporated herein by reference in their entirety.

[0354] Sites on the aromatic ring portion of the compounds shown in any of Formulas (I)-(XLIIIc) may be susceptible to various metabolic reactions, and thus incorporation of appropriate substituents (such as, by way of example only, halogens) on the aromatic ring structure may reduce, minimize, or eliminate this metabolic pathway.

[0355] The compounds described herein include isotopically labeled compounds, which are identical to the compounds described in the various formulas and structures presented herein, but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, such as 2 H. 3 H. 13 C. 14 C. 15 N.18 O. 17 O. 35 S. 18 F. 36 Certain isotopically labeled compounds of the present invention (e.g., compounds incorporating 3 H and 14 Compounds containing radioactive isotopes of C) are useful in drug and / or substrate tissue distribution assays. In addition, compounds containing radioactive isotopes such as deuterium (i.e. 2 Isotopic substitution of H) may afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements.

[0356] In additional or some embodiments, the compounds described herein, when administered to an organism in need thereof, are metabolized to produce metabolites, which are subsequently used to produce a desired effect, including a desired therapeutic effect.

[0357] The compounds of the present invention can be formed and / or used in the form of pharmaceutically acceptable salts. Types of pharmaceutically acceptable salts include, but are not limited to: (1) acid addition salts, which are formed by reacting the free base form of the compound with: a pharmaceutically acceptable inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; or an organic acid such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid , benzenesulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptanoic acid, 4,4'-methylenebis-3-(hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and the like; (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion (e.g., an alkali metal ion (e.g., lithium, sodium, potassium), an alkaline earth metal ion (e.g., magnesium or calcium), or an aluminum ion); or salts formed when coordinated with an organic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide and the like.

[0358] The corresponding counterions of the pharmaceutically acceptable salts can be analyzed and identified using various methods including, but not limited to, ion exchange chromatography, ion chromatography, capillary electrophoresis, inductively coupled plasma, atomic absorption spectroscopy, mass spectrometry, or any combination thereof.

[0359] The salt may be recovered by using at least one of the following techniques: filtration, precipitation with a non-solvent followed by filtration, evaporation of the solvent, or, in the case of aqueous solutions, lyophilization.

[0360] It should be understood that reference to pharmaceutically acceptable salts includes solvent addition forms or crystalline forms thereof, particularly solvates or polymorphs. Solvates contain a stoichiometric or non-stoichiometric amount of solvent and can be formed in the process of crystallization with a pharmaceutically acceptable solvent such as water, ethanol or its analogue. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds of the present invention are preferably prepared or formed during the process of the present invention. In addition, compounds provided by the present invention can exist in non-solvated form as well as solvated form. Generally speaking, for the purposes of compounds and methods provided by the present invention, solvated form is considered to be equivalent to non-solvated form.

[0361] It should be understood that reference to a salt includes solvent addition forms or crystal forms thereof, particularly solvates or polymorphs. Solvates contain stoichiometric or non-stoichiometric amounts of a solvent and are typically formed during the process of crystallization with a pharmaceutically acceptable solvent such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Polymorphs include different crystal packing arrangements of the same elemental composition of a compound. Polymorphs typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Various factors such as the recrystallization solvent, the rate of crystallization, and the storage temperature may contribute to the dominance of a single crystalline form.

[0362] The compounds of the present invention may be in various forms, including but not limited to amorphous forms, ground forms, and nanoparticle forms. In addition, the compounds of the present invention include crystalline forms, also known as polymorphs. Polymorphs include different crystal packing arrangements of the same elemental composition of a compound. Polymorphs typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Various factors such as the recrystallization solvent, the rate of crystallization, and the storage temperature can cause a single crystal form to dominate.

[0363] Screening and characterization of pharmaceutically acceptable salts, polymorphs, and / or solvates can be accomplished using a variety of techniques, including but not limited to thermal analysis, X-ray diffraction, spectroscopy, vapor sorption, and microscopy. Thermal analysis methods address thermochemical degradation or thermophysical processes, including but not limited to polymorphic transitions, and are used to analyze relationships between polymorphic forms, determine weight loss, discover glass transition temperatures, or for excipient compatibility studies. Such methods include but are not limited to differential scanning calorimetry (DSC), modulated differential scanning calorimetry (MDCS), thermogravimetric analysis (TGA), and thermogravimetric and infrared analysis (TG / IR). X-ray diffraction methods include but are not limited to single crystal and powder diffractometers and synchrotron sources. Various spectroscopic techniques are used, including but not limited to Raman, FTIR, UV-Vis, and NMR (liquid and solid state). Various microscopy techniques include, but are not limited to, polarized light microscopy, scanning electron microscopy (SEM) with energy dispersive X-ray analysis (EDX), environmental scanning electron microscopy (in gas or water vapor atmosphere) with EDX, IR microscopy, and Raman microscopy.

[0364] Throughout the specification, groups and substituents thereof can be selected by one skilled in the art to provide stable moieties and compounds. Pharmaceutical compositions / preparations

[0365] Pharmaceutical compositions can be formulated in a conventional manner using one or more physiologically acceptable carriers (including excipients and adjuvants) that facilitate processing of the active compound into a pharmaceutically acceptable formulation. The appropriate formulation depends on the chosen route of administration. Any known techniques, carriers, and excipients can be used as appropriate and understood in the art. A general overview of the pharmaceutical compositions of the present invention can be found in, for example, Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference in their entireties.

[0366] As used herein, a pharmaceutical composition refers to a mixture of a compound of the present invention (such as any of Formulas (I)-(XLIIIc)) with other chemical components (such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients). Pharmaceutical compositions facilitate administration of a compound to an organism. In practicing the methods of treatment or use provided herein, a therapeutically effective amount of a compound of the present invention is administered as a pharmaceutical composition to a mammal suffering from the disease, disorder, or condition to be treated. The mammal is preferably a human. The therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the individual, the potency of the compound used, and other factors. The compound can be used alone or in combination with one or more therapeutic agents as components of a mixture.

[0367] In certain embodiments, the composition may also include one or more pH adjusters or buffers, including acids such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, and hydrochloric acid; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and tris-hydroxymethylaminomethane; and buffers such as citrate / dextrose, sodium bicarbonate, and ammonium chloride. Such acids, bases, and buffers are included in amounts necessary to maintain the pH of the composition within an acceptable range.

[0368] In some embodiments, the composition may also include one or more salts in an amount required to bring the osmolality of the composition into an acceptable range. Such salts include salts having sodium, potassium, or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.

[0369] As used herein, the term "drug combination" refers to a product resulting from the mixing or combining of more than one active ingredient and includes fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that, for example, the active ingredients of a compound described herein and a co-agent are administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that, for example, the active ingredients of a compound described herein and a co-agent are administered to a patient simultaneously, concurrently or sequentially in the form of separate entities, without specific intervening time limits, wherein such administration provides effective levels of both compounds in the patient's body. The latter also applies to cocktail therapy, for example, the administration of three or more active ingredients.

[0370] The pharmaceutical compositions of the present invention can be administered to a subject via a variety of routes of administration, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration. The pharmaceutical compositions of the present invention include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, delayed release formulations, sustained release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

[0371] Pharmaceutical compositions comprising the compounds of the present invention may be manufactured in conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, coating or compression processes.

[0372] The pharmaceutical composition will include at least one compound of the present invention, such as any of the compounds shown in Formula (I)-(XLIIIc), in free acid or free base form or in pharmaceutically acceptable salt form, as an active ingredient. In addition, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs), and active metabolites of such compounds having the same type of activity. In some cases, the compounds may exist as tautomers. All tautomers are included within the scope of the compounds presented herein. In addition, the compounds of the present invention may exist in unsolvated form as well as in solvated form with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0373] "Antifoaming agents" reduce foaming during processing, which can cause coagulation of the aqueous dispersion, bubbles in the finished film, or generally impair processing. Exemplary antifoaming agents include silicone emulsions or sorbitan sesquioleate.

[0374] "Antioxidants" include, for example, butylated hydroxytoluene (BHT), sodium ascorbate, ascorbic acid, sodium metabisulfite, and tocopherol. In certain embodiments, antioxidants can improve chemical stability, if desired.

[0375] In certain embodiments, the compositions provided herein may also include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as phenylmercuric nitrate (merfen) and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride.

[0376] The formulations of the present invention may benefit from the addition of antioxidants, metal chelators, thiol-containing compounds, and other general stabilizers. Examples of such stabilizers include, but are not limited to: (a) about 0.5% to about 2% w / v glycerol, (b) about 0.1% to about 1% w / v methionine, (c) about 0.1% to about 2% w / v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w / v ascorbic acid, (f) 0.003% to about 0.02% w / v polysorbate 80, (g) 0.001% to about 0.05% w / v polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (l) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof.

[0377] "Binders" impart cohesive qualities and include, for example, alginic acid and its salts; cellulose derivatives such as carboxymethyl cellulose, methyl cellulose (e.g. ), hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. ), ethyl cellulose (e.g. ) and microcrystalline cellulose (e.g. ); microcrystalline dextrose; amylose; magnesium aluminum silicate; polysaccharide acids; bentonites; gelatin; polyvinylpyrrolidone / vinyl acetate copolymer; cross-linked polyvinylpyrrolidone; povidone; starch; pregelatinized starch; tragacanth gum, dextrin; sugars such as sucrose (e.g. ), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g. ) and lactose; natural or synthetic gums such as acacia, tragacanth, ghatti gum, mucilage of isapol husk, polyvinylpyrrolidone (e.g. CL, CL, XL-10), larch arabinogalactan, Polyethylene glycol, waxes, sodium alginate and their analogues.

[0378] "Carrier" or "carrier material" includes any commonly used excipient in pharmacy and should be selected based on compatibility with the compounds disclosed herein, such as the compound of any of Formulas (I)-(XLIIIc), and the release profile characteristics of the desired dosage form. Exemplary carrier materials include, for example, binders, suspending agents, disintegrants, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, and the like. "Pharmaceutically compatible carrier materials" may include, but are not limited to, gum arabic, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerol, magnesium silicate, polyvinylpyrrolidone (PVP), cholesterol, cholesterol esters, sodium caseinate, soy lecithin, taurocholic acid, phosphatidylcholine, sodium chloride, tricalcium phosphate, dipotassium hydrogen phosphate, cellulose and cellulose conjugates, sodium stearoyl lactylate, carrageenan, monoglycerides, diglycerides, pregelatinized starch, and the like. See, for example, Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999).

[0379] "Dispersants" and / or "viscosity modifiers" include materials that control the diffusion and homogeneity of the drug in a liquid medium or during a granulation process or a blending process. In some embodiments, these agents also promote the effectiveness of coating or eroding a matrix. Exemplary diffusion enhancers / dispersants include, for example, hydrophilic polymers, electrolytes, 60 or 80, PEG, polyvinylpyrrolidone (PVP; commercially known as ), and carbohydrate-based dispersants such as hydroxypropylcelluloses (e.g., HPC, HPC-SL, and HPC-L), hydroxypropylmethylcelluloses (e.g., HPMC K100, HPMC K4M, HPMC K15M, and HPMC K100M), sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate stearate (HPMCAS), non-crystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), vinylpyrrolidone / vinyl acetate copolymer (S630), 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde (also known as tyloxapol), poloxamers (e.g., Pluronics and which are block copolymers of ethylene oxide and propylene oxide); and poloxamines (such as Tetronic Also known as poloxamine It is a tetrafunctional block copolymer derived by sequentially adding propylene oxide and ethylene oxide to ethylenediamine (BASF Corporation, Parsippany, NJ), polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25 or polyvinylpyrrolidone K30, polyvinylpyrrolidone / vinyl acetate copolymer (S-630), polyethylene glycol (for example, the polyethylene glycol may have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400), sodium carboxymethylcellulose, methylcellulose, polysorbate 60. Dispersants include polysorbate 80, sodium alginate, gums (such as tragacanth and gum arabic, guar gum, and xanthan gum), sugars, cellulosic materials such as sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, polysorbate 80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, carbomers, polyvinyl alcohol (PVA), alginates, chitosans, and combinations thereof. Plasticizers such as cellulose or triethylcellulose can also be used as dispersants. Dispersants particularly suitable for lipid dispersions and self-emulsifying dispersions are dimyristoylphosphatidylcholine, natural phosphatidylcholine from eggs, natural phosphatidylglycerol from eggs, cholesterol, and isopropyl myristate.

[0380] Combinations of one or more erosion enhancers and one or more diffusion enhancers may also be used in the compositions of the present invention.

[0381] The term "diluent" refers to a compound used to dilute the compound of interest prior to delivery. Diluents can also be used to stabilize the compound because they can provide a more stable environment. Salts dissolved in buffered solutions (which can also provide pH control or maintenance) are used as diluents in the art, including but not limited to phosphate buffered saline solutions. In certain embodiments, the diluent increases the volume of the composition to facilitate compression or to create sufficient volume for homogeneous blending for capsule filling. Such compounds include, for example, lactose, starch, mannitol, sorbitol, dextrose, microcrystalline cellulose such as Dicalcium phosphate, dicalcium phosphate dihydrate; tricalcium phosphate, calcium phosphate; anhydrous lactose, spray-dried lactose; pregelatinized starch, compressible sugars, such as (Amstar); mannitol, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate stearate, sucrose-based diluents, confectioner's sugar; calcium dihydrogen sulfate monohydrate, calcium sulfate dihydrate; calcium lactate trihydrate, dextrates; hydrolyzed cereal solids, amylose; powdered cellulose, calcium carbonate; glycine, kaolin; mannitol, sodium chloride; inositol, bentonite, and the like.

[0382] The term "disintegrate" includes the dissolution and dispersion of a dosage form upon contact with gastrointestinal fluids. A "disintegration agent" or "disintegrant" promotes the breakdown or disintegration of a substance. Examples of disintegrants include starches, e.g., natural starches such as corn starch or potato starch; pregelatinized starches such as National 1551 or or sodium starch glycolate, such as or Cellulose, such as wood products; methylcrystalline cellulose, e.g. PH101, PH102, PH105, P100, Ming and Methylcellulose, croscarmellose, or a cross-linked cellulose such as croscarmellose sodium Cross-linked carboxymethyl cellulose or cross-linked croscarmellose; cross-linked starch, such as sodium starch glycolate; cross-linked polymer, such as cross-linked polyvinyl pyrrolidone; alginates, such as alginic acid or a salt of alginic acid, such as sodium alginate; clays, such as HV (magnesium aluminum silicate), gums (such as agar, guar gum, locust bean gum, karaya, pectin or tragacanth); sodium starch glycolate; bentonite; natural sponge; surfactants; resins such as cation exchange resins; citrus pulp; sodium lauryl sulfate; a combination of sodium lauryl sulfate and starch; and the like.

[0383] "Drug absorption" or "absorption" generally refers to the process by which a drug moves from the site of drug administration across a barrier to the blood vessels or site of action, for example, from the gastrointestinal tract to the portal vein or lymphatic system.

[0384] An "enteric coating" is a material that remains substantially intact in the stomach but dissolves and releases the drug in the small intestine or colon. Generally, an enteric coating comprises a polymeric material that prevents release in the low pH environment of the stomach but ionizes at a higher pH (typically pH 6 to 7) and thus dissolves sufficiently in the small intestine or colon to release the active agent therein.

[0385] "Erosion enhancers" include materials that control the erosion of a particular material in gastrointestinal fluids. Erosion enhancers are generally known to those of ordinary skill in the art. Exemplary erosion enhancers include, for example, hydrophilic polymers, electrolytes, proteins, peptides, and amino acids.

[0386] "Bulking agents" include compounds such as lactose, calcium carbonate, calcium phosphate, calcium hydrogen phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starches, pregelatinized starch, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

[0387] Suitable “flavoring agents” and / or “sweeteners” for use in the formulations of the present invention include, for example, gum arabic syrup, acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream, berry, black currant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, marshmallow, cocoa, cola, cool cherry, cool citrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, licorice syrup (licorice juice), grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glycyrrhizate, Maltitol, Mannitol, Maple, Marshmallow, Menthol, Mint Cream, Mixed Berry, Neohesperidin DC, Neotame, Orange, Pear, Peach, Peppermint, Peppermint Cream, powder, raspberry, root beer, rum, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, saccharin sodium, saccharin, aspartame, acesulfame potassium, mannitol, talin, sylitol, sucralose, sorbitol, Swiss cream, tagatose, tangerine, thaumatin, tutti fruitti, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol, or any combination of these flavoring ingredients, such as anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint, and mixtures thereof.

[0388] "Lubricants" and "glidants" are compounds that prevent, reduce, or inhibit the sticking or friction of materials. Exemplary lubricants include, for example, stearic acid; calcium hydroxide; talc; sodium stearyl fumarate; hydrocarbons such as mineral oil; or hydrogenated vegetable oils such as hydrogenated soybean oil. Higher fatty acids and alkali metal salts and alkaline earth metal salts thereof, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearate, glycerol, talc, wax, Boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol (e.g., PEG-4000), or methoxy polyethylene glycol such as Carbowax TM , sodium oleate, sodium benzoate, glyceryl behenate, polyethylene glycol, magnesium lauryl sulfate or sodium lauryl sulfate; colloidal silicon dioxide, such as Syloid TM 、 Starches, such as corn starch, silicone oils, surfactants and the like.

[0389] "Measurable serum concentration" or "measurable plasma concentration" describes the serum or plasma concentration of a therapeutic agent absorbed into the bloodstream following administration, and is typically measured in mg, μg, or ng of therapeutic agent per ml, dl, or 1 of serum. As used herein, measurable plasma concentration is typically measured in ng / ml or μg / ml.

[0390] "Pharmacodynamics" refers to the factors that determine the biological response observed relative to the concentration of the drug at the site of action.

[0391] "Pharmacokinetics" refers to the factors that determine whether an appropriate drug concentration is achieved or maintained at the site of action.

