WO2022132936A1 - Multi-cyclic irak and flt3 inhibiting compounds and uses thereof - Google Patents

Multi-cyclic irak and flt3 inhibiting compounds and uses thereof Download PDF

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Publication number
WO2022132936A1
WO2022132936A1 PCT/US2021/063567 US2021063567W WO2022132936A1 WO 2022132936 A1 WO2022132936 A1 WO 2022132936A1 US 2021063567 W US2021063567 W US 2021063567W WO 2022132936 A1 WO2022132936 A1 WO 2022132936A1
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WIPO (PCT)
Prior art keywords
inhibitor
compound
alkyl
cycloalkyl
halogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/US2021/063567
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English (en)
French (fr)
Inventor
Scott Bryan HOYT
Craig Joseph THOMAS
Daniel T. STARCZYNOWSKI
Patrick Joseph SUTTER
Gregory James TAWA
Chris James FINOCCHIO
Jan Susan Rosenbaum
Gabriel GRACIA MALDONADO
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Cincinnati Childrens Hospital Medical Center
US Department of Health and Human Services
Kurome Therapeutics Inc
Original Assignee
Cincinnati Childrens Hospital Medical Center
US Department of Health and Human Services
Kurome Therapeutics Inc
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Application filed by Cincinnati Childrens Hospital Medical Center, US Department of Health and Human Services, Kurome Therapeutics Inc filed Critical Cincinnati Childrens Hospital Medical Center
Priority to AU2021403015A priority Critical patent/AU2021403015A1/en
Priority to US18/257,746 priority patent/US12534469B2/en
Priority to EP21907719.5A priority patent/EP4262802A4/en
Priority to CA3201690A priority patent/CA3201690A1/en
Priority to CN202180093259.3A priority patent/CN116887834A/zh
Priority to JP2023535992A priority patent/JP2024500378A/ja
Priority to IL303709A priority patent/IL303709A/en
Priority to MX2023006937A priority patent/MX2023006937A/es
Publication of WO2022132936A1 publication Critical patent/WO2022132936A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present disclosure generally relates to compounds and compositions which are kinase inhibitors and the use of the same in treating diseases and disorders, including cancers.
  • MDS Myelodysplastic syndromes
  • AML acute myeloid leukemia
  • sAML chemotherapy-resistant secondary acute myeloid leukemia
  • AML acute myeloid leukemia
  • MDS are heterogeneous diseases with few treatment options, as there is a lack of effective medicines capable of providing a durable response.
  • HSC hemopoeitic stem cell
  • MDS clones can persist in the marrow even after HSC transplantation, and the disease invariably advances (Tehranchi et al., 2010).
  • patients may also receive immunosuppressive therapy, epigenetic modifying drugs, and/or chemotherapy (Greenberg, 2010).
  • AML hematopoietic stem/progenitor cell
  • the present disclosure relates to a compound of Formula (I) (I) or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof, wherein: R 1 is selected from H, halogen, hydroxy, oxo, -CN, amido, methanoyl (-COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 1 -C 7 heteroalkyl, C 1 -C 7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, wherein the amido, methanoyl (-COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, C 2 -
  • the compound of Formula (I) is a compound of Formula (IIf) Formula (IIf), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: R 20f is selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and -O-(C 3 -C 6 cycloalkyl), wherein C 1 -C 6 alkyl and C 1 -C 6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, and C 3 -C 6 cycloalkyl and -O-(C 3 -C 6 cycloalkyl) are each optionally substituted with one or more substituents selected from C 1 -C 6 alkyl and halogen; R 21f , R 22f , and R 23f are each independently selected from H and
  • R 24fa , R 24fb , R 25fa , R 25fb , R 26fa , and R 26fb is independently selected from halogen, -OH, optionally substituted C 1 -C 6 alkyl, and optionally substituted C 1 -C 6 alkoxy.
  • R 20f is H.
  • At least one of (i)-(iii) applies: (i) R 20f is selected from Cl, , unsubstituted C 3 cycloalkyl, and ; (ii) R21f, R 22f , and R 23f are each H; (iii) R 25fa , R fa25fb , R, 26fa , and R 26fb are each H and 24 R 24fb is F.
  • the compound is selected from: [0011]
  • the compound of Formula (I) is a compound of Formula (IIg) formula (IIg), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: R 20g is selected from H and C 1 -C 6 alkoxy; R 21g is selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, -O-(C 6 -C 12 aryl), C 3 -C 9 heterocyclyl, and -NR 28ga R 28gb , wherein C 1 -C 6 alkyl and C 1 -C 6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, C 3 -C 6 cycloalkyl is optionally substituted with one or more substituents selected from C 1 - C 6 alkyl
  • R 25ga , R 25gb , R 26ga , R and R 27gb is independently selected from halogen, -OH, optionally substituted C 1 -C 6 alkyl, and optionally substituted C 1 -C 6 alkoxy.
  • R 20g is H.
  • R 20g is selected from -OCH 3 and ;
  • R 21g is selected from t-butyl u nsubstituted C 3 cycloalkyl , morpholinyl, azetidinyl, piperdinyl, isoxazolyl , Cl, -CF 3 , -OCH 3 , -O- phenyl, wherein G is N or CH, and wherein c is 1 or 2;
  • R 21g is wherein R 29g is selected from H, isopropyl, unsubstituted C 3 cycloalkyl, azetidinyl, F tetrahydropyranyl -CH 3 , , and ;
  • R 21g -NR 28ga R 28gb wherein R 28ga is H and R 28gb is selected from -CH 3 , cyclobutyl, and cyclo
  • the compound of Formula (I) is a compound of Formula (IIh) Formula (IIh) or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: R 20h is selected from H and C 1 -C 6 alkoxy; R 21h is selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and C 3 -C 9 heterocyclyl, wherein C 1 -C 6 alkyl is optionally substituted with one or more substituents selected from -OH and halogen and C 3 -C 6 cycloalkyl, and C 3 -C 9 heterocyclyl are each optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, -OH, and halogen; R 22ha , R 22hb , R 23ha , and R 23hb are each independently selected from H and C 1 -C 6 alkyl, where
  • At least one of (i)-(iv) applies: (i) R 20h is H; (ii) R 21h is ; (iii) R 22ha , R 22hb , R 23ha , and R 23hb are each H; (iii) R 24h , R 25h , and R 26h are each H.
  • the compound is [0013]
  • the compound of Formula (I) is a compound of Formula (IIi) Formula (IIi), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: is selected from R 20i is selected from H, and C 1 -C 6 alkoxy; R 21i is selected from C 1 -C 6 alkyl,.
  • R 25ia , R 25ib , R 26ia , R 26ib , R 27ia , R 27ib , R 28ia , R 28ib , R 29ia , and R 29ib is independently selected from halogen, -OH, and C 1 -C 6 alkyl.
  • each of R 25ia , R 25ib , R 26ia , R 26ib , R 27ia , R 27ib , R 28ia , R 28ib , R 29ia , and R 29ib is H.
  • R 20i is selected from H and -OCH 3 ;
  • R 21i is selected from , unsubstituted C 3 cycloalkyl, wherein J is N or CH, and ;
  • R 21i is wherein R 220i is selected from H, -CH 3 , , and unsubstituted C 3 cycloalkyl;
  • R 22i , R 23i , and R 24i are each H;
  • R 22i and R 24i are each F and R 23i is H;
  • R 22i and R 24i are each H and R 23i is F;
  • (vii) is , each of R 25ia , R 26ia , R 26ib , R 27ia , R 27ib , R 28ia , and R 28ib is H and R 25ib is F;
  • (viii) is , each of R 25ia , R 26ia , R 26ib , R 27ia , R 27ib , R 28
  • at least one of (i)-(iv) applies: (i) R 20j is selected from H, and C 1 -C 6 alk
  • R 2ij is unsubstituted C 3 cycloalkyl;
  • R 22j , R 23j , and R 24j are each H;
  • (iv) is .
  • the compound is selected from:
  • the compound of Formula (I) is a compound of Formula
  • R 30q is selected from H and C 1 -C 6 alkoxy
  • R 31q is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and C 3 -C 9 heterocyclyl, wherein C 1 -C 6 alkyl and C 1 -C 6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, C 3 -C 6 cycloalkyl is optionally substituted with one or more substituents selected from C 1 -C 6 alkyl and halogen, and C 3 -C 9 heterocycyl is optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, C 3 -C 6 -cycloalkyl, C 3 -C 9
  • At least one of (i)-(iv) applies: (i) R 30q is H; (ii) R 31q is selected from , wherein d is 1 or 2, and wherein K is N or CH; (iii) R 31q is wherein R 35q is selected from H, -CH 3 , isopropyl, phenyl, azetidinyl, and tetrahydropyranyl; (iv) R 32q , R 33q , and R 34q are each H.
  • the compound is selected from:
  • the compound of Formula (I) is a compound of Formula (IIIr) Formula (IIIr), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: R 30r is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and C 3 -C 9 heterocyclyl, wherein C 1 -C 6 alkyl and C 1 -C 6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, C 3 -C 6 cycloalkyl is optionally substituted with one or more substituents selected from C 1 -C 6 alkyl and halogen, and C 3 -C 9 heterocycyl is optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, C 3 -C 6 -cycloalkyl, C 3 -C
  • R 30r is selected from wherein L is N or CH and ;
  • R 30r is wherein R 35r is selected from H, -CH 3 , isopropyl, phenyl, azetidinyl, and tetrahydropyranyl;
  • R 31r is H;
  • R 32r , R 33r , and R 34r are each H.
  • the compound is selected from:
  • the compound of Formula (I) is a compound of Formula
  • R 30s is selected from H and C 1 -C 6 alkoxy
  • R 31s is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and C 3 -C 9 heterocyclyl, wherein C 1 -C 6 alkyl and C 1 -C 6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, C 3 -C 6 cycloalkyl is optionally substituted with one or more substituents selected from C 1 -C 6 alkyl and halogen, and C 3 -C 9 heterocycyl is optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, C 3 -C 6 -cycloalkyl, C 3 -C 9 -hetero
  • R 30s is H;
  • R 31s is selected from wherein M is N or CH and ;
  • R 31s is wherein R 35s is selected from H, -CH 3 , isopropyl, phenyl, azetidinyl, and tetrahyd ropyranyl;
  • R 32s , R 33s , and R 34s are each H.
  • the compound is selected from:
  • the present disclosure relates to a compound of any of the formula disclosed herein, wherein the compound is an inhibitor of at least one of IRAK1, IRAK4, and FLT3.
  • the compound is an inhibitor of at least two of IRAK1, IRAK4, and FLT3.
  • the compound is an inhibitor of IRAK1 and IRAK4.
  • the compound is an inhibitor of IRAK1, IRAK4, and FLT3.
  • FLT3 is selected from WT FLT3, activated FLT3, and mutated FLT3.
  • the mutated FLT3 is D835Y mutated FLT3 or F691L mutated FLT3.
  • the present disclosure relates to a composition
  • a composition comprising a compound of any one of formula disclosed herein, wherein the composition further comprises a formulary ingredient, an adjuvant, or a carrier.
  • the composition is used in combination with one or more of: a chemotherapy agent, a BCL2 inhibitor, an immune modulator, a BTK inhibitor, a DNA methyltransferase inhibitor/hypomethylating agent, an anthracycline, a histone deacetylase (HDAC) inhibitor, a purine nucleoside analogue (antimetabolite), an isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH2) inhibitor, an antibody-drug conjugate, an mAbs/immunotherapy, a Plk inhibitor, a MEK inhibitor, a CDK inhibitor, a CDK9 inhibitor, a CDK8 inhibitor, a retinoic acid receptor agonist, a TP53 activator, a CELMoD,
  • the composition is used in combination with a BCL2 inhibitor.
  • the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof.
  • the present disclosure relates to a method of treating a disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of any of the formula disclosed herein or a composition comprising a compound of any of the formula disclosed herein.
  • the method comprises administering to the subject a composition comprising the therapeutically effective amount of the compound of Formula (I) and a formulary ingredient, an adjuvant, or a carrier.
  • the disease or disorder is responsive to at least one of interleukin-1 receptor-associated kinase (IRAK) inhibition and fms-like tyrosine kinase 3 (FLT3) inhibition.
  • the administration comprises parenteral administration, a mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration.
  • the compound is administered to the subject in an amount of from about 0.005 mg/kg subject body weight to about 1,000 mg /kg subject body weight.
  • the disease or disorder comprises a hematopoietic cancer.
  • the disease or disorder comprises myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML).
  • the disease or disorder comprises lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin lymphoma, Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL with MYD88 mutation, follicular lymphoma, or marginal zone lymphoma.
  • the disease or disorder comprises at least one cancer selected from glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, Glioma, oral cancer, nasopharyngeal carcinoma, rectal cancer, stomach cancer, and uterine cancer, or one or more inflammatory diseases or autoimmune disease characterized by overactive IRAK1 and/or IRAK4, or combinations thereof.
  • the disease or disorder comprises one or more inflammatory diseases or autoimmune disease selected from chronic inflammation, sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, or combinations thereof.
  • inflammatory diseases or autoimmune disease selected from chronic inflammation, sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, or combinations thereof.
  • the disease or disorder comprises: (i) MDS, MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, MDS with a mutation in isocitrate dehydrogenase 2; or (ii) AML with a splicing factor mutation, AML having enhanced IRAK4-Long expression and/or activity relative to IRAK4-Short, and/or wherein the AML is not driven by FLT3 mutations but expresses IRAK4-Long.
  • the MDS with a splicing factor mutation comprises MDS with a splicing factor mutation in U2AF1 or SF3B1 and the AML splicing factor mutation comprises AML with a splicing factor mutation in U2AF1 or SF3B1.
  • the disease or disorder comprises DLBCL, and wherein the DLBCL comprises a L265P MYD88 mutant (ABC) subtype of DLBCL or a S219C MYD88 mutant (GCB) subtype of DLBCL.
  • the method further comprises administering to the subject one or more additional therapies selected from: a chemotherapy agent, a BCL2 inhibitor, an immune modulator, a BTK inhibitor, a DNA methyltransferase inhibitor/hypomethylating agent, an anthracycline, a histone deacetylase (HDAC) inhibitor, a purine nucleoside analogue (antimetabolite), an isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH2) inhibitor, an antibody-drug conjugate, an mAbs/immunotherapy, a Plk inhibitor, a MEK inhibitor, a CDK inhibitor, a CDK9 inhibitor, a CDK8 inhibitor, a retinoic acid receptor agonist, a TP53 activator, a CELMoD, a smoothened receptor antagonist, an ERK inhibitor including an ERK2/MAPK1 or ERK1/MAPK3 inhibitor, a PI3K inhibitor, an mTOR inhibitor, a
  • additional therapies
  • the method further comprises administering a BCL2 inhibitor to the subject.
  • the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof.
  • the disease or disorder is a BCL2 inhibitor resistant disease or disorder.
  • the disease or disorder is a venetoclax resistant disease or disorder.
  • the disease or disorder is a FLT3 inhibitor resistant disease or disorder.
  • the disease or disorder is BCL2 inhibitor resistant acute myeloid leukemia (AML).
  • the disease or disorder is venetoclax resistant acute myeloid leukemia (AML).
  • the disease or disorder is FLT3 inhibitor resistant acute myeloid leukemia (AML).
  • the disease or disorder is BCL2 inhibitor resistant refractory acute myeloid leukemia (AML). In one embodiment, the disease or disorder is venetoclax resistant refractory acute myeloid leukemia (AML). In one embodiment, the disease or disorder is FLT3 inhibitor resistant refractory acute myeloid leukemia (AML). In one embodiment, the disease or disorder is BCL2 inhibitor resistant relapsed acute myeloid leukemia (AML). In one embodiment, the disease or disorder is venetoclax resistant relapsed acute myeloid leukemia (AML). In one embodiment, the disease or disorder is FLT3 inhibitor resistant relapsed acute myeloid leukemia (AML).
  • the compound of any one of the formula disclosed herein or the composition comprising a compound of any one of the formula disclosed herein and the one or more additional therapies are administered together in one administration or composition. In one embodiment, the compound of any of the formula disclosed herein or the composition comprising a compound of any of the formula disclosed herein and the one or more additional therapies are administered separately in more than one administration or more than one composition. In one embodiment, the disease or disorder is alleviated by inhibiting at least one of IRAK1, IRAK4, and FLT3 in the subject. In one embodiment, the disease or disorder is alleviated by inhibiting at least two of IRAK1, IRAK4, and FLT3 in the subject.
  • the disease or disorder is alleviated by inhibiting IRAK1 and IRAK4 in the subject. In one embodiment, the disease or disorder is alleviated by inhibiting IRAK1, IRAK4, and FLT3 in the subject.
  • FLT3 is selected from WT FLT3, activated FLT3, and mutated FLT3. In one embodiment, the mutated FLT3 is D835Y mutated FLT3 or F691L mutated FLT3.
  • FIG.1A A 10 x 10 combination of Venetoclax with Compound 106 in MOLM14 (D835Y) cells. The numbers in each cell represent the % response at each given concentration combination.
  • FIG.1B A 10 x 10 combination of Venetoclax with Compound 106 in MOLM14 (D835Y) cells. The numbers in each cell represent the excess HSA score at each given concentration combination.
  • a negative excess HSA score illustrates that the drug combination is better than either drug alone, and greater synergy is observed at larger negative values of the excess HSA score.
  • FIGS.2A-2B depict the concentration (nM) response of Compound 108 and Venetoclax for inhibition of cell viability, measured at 48 hours.
  • the numbers in each cell represent the % of viable cells (FIG. 2A) or the excess HSA scores (FIG. 2B) at each given concentration combination.
  • FIG.2A A 10 x 10 combination of Venetoclax with Compound 108 in MOLM14 (D835Y) cells.
  • the numbers in each cell represent the % response at each given concentration combination.
  • FIG.2B A 10 x 10 combination of Venetoclax with Compound 108 in MOLM14 (D835Y) cells.
  • the numbers in each cell represent the excess HSA scores at each given concentration combination.
  • FIGS. 3A-3B depict the relative potency for various compounds to synergize with Venetoclax in a 10 x 10 combination in MOLM14 (D835Y) cells.
  • relative potency is expressed as the concentration of compound required to fully potentiate a 7.8 nM concentration of Venetoclax to ⁇ 5% of the maximum response in the cell viability experiment.
  • the numbers in each cell represent the % response at each given concentration combination.
  • FIG.3A Compound 106 (see structure below the chart) fully potentiates the 7.8 nM Venetoclax response at 3.1 nM, whereas the FLT3/BTK inhibitor CG-806 (see structure to the right of the chart) requires substantially higher concentrations to reach a similar level of potentiation with the same 7.8 nM Venetoclax concentration.
  • FIG.3B Other FLT3 inhibitors Gilteritinib hemifumarate (see structure below the chart), Quizartinib (see structure to the right of the chart), and CA-4948 (see structure to the right of the chart) also require substantially higher concentrations to reach a similar level of potentiation as Compound 106 with the same 7.8 nM Venetoclax concentration.
  • inventive compounds e.g., compounds of Formula (I)
  • compositions e.g., pharmaceutical compositions
  • compositions for treating for example, certain diseases using the inventive compounds.
  • Some embodiments include methods of using the inventive compound (e.g., in compositions or in pharmaceutical compositions) for administering and treating. Further embodiments include methods for making the inventive compound.
  • Yet further embodiments include methods for determining whether a particular patient is likely to be responsive to such treatment with the inventive compounds and compositions.
  • alkyl means a monovalent, straight or branched hydrocarbon chain, which can be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e., C 1 -C 10 means one to ten carbons).
  • C 1 -C 7 alkyl or C 1 - C 4 alkyl refer to straight- or branched-chain saturated hydrocarbon groups having from 1 to 7 (e.g., 1, 2, 3, 4, 5, 6, or 7), or 1 to 4 (e.g., 1, 2, 3, or 4), carbon atoms, respectively.
  • C 1 -C 7 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s- butyl, t-butyl, n-pentyl, s-pentyl, n-hexyl, and n-heptyl.
  • Examples of C 1 -C 4 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, and t-butyl.
  • alkenyl means a monovalent, straight or branched hydrocarbon chain that includes one or more (e.g., 1, 2, 3, or 4) double bonds. Double bonds can occur in any stable point along the chain and the carbon-carbon double bonds can have either the cis or trans configuration.
  • this definition shall include but is not limited to ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, 1,5-octadienyl, 1,4,7-nonatrienyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, ethylcyclohexenyl, butenylcyclopentyl, l-pentenyl-3-cyclohexenyl, and the like.
  • heteroalkenyl refers to heteroalkyl having one or more double bonds.
  • alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 2- propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1- hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, and 5-hexenyl.
  • alkynyl means a monovalent, straight or branched hydrocarbon chain that includes one or more (e.g., 1, 2, 3, or 4) triple bonds and that also may optionally include one or more (e.g.1, 2, 3, or 4) double bonds in the chain.
  • alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2- propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1- hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl.
  • alkoxy means any of the above alkyl, alkenyl, or alkynyl groups which is attached to the remainder of the molecule by an oxygen atom (alkyl-O-).
  • alkoxy groups include, but are not limited to, methoxy (sometimes shown as MeO-), ethoxy, isopropoxy, propoxy, and butyloxy.
  • alkylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, alkenyl, or alkynyl group, as exemplified, but not limited by, -CH 2 CH 2 CH 2 CH 2 -.
  • an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the compounds disclosed herein.
  • a “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
  • cycloalkyl means a monovalent, monocyclic or bicyclic, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 membered hydrocarbon group. The rings can be saturated or partially unsaturated.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and bicycloalkyls (e.g., bicyclooctanes such as [2.2.2]bicyclooctane or [3.3.0]bicyclooctane, bicyclononanes such as [4.3.0]bicyclononane, and bicyclodecanes such as [4.4.0]bicyclodecane (decalin), or spiro compounds).
  • the ring is not aromatic.
  • heteroalkyl means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, consisting of at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, and wherein the nitrogen and sulfur atoms can optionally be oxidized, and the nitrogen heteroatom can optionally be quaternized.
  • the heteroatom(s) O, N, P, S, and Si can be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule.
  • heteroalkylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH 2 -CH 2 -S-CH 2 -CH 2 - and -CH 2 -S-CH 2 -CH 2 -NH-CH 2 -.
  • heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like).
  • heteroalkyl groups include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(O)R', -C(O)NR', -NR'R'', -OR', -SR', and/or -SO 2 R'.
  • heteroalkyl is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R'' or the like, it will be understood that the terms heteroalkyl and -NR'R'' are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R'' or the like. [0039] As used herein (unless otherwise specified), the term “halogen” or “halo” means monovalent Cl, F, Br, or I.
  • haloalkyl are meant to include monohaloalkyl and polyhaloalkyl.
  • halo(C 1 -C 4 )alkyl includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3- bromopropyl, and the like.
  • aryl means a monovalent, monocyclic or bicyclic, 5, 6, 7, 8, 9, 10, 11, or 12 member aromatic hydrocarbon group and also means polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently.
  • a fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, tolyl, and xylyl.
  • heteroaryl means a monovalent, monocyclic or bicyclic, 5, 6, 7, 8, 9, 10, 11, or 12 membered, hydrocarbon group, where 1, 2, 3, 4, 5, or 6 carbon atoms are replaced by a hetero atom independently selected from nitrogen, oxygen, or sulfur atom, and the monocyclic or bicyclic ring system is aromatic.
  • Heteroaryl groups (or rings) can contain from one to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
  • heteroaryl includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring).
  • a 5,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring.
  • a 6,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring.
  • a 6,5- fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring.
  • a heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom.
  • heteroaryl groups include, but are not limited to, thienyl (or thiophenyl), furyl, indolyl, pyrrolyl, pyridinyl, pyrazinyl, oxazolyl, thiaxolyl, quinolinyl, pyrimidinyl, imidazolyl, triazolyl, tetrazolyl, 1H-pyrazol-4-yl, 1-Me-pyrazol-4-yl, pyridin-3-yl, pyridin-4-yl, 3,5-dimethylisoxazolyl, 1H- pyrrol-3-yl, 3,5-di-Me-pyrazolyl, and 1H-pyrazol-4-yl.
  • arylene and a “heteroarylene,” alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively.
  • aryl can represent an unsubstituted, mono-, di- or trisubstituted monocyclic, polycyclic, biaryl and heterocyclic aromatic groups covalently attached at any ring position capable of forming a stable covalent bond, certain preferred points of attachment being apparent to those skilled in the art (e. g.3-indolyl, 4-imidazolyl).
  • the aryl substituents are independently selected from the group consisting of halo, nitro, cyano, trihalomethyl, C 1-16 alkyl, arylC 1-16 alkyl, C 0-16 alkyloxy C 0-16 alkyl, aryl C 0-16 alkyloxyC 0-16 alkyl, C 0-16 alkylthioC 0-16 alkyl, arylC 0-16 alkylthioC 0-16 alkyl, C 0 - 16 alkylaminoC 0-16 alkyl, arylC 0-16 alkylaminoC 0-16 alkyl, di(arylC 1-16 alkyl)aminoC 0-16 alkyl, C 1 - 16 alkylcarbonylC 0-16 alkyl, arylC 1-16 alkylcarbonylC 0-16 alkyl, C 1-16 alkylcarboxyC 0-16 alkyl, arylC 1 - 16 alkylcarboxyC
  • Aryl includes but is not limited to pyrazolyl and triazolyl.
  • aryl when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above.
  • arylalkyl “aralkyl” and the like are meant to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, and the like) including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like), or a sulfur atom.
  • an oxygen atom e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like
  • sulfur atom e.g.
  • cycloalkyl (4- hydroxyphenyl)ethyl, (2-aminonaphthyl)hexyl, pyridylcyclopentyl) represents an aryl group as defined above attached through an alkyl group as defined above having the indicated number of carbon atoms.
  • cycloalkyl and heterocycloalkyl also referred to as “heterocyclyl”, by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl,” respectively.
  • cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocycloalkyl or “heterocyclyl” means a monovalent, monocyclic or bicyclic, 5, 6, 7, 8, 9, 10, 11, or 12 membered, hydrocarbon, where 1, 2, 3, 4, 5, or 6 carbon atoms are replaced by a hetero atom independently selected from nitrogen atom, oxygen atom, or sulfur atom, and the monocyclic or bicyclic ring system is not aromatic.
  • heterocycloalkyl a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule.
  • heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2- piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3- yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, tetrahydropyran, pyrolidinyl (e.g., pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, or pyrrolidin-4-yl), piperazinyl (e.g., piperazin-1-yl, piperazin-2-y
  • a bicyclic heterocyclyl if one ring is aromatic (e.g., monocyclic aryl or heteroaryl), then the other ring is not aromatic.
  • one or both rings can have one or more hetero atoms.
  • one or both rings can be substituted and the like.
  • the term “hetero atom” means an atom selected from nitrogen atom, oxygen atom, or sulfur atom.
  • hydroxy or “hydroxyl” means a monovalent -OH group.
  • acyl means, unless otherwise stated, -C(O)R where R is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • oxo as used herein, means an oxygen that is double bonded to a carbon atom.
  • alkylsulfonyl means a moiety having the formula -S(O 2 )-R', where R' is an alkyl group as defined above. R' can have a specified number of carbons (e.g., “C 1 -C 4 alkylsulfonyl”).
  • carbonyloxy represents a carbonyl group attached through an oxygen bridge.
  • alkyl and alkenyl can be used interchangeably in so far as a stable chemical entity is formed, as would be apparent to those skilled in the art.
  • linker refers to attachment groups interposed between substituents.
  • the linker includes amido (-CONH-R n or -NHCO-R n ), thioamido (-CSNH-R n or -NHCS-R n ), carboxyl (-CO 2 -R n or -OCOR n ), carbonyl (-CO-R n ), urea (-NHCONH-R n ), thiourea (-NHCSNH-R n ), sulfonamido (-NHSO 2 -R n or -SO 2 NH-R n ), ether (-O-R n ), sulfonyl (-SO 2 -R n ), sulfoxyl (-SO-R n ), carbamoyl (-NHCO 2 -R n or -OCONH-R n ), or amino (-NHR n ) linking moieties.
  • each of the above terms includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided herein.
  • substituted e.g., as in substituted alkyl
  • substituted alkyl means that one or more hydrogen atoms of a chemical group (with one or more hydrogen atoms) can be replaced by one or more non-hydrogen substituents selected from the specified options. The replacement can occur at one or more positions.
  • a “substituent group,” as used herein, means a non-hydrogen substituent group that may be, and preferably is, a group selected from the following moieties: (A) -NH 2 , -SH, -CN, -CF 3 , -NO 2 , halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO 2 H), nitro (-NO 2 ), -N(CH 3 ) 2 , ethynyl (-CCH), propynyl, sulfo (-SO 3 H), -CONH 2 , - CONHCH 3 , -CON(CH 3 ) 2 , unsubstituted C 1 -C 7 alkyl, unsubstituted C 1 -
  • a “size-limited substituent” or “ size-limited substituent group,” as used herein, means a group, e.g., selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C 1 -C 20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2-20- membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 4 -C 8 cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 4-8-membered heterocycloalkyl.
  • a “lower substituent” or “lower substituent group,” as used herein, means a group, e.g., selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C 1 -C 8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2-8-membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 5 -C 7 cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 5-7-membered heterocycloalkyl.
  • Some compounds of the invention can have one or more chiral centers and can exist in and be isolated in optically active and racemic forms, for any of the one or more chiral centers. Some compounds can exhibit polymorphism.
  • the compounds of the present invention (e.g., Formula I) encompass any optically active, racemate, stereoisomer form, polymorphism, or mixtures thereof. If a chiral center does not provide an indication of its configuration (i.e., R or S) in a chemical structure, it should be considered to represent R, S or a racemate.
  • sample encompasses a sample obtained from a subject or patient.
  • the sample can be of any biological tissue or fluid.
  • samples include, but are not limited to, sputum, saliva, buccal sample, oral sample, blood, serum, mucus, plasma, urine, blood cells (e.g., white cells), circulating cells (e.g. stem cells or endothelial cells in the blood), tissue, core or fine needle biopsy samples, cell-containing body fluids, free floating nucleic acids, urine, stool, peritoneal fluid, and pleural fluid, tear fluid, or cells therefrom. Samples can also include sections of tissues such as frozen or fixed sections taken for histological purposes or microdissected cells or extracellular parts thereof.
  • a sample to be analyzed can be tissue material from a tissue biopsy obtained by aspiration or punch, excision or by any other surgical method leading to biopsy or resected cellular material.
  • a sample can comprise cells obtained from a subject or patient.
  • the sample is a body fluid that include, for example, blood fluids, serum, mucus, plasma, lymph, ascitic fluids, gynecological fluids, or urine but not limited to these fluids.
  • the sample can be a non-invasive sample, such as, for example, a saline swish, a buccal scrape, a buccal swab, and the like.
  • blood can include, for example, plasma, serum, whole blood, blood lysates, and the like.
  • assessing includes any form of measurement, and includes determining if an element is present or not.
  • the terms “determining,” “measuring,” “evaluating,” “assessing,” “analyzing,” and “assaying” can be used interchangeably and can include quantitative and/or qualitative determinations.
  • the term “monitoring” with reference to a type of cancer refers to a method or process of determining the severity or degree of the type of cancer or stratifying the type of cancer based on risk and/or probability of mortality.
  • monitoring relates to a method or process of determining the therapeutic efficacy of a treatment being administered to a patient.
  • “outcome” can refer to an outcome studied.
  • “outcome” can refer to survival / mortality over a given time horizon.
  • “outcome” can refer to survival / mortality over 1 month, 3 months, 6 months, 1 year, 5 years, or 10 years or longer.
  • an increased risk for a poor outcome indicates that a therapy has had a poor efficacy
  • a reduced risk for a poor outcome indicates that a therapy has had a good efficacy.
  • the term “high risk clinical trial” refers to one in which the test agent has “more than minimal risk” (as defined by the terminology used by institutional review boards, or IRBs). In some embodiments, a high risk clinical trial is a drug trial.
  • the term “low risk clinical trial” refers to one in which the test agent has “minimal risk” (as defined by the terminology used by IRBs). In some embodiments, a low risk clinical trial is one that is not a drug trial. In some embodiments, a low risk clinical trial is one that that involves the use of a monitor or clinical practice process. In some embodiments, a low risk clinical trial is an observational clinical trial.
  • the terms “modulated” or “modulation,” or “regulated” or “regulation” and “differentially regulated” can refer to both up regulation (i.e., activation or stimulation, e.g., by agonizing or potentiating) and down regulation (i.e., inhibition or suppression, e.g., by antagonizing, decreasing or inhibiting), unless otherwise specified or clear from the context of a specific usage.
  • the term “subject” refers to any suitable (e.g., treatable) member of the animal kingdom. In the methods, the subject is preferably a mammal. In the methods, the subject is preferably a human patient.
  • the subject may be a mammalian pediatric patient.
  • the pediatric patient is a mammalian (e.g., preferably human) patient under 18 years of age, while an adult patient is 18 or older.
  • the term “treating” is, unless stated otherwise, to be considered in its broadest context and refers to obtaining a desired pharmacologic and/or physiologic effect. In particular, for example, the term “treating” may not necessarily imply or require that an animal is treated until total recovery.
  • “treating” includes amelioration of the symptoms, relief from the symptoms or effects associated with a condition, decrease in severity of a condition, or preventing, preventively ameliorating symptoms, or otherwise reducing the risk of developing a particular condition. In some aspects, “treating” may not require or include prevention.
  • reference to “treating” an animal includes but is not limited to prophylactic treatment and therapeutic treatment. The effect can be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or can be therapeutic in terms of a partial or complete cure for a disease and/or adverse effect attributable to the disease.
  • Treatment covers any treatment of a disease in a subject, preferably in a mammal (e.g., in a human), and may include one or more of: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., causing regression or elimination of the disease and/or relieving one or more disease symptoms.
  • treatment may be or include reducing such expression or signaling.
  • Treatment can also encompass delivery of an agent or administration of a therapy in order to provide for a pharmacologic effect, even in the absence of a disease or condition. Any of the compositions (e.g., pharmaceutical compositions) described herein can be used to treat a suitable subject.
  • “Therapeutically effective amount” means an amount effective to achieve a desired and/or beneficial effect. An effective amount can be administered in one or more administrations. In the methods, a therapeutically effective amount is an amount appropriate to treat an indication. By treating an indication is meant achieving any desirable effect, such as one or more of palliate, ameliorate, stabilize, reverse, slow, or delay disease progression, increase the quality of life, or to prolong life.
  • the term “marker” or “biomarker” refers to a biological molecule, such as, for example, a nucleic acid, peptide, protein, hormone, and the like, whose presence or concentration can be detected and correlated with a known condition, such as a disease state. It can also be used to refer to a differentially expressed gene whose expression pattern can be utilized as part of a predictive, prognostic or diagnostic process in healthy conditions or a disease state, or which, alternatively, can be used in methods for identifying a useful treatment or prevention therapy.
  • an mRNA “isoform” is an alternative transcript for a specific mRNA or gene. This term includes pre-mRNA, immature mRNA, mature mRNA, cleaved or otherwise truncated, shortened, or aberrant mRNA, modified mRNA (e.g. containing any residue modifications, capping variants, polyadenylation variants, etc.), and the like.
  • “Antibody” or “antibody peptide(s)” refer to an intact antibody, or a binding fragment thereof that competes with the intact antibody for specific binding; this definition also encompasses monoclonal and polyclonal antibodies.
  • Binding fragments are produced by recombinant DNA techniques, or by enzymatic or chemical cleavage of intact antibodies. Binding fragments include Fab, Fab', F(ab') 2 , Fv, and single-chain antibodies. An antibody other than a “bispecific” or “bifunctional” antibody is understood to have each of its binding sites identical. An antibody, for example, substantially inhibits adhesion of a receptor to a counterreceptor when an excess of antibody reduces the quantity of receptor bound to counterreceptor by at least about 20%, 40%, 60% or 80%, and more usually greater than about 85% (as measured in an in vitro competitive binding assay).
  • Embodiments of the invention set forth herein include inventive compounds (e.g., compounds of Formula (I), such as compounds of Formula (II) and Formula (III)).
  • inventive compounds e.g., compounds of Formula (I), such as compounds of Formula (II) and Formula (III)
  • Other embodiments include compositions (e.g., pharmaceutical compositions) comprising the inventive compound.
  • Still other embodiments of the invention include compositions (e.g., pharmaceutical compositions) for treating, for example, certain diseases using the inventive compounds.
  • Some embodiments include methods of using the inventive compound (e.g., in compositions or in pharmaceutical compositions) for administering and treating (e.g., diseases such as cancer or blood disorders).
  • Some embodiments include methods of determining whether a patient is suitable for, or likely to respond favorably to, a particular treatment. Further embodiments include methods for making the inventive compounds.
  • Some embodiments of the invention include compounds having a structure according to Formula (I-5008): (I-5008): or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof.
  • the compound is a pharmaceutically acceptable salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative of a compound of Formula (I-5008).
  • the compound is not an ester, not a solvate, and not a prodrug.
  • R 1 , R 2 , R 3 , R 4 , and R 5 are independently selected from H, halogen, hydroxy, oxo, -CN, amido, methanoyl (-COH), carboxy (-CO 2 H), C 1 - C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 1 -C 7 heteroalkyl, C 1 -C 7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, which amido, methanoyl (- COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 2 -C 6 alkoxy, cycloalkyl, spiro-fused cycloalkyl,
  • R 1 can be H, halogen, hydroxy, oxo, -CN, amido, methanoyl (-COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 1 -C 7 heteroalkyl, C 1 -C 7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, which amido, methanoyl (-COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 2 -C 6 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, which amido, methan
  • R 6 can be (Ia), or (Ib); [0079] R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 can be H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 1 -C 7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, which methanoyl (-COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 1 -C 7 alkoxy, cycloalkyl, spiro-fused cycloal
  • R 1 is H, halogen, -CONH 2 , -CONHCH 3 , - CON(CH 3 ) 2 , benzyl, C 1 -C 7 alkyl, C 1 -C 7 alkoxy, or cycloalkyl, which C 1 -C 7 alkyl, C 1 -C 7 alkoxy, or cycloalkyl is optionally substituted with one or more halogen, hydroxyl, C 1 -C 7 alkyl, or C 1 -C 7 haloalkyl.
  • R 1 is H, Cl, -CONH 2 , -CONHCH 3 , methoxy, ethoxy, cyclopropyl, or C 1 -C 4 alkyl, which methoxy, ethoxy, cyclopropyl, or C 1 -C 4 alkyl is optionally substituted with one or more F, -OH, methyl, or CF 3 . In some embodiments, R 1 is not H.
  • R 2 is H, halogen, hydroxy, O-aryl, amino, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 1 -C 7 alkoxy, cycloalkyl, heterocyclyl, aryl, fused ring aryl, heteroaryl, or fused ring heteroaryl, which O-aryl, amino, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 2 -C 6 alkoxy, cycloalkyl, heterocyclyl, aryl, fused ring aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, -CN, amino, cycloalkyl, heterocyclyl, aryl, heteroaryl, fused ring aryl, fused ring heteroaryl,
  • R 2 is H, halogen, hydroxy, O-aryl, amino, C 1 -C 7 alkyl, C 1 -C 7 alkoxy, cycloalkyl, heterocyclyl, aryl, fused ring aryl, heteroaryl, or fused ring heteroaryl which O-aryl, amino, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 - C 7 alkynyl, C 2 -C 6 alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, amino, cycloalkyl, heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, C 1 -C 7 alkyl, C 1 -C 7 haloalkyl, C 1 -C 7 perfluorinated alkyl, C 1
  • R 2 is H, Cl, hydroxy, -NHCH 3 , -N(CH 3 ) 2 , -OCH 3 , -OCF 3 , -OCHF 2 , -OPh, - CF 3 , -CHF 2 , unsubstituted C 1 -C 7 alkyl, substituted amino, substituted C 1 -C 7 alkyl, substituted cycloalkyl, unsubstituted cycloalkyl, unsubstituted heterocyclyl, substituted pyrazolyl, substituted fused ring heteroaryl, or unsubstituted fused ring heteroaryl. In some embodiments, R 2 is not H.
  • R 3 is H, halogen, hydroxy, -CN, methanoyl (-COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, or C 1 -C 7 alkoxy, which C 1 -C 7 alkyl, or C 2 -C 6 alkoxy, is optionally substituted with one or more of halogen, hydroxy, methanoyl (-COH), carboxy (-CO 2 H), nitro (-NO 2 ), -NH 2 , -N(CH 3 ) 2 , cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO 3 H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO-morpholin-4-yl, -CONH 2 , - CONHCH 3 , -CON(CH 3 ) 2 ,
  • R 3 is H, halogen, hydroxy, -CN, methyl, -CF 3 , or methoxy.
  • R 4 is H, halogen, hydroxy, -CN, methanoyl (-COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, or C 1 -C 7 alkoxy, which C 1 -C 7 alkyl, or C 2 -C 6 alkoxy, is optionally substituted with one or more of halogen, hydroxy, methanoyl (-COH), carboxy (-CO 2 H), nitro (-NO 2 ), -NH 2 , -N(CH 3 ) 2 , cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO 3 H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -
  • R 4 is H, halogen, hydroxy, -CN, methyl, -CF 3 , or methoxy.
  • R 5 is H, halogen, hydroxy, -CN, methanoyl (-COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, or C 1 -C 7 alkoxy, which C 1 -C 7 alkyl, or C 2 -C 6 alkoxy, is optionally substituted with one or more of halogen, hydroxy, methanoyl (-COH), carboxy (-CO 2 H), nitro (-NO 2 ), -NH 2 , -N(CH 3 ) 2 , cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO 3 H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -
  • R 5 is H, halogen, hydroxy, -CN, methyl, -CF 3 , or methoxy.
  • R 4 is methyl or -CF 3 , and at least one of R 3 and R 5 is H or halogen.
  • the chiral center is an R chiral center.
  • the chiral center is an S chiral center.
  • the chiral center can be represented by the following bonds.
  • R 6 is (Ia), or (Ib).
  • R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 are independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 1 -C 7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, which methanoyl (-COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, C 2 - C 7 alkenyl, C 2 -C 7 alkynyl, C 2 -C 6 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, ary
  • R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 are independently selected from H, halogen, hydroxy, oxo, -CN, methanoyl (-COH), carboxy (- CO 2 H), C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 1 -C 7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, which methanoyl (-COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 2 -C 6 alkoxy
  • m, n, o, p, q, r, s, t, u, v, w, and x are independently selected from 0, 1, 2, 3, 4, or 5, where q+r+s+t is at least 1, and where u+v+w+x is at least 1.
  • at least one of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 is not H.
  • each of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 if present, is H.
  • R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 is not H.
  • each of R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 if present, is H.
  • R 6 is (Ia).
  • R 6 is (Ib).
  • Some embodiments of the invention include compounds having a structure according to Formula (I):
  • the wavy bond from Y to R 6 indicates that, i n some instances, there is a chiral center at the R 6 attachment carbon.
  • the wavy bond can indicate an R chiral center, an S chiral center, or a racemate.
  • R 6 is (Ia), giving a structure of Formula (II), as follows: [0095] In some embodiments according to Formula (II), m is 0 or 1, n is 0 or 1, o is 0 or 1, and p is 0 or 1.
  • R 7 , R 8 , R 9 , and R 10 are H, and at least one of R 11 , R 12 , R 13 , and R 14 is not H, and/or R 11 , R 12 , R 13 , and R 14 are H, and at least one of R 7 , R 8 , R 9 , and R 10 is not H.
  • R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 are independently selected from H, halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, C 1 -C 7 alkoxy, or spiro-fused cycloalkyl, which methanoyl (-COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 2 -C 6 alkoxy, or spiro-fused cycloalkyl is optionally substituted with one or more halogen.