[0392] "Plasticizers" are compounds used to soften the microcapsule material or film coating to make it less brittle. Suitable plasticizers include, for example, polyethylene glycols (such as PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800), stearic acid, propylene glycol, oleic acid, triethylcellulose, and triacetin. In some embodiments, plasticizers may also act as dispersants or wetting agents.

[0393] "Solubilizers" include compounds such as triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, sodium lauryl sulfate, sodium doccusate, vitamin E TPGS, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, n-butanol, isopropanol, cholesterol, bile salts, polyethylene glycol 200-600, glycofurol, diethylene glycol monoethyl ether, propylene glycol, and dimethyl isosorbide, and the like.

[0394] "Stabilizers" include compounds such as any antioxidants, buffers, acids, preservatives, and the like.

[0395] As used herein, "steady state" is the state when the amount of drug administered during a dosing interval is equal to the amount of drug eliminated, thereby producing a plateau or constant plasma drug exposure.

[0396] "Suspending agents" include compounds such as polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30; vinylpyrrolidone / vinyl acetate copolymer (S630); polyethylene glycol, e.g., polyethylene glycol having a molecular weight of from about 300 to about 6000, or from about 3350 to about 4000, or from about 7000 to about 5400; sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, Hydroxymethylcellulose acetate stearate; polysorbate 80; hydroxyethylcellulose; sodium alginate; gums such as gum tragacanth and gum acacia, guar gum, and safflower gums (including xanthan gum); sugars; cellulosic materials such as sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose; polysorbate 80; sodium alginate; polyethoxylated sorbitan monolaurate; polyethoxylated sorbitan monolaurate; povidone and its analogs.

[0397] "Surfactants" include compounds such as sodium lauryl sulfate, sodium docusate, Tween 60 or 80, triacetin, vitamin E TPGS, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide (e.g., (BASF) and its analogs. Some other surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, such as polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkyl ethers and alkylphenyl ethers, such as octoxynol 10 and octoxynol 40. In some embodiments, surfactants may be included to improve physical stability or for other purposes.

[0398] "Viscosity enhancers" include, for example, methylcellulose, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, hydroxypropylmethylcellulose phthalate, carbomer, polyvinyl alcohol, alginates, gum arabic, chitosans, and combinations thereof.

[0399] "Wetting agents" include compounds such as oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, docusate sodium, sodium oleate, sodium lauryl sulfate, docusate sodium, triacetin, Tween 80, vitamin E TPGS, ammonium salts, and the like. Dosage form

[0400] The compositions of the present invention can be formulated for administration to a subject via any conventional means, including but not limited to oral, parenteral (e.g., intravenous, subcutaneous, or intramuscular), buccal, intranasal, rectal, or transdermal routes of administration. As used herein, the term "subject" is used to refer to an animal, preferably a mammal, including humans or non-humans. The terms patient and subject are used interchangeably.

[0401] In addition, the pharmaceutical compositions of the present invention comprising a compound represented by any one of Formulas (I)-(XLIIIc) can be formulated into any suitable dosage form, including (but not limited to) aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions and the like for oral ingestion by a patient to be treated, solid oral dosage forms, aerosols, controlled release formulations, fast melt formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, capsules, delayed release formulations, sustained release formulations, pulsed release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

[0402] Pharmaceutical preparations for oral use can be prepared by mixing one or more solid excipients with one or more compounds of the present invention, optionally grinding the resulting mixture and, if necessary, processing the granular mixture to obtain tablets or dragee cores after adding suitable auxiliary agents. Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose; or other excipients such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If necessary, disintegrants such as cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof (such as sodium alginate) can be added.

[0403] Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquers and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablets or dragee coatings to identify or characterize different combinations of active compound doses.

[0404] Pharmaceutical formulations for oral administration include push-in capsules made of gelatin and sealed soft capsules made of gelatin and a plasticizer (such as glycerol or sorbitol). Push-in capsules can contain the active ingredient, mixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In the soft capsule, the active compound can be dissolved or suspended in a suitable liquid such as a fatty oil, liquid paraffin, or liquid polyethylene glycol. In addition, a stabilizer can be added. All formulations for oral administration should be in a dosage suitable for such administration.

[0405] In some embodiments, the solid dosage forms disclosed herein may be in the form of tablets (including suspension tablets, fast-melt tablets, chewable disintegrating tablets, rapidly disintegrating tablets, effervescent tablets, or caplets), pills, powders (including sterile packaged powders, dispensable powders, or effervescent powders), capsules (including soft capsules or hard capsules, such as capsules made of animal-derived gelatin or plant-derived HPMC, or "pellet capsules"), solid dispersions, solid solutions, bioerodible dosage forms, controlled-release formulations, pulsed-release dosage forms, multiparticulate dosage forms, pellets, granules, or aerosols. In some embodiments, the pharmaceutical composition is in the form of a powder. In some embodiments, the pharmaceutical composition is in the form of a tablet, including but not limited to a fast-melt tablet. In addition, the pharmaceutical composition described herein may be administered in a single capsule or in multiple capsule dosage forms. In some embodiments, the pharmaceutical composition is administered in the form of two, three, or four capsules or tablets.

[0406] In some embodiments, solid dosage forms, such as tablets, effervescent tablets, and capsules, are prepared by mixing particles of a compound of Formula (I)-(XLIIIc) described herein with one or more pharmaceutical excipients to form a bulk blend composition. When referring to these bulk blend compositions as uniform, it is meant that the particles of the compound of any of Formula (I)-(XLIIIc) are uniformly dispersed throughout the composition, allowing the composition to be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules. Individual unit doses may also include a film coating that disintegrates upon oral ingestion or upon contact with a diluent. Such formulations can be prepared by conventional pharmacological techniques.

[0407] Conventional pharmacological techniques include, for example, one or a combination of the following methods: (1) dry mixing, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) melting. See, for example, Lachman et al., The Theory and Practice of Industrial Pharmacy (1986). Other methods include, for example, spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., wurster coating), tangential coating, top spraying, tableting, extrusion, and the like.

[0408] The solid pharmaceutical dosage form of the present invention may include the compound of the present invention and one or more pharmaceutically acceptable additives, such as compatible carriers, adhesives, fillers, suspending agents, flavorings, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, wetting agents, defoamers, antioxidants, preservatives, or one or more combinations thereof. In some embodiments, a standard coating procedure is used, such as the procedure described in Remington's Pharmaceutical Sciences, 20th Edition (2000), to provide a film coat around the preparation of any compound shown in formula (I)-(XVII). In some embodiments, some or all particles of any compound shown in formula (I)-(XLIIIc) are coated. In some embodiments, some or all particles of any compound shown in formula (I)-(XVII) are microencapsulated. In yet other embodiments, the particles of any compound shown in formula (I)-(XLIIIc) are not microencapsulated and are not coated.

[0409] Suitable carriers for the solid dosage forms of the present invention include, but are not limited to, gum arabic, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerol, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglycerides, diglycerides, pregelatinized starch, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate stearate, sucrose, microcrystalline cellulose, lactose, mannitol, and the like.

[0410] Suitable fillers that can be used in the solid dosage forms of the present invention include, but are not limited to, lactose, calcium carbonate, calcium phosphate, calcium hydrogen phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starch, pregelatinized starch, hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

[0411] In order to release the compound of any of Formulas (I)-(XLIIIc) from the solid dosage form matrix as efficiently as possible, a disintegrant is typically used in the formulation, particularly when the dosage form is compressed with a binder. Disintegrants aid in the rupture of the dosage form matrix by swelling or capillary action when moisture is adsorbed onto the dosage form. Suitable disintegrants for use in the solid dosage forms of the present invention include, but are not limited to, natural starches such as corn starch or potato starch; pregelatinized starches such as National 1551 or or sodium starch glycolate, such as or Cellulose, such as wood products; methylcrystalline cellulose, e.g. PH101, PH102, PH105, P100, Ming and Methylcellulose, croscarmellose, or a cross-linked cellulose such as croscarmellose sodium Cross-linked carboxymethyl cellulose or cross-linked croscarmellose; cross-linked starch, such as sodium starch glycolate; cross-linked polymer, such as cross-linked polyvinyl pyrrolidone; alginates, such as alginic acid or a salt of alginic acid, such as sodium alginate; clays, such as HV (magnesium aluminum silicate), gums (such as agar, guar gum, locust bean gum, galaya gum, pectin, or tragacanth); sodium starch glycolate; bentonite; natural sponge; surfactants; resins such as cation exchange resins; citrus pulp; sodium lauryl sulfate; sodium lauryl sulfate in combination with starch; and the like.

[0412] Binders impart cohesion to solid oral dosage form formulations: for powder-filled capsule formulations, they aid in plug formation that can be filled into soft or hard shell capsules, and for tablet formulations, they ensure that the tablet remains intact after compression and help ensure blend uniformity prior to the compression or filling step. Materials suitable for use as binders in the solid dosage forms of the present invention include, but are not limited to, carboxymethyl cellulose, methyl cellulose (e.g., ), hydroxypropyl methylcellulose (e.g., Hydroxypropyl methylcellulose USP Pharmacoat-603, Hydroxypropyl methylcellulose acetate stearate (Aqoate HS-LF and HS), Hydroxyethylcellulose, Hydroxypropyl cellulose (e.g., ), ethyl cellulose (e.g. ) and microcrystalline cellulose (e.g. ), microcrystalline dextrose, amylose, magnesium aluminum silicate, polysaccharide acids, bentonites, gelatin, polyvinyl pyrrolidone / vinyl acetate copolymer, cross-linked polyvinylpyrrolidone, povidone, starch, pregelatinized starch, tragacanth gum, dextrin, sugars (such as sucrose (e.g. ), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g. ), lactose), natural or synthetic gums (such as gum arabic, gum tragacanth, gum ghatti), mucilage of the husk of the sapote, starch, polyvinyl pyrrolidone (e.g. CL, CL, XL-10 and K-12), larch arabinogalactan, Polyethylene glycol, waxes, sodium alginate and their analogues.

[0413] Generally, a binder content of 20-70% is used in powder-filled gelatin capsule formulations. The amount of binder used in tablet formulations varies depending on the use of direct compression, wet granulation, roller compaction, or other excipients (such as fillers that can themselves act as a moderate binder). The binder content of the formulation can be determined by those skilled in the art, but typically, the binder content in tablet formulations is no more than 70%.

[0414] Suitable lubricants or glidants that can be used in the solid dosage form of the present invention include, but are not limited to, stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, alkali metal and alkaline earth metal salts (such as aluminum, calcium, magnesium, zinc), stearic acid, sodium stearate, magnesium stearate, zinc stearate, waxes, Boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol or methoxy polyethylene glycol (such as Carbowax TM, PEG 4000, PEG 5000, PEG 6000), propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium lauryl sulfate, or sodium lauryl sulfate, and the like.

[0415] Suitable diluents that can be used in the solid dosage forms of the present invention include, but are not limited to, sugars (including lactose, sucrose, and dextrose), polysaccharides (including dextrates and maltodextrin), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins, and the like.

[0416] The term "water-insoluble diluent" refers to compounds typically used in pharmaceutical formulations, such as calcium phosphate, calcium sulfate, starches, modified starches, and microcrystalline cellulose, and microcellulose (e.g., with a density of about 0.45 g / cm 3 , such as Avicel, powdered cellulose), and talc.

[0417] Suitable wetting agents that can be used in the solid dosage forms of the present invention include, for example, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, quaternary ammonium compounds (e.g., Polyquat ), sodium oleate, sodium lauryl sulfate, magnesium stearate, docusate sodium, triacetin, vitamin E TPGS and their analogs.

[0418] Suitable surfactants that can be used in the solid dosage forms of the present invention include, for example, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, for example (BASF) and its analogs.

[0419] Suitable suspending agents that can be used in the solid dosage forms of the present invention include, but are not limited to, polyvinyl pyrrolidone, such as polyvinyl pyrrolidone K12, polyvinyl pyrrolidone K17, polyvinyl pyrrolidone K25, or polyvinyl pyrrolidone K30; polyethylene glycol, such as polyethylene glycol having a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400; vinyl pyrrolidone / vinyl acetate copolymer (S630), sodium carboxymethyl cellulose, methylcellulose cellulose, hydroxypropyl methylcellulose, polysorbate 80, hydroxyethylcellulose; sodium alginate; gums such as gum tragacanth and gum arabic, guar gum, and xanthan gum; sugars; cellulosic materials such as sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose; polysorbate 80; sodium alginate; polyethoxylated sorbitan monolaurate; polyethoxylated sorbitan monolaurate; povidone; and the like.

[0420] Suitable antioxidants that can be used in the solid dosage forms of the present invention include, for example, butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol.

[0421] It should be understood that there is a substantial overlap between the additives used in the solid dosage forms of the present invention. Therefore, the additives listed above should be considered merely as illustrative and not limiting of the types of additives that may be included in the solid dosage forms of the present invention. One skilled in the art will readily determine the amounts of such additives based on the specific properties desired.

[0422] In some embodiments, one or more layers of the pharmaceutical composition are plasticized. Illustratively, the plasticizer is generally a high-boiling point solid or liquid. A suitable plasticizer may be added in an amount ranging from about 0.01% to about 50% by weight (w / w) of the coating composition. Plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, grease agents, stearates, and castor oil.

[0423] Compressed tablets are solid dosage forms made by compacting the bulk blend of the formulations described above. In various embodiments, compressed tablets designed to dissolve in the mouth will include one or more flavorings. In some embodiments, the tablet will include a film surrounding the final compressed tablet. In some embodiments, the film coating can provide delayed release of the compound of any of Formulas (I)-(XLIIIc) from the formulation. In some embodiments, the film coating helps achieve patient compliance (e.g., coated or sugar coated). Includes The film coating generally ranges from about 1% to about 3% of the tablet weight. In some embodiments, the compressed tablet includes one or more excipients.

[0424] Capsules can be prepared, for example, by placing a bulk blend of a preparation of a compound shown in any of the above-mentioned formulas (I)-(XVII) inside a capsule. In some embodiments, the preparation (non-aqueous suspension and solution) is placed in a soft gelatin capsule. In some embodiments, the preparation is placed in a standard gelatin capsule or a non-gelatin capsule (such as a capsule comprising HPMC). In some embodiments, the preparation is placed in a pellet-type capsule, wherein the capsule can be swallowed as a whole or the capsule can be opened and the contents sprayed on food before consumption. In some embodiments, the therapeutic dose is divided into multiple (e.g., two, three, or four) capsules. In some embodiments, the total dose of the preparation is delivered in a capsule form.

[0425] In various embodiments, particles of a compound of any one of Formula (I)-(XLIIIc) are dry blended with one or more excipients and compressed into a mass, such as a tablet, having a hardness sufficient to provide a pharmaceutical composition that substantially disintegrates in less than about 30 minutes, less than about 35 minutes, less than about 40 minutes, less than about 45 minutes, less than about 50 minutes, less than about 55 minutes, or less than about 60 minutes after oral administration, thereby releasing the formulation into the gastrointestinal fluid.

[0426] In some embodiments, the dosage form may include a microencapsulated formulation. In some embodiments, one or more other compatible materials are present in the microencapsulation material. Exemplary materials include, but are not limited to, pH adjusters, erosion accelerators, defoamers, antioxidants, flavoring agents, and carrier materials such as binders, suspending agents, disintegrants, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, and diluents.

[0427] Suitable materials for microencapsulation according to the present invention include materials compatible with the compound of any of Formulas (I)-(XLIIIc) that sufficiently separate the compound of any of Formulas (I)-(XLIIIc) from other incompatible excipients. Materials compatible with the compound of any of Formulas (I)-(XLIIIc) are those that delay the release of the compound of any of Formulas (I)-(XVII) in vivo.

[0428] Exemplary microencapsulation materials suitable for delayed release of formulations containing the compounds of the invention include, but are not limited to, hydroxypropyl cellulose ethers (HPC), such as or Nisso HPC; low-substituted hydroxypropyl cellulose ethers (L-HPC); hydroxypropyl methylcellulose ethers (HPMC), such as Seppifilm-LC, Metolose SR, -E, Opadry YS, Primaflo, Benecel MP824 and Benecel MP843; methylcellulose polymers such as -A; Hydroxypropyl methylcellulose acetate stearate Aqoat (HF-LS, HF-LG, HF-MS) and Ethyl cellulose (EC) and its mixtures, such as E461, -EC, Polyvinyl alcohol (PVA), such as Opadry AMB; hydroxyethyl cellulose, such as Carboxymethyl celluloses and salts of carboxymethyl cellulose (CMC), such as -CMC; polyvinyl alcohol and polyethylene glycol copolymers, such as Kollicoat Monoglycerides (Myverol); triglycerides (KLX); polyethylene glycol; modified food starch; acrylic acid polymers, and mixtures of acrylic acid polymers and cellulose ethers, such as EPO, L30D-55, FS 30D L100-55, L100, S100, RD100, E100, L12.5, S12.5, NE30D, and NE 40D; cellulose acetate phthalate, sepifilms, such as mixtures of HPMC and stearic acid; cyclodextrins; and mixtures of these materials.

[0429] In some embodiments, plasticizers (such as polyethylene glycol, e.g., PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800), stearic acid, propylene glycol, oleic acid, and triacetin are incorporated into the microencapsulation material. In some embodiments, the microencapsulation material suitable for delaying the release of the pharmaceutical composition is from USP or National Formulary (NF). In some embodiments, the microencapsulation material is Klucel. In some embodiments, the microencapsulation material is methylcellulose.

[0430] Microencapsulated compounds of any of formulas (I)-(XLIIIc) can be formulated by methods known to those skilled in the art. Such known methods include, for example, spray drying, rotary disc-solvent methods, hot melt methods, spray cooling methods, fluidized beds, electrostatic deposition, centrifugal extrusion, rotary suspension separation, polymerization at a liquid-gas or solid-gas interface, pressurized extrusion, or spray solvent extraction baths. In addition, several chemical techniques such as complex coacervation, solvent evaporation, polymer-polymer incompatibility, interfacial polymerization in a liquid medium, in situ polymerization, drying in a liquid, and desolvation in a liquid medium may also be used. In addition, other methods such as roller compaction, extrusion / spheronization, coacervation, or nanoparticle coating may also be used.