  • R 7 , R 8 , R 9 , and R 10 are H, and at least one of R 11 , R 12 , R 13 , and R 14 is halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, C 1 -C 7 alkoxy, or spiro-fused cycloalkyl, which methanoyl (-COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 2 -C 6 alkoxy, or spiro-fused cycloalkyl is optionally substituted with one or more halogen.
  • R 11 , R 12 , R 13 , and R 14 are H, and at least one of R 7 , R 8 , R 9 , and R 10 is halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, C 1 -C 7 alkoxy, or spiro-fused cycloalkyl, which methanoyl (-COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 2 -C 6 alkoxy, or spiro-fused cycloalkyl is optionally substituted with one or more halogen.
  • At least one of R 7 , R 8 , R 9 , and R 10 is halogen, hydroxyl, C 1 -C 7 alkyl, C 1 -C 7 haloalkyl, C 1 -C 7 alkoxy, or spiro-fused cycloalkyl.
  • at least one of R 7 , R 8 , R 9 , and R 10 is F, hydroxyl, methyl, methoxy, -CHF 2 , -CF 3 , spiro-fused cyclopropyl, spiro-fused cyclobutyl, or spiro-fused cyclopentyl.
  • both of R 7 and R 8 or both of R 9 and R 10 are F, or both of R 7 and R 8 or both of R 9 and R 10 are methyl.
  • at least one of R 11 , R 12 , R 13 , and R 14 is halogen, hydroxyl, C 1 -C 7 alkyl, C 1 -C 7 haloalkyl, C 1 -C 7 alkoxy, or spiro-fused cycloalkyl.
  • At least one of R 11 , R 12 , R 13 , and R 14 is F, hydroxyl, methyl, methoxy, -CHF 2 , -CF 3 , spiro-fused cyclopropyl, spiro-fused cyclobutyl, or spiro-fused cyclopentyl.
  • both of R 11 and R 12 or both of R 13 and R 14 are F, or wherein both of R 11 and R 12 or both of R 13 and R 14 are methyl
  • the compound can have a structure according to any of (IIa)-(IIe), wherein V, W, X, Y, and Z can independently represent any of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , or R 14 , and wherein at least one of V, W, X, Y, and Z is not H.
  • the compound of Formula (II) is a compound of Formula (IIf) Formula (IIf), or a salt,ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: R 20f is selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and -O-(C 3 - C 6 cycloalkyl), wherein C 1 -C 6 alkyl and C 1 -C 6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, and C 3 -C 6 cycloalkyl and -O-(C 3 -C 6 cycloalkyl) are each optionally substituted with one or more substituents selected from C 1 -C 6 alkyl and halogen; R 21f , R 22f , and
  • R 24fa , R 24fb , R 25fa , R 25fb , R 26fa , and R 26fb is independently selected from halogen, -OH, optionally substituted C 1 -C 6 alkyl, and optionally substituted C 1 -C 6 alkoxy.
  • each of R 24fa , R 24fb , R 25fa , R 25fb , R 26fa , and R 26fb is H.
  • R 20f is H.
  • R 20f is not H.
  • R 20f is halogen.
  • R 20f is Cl.
  • R 20f is unsubstituted C 1 -C 6 alkoxy. In one embodiment, R 20f is . In another embo diment, R 20f is C 1 -C 6 alkoxy substituted with one or more fluorine atoms. In one embodiment, R 20f is . In another embodiment, R 21g is C 1 -C 6 alkyl substituted with one or more -OH. In one embodiment, R 20f is . I n another embodiment, R 20f is C 3 -C 6 cycloalkyl. In one embodiment, R 20f is unsubstituted C 3 cycloalkyl. In one embodiment, R 20f is .
  • each of R 21f , R 22f , and R 23f is H. In an embodiment, R 21f and R 23f are each independently halogen and R 22f is H. In one embodiment, R 21f and R 23f are each F and R 22f is H. In an embodiment, R 21f and R 23f are each H and R 22f is halogen. In one embodiment, R 21f and R 23f are each H and R 22f is F. [00102] In an embodiment, each of R 24fa , R 24fb , R 25fa , R 25fb , R 26fa , and R 26fb is H.
  • each of R 25fa , R 25fb , R 26fa , and R 26fb is H and R 24fa and/or R 24fb is halogen. In one embodiment, each of R 24fb , R 25fa , R 25fb , R 26fa , and R 26fb is H and R 24fa is F. In one embodiment, each of R 25fa , R 25fb , R 26fa , and R 26fb is H and each of R 24fa and R 24fb is F. In an embodiment, R 25fa , R 25fb , R 26fa , and R 26fb are each H and R 24fa and/or R 24fb is C 1 -C 6 alkyl.
  • each of R 25fa , R 25fb , R 26fa , and R 26fb is H and each of R 24fa and R 24fb is -CH 3 .
  • each of R 24fb , R 25fa , R 25fb , R 26fa , and R 26fb is H and R 24fa is -CH 3 .
  • the compound of Formula (IIf) has one or more stereocenters.
  • the compouind of Formula (IIf) comprises a stereocenter where the moiety connects to the remaining portion of Formula (IIf).
  • the compound of Formula (IIf) comprises a stereocenter at one or more of R 24fa , R 24fb , R 25fa , R 25fb , R 26fa , and/or R 26fb . In one embodiment, the compound of Formula (IIf) comprises a stereocenter on R 20f .
  • the compound of Formula (IIf) is selected from: [00105]
  • the compound of Formula (II) is a compound of Formula (IIg) formula (IIg) or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: R 20g is selected from H and C 1 -C 6 alkoxy; R 21g is selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, -O-(C 6 -C 12 aryl), C 3 -C 9 heterocyclyl, and -NR 28ga R 28gb , wherein C 1 -C 6 alkyl and C 1 -C 6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, C 3 -C 6 cycloalkyl is optionally substituted with one or more substituents
  • R 25ga , R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb is independently selected from halogen, -OH, optionally substituted C 1 -C 6 alkyl, and optionally substituted C 1 -C 6 alkoxy.
  • each of R 25ga , R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb is H.
  • R 20g is H.
  • R 20g is unsubstituted C 1 - C 6 alkoxy.
  • R 20g is selected from -OCH 3 , -OCH 2 CH 3 , and .
  • R 21g is halogen.
  • R 21g is Cl.
  • R 21g is unsubstituted C 1 -C 6 alkyl.
  • R 21g is t-butyl.
  • R 21g is C 1 -C 6 alkyl substituted with one or more F and/or -OH.
  • R 21g is selected from -CF 3 , , , .
  • R 21g is unsubstituted C 1 -C 6 alkoxy.
  • R 21g is -OCH 3 .
  • R 21g is C 1 -C 6 alkoxy substituted with one or more halogen atoms. In another embodiment, R 21g is - O- (C 6 -C 12 aryl). In one embodiment, R 21g is -O-phenyl. In another embodiment, R 21g is unsubstituted C 3 -C 6 cycloalkyl. In one embodiment, R 21g is unsubstituted C 3 cycloalkyl. In one embodiment, R 21g is C 3 cycloalkyl substituted with one or more fluorine atoms. In one embodiment, R 21g is . n another embodiment, R 21g is unsubstituted C 3 -C 9 heterocyclyl.
  • R 21g is selected from morpholinyl, azetidinyl, piperdinyl, isoxazolyl, pyrazolyl, wherein G is N or CH, and wherein c is 1 or 2.
  • R 21g is C 3 -C 9 heterocycyl substituted with one or more substituents selected from C 1 -C 6 alkyl, C 3 -C 6 -cycloalkyl, C 3 -C 9 -heterocyclyl, -OH, and halogen.
  • R 21g is wherein R 29g is selected from H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and C 3 -C 9 heterocyclyl, wherein C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl are each optionally substituted with one or more halogen and/or -OH.
  • R 21g is wherein R 29g is H.
  • R 21g is wherein R 29g is unsubstituted C 1 -C 6 alkyl.
  • R 21g is wherein R 29g is selected from -CH 3 and isopropyl.
  • R 21g is wherein R 29 g is C 1 -C 6 alkyl substituted with one or more -OH and/or F. In one embodiment, R 21g is wherein R 29g is selected from and In another embodiment, R 21g is wherein R 29g is selected from unsubstituted C 3 cycloalkyl, azetidinyl, and 21g tetrahydropyranyl. In another embodiment, R is , wherein a is 1, 2, or 3, G is N or CH, and each X is independently halogen. In one embodiment, R 21g is selected from and .
  • R 21g is , wherein b is 0, 1, 2, 3, 4, 5, or 6, c is 1 or 2, and each R220g is independently C 1 -C 6 alkyl. In one embodiment, R 21g is . In another embodiment, R 21g is isoxazolyl substituted with C 1 -C 6 alkyl. In one embodiment, R 21g is isoxazolyl monosubstituted with -CH 3 . In another embodiment, R 21g is - NR 28ga R 28gb wherein R 28ga is H and R 28gb is selected from -CH 3 , cyclobutyl, and cyclohexyl.
  • R 21g is -NR 28ga R 28gb wherein R 28ga and R 28gb are each independently C 1 -C 6 alkyl. In one embodiment, R 21g is -NR28gaR28gb wherein R28ga and R28gb are each -CH 3 . [00109] In an embodiment, R 22g , R 23g , and R 24g are each H. In an embodiment, R 22g and R 24g are each independently halogen and R 23g is H. In one embodiment, R 22g and R 24g are each F and R 23g is H. In an embodiment, R 22g and R 24g are each H and R 23g is halogen.
  • R 22g and R 24g are each H and R 23g is F.
  • each of R 25ga , R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb is H.
  • each of R 26ga , R 26gb , R 27ga , and R 27gb is H and R 25ga and/or R 25gb is halogen.
  • each of R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb is H and R25ga is F.
  • each of R 26ga , R 26gb , R 27ga , and R 27gb is H and each of R 25ga and R 25gb is F.
  • R 26ga , R 26gb , R 27ga , and R 27gb are each H and R 25ga and/or R 25gb is C 1 -C 6 alkyl.
  • R 26ga , R 26gb , R 27ga , and R 27gb are each H and R25ga and R 25gb are each -CH 3 .
  • each of R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb is H and R25ga is -CH 3 .
  • each of R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb is H and R 25ga is selected from substituted C 1 -C 6 alkyl and -OH.
  • each of R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb is H and R25ga is -OH.
  • each of R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb is H and R25ga is selected from -CF 3 and In another embodiment, each of R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb is H and R 25ga is unsubstituted C 1 -C 6 alkoxy. In one embodiment, each of R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb is H and R 25ga is -OCH 3 .
  • each of R 25ga , R 25gb , R 26gb , R 27ga , and R 27gb is H and R 26ga is unsubstituted C 1 -C 6 alkyl.
  • each of R 25ga , R 25gb , R 26gb , R 27ga , and R 27gb is H and R 26ga is -CH 3 .
  • each of R 25ga , R 25gb , R 26ga , and R 26gb is H and each of R 27ga and R 27gb is unsubstituted C 1 -C 6 alkyl.
  • each of R 25ga , R 25gb , R 26ga , and R 26gb is H and each of R 27ga and R 27gb is -CH 3 .
  • the compound of Formula (IIg) comprises one or more stereocenters. In one embodiment, the compound of Formula (IIg) comprises a stereocenter on R 21g . In one embodiment, the compound of Formula (IIg) comprises a stereocenter where the moiety connects to the remaining portion of Formula (IIg).
  • the compound of Formula (IIg) comprises one or more stereocenters at R25ga, R 25gb , R 26ga , R 26gb , R 27ga , and/or R 27gb .
  • the compound of Formula (IIg) is selected from:
  • the compound of Formula (II) is a compound of Formula (IIh) Formula (IIh), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: R 20h is selected from H and C 1 -C 6 alkoxy; R 21h is selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and C 3 -C 9 heterocyclyl, wherein C 1 -C 6 alkyl is optionally substituted with one or more substituents selected from -OH and halogen and C 3 -C 6 cycloalkyl, and C 3 -C 9 heterocyclyl are each optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, -OH, and halogen; R 22ha , R 22hb , R 23ha , and R 23hb are each independently selected from H and C 1 -C 6 alkyl
  • R 20h is H.
  • R 21h is C 3 -C 9 heterocyclyl substituted with one or more substituents selected from C 1 -C 6 alkyl, -OH, and halogen.
  • R 21h is pyrazolyl substituted with C 1 -C 6 alkyl and F.
  • R 21h is pyrazolyl substituted with .
  • R 21h is [00118] In an embodiment, one or more of R 22ha , R 22hb , R 23ha , and R 23hb is independently optionally substituted C 1 -C 6 alkyl.
  • each of R 22ha , R 22hb , R 23ha , and R 23hb is H.
  • each of R 22ha , R 22hb are H and R 23ha and/or R 23hb is C 1 -C 6 alkyl.
  • each of R 22ha , R 22hb , and R 23ha is H and R 23hb is -CH 3 .
  • each of R 22ha and R 22hb is H and each of R 23ha and R 23hb is -CH 3 .
  • R 24h , R 25h , and R 26h are each H.
  • R 24h and R 26h are each independently halogen and R 25h is H.
  • R 24h and R 26h are each F and R 25h is H. In an embodiment, R 24h and R 26h are each H and R 25h is halogen. In one embodiment, R 24h and R 26h are each H and R 25h is F. [00120] In an embodiment, the compound of Formula (IIh) comprises one or more stereocenters. In one embodiment, the compound of Formula (IIh) comprises a stereocenter on R 21h . In one embodiment, the compound of Formula (IIh) comprises a stereocenter where the moiety connects to the remaining portion of Formula (IIh). In one embodiment, one or more of R 22ha , R 22hb , R 23ha , and/or R 23hb comprises a stereocenter.
  • the compound of Formula (IIh) is [00122]
  • the compound of Formula (II) is a compound of Formula (IIi) Formula (IIi), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: is selected from and ; R 20i is selected from H, and C 1 -C 6 alkoxy; R 21i is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and C 3 -C 9 heterocyclyl, wherein C 1 -C 6 alkyl and C 1 -C 6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, C 3 -C 6 cycloalkyl is optionally substituted with one or more substituents selected from C 1 -C 6 alkyl and halogen, and C 3 -C 9 heterocy
  • R 25ia , R 25ib , R 26ia , R 26ib , R 27ia , R 27ib , R 28ia , R 28ib , R 29ia , and R 29ib is independently selected from halogen, -OH, and C 1 -C 6 alkyl.
  • each of R 25ia , R 25ib , R 26ia , R 26ib , R 27ia , R 27ib , R 28ia , R 28ib , R 29ia , and R 29ib is H.
  • R 20i is H.
  • R 20i is unsubstituted C 1 -C 6 alkoxy. In one embodiment, R 20i is -OCH 3 .
  • R 21i is C 1 -C 6 alkyl substituted with one or more F and/or -OH. In one embodiment, R 21i is selected from , , and .
  • R 21i is unsubstituted C 3 -C 6 cycloalkyl. In one embodiment, R 21i is unsubstituted C 3 cycloalkyl. In one embodiment, R 21i is C 3 cycloalkyl substituted with C 1 -C 6 alkyl. In one embodiment, R 21i is .
  • R 21i is wherein R 220i is -CH 3 . In one embodiment, R 21i is wheren R 220i is 1 C alkyl substituted with one or more -OH and/or F. In one i C- 6 2 1i n R 220i is selected from and OH embodiment, R is wherei . In another embodiment, R 21i is wherein R 220i is unsubstituted C 3 cycloalkyl. [00126] In an embodiment, each of R 22i , R 23i , and R 24i is H. In an embodiment, R 22i and R 24i are each independently halogen and R 23i is H. In one embodiment, R 22i and R 24i are each F and R 23i is H.
  • R 22i and R 24i are each H and R 23i is halogen. In one embodiment, R 22i and R 24i are each H and R 23i is F. [00127] In an embodiment, is , each o f R 25ia , R 25ib , R 26ia , R 26ib , R 27ia , R 27ib , R 28ia , and R 28ib is H. In an embodiment, each of R 26ia , R 26ib , R 27ia , R 27ib , R 28ia , and R 28ib is H and R 25ia and/or R 25ib is halogen.
  • each of R 26ia , R 26ib , R 27ia , R 27ib , R 28ia , and R 28ib is H and each of R 25ia and R 25ib is F.
  • each of R 25ia , R 26ia , R 26ib , R 27ia , R 27ib , R 28ia , and R 28ib is H and R 25ib is F.
  • each o f R 25ia , R 25ib , R 27ia , R 27ib , R 28ia , R 28ib , R 29ia , and R 29ib is H.
  • each of R 25ia , R 25ib , R 27ia , R 27ib , R 29ia , and R 29ib is H and R 28ia and/or R 28ib is halogen.
  • each of R 25ia , R 25ib , R 27ia , R 27ib , R 29ia , and R 29ib is H and each of R 28ia and R 28ib is F.
  • each of R 25ia , R 25ib , R 27ia , R 27ib , R 28ia , R 29ia , and R 29ib is H and R 28ib is F.
  • each of R 25ia , R 25ib , R 28ia , R 28ib , R 29ia , and R 29ib is H and R 27ia and/or R 27ib is halogen.
  • each of R 25ia , R 25ib , R 27ia , R 28ia , R 28ib , R 29ia , and R 29ib is H and R 27ib is F.
  • each of R 25ia , R 25ib , R 27ia , R 28ia , R 28ib , R 29ia , and R 29ib is H and each of R 27ia and R 27ib is F.
  • the compound of Formula (IIi) comprises one or more stereocenters. In one embodiment, the compound of Formula (IIi) comprises a stereocenter on R 20i . In one embodiment, the compound of Formula (IIi) comprises a stereocenter on R 21i . In one embodiment, the compound of Formula (IIi) comprises a stereocenter where the moiety connects to the remaining portion of Formula (IIi). In one embodiment, one or more of R 25ia , R 25ib , R 26ia , R 26ib , R 27ia , R 27ib , R 28ia , R 28ib , R 29ia , and/or R 29ib comprises a stereocenter. [00130] In an embodiment the compound of Formula (IIi) is selected from:
  • the compound of Formula (II) is a compound of Formula (IIj) Formula (IIj), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: is selected from R 20j is selected from H, and C 1 -C 6 alkoxy; R 21j is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and C 3 -C 6 cycloalkyl, wherein C 1 -C 6 alkyl and C 1 -C 6 alkoxy are each optionally substituted with one or more substituents selected from halogen and -OH, and C 3 -C 6 cycloalkyl is optionally substituted with one or more substituents selected from C 1 -C 6 alkyl and halogen; and R 22j , R 23j , and R 24j are each independently selected from H and halogen.
  • R 20j is H. In another embodiment, R 20j is optionally substituted C 1 -C 6 alkoxy. In one embodiment, R 20j is unsubstituted C 1 -C 6 alkoxy. In one embodiment, R 20j is -OCH 3 . [00133] In an embodiment, R 21j is optionally substituted C 3 -C 6 cycloalkyl. In one embodiment, R 21j is optionally substituted C 3 cycloalky. In one embodiment, R 21j is unsubstituted C 3 cycloalkyl. [00134] In an embodiment, R 22j , R 23j , and R 24j are each H.
  • R 22j and R 24j are each independently halogen and R 23j is H. In one embodiment, R 22j and R 24j are each F and R 23j is H. In an embodiment, R 22j and R 24j are each H and R23j is halogen. In one embodiment, R 22j and R 24j are each H and R 23j is F. [00135] In an embodiment, is [00136] In an embodiment, the compound of Formula (IIj) comprises one or more stereocenters. In one embodiment, the compound of Formula (IIj) comprises a stereocenter on R 21j . In one embodiment, the compound of Formula (IIj) comprises a stereocenter where the moiety connects to the remaining portion of Formula (IIj). [00137] In an embodiment, the compound of Formula (IIj) is selected from:
  • R 6 is (Ib), giving a structure of Formula (III), as follows: (III) [00139] In some embodiments according to Formula (III), q, r, s, t, u, v, w, and x are independently 0, 1, or 2. In some embodiments, q is 0 or 1, r is 0 or 1, s is 0 or 1, t is 0 or 1, u is 0 or 1, v is 0 or 1, w is 0 or 1, and x is 0 or 1.
  • R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 are independently selected from H, halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, C 1 -C 7 alkoxy, or spiro-fused cycloalkyl, which methanoyl (-COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 2 -C 6 alkoxy, or spiro-fused cycloalkyl is optionally substituted with one or more halogen.
  • R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 are H.
  • all of R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 are H.
  • the compound can have a structure according to any of (IIIa)-(IIIp), as follows: (IIIa) (IIIb)
  • the compound of Formula (III) is a compound of Formula (IIIq) Formula (IIIq), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: R 30q is selected from H and C 1 -C 6 alkoxy; R 31q is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and C 3 -C 9 heterocyclyl, wherein C 1 -C 6 alkyl and C 1 -C 6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, C 3 -C 6 cycloalkyl is optionally substituted with one or more substituents selected from C 1 -C 6 alkyl and halogen, and C 3 -C 9 heterocycyl is optionally substituted with one or more substituents selected from C 1 -C 6 alkyl and halogen; and C 3
  • R 30q is H.
  • R 31q is unsubstituted C 3 -C 9 heterocyclyl.
  • R 31q is pyrazolyl.
  • R 31q is selected from wherein is N or CH, wherein d is 1 or 2.
  • R 31q is wherein d is 2.
  • R 31q is wherein R 35q is selected from H, unsubstituted C 1 -C 6 alkyl, unsubstituted C 6 -C 12 aryl, and unsubstituted C 3 -C 9 heterocyclyl. In one embodiment, R 31q is wherein R 35q is H. In one embodiment, R 31q is wherein R 35q is selected from -CH 3 , isopropyl, phenyl, azetidinyl, and tetrahydropyranyl. In another embodiment, R 31q is isoxazolyl substituted with C 1 -C 6 alkyl. In one embodiment, R 31q is isoxazolyl monosubstituted with -CH 3 .