[0431] In some embodiments, particles of the compound of any of Formulas (I)-(XLIIIc) are microencapsulated prior to formulation into one of the above forms. In yet other embodiments, some or most of the particles are coated prior to further formulation using standard coating procedures such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000).

[0432] In some embodiments, the solid dosage formulation of the compound of any of Formulas (I)-(XLIIIc) is plasticized (coated) with one or more layers. Illustratively, the plasticizer is generally a high-boiling point solid or liquid. A suitable plasticizer may be added in an amount ranging from about 0.01% to about 50% by weight (w / w) of the coating composition. Plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, grease agents, stearates, and castor oil.

[0433] In some embodiments, powders or granules comprising a formulation comprising a compound of any of Formulas (I)-(XVII) of the present invention may be formulated to include one or more pharmaceutical excipients and flavoring agents. Such powders or granules may be prepared, for example, by mixing the formulation with optionally selected pharmaceutical excipients to form a bulk blend composition. Other embodiments also include a suspending agent and / or a wetting agent. This bulk blend is uniformly subdivided into unit dose packages or multi-dose packaging units.

[0434] In some other embodiments, effervescent powders are also prepared according to the present invention. Effervescent salts have been used to disperse drugs in water for oral administration. Effervescent salts are granules or coarse powders containing a medicament in a dry mixture generally consisting of sodium bicarbonate, citric acid and / or tartaric acid. When the salt of the composition of the present invention is added to water, the acid and base react to release carbon dioxide gas, thereby causing "effervescence". Examples of effervescent salts include, for example, the following ingredients: sodium bicarbonate or a mixture of sodium bicarbonate and sodium carbonate, citric acid and / or tartaric acid. Any acid-base combination that causes carbon dioxide release can be used instead of the combination of sodium bicarbonate, citric acid and tartaric acid, as long as the ingredients are suitable for medical use and produce a pH of about 6.0 or higher.

[0435] In some embodiments, the formulation of the present invention comprising a compound shown in formula (A) is a solid dispersion. Methods for producing such solid dispersions are known in the art and include, but are not limited to, for example, U.S. Patent Nos. 4,343,789, 5,340,591, 5,456,923, 5,700,485, 5,723,269 and U.S. Published Application No. 2004 / 0013734, each of which is specifically incorporated herein by reference. In some embodiments, the formulation of the present invention is a solid solution. The solid solution comprises a substance and an active agent and other excipients such that heating the mixture causes the drug to dissolve and the resulting composition is subsequently cooled to obtain a solid blend, which can be further formulated into or directly added to a capsule or compressed into a tablet. Methods for producing such solid solutions are known in the art and include, but are not limited to, for example, U.S. Patent Nos. 4,151,273, 5,281,420 and 6,083,518, each of which is specifically incorporated herein by reference.

[0436] Pharmaceutical solid oral dosage forms comprising the formulations of the present invention (which include a compound shown in any of Formulas (I)-(XLIIIc)) can be further formulated to provide controlled release of a compound of Formula (A). Controlled release refers to the release of a compound shown in any of Formulas (I)-(XLIIIc) from a dosage form (in which the compound is incorporated according to the desired characteristics) over an extended period of time. Controlled release characteristics include, for example, sustained release, extended release, pulsed release, and delayed release characteristics. Compared to immediate release compositions, controlled release compositions deliver the agent to an individual over a longer period of time according to predetermined characteristics. Compared to conventional rapid release dosage forms, such release rates can provide therapeutically effective levels of the agent over an extended period of time and thereby provide a longer drug response period while minimizing side effects. Such longer response periods provide many inherent benefits that are not available with corresponding short-acting, immediate release formulations.

[0437] In some embodiments, the solid dosage form of the present invention can be formulated as a delayed release oral dosage form coated with an enteric coating, that is, formulated as an oral dosage form of a pharmaceutical composition as described in the present invention that is released in the small intestine of the gastrointestinal tract using an enteric coating. The enteric-coated dosage form can be a compressed or molded or extruded tablet / mold (coated or uncoated) of granules, powders, pills, beads or particles containing active ingredients and / or other composition components, and the granules, powders, pills, beads or particles themselves are coated or uncoated. The enteric-coated oral dosage form can also be a capsule (coated or uncoated) of a pellet, bead or particle containing a solid carrier or composition that is itself coated or uncoated with a coating.

[0438] As used herein, the term "delayed release" refers to delivery that allows release at some generally predictable location in the intestine, which is further away than the location where release is achieved when there is no delayed release change. In some embodiments, the method for delayed release is coating. Any coating should be applied to a sufficient thickness so that the entire coating does not dissolve in gastrointestinal fluids at a pH lower than about 5, but dissolves at a pH of about 5 and above. It is expected that any anionic polymer that exhibits pH-dependent solubility characteristics can be used as an enteric coating in the methods and compositions of the present invention, thereby delivering to the lower gastrointestinal tract. In some embodiments, the polymer described in the present invention is an anionic carboxylic acid polymer. In some embodiments, the polymer and its compatible mixture and some of its characteristics include (but are not limited to):

[0439] Shellac, also known as purified shellac, is a refined product obtained from the resin secretions of insects. This coating dissolves in media with a pH > 7;

[0440] Acrylic polymers. The performance of acrylic polymers (primarily their solubility in biological fluids) can vary based on the degree of substitution and type. Examples of suitable acrylic polymers include methacrylic acid copolymers and ammonium methacrylate copolymers. Eudragit series E, L, S, RL, RS and NE (Rohm Pharma) are available soluble in organic solvents, aqueous dispersions or dry powders. Eudragit series RL, NE and RS are insoluble in the gastrointestinal tract but are permeable and are primarily used for colon targeting. Eudragit series E dissolves in the stomach. Eudragit series L, L-30D and S are insoluble in the stomach but soluble in the intestine;

[0441] Cellulose derivatives. Examples of suitable cellulose derivatives include ethyl cellulose; reaction mixtures of cellulose acetate esters and phthalic anhydride. Performance may vary based on the degree of substitution and type. Cellulose acetate phthalate (CAP) dissolves at pH > 6. Aquateric (FMC) is an aqueous solution-based system and is a spray-dried CAP pseudolatex with particles < 1 μm. Other components in Aquateric may include pluronics, Tweens, and acetylated monoglycerides. Other suitable cellulose derivatives include cellulose acetate trimellitate (Eastman); methylcellulose (Pharmacoat, Methocel); hydroxypropyl methylcellulose phthalate (HPMCP); hydroxypropyl methylcellulose succinate (HPMCS); and hydroxypropyl methylcellulose acetate succinate (e.g., AQOAT (ShinEtsu)). Performance may vary based on the degree of substitution and type. For example, HPMCP grades such as HP-50, HP-55, HP-55S, and HP-55F are suitable. The performance may vary based on the degree and type of substitution. For example, suitable grades of hydroxypropylmethylcellulose acetate succinate include, but are not limited to, AS-LG (LF), which dissolves at pH 5; AS-MG (MF), which dissolves at pH 5.5; and AS-HG (HF), which dissolves at higher pH. These polymers are provided in granular form or as a fine powder for aqueous dispersions.

[0442] Polyvinyl acetate phthalate (PVAP). PVAP dissolves in pH > 5 and has low permeability to water vapor and gastric fluid.

[0443] In some embodiments, the coating may contain and generally contains plasticizers and possible other coating excipients well known in the art, such as colorants, talc and / or magnesium stearate. Suitable plasticizers include triethyl citrate (Citroflex2), triacetin (triacetin), acetyl triethyl citrate (CitroflecA2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetylated monoglycerides, glycerol, fatty acid esters, propylene glycol, and dibutyl phthalate. In particular, anionic carboxylic acid acrylic polymers will typically contain 10-25% by weight plasticizer, especially dibutyl phthalate, polyethylene glycol, triethyl citrate and triacetin. The coating is applied using conventional coating techniques such as spray or pan coating. The coating thickness must be sufficient to ensure that the oral dosage form remains intact until it reaches the desired local delivery site in the intestine.

[0444] In addition to plasticizers, colorants, anti-sticking agents, surfactants, defoaming agents, lubricants (such as carnauba wax or PEG) can be added to the coating to dissolve or disperse the coating material and improve the coating efficiency and coated product.

[0445] In some embodiments, the formulations of the present invention comprising a compound of formula (A) are delivered using a pulsatile dosage form. A pulsatile dosage form can provide one or more immediate release pulses at a predetermined time point or at a specific location after a controlled lag time. Pulsatile dosage forms comprising the formulations of the present invention (which include a compound shown in any of formulas (I)-(XLIIIc)) can be administered using a variety of pulsatile formulations known in the art. For example, such formulations include, but are not limited to, those described in U.S. Patent Nos. 5,011,692, 5,017,381, 5,229,135, and 5,840,329, each of which is specifically incorporated herein by reference. Other pulsatile release formulations suitable for the formulations of the present invention include, but are not limited to, those described in, for example, U.S. Patent Nos. 4,871,549, 5,260,068, 5,260,069, 5,508,040, 5,567,441, and 5,837,284, all of which are specifically incorporated herein by reference. In some embodiments, the controlled release dosage form is a pulsed release solid oral dosage form comprising at least two groups of particles (i.e., multiparticulates) each comprising a formulation of the invention. The first group of particles provides a substantially immediate dose of the compound of any one of Formula (I)-(XLIIIc) upon ingestion by a mammal. The first group of particles may be uncoated or include a coating and / or a sealant. The second group of particles comprises coated particles comprising from about 2% to about 75% by weight, from about 2.5% to about 70% by weight, or from about 40% to about 70% by weight of the total dose of the compound of any one of Formula (I)-(XLIIIc) in the formulation, mixed with one or more binders. The coating comprises an amount of pharmaceutically acceptable ingredient sufficient to provide a delay of from about 2 hours to about 7 hours after ingestion before the second dose is released. Suitable coatings include one or more coatings that are degradable to varying degrees, such as, by way of example only, pH sensitive coatings (enteric coatings), such as acrylic resins (e.g. EPO, L30D-55, FS 30D L100-55, L100, S100, RD100, E100, L12.5, S12.5 and NE30D, NE ), alone or in admixture with a cellulose derivative (e.g., ethylcellulose); or a non-enteric coating having a variable thickness to provide differential release of the formulation comprising any one of the compounds represented by formula (I).

[0446] Many other types of controlled-release systems are known to those of ordinary skill and are suitable for use with the formulations described herein. Examples of such delivery systems include, for example, polymer-based systems such as polylactic and polyglycolic acid, polyanhydrides, and polycaprolactones; porous matrices; non-polymer-based systems that are lipids, including sterols such as cholesterol, cholesterol esters, and fatty acids; or neutral fats such as monoglycerides, diglycerides, and triglycerides; hydrogel release systems; silicone rubber systems; peptide-based systems; wax coatings; bioerodible dosage forms; compressed tablets using conventional binders, and the like. See, for example, Liberman et al., Pharmaceutical Dosage Forms, 2 Ed., Vol. 1, pp. 209-214 (1990); Singh et al., Encyclopedia of Pharmaceutical Technology, 2 nd Ed., pp. 751-753 (2002); U.S. Patent Nos. 4,327,725, 4,624,848, 4,968,509, 5,461,140, ​​5,456,923, 5,516,527, 5,622,721, 5,686,105, 5,700,410, 5,977,175, 6,465,014, and 6,932,983, each of which is specifically incorporated herein by reference.

[0447] In some embodiments, a pharmaceutical composition comprising particles of a compound of any one of Formulas (I)-(XVII) described herein and at least one dispersant or suspending agent is provided for oral administration to a subject. The formulation can be a powder and / or granules for suspension, and when mixed with water, produces a substantially uniform suspension.

[0448] Liquid dosage forms for oral administration may be aqueous suspensions selected from the group consisting of, but not limited to, pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups. See, for example, Singh et al., Encyclopedia of Pharmaceutical Technology, 2 ndEd., pp. 754-757 (2002). In addition to the granules of the compound represented by Formula (A), the liquid dosage form may include additives such as: (a) a disintegrant, (b) a dispersant, (c) a wetting agent, (d) at least one preservative, (e) a viscosity enhancer, (f) at least one sweetener, and (g) at least one flavoring. In some embodiments, the aqueous dispersion may further include a crystallization inhibitor.

[0449] As defined in the USP Pharmacists' Pharmacopeia (2005 edition, Chapter 905), the aqueous suspensions and dispersions of the present invention can maintain a homogeneous state for at least 4 hours. Homogeneity is determined by a sampling method that conforms to the determination of the homogeneity of the entire composition. In some embodiments, the aqueous suspension can be resuspended into a homogeneous suspension by physical stirring for less than 1 minute. In some embodiments, the aqueous suspension can be resuspended into a homogeneous suspension by physical stirring for less than 45 seconds. In other embodiments, the aqueous suspension can be resuspended into a homogeneous suspension by physical stirring for less than 30 seconds. In other embodiments, stirring is not required to maintain a homogeneous aqueous dispersion.

[0450] Examples of disintegrants that can be used in aqueous suspensions and dispersions include, but are not limited to, starches, e.g., natural starches such as corn starch or potato starch; pregelatinized starches such as National 1551 or or sodium starch glycolate, such as or Cellulose, such as wood products; methylcrystalline cellulose, e.g. PH101, PH102, PH105, P100, Ming and Methylcellulose; croscarmellose; or a cross-linked cellulose, such as croscarmellose sodium Cross-linked carboxymethyl cellulose or cross-linked croscarmellose; cross-linked starch, such as sodium starch glycolate; cross-linked polymer, such as cross-linked polyvinyl pyrrolidone; alginates, such as alginic acid or a salt of alginic acid, such as sodium alginate; clays, such as HV (magnesium aluminum silicate); gums such as agar, guar gum, locust bean gum, karaya gum, pectin, or tragacanth; sodium starch glycolate; bentonite; natural sponge; surfactants; resins such as cation exchange resins; citrus pulp; sodium lauryl sulfate; a combination of sodium lauryl sulfate and starch; and the like.

[0451] In some embodiments, dispersants suitable for the aqueous suspensions and dispersions of the present invention are known in the art and include, for example, hydrophilic polymers, electrolytes, 60 or 80, PEG, polyvinylpyrrolidone (PVP; commercially known as ); and carbohydrate-based dispersants such as hydroxypropyl cellulose and hydroxypropyl cellulose ethers (e.g., HPC, HPC-SL, and HPC-L), hydroxypropyl methylcellulose and hydroxypropyl methylcellulose ethers (e.g., HPMC K100, HPMC K4M, HPMC K15M, and HPMC K100M), sodium carboxymethylcellulose, methylcellulose, hydroxyethyl cellulose, hydroxypropyl methyl-cellulose phthalate, hydroxypropyl methylcellulose acetate stearate, non-crystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), polyvinyl pyrrolidone / vinyl acetate copolymer ( For example, S-630), 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde (also known as tyloxapol), poloxamers (such as Pluronics and which are block copolymers of ethylene oxide and propylene oxide); and poloxamines (such as Tetronic Also known as Poloxamine It is a tetrafunctional block copolymer derived from the sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Corporation, Parsippany, NJ). In some embodiments, the dispersant is selected from the group not comprising one of the following agents: hydrophilic polymers; electrolytes; 60 or 80; PEG; polyvinylpyrrolidone (PVP); hydroxypropyl cellulose and hydroxypropyl cellulose ethers (such as HPC, HPC-SL and HPC-L); hydroxypropyl methylcellulose and hydroxypropyl methylcellulose ethers (such as HPMC K100, HPMC K4M, HPMC K15M, HPMC K100M and USP 2910 (Shin-Etsu); sodium carboxymethylcellulose; methylcellulose; hydroxyethylcellulose; hydroxypropylmethyl-cellulose phthalate; hydroxypropylmethyl-cellulose acetate stearate; non-crystalline cellulose; magnesium aluminum silicate; triethanolamine; polyvinyl alcohol (PVA); 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde; poloxamers (e.g., Pluronics and which are block copolymers of ethylene oxide and propylene oxide); or poloxamines (such as Tetronic Also known as Poloxamine ).

[0452] Suitable wetting agents for the aqueous suspensions and dispersions of the present invention are known in the art and include, but are not limited to, cetyl alcohol, glyceryl monostearate, polyoxyethylene sorbitan fatty acid esters (e.g., commercially available Such as Twain Twain (ICI Specialty Chemicals), and polyethylene glycols (such as Carbowaxs and and Carbopol (Union Carbide), oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium oleate, sodium lauryl sulfate, docusate sodium, triacetin, vitamin E TPGS, sodium taurocholate, simethicone, phosphatidylcholine, and the like.

[0453] Suitable preservatives for the aqueous suspensions or dispersions of the present invention include, for example, potassium sorbate; parabens (e.g., methylparaben and propylparaben); benzoic acid and its salts; other esters of parabens, such as butylparaben; alcohols, such as ethanol or benzyl alcohol; phenolic compounds, such as phenol; or quaternary compounds, such as benzalkonium chloride. As used herein, the preservative is incorporated into the dosage form at a concentration sufficient to inhibit the growth of microorganisms.

[0454] Suitable viscosity enhancers for the aqueous suspension or dispersion of the present invention include, but are not limited to, methylcellulose, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, S-630, carbomer, polyvinyl alcohol, alginates, gum arabic, chitosans, and combinations thereof. The concentration of the viscosity enhancer will depend on the selected reagent and the desired viscosity.

[0455] Examples of sweeteners suitable for the aqueous suspensions or dispersions of the present invention include, for example, gum arabic syrup, acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream, berries, red currants, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, marshmallow, cocoa, cola, cherry cooler, citrus cooler, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, licorice syrup (licorice juice), grapes, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glycyrrhizate, Maltitol, Mannitol, Maple, Marshmallow, Menthol, Mint Cream, Mixed Berry, Neohesperidin DC, Neotame, Orange, Pear, Peach, Peppermint, Peppermint Cream, In some embodiments, the aqueous liquid dispersion may comprise a sweetener or flavoring agent at a concentration ranging from about 0.001% to about 1.0% of the volume of the aqueous dispersion. In some embodiments, the aqueous liquid dispersion may include a sweetener or flavoring agent at a concentration ranging from about 0.005% to about 0.5% by volume of the aqueous dispersion. In further embodiments, the aqueous liquid dispersion may include a sweetener or flavoring agent at a concentration ranging from about 0.01% to about 1.0% by volume of the aqueous dispersion.

[0456] In addition to the additives listed above, the liquid preparation may also include inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers. Exemplary emulsifiers include ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, sodium lauryl sulfate, docusate sodium, cholesterol, cholesterol esters, taurocholic acid, phosphatidylcholine, oils (such as cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, fatty acid esters of sorbitan, or mixtures thereof, and the like.

[0457] In some embodiments, the pharmaceutical composition of the present invention may be a self-emulsifying drug delivery system (SEDDS). An emulsion is a dispersion of one immiscible phase, usually in the form of droplets, in another phase. Generally speaking, an emulsion is formed by vigorous mechanical dispersion. Unlike emulsions or microemulsions, SEDDS spontaneously forms an emulsion when added to excess water without any external mechanical dispersion or stirring. The advantage of SEDDS is that only gentle mixing is required to distribute the droplets throughout the solution. In addition, water or an aqueous phase can be added just before administration, which ensures the stability of unstable or hydrophobic active ingredients. Therefore, SEDDS provides an effective delivery system for oral and parenteral delivery of hydrophobic active ingredients. SEDDS can provide improved bioavailability of hydrophobic active ingredients. Methods for preparing self-emulsifying dosage forms are known in the art and include, but are not limited to, those described in, for example, U.S. Patent Nos. 5,858,401, 6,667,048, and 6,960,563, each of which is specifically incorporated herein by reference.

[0458] It should be understood that there is overlap between the additives listed above that can be used in the aqueous dispersions or suspensions described herein, as a given additive is often categorized differently by different practitioners in the field or is typically used for any of several different functions. Therefore, the additives listed above should be considered merely as illustrative and not limiting of the types of additives that can be included in the formulations described herein. The amount of such additives can be readily determined by one skilled in the art based on the specific properties desired. Nasal preparations

[0459] Nasal formulations are known in the art and are described, for example, in U.S. Patent Nos. 4,476,116, 5,116,817, and 6,391,452, each of which is specifically incorporated herein by reference. Formulations comprising a compound of any of Formulas (I)-(XLIIIc) prepared according to these and other techniques well known in the art are prepared as saline solutions using benzyl alcohol or other suitable preservatives, fluorocarbons, and / or other solubilizers or dispersants known in the art. See, for example, Ansel, HC et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, Sixth Ed. (1995). Preferably, these compositions and formulations are prepared using suitable pharmaceutically acceptable non-toxic ingredients. These ingredients are known to those skilled in the art of nasal dosage forms and some of them can be found in Remington: The Science and Practice of Pharmacy, 21st ed., 2005, a standard reference in this field. The choice of a suitable carrier is highly dependent on the exact nature of the desired nasal dosage form, such as a solution, suspension, ointment, or gel. In addition to the active ingredient, nasal dosage forms generally contain a large amount of water. Small amounts of other ingredients such as pH adjusters, emulsifiers or dispersants, preservatives, surfactants, gelling agents or buffers, and other stabilizers and solubilizers may also be present. Nasal dosage forms should be isotonic with nasal secretions.

[0460] For administration by inhalation, any of the compounds shown in formula (I)-(XVII) of the present invention can be in the form of an aerosol, mist, or powder. The pharmaceutical composition of the present invention can be delivered in the form of an aerosol spray using a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas) in a pressurized package or a nebulizer. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver the metered amount. Capsules and cartridges such as, for example, gelatin for use in an inhaler or insufflator can be formulated containing a powder mixture of the compound of the present invention and a suitable powder base (such as lactose or starch). Buccal preparations

[0461] Buccal formulations comprising a compound of any of Formulas (I)-(XLIIIc) can be administered using a variety of formulations known in the art. For example, such formulations include, but are not limited to, U.S. Patent Nos. 4,229,447, 4,596,795, 4,755,386, and 5,739,136, each of which is specifically incorporated herein by reference. In addition, the buccal dosage forms of the present invention may further include a bioerodible (hydrolyzable) polymer carrier that also serves to adhere the dosage form to the buccal mucosa. The buccal dosage form is prepared so as to gradually erode over a predetermined period of time, substantially continuously providing delivery of the compound of any of Formulas (I)-(XVII). As will be appreciated by those skilled in the art, buccal drug delivery avoids the drawbacks encountered with oral drug administration, such as slow absorption, breakdown of the active agent by fluids present in the gastrointestinal tract, and / or first-pass inactivation in the liver. With respect to bioerodible (hydrolyzable) polymeric carriers, it will be appreciated that virtually any such carrier may be used, provided that the desired drug release profile is not compromised and the carrier is compatible with the compound of any of Formulas (I)-(XVII) and any other components present in the buccal dosage unit. Generally, the polymeric carrier comprises a hydrophilic (water-soluble and water-swellable) polymer that adheres to the wetted surfaces of the buccal mucosa. Examples of polymeric carriers suitable for use in the present invention include acrylic acid polymers and copolymers, such as those known as "carbomers" ( Other components that may be incorporated into the buccal dosage forms of the present invention include, but are not limited to, disintegrants, diluents, binders, lubricants, flavorings, colorants, preservatives, and the like. For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, or gels formulated in conventional manner. Transdermal preparations

[0462] The transdermal formulations of the present invention can be administered using a variety of devices described in the art. For example, such devices include, but are not limited to, U.S. Pat. Nos. 3,598,122, 3,598,123, 3,710,795, 3,731,683, 3,742,951, 3,814,097, 3,921,636, 3,972,995, 3,993,072, 3,993,073, 3,996,934, 4,031,894, 4,060,084 , 4,069,307, 4,077,407, 4,201,211, 4,230,105, 4,292,299, 4,292,303, 5,336,168, 5,665,378, 5,837,280, 5,869,090, 6,923,983, 6,929,801, and 6,946,144, each of which is specifically incorporated herein by reference in its entirety.

[0463] The transdermal dosage forms of the present invention may incorporate certain pharmaceutically acceptable excipients conventional in the art. In some embodiments, the transdermal formulations of the present invention include at least three components: (1) a formulation of any of the compounds shown in formula (I); (2) a penetration enhancer; and (3) an aqueous adjuvant. In addition, the transdermal formulations may include additional components such as, but not limited to, gelling agents, creams and ointment bases, and the like. In some embodiments, the transdermal formulations may further include a woven or non-woven backing material to enhance absorption and prevent the transdermal formulation from being removed from the skin. In some embodiments, the transdermal formulations of the present invention may maintain a saturated or supersaturated state to facilitate diffusion into the skin.

[0464] Preparations suitable for transdermal administration of the compounds of the present invention can be prepared using transdermal delivery devices and transdermal delivery patches, and can be lipophilic emulsions or buffered aqueous solutions, dissolved and / or dispersed in polymers or adhesives. Such patches can be constructed for continuous, pulsed, or on-demand delivery of pharmaceutical agents. Furthermore, transdermal delivery of the compounds of the present invention can be achieved by iontophoresis patches and the like. In addition, transdermal patches can provide controlled delivery of the compounds shown in any of formulas (I)-(XVII). The absorption rate can be slowed down by using a rate-controlling membrane or by capturing the compound in a polymer matrix or gel. In contrast, absorption enhancers can be used to increase absorption. Absorption enhancers or carriers can include pharmaceutically acceptable absorbable solvents to help pass through the skin. For example, a transdermal device is in the form of a bandage comprising a substrate component, a reservoir containing the compound and optionally a carrier, an optionally present rate-controlling barrier to deliver the compound to the host skin at a controlled and predetermined rate over a long period of time, and a member for fixing the device to the skin. Injectable preparations

[0465] Preparations suitable for intramuscular, subcutaneous or intravenous injections including any of the compounds shown in formula (I)-(XVII) may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, polyoxyethylene hydrogenated castor oil and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate). Suitable fluidity can be maintained, for example, by using coating materials such as lecithin, in the case of dispersions, by maintaining the desired particle size and by using surfactants. Preparations suitable for subcutaneous injection may also contain additives such as preservatives, wetting agents, emulsifiers and dispensing agents. Microbial growth can be prevented by a variety of antibacterial and antifungal agents (such as parabens, chlorobutanol, phenol, sorbic acid and the like). It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, such as aluminum monostearate and gelatin.

[0466] For intravenous injection, the compounds described herein can be formulated in an aqueous solution, preferably in a physiologically compatible buffer such as Hank's solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art. For other parenteral injections, appropriate formulations may include aqueous or non-aqueous solutions, preferably with physiologically compatible buffers or excipients. Such excipients are generally known in the art.

[0467] Parenteral injections may involve rapid injection or continuous infusion. Injectable formulations may be presented in unit dosage form, such as ampoules or multidose containers, with the addition of a preservative. The pharmaceutical compositions of the present invention may be in the form of sterile suspensions, solutions, or emulsions in oily or aqueous vehicles suitable for parenteral injection and may contain formulating agents such as suspending agents, stabilizers, and / or dispersing agents. Pharmaceutical compositions for parenteral administration include aqueous solutions of the active compound in water-soluble form. Alternatively, suspensions of the active compound may be prepared as oily injection suspensions, if desired. Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil; or synthetic fatty acid esters, such as ethyl oleate or triglycerides; or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound to allow the preparation of highly concentrated solutions. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle (eg, sterile pyrogen-free water) before use. Preparation formula

[0468] In certain embodiments, delivery systems for pharmaceutical compounds such as liposomes and emulsions may be used. In certain embodiments, the compositions provided herein may also include a mucoadhesive polymer selected from, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate, and dextran.

[0469] In some embodiments, the compounds of the present invention can be administered topically and can be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, or ointments. Such pharmaceutical compounds may contain solubilizers, stabilizers, tonicity enhancing agents, buffers, and preservatives.

[0470] The compounds described herein may also be formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas containing conventional suppository bases such as cocoa butter or other glycerides in combination with synthetic polymers such as polyvinylpyrrolidone, PEG, and the like. In suppository forms of the compositions, a low melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter, is first melted. Examples of drug administration and treatment regimens

[0471] The compounds described herein can be used to prepare medicaments for inhibiting menin or its homologues, or for treating diseases or conditions that would benefit, at least in part, from the inhibition of menin or its homologues. Furthermore, methods for treating any of the diseases or conditions described herein in a subject in need of such treatment involve administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising at least one compound of any one of Formulas (I)-(XVII) of the present invention, or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof.

[0472] Compositions containing the compound(s) described herein can be administered for prophylactic and / or therapeutic treatment. In therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. An amount effective for this use will depend on the severity and course of the disease or condition, previous therapy, the patient's health, weight, and response to the drugs, and the judgment of the treating physician. Determination of such therapeutically effective amounts by routine experimentation (including, but not limited to, dose escalation clinical trials) is considered well within the skill of those skilled in the art.

[0473] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk for developing a particular disease, disorder, or condition. This amount is defined as a "prophylactically effective amount or prophylactically effective dose." In this application, the exact amount will also depend on the patient's health, weight, and similar factors. It is believed that one of ordinary skill in the art will be able to determine such a prophylactically effective amount through routine experimentation (e.g., a dose-escalation clinical trial). When administered to a patient, the effective amount for this application will depend on the severity and course of the disease, disorder, or condition, previous therapy, the patient's health and response to the drugs, and the judgment of the treating physician.

[0474] In cases where the patient's condition does not improve, the compound may be administered chronically, that is, for an extended period of time, including the entire duration of the patient's life, to ameliorate or otherwise control or limit the symptoms of the patient's disease or disorder, at the physician's discretion.

[0475] If the patient's condition does improve, the compound may be continued at the physician's discretion; alternatively, the drug dosage may be temporarily reduced or temporarily suspended for a period of time (i.e., a "drug holiday"). The duration of a drug holiday may vary between 2 days and 1 year, including, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. The dose reduction during a drug holiday may be from 10% to 100%, including by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[0476] Once the patient's condition improves, a maintenance dose is administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced to a level at which the improved disease, disorder, or condition is maintained, depending on the symptoms. However, the patient may require intermittent treatment on a long-term basis, depending on any recurrence of symptoms.

[0477] The amount of a given drug corresponding to such dosage will vary depending on factors such as the specific compound, the disease or condition and its severity, the identity of the individual or host in need of treatment (e.g., body weight), but is generally determined in a manner known in the art based on the specific circumstances surrounding each case (including, for example, the specific drug being administered, the route of administration, the condition being treated, and the individual or host being treated). However, in general, dosages employed for adult treatment are generally in the range of 0.02 mg per day to 5000 mg per day, or about 1 mg per day to 1500 mg per day. The desired dosage may be conveniently presented in a single dosage form, or as divided doses administered simultaneously (or over a shorter period of time), or at appropriate intervals, for example, as sub-doses twice, three times, four times, or more per day.

[0478] The pharmaceutical compositions of the present invention may be in the form of unit dosage forms suitable for single administration of precise doses. In a unit dosage form, the formulation is divided into unit doses containing appropriate amounts of one or more compounds. The unit doses may be in a packaged form containing discrete amounts of the formulation. Non-limiting examples are encapsulated tablets or capsules and powders in vials or ampoules. Aqueous suspension compositions may be packaged in single-dose non-reclosable containers. Alternatively, multi-dose reclosable containers may be used, in which case a preservative is typically included in the composition. By way of example only, formulations for parenteral injection may be in unit dosage form, including but not limited to ampoules or multi-dose containers, with a preservative added.

[0479] The foregoing ranges are only suggestions, as the number of variables regarding individual treatment regimens is large, and it is not uncommon for deviations from these recommended values ​​to occur. Such dosages vary depending on many variables, including but not limited to the activity of the compound used, the disease or condition being treated, the mode of administration, the requirements of the individual patient, the severity of the disease or condition being treated, and the judgment of the physician.

[0480] Toxicity and therapeutic efficacy of such treatment regimens can be determined by standard pharmaceutical methods in cell cultures or experimental animals, including but not limited to, determination of the LD 50 (50% group lethal dose) and ED 50 The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD 50 / ED 50 Compounds that exhibit high therapeutic indices are preferred. Data obtained from cell culture assays and animal studies can be used in formulating a dosage range for use in humans. The dosage of such compounds is preferably within the range that includes the ED with minimal toxicity. 50 The dosage may vary within this range depending on the dosage form employed and the route of administration utilized. Combination therapy

[0481] The Menin-MLL inhibitor compositions of the present invention may also be used in combination with other well-known therapeutic agents selected for their therapeutic value for the condition being treated. Generally speaking, in embodiments employing combination therapy, the compositions of the present invention and the other agents need not be administered in the same pharmaceutical composition and may necessitate administration by different routes due to different physical and chemical characteristics. The determination of the mode of administration and, where possible, the rationale for administering the drugs in the same pharmaceutical composition are well within the knowledge of the skilled clinician. Initial administration may be performed according to established protocols known in the art, and the skilled clinician may subsequently modify the dosage, mode of administration, and time of administration based on the observed effects.

[0482] In some cases, it may be appropriate to administer at least one Menin-MLL inhibitor compound described herein in combination with another therapeutic agent. By way of example only, if one of the side effects experienced by a patient while receiving one of the Menin-MLL inhibitor compounds described herein is nausea, it may be appropriate to administer the initial therapeutic agent in combination with an anti-nausea agent. Alternatively, by way of example only, the therapeutic effectiveness of one of the compounds described herein may be enhanced by administering an adjuvant (i.e., the adjuvant may have minimal therapeutic benefit on its own, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Alternatively, by way of example only, the benefit experienced by a patient may be increased by administering one of the compounds described herein together with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit. In any case, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient may be simply additive of the two therapeutic agents, or the patient may experience a synergistic benefit.

[0483] The specific choice of compound to be used will depend on the attending physician's diagnosis and judgment of the patient's condition and the appropriate treatment regimen. Depending on the nature of the disease, disorder or condition, the patient's condition and the actual choice of compound to be used, the compounds may be administered concurrently (e.g., simultaneously, substantially simultaneously or within the same treatment regimen) or sequentially. After evaluating the disease being treated and the patient's condition, it is well within the knowledge of the skilled physician to determine the order of administration and the number of repetitions of administration of each therapeutic agent during the treatment regimen.

[0484] It is known to those skilled in the art that when drugs are used in therapeutic combinations, the therapeutically effective dose may vary. Methods for experimentally determining the therapeutically effective dose of drugs and other agents used in combination therapy regimens are described in the literature. For example, the use of metronomic dosing (i.e., providing more frequent, lower doses to minimize toxic side effects) has been widely described in the literature. Combination therapy further includes cyclical treatment that is started and terminated at multiple times to aid in the clinical management of patients.

[0485] For the combination therapies described herein, the dosage of the co-administered compounds will, of course, vary depending on the type of co-drug employed, the specific drug employed, the disease or condition being treated, and the like. Furthermore, when co-administered with one or more biologically active agents, the compounds provided herein can be administered simultaneously with the biologically active agent(s), or sequentially. If administered sequentially, the attending physician will determine the appropriate order in which the protein and the biologically active agent(s) are administered in combination.

[0486] In any case, the multiple therapeutic agents (one of which is a compound of formula (I)-(XVII) of the present invention) can be administered in any order or even simultaneously. If simultaneous, the multiple therapeutic agents can be provided in a single, unified form or in multiple forms (by way of example only, in a single pill form or in two separate pill forms). One of the therapeutic agents can be administered in multiple doses, or both can be administered in multiple dosage forms. If not simultaneous, the time interval between multiple administrations can vary from more than zero weeks to less than four weeks. In addition, the combined methods, compositions, and formulations are not limited to the use of only two agents; the use of multiple therapeutic combinations is also contemplated.