  • R 31q is . In anothe r embodiment, R 31q is , wherein e is, 12, or 3, K is N or CH and each X is independently halogen. In one embodiment, R 31q is [00145] In an embodiment, R 32q , R 33q , and R 34q are each H. In an embodiment, R 32q and R 34q are each independently halogen and R 33q is H. In one embodiment, R 32q and R 34q are each F and R 33q is H. In an embodiment, R 32q and R 34q are each H and R 33q is halogen. In one embodiment, R 32q and R 34q are each H and R 33q is F. [00146] In an embodiment, the compound of Formula (IIIq) comprises one or more stereocenters. [00147] In an embodiment, the compound of Formula (IIIq) is selected from:
  • the compound of Formula (III) is a compound of Formula (IIIr) Formula (IIIr), or a ( salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: R 30r is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and C 3 -C 9 heterocyclyl, wherein C 1 -C 6 alkyl and C 1 -C 6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, C 3 -C 6 cycloalkyl is optionally substituted with one or more substituents selected from C 1 -C 6 alkyl and halogen, and C 3 -C 9 heterocycyl is optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, C 3 -C 6 -cycloalkyl, C 3 -
  • R 30r is whe rein R 35r is selected from H, unsubstituted C 1 -C 6 alkyl, unsubstituted C 6 -C 12 aryl, and unsubstituted C 3 -C 9 heterocyclyl.
  • R 30r is wherein R 35r is H.
  • R 30r is wherein R35r is selected from -CH 3 , isopropyl, phenyl, azetidinyl, and tetrahydropyranyl.
  • R 30r is isoxazolyl substituted with C 1 -C 6 alkyl.
  • R 30r is isoxazolyl monosubstituted with -CH 3 .
  • R 30r is . In another embodiment, R 30r is , wherein g is 1, 2, or 3, L is N or CH and each X is independently halogen. In one embodiment, R 30r is . [00150] In an embodiment, R 31r is H. [00151] In an embodiment, R 32r , R 33r , and R 34r are each H. In an embodiment, R 32r and R 34r are each independently halogen and R 33r is H. In one embodiment, R 32r and R 34r are each F and R 33r is H. In an embodiment, R 32r and R 34r are each H and R 33r is halogen. In one embodiment, R 32r and R 34r are each H and R 33r is F. [00152] In an embodiment, the compound of Formula (IIIr) comprises one or more stereocenters. [00153] In an embodiment, the compound of Formula (IIIr) is selected from:
  • the compound of Formula (III) is a compound of Formula (IIIs) Formula (IIIs), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: R 30s is selected from H and C 1 -C 6 alkoxy; R 31s is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and C 3 -C 9 heterocyclyl, wherein C 1 -C 6 alkyl and C 1 -C 6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, C 3 -C 6 cycloalkyl is optionally substituted with one or more substituents selected from C 1 -C 6 alkyl and halogen, and C 3 -C 9 heterocycyl is optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, C
  • R 30s is H.
  • R 31s is unsubstituted C 3 -C 9 heterocyclyl.
  • R 31s is pyrazolyl.
  • R 31s is selected from wherein M N s N or CH, , and wherein h i h N i s 1 or 2. In one embodiment, R 31s is wherein h is 2.
  • R 31s is wherein R35s is selected from H, unsubstituted C 1 -C 6 alkyl, unsubstituted C 6 -C 12 aryl, and unsubstituted C 3 -C 9 heterocyclyl.
  • R 31s is wherein R 35s is H.
  • R 31s is wherein R 35s is selected from -CH 3 , isopropyl, phenyl, azetidinyl, and tetrahydropyranyl.
  • R 31s is isoxazolyl substituted with C 1 -C 6 alkyl.
  • R 31s is isoxazolyl monosubstituted with -CH 3 .
  • R 31s is .
  • R 31s is , wherein i is 1, 2, or 3, M is N or CH and each X is independently halogen.
  • R 31s is [00157]
  • R 32s , R 33s , and R 34s are each H.
  • R 32s and R 34s are each independently halogen and R 33s is H. In one embodiment, R 32s and R 34s are each F and R 33s is H. In an embodiment, R 32s and R 34s are each H and R 33s is halogen. In one embodiment, R 32s and R 34s are each H and R 33s is F. [00158] In an embodiment, the compound of Formula (IIIs) comprises one or more stereocenters. [00159] In an embodiment, the compound of Formula (IIIs) is selected from:
  • the compounds of Formula (I), such as compounds of Formula (II) or Formula (III), can be any of those specified in Compounds 1-137, as listed in Tables 1-15.
  • the compound can be Compound 1, Compound 9, Compound 19, Compound 20, Compound 21, Compound 26, Compound 31, Compound 38, Compound 45, Compound 56, Compound 60, Compound 61, Compound 62, Compound 63, Compound 81, Compound 84, Compound 96, Compound 97, or Compound 99.
  • the compounds of Formula (I), such as compounds of Formula (II) or Formula (III) can be in the form of salts, optical and geometric isomers, and salts of isomers.
  • the compounds can be in various forms, such as uncharged molecules, components of molecular complexes, or non-irritating pharmacologically acceptable salts, including but not limited to hydrochloride, hydrobromide, sulphate, phosphate, nitrate, borate, acetate, maleate, tartrate, and salicylate.
  • salts can include metals, amines, or organic cations (e.g. quaternary ammonium).
  • simple derivatives of the compounds e.g., ethers, esters, or amides
  • which have desirable retention and release characteristics but which are easily hydrolyzed by body pH, enzymes, or other suitable means can be employed.
  • the compounds of the disclosure having a chiral center and can exist in and be isolated in optically active and racemic forms. In other embodiments, compounds may exhibit polymorphism. Some embodiments of the present disclosure encompass any racemic, optically active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound described herein, including isotopically-labeled and radio-labeled compounds. See e.g., Goding, 1986, Monoclonal Antibodies Principles and Practice; Academic Press, p. 104. Such isomers can be isolated by standard resolution techniques, including e.g., fractional crystallization, chiral chromatography, and the like. See e.g., Eliel, E. L.
  • optically active forms can be accomplished by any suitable method, including but not limited to, resolution of the racemic form by recrystallization techniques, synthesis from optically-active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase.
  • compounds disclosed herein have asymmetric centers and can occur as racemates, racemic mixtures, and as individual enantiomers or diastereoisomers, with all isomeric forms as well as mixtures thereof being contemplated for use in the compounds and methods described herein.
  • the compounds contemplated for use in the compounds and methods described herein do not include those that are known in the art to be too unstable to synthesize and/or isolate.
  • the compounds disclosed herein can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compounds can be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine- 125 ( 125 I), or carbon-14 ( 14 C). All isotopic variations of the compounds disclosed herein, whether radioactive or not, are encompassed within the contemplated scope.
  • metabolites of the compounds disclosed herein are useful for the methods disclosed herein.
  • prodrug refers to a compound that can be converted into a compound (e.g., a biologically active compound) described herein in vivo.
  • Prodrugs can be useful for a variety of reason known in the art, including e.g., ease of administration due e.g., to enhanced bioavailability in oral administration, and the like.
  • the prodrug can also have improved solubility in pharmaceutical compositions over the biologically active compounds.
  • prodrug is a compound which is administered as an ester (i.e., the "prodrug") to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water solubility is beneficial.
  • ester i.e., the "prodrug”
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, (ed. H. Bundgaard, Elsevier, 1985), which is hereby incorporated herein by reference for the limited purpose describing procedures and preparation of suitable prodrug derivatives.
  • Certain compounds disclosed herein can exist in unsolvated forms as well as solvated forms, including hydrated forms.
  • solvated forms are equivalent to unsolvated forms and are encompassed within the scope of contemplated compounds.
  • Certain compounds of the present disclosure can exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the compounds and methods contemplated herein and are intended to be within the scope disclosed herein.
  • one or more compounds of the disclosure can be part of a composition and can be in an amount (by weight of the total composition) of at least about 0.0001%, at least about 0.001%, at least about 0.10%, at least about 0.15%, at least about 0.20%, at least about 0.25%, at least about 0.50%, at least about 0.75%, at least about 1%, at least about 10%, at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, at least about 99%, at least about 99.99%, no more than about 75%, no more than about 90%, no more than about 95%, no more than about 99%, or no more than about 99.99%, from about 0.0001% to about 99%, from about 0.0001% to about 50%, from about 0.01% to about 95%, from about 1% to about 95%, from about 10% to about 90%, or from about 25% to about 75%.
  • one or more compounds of the disclosure can be purified or isolated in an amount (by weight of the total composition) of at least about 0.0001%, at least about 0.001%, at least about 0.10%, at least about 0.15%, at least about 0.20%, at least about 0.25%, at least about 0.50%, at least about 0.75%, at least about 1%, at least about 10%, at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, at least about 99%, at least about 99.99%, no more than about 75%, no more than about 90%, no more than about 95%, no more than about 99%, no more than about 99.99%, from about 0.0001% to about 99%, from about 0.0001% to about 50%, from about 0.01% to about 95%, from about 1% to about 95%, from about 10% to about 90%, or from about 25% to about 75%.
  • compositions comprising one or more compounds of the disclosure (e.g., Formula (I)).
  • the composition is a pharmaceutical composition, such as compositions that are suitable for administration to animals (e.g., mammals, primates, monkeys, humans, canine, feline, porcine, mice, rabbits, rats, etc.).
  • a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient.
  • the compound can be a compound of any of Formulae (I)-(III) as disclosed herein, a compound as set forth in Tables 1-16, or a pharmaceutically acceptable salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof.
  • the compound is set forth in any of Tables 1-16 herein.
  • compositions including a compound as described above.
  • the amount of the compound can be from about 0.0001% (by weight total composition) to about 99%.
  • the composition can further include a formulary ingredient, an adjuvant, or a carrier.
  • the composition can further include a BCL2 inhibitor.
  • the composition can be used in combination with a second composition including a BCL2 inhibitor.
  • the BCL2 can be venetoclax, or a salt, isomer, derivative or analog thereof.
  • salts are meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and the like.
  • inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic,
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galacturonic acids and the like (see, for example, Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19).
  • Certain specific compounds disclosed herein contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • Compounds disclosed herein can exist as salts, such as with pharmaceutically acceptable acids. Accordingly, the compounds contemplated herein include such salts.
  • salts examples include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid.
  • These salts can be prepared by methods known to those skilled in the art.
  • the neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.
  • Pharmaceutically acceptable salts of the compounds above, where a basic or acidic group is present in the structure are also included within the scope of compounds contemplated herein.
  • an acidic substituent such as -NHSO 3 H, -COOH and -P(O)(OH) 2
  • Basic groups such as amino or basic heteroaryl radicals, or pyridyl and acidic salts, such as hydrochloride, hydrobromide, acetate, maleate, palmoate, methanesulfonate, p-toluenesulfonate, and the like, can be used as the dosage form.
  • R-COOH pharmaceutically acceptable esters
  • pharmaceutically acceptable esters can be employed, e. g. , methyl, ethyl, tert-butyl, pivaloyloxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.
  • the pharmaceutical composition is non-toxic, does not cause side effects, or both. In some embodiments, there may be inherent side effects (e.g., it may harm the patient or may be toxic or harmful to some degree in some patients).
  • one or more compounds of the disclosure can be part of a pharmaceutical composition and can be in an amount of at least about 0.0001%, at least about 0.001%, at least about 0.10%, at least about 0.15%, at least about 0.20%, at least about 0.25%, at least about 0.50%, at least about 0.75%, at least about 1%, at least about 10%, at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, at least about 99%, at least about 99.99%, no more than about 75%, no more than about 90%, no more than about 95%, no more than about 99%, no more than about 99.99%, from about 0.001% to about 99%, from about 0.001% to about 99%, from about 0.001% to about 99%, from about 0.001% to
  • the pharmaceutical composition can be presented in a dosage form which is suitable for the topical, subcutaneous, intrathecal, intraperitoneal, oral, parenteral, rectal, cutaneous, nasal, vaginal, or ocular administration route.
  • the pharmaceutical composition can be presented in a dosage form which is suitable for parenteral administration, a mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration.
  • the pharmaceutical composition can be in the form of, for example, tablets, capsules, pills, powders granulates, suspensions, emulsions, solutions, gels (including hydrogels), pastes, ointments, creams, plasters, drenches, delivery devices, suppositories, enemas, injectables, implants, sprays, aerosols or other suitable forms.
  • the compounds disclosed herein can be administered orally as tablets, aqueous or oily suspensions, lozenges, troches, powders, granules, emulsions, capsules, syrups or elixirs.
  • compositions for oral use can contain one or more agents selected from the group of sweetening agents, flavoring agents, coloring agents and preserving agents in order to produce pharmaceutically elegant and palatable preparations. Accordingly, there are also provided pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and one or more compounds disclosed herein. [00181] In some embodiments, tablets contain the acting ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets.
  • excipients can be, for example, (1) inert diluents, such as calcium carbonate, lactose, calcium phosphate, carboxymethylcellulose, or sodium phosphate; (2) granulating and disintegrating agents, such as corn starch or alginic acid; (3) binding agents, such as starch, gelatin or acacia; and (4) lubricating agents, such as magnesium stearate, stearic acid or talc.
  • inert diluents such as calcium carbonate, lactose, calcium phosphate, carboxymethylcellulose, or sodium phosphate
  • granulating and disintegrating agents such as corn starch or alginic acid
  • binding agents such as starch, gelatin or acacia
  • lubricating agents such as magnesium stearate, stearic acid or talc.
  • These tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier can be one or more substance that can also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • a compound disclosed herein, in the form of a free compound or a pharmaceutically-acceptable pro-drug, metabolite, analogue, derivative, solvate or salt can be administered, for in vivo application, parenterally by injection or by gradual perfusion over time.
  • Administration can be intravenously, intraperitoneally, intramuscularly, subcutaneously, intracavity, or transdermally.
  • the compounds can be added or dissolved in an appropriate biologically acceptable buffer and added to a cell or tissue.
  • the carrier is a finely divided solid in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from 5% to 70% of the active compound.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • the term “preparation” is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter
  • the active component is dispersed homogeneously therein, as by stirring.
  • the molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
  • Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions.
  • liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
  • injectable, sterile solutions preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants, including suppositories.
  • This suspension can be formulated according to known methods using those suitable dispersing or wetting agents and suspending agents that have been mentioned above.
  • the sterile injectable preparation can also a sterile injectable solution or suspension in a non-toxic parenterally- acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • acceptable vehicles, carriers, and solvents that can be employed are water, Ringer’s solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono-or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • carriers for parenteral administration include aqueous solutions of dextrose, saline, pure water, ethanol, glycerol, propylene glycol, peanut oil, sesame oil, polyoxyethylene-block polymers, and the like. Ampoules are convenient unit dosages.
  • the compounds disclosed herein can also be incorporated into liposomes or administered via transdermal pumps or patches.
  • preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • Frequently used carriers or auxiliaries include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, vitamins, cellulose and its derivatives, animal and vegetable oils, polyethylene glycols and solvents, such as sterile water, alcohols, glycerol and polyhydric alcohols.
  • Intravenous vehicles include fluid and nutrient replenishers.
  • Parenteral vehicles include sodium chloride solution, Ringer’s dextrose, dextrose and sodium chloride, lactated Ringer’s intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer’s dextrose), and the like.
  • Preservatives and other additives can also be present such as, for example, antimicrobials, anti-oxidants, chelating agents, growth factors and inert gases and the like.
  • Preservatives include antimicrobial, anti-oxidants, chelating agents and inert gases.
  • compositions include aqueous solutions, non-toxic excipients, including salts, preservatives, buffers and the like, as described, for instance, in Remington’s Pharmaceutical Sciences, 15th ed. Easton: Mack Publishing Co. , 1405-1412, 1461- 1487 (1975) and The National Formulary XIV., 14th ed. Washington: American Pharmaceutical Association (1975), the contents of which are hereby incorporated by reference.
  • the pH and exact concentration of the various components of the pharmaceutical composition are adjusted according to routine skills in the art. See e.g., Goodman and Gilman (eds.), 1990, THE PHARMACOLOGICAL BASIS FOR THERAPEUTICS (7th ed.).
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, me thylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
  • Aqueous suspensions normally contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspension.
  • excipients can be (1) suspending agent such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; (2) dispersing or wetting agents which can be (a) naturally occurring phosphatide such as lecithin; (b) a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate ; (c) a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadecaethylenoxycetanol; (d) a condensation product of ethylene oxide with a partial ester derived from a fatty acid and hexitol such as polyoxyethylene sorbitol monooleate, or (e) a condensation product of ethylene oxide with a partial ester derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monoole
  • Such liquid forms include solutions, suspensions, and emulsions. These preparations can contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • the pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • the pharmaceutical composition can include one or more formulary ingredients.
  • a “formulary ingredient” can be any suitable ingredient (e.g., suitable for the drug(s), for the dosage of the drug(s), for the timing of release of the drugs(s), for the disease, for the disease state, or for the delivery route) including, but not limited to, water (e.g., boiled water, distilled water, filtered water, pyrogen-free water, or water with chloroform), sugar (e.g., sucrose, glucose, mannitol, sorbitol, xylitol, or syrups made therefrom), ethanol, glycerol, glycols (e.g., propylene glycol), acetone, ethers, DMSO, surfactants (e.g., anionic surfactants, cationic surfactants, zwitterionic surfactants, or nonionic surfactants (e.g., polysorbates)), oils (e.g., animal oils, plant oils, and solubility,
  • compositions can be formulated to release the active ingredient (e.g., one or more compounds of the disclosure such as Formula (I)) substantially immediately upon the administration or any substantially predetermined time or time after administration.
  • active ingredient e.g., one or more compounds of the disclosure such as Formula (I)
  • Such formulations can include, for example, controlled release formulations such as various controlled release compositions and coatings.
  • Other formulations e.g., formulations of a pharmaceutical composition
  • Some compounds can have limited solubility in water and therefore can require a surfactant or other appropriate co-solvent in the composition.
  • Such co-solvents include: Polysorbate 20, 60, and 80; Pluronic F-68, F-84, and P-103; cyclodextrin; and polyoxyl 35 castor oil. Such co-solvents are typically employed at a level between about 0.01 % and about 2% by weight. [00198] Viscosity greater than that of simple aqueous solutions can be desirable to decrease variability in dispensing the formulations, to decrease physical separation of components of a suspension or emulsion of formulation, and/or otherwise to improve the formulation.
  • Such viscosity building agents include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxy propyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propyl cellulose, chondroitin sulfate and salts thereof, hyaluronic acid and salts thereof, and combinations of the foregoing. Such agents are typically employed at a level between about 0.01% and about 2% by weight. [00199]
  • the compositions disclosed herein can additionally include components to provide sustained release and/or comfort. Such components include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides, and finely-divided drug carrier substrates.
  • compositions useful for ameliorating certain diseases and disorders are prepared by formulating a compound disclosed herein in the form of a free compound or a pharmaceutically-acceptable pro-drug, metabolite, analogue, derivative, solvate or salt, either alone or together with other pharmaceutical agents, suitable for administration to a subject using carriers, excipients and additives or auxiliaries.
  • Frequently used carriers or auxiliaries include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, vitamins, cellulose and its derivatives, animal and vegetable oils, polyethylene glycols and solvents, such as sterile water, alcohols, glycerol and polyhydric alcohols.
  • Intravenous vehicles include fluid and nutrient replenishers.
  • compositions according to one embodiment are prepared by formulating a compound disclosed herein in the form of a free compound or a pharmaceutically-acceptable pro-drug, metabolite, analogue, derivative, solvate or salt, either alone or together with other pharmaceutical agents, suitable for administration to a subject using carriers, excipients and additives or auxiliaries.
  • carriers or auxiliaries include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, vitamins, cellulose and its derivatives, animal and vegetable oils, polyethylene glycols and solvents, such as sterile water, alcohols, glycerol and polyhydric alcohols.
  • Intravenous vehicles include fluid and nutrient replenishers.
  • compositions may be the same or different if there is more than one administration.
  • at least one of the one or more compositions further includes a formulary ingredient.
  • at least one of the one or more compositions includes a composition including a compound as described above.
  • at least one of the one or more administrations includes parenteral administration, a mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration.
  • At least one composition used for at least one administration is different from the composition of at least one other administration.
  • the compound of at least one of the one or more compositions can be administered to the subject in an amount of from about 0.005 mg/kg subject body weight to about 50 mg /kg subject body weight.
  • the subject is a mammal, preferably a human, a rodent, or a primate.
  • Further embodiments of the disclosure relate to methods for treating a disease or disorder, where the method includes one or more administrations to a subject of one or more compositions including a compound as described above, where the compositions may be the same or different if there is more than one administration.
  • the disease or disorder can be responsive to at least one of interleukin-1 receptor-associated kinase (IRAK) inhibition or fms-like tyrosine kinase 3 (FLT3) inhibition.
  • at least one of the one or more compositions further includes a formulary ingredient.
  • at least one of the one or more compositions includes a composition as described above. [00204]
  • at least one of the one or more administrations includes parenteral administration, a mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, transdermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration.
  • At least one of the one or more administrations includes an oral administration. In some embodiments, if there is more than one administration at least one composition used for at least one administration is different from the composition of at least one other administration. In some embodiments, the compound of at least one of the one or more compositions is administered to the subject in an amount of from about 0.005 mg/kg subject body weight to about 50 mg /kg subject body weight. In some embodiments, the subject can be a mammal, preferably a human, a rodent, or a primate. In some embodiments, the subject is in need of the treatment. [00205] In some embodiments, the method is for treating a hematopoietic cancer.
  • the method is for treating a myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML).
  • MDS myelodysplastic syndrome
  • AML acute myeloid leukemia
  • the method is for treating at least one of lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin lymphoma, Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL with MYD88 mutation, follicular lymphoma, or marginal zone lymphoma.
  • CLL chronic lymphocytic leukemia
  • CML chronic myeloid leukemia
  • ALL acute lymphoblastic leukemia
  • bone marrow cancer non-Hodgkin lymphoma
  • Waldenstrom’s macroglobulinemia B cell lymphom
  • the method is for treating at least one cancer selected from glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, Glioma, oral cancer, nasopharyngeal carcinoma, rectal cancer, stomach cancer, and uterine cancer, or one or more inflammatory diseases or autoimmune disease characterized by overactive IRAK1 and/or IRAK4, or combinations thereof.