[0487] It should be understood that the dosage regimen for treating, preventing or improving the (one or more) conditions for which relief is sought may be modified according to a variety of factors. These factors include the conditions from which the individual suffers, as well as the individual's age, weight, sex, diet, and medical condition. Therefore, the dosage regimen actually employed may vary greatly, and therefore may deviate from the dosage regimen set forth herein.

[0488] The agents constituting the combination therapy disclosed herein can be in combination dosage form or in separate dosage forms intended for substantially simultaneous administration. The agents constituting the combination therapy can also be administered sequentially with any therapeutic compound administered by a two-step administration regimen. A two-step administration regimen may require sequential administration of the active agents or intermittent administration of separate active agents. The time period between multiple administration steps can vary from several minutes to several hours, depending on the properties of each agent, such as the efficacy, solubility, bioavailability, plasma half-life, and kinetic characteristics of the agent. Circadian variations in the concentration of the target molecule can also determine the optimal dosage interval.

[0489] Additionally, the compounds disclosed herein may be used in combination with procedures that may provide additional or synergistic benefits to the patient. By way of example only, a patient may be expected to find therapeutic and / or prophylactic benefit in the methods described herein where pharmaceutical compositions of the disclosed compounds and / or combinations with other therapeutic agents are combined with genetic testing to determine whether the individual is a carrier of a mutation known to be associated with certain diseases or conditions.

[0490] The compounds and combination therapies of the present invention can be applied before, during or after the occurrence of a disease or condition, and the timing of applying the composition containing the compound can be different. Therefore, for example, the compound can be used as a prophylactic and can be continuously applied to individuals with a tendency to develop a condition or disease in order to prevent the occurrence of a disease or condition. The compound and composition can be applied to an individual as quickly as possible during or after the onset of symptoms. The application of the compound can be started within the first 48 hours of the onset of symptoms, within the first 6 hours of the onset of symptoms, or within 3 hours of the onset of symptoms. The initial application can be via any feasible route, such as intravenous injection, push injection, infusion within 5 minutes to about 5 hours, pills, capsules, transdermal patches, buccal delivery, and similar routes, or a combination thereof. The compound should be applied immediately after the onset of a disease or condition, where feasible, and the time length required for the treatment of the disease should be continued, such as about 1 month to about 3 months. The treatment length can be different for each individual, and the length can be determined using known criteria. For example, a compound or a preparation containing the compound can be applied for at least 2 weeks, between about 1 month and about 5 years, or about 1 month to about 3 years. Exemplary Therapeutic Agents for Use in Combination with Menin-MLL Inhibitor Compounds

[0491] In individuals who have or are at risk for developing an autoimmune, inflammatory, or allergic disease, a Menin-MLL inhibitor compound can be used in any combination with one or more of the following therapeutic agents: immunosuppressants (e.g., tacrolimus, cyclosporin, rapamicin, methotrexate, cyclophosphamide, azathioprine, mercaptopurine, mycophenolate mofetil, or FTY720), glucocorticoids (e.g., prednisone, cortisone acetate, tacrolimus, cyclosporine, rapamicin, methotrexate, cyclophosphamide, azathioprine, mercaptopurine, mycophenolate mofetil, or FTY720), acetate, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclometasone, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone), nonsteroidal anti-inflammatory drugs (e.g., salicylates, arylalkanoic acids, 2-arylpropionic acids, N-arylanthranilic acids, oxicams, coxibs, or sulphonanilides), Cox-2 specific inhibitors (e.g., valdecoxib, celecoxib, or rofecoxib), leflunomide, gold thioglucose thioglucose, goldthiomalate, aurofin, sulfasalazine, hydroxychloroquinine, minocycline, TNF-alpha binding proteins (such as infliximab, etanercept, or adalimumab), abatacept, anakinra, interferon-beta, interferon-gamma, interleukin-2, allergy vaccines, antihistamines, antileukotrienes, beta-agonists, theophylline, or anticholinergics.

[0492] When an individual has a B-cell proliferative disorder (e.g., plasma cell myeloma) or is at risk of developing such a disorder, the individual may be treated with a Menin-MLL inhibitor compound in any combination with one or more other anticancer agents. In some embodiments, the one or more anticancer agents are pro-apoptotic agents. Examples of anticancer agents include, but are not limited to, any of the following: gossyphol, genasense, polyphenol E, chlorofusin, all-trans retinoic acid (ATRA), bryostatin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), 5-aza-2'-deoxycytidine, all-trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib, Geldanamycin, 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), flavopiridol, LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, or PD184352, Taxol TM , also known as "paclitaxel," is a well-known anticancer drug that works by enhancing and stabilizing microtubule formation, and Taxol TM Analogs (such as Taxotere TM Compounds that share the basic taxane structure as a structural feature have also been shown to have the ability to arrest cells in the G2-M phase due to stabilization of microtubules and may be suitable for use in combination with the compounds of the present invention to treat cancer.

[0493] Other anticancer agents that can be used in combination with Menin-MLL inhibitor compounds include adriamycin, dactinomycin, bleomycin, vinblastine, cisplatin, acivicin, aclarubicin, acodazole hydrochloride, acronine, adozelesin, aldesleukin, altretamine, ambomycin, and ametantron acetate. acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; biscafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin;dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride hydrochloride); ifosfamide; iimofosine; interleukin Il (including recombinant interleukin II or rIL2), interferon α-2a, interferon α-2b, interferon α-n1, interferon α-n3, interferon β-la, interferon γ-lb; iproplatin; irinotecan hydrochloride;Lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrolacetate; melenestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin;Puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazene; sparrosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalansodium; tegafur; teloxantrone hydrochloride hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;Vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride.

[0494] Other anticancer agents that may be used in combination with Menin-MLL inhibitor compounds include: 20-epi-1,25-dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adenosine; adolesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; irreversible angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsal morphogenetic protein-1; anti-androgen prostate cancer; anti-estrogen; anti-neoplaston; antisense oligonucleotides; glycine aphidicolin; glycinate; apoptosis gene regulators; apoptosis regulators; apurinic nucleic acid; ara-CDP-DL-PTBA; arginine deaminase: asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; diazotyrosine; baccatin III derivatives derivatives; balanol; batimastat; BCR / ABL antagonists; benzochlorins; benzoylstaurosporine; beta-lactam derivatives; beta-alethine; beta-clarithromycin B; betulinic acid; bFGF inhibitors; bicalutamide; bisantrene; bisaziridinylspermine; binefad; bistratene A; bizelesin; breflate; bropiridamine; budotitane; buthionine sulfoximine; calcipotriol; calcitropin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamide-triazole; CaRest M3; CARN 700; cartilage-derived inhibitor; carzelesin; casein kinase irreversible inhibitor (ICOS); castanospermine; cecropin B;Cetrorelix; chlorlins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; colismycin A; climycin B; combretastatin A4; combretastatin analogues; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinone; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; 9-dioxamycin; diphenylspiromustine; docosanol; dolasetron dolasetron; doxiluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; ethiprofen; epirubicin; epristeride; estrogen mustard analogs; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine;Fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; irreversible gelatinase inhibitors; gemcitabine; irreversible glutathione inhibitors; hepsulfam; heregulin; hexamethylenediethylamide; hypericin; ibandronic acid acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulatory peptides; insulin-like growth factor 1 receptor inhibitors; interferon agonists; interferons; interleukins; iobenguane; iodoxorubicin; 4-naphthoic acid; iroplact; irsogladine; isobengazole; isohomohalicondrinb; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibitory factor; interferon-alpha; leuprolide+estrogen+progesterone; leuprolide; levamisole; liarozole; linear polyamine analogs; lipophilic disaccharide peptides; lipophilic platinum compounds; lissoclinamide7; lobaplatin; lombricine; lometrexol; lonidamine;losoxantrone; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; irreversible inhibitors of matrix metalloproteinases; irreversible inhibitors of matrix metalloproteinases; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitors; mifepristone; miltefosine; mirimostim; mitoguazone; dibromodulcitol, mitomycin analogs; mitonafide; mitotoxin fibroblast growth factor-saporin factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibodies, human chorionic gonadotropin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol, multidrug resistance gene inhibitor; multiple tumor suppressor 1-based therapy; nitrogen mustard anticancer agent; Indian Ocean sponge B (mycaperoxide B); mycobacterial cell wall extracts; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone + pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; nilutamide; nisamycin; nitric oxide modulators; nitric oxide antioxidants; nitrullyn, O6-benzylguanine;Octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducers; ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronate acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; irreversible phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A A); platinum B; plasminogen activator inhibitors; platinum complexes; platinum compounds; platinum-triamine complexes; porfimer sodium; porfiromycin; prednisone; propyldiacridone; prostaglandin J2; irreversible proteasome inhibitors; protein A-based immunomodulators; protein kinase C inhibitors; irreversible protein kinase C inhibitors; microalgae; irreversible protein tyrosine phosphatase inhibitors; irreversible purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylerie conjugate; RAF antagonists; raltitrexed; ramosetron; irreversible inhibitors of ras farnesyl-protein transferase; irreversible ras inhibitors; ras-GAP inhibitors; demethylated retiptine; rhenium (Re) 186 etidronate; rhizobactin; ribozymes; RII retinamide; rogletimide; rohitukine; romurtide; roquinimex;rubiginone B1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetic; semustine; senescence-derived inhibitor 1; sense oligonucleotides; irreversible inhibitors of signal transduction; signal transduction regulators; single-chain antigen-binding protein; sizofiran; sobuzoxane; borcaine sodium; sodium phenylacetate; solverol; somatomedin-binding protein; sonermin; sparsosic acid; skamycin D; spiromustine; splenopentin; spongistatin 1 1); squalamine; stem cell inhibitors; irreversible inhibitors of stem cell division; stipiamide; irreversible inhibitors of stromelysin; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium sodium); fluazifopylamine; tellurapyrylium; irreversible telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetics; thymalfasin; thymopoietin receptor agonists; thymotrinan; thyroid-stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocenyl dichloride; topsentin; toremifene; totipotent stem cell factor; irreversible translation inhibitors; tretinoin; triacetyluridine;Triciribine; trimetrexate; triptorelin; tropisetron; turosteride; irreversible tyrosine kinase inhibitors; tyrphostins; irreversible UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B B); vector systems, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and statins.

[0495] Other anticancer agents that can be used in combination with Menin-MLL inhibitor compounds include alkylating agents, antimetabolites, natural products, or hormones, such as nitrogen mustards (e.g., dichloromethane, cyclophosphamide, chlorambucil, etc.), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomustine, etc.), or triazenes (decarbazine, etc.). Examples of antimetabolites include, but are not limited to, folic acid analogs (e.g., methotrexate), or pyrimidine analogs (e.g., cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin).

[0496] Examples of natural products suitable for combination with Menin-MLL inhibitor compounds include, but are not limited to, vinca alkaloids (e.g., vinblastine, vincristine), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunomycin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), or biological response modifiers (e.g., interferon alpha).

[0497] Examples of alkylating agents that can be used in combination with Menin-MLL inhibitor compounds include, but are not limited to, nitrogen mustards (e.g., dichloromethane, cyclophosphamide, chlorambucil, melphalan, etc.), ethyleneimines and methylmelamines (e.g., hexamethylmelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomustine, semustine, streptozotocin, etc.), or triazenes (decarbazine, etc.). Examples of antimetabolites include, but are not limited to, folic acid analogs (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxouridine, cytarabine), or purine analogs (e.g., mercaptopurine, thioguanine, pentostatin).

[0498] Examples of hormones and antagonists suitable for use in combination with Menin-MLL inhibitor compounds include, but are not limited to, adrenocortical steroids (e.g., prednisone), progestogens (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethylstilbestrol, ethinyl estradiol), antiestrogens (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymethylenetetracycline), antiandrogens (e.g., flutamide), and gonadotropin-releasing hormone analogs (e.g., leuprolide). Other agents useful in the methods and compositions for treating or preventing cancer described herein include platinum complexes (e.g., cisplatin, carboplatin), anthraquinones (e.g., mitoxantrone), substituted ureas (e.g., hydroxyurea), methylhydrazine derivatives (e.g., procarbazine), and adrenocortical suppressants (e.g., mitotane, aminoglutethimide).

[0499] Since stabilized microtubules act by arresting cells in the G2-M phase, examples of anticancer agents that can be used in combination with Menin-MLL inhibitor compounds include, but are not limited to, the following marketed drugs and drugs in development: erbulazole (also known as R-55104), dolastatin 10 (also known as DLS-10 and NSC-376128), mivobulin isethionate (also known as selenoflagellate), and selenoflagellate. isethionate (also known as CI-980), vincristine, NSC-639829, discodermolide (also known as NVP-XX-A-296), ABT-751 (Abbott, also known as E-7010), altorhyrtins (such as altohexitin A and altohexitin C), spongistatins (such as spongistatin 1, 2, 3, 4, 5, 6, 7, 8, and 9), cemadotin hydrochloride (also known as cytoxan), cytoxan ... hydrochloride, also known as LU-103793 and NSC-D-669356), epothilones (epothilones such as epothilone A, epothilone B, epothilone C (also known as deoxyepothilone A or dEpoA), epothilone D (also known as KOS-862, dEpoB, and deoxyepothilone B), epothilone E, epothilone F, epothilone B N-oxide, epothilone AN-oxide, 16-aza-epothilone B, 21-aminoepothilone B (also known as BMS-310705), 21-hydroxyepothilone D (also known as deoxyepothilone F and dEpoF), 26-fluoroepothilone, auristatin PE (also known as NSC-654663), soblidotin (also known as TZT-1027), LS-4559-P (Pharmacia, also known as LS-4577), LS-4578 (P harmacia, also known as LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis), vincristine sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, also known as WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences), BSF-223651 (BASF,Also known as ILX-651 and LU-223651), SAH-49960 (Lilly / Novartis), SDZ-268970 (Lilly / Novartis), AM-97 (Armad / KyowaHakko), AM-132 (Armad), AM-138 (Armad / Kyowa Hakko), IDN-5005 (Indena), Nostoc 52 (also known as LY-355703), AC-7739 (Ajinomoto, also known as AVE-8063A and CS-39.HCl), AC-7700 (Ajinomoto, also known as AVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and RPR-258062A), Vitilevuamide, Tubulysin A, Canadensol, Cyanidin (also known as NSC-106969), T-138067 (Tularik, also known as T-67, TL-138067, and TI-138067), COBRA-1 (Parker Hughes Institute, also known as DDE-261 and WHI-261), H10 (Kansas State University), University), H16 (Kansas State University), Oncocidin A1 (also known as BTO-956 and DIME), DDE-313 (Parker Hughes Institute), Fijianolide B, Laulimalide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute, also known as SPIKET-P), 3-IAABU (Cytoskeleton / Mt. Sinai School of Medicine, also known as MF-569), Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica), A-105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton / Mt. Sinai School of Medicine,Also known as MF-191), TMPN (Arizona State University), Vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, Inanocine (also known as NSC-698666), 3-lAABE (Cytoskeleton / Mt. Sinai School of Medicine), A-204197 (Abbott), T-607 (Tuiarik, also known as T-900607), RPR-115781 (Aventis), Eleutherobins (such as desmethyleleutherobin, desacetyleleutherobin, isoeleutherobin A and Z-eleutherobin), Caribaeolin, Halichondrin B, D-64131 (Asta Medica), D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), Taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott), Diozostatin, (-)-Phenylahistin (also known as NSCL-96F037), D-68838 (AstaMedica), D-68836 (Asta Medica), Myoseverin B, D-43411 (Zentaris, also known as D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286 (also known as SPA-110, trifluoroacetate) (Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC-12983 (NCI), Resverastatin sodium phosphate, BPR-OY-007 (National Health Research Institutes), and SSR-250411 (Sanofi).

[0500] When a subject suffers from, or is at risk of suffering from, a thromboembolic disorder (e.g., stroke), the subject may be treated with any combination of a Menin-MLL inhibitor compound and one or more other anti-thromboembolic agents. Examples of anti-thromboembolic agents include, but are not limited to, any of the following: thrombolytics (e.g., alteplase, anistreplase, streptokinase, urokinase, or tissue plasminogen activator), heparin, tinzaparin, warfarin, dabigatran (e.g., dabigatran etexilate), irreversible factor Xa inhibitors (e.g., fondaparinux, draparinux, rivaroxaban, DX-9065A, omixaban, LY517717, or YM150), ticlopidine, clopidogrel, CS-747 (prasugrel, LY640315), ximelagatran, or BIBR 1048. Kits / Products

[0501] The present invention also describes kits and articles of manufacture for use in the therapeutic applications described herein. Such kits may include a carrier, package, or container compartmentalized to receive one or more containers (such as vials, tubes, and the like), each container containing one of the individual elements to be used in the methods described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. Containers may be made of various materials, such as glass or plastic.

[0502] The articles provided herein contain packaging materials. Packaging materials used to package pharmaceutical products are well known to those skilled in the art. See, for example, U.S. Patent Nos. 5,323,907, 5,052,558, and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packages, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for the selected formulation and intended mode of administration and treatment. A variety of formulations of the compounds and compositions provided herein are contemplated for use in a variety of treatments for any disease, disorder, or condition that would benefit from the inhibition of menin, or in which menin is a mediator or contributor to the symptoms or etiology.

[0503] For example, a container may contain one or more compounds described herein, optionally in the form of a composition or in combination with another agent as disclosed herein. The container may optionally have a sterile access port (e.g., the container may be an intravenous solution bag or a vial with a stopper pierceable by a hypodermic needle). Such kits may optionally contain the compound and an identifying description or label or instructions for its use in the methods described herein.

[0504] Kits typically include one or more additional containers, each containing one or more of the various materials necessary for commercial and user use of the compound (such as reagents, optionally in concentrated form, and / or devices). Non-limiting examples of such materials include, but are not limited to, buffers, diluents, filters, needles, syringes; carriers, packaging, containers, vials, and / or tube labels listing the contents and / or instructions for use, and package inserts containing instructions for use. A set of instructions is also typically included.