  • the method is for treating one or more inflammatory diseases or autoimmune disease selected from chronic inflammation (i.e., associated with viral and bacterial infection), sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, or combinations thereof.
  • chronic inflammation i.e., associated with viral and bacterial infection
  • sepsis rheumatoid arthritis
  • systemic lupus erythematosus inflammatory bowel disease
  • multiple sclerosis multiple sclerosis
  • psoriasis psoriasis
  • Sjögren’s syndrome Ankylosing spondylitis
  • systemic sclerosis Type 1 diabetes mellitus, or combinations thereof.
  • the method is for treating MDS, MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, MDS with a mutation in isocitrate dehydrogenase 2, or the method is for treating AML having enhanced IRAK4-Long expression and/or activity relative to IRAK4-Short, and/or where the AML is not driven by FLT3 mutations but expresses IRAK4-Long.
  • the method is for treating DLBCL, and the DLBCL includes a L265P MYD88 mutant (ABC) subtype of DLBCL.
  • the method further includes administration of a composition including a BTK inhibitor.
  • the BTK inhibitor includes ibrutinib.
  • the subject is susceptible to AML and/or MDS, and/or the method prevents or ameliorates future AML and/or MDS.
  • the method occurs after one or more of having myelodysplastic syndrome, having myeloproliferative disease, an occurrence of chemical exposure, an exposure to ionizing radiation, or a treatment for cancer.
  • the method further includes administration of a composition including a BCL2 inhibitor, or at least one of said compositions including a compound as described above further includes a BCL2 inhibitor.
  • the compound as described above and the BCL2 inhibitor may be administered together or separately, in one or more administrations of one or more compositions.
  • the BCL2 inhibitor includes venetoclax, or a salt, isomer, derivative or analog thereof.
  • the method further includes administration of one or more additional therapy selected from one or more chemotherapy, DNA methyltransferase inhibitor/hypomethylating agent, anthracycline, histone deacetylase (HDAC) inhibitor, purine nucleoside analogue (antimetabolite), isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH2) inhibitor, antibody-drug conjugate, mAbs/immunotherapy, CAR-T cell therapy, Plk inhibitor, MEK inhibitor, CDK9 inhibitor, CDK8 inhibitor, retinoic acid receptor agonist, TP53 activator, smoothened receptor antagonist, ERK inhibitor, PI3K inhibitor, mTOR inhibitor, glucocorticoid receptor modulator, or EZH2 inhibitor, or one or more combinations thereof.
  • additional therapy selected from one or more chemotherapy, DNA methyltransferase inhibitor/hypomethylating agent, anthracycline, histone deacetylase (HDAC) inhibitor, purine nucleoside an
  • the DNA methyltransferase inhibitor/hypomethylating agent includes azacytidine, decitabine, cytarabine, and/or guadecitabine;
  • the anthracycline includes daunorubicin, idarubicin, doxorubicin, mitoxantrone, epirubicin, and/or CPX-351 (a combination cytarabine and daunorubicin in a fixed 5:1 molar ratio);
  • the histone deacetylase (HDAC) inhibitor includes vorinostat, panobinostat, valproic acid, and/or pracinostat;
  • the purine nucleoside analogue (antimetabolite) includes fludarabine, cladribine, and/or clofarabine;
  • the isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH2) inhibitor includes ivosidenib and/or enasidenib; the antibody-
  • the mAbs/Immunotherapy includes Anti- CD70 (e.g. ARGX-110, cusatuzumab), a bispecific antibody (e.g. floteuzumab (CD123 x CD3)), Anti-CTLA4 (e.g. ipilimumab), Anti-PD1/PDL1 (e.g.
  • Anti- CD70 e.g. ARGX-110, cusatuzumab
  • a bispecific antibody e.g. floteuzumab (CD123 x CD3)
  • Anti-CTLA4 e.g. ipilimumab
  • Anti-PD1/PDL1 e.g.
  • the Plk inhibitor includes volasertib and/or rigosertib;
  • the MEK inhibitor includes trametinib, cobimetinib, selumetinib, pimasertib, and/or refametinib;
  • the CDK9 inhibitor includes alvocidib and/or voruciclib;
  • the CDK8 inhibitor includes SEL120;
  • the retinoic acid receptor agonist includes ATRA (all-trans retinoic acid) and/or SY-1425 (a selective RAR ⁇ agonist);
  • the TP53 activator includes APR-246 (Eprenetapopt);
  • the smoothened receptor antagonist includes glasdegib;
  • the ERK inhibitor includes an ERK2/MAPK1 or ERK1/MAPK3 inhibitor including ulix
  • compositions for use in a method for treating a disease or disorder, the method including inhibiting at least one of IRAK and FLT3 by administering one or more compositions including the compound, where the compositions may be the same or different if there is more than one administration.
  • disease or disorder can be responsive to at least one of interleukin-1 receptor- associated kinase (IRAK) inhibition or fms-like tyrosine kinase 3 (FLT3) inhibition.
  • IRAK interleukin-1 receptor- associated kinase
  • FLT3 fms-like tyrosine kinase 3
  • at least one of the one or more compositions further includes a formulary ingredient.
  • at least one of the one or more compositions includes the composition as described above.
  • At least one of the one or more administrations includes parenteral administration, a mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, transdermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration. In some embodiments, at least one of the one or more administrations includes an oral administration. In some embodiments, if there is more than one administration at least one composition used for at least one administration is different from the composition of at least one other administration. [00211] In some embodiments, the compound of at least one of the one or more compositions can be administered to the subject in an amount of from about 0.005 mg/kg subject body weight to about 50 mg /kg subject body weight.
  • the subject is a mammal, preferably a human, a rodent, or a primate. In some embodiments, the subject is in need of the treatment. [00212] In some embodiments, the method is for treating a hematopoietic cancer. In some embodiments, the method is for treating MDS and/or AML.
  • the method is for treating at least one of lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin lymphoma, Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B- cell lymphoma (DLBCL), DLBCL with MYD88 mutation, follicular lymphoma, or marginal zone lymphoma.
  • CLL chronic lymphocytic leukemia
  • CML chronic myeloid leukemia
  • ALL acute lymphoblastic leukemia
  • bone marrow cancer non-Hodgkin lymphoma
  • Waldenstrom’s macroglobulinemia B cell lymphoma
  • DLBCL diffuse large B- cell lymphoma
  • DLBCL with MYD88 mutation follicular lymphoma
  • marginal zone lymphoma marginal zone lymphoma
  • the method is for treating at least one cancer selected from glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, Glioma, oral cancer, nasopharyngeal carcinoma, rectal cancer, stomach cancer, and uterine cancer, or one or more inflammatory diseases or autoimmune disease characterized by overactive IRAK1 and/or IRAK4, or combinations thereof.
  • the method is for treating one or more inflammatory diseases or autoimmune disease selected from chronic inflammation (i.e., associated with viral and bacterial infection), sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, or combinations thereof.
  • chronic inflammation i.e., associated with viral and bacterial infection
  • sepsis rheumatoid arthritis
  • systemic lupus erythematosus inflammatory bowel disease
  • multiple sclerosis multiple sclerosis
  • psoriasis psoriasis
  • Sjögren’s syndrome Ankylosing spondylitis
  • systemic sclerosis Type 1 diabetes mellitus, or combinations thereof.
  • the method is for treating MDS, MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, MDS with a mutation in isocitrate dehydrogenase 2, or the method is for treating AML having enhanced IRAK4-Long expression and/or activity relative to IRAK4-Short, and/or the AML is not driven by FLT3 mutations but expresses IRAK4-Long.
  • the method is for treating DLBCL, and the DLBCL includes a L265P MYD88 mutant (ABC) subtype of DLBCL.
  • the method further includes administration of a composition including a BTK inhibitor.
  • the BTK inhibitor includes ibrutinib.
  • the subject is susceptible to AML and/or MDS, and/or the method prevents or ameliorates future AML and/or MDS.
  • the method occurs after one or more of having myelodysplastic syndrome, having myeloproliferative disease, an occurrence of chemical exposure, an exposure to ionizing radiation, or a treatment for cancer.
  • method further includes administration of a composition including a BCL2 inhibitor, or at least one of said compositions including the compound of any of claims 1- 39 further includes a BCL2 inhibitor.
  • the compound of any of claims 1-39 and the BCL2 inhibitor can be administered together or separately, in one or more administrations of one or more compositions.
  • the BCL2 inhibitor includes venetoclax, or a salt, isomer, derivative or analog thereof.
  • the method further includes administration of one or more additional therapy selected from one or more chemotherapy, DNA methyltransferase inhibitor/hypomethylating agent, anthracycline, histone deacetylase (HDAC) inhibitor, purine nucleoside analogue (antimetabolite), isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH2) inhibitor, antibody-drug conjugate, mAbs/immunotherapy, CAR-T cell therapy, Plk inhibitor, MEK inhibitor, CDK9 inhibitor, CDK8 inhibitor, retinoic acid receptor agonist, TP53 activator, smoothened receptor antagonist, ERK inhibitor, PI3K inhibitor, mTOR inhibitor, glucocorticoid receptor modulator, or EZH2 inhibitor, or one or more combinations thereof.
  • additional therapy selected from one or more chemotherapy, DNA methyltransferase inhibitor/hypomethylating agent, anthracycline, histone deacetylase (HDAC) inhibitor, purine nucleoside an
  • the DNA methyltransferase inhibitor/hypomethylating agent includes azacytidine, decitabine, cytarabine, and/or guadecitabine;
  • the anthracycline includes daunorubicin, idarubicin, doxorubicin, mitoxantrone, epirubicin, and/or CPX-351 (a combination cytarabine and daunorubicin in a fixed 5:1 molar ratio);
  • the histone deacetylase (HDAC) inhibitor includes vorinostat, panobinostat, valproic acid, and/or pracinostat;
  • the purine nucleoside analogue (antimetabolite) includes fludarabine, cladribine, and/or clofarabine;
  • the isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH2 ) inhibitor includes ivosidenib and/or enasidenib; the
  • the mAbs/Immunotherapy includes Anti- CD70 (e.g. ARGX-110, cusatuzumab), a bispecific antibody (e.g. floteuzumab (CD123 x CD3)), Anti-CTLA4 (e.g. ipilimumab), Anti-PD1/PDL1 (e.g.
  • Anti- CD70 e.g. ARGX-110, cusatuzumab
  • a bispecific antibody e.g. floteuzumab (CD123 x CD3)
  • Anti-CTLA4 e.g. ipilimumab
  • Anti-PD1/PDL1 e.g.
  • the Plk inhibitor includes volasertib and/or rigosertib;
  • the MEK inhibitor includes trametinib, cobimetinib, selumetinib, pimasertib, and/or refametinib;
  • the CDK9 inhibitor includes alvocidib and/or voruciclib;
  • the CDK8 inhibitor includes SEL120;
  • the retinoic acid receptor agonist includes ATRA (all-trans retinoic acid) and/or SY-1425 (a selective RAR ⁇ agonist);
  • the TP53 activator includes APR-246 (Eprenetapopt);
  • the smoothened receptor antagonist includes glasdegib;
  • the ERK inhibitor includes an ERK2/MAPK1 or ERK1/MAPK3 inhibitor including ulix
  • IRAK inhibitors In addition to their ability to inhibit IRAK, IRAK inhibitors have been demonstrated to have selectivity for multiple kinases.
  • IRAK interleukin-1 receptor-associated kinase
  • FLT3 FMS-like tyrosine kinase 3
  • the inhibitory action against one or more kinase can allow for treatment and/or prevention of diseases in an animal (e.g., mammals, porcine, canine, avian (e.g., chicken), bovine, feline, primates, rodents, monkeys, rabbits, mice, rats, and humans) using a compound of the disclosure (e.g., Formula (I)) including, but not limited to hematopoietic cancers (e.g., disorders of hematopoietic stem cells in the bone marrow or disorders related to myeloid lineage), MDS, AML, myeloproliferative disease, and diseases (e.g., hematopoietic cancers) related to mutations in IRAK1, IRAK4, and/or FLT3 (e.g., mutations in the juxtamembrane region of FLT3, mutations in the kinase domain of FLT3, FLT3 point mutations, FLT3 internal tandem
  • the compounds of the disclosure can inhibit the activity of one or more of FLT3, mutations of FLT3 (e.g., mutations in the juxtamembrane region of FLT3, mutations in the kinase domain of FLT3, FLT3 point mutations, FLT3 internal tandem duplication mutations, the FLT3-ITD mutation, the D835Y FLT3 mutation, the D835V FLT3 mutation, the F691L FLT3 mutation, or the R834Q FLT3 mutation), IRAK4 (interleukin-1 receptor associated kinase 4), isoforms of IRAK4, mutations of IRAK4, IRAK1 (interleukin-1 receptor associated kinase 1), isoforms of IRAK1, and/or mutations of IRAK1.
  • FLT3, mutations of FLT3 e.g., mutations in the juxtamembrane region of FLT3, mutations in the kinase domain of FLT3, FLT3 point
  • the compounds of the disclosure can inhibit the activity of one or both of FLT3 and mutations of FLT3 (e.g., mutations in the juxtamembrane region of FLT3, mutations in the kinase domain of FLT3, FLT3 point mutations, FLT3 internal tandem duplication mutations, the FLT3- ITD mutation, the D835Y FLT3 mutation, the D835V FLT3 mutation, the F691L FLT3 mutation, or the R834Q FLT3 mutation) and optionally inhibits one or more of IRAK4, isoforms of IRAK4, mutations of IRAK4, IRAK1, isoforms of IRAK1, or mutations of IRAK1.
  • FLT3 and mutations of FLT3 e.g., mutations in the juxtamembrane region of FLT3, mutations in the kinase domain of FLT3, FLT3 point mutations, FLT3 internal tandem duplication mutations, the FLT3- ITD mutation
  • the compounds of the disclosure can inhibit the activity of one or both of FLT3 and mutations of FLT3 (e.g., mutations in the juxtamembrane region of FLT3, mutations in the kinase domain of FLT3, FLT3 point mutations, FLT3 internal tandem duplication mutations, the FLT3-ITD mutation, the D835Y FLT3 mutation, the D835V FLT3 mutation, the F691L FLT3 mutation, or the R834Q FLT3 mutation) and optionally inhibits one or both of IRAK4 and IRAK1, or an isoform or mutation thereof.
  • FLT3 and mutations of FLT3 e.g., mutations in the juxtamembrane region of FLT3, mutations in the kinase domain of FLT3, FLT3 point mutations, FLT3 internal tandem duplication mutations, the FLT3-ITD mutation, the D835Y FLT3 mutation, the D835V FLT3 mutation, the F
  • the compounds of the disclosure can inhibit FLT3 in combination with IRAK4, IRAK1, or with IRAK4 and IRAK1.
  • compounds exhibit inhibitory activity against IRAK and/or FLT-3 with activities ⁇ 1 ⁇ M, e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000 nM, or even greater.
  • the compounds exhibit inhibitory activity against IRAK and/or FLT-3 with activities between 0.1 nM and 1 nM, e.g., about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 or 1.0 nM.
  • compounds described herein exhibit inhibitory activity against IRAK and/or FLT-3 with activities ⁇ 0.1 ⁇ M, e.g., about 1, 2, 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, or 100 nM.
  • Ranges of values using a combination of any of the values recited herein as upper and/or lower limits are also contemplated, for example, but not limited to, 1-10 nM, 10-100 nM, 1-100 nM, 0.1-1 nM, 0.1-100 nM, 0.1-200 nM, 1-200 nM, 10-200 nM, 100-200 nM, 200-500 nM, 0.1-500 nM, 1-500 nM, 10-500 nM, 500-1000 nM, 0.1-1000 nM, 1-1000 nM, 10-1000 nM, or 100- 1000 nM.
  • the inhibitory activity is less than 0.1 nM, less than 1 nM, less than 10 nM, less than 100 nM, or less than 1000 nM. In some embodiments, the inhibitory activity is in the range of about 1-10 nM, 10-100 nM, 0.1-1 ⁇ M, 1-10 ⁇ M, 10-100 ⁇ M, 100-200 ⁇ M, 200- 500 ⁇ M, or even 500-1000 ⁇ M.
  • IC 50 in the customary sense (i.e., concentration to achieve half-maximal inhibition.
  • hematopoietic cancers that can be treated in an animal (e.g., mammals, porcine, canine, avian (e.g., chicken), bovine, feline, primates, rodents, monkeys, rabbits, mice, rats, and humans) using a compound of the disclosure (e.g., Formula (I)) include, but are not limited to hematopoietic cancers and cancers of the myeloid line of blood cells, cancers with an increased risk of occurrence due to other blood disorders, cancers with an increased risk of occurrence due to chemical exposure (e.g., anti-cancer therapies or occupational chemical exposure), cancers with an increased risk of occurrence due to ionizing radiation (e.g., anti-cancer therapies), cancers evolving from myelodysplastic syndromes, cancers evolving from myeloproliferative disease, and cancers of the B cells.
  • an animal e.g., mammals, porcine, canine, avian (e.g., chicken), bovine, feline
  • hematopoietic cancers that can be treated include, but are not limited to, MDS, AML, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin lymphoma, Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B- cell lymphoma (DLBCL) (e.g. ABC DLBCL with MYD88 mutation (e.g., L265P)), follicular lymphoma, or marginal zone lymphoma, or combinations thereof.
  • MDS MDS
  • AML lymphoma
  • leukemia chronic lymphocytic leukemia
  • CML chronic myeloid leukemia
  • ALL acute lymphoblastic leukemia
  • bone marrow cancer non-Hodgkin lymphoma
  • Waldenstrom’s macroglobulinemia B cell lymphoma
  • cancers characterized by dysregulated IRAK expression can be treated, and include, but are not limited to, glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, Glioma, oral cancer, nasopharyngeal carcinoma, rectal cancer, stomach cancer, and uterine cancer, and the like, and combinations thereof.
  • compounds of the present disclosure can be used to inhibit targets in the context of additional conditions characterized by overactive IRAK1 and/or IRAK4.
  • compounds of the present disclosure can be used to inhibit overactive IRAK1 and/or IRAK4 in conditions such as inflammatory diseases and autoimmune disease, wherein said inflammatory diseaess and autoimmune diseases are characterized by overactive IRAK1 and/or IRAK4.
  • inflammatory and autoimmune diseases characterized by dysregulated (e.g., hyperactive) IRAK expression (IRAK1 and/or IRAK4) and/or IRAK-meidated intracellular signaling can be treated, and include, but are not limited to, chronic inflammation (i.e., associated with viral and bacterial infection), sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, and the like, and combinations thereof.
  • chronic inflammation i.e., associated with viral and bacterial infection
  • sepsis rheumatoid arthritis
  • systemic lupus erythematosus inflammatory bowel disease
  • multiple sclerosis psoriasis
  • Sjögren’s syndrome Ankylosing spondylitis
  • MDS that can be treated in a subject include but are not limited to MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, MDS with a mutation in isocitrate dehydrogenase 2, refractory cytopenia with unilineage dysplasia (e.g., refractory anemia, refractory neutropenia, and refractory thrombocytopenia), refractory anemia with ring sideroblasts, refractory cytopenia with multilineage dysplasia (e.g., refractory cytopenia with multilineage dysplasia and ring sideroblasts
  • MDS that can be treated include, but are not limited to, MDS that is inherited, MDS with an increased risk of occurrence due to an inherited predisposition, MDS with an increased risk of occurrence due to other blood disorders, MDS with an increased risk of occurrence due to chemical exposure, MDS with an increased risk of occurrence due to ionizing radiation, MDS with an increased risk of occurrence due to cancer treatment (e.g., a combination of radiation and the radiomimetic alkylating agents such as busulfan, nitrosourea, or procarbazine (with a latent period of 5 to 7 years) or DNA topoisomerase inhibitors), MDS evolving from acquired aplastic anemia following immunosuppressive treatment and Fanconi's anemia, MDS with an increased risk due to an mutation in splicing factors, MDS with an increased risk due to a mutation in isocitrate dehydrogenase 1, and MDS with an increased risk due to a mutation in isocitrate dehydrogen
  • Animals that can be treated include but are not limited to mammals, rodents, primates, monkeys (e.g., macaque, rhesus macaque, pig tail macaque), humans, canine, feline, porcine, avian (e.g., chicken), bovine, mice, rabbits, and rats.
  • the term “subject” may refer to both human and non-human subjects.
  • the subject is in need of the treatment (e.g., by showing signs of disease, e.g. MDS, AML, cancer, autoimmune disease, inflammatory condition, etc., or by having a low blood cell count).
  • MDS that can be treated in a subject include, but are not limited to MDS that can be treated by inhibiting one or more of FLT3 (e.g., using FLT3 inhibitors), mutations of FLT3 (e.g., using inhibitors of FLT3 mutants), IRAK4 (e.g., using IRAK4 inhibitors), mutations of IRAK4 (e.g., using inhibitors of IRAK4 mutants), IRAK1 (e.g., using IRAK 1 inhibitors), and/or mutations of IRAK1 (e.g., using inhibitors of IRAK1 mutant).
  • FLT3 e.g., using FLT3 inhibitors
  • FLT3 e.g., using FLT3 inhibitors
  • IRAK4 e.g., using IRAK4 inhibitors
  • mutations of IRAK4 e.g., using inhibitors of IRAK4 mutants
  • IRAK1 e.g., using IRAK 1 inhibitors
  • MDS that can be treated include, but are not limited to MDS that can be treated by inhibiting IRAK4 (or its mutations), MDS that can be treated by inhibiting and IRAK1 (or its mutations), or MDS that can be treated by inhibiting IRAK4 (or its mutations) and IRAK1 (or its mutations).
  • MDS that can be treated include, but are not limited to MDS that can be treated by inhibiting FLT3 in combination with IRAK4, IRAK1, or both IRAK4 and IRAK1.
  • inhibiting FLT3 in combination with IRAK4, IRAK1, or both IRAK4 and IRAK1 provides for treating tumors with FLT3 mutations, which can be or become resistant to FLT3 inhibitors due to adaptive resistance mechanism(s), e.g., driven by IRAK.