[0505] The label can be located on or associated with the container. A label can be located on the container when the letters, numbers, or other characters forming the label are attached, molded, or etched into the container itself. A label can be associated with the container when the label is present within a receptacle or carrier that also holds the container, such as in the form of a packaging insert. Labels can be used to indicate that the contents are intended for a specific therapeutic application. Labels can also indicate directions for use of the contents, such as in the methods described herein.

[0506] In certain embodiments, the pharmaceutical composition can be presented in a package or dispenser device that can contain one or more unit dosage forms containing the compounds provided herein. The package can, for example, contain metal or plastic foil, such as a blister package. The package or dispenser device can be accompanied by instructions for administration. The package or dispenser can also be accompanied by instructions for use associated with the container, the form of which is regulated by a government agency that regulates the manufacture, use, or sale of pharmaceuticals, and the instructions reflect that the agency approves the pharmaceutical form for human or veterinary administration. For example, such instructions can be a label approved by the U.S. Food and Drug Administration for prescription drugs or an approved product insert. Compositions containing compounds provided herein formulated in a compatible pharmaceutical carrier can also be prepared, placed in an appropriate container, and labeled for use in treating the indicated condition. Example

[0507] The following specific and non-limiting examples are intended to be illustrative only and are not intended to limit the present invention in any way. Without further detailed description, it is believed that those skilled in the art can utilize the present invention to the greatest extent possible based on the description of the present invention. All publications cited herein are incorporated herein by reference in their entirety. Where URLs or other such identifiers or addresses are mentioned, it should be understood that although such identifiers may change and specific information on the Internet may come and go, equivalent information may be found by searching the Internet. Reference to such information confirms the availability and public dissemination of such information.

[0508] In the following examples and throughout this application, the following abbreviations have the following meanings. If not defined, the terms have their generally accepted meanings. aq = aqueous solution Boc = tert-butyloxycarbonyl t-BuOH = tert-butyl alcohol DCE = 1,2-dichloroethane DCM = dichloromethane DIAD = diisopropyl azodicarboxylate DIEA or DIPEA = N,N-diisopropylethylamine DMAP = dimethylaminopyridine DMF = dimethylformamide DMSO = dimethyl sulfoxide ESI = Electrospray Ionization EA = ethyl acetate g = grams HCl = hydrochloric acid HPLC = High Performance Liquid Chromatography hr = hours 1 H NMR = Proton Nuclear Magnetic Resonance IPA = Isopropyl alcohol KOAc = potassium acetate LC-MS = Liquid Chromatography Mass Spectrometry M = molar concentration MeCN = acetonitrile MeOH = methanol mg = milligrams min = minutes ml = milliliters mM = millimolar concentration mmol = millimole mp = melting point MS = Mass Spectrometry m / z = mass-to-charge ratio N = Normal NIS = N-iodosuccinimide nM = nanomolar concentration nm = nanometers Pd(dppf)Cl2=[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride PE = Petroleum Ether PyBOP = Benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate quant.=quantitative RP = reverse phase rt or rt = room temperature Sat.=Saturation TEA = triethylamine TFA = trifluoroacetic acid μL = microliter μM = micromolar concentration General synthetic scheme Among them, Cy, Cy 2 , L, R 2 、R 6a 、R 6b and R 6c All as described in the present invention. General synthesis of intermediates 3A and / or 5A General method for preparing intermediate 3A -

[0509] Morpholine (3.12 g, 35.7 mmol, 3.15 mL, 2 equivalents) was reacted with a solution of Intermediate 1A (5.00 g, 17.8 mmol, 1 equivalent) in n-butanol (25.0 mL) at 100°C for 12 h. The color of the solution turned white. TLC (dichloromethane / methanol = 10 / 1, R f =0.60) indicated complete consumption of the starting material. The reaction mixture was diluted with H2O (200.0 mL) and then extracted with EtOAc (100.0 mL x 3). The combined organic layers were washed with brine (100.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The resulting compound was used in the next step without further purification. NMR showed that Intermediate 3A (5.08 g, 15.3 mmol, 86.0% yield) was obtained as a white solid. General method for the preparation of intermediate 5A -

[0510] A solution of (4-aminophenyl)boronic acid (2.49 g, 18.1 mmol, 1.5 equiv), intermediate 3A (4.00 g, 12.1 mmol, 1 equiv) and K2CO3 (10.0 g, 72.7 mmol, 6 equiv) in dioxane (20.0 mL) and H2O (4.00 mL) was degassed with argon for 30 minutes. Cyclopentyl(diphenyl)phosphine, palladium dichloride, and iron (886.5 mg, 1.21 mmol, 0.1 equiv) were added to the reactor. The mixture was refluxed at 100°C for 12 hours. The color of the solution turned black. TLC (dichloromethane / methanol = 10 / 1, R f=0.57) indicating complete consumption of the starting material. The reaction mixture was diluted with H2O (300.0 mL) and then extracted with EtOAc (300.0 mL x 3). The combined organic layers were washed with brine (300.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 5 / 1) to obtain Intermediate 5A (3.00 g, 10.1 mmol, 83.8% yield) as a white solid. Example Example 1 Synthesis of compound 1 General method for preparing intermediate 3-

[0511] A solution of Intermediate 1 (11.0 g, 69.3 mmol, 1 eq), Intermediate 2 (21.7 g, 104.0 mmol, 1.5 eq, HCl) and NaHCO3 (14.5 g, 173.4 mmol, 6.75 mL, 2.5 eq) in DMSO (100.0 mL) was stirred at 70°C for 16 hours. TLC (petroleum ether / ethyl acetate = 1 / 1, R f =0.24) shows that the raw material is completely consumed. The combined reaction mixture is then diluted with H2O (50.0mL) and extracted with EtOAc (20.0mL x 3). The combined organic layer is washed with H2O (50.0mL x 5) and salt solution (20.0mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain residue. Residue is purified by column chromatography (SiO2, petroleum ether / ethyl acetate=20 / 1 to 1 / 1). Intermediate 3 (15.0g, 50.9mmol, 73.4% yield) is obtained as a yellow solid. 1 H NMR:MeOD Varian (USA)_Y_400MHz 8.07(d,J=5.7Hz,1H),7.19(d,J=2.2Hz,1H),6.66(dd,J=2.2,5.7Hz,1H),4.60(br s, 1H), 4.37 (t, J = 8.2Hz, 2H), 3.93 (dd, J = 5.6, 8.5Hz, 2H), 1.45 (s, 9H). General method for preparing intermediate 4-

[0512] To a solution of intermediate 3 (13.0 g, 44.1 mmol, 1 eq) in MeOH (80.0 mL) under N2 was added Pd / C (5.00 g, 10% purity). The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred at 25°C under H2 (50 psi) for 2 hours. TLC (dichloromethane / methanol = 10 / 1, R f =0.24) indicated that reactant 1 had been completely consumed and a new spot had formed. The reaction mixture was filtered and the filtrate was concentrated to obtain a residue. The residue was washed with DCM / EtOAc = 1 / 2 (100.0 mL). Intermediate 4 (8.00 g, 30.2 mmol, 68.5% yield) was obtained as a white solid. 1 H NMR:DMSOVarian_S_400MHz 7.55(d,J=5.7Hz,2H),5.65(dd,J=1.8,5.7Hz,1H),5.43(s,2H),5.36(d,J=1.5H z, 1H), 4.34-4.45 (m, 1H), 4.02 (t, J = 7.6Hz, 2H), 3.53-3.60 (m, 2H), 1.38 (s, 9H). General method for the preparation of intermediate 5 -

[0513] To a solution of intermediate 5 (1.00 g, 3.39 mmol, 1 eq) in THF (30.0 mL) was added K2CO3 (1.40 g, 10.1 mmol, 3 eq) at 25°C. After 30 minutes, phenyl chloroformate (636.1 mg, 4.06 mmol, 508.9 uL, 1.2 eq) was added to the reaction. The reaction was then stirred at 25°C for 2 hours. Intermediate 4 (894.9 mg, 3.39 mmol, 1 eq), TEA (1.71 g, 16.9 mmol, 2.36 mL, 5 eq) and DMAP (206.8 mg, 1.69 mmol, 0.5 eq) were then added to the reaction. The reaction was stirred at 50°C for 12 hours. LCMS showed that the reaction was not complete, but the desired intermediate was detected by LCMS. The reaction was concentrated to give a residue. The resulting residue was purified by preparative HPLC (column: Phenomenex luna C18 250*50mm*10um; mobile phase: [water (0.1% TFA)-ACN]; B%: 10%-40%, 18 minutes) to afford Intermediate 5 (230.0 mg, 328.7 umol, 9.7% yield, TFA) as an off-white solid. General method for the preparation of intermediate 6 -

[0514] To a solution of intermediate 5 (200.0 mg, 285.8 μmol, 1 equivalent, TFA) in MeOH (5.00 mL) was added HCl / dioxane (4 M, 10.0 mL, 139.9 equivalents), and the reaction was stirred at 25 ° C for 2 hours. LCMS showed that the reaction was complete and the desired intermediate was detected by LCMS. The reaction solution was concentrated to obtain an unpurified residue. Intermediate 6 (160.0 mg, crude product, HCl) was obtained as a brown solid. General method for preparing compound 1-

[0515] A solution of intermediate 6 (140.0 mg, 288.3 umol, 1 equiv), prop-2-enoyl chloride (31.3 mg, 346.0 umol, 28.2 uL, 1.2 equiv) and TEA (87.5 mg, 865.0 umol, 120.4 uL, 3 equiv) in DCM (3.00 mL) was stirred at 25° C. for 1 hour. LCMS showed that the reaction was not complete, but the desired intermediate was detected by LCMS. The reaction was concentrated to obtain a residue. The resulting residue was purified by preparative HPLC (column: Luna C18100*305u; mobile phase: [water (0.2% FA)-ACN]; B%: 1%-22%, 15 minutes). Intermediate compound 1 (17.0 mg, 30.4 umol, 10.5% yield, 96.5% purity) was obtained as an off-white solid. 1 H NMR:DMSOVarian_Y_400MHz 12.17(s,1H),11.49-11.54(m,1H),11.35(s,1H),9.24(s,1H),8.83(br d,J=7.1Hz,1H),8.12-8.18(m,1H),7.92(d,J=5.7Hz,1H),7.85(d,J=8.6Hz,1H),7.83-7.88(m,1H),7.58(d,J=8.8Hz,2H),7.08(s,1H),6.28(br s,1H),6.13-6.19(m,2H),5.62-5.69(m,1H),4.71(br d,J=7.1Hz,1H),4.24(br s,2H),3.87(br d, J=4.9Hz, 4H), 3.75 (br d,J=4.6Hz, 6H). Example 2 Synthesis of compound 3 General method for the preparation of intermediate 2-

[0516] A mixture of intermediate 1 (20.0 g, 116.2 mmol, 1 equivalent), diethyl carbonate (17.8 g, 151.1 mmol, 18.3 mL, 1.3 equivalents), and LDA (2 M, 145.3 mL, 2.5 equivalents) in THF (100.0 mL) was degassed and purged with N 2 three times, and then the mixture was stirred at -70-25° C. under N 2 atmosphere for 4 hours. TLC (petroleum ether / ethyl acetate=3 / 1, R f =0.68) indicated the reaction was complete. The reaction mixture was partitioned between H2O (100.0 mL) and EtOAc (250.0 mL). The organic phase was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel chromatography using petroleum ether / ethyl acetate = 3 / 1 to 0 / 1 as the eluent. Intermediate 2 (18.0 g, 73.7 mmol, 63.4% yield) was obtained as a yellow liquid. General method for preparing intermediate 4-

[0517] A mixture of intermediate 2 (10.0 g, 40.9 mmol, 1 equivalent), intermediate 3 (8.21 g, 40.9 mmol, 1 equivalent), K2CO3 (5.66 g, 40.9 mmol, 1 equivalent) in DMF (50.0 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 120°C under N2 atmosphere for 16 h. TLC (petroleum ether / ethyl acetate = 0 / 1, R f =0.79) indicated the reaction was complete. The reaction mixture was partitioned between H2O (100.0 mL) and EtOAc (500.0 mL). The organic phase was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The resulting residue was purified by silica gel chromatography using petroleum ether / ethyl acetate = 0 / 1 as the eluent. Intermediate 4 (10.0 g, 27.5 mmol, 67.1% yield) was obtained as a brown oil. 1 H NMR:CDCl3400 MHz 8.17(d,J=6.1Hz,1H),6.66(d,J=2.3Hz,1H),6.59(dd,J=2.3,5.9Hz,1H),4.70(br d,J=5.7Hz,1H),4.16(q,J=7.1Hz,2H),3.68(s,2H),3.41(br d,J=11.6Hz,1H),3.08-3.20(m,1H),3.02(br dd,J=7.5,11.5Hz,1H),2.11(br s,1H),1.91(br d,J=4.4Hz,1H),1.71-1.80(m,1H),1.64(dtd,J=4.2,8.8,13.2Hz,1H),1.47-1.56(m,2H),1.43(br s,9H),1.21-1.27(m,3H). General method for the preparation of intermediate 5 -

[0518] To a solution of intermediate 4 (5.00 g, 13.7 mmol, 1 equivalent) in EtOAc (25 mL) was added HCl / EtOAc (4 M, 376.9 uL). The mixture was stirred at 25°C for 1 hour. TLC (dichloromethane / methanol = 10 / 1, R f =0.03) indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure to remove EtOAc. The residue was diluted with H2O (50.0 mL) and then extracted with EtOAc (50.0 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain an unpurified residue. Intermediate 5 (4.00 g, crude) was obtained as a brown solid. 1 H NMR:MeOD 400MHz 8.18(d,J=7.3Hz,1H),7.27(d,J=2.8Hz,1H),7.20(dd,J=3.0,7.4Hz,1H),4.27-4.34(m,1H),4.23(q,J=7.1Hz,2H),3.99(s,2H),3 .42-3.50(m,2H),2.23(td,J=4.1,8.3Hz,1H),1.94-1.99(m,1H),1.73-1.86(m,2H),1.29(t,J=7.1Hz,3H),1.24(t,J=7.2Hz,2H). General method for the preparation of intermediate 6 -

[0519] To a solution of ethyl intermediate 5 (2.00 g, 7.59 mmol, 1 eq) in DCM (14.0 mL) was added TEA (1.54 g, 15.19 mmol, 2.11 mL, 2 eq), but-2-ynoic acid (638.5 mg, 7.59 mmol, 1 eq) and HATU (3.00 g, 7.90 mmol, 1.04 eq). The mixture was stirred at 25 ° C for 4 hours. TLC (dichloromethane: methanol = 10: 1, R f =0.55) indicated the reaction was complete. The reaction mixture was partitioned between H2O (10.0 mL) and EtOAc (30.0 mL). The organic phase was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give an unpurified residue. Intermediate 6 (1.50 g, crude) was obtained as a brown gum. 1 H NMR:DMSO 400MHz 8.74-8.69(m,1H),8.23(d,J=7.3Hz,1H),7.20(br s,1H),7.08(br d,J=5.7Hz,1H),4.15(q,J=7.1Hz,2H),3.93(s,2H),3.69-3.80(m,1H),3.33(br d,J=9.3Hz,2H),3.07-3.12(m,2H),1.95(s,3H),1.80-1.90(m,2H),1.46-1.64(m,2H),1.22(t,J=7.2Hz,3H). General method for the preparation of intermediate 7 -

[0520] To a solution of intermediate 6 (0.50 g, 1.52 mmol, 1 eq) in THF (3.00 mL) was added a solution of LiOH·H2O (191.1 mg, 4.55 mmol, 3 eq) in H2O (3.00 mL). The mixture was stirred at 25°C for 3 hours. TLC (dichloromethane / methanol = 10 / 1, R f =0) indicated the reaction was complete. The reaction mixture was partitioned between EtOAc (30.0 mL) and H2O (10.0 mL). The organic phase was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give an unpurified residue. Intermediate 7 (0.50 g, crude) was obtained as a brown gum. General method for preparing compound 3-

[0521] To a solution of Intermediate 7 (0.40 g, 1.33 mmol, 1 eq) in DMF (10.0 mL) was added Intermediate 3A (392.0 mg, 1.33 mmol, 1 eq), HATU (757.0 mg, 1.99 mmol, 1.5 eq), and pyridine (524.9 mg, 6.64 mmol, 535.7 uL, 5 eq). The mixture was stirred at 25°C for 10 hours. LCMS indicated the reaction was complete. The mixture was poured into H2O (30.0 mL) and filtered, and the filter cake was concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 200*40 mm*10 um; mobile phase: [water (0.05% HCl)-ACN]; B%: 10%-30%, 10 min). Compound 3 (106.0 mg, 179.8 umol, 13.5% yield, 98.2% purity) was obtained as a yellow solid. 1 H NMR:DMSO 400MHz 13.56(br d,J=3.7Hz,1H),12.89(br s,1H),10.75(br s,1H),8.73(d,J=7.1Hz,1H),8.31(s,1H),8.21-8.27(m,1H),7.91(d,J=8.6Hz,2H),7.71(d,J=8.8Hz,2H),7.33(br s,1H),7.25(br s,1H),7.09(br s,1H),4.01(s,2H),3.94-3.99(m,6H),3.78-3.83(m,5H),3.72-3.77(m,2H),1.95(s,3H),1.87(br s, 2H), 1.51-1.63 (m, 2H). General method for the preparation of intermediate 3A General method for preparing intermediate 3-

[0522] To a solution of Intermediate 1 (50.0 g, 325.5 mmol, 1 eq.) and sodium 2-methylpropane-2-oleate (32.8 g, 341.8 mmol, 1.05 eq.) in THF (350.0 mL) was added Intermediate 2 (62.6 g, 354.8 mmol, 45.4 mL, 1.09 eq.) dropwise at 10° C. The mixture was stirred at 25° C. for 2 hours. TLC (petroleum ether / ethyl acetate = 1 / 1, R f=0.59) indicated the reaction was complete. H2O (100.0 mL) was added to the reaction mixture, filtered, and the filter cake was washed with MeOH (50.0 mL x 3) and concentrated in vacuo. The residue was used in the next step without further purification. Intermediate 3 (80.0 g, 272.3 mmol, 83.6% yield) was obtained as a white solid. 1 H NMR:DMSO 400MHz 8.79-8.85(m,1H),8.11-8.20(m,3H),7.74-7.81(m,1H),7.64-7.72(m,2H),6.97(d,J=4.0Hz,1H). General method for preparing intermediate 4-

[0523] To a solution of intermediate 3 (50.0 g, 170.2 mmol, 1 eq) in THF (300.0 mL) was added LDA (2 M, 127.6 mL, 1.5 eq) dropwise at -78°C. The mixture was then stirred at -78°C for 1 hour. A solution of I2 (56.1 g, 221.2 mmol, 44.5 mL, 1.3 eq) in THF (100.0 mL) was then added to the mixture. The mixture was stirred at -78°C for 1 hour. TLC (petroleum ether / ethyl acetate = 1 / 1, R f =0.71) shows that the reaction is complete. HCl (1M, 200.0mL) is added to the mixture. The mixture is then concentrated in vacuo to remove THF. The residue is diluted with H2O (100.0mL), then extracted with EtOAc (300.0mLx 3). The combined organic layer is washed with brine (500.0mL), dried over Na2SO4, and concentrated in vacuo. At 25°C, the crude product is ground together with MeCN (200.0mL) for 2 hours. Intermediate 4 (50.0g, 119.1mmol, 70.0% yield) is obtained as an off-white solid. 1 H NMR:DMSO 400MHz 8.75-8.79(m,1H),8.08-8.14(m,2H),7.75-7.82(m,1H),7.65-7.73(m,2H),7.38(s,1H). General method for preparing intermediate 1A -

[0524] To a solution of intermediate 4 (70.0 g, 166.8 mmol, 1 eq) in THF (400.0 mL) was added NaOH / MeOH (5 M, 237.8 mL, 7.13 eq). The mixture was then stirred at 25°C for 1 hour. TLC (petroleum ether / ethyl acetate = 0 / 1, R f =0.62) indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure to remove THF and MeOH. The residue was diluted with NH4Cl (aqueous solution, 500.0 mL), filtered, and the filter cake was concentrated under reduced pressure to obtain a residue. The crude product was triturated with MeCN (50.0 mL) at 25°C for 2 hours. Intermediate 1A (40.0 g, 143.1 mmol, 85.8% yield) was obtained as a brown solid. 1 H NMR:DMSO 400MHz 13.14(br s,1H),8.47-8.59(m,1H),6.89(s,1H). General method for preparing intermediate 2A -

[0525] A mixture of Intermediate 1A (40.0 g, 143.1 mmol, 1 equivalent) and morpholine (24.9 g, 286.2 mmol, 25.1 mL, 2 equivalents) in n-butanol (200.0 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 100°C under N2 atmosphere for 12 hours. TLC (dichloromethane / methanol = 10 / 1, R f =0.62) indicated the reaction was complete. The reaction mixture was filtered and the filter cake was concentrated. The crude product was used in the next step without purification. Intermediate 2A (40.0 g, 121.1 mmol, 84.6% yield) was obtained as a brown solid. 1 H NMR:DMSO 400MHz 12.27(br s,1H),8.08(s,1H),6.88(s,1H),3.77-3.82(m,4H),3.67-3.72(m,4H). General method for the preparation of intermediate 3A –

[0526] A solution of Intermediate 2A (20.0 g, 60.5 mmol, 1 eq), (4-aminophenyl)boronic acid (15.7 g, 90.8 mmol, 1.5 eq, HCl), K2CO3 (50.2 g, 363.5 mmol, 6 eq) in dioxane (100.0 mL) and H2O (25.0 mL) was stirred at 25°C for 0.5 h. Pd(dppf)Cl2 (4.43 g, 6.06 mmol, 0.1 eq) was then added. The mixture was stirred at 100°C for 12 h. TLC (dichloromethane / methanol = 10 / 1, R f =0.47) indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure to remove dioxane. The residue was diluted with H2O (150.0 mL) and then extracted with EtOAc (300.0 mL×5). The combined organic layers were washed with brine (300.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The crude product was triturated with MeOH (60.0 mL) at 25°C for 2 hours. Intermediate 3A (8.50 g, 28.7 mmol, 47.5% yield) was obtained as a brown solid. 1 H NMR:DMSO 400MHz 11.92(br s,1H),8.12(s,1H),7.57(br d,J=8.4Hz,3H),6.83(s,1H),6.59(brd,J=8.4Hz,2H),5.32(s,2H),3.83(br d,J=4.6Hz,4H),3.74(br d,J=4.6Hz,4H). Example 3 Synthesis of compound 4 General method for the preparation of intermediate 2-

[0527] To a solution of Intermediate 3A (1.50 g, 5.08 mmol, 1 eq), Intermediate 1 (920.0 mg, 5.08 mmol, 1 eq), and BOP (2.25 g, 5.08 mmol, 1 eq) in DMF (10.0 mL) was added TEA (3.60 g, 35.5 mmol, 4.95 mL, 7 eq). The mixture was stirred at 25 ° C for 12 hours. LCMS showed that the reaction was complete. The mixture was poured into H2O (30.0 mL), filtered, and the filter cake was concentrated in vacuo. The crude product was used in the next step without purification. Intermediate 2 (2.80 g, crude product) was obtained as a yellow solid. 1 H NMR:DMSO 400MHz 12.17(br s,1H),10.39(br s,1H),8.12-8.26(m,3H),7.86(br d,J=7.94Hz,2H),7.64(br t,J=9.70Hz,4H),7.10(br s,1H),3.86(br s,6H),3.74(br s,4H). General method for preparing intermediate 3-

[0528] To a solution of SnCl2·2H2O (2.95 g, 13.0 mmol, 6 equivalents) in HCl (1.2 M, 10.0 mL, 5.5 equivalents) was added intermediate 2 (1.00 g, 2.18 mmol, 1 equivalent) and EtOH (3 mL), and the mixture was stirred at 60 ° C for 24 hours. LCMS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to remove EtOH. The residue was diluted with H2O (20.0 mL) and then a NaHCO3 aqueous solution was added to adjust the pH = 8. The mixture was then filtered and the filter cake was concentrated in vacuo. The crude product was used in the next step without purification. Intermediate 3 (0.52 g, 1.21 mmol, 55.6% yield) was obtained as a yellow solid. General method for preparing intermediate 4-

[0529] To a solution of intermediate 3 (0.50 g, 1.17 mmol, 1 eq) in DMF (10.0 mL) was added TEA (236.1 mg, 2.33 mmol, 324.8 uL, 2 eq) and prop-2-enoyl chloride (105.6 mg, 1.17 mmol, 95.1 uL, 1 eq). The mixture was then stirred at 20°C for 12 hours. LCMS indicated the reaction was complete. The mixture was poured into H2O (30.0 mL), filtered, and the filter cake was concentrated under vacuum. The crude product was purified by reverse phase HPLC (column: Luna C18100*305u; mobile phase: [water (0.04% HCl)-ACN]; B%: 10%-32%, 11 min). Compound 4 (53.0 mg, 101.7 umol, 8.72% yield, 99.6% purity, HCl) was obtained as a yellow solid. 1 H NMR:DMSO 400MHz 13.06(br s,1H),10.42(s,1H),10.19(s,1H),8.34(s,1H),7.89(d,J=8.60Hz,2H),7.72(d,J=8.82Hz,2H),7.63(d,J=8.60Hz,2H),7.38(s,1H ),7.30(d,J=8.38Hz,2H),6.45(dd,J=16.98,10.14Hz,1H),6.24(dd,J=16.98,1.76Hz,1H),5.74(dd,J=10.03,1.87Hz,1H),3.99(br t,J=4.41Hz,4H),3.81(br t,J=4.41Hz,4H),3.63(s,2H). Example 4 Synthesis of compound 5 General method for the preparation of intermediate 2-

[0530] To a solution of Intermediate 3A (1.50 g, 5.08 mmol, 1 eq), Intermediate 1 (920.0 mg, 5.08 mmol, 1 eq), and BOP (2.25 g, 5.08 mmol, 1 eq) in DMF (10.0 mL) was added TEA (3.60 g, 35.5 mmol, 4.95 mL, 7 eq). The mixture was stirred at 25 °C for 12 hours. LCMS showed that the reaction was complete. The mixture was poured into H2O (30.0 mL), filtered, and the filter cake was concentrated in vacuo. The crude product was used in the next step without purification. Intermediate 2 (2.80 g, crude product) was obtained as a yellow solid. 1 H NMR:DMSO 400MHz 12.17(br s,1H),10.39(br s,1H),8.12-8.26(m,3H),7.86(br d,J=7.94Hz,2H),7.64(br t,J=9.70Hz,4H),7.10(br s,1H),3.86(br s,6H),3.74(br s,4H). General method for the preparation of intermediate 3 –

[0531] To a solution of SnCl2·2H2O (2.95 g, 13.0 mmol, 6 equiv) in HCl (1.2 M, 10.0 mL, 5.5 equiv) was added intermediate 2 (1.00 g, 2.18 mmol, 1 equiv) and EtOH (3.00 mL), and the mixture was stirred at 60 ° C for 24 hours. LCMS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to remove EtOH. The residue was diluted with H2O (20.0 mL) and a NaHCO3 aqueous solution was added to adjust the pH = 8. The mixture was then filtered and the filter cake was concentrated in vacuo. The crude product was used in the next step without purification. Intermediate 3 (0.52 g, 1.21 mmol, 55.6% yield) was obtained as a yellow solid. General method for preparing compound 5-

[0532] To a solution of Intermediate 3 (0.20 g, 466.7 umol, 1 eq), (E)-4-(dimethylamino)but-2-enoic acid (77.3 mg, 466.7 umol, 1 eq, HCl), and TEA (330.6 mg, 3.27 mmol, 454.7 uL, 7 eq) in DMF (10.0 mL) was added HATU (266.2 mg, 700.1 umol, 1.5 eq). The mixture was stirred at 25°C for 12 hours. LCMS indicated the reaction was complete. The mixture was poured into H2O (30.0 mL), then filtered, and the filter cake was concentrated in vacuo. The crude product was purified by reverse phase HPLC (column: Luna C18 100*305 u; mobile phase: [water (0.04% HCl)-ACN]; B%: 1% to 25%, 11 min). Compound 5 (31.0 mg, 53.1 umol, 11.4% yield, 98.8% purity, HCl) was obtained as a yellow solid. 1 H NMR:DMSO 400MHz 13.22(br s,1H),10.80(br s,1H),10.51(d,J=19.85Hz,2H),8.36(s,1H),7.90(d,J=8.60Hz,2H),7.74(d,J=8.60Hz,2H),7.65(d,J=8.60Hz,2H),7.42(s,1H),7 .31(d,J=8.60Hz,2H),6.73-6.85(m,1H),6.50(d,J=15.21Hz,1H),3.99-4.04(m,4H),3.89-3.94(m,2H),3.79-3.85(m,5H),3.65(br s, 1H), 2.75 (d, J = 4.63Hz, 6H). Example 5 Synthesis of compound 6 General method for preparing intermediate 3-

[0533] To a solution of Intermediate 1 (5.00 g, 31.5 mmol, 1 eq.) and Intermediate 2 (12.6 g, 63.0 mmol, 2 eq.) in EtOH (30.0 mL) was added TEA (6.38 g, 63.0 mmol, 8.78 mL, 2 eq.). The mixture was stirred at 75° C. for 8 hours. TLC (petroleum ether / ethyl acetate = 3 / 1, R f =0.22) showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to remove EtOH. The residue was diluted with H2O (30.0mL) and then extracted with EtOAc (30.0mL×3). The combined organic layer was washed with brine (50.0mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=50 / 1 to 0 / 1). Intermediate 3 (8.00g, 24.8mmol, 78.6% yield) was obtained as a yellow solid. 1 H NMR:CDCl3400 MHz 8.20(d,J=5.9Hz,1H),7.58(d,J=2.4Hz,1H),6.94(br d,J=3.5Hz,1H),4.57(br s,1H),3.86(br d,J=12.3Hz,1H),3.57-3.74(m,2H),3.14-3.33(m,2H),2.02-1.98(m,1H),1.77-1.90(m,1H),1.64-1.71(m,1H),1.52-1.61(m,1H),1.44(br s,9H). General method for preparing intermediate 4-

[0534] To a solution of intermediate 3 (7.00 g, 21.71 mmol, 1 eq) in EtOAc (25.0 mL) was added HCl / EtOAc (4 M, 70.0 mL, 12.8 eq). The mixture was stirred at 25°C for 3 hours. TLC (petroleum ether / ethyl acetate = 3 / 1, R f =0.02) indicated the reaction was complete. The reaction mixture was filtered and the filter cake was concentrated in vacuo. The residue was used in the next step without further purification. Intermediate 4 (4.00 g, 15.4 mmol, 71.2% yield, HCl) was obtained as a yellow solid. General method for the preparation of intermediate 5 -

[0535] To a solution of intermediate 4 (4.00 g, 15.4 mmol, 1 eq., HCl), but-2-ynoic acid (1.30 g, 15.4 mmol, 1 eq.) and BOP (6.84 g, 15.4 mmol, 1 eq.) in DMF (20.0 mL) was added TEA (9.39 g, 92.7 mmol, 12.9 mL, 6 eq.). The mixture was stirred at 25° C. for 4 hours. TLC (petroleum ether / ethyl acetate = 0 / 1, R f =0.43) showed that the reaction was complete. The reaction mixture was poured into water (100.0 mL) and then extracted with EtOAc (60.0 mL×3). The combined organic layer was washed with brine (50.0 mL×3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=50 / 1 to 1 / 1). Intermediate 5 (3.50 g, 12.1 mmol, 78.5% yield) was obtained as a yellow solid. 1 H NMR:DMSO 400MHz 8.63(br d,J=7.1Hz,1H),8.14(d,J=6.0Hz,1H),7.56(d,J=2.4Hz,1H),7.16(dd,J=2.6,6.0Hz,1H),3.78-3.9 1(m,2H),3.61-3.76(m,1H),3.10-3.30(m,1H),3.02(dd,J=9.2,13.0Hz,1H),1.93-1.99(m,3H),1.72 -1.91(m,2H),1.43-1.60(m,2H). General method for preparing intermediate 5a -

[0536] To a solution of intermediate 5 (3.00 g, 10.4 mmol, 1 eq) in EtOH (10.0 mL) and H2O (10.0 mL) were added Fe (2.91 g, 52.0 mmol, 5 eq) and NH4Cl (2.78 g, 52.0 mmol, 5 eq). The mixture was stirred at 80°C for 10 hours. TLC (petroleum ether / ethyl acetate = 0 / 1, R f=0.05) indicated that the reaction was complete. The reaction mixture was filtered and the filtrate was concentrated. The residue was basified to pH = 8 and extracted with EtOAc (100.0 mL x 3). The combined organic layers were washed with brine (50.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The crude product was used in the next step without purification. Intermediate 5a (2.00 g, 7.74 mmol, 74.4% yield) was obtained as a brown solid. 1 H NMR:DMSO 400MHz 8.54(br d,J=7.2Hz,1H),7.53-7.59(m,1H),6.06-6.13(m,1H),5.82(d,J=2.2Hz,1H),5.50(s,2H),3.67-3.53(m,3H) ,2.72-2.81(m,1H),2.68-2.59(m,1H),1.95(s,3H),1.77-1.84(m,1H),1.67-1.75(m,1H),1.39-1.51(m,2H). General method for the preparation of intermediate 6 -

[0537] To a solution of intermediate 5a (0.20 g, 677.1 μmol, 1 equivalent) and KCO (280.7 mg, 2.03 mmol, 3 equivalents) in THF (5.00 mL) was added phenyl chloroformate (106.0 mg, 677.1 μmol, 84.8 μL, 1 equivalent), and the mixture was stirred at 25° C. for 2 hours. LCMS showed that the reaction was complete. The reaction mixture was used in the next step in the THF solvent without post-treatment. Intermediate 6 (281.0 mg, crude product) was obtained in the brown solvent THF and used in the next step. General method for preparing compound 6-

[0538] To a solution of Intermediate 6 (0.28 g, 673.9 μmol, 1 eq), Intermediate 3A (156.6 mg, 606.5 μmol, 0.9 eq), and DMAP (8.23 mg, 67.4 μmol, 0.1 eq) in THF (1.00 mL) was added TEA (409.2 mg, 4.04 mmol, 562.8 μL, 6 eq). The mixture was stirred at 70°C for 10 hours. LCMS indicated the reaction was complete. The reaction mixture was filtered and the filtrate was concentrated to obtain a residue. The residue was purified by preparative HPLC (column: Luna C18100*305u; mobile phase: [water (0.04% HCl)-ACN]; B%: 10%-30%, 11 minutes). Compound 6 (40.0 mg, 64.9 μmol, 9.63% yield, HCl, 95.9% purity) was obtained as an off-white solid. 1 H NMR:DMSO 400MHz 13.32(br s,1H),11.21(br s,1H),10.33(br s,1H),8.70(br d,J=7.3Hz,1H),8.33(s,1H),7.93(br d,J=8.4Hz,2H),7.84(br d,J=7.5Hz,1H),7.56(br d,J=8.4Hz,2H),7.43(s,1H),6.86(br s,1H),6.50(br s,1H),4.02(br s,4H),3.80(br s,4H),3.74-3.76(m,3H),3.13-3.31(m,2H),1.92(s,3H),1.83(br s, 2H), 1.46-1.62 (m, 2H). Example 6 Synthesis of compound 7 General method for the preparation of intermediate 2-