  • MDS that can be treated is characterized by MDS having enhanced IRAK4- Long expression and/or activity relative to IRAK4-Short, and/or wherein the MDS is not driven by FLT3 mutations but expresses IRAK4-Long, based on the use of IRAK4L and the ratio of IRAK4L to IRAK4S (e.g. as described in U.S.
  • AML that can be treated in a subject include, but are not limited to AML that is inherited, AML with an increased risk of occurrence due to an inherited predisposition, AML with one or more recurrent genetic abnormality (e.g., with inversions or translocations, such as MLLT3/MLL which is a translocation between chromosome 9 and 11 (“MLL”) AML with translocation between chromosomes 8 and 21, AML with translocation or inversion in chromosome 16, AML with translocation between chromosomes 9 and 11, APL (M3) with translocation between chromosomes 15 and 17, AML with translocation between chromosomes 6 and 9, AML with translocation or inversion
  • AML that can be treated include AML that by inhibiting one or more of FLT3 (e.g., using FLT3 inhibitors), mutations of FLT3 (e.g., using inhibitors of FLT3 mutants), IRAK4 (e.g., using IRAK4 inhibitors), mutations of IRAK4 (e.g., using inhibitors of IRAK4 mutants), IRAK1 (e.g., using IRAK 1 inhibitors), and/or mutations of IRAK1 (e.g., using inhibitors of IRAK1 mutant).
  • FLT3 e.g., using FLT3 inhibitors
  • mutations of FLT3 e.g., using inhibitors of FLT3 mutants
  • IRAK4 e.g., using IRAK4 inhibitors
  • mutations of IRAK4 e.g., using inhibitors of IRAK4 mutants
  • IRAK1 e.g., using IRAK 1 inhibitors
  • IRAK1 e.
  • AML that can be treated include, but are not limited to AML that can be treated by inhibiting IRAK4 (or its mutations), MDS that can be treated by inhibiting and IRAK1 (or its mutations), or AML that can be treated by inhibiting IRAK4 (or its mutations) and IRAK1 (or its mutations).
  • AML that can be treated include, but are not limited to AML that can be treated by inhibiting FLT3 in combination with IRAK4, IRAK1, or both IRAK4 and IRAK1.
  • inhibiting FLT3 in combination with IRAK4, IRAK1, or both IRAK4 and IRAK1 provides for treating tumors with FLT3 mutations which can be or become resistant to FLT3 inhibitors due to adaptive resistance mechanism(s), e.g. driven by IRAK.
  • AML that can be treated is characterized by AML having enhanced IRAK4-Long expression and/or activity relative to IRAK4-Short, and/or wherein the AML is not driven by FLT3 mutations but expresses IRAK4-Long, based on the use of IRAK4L and the ratio of IRAK4L to IRAK4S (e.g. as described in U.S.
  • FLT3 e.g., using FLT3 inhibitors
  • mutations of FLT3 e.g., using inhibitors of FLT3 mutants
  • IRAK4 e.g., using IRAK4 inhibitors
  • isoforms of IRAK4
  • hematopoietic cancers that can be treated include, but are not limited to cancers that can be treated by inhibiting (e.g., reducing the activity or expression of) FLT3 (or its mutations) and IRAK4 (or its mutations), hematopoietic cancers that can be treated by inhibiting (e.g., reducing the activity or expression of) FLT3 (or its mutations) and IRAK1 (or its mutations), or hematopoietic cancers that can be treated by inhibiting (e.g., reducing the activity or expression of) FLT3 (or its mutations), IRAK4 (or its isoforms or mutations), and IRAK1 (or its isoforms or mutations).
  • hematopoietic cancer that can be treated include, but are not limited to hematopoietic cancer that can be treated by inhibiting FLT3 in combination with IRAK4, IRAK1, or both IRAK4 and IRAK1.
  • inhibiting FLT3 in combination with IRAK4, IRAK1, or both IRAK4 and IRAK1 provides for treating tumors with FLT3 mutations which can be or become resistant to FLT3 inhibitors due to adaptive resistance mechanism(s), e.g. driven by IRAK.
  • hematopoietic cancer that can be treated is characterized by hematopoietic cancer having enhanced IRAK4-Long expression and/or activity relative to IRAK4- Short, and/or wherein the hematopoietic cancer is not driven by FLT3 mutations but expresses IRAK4-Long, based on the use of IRAK4L and the ratio of IRAK4L to IRAK4S (e.g. as described in U.S. Patent Application No.16/339,692; and Smith, M. A., et al. (2019).
  • cancers that can be treated include, but are not limited to, glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, Glioma, oral cancer, nasopharyngeal carcinoma, rectal cancer, stomach cancer, and uterine cancer, and the like, and combinations thereof, that can be treated by inhibiting FLT3 in combination with IRAK4, IRAK1, or both IRAK4 and IRAK1.
  • inhibiting FLT3 in combination with IRAK4, IRAK1, or both IRAK4 and IRAK1 provides for treating tumors with FLT3 mutations which can be or become resistant to FLT3 inhibitors due to adaptive resistance mechanism(s), e.g., driven by IRAK.
  • cancer that can be treated is characterized by cancer having enhanced IRAK4-Long expression and/or activity relative to IRAK4-Short, and/or wherein the cancer is not driven by FLT3 mutations but expresses IRAK4-Long, based on the use of IRAK4L and the ratio of IRAK4L to IRAK4S (e.g. as described in U.S.
  • inflammatory and autoimmune diseases characterized by dysregulated (e.g., hyperactive) IRAK expression (IRAK1 and/or IRAK4) and/or IRAK-meidated intracellular signaling that can be treated include, but are not limited to, chronic inflammation (i.e., associated with viral and bacterial infection), sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, and the like, and combinations thereof, that can be treated by inhibiting FLT3 in combination with IRAK4, IRAK1, or both IRAK4 and IRAK1.
  • chronic inflammation i.e., associated with viral and bacterial infection
  • sepsis rheumatoid arthritis
  • systemic lupus erythematosus inflammatory bowel disease
  • inhibiting FLT3 in combination with IRAK4, IRAK1, or both IRAK4 and IRAK1 provides for treating inflammatory and autoimmune diseases with FLT3 mutations which can be or become resistant to FLT3 inhibitors due to adaptive resistance mechanism(s), e.g., driven by IRAK.
  • inflammatory and autoimmune disease that can be treated is characterized by inflammatory and autoimmune disease having enhanced IRAK4-Long expression and/or activity relative to IRAK4-Short, and/or wherein the inflammatory and autoimmune disease is not driven by FLT3 mutations but expresses IRAK4- Long, based on the use of IRAK4L and the ratio of IRAK4L to IRAK4S (e.g.
  • MDS e.g., MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2
  • treating can include but is not limited to prophylactic treatment and therapeutic treatment.
  • treatment can include, but is not limited to: preventing MDS (e.g., MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2); reducing the risk of MDS (e.g., MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2); ameliorating or relieving symptoms of MDS (e.g., MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2); eliciting a bodily response against MDS (e.g., MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 2
  • treating does not include prophylactic treatment of MDS (e.g., preventing or ameliorating future MDS).
  • MDS e.g., preventing or ameliorating future MDS.
  • treating can include but is not limited to prophylactic treatment and therapeutic treatment.
  • treatment can include, but is not limited to: preventing cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin lymphoma, or Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof, and the like); reducing the risk of cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin lymphoma, or Waldenstrom’s macroglobulinemia, B cell lymphoma
  • treating does not include prophylactic treatment of cancer (e.g., preventing or ameliorating future cancer).
  • Treatment of a subject can occur using any suitable administration method (such as those disclosed herein) and using any suitable amount of a compound of the disclosure (e.g., Formula (I)).
  • methods of treatment comprise treating an animal or human for MDS (e.g., MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2).
  • methods of treatment comprise treating an animal or human for a hematopoietic cancer (e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin lymphoma, Waldenstrom’s macroglobulinemia Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL MYD88 mutation, follicular lymphoma, or marginal zone lymphoma, and combinations thereof, and the like).
  • a hematopoietic cancer e.g., acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non-Hodgkin lymph
  • inventions include treatment after one or more of having a blood disorder, having myelodysplastic syndrome, having myeloproliferative disease, an occurrence of chemical exposure, an exposure to ionizing radiation, or a treatment for a hematopoietic cancer (e.g., with chemotherapy, ionizing radiation, or both).
  • Some embodiments of the disclosure include a method for treating a subject (e.g., an animal such as a human or primate) with a composition comprising a compound of the disclosure (e.g., Formula (I)) (e.g., a pharmaceutical composition) which comprises one or more administrations of one or more such compositions; the compositions may be the same or different if there is more than one administration.
  • a subject e.g., an animal such as a human or primate
  • a composition comprising a compound of the disclosure (e.g., Formula (I)) (e.g., a pharmaceutical composition) which comprises one or more administrations of one or more such compositions
  • the method of treatment includes administering to a subject an effective amount of a composition comprising a compound of the disclosure (e.g., Formula (I)).
  • the term “effective amount” refers to a dosage or a series of dosages sufficient to affect treatment (e.g., to treat MDS such as but not limited to MDS (e.g., MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, or MDS with a mutation in isocitrate dehydrogenase 2); or to treat a hematopoietic cancer, such as but not limited to acute myeloid leukemia, lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non- Hodgkin lymphoma, Waldenstrom’s macroglobulinemia, B cell lymphom
  • MDS e.g., M
  • an effective amount can encompass a therapeutically effective amount, as disclosed herein.
  • an effective amount can vary depending on the subject and the particular treatment being affected. The exact amount that is required can, for example, vary from subject to subject, depending on the age and general condition of the subject, the particular adjuvant being used (if applicable), administration protocol, and the like. As such, the effective amount can, for example, vary based on the particular circumstances, and an appropriate effective amount can be determined in a particular case.
  • An effective amount can, for example, include any dosage or composition amount disclosed herein.
  • an effective amount of at least one compound of the disclosure (e.g., Formula (I) such as but not limited to Compounds 1-137, as listed in Tables 1-15) (which can be administered to a subject such as mammals, primates, monkeys or humans) can be an amount of about 0.005 to about 50 mg/kg body weight, about 0.01 to about 15 mg/kg body weight, about 0.1 to about 10 mg/kg body weight, about 0.5 to about 7 mg/kg body weight, about 0.005 mg/kg, about 0.01 mg/kg, about 0.05 mg/kg, about 0.1 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 3 mg/kg, about 5 mg/kg, about 5.5 mg/kg, about 6 mg/kg, about 6.5 mg/kg, about 7 mg/kg, about 7.5 mg/kg, about 8 mg/kg, about 10 mg/kg, about 12 mg/kg, or about 15 mg/kg.
  • Formula (I) such as but not limited to Compounds 1-137, as listed in Tables 1-15
  • the dosage can be about 0.5 mg/kg body weight or about 6.5 mg/kg body weight.
  • an effective amount of at least one compound of the disclosure e.g., Formula (I) such as but not limited to Compounds 1-137, as listed in Tables 1-15
  • an effective amount of at least one compound of the disclosure can be an amount of about 0.005 to about 50 mg/kg body weight, about 0.01 to about 15 mg/kg body weight, about 0.1 to about 10 mg/kg body weight, about 0.5 to about 7 mg/kg body weight, about 0.005 mg/kg, about 0.01 mg/kg, about 0.05 mg/kg, about 0.1 mg/kg, about 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 20 mg/kg, about 30 mg/kg, about 40 mg/kg, about 50 mg/kg, about 80 mg/kg, about 100 mg/kg, or about 150 mg/kg.
  • Formula (I) such as but not limited to Compounds 1-137, as listed in Tables 1-15
  • an effective amount of at least one compound of the disclosure (e.g., Formula (I) such as but not limited to Compounds 1-1137, as listed in Tables 1-15) (which can be administered to an animal such as mammals, primates, monkeys or humans) can be an amount of about 1 to about 1000 mg/kg body weight, about 5 to about 500 mg/kg body weight, about 10 to about 200 mg/kg body weight, about 25 to about 100 mg/kg body weight, about 1 mg/kg, about 2 mg/kg, about 5 mg/kg, about 10 mg/kg, about 25 mg/kg, about 50 mg/kg, about 100 mg/kg, about 150 mg/kg, about 200 mg/kg, about 300 mg/kg, about 400 mg/kg, about 500 mg/kg, about 600 mg/kg, about 700 mg/kg, about 800 mg/kg, about 900 mg/kg, or about 1000 mg/kg.
  • Formula (I) such as but not limited to Compounds 1-1137, as listed in Tables 1-15
  • an effective amount of at least one compound of the disclosure
  • the dosage can be about 20 mg/kg human body weight or about 100 mg/kg human body weight.
  • an effective amount of at least one compound of the disclosure e.g., Formula (I) such as but not limited to Compounds 1-137, as listed in Tables 1-15
  • an effective amount of at least one compound of the disclosure can be an amount of about 1 to about 1000 mg/kg body weight, about 5 to about 500 mg/kg body weight, about 10 to about 200 mg/kg body weight, about 25 to about 100 mg/kg body weight, about 1 mg/kg, about 2 mg/kg, about 5 mg/kg, about 10 mg/kg, about 25 mg/kg, about 50 mg/kg, about 100 mg/kg, about 150 mg/kg, about 200 mg/kg, about 300 mg/kg, about 400 mg/kg, about 500 mg/kg, about 600 mg/kg, about 700 mg/kg, about 800 mg/kg, about 900 mg/kg, or about 1000 mg/
  • the treatments can also include one or more of surgical intervention, chemotherapy, radiation therapy, hormone therapies, immunotherapy, and adjuvant systematic therapies.
  • Adjuvants may include but are not limited to chemotherapy (e.g., temozolomide), radiation therapy, antiangiogenic therapy (e.g., bevacizumab), and hormone therapies, such as administration of LHRH agonists; anti-estrogens, such as tamoxifen; high-dose progestogens; aromatase inhibitors; and/or adrenalectomy.
  • chemotherapy e.g., temozolomide
  • radiation therapy e.g., antiangiogenic therapy (e.g., bevacizumab)
  • hormone therapies such as administration of LHRH agonists
  • anti-estrogens such as tamoxifen
  • high-dose progestogens aromatase inhibitors
  • aromatase inhibitors and/or adrenalectomy.
  • Chemotherapy can be used as a single- agent or as a
  • the administration to a subject of at least one compound of the disclosure is an adjuvant cancer therapy or part of an adjuvant cancer therapy.
  • Adjuvant treatments include treatments by the mechanisms disclosed herein and of cancers as disclosed herein, including, but not limited to tumors.
  • Corresponding primary therapies can include, but are not limited to, surgery, chemotherapy, or radiation therapy.
  • the adjuvant treatment can be a combination of chemokine receptor antagonists with traditional chemotoxic agents or with immunotherapy that increases the specificity of treatment to the cancer and potentially limits additional systemic side effects.
  • a compound of the disclosure can be used as adjuvant with other chemotherapeutic agents.
  • the use of a compound of the disclosure may, in some instances, reduce the duration of the dose of both drugs and drug combinations reducing the side effects.
  • the administration to a subject may decrease the incidence of one or more symptoms associated with MDS / AML / a type of hematopoietic cancer.
  • the administration may decrease marrow failure, immune dysfunction, transformation to overt leukemia, or combinations thereof in said subject, as compared to a subject not receiving said composition.
  • the method may decrease a marker of viability of MDS cells AML cells, or cancer cells in a subject.
  • the method may decrease a marker of viability of MDS, AML, and/or cancer cells.
  • the marker may be selected from survival over time, proliferation, growth, migration, formation of colonies, chromatic assembly, DNA binding, RNA metabolism, cell migration, cell adhesion, inflammation, or a combination thereof.
  • Combination Therapies [00237]
  • the treatments disclosed herein can include use of other drugs (e.g., antibiotics) or therapies for treating disease, e.g. MDS / AML / a type of hematopoietic cancer.
  • antibiotics can be used to treat infections and can be combined with a compound of the disclosure to treat disease (e.g., infections).
  • intravenous immunoglobulin (IVIG) therapy can be used as part of the treatment regime (i.e., in addition to administration of the compound(s) of the disclosure).
  • treatment regimens for various types of cancers can involve one or more elements selected from chemotherapy, targeted therapy, alternative therapy, immunotherapy, and the like.
  • the compounds and/or compositions described herein can be used in one or more administrations to a subject, in combination with one or more BCL2 inhibitor, BTK inhibitor, chemotherapy, targeted therapy, alternative therapy, immunotherapy, DNA methyltransferase inhibitor/hypomethylating agent, anthracycline, histone deacetylase (HDAC) inhibitor, purine nucleoside analogue (antimetabolite), isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH2) inhibitor, antibody-drug conjugate, mAbs/immunotherapy, CAR-T cell therapy, Plk inhibitor, MEK inhibitor, CDK9 inhibitor, CDK8 inhibitor, retinoic acid receptor agonist, TP53 activator, smoothened receptor antagonist, ERK inhibitor, PI3K inhibitor, mTOR inhibitor, glucocorticoid receptor modulator, or EZH2 inhibitor, and the like, or one or more combinations thereof, where the compositions may be used in one or more BCL2 inhibitor, BTK
  • IRAK inhibitors have been demonstrated to have synergistic effects when administered in combination with an apoptosis modulator/inhibitor, such as a BCL2 inhibitor.
  • an exemplary apoptosis/BCL2 inhibitor has been shown to have a synergistic effect when used in combination with an exemplary IRAK inhibitor in multiple AML cell lines. Venetoclax was used as a representative apoptosis/BCL2 inhibitor.
  • the present disclosure encompasses methods for treating a disease or disorder which is responsive to inhibition of IRAK, comprising administration to a subject of a composition comprising an IRAK inhibiting compound, wherein some embodiments of the method can further involve administration of an apoptotic modulator.
  • the apoptotic modulator may comprise a BTK and/or a BCL2 inhibitor.
  • BTK and BCL2 inhibitors may be, for example, those known in the art.
  • the method may comprise the step of administering to the subject an apoptotic modulator.
  • the apoptotic modulator may comprise a BCL2 inhibitor selected from ABT-263 (Navitoclax), ABT-737, ABT- 199 (venetoclax), GDC-0199, GX15-070 (Obatoclax) (all available from Abbott Laboratories), HA14-1, S1, 2-methoxy antimycin A3, gossypol, AT-101, apogossypol, WEHI-539, A-1155463, BXI-61, BXI-72, TW37, MIM1, UMI-77, and the like, and combinations thereof.
  • BCL2 inhibitor selected from ABT-263 (Navitoclax), ABT-737, ABT- 199 (venetoclax), GDC-0199, GX15-070 (Obatoclax) (all available from Abbott Laboratories), HA14-1, S1, 2-methoxy antimycin A3, gossypol, AT-101, apogossypol, WEHI-539, A-1155463,
  • the BCL2 inhibitor comprises venetoclax.
  • the administration step comprises administration to a subject of a composition comprising an IRAK inhibiting compound and a BCL2 inhibitor. In some embodiments, the administration step comprises administration of a composition comprising an IRAK inhibiting compound in combination with a composition comprising a BCL2 inhibitor.
  • the IRAK inhibiting compound is selected from Compounds 1-137, or a salt, isomer, derivative or analog thereof, and the BCL2 inhibitor is venetoclax, or a a salt, isomer, derivative or analog thereof.
  • the method can further involve administration to a subject of an immune modulator.
  • the immune modulator can include, for example, Lenalidomide (Revlamid; Celgene Corporation).
  • the method can involve administration of an epigenetic modulator.
  • the epigenetic modulator can include, for example, a hypomethylating agent such as azacitidine, decitabine, or a combination thereof.
  • a hypomethylating agent such as azacitidine, decitabine, or a combination thereof.
  • the compounds and/or compositions described herein can be used in one or more administrations to a subject, together with or in combination with one or more BTK inhibitor, such as, for example, ibrutinib, or a salt, isomer, derivative or analog thereof.
  • the compounds and/or compositions described herein can be used in one or more administrations, together with or in combination with a DNA methyltransferase inhibitor/hypomethylating agent, such as, for example, azacytidine, decitabine, cytarabine, and/or guadecitabine; an anthracycline, such as, for example, daunorubicin, idarubicin, doxorubicin, mitoxantrone, epirubicin, and/or CPX-351 (a combination cytarabine and daunorubicin in a fixed 5:1 molar ratio), and the like; a histone deacetylase (HDAC) inhibitor, such as, for example, vorinostat, panobinostat, valproic acid, and/or pracinostat, and the like; a purine nucleoside analogue (antimetabolite), such as, for example, fludarabine, cladrib
  • Anti-CD70 e.g. ARGX-110, cusatuzumab
  • a bispecific antibody e.g. floteuzumab (CD123 x CD3)
  • Anti-CTLA4 e.g. ipilimumab
  • Anti-PD1/PDL1 e.g.
  • nivolumab pembrolizumab, atezolizumab, avelumab, PDR001, MBG453), and/or Anti-CD47 (e.g. 5F9 (Magrolimab)), and the like; a Plk inhibitor, such as, for example, volasertib and/or rigosertib, and the like; a MEK inhibitor, such as, for example, trametinib, cobimetinib, selumetinib, pimasertib, and/or refametinib, and the like; a CDK9 inhibitor, such as, for example, alvocidib and/or voruciclib, and the like; a CDK8 inhibitor, such as, for example, SEL120, and the like; a retinoic acid receptor agonist, such as, for example, ATRA (all-trans retinoic acid) and/or SY-1425 (a selective RAR ⁇ agonist), and the like
  • compounds and pharmaceutical compositions including the same can be used in prevention of secondary malignancies when used in combination with an EZH2 inhibitor.
  • Further therapies are described below and are contemplated in combination therapies in the context of the present disclosure.
  • Chemotherapy / Targeted Therapy / Alternative Therapy Cancers are commonly treated with chemotherapy and/or targeted therapy and/or alternative therapy. Chemotherapies act by indiscriminately targeting rapidly dividing cells, including healthy cells as well as tumor cells, whereas targeted cancer therapies rather act by interfering with specific molecules, or molecular targets, which are involved in cancer growth and progression. Targeted therapy generally targets cancer cells exclusively, having minimal damage to normal cells.