[0539] To a solution of Intermediate 2A (2.00 g, 6.06 mmol, 1 eq), Intermediate 1 (1.64 g, 9.09 mmol, 1.5 eq), K2CO3 (5.02 g, 36.3 mmol, 6 eq) in dioxane (12.0 mL) and H2O (3.00 mL) was added Pd(dppf)Cl2 (443.2 mg, 605.8 umol, 0.1 eq). The mixture was stirred at 100°C for 12 hours. TLC (dichloromethane / methanol = 10 / 1, R f=0.05) indicated that the reaction was complete. The reaction mixture was concentrated in vacuo. The residue was diluted with H2O (20.0 mL) and extracted with EtOAc (30.0 mL×3). The aqueous phase was acidified with HCl (0.50 M, 20.0 mL). The precipitate was filtered and concentrated in vacuo. The residue was used in the next step without purification. Intermediate 2 (1.10 g, 3.25 mmol, 53.6% yield) was obtained as a brown solid. 1 H NMR:DMSO 400MHz 12.98(br s,1H),8.34(s,1H),7.90(br d,J=7.5Hz,2H),7.33-7.45(m,3H),3.99(br s,4H),3.82(br s,4H),3.63(br s,2H). General method for preparing compound 7-

[0540] To a solution of Intermediate 2 (0.20 g, 591.0 μmol, 1 eq), Intermediate 5a (158.8 mg, 614.7 μmol, 1.04 eq), and TEA (119.6 mg, 1.18 mmol, 164.5 μL, 2 eq) in DMF (5.00 mL) was added HATU (233.7 mg, 614.7 μmol, 1.04 eq). The mixture was stirred at 25°C for 5 hours. LCMS indicated the reaction was complete. The reaction mixture was diluted with EtOAc (20.0 mL), filtered, and the filtrate washed with H₂O (10.0 mL x 3) and brine (20.0 mL), dried over Na₂SO₄, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Luna C18100*305u; mobile phase: [water (0.04% HCl)-ACN]; B%: %-%, 11 min). Compound 7 (50.0 mg, 86.4 umol, 14.6% yield, 92.5% purity) was obtained as a yellow solid. 1 H NMR:DMSO 400MHz 13.46(br s,1H),13.09(br s,1H),12.55-12.94(m,1H),8.75(br d,J=7.3Hz,1H),8.38(s,1H),7.98(d,J=8.4Hz,2H),7.89(d,J=7.5Hz,1H),7.49-7.56(m,3H),7.10-6.82(m,2H) ,4.04-4.09(m,4H),3.92(s,2H),3.81-3.86(m,5H),3.70-3.80(m,2H),3.15-3.34(m,2H),1.95(s,3H),1.86(br s,2H),1.48-1.65(m,2H). General method for preparing intermediate 3-

[0541] To a solution of Intermediate 1 (5.00 g, 31.5 mmol, 1 eq.) and Intermediate 2 (12.6 g, 63.0 mmol, 2 eq.) in EtOH (30.0 mL) was added TEA (6.38 g, 63.0 mmol, 8.78 mL, 2 eq.). The mixture was stirred at 75° C. for 8 hours. TLC (petroleum ether / ethyl acetate = 3 / 1, R f =0.22) showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to remove EtOH. The residue was diluted with H2O (30.0mL) and then extracted with EtOAc (30.0mL×3). The combined organic layer was washed with brine (50.0mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=50 / 1 to 0 / 1). Intermediate 3 (8.00g, 24.8mmol, 78.6% yield) was obtained as a yellow solid. 1 H NMR:CDCl3400 MHz 8.20(d,J=5.9Hz,1H),7.58(d,J=2.4Hz,1H),6.94(br d,J=3.5Hz,1H),4.57(br s,1H),3.86(br d,J=12.3Hz,1H),3.57-3.74(m,2H),3.14-3.33(m,2H),2.02-1.98(m,1H),1.77-1.90(m,1H),1.64-1.71(m,1H),1.52-1.61(m,1H),1.44(br s,9H). General method for preparing intermediate 4-

[0542] To a solution of intermediate 3 (7.00 g, 21.71 mmol, 1 eq) in EtOAc (25.0 mL) was added HCl / EtOAc (4 M, 70.0 mL, 12.8 eq). The mixture was stirred at 25°C for 3 hours. TLC (petroleum ether / ethyl acetate = 3 / 1, R f =0.02) indicated the reaction was complete. The reaction mixture was filtered and the filter cake was concentrated in vacuo. The residue was used in the next step without further purification. Intermediate 4 (4.00 g, 15.4 mmol, 71.2% yield, HCl) was obtained as a yellow solid. General method for the preparation of intermediate 5 -

[0543] To a solution of intermediate 4 (4.00 g, 15.4 mmol, 1 eq., HCl), but-2-ynoic acid (1.30 g, 15.4 mmol, 1 eq.) and BOP (6.84 g, 15.4 mmol, 1 eq.) in DMF (20.0 mL) was added TEA (9.39 g, 92.7 mmol, 12.9 mL, 6 eq.). The mixture was stirred at 25° C. for 4 hours. TLC (petroleum ether / ethyl acetate = 0 / 1, R f =0.43) showed that the reaction was complete. The reaction mixture was poured into water (100.0 mL) and extracted with EtOAc (60 mL x 3). The combined organic layer was washed with brine (50.0 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 1 / 1). Intermediate 5 (3.50 g, 12.1 mmol, 78.5% yield) was obtained as a yellow solid. 1 H NMR:DMSO 400MHz 8.63(br d,J=7.1Hz,1H),8.14(d,J=6.0Hz,1H),7.56(d,J=2.4Hz,1H),7.16(dd,J=2.6,6.0Hz,1H),3.78-3.9 1(m,2H),3.61-3.76(m,1H),3.10-3.30(m,1H),3.02(dd,J=9.2,13.0Hz,1H),1.93-1.99(m,3H),1.72 -1.91(m,2H),1.43-1.60(m,2H). General method for the preparation of intermediate 5a –

[0544] To a solution of intermediate 5 (3.00 g, 10.4 mmol, 1 eq) in EtOH (10.0 mL) and H2O (10.0 mL) were added Fe (2.91 g, 52.0 mmol, 5 eq) and NH4Cl (2.78 g, 52.0 mmol, 5 eq). The mixture was stirred at 80°C for 10 hours. TLC (petroleum ether / ethyl acetate = 0 / 1, R f =0.05) indicated that the reaction was complete. The reaction mixture was filtered and the filtrate was concentrated. The residue was basified to pH = 8 and extracted with EtOAc (100.0 mL x 3). The combined organic layers were washed with brine (50.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The crude product was used in the next step without purification. Intermediate 5a (2.00 g, 7.74 mmol, 74.4% yield) was obtained as a brown solid. 1 H NMR:DMSO 400MHz 8.54(br d,J=7.2Hz,1H),7.53-7.59(m,1H),6.06-6.13(m,1H),5.82(d,J=2.2Hz,1H),5.50(s,2H),3.53-3.67(m,3H) ,2.72-2.81(m,1H),2.59-2.68(m,1H),1.95(s,3H),1.77-1.84(m,1H),1.67-1.75(m,1H),1.39-1.51(m,2H). Example 7 Synthesis of compound 8 General method for the preparation of intermediate 2-

[0545] To a solution of intermediate 3A (1.50 g, 5.08 mmol, 1 eq) in DMSO (15.0 mL) was added intermediate 1 (2.39 g, 10.1 mmol, 2 eq) and pyridine (803.4 mg, 10.1 mmol, 819.8 uL, 2 eq). The mixture was then stirred at 80 ° C for 12 hours. LC-MS showed that the starting material remained. A new peak appeared on LC-MS, and the desired intermediate was detected. The mixture was poured into H2O (50.0 mL), then filtered, and the filter cake was concentrated in vacuo. The crude product was used in the next step without purification. Intermediate 2 (2.50 g, crude product) was obtained as a yellow solid. General method for preparing intermediate 3-

[0546] To a solution of SnCl2·2H2O (5.48 g, 24.2 mmol, 8 equivalents) in HCl (1.20 M, 13.9 mL, 5.5 equivalents) was added intermediate 2 (1.50 g, 3.03 mmol, 1 equivalent) and EtOH (5.00 mL). The mixture was stirred at 80 ° C for 12 hours. LCMS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to remove EtOH. The residue was diluted with H2O (40.0 mL) and a NaHCO3 aqueous solution was added to adjust the pH to 8. The mixture was then filtered and the filter cake was concentrated in vacuo. The crude product was used in the next step without purificat...

Claims

1. A compound according to formula (I): or a pharmaceutically acceptable salt or stereoisomer thereof, in: A is N; Cy X is -NR 3a -、-C(R 3b )2-, or -O-; Y is a single bond, -NR 3a -、-C(R 3b )2-, or -O-; W is -C(O)-, -S(O)-, or -S(O)2-; (i)R 1 H, halogen, CN, C 1-6 Alkyl or C 1-6 haloalkyl; and R 2 CH2-Cy 2 -NHC(O)-C(R 6a )=C(R 6b )(R 6c ) or Cy 2 -NHC(O)-C(R 6a )=C(R 6b )(R 6c );or (ii) R 1 CH2-Cy 2 -NHC(O)-C(R 6a )=C(R 6b )(R 6c ) or Cy 2 -NHC(O)-C(R 6a )=C(R 6b )(R 6c );and R 2 H, halogen, CN, C 1-6 Alkyl or C 1-6 Haloalkyl; Cy 2 is a substituted or unsubstituted 4-7 membered heterocycloalkyl ring, a substituted or unsubstituted phenyl, or a substituted or unsubstituted pyridyl group, wherein the 4-7 membered heterocycloalkyl ring has 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each R 3a independently H or C 1-6 alkyl; Each R 3b independently H or C 1-6 alkyl; Each R 4a are independently H, halogen, CN, C 1-6 Alkyl, C(O)R, C(O)N(R)2, C(O)OR, N(R)2, NRC(O)R, OR, S(O)2R, C 3-7 Cycloalkyl, a 4-7 membered heterocycloalkyl ring, a phenyl, an 8-10 membered bicyclic aryl ring, or a 5- or 6-membered heteroaryl ring, wherein the 4-7 membered heterocycloalkyl ring has 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and the 5- or 6-membered heteroaryl ring has 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each R 4b are independently H, halogen, CN, C 1-6 Alkyl, C(O)R, C(O)N(R)2, C(O)OR, N(R)2, NRC(O)R, OR, S(O)2R, C 3-7 Cycloalkyl, a 4-7 membered heterocycloalkyl ring, a phenyl, an 8-10 membered bicyclic aryl ring, or a 5- or 6-membered heteroaryl ring, wherein the 4-7 membered heterocycloalkyl ring has 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and the 5- or 6-membered heteroaryl ring has 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each R is independently H, C 1-6 an aliphatic, saturated or partially unsaturated 4-7 membered heterocyclic ring, phenyl, an 8-10 membered bicyclic aryl ring, or a 5- or 6-membered heteroaryl ring, wherein the saturated or partially unsaturated 4-7 membered heterocyclic ring has 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and the 5- or 6-membered heteroaryl ring has 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or: The two geminal R groups together with the nitrogen atom to which they are attached form a saturated or partially unsaturated 4-7 membered heterocyclic ring, or a 5- or 6-membered heteroaryl ring, wherein the 4- or 5-membered heterocyclic ring or the 5- or 6-membered heteroaryl ring has 0, 1, 2 or 3 additional heteroatoms independently selected from nitrogen, oxygen and sulfur; R 6a H or C 1-6 alkyl; R 6b H or C 1-6 Alkyl; or R 6a and R 6b Linked together, forming a single bond; R 6c is H, or unsubstituted C 1-6 Alkyl; or R 6a and R 6b Each is H, and R 6c C 1-6 Alkyl; wherein the C 1-6 The alkyl group is substituted with N(CH3)2 or is unsubstituted; R 7 for i) independently, a 4-7 membered heterocycloalkyl ring, a phenyl ring, an 8-10 membered bicyclic aryl ring, or a 5- or 6-membered heteroaryl ring, wherein the 4-7 membered heterocycloalkyl ring independently has 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and the 5- or 6-membered heteroaryl ring independently has 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; ii) a 4-7 membered heterocycloalkyl ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and substituted by Me, Et or i-Pr; iii) halogen, hydroxyl, CN, C 1-6 Alkyl, amino, CF3, or C 1-8 an alkoxy-substituted pyridyl group; or iv) imidazolyl substituted by Me, Et, i-Pr, Cl, F, CF3, or CN; m is 1, 2, or 3; and n is 1, 2, 3 or 4.

2. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein -XWY- is -CH2C(O)NH-, -CH2S(O)NH-, -CH2S(O)2NH-, -NHC(O)-, -NHC(O)CH2-, -NHC(O)NH-, -NHS(O)CH2-, -NHS(O)NH-, -NHS(O)2CH2- or -NHS(O)2NH-.

3. A compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt or stereoisomer thereof, in: R 7 is pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, imidazolyl, pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, triazolyl, thiazolyl, oxadiazolyl, or thiadiazolyl; wherein the imidazolyl group is substituted by F, Cl, CN, CH3, CF3, CH2CH3 and CH(CH3)2 or is unsubstituted; and wherein the pyridyl group is substituted by F, Cl, CN, CH3, CF3, CH2CH3, CH(CH3)2, NH2 and OH.

4. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Cy 2 is a substituted or unsubstituted azetidinyl, pyrrolidinyl, piperidinyl, azepine yl or phenyl.

5. The compound according to claim 1, wherein the compound is according to formula (IIc) or formula (IId): or a pharmaceutically acceptable salt or stereoisomer thereof, Where R 2 It is H, F, Cl, CN, CH3, CH2CH3, CH(CH3)2 or CF3.

6. The compound according to claim 1, wherein the compound is according to formula (IIIc) or formula (IIId): or a pharmaceutically acceptable salt or stereoisomer thereof.

7. The compound according to claim 1, wherein the compound is according to formula (XXIIa) or formula (XXIIb): or a pharmaceutically acceptable salt or stereoisomer thereof.

8. The compound according to claim 1, wherein the compound is according to Formula (IVa), Formula (IVb), Formula (XXIIIa) or Formula (XXIIIb): or a pharmaceutically acceptable salt or stereoisomer thereof, Where p is 0, 1, 2 or 3.

9. The compound of claim 1, wherein the compound is according to Formula (Va), Formula (Vb), Formula (XXIVa), or Formula (XXIVb): or a pharmaceutically acceptable salt or stereoisomer thereof, Where p is 0, 1, 2 or 3.

10. A compound according to any one of claims 1 to 9, wherein R 7 is pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, triazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyridinyl or pyrimidinyl; and wherein pyridinyl is unsubstituted or substituted with Me, Et, i-Pr, OH, Cl, F, CF3, CN or NH2; and wherein imidazolyl is unsubstituted or substituted with Me, Et, i-Pr, Cl, F, CF3 or CN.

11. The compound of claim 1, wherein the compound is according to Formula (VIa), Formula (VIb), Formula (XXVa), or Formula (XXVb): or a pharmaceutically acceptable salt or stereoisomer thereof, Where p is 0, 1, 2 or 3.

12. The compound according to claim 1, wherein the compound is according to Formula (VIIa), Formula (VIIb), Formula (VIIc), Formula (VIIIa), Formula (VIIIb), Formula (VIIIc), Formula (XXVIa), Formula (XXVIb) or Formula (XXVIc): or a pharmaceutically acceptable salt or stereoisomer thereof.

13. A compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt or stereoisomer thereof, in i)R 6a is H; R 6b is H; and R 6c is H; or ii) R 6a is H; R 6b is H; and R 6c is CH3 or CH2CH3; or iii) R 6a is H; R 6b is H; and R 6c is CH2N(CH3)2; or iv) R 6a and R 6b join together to form a single bond; and R 6c For CH3.

14. The compound according to claim 1, wherein the compound is according to Formula (IXa), Formula (IXb), Formula (Xa), Formula (XIc) or Formula (XIIc): or a pharmaceutically acceptable salt or stereoisomer thereof.

15. The compound according to claim 1, wherein the compound is according to formula (XIIIa) or formula (XIIIb): or a pharmaceutically acceptable salt or stereoisomer thereof.

16. The compound according to claim 1, wherein the compound is according to formula (XVI) or formula (XVII): or a pharmaceutically acceptable salt or stereoisomer thereof.

17. The compound according to claim 1, wherein the compound is or a pharmaceutically acceptable salt or stereoisomer thereof.

18. The compound according to claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

19. The compound according to claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

20. The compound according to claim 1, wherein the compound is or a pharmaceutically acceptable salt or stereoisomer thereof.

21. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt or stereoisomer thereof and a pharmaceutically acceptable additive.

22. The pharmaceutical composition of claim 21, formulated for a route of administration selected from oral, parenteral, buccal, nasal, topical and rectal administration.

23. Use of a compound according to any one of claims 1 to 20 or a pharmaceutical composition according to claim 21 or 22 in the preparation of a medicament for treating an autoimmune disease or condition.

24. Use of a compound according to any one of claims 1 to 20 or a pharmaceutical composition according to claim 21 or 22 in the preparation of a medicament for treating a heteroimmune disease or condition.

25. Use of the compound according to any one of claims 1 to 20 or the pharmaceutical composition according to claim 21 or 22 in the preparation of a medicament for treating diabetes.

26. The use according to claim 25, wherein the diabetes is type 1 diabetes or type 2 diabetes.

27. Use of a compound according to any one of claims 1 to 20 or a pharmaceutical composition according to claim 21 or 22 in the preparation of a medicament for treating cancer.

28. The use according to claim 27, wherein the cancer is a B-cell proliferative disorder.

29. The use according to claim 28, wherein the B-cell proliferative disorder is diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, lymphoid leukemia, acute lymphoblastic lymphoma (ALL), soft tissue tumor, glioblastoma, pancreatic tumor or renal cell carcinoma.

30. Use of a compound according to any one of claims 1 to 20 or a pharmaceutical composition according to claim 21 or 22 for the preparation of a medicament for inhibiting menin activity in a patient in need thereof.

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