  • approved chemotherapies include abitrexate (Methotrexate Injection), abraxane (Paclitaxel Injection), adcetris (Brentuximab Vedotin Injection), adriamycin (Doxorubicin), adrucil Injection (5-FU (fluorouracil)), Armitor (Everolimus), Armitor Disperz (Everolimus), alimta (PEMETREXED), alkeran Injection (Melphalan Injection), alkeran Tablets (Melphalan), aredia (Pamidronate), arimidex (Anastrozole), aromasin (Exemestane), arranon (Nelarabine), arzerra (Ofatumumab Injection), ava
  • approved targeted therapies include ado- trastuzumab emtansine (Kadcyla), afatinib (Gilotrif), aldesleukin (Proleukin), alectinib (Alecensa), alemtuzumab (Campath), axitinib (Inlyta), belimumab (Benlysta), belinostat (Beleodaq), bevacizumab (Avastin), bortezomib (Velcade), bosutinib (Bosulif), brentuximab vedotin (Adcetris), cabozantinib (Cabometyx [tablet], Cometriq [capsule]), canakinumab (Ilaris), carfilzomib (Kyprolis), ceritinib (Zykadia), cetuximab (Erbitux), cobimetini
  • Those skilled in the art can determine appropriate chemotherapy and/or targeted therapy and/or alternative therapy options, including treatments that have been approved and those that in clinical trials or otherwise under development. Some targeted therapies are also immunotherapies. Any relevant chemotherapy, target therapy, and alternative therapy treatment strategies can be utilized, alone or in combination with one or more additional cancer therapy, in the practice of the present disclosure.
  • immunotherapies include cell-based immunotherapies, such as those involving cells which effect an immune response (such as, for example, lymphocytes, macrophages, natural killer (NK) cells, dendritic cells, cytotoxic T lymphocytes (CTL), antibodies and antibody derivatives (such as, for example, monoclonal antibodies, conjugated monoclonal antibodies, polyclonal antibodies, antibody fragments, radiolabeled antibodies, chemolabeled antibodies, etc.), immune checkpoint inhibitors, vaccines (such as, for example, cancer vaccines (e.g. tumor cell vaccines, antigen vaccines, dendritic cell vaccines, vector-based vaccines, etc.), e.g.
  • an immune response such as, for example, lymphocytes, macrophages, natural killer (NK) cells, dendritic cells, cytotoxic T lymphocytes (CTL), antibodies and antibody derivatives (such as, for example, monoclonal antibodies, conjugated monoclonal antibodies, polyclonal antibodies, antibody fragments, radiolabeled
  • Immune checkpoint inhibitor immunotherapies are those that target one or more specific proteins or receptors, such as PD-1, PD-L1, CTLA-4, and the like.
  • Immune checkpoint inhibitor immunotherapies include ipilimumab (Yervoy), nivolumab (Opdivo), pembrolizumab (Keytruda), and the like.
  • Non-specific immunotherpaies include cytokines, interleukins, interferons, and the like.
  • an immunotherapy assigned or administered to a subject can include an interleukin, and/or interferon (IFN), and/or one or more suitable antibody-based reagent, such as denileukin diftitox and/or administration of an antibody-based reagent selected from the group consisting of ado-trastuzumab emtansine, alemtuzumab, atezolizumab, bevacizumab, blinatumomab, brentuximab vedotin, cetuximab, catumaxomab, gemtuzumab, ibritumomab tiuxetan, ilipimumab, natalizumab, nimotuzumab, nivolumab, ofatumumab, panitumumab, pembrolizumab, rituximab, tositumomab, trastuzumab
  • IFN
  • an immunotherapy assigned or administered to a subject can include an indoleamine 2,3-dioxygenase (IDO) inhibitor, adoptive T-cell therapy, virotherapy (T-VEC), and/or any other immunotherapy whose efficacy extensively depends on anti-tumor immunity.
  • IDO indoleamine 2,3-dioxygenase
  • T-VEC virotherapy
  • any other immunotherapy whose efficacy extensively depends on anti-tumor immunity.
  • Those skilled in the art can determine appropriate immunotherapy options, including treatments that have been approved and those that in clinical trials or otherwise under development. Any relevant immunotherapy treatment strategies, alone or in combination with one or more additional cancer therapy, can be utilized in the practice of the present disclosure.
  • Other Cancer Treatments [00252] In addition to chemotherapies, targeted therapies, alternative therapies, and immunotherapies, cancer can additionally be treated by other strategies.
  • compositions can include methods of administering or treating an animal/human, which can involve treatment with an amount of at least one compound of the disclosure (e.g., Formula (I)) that is effective to treat the disease, condition, or disorder that the organism has, or is suspected of having, or is susceptible to, or to bring about a desired physiological effect.
  • a compound of the disclosure e.g., Formula (I)
  • the composition or pharmaceutical composition comprises at least one compound of the disclosure (e.g., Formula (I)) which can be administered to an animal (e.g., mammals, primates, monkeys, or humans) in an amount of about 0.005 to about 50 mg/kg body weight, about 0.01 to about 15 mg/kg body weight, about 0.1 to about 10 mg/kg body weight, about 0.5 to about 7 mg/kg body weight, about 0.005 mg/kg, about 0.01 mg/kg, about 0.05 mg/kg, about 0.1 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 3 mg/kg, about 5 mg/kg, about 5.5 mg/kg, about 6 mg/kg, about 6.5 mg/kg, about 7 mg/kg, about 7.5 mg/kg, about 8 mg/kg, about 10 mg/kg, about 12 mg/kg, or about 15 mg/kg.
  • an animal e.g., mammals, primates, monkeys, or humans
  • an animal e.g., mammals, primates, monkeys, or humans
  • the dosage can be about 0.5 mg/kg human body weight or about 6.5 mg/kg human body weight.
  • some subjects e.g., mammals, mice, rabbits, feline, porcine, or canine
  • a dose or a therapeutically effective dose of a compound disclosed herein will be that which is sufficient to achieve a plasma concentration of the compound or its active metabolite(s) within a range set forth herein, e.g., 1-10 nM, 10-100 nM, 1-100 nM, 0.1-1 nM, 0.1-100 nM, 0.1-200 nM, 1-200 nM, 10-200 nM, 100-200 nM, 200-500 nM, 0.1-500 nM, 1-500 nM, 10-500 nM, 500-1000 nM, 0.1-1000 nM, 1-1000 nM, 10-1000 nM, or 100-1000 nM.
  • the inhibitory activity is less than 0.1 nM, less than 1 nM, less than 10 nM, less than 100 nM, or less than 1000 nM, 0.1-1 ⁇ M, 1-10 ⁇ M, 10-100 ⁇ M, 100-200 ⁇ M, 200- 500 ⁇ M, or even 500-1000 ⁇ M, preferably about 1-10 nM, 10-100 nM, or 0.1-1 ⁇ M.
  • hematopoietic cancers such as, for example, MDS and/or AML and/or DLBCL, etc., other types of cancers, inflammatory conditions, and/or autoimmune diseases, as described herein,.
  • the compounds and/or pharmaceutical compounds of the disclosure can be administered in combination with one or more other therapeutic agents for a given disease, condition, or disorder.
  • the compounds and pharmaceutical compositions are preferably prepared and administered in dose units. Solid dose units are tablets, capsules and suppositories. For treatment of a subject, depending on activity of the compound, manner of administration, nature and severity of the disease or disorder, age and body weight of the subject, different daily doses can be used. [00257] Under certain circumstances, however, higher or lower daily doses can be appropriate.
  • the administration of the daily dose can be carried out both by single administration in the form of an individual dose unit or else several smaller dose units and also by multiple administrations of subdivided doses at specific intervals.
  • the compounds and pharmaceutical compositions contemplated herein can be administered locally or systemically in a therapeutically effective dose. Amounts effective for this use will, of course, depend on the severity of the disease or disorder and the weight and general state of the subject. Typically, dosages used in vitro can provide useful guidance in the amounts useful for in situ administration of the pharmaceutical composition, and animal models can be used to determine effective dosages for treatment of particular disorders. [00259] Various considerations are described, e. g.
  • parenteral dosage in mg/mL times 1.8 the corresponding oral dosage in milligrams (“mg”).
  • parenteral dosage in mg/mL times 1.6 the corresponding oral dosage in mg.
  • An average adult weighs about 70 kg.
  • the compounds and/or pharmaceutical compositions can include a unit dose of one or more compounds of the disclosure (e.g., compounds of Formula (I) and pharmaceutical compositions including the same) in combination with a pharmaceutically acceptable carrier and, in addition, can include other medicinal agents, pharmaceutical agents, carriers, adjuvants, diluents, and excipients.
  • the carrier, vehicle or excipient can facilitate administration, delivery and/or improve preservation of the composition.
  • the one or more carriers include but are not limited to, saline solutions such as normal saline, Ringer's solution, PBS (phosphate-buffered saline), and generally mixtures of various salts including potassium and phosphate salts with or without sugar additives such as glucose.
  • Carriers can include aqueous and non-aqueous sterile injection solutions that can contain antioxidants, buffers, bacteriostats, bactericidal antibiotics, and solutes that render the formulation isotonic with the bodily fluids of the intended recipient; and aqueous and non-aqueous sterile suspensions, which can include suspending agents and thickening agents.
  • the one or more excipients can include, but are not limited to water, saline, dextrose, glycerol, ethanol, or the like, and combinations thereof.
  • Nontoxic auxiliary substances such as wetting agents, buffers, or emulsifiers may also be added to the composition.
  • Oral formulations can include such normally employed excipients as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, and magnesium carbonate.
  • the quantity of active component in a unit dose preparation can be varied or adjusted from 0.1 mg to 10000 mg, more typically 1.0 mg to 1000 mg, most typically 10 mg to 500 mg, according to the particular application and the potency of the active component.
  • the composition can, if desired, also contain other compatible therapeutic agents.
  • the compounds of the disclosure e.g., compounds according to Formula (I)
  • the compounds of the disclosure (e.g., Formula (I)) of the disclosure can also be used to treat subjects for a variety of diseases.
  • Subjects include but are not limited to mammals, primates, monkeys (e.g., macaque, rhesus macaque, or pig tail macaque), humans, canine, feline, bovine, porcine, avian (e.g., chicken), mice, rabbits, and rats.
  • the route of administration of the compounds of the disclosure can be of any suitable route. Administration routes can be, but are not limited to the oral route, the parenteral route, the cutaneous route, the nasal route, the rectal route, the vaginal route, and the ocular route.
  • administration routes can be parenteral administration, a mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration.
  • the choice of administration route can depend on the compound identity (e.g., the physical and chemical properties of the compound) as well as the age and weight of the animal/human, the particular disease (e.g., cancer or MDS), and the severity of the disease (e.g., stage or severity of cancer or MDS).
  • combinations of administration routes can be administered, as desired.
  • Some embodiments of the disclosure include a method for providing a subject with a composition comprising one or more compounds of the disclosure (e.g., Formula (I)) described herein (e.g., a pharmaceutical composition) which comprises one or more administrations of one or more such compositions; the compositions may be the same or different if there is more than one administration.
  • Toxicity [00266] The ratio between toxicity and therapeutic effect for a particular compound is its therapeutic index and can be expressed as the ratio between LD50 (the amount of compound lethal in 50% of the population) and ED 50 (the amount of compound effective in 50% of the population). Compounds that exhibit high therapeutic indices are preferred.
  • Therapeutic index data obtained from in vitro assays, cell culture assays and/or animal studies can be used in formulating a range of dosages for use in humans.
  • the dosage of such compounds preferably lies within a range of plasma concentrations that include the ED 50 with little or no toxicity.
  • the dosage can vary within this range depending upon the dosage form employed and the route of administration utilized. See, e.g. Fingl et al., In: THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, Ch.1, p.l, 1975.
  • the exact formulation, route of administration, and dosage can be chosen by the individual practitioner in view of the patient’s condition and the particular method in which the compound is used.
  • Clause 2 The compound of Clause 1, wherein R 1 is H, halogen, -CONH 2 , -CONHCH 3 , -CON(CH 3 ) 2 , benzyl, C 1 -C 7 alkyl, C 1 -C 7 alkoxy, or cycloalkyl, which C 1 -C 7 alkyl, C 1 -C 7 alkoxy, or cycloalkyl is optionally substituted with one or more halogen, hydroxyl, C 1 -C 7 alkyl, or C 1 -C 7 haloalkyl.
  • R 2 is H, halogen, hydroxy, O-aryl, amino, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 1 -C 7 alkoxy, cycloalkyl, heterocyclyl, aryl, fused ring aryl, heteroaryl, or fused ring heteroaryl, which O-aryl, amino, C 1 - C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 2 -C 6 alkoxy, cycloalkyl, heterocyclyl, aryl, fused ring aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, -CN, amino, cycloalkyl, heterocyclyl, aryl, heteroaryl, fused ring aryl, fused ring heteroaryl, fused ring heteroaryl, fuse
  • Clause 6 The compound of any of Clauses 1-5, wherein R 2 is H, halogen, hydroxy, O-aryl, amino, C 1 -C 7 alkyl, C 1 -C 7 alkoxy, cycloalkyl, heterocyclyl, aryl, fused ring aryl, heteroaryl, or fused ring heteroaryl which O-aryl, amino, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 2 -C 6 alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more of halogen, hydroxy, amino, cycloalkyl, heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, C 1 -C 7 alkyl, C 1 -C 7 haloalkyl, C
  • Clause 7 The compound of any of Clauses 1-6, wherein R 2 is H, Cl, hydroxy, -NHCH 3 , -N(CH 3 ) 2 , -OCH 3 , -OCF 3 , -OCHF 2 , -OPh, -CF 3 , -CHF 2 , unsubstituted C 1 -C 7 alkyl, substituted amino, substituted C 1 -C 7 alkyl, substituted cycloalkyl, unsubstituted cycloalkyl, unsubstituted heterocyclyl, substituted pyrazolyl, substituted fused ring heteroaryl, or unsubstituted fused ring heteroaryl.
  • Clause 8 The compound of Clause 1 or Clause 5, wherein R 2 is not H.
  • Clause 9. The compound of any of Clauses 1-8, wherein R 3 is H, halogen, hydroxy, -CN, methanoyl (-COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, or C 1 -C 7 alkoxy, which C 1 -C 7 alkyl, or C 2 -C 6 alkoxy, is optionally substituted with one or more of halogen, hydroxy, methanoyl (-COH), carboxy (-CO 2 H), nitro (-NO 2 ), -NH 2 , -N(CH 3 ) 2 , cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO 3 H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl
  • Clause 10 The compound of any of Clauses 1-9, wherein R 3 is H, halogen, hydroxy, -CN, methyl, -CF 3 , or methoxy.
  • Clause 11 The compound of any of Clauses 1-10, wherein R 4 is H, halogen, hydroxy, -CN, methanoyl (-COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, or C 1 -C 7 alkoxy, which C 1 -C 7 alkyl, or C 2 -C 6 alkoxy, is optionally substituted with one or more of halogen, hydroxy, methanoyl (-COH), carboxy (-CO 2 H), nitro (-NO 2 ), -NH 2 , -N(CH 3 ) 2 , cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO 3 H), heterocyclyl, aryl, hetero
  • Clause 12. The compound of any of Clauses 1-11, wherein R 4 is H, halogen, hydroxy, -CN, methyl, -CF 3 , or methoxy.
  • Clause 13 The compound of any of Clauses 1-12, wherein R 5 is H, halogen, hydroxy, -CN, methanoyl (-COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, or C 1 -C 7 alkoxy, which C 1 -C 7 alkyl, or C 2 -C 6 alkoxy, is optionally substituted with one or more of halogen, hydroxy, methanoyl (-COH), carboxy (-CO 2 H), nitro (-NO 2 ), -NH 2 , -N(CH 3 ) 2 , cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO 3 H), heterocyclyl, aryl, heteroary
  • Clause 14 The compound of any of Clauses 1-13, wherein R 5 is H, halogen, hydroxy, -CN, methyl, -CF 3 , or methoxy.
  • Clause 15 The compound of any of Clauses 1-11, wherein R 4 is methyl or -CF 3 , and wherein at least one of R 3 and R 5 is H or halogen.
  • Clause 16 The compound of any of Clauses 1-15, wherein R 6 is (Ia).
  • Clause 17. The compound of any of Clauses 1-16, wherein m is 0 or 1, wherein n is 0 or 1, wherein o is 0 or 1, and wherein p is 0 or 1.
  • Clause 18 The compound of any of Clauses 1-17, wherein R 7 , R 8 , R 9 , and R 10 are H, and wherein at least one of R 11 , R 12 , R 13 , and R 14 is not H.
  • Clause 19 The compound of any of Clauses 1-18, wherein R 11 , R 12 , R 13 , and R 14 are H, and wherein at least one of R 7 , R 8 , R 9 , and R 10 is not H.
  • Clause 20 The compound of any of Clauses 1-17, wherein all of R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 are H.
  • Clause 21 The compound of any of Clauses 1-20, wherein R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 are independently selected from H, halogen, hydroxy, oxo, methanoyl (- COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, C 1 -C 7 alkoxy, or spiro-fused cycloalkyl, which methanoyl (-COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 2 -C 6 alkoxy, or spiro-fused cycloalkyl is optionally substituted with one or more halogen.
  • R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 are independently selected from H, halogen, hydroxy,
  • Clause 22 The compound of Clause 21, wherein R 7 , R 8 , R 9 , and R 10 are H, and wherein at least one of R 11 , R 12 , R 13 , and R 14 is halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, C 1 -C 7 alkoxy, or spiro-fused cycloalkyl, which methanoyl (-COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 2 -C 6 alkoxy, or spiro-fused cycloalkyl is optionally substituted with one or more halogen.
  • Clause 23 The compound of Clause 21, wherein R 11 , R 12 , R 13 , and R 14 are H, and wherein at least one of R 7 , R 8 , R 9 , and R 10 is halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, C 1 -C 7 alkoxy, or spiro-fused cycloalkyl, which methanoyl (-COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 2 -C 6 alkoxy, or spiro-fused cycloalkyl is optionally substituted with one or more halogen.
  • Clause 24 The compound of any of Clauses 1-23, wherein at least one of R 7 , R 8 , R 9 , and R 10 is halogen, hydroxyl, C 1 -C 7 alkyl, C 1 -C 7 haloalkyl, C 1 -C 7 alkoxy, or spiro- fused cycloalkyl. [00293] Clause 25.
  • Clause 32 The compound of any of Clauses 1-15 or 30, wherein q, r, s, t, u, v, w, and x are independently 0, 1, or 2.
  • Clause 32 The compound of any of Clauses 1-15 or 30-31, wherein q is 0 or 1, wherein r is 0 or 1, wherein s is 0 or 1, wherein t is 0 or 1, wherein u is 0 or 1, wherein v is 0 or 1, wherein w is 0 or 1, and wherein x is 0 or 1.
  • Clause 33 Clause 33.
  • R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 are independently selected from H, halogen, hydroxy, oxo, methanoyl (-COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, C 1 -C 7 alkoxy, or spiro-fused cycloalkyl, which methanoyl (-COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 2 -C 6 alkoxy, or spiro-fused cycloalkyl is optionally substituted with one or more halogen.
  • Clause 34 The compound of any of Clauses 1-15 or 30-33, wherein one or more of R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 are H, or wherein all of R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 29 , R 29 , and R 30 are H.
  • Clause 35 The compound of any of Clauses 1-15 or 30-34, wherein R 6 is:
  • Clause 36 The compound of any of Clause 1-15 or 30-35, wherein R 6 is:
  • Clause 37 The compound of any of Clauses 1-36, wherein the compound is selected from Compounds 1-107, as listed in Tables 1-9.
  • Clause 38 The compound of any of Clauses 1-37, wherein the compound is selected from Compound 1, Compound 9, Compound 19, Compound 20, Compound 21, Compound 26, Compound 31, Compound 38, Compound 45, Compound 56, Compound 60, Compound 61, Compound 62, Compound 63, Compound 81, Compound 84, Compound 96, Compound 97, and Compound 99.
  • Clause 39 The compound of any of Clauses 1-36, wherein the compound is selected from Compounds 1-107, as listed in Tables 1-9.
  • Clause 40 A composition comprising a compound of any of Clauses 1-39.
  • Clause 41 The composition of Clause 40, wherein the amount of the compound is from about 0.0001% (by weight total composition) to about 99%.
  • Clause 42 The composition of Clause 40, wherein the amount of the compound is from about 0.0001% (by weight total composition) to about 99%.
  • Clause 40 or Clause 41 further comprising a formulary ingredient, an adjuvant, or a carrier.
  • Clause 43 The composition of any of Clauses 40-42, wherein the composition further comprises a BCL2 inhibitor.
  • Clause 44 The composition of any of Clauses 40-42, wherein the composition is used in combination with a second composition comprising a BCL2 inhibitor.
  • Clause 45 The composition of any of Clauses 40-44, wherein the BCL2 comprises venetoclax, or a salt, isomer, derivative or analog thereof.
  • composition of any of Clauses 40-45 wherein the composition is used in combination with one or more chemotherapy, DNA methyltransferase inhibitor/hypomethylating agent, anthracycline, histone deacetylase (HDAC) inhibitor, purine nucleoside analogue (antimetabolite), isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH2) inhibitor, antibody-drug conjugate, mAbs/immunotherapy, CAR-T cell therapy, Plk inhibitor, MEK inhibitor, CDK9 inhibitor, CDK8 inhibitor, retinoic acid receptor agonist, TP53 activator, smoothened receptor antagonist, ERK inhibitor, PI3K inhibitor, mTOR inhibitor, glucocorticoid receptor modulator, or EZH2 inhibitor, or one or more combinations thereof.
  • HDAC histone deacetylase
  • IDH1 and/or IDH2 isocitrate dehydrogenase 1 or 2
  • Clause 47 The composition of any of Clauses 40-46, wherein the DNA methyltransferase inhibitor/hypomethylating agent comprises azacytidine, decitabine, cytarabine, and/or guadecitabine; wherein the anthracycline comprises daunorubicin, idarubicin, doxorubicin, mitoxantrone, epirubicin, and/or CPX-351 (a combination cytarabine and daunorubicin in a fixed 5:1 molar ratio); wherein the histone deacetylase (HDAC) inhibitor comprises vorinostat, panobinostat, valproic acid, and/or pracinostat; wherein the purine nucleoside analogue (antimetabolite) comprises fludarabine, cladribine, and/or clofarabine; wherein the isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH2) inhibitor
  • the mAbs/Immunotherapy comprises Anti-CD70 (e.g. ARGX-110, cusatuzumab), a bispecific antibody (e.g. floteuzumab (CD123 x CD3)), Anti-CTLA4 (e.g. ipilimumab), Anti-PD1/PDL1 (e.g.
  • Anti-CD70 e.g. ARGX-110, cusatuzumab
  • a bispecific antibody e.g. floteuzumab (CD123 x CD3)
  • Anti-CTLA4 e.g. ipilimumab
  • Anti-PD1/PDL1 e.g.
  • the Plk inhibitor comprises volasertib and/or rigosertib; wherein the MEK inhibitor comprises trametinib, cobimetinib, selumetinib, pimasertib, and/or refametinib; wherein the CDK9 inhibitor comprises alvocidib and/or voruciclib; wherein the CDK8 inhibitor comprises SEL120; wherein the retinoic acid receptor agonist comprises ATRA (all-trans retinoic acid) and/or SY-1425 (a selective RAR ⁇ agonist); wherein the TP53 activator comprises APR-246 (Eprenetapopt); wherein the smoothened receptor antagonist comprises glasdegib; wherein the ERK inhibitor comprises an ERK2/
  • Clause 48 A method for providing a subject with a compound comprising one or more administrations of one or more compositions comprising the compound of any of Clauses 1-39, wherein the compositions may be the same or different if there is more than one administration.
  • Clause 49 The method of Clause 48, wherein at least one of the one or more compositions further comprises a formulary ingredient.
  • Clause 50 The method of Clause 48 or Clause 49, wherein at least one of the one or more compositions comprises the composition of any of Clauses 40-47. [00319] Clause 51.
  • Clause 52 The method of any of Clauses 48-51, wherein if there is more than one administration at least one composition used for at least one administration is different from the composition of at least one other administration. [00321] Clause 53.
  • Clause 54 The method of any of Clauses 48-52, wherein the compound of at least one of the one or more compositions is administered to the subject in an amount of from about 0.005 mg/kg subject body weight to about 50 mg /kg subject body weight.
  • Clause 54 The method of any of Clauses 48-53, wherein the subject is a mammal, preferably wherein the subject is a human, a rodent, or a primate.
  • Clause 55 A method for treating a disease or disorder, comprising one or more administrations to a subject of one or more compositions comprising the compound of any of Clauses 1-39, wherein the compositions may be the same or different if there is more than one administration.
  • Clause 56 A method for treating a disease or disorder, comprising one or more administrations to a subject of one or more compositions comprising the compound of any of Clauses 1-39, wherein the compositions may be the same or different if there is more than one administration.
  • Clause 55 wherein the disease or disorder is responsive to at least one of interleukin-1 receptor-associated kinase (IRAK) inhibition or fms-like tyrosine kinase 3 (FLT3) inhibition.
  • IRAK interleukin-1 receptor-associated kinase
  • FLT3 fms-like tyrosine kinase 3
  • Clause 57 The method of Clause 55 or Clause 56, wherein at least one of the one or more compositions further comprises a formulary ingredient.
  • Clause 58 The method of any of Clauses 55-57, wherein at least one of the one or more compositions comprises the composition of any of Clauses 40-47.
  • Clause 59 Clause 59.
  • Clause 60 The method of any of Clauses 55-58, wherein at least one of the one or more administrations comprises parenteral administration, a mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, transdermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration.
  • Clause 60 The method of any of Clauses 55-59, wherein at least one of the one or more administrations comprises an oral administration.
  • Clause 61 The method of any of Clauses 55-60, wherein if there is more than one administration at least one composition used for at least one administration is different from the composition of at least one other administration.
  • Clause 62 The method of any of Clauses 55-60, wherein if there is more than one administration at least one composition used for at least one administration is different from the composition of at least one other administration.
  • Clause 63 The method of any of Clauses 55-62, wherein the subject is a mammal, preferably wherein the subject is a human, a rodent, or a primate.
  • Clause 64 The method of any of Clauses 55-63, wherein the subject is in need of the treatment.
  • Clause 65 The method of any of Clauses 55-64, wherein the method is for treating a hematopoietic cancer.
  • Clause 66 The method of any of Clauses 55-65, wherein the method is for treating a myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML).
  • MDS myelodysplastic syndrome
  • AML acute myeloid leukemia
  • any of Clauses 55-64 wherein the method is for treating at least one cancer selected from glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, Glioma, oral cancer, nasopharyngeal carcinoma, rectal cancer, stomach cancer, and uterine cancer, or one or more inflammatory diseases or autoimmune disease characterized by overactive IRAK1 and/or IRAK4, or combinations thereof.
  • Clause 69 The method of Clause 68, wherein the method is for treating one or more inflammatory diseases or autoimmune disease selected from chronic inflammation (i.e., associated with viral and bacterial infection), sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, or combinations thereof.
  • chronic inflammation i.e., associated with viral and bacterial infection
  • sepsis rheumatoid arthritis
  • systemic lupus erythematosus inflammatory bowel disease
  • multiple sclerosis multiple sclerosis
  • psoriasis psoriasis
  • Sjögren’s syndrome Ankylosing spondylitis
  • systemic sclerosis Type 1 diabetes mellitus, or combinations thereof.
  • Clause 72 The method of Clause 71, wherein the method further comprises administration of a composition comprising a BTK inhibitor.
  • Clause 73 The method of Clause 71, wherein the BTK inhibitor comprises ibrutinib.
  • Clause 74 The method of any of Clauses 55-73, wherein the subject is susceptible to AML and/or MDS, and/or wherein the method prevents or ameliorates future AML and/or MDS. [00343] Clause 75.
  • Clause 76 The method of any of Clauses 55-74, wherein the method occurs after one or more of having myelodysplastic syndrome, having myeloproliferative disease, an occurrence of chemical exposure, an exposure to ionizing radiation, or a treatment for cancer.
  • Clause 76 The method of any of Clauses 55-74, wherein the method further comprises administration of a composition comprising a BCL2 inhibitor, or wherein at least one of said compositions comprising the compound of any of Clauses 1-39 further comprises a BCL2 inhibitor.
  • Clause 77 Clause 77.
  • Clauses 55-76 wherein the compound of any of Clauses 1-39 and the BCL2 inhibitor may be administered together or separately, in one or more administrations of one or more compositions.
  • Clause 78 The method of any of Clauses 55-77, wherein the BCL2 inhibitor comprises venetoclax, or a salt, isomer, derivative or analog thereof.
  • Clause 79 The method of any of Clauses 55-77, wherein the BCL2 inhibitor comprises venetoclax, or a salt, isomer, derivative or analog thereof.
  • any of Clauses 55-78 wherein the method further comprises administration of one or more additional therapy selected from one or more chemotherapy, DNA methyltransferase inhibitor/hypomethylating agent, anthracycline, histone deacetylase (HDAC) inhibitor, purine nucleoside analogue (antimetabolite), isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH2) inhibitor, antibody-drug conjugate, mAbs/immunotherapy, CAR-T cell therapy, Plk inhibitor, MEK inhibitor, CDK9 inhibitor, CDK8 inhibitor, retinoic acid receptor agonist, TP53 activator, smoothened receptor antagonist, ERK inhibitor, PI3K inhibitor, mTOR inhibitor, glucocorticoid receptor modulator, or EZH2 inhibitor, or one or more combinations thereof.
  • additional therapy selected from one or more chemotherapy, DNA methyltransferase inhibitor/hypomethylating agent, anthracycline, histone deacetylase (HDAC
  • Clause 80 The method of any of Clauses 55-79, wherein the DNA methyltransferase inhibitor/hypomethylating agent comprises azacytidine, decitabine, cytarabine, and/or guadecitabine; wherein the anthracycline comprises daunorubicin, idarubicin, doxorubicin, mitoxantrone, epirubicin, and/or CPX-351 (a combination cytarabine and daunorubicin in a fixed 5:1 molar ratio); wherein the histone deacetylase (HDAC) inhibitor comprises vorinostat, panobinostat, valproic acid, and/or pracinostat; wherein the purine nucleoside analogue (antimetabolite) comprises fludarabine, cladribine, and/or clofarabine; wherein the isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH2) inhibitor
  • the mAbs/Immunotherapy comprises Anti-CD70 (e.g. ARGX-110, cusatuzumab), a bispecific antibody (e.g. floteuzumab (CD123 x CD3)), Anti-CTLA4 (e.g. ipilimumab), Anti-PD1/PDL1 (e.g.
  • Anti-CD70 e.g. ARGX-110, cusatuzumab
  • a bispecific antibody e.g. floteuzumab (CD123 x CD3)
  • Anti-CTLA4 e.g. ipilimumab
  • Anti-PD1/PDL1 e.g.
  • the Plk inhibitor comprises volasertib and/or rigosertib; wherein the MEK inhibitor comprises trametinib, cobimetinib, selumetinib, pimasertib, and/or refametinib; wherein the CDK9 inhibitor comprises alvocidib and/or voruciclib; wherein the CDK8 inhibitor comprises SEL120; wherein the retinoic acid receptor agonist comprises ATRA (all-trans retinoic acid) and/or SY-1425 (a selective RAR ⁇ agonist); wherein the TP53 activator comprises APR-246 (Eprenetapopt); wherein the smoothened receptor antagonist comprises glasdegib; wherein the ERK inhibitor comprises an ERK2/
  • Clause 81 A compound according to any one of Clauses 1-39, for use in a method for treating a disease or disorder, the method comprising inhibiting at least one of IRAK and FLT3 by administering one or more compositions comprising the compound, wherein the compositions may be the same or different if there is more than one administration.
  • Clause 82 The compound of Clause 81, wherein the disease or disorder is responsive to at least one of interleukin-1 receptor-associated kinase (IRAK) inhibition or fms-like tyrosine kinase 3 (FLT3) inhibition.
  • IRAK interleukin-1 receptor-associated kinase
  • FLT3 fms-like tyrosine kinase 3
  • Clause 81 or Clause 82 wherein at least one of the one or more compositions further comprises a formulary ingredient.
  • Clause 84 The compound of any of Clauses 81-83, wherein at least one of the one or more compositions comprises the composition of any of Clauses 40-47.
  • Clause 85 The compound of any of Clauses 81-84, wherein at least one of the one or more administrations comprises parenteral administration, a mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, transdermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration.
  • Clause 86 Clause 86.
  • Clause 87 The compound of any of Clauses 81-86, wherein at least one of the one or more administrations comprises an oral administration.
  • Clause 87 The compound of any of Clauses 81-86, wherein if there is more than one administration at least one composition used for at least one administration is different from the composition of at least one other administration.
  • Clause 88 The compound of any of Clauses 81-87, wherein the compound of at least one of the one or more compositions is administered to the subject in an amount of from about 0.005 mg/kg subject body weight to about 50 mg /kg subject body weight.
  • Clause 89 Clause 89.
  • Clause 90 The compound of any of Clauses 81-88, wherein the subject is a mammal, preferably wherein the subject is a human, a rodent, or a primate.
  • Clause 90 The compound of any of Clauses 81-89, wherein the subject is in need of the treatment.
  • Clause 91 The compound of any of Clauses 81-90, wherein the method is for treating a hematopoietic cancer.
  • Clause 92 The compound of any of Clauses 81-91, wherein the method is for treating MDS and/or AML.
  • Clause 93 The compound of any of Clauses 81-91, wherein the method is for treating MDS and/or AML.
  • CLL chronic lymphocytic leukemia
  • CML chronic myeloid leukemia
  • ALL acute lymphoblastic leukemia
  • bone marrow cancer non- Hodgkin lymphoma
  • Waldenstrom’s macroglobulinemia B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL with MYD88 mutation, follicular lymphoma, or marginal zone lymphoma
  • glioblastoma multiforme endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblasto
  • Clause 95 The compound of Clause 94, wherein the method is for treating one or more inflammatory diseases or autoimmune disease selected from chronic inflammation (i.e., associated with viral and bacterial infection), sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, or combinations thereof.
  • chronic inflammation i.e., associated with viral and bacterial infection
  • sepsis rheumatoid arthritis
  • systemic lupus erythematosus inflammatory bowel disease
  • multiple sclerosis multiple sclerosis
  • psoriasis psoriasis
  • Sjögren’s syndrome Ankylosing spondylitis
  • systemic sclerosis Type 1 diabetes mellitus, or combinations thereof.
  • Clause 101 The compound of any of Clauses 81-93, wherein the method is for treating DLBCL, and wherein the DLBCL comprises a L265P MYD88 mutant (ABC) subtype of DLBCL.
  • Clause 98 The compound of Clause 97, wherein the method further comprises administration of a composition comprising a BTK inhibitor.
  • Clause 99 The compound of Clause 98, wherein the BTK inhibitor comprises ibrutinib.
  • Clause 100 The compound of any of Clauses 81-99, wherein the subject is susceptible to AML and/or MDS, and/or wherein the method prevents or ameliorates future AML and/or MDS. [00369] Clause 101.
  • Clause 102 The compound of any of Clauses 81-101, wherein the method further comprises administration of a composition comprising a BCL2 inhibitor, or wherein at least one of said compositions comprising the compound of any of claims 1-39 further comprises a BCL2 inhibitor.
  • Clause 103 Clause 103.
  • Clause 104 The compound of any of Clauses 81-103, wherein the BCL2 inhibitor comprises venetoclax, or a salt, isomer, derivative or analog thereof.
  • Clause 105 The compound of any of Clauses 81-102, wherein the compound of any of claims 1-39 and the BCL2 inhibitor may be administered together or separately, in one or more administrations of one or more compositions.
  • the compound of any of Clauses 81-104 wherein the method further comprises administration of one or more additional therapy selected from one or more chemotherapy, DNA methyltransferase inhibitor/hypomethylating agent, anthracycline, histone deacetylase (HDAC) inhibitor, purine nucleoside analogue (antimetabolite), isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH2) inhibitor, antibody-drug conjugate, mAbs/immunotherapy, CAR-T cell therapy, Plk inhibitor, MEK inhibitor, CDK9 inhibitor, CDK8 inhibitor, retinoic acid receptor agonist, TP53 activator, smoothened receptor antagonist, ERK inhibitor, PI3K inhibitor, mTOR inhibitor, glucocorticoid receptor modulator, or EZH2 inhibitor, or one or more combinations thereof.
  • additional therapy selected from one or more chemotherapy, DNA methyltransferase inhibitor/hypomethylating agent, anthracycline, histone deacety
  • Clause 106 The compound of any of Clauses 81-105, wherein the DNA methyltransferase inhibitor/hypomethylating agent comprises azacytidine, decitabine, cytarabine, and/or guadecitabine; wherein the anthracycline comprises daunorubicin, idarubicin, doxorubicin, mitoxantrone, epirubicin, and/or CPX-351 (a combination cytarabine and daunorubicin in a fixed 5:1 molar ratio); wherein the histone deacetylase (HDAC) inhibitor comprises vorinostat, panobinostat, valproic acid, and/or pracinostat; wherein the purine nucleoside analogue (antimetabolite) comprises fludarabine, cladribine, and/or clofarabine; wherein the isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH
  • the mAbs/Immunotherapy comprises Anti-CD70 (e.g. ARGX-110, cusatuzumab), a bispecific antibody (e.g. floteuzumab (CD123 x CD3)), Anti-CTLA4 (e.g. ipilimumab), Anti-PD1/PDL1 (e.g.
  • Anti-CD70 e.g. ARGX-110, cusatuzumab
  • a bispecific antibody e.g. floteuzumab (CD123 x CD3)
  • Anti-CTLA4 e.g. ipilimumab
  • Anti-PD1/PDL1 e.g.
  • the Plk inhibitor comprises volasertib and/or rigosertib; wherein the MEK inhibitor comprises trametinib, cobimetinib, selumetinib, pimasertib, and/or refametinib; wherein the CDK9 inhibitor comprises alvocidib and/or voruciclib; wherein the CDK8 inhibitor comprises SEL120; wherein the retinoic acid receptor agonist comprises ATRA (all-trans retinoic acid) and/or SY-1425 (a selective RAR ⁇ agonist); wherein the TP53 activator comprises APR-246 (Eprenetapopt); wherein the smoothened receptor antagonist comprises glasdegib; wherein the ERK inhibitor comprises an ERK2/
  • R 1 is selected from H, halogen, hydroxy, oxo, -CN, amido, methanoyl (-COH), carboxy (- CO 2 H), C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 1 -C 7 heteroalkyl, C 1 -C 7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl, wherein the amido, methanoyl (-COH), carboxy (-CO 2 H), C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 1 -C 7 alkoxy, cycloal
  • Clause 202 The compound of clause 201, wherein the compound of Formula (I) is a compound of Formula (IIf) Formula (IIf), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: R 20f is selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and -O-(C 3 - C 6 cycloalkyl), wherein C 1 -C 6 alkyl and C 1 -C 6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, and wherein C 3 -C 6 cycloalkyl and -O-(C 3 -C 6 cycloalkyl) are each optionally substituted with one or more substituents selected from C 1 -C 6 alkyl and halogen; R 21f , R 22f
  • Clause 203 The compound of clause 202, wherein one or more of R 24fa , R 24fb , R 25fa , R 25fb , R 26fa , and R 26fb is independently selected from halogen, -OH, optionally substituted C 1 -C 6 alkyl, and optionally substituted C 1 -C 6 alkoxy.
  • Clause 204 The compound of clause 202 or 203, wherein R 20f is H.
  • Clause 205 Clause 205.
  • the compound of Formula (I) is a compound of Formula (IIg) formula (IIg), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: R 20g is selected from H and C 1 -C 6 alkoxy; R 21g is selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, -O-(C 6 -C 12 aryl), C 3 -C 9 heterocyclyl, and -NR 28ga R 28gb , wherein C 1 -C 6 alkyl and C 1 -C 6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, wherein C 3 - C 6 cycloalkyl is optionally substituted with one or more substituents selected from C 1 -C 6 alkyl and halogen, and wherein: R 20g is selected from
  • Clause 208 The compound of clause 207, wherein one or more of R 25ga , R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb is independently selected from halogen, -OH, optionally substituted C 1 -C 6 alkyl, and optionally substituted C 1 -C 6 alkoxy.
  • Clause 209 The compound of clause 207 or 208, wherein R 20g is H.
  • Clause 210 Clause 210.
  • R 20g is selected from -OCH 3 and ;
  • R 21g is selected from t-butyl, unsubstituted C 3 cycloalkyl, morpholinyl, azetidinyl, piperdinyl, isoxazolyl, Cl, -CF 3 , -OCH 3 , -O-phenyl, , , , , wherein G is N or CH, and wherein c is 1 or 2;
  • R 21g is wherein R29g is selected from H, isopropyl, unsubstituted C 3 cycloalkyl, azetidinyl, tetrahydropyranyl -CH 3 , , and ;
  • R 21g is -NR 28ga R 28gb wherein R 28ga is H and R 28gb
  • Clause 212 The compound of clause 201, wherein the compound of Formula (I) is a compound of Formula (IIh) Formula (IIh), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: R 20h is selected from H and C 1 -C 6 alkoxy; R 21h is selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and C 3 -C 9 heterocyclyl, wherein C 1 - C 6 alkyl is optionally substituted with one or more substituents selected from -OH and halogen and wherein C 3 -C 6 cycloalkyl, and C 3 -C 9 heterocyclyl are each optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, -OH, and halogen; R 22ha , R 22hb , R 23ha , and R 23hb are each independently selected from
  • Clause 213. The compound of clause 212, wherein at least one of (i)-(iv) applies: (i) R 20h is H; (ii) R 21h is ; (iii) R 22ha , R 22hb , R 23ha , and R 23hb are each H; (iii) R 24h , R 25h , and R 26h are each H. [00388] Clause 214. The compound of clause 212 or 213, wherein the compound is . [00389] Clause 215.
  • the compound of Formula (I) is a compound of Formula (IIi) Formula (IIi), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: is selected from and ; R 20i is selected from H, and C 1 -C 6 alkoxy; R 21i is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and C 3 -C 9 heterocyclyl, wherein C 1 -C 6 alkyl and C 1 -C 6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, wherein C 3 -C 6 cycloalkyl is optionally substituted with one or more substituents selected from C 1 -C 6 alkyl and halogen, and wherein C 3 -C 9 heterocycyl is optionally substituted with one or more substituent
  • Clause 216 The compound of clause 215, wherein one or more of R 25ia , R 25ib , R 26ia , R 26ib , R 27ia , R 27ib , R 28ia , R 28ib , R 29ia , and R 29ib is independently selected from halogen, - OH, and C 1 -C 6 alkyl.
  • Clause 217 The compound of clause 215, wherein each of R 25ia , R 25ib , R 26ia , R 26ib , R 27ia , R 27ib , R 28ia , R 28ib , R 29ia , and R 29ib is H.
  • Clause 220 The compound of clause 201, wherein the compound of Formula (I) is a compound of Formula (IIj) Formula (IIj), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: is selected from , , ; R 20j is selected from H, and C 1 -C 6 alkoxy; R 21j is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and C 3 -C 6 cycloalkyl, wherein C 1 -C 6 alkyl and C 1 -C 6 alkoxy are each optionally substituted with one or more substituents selected from halogen and -OH, and wherein C 3 -C 6 cycloalkyl is optionally substituted with one or more substituents selected from C 1 -C 6 alkyl and halogen; and R 22j , R 23j , and R 24j are each independently selected from H
  • Clause 224 The compound of clause 223, wherein at least one of (i)-(iv) applies: (i) R 30q is H; (ii) R 31q is selected from , , wherein d is 1 or 2, and wherein K is N or CH; (iii) R 31q is wherein R 35q is selected from H, -CH 3 , isopropyl, phenyl, azetidinyl, and tetrahydropyranyl; (iv) R 32q , R 33q , and R 34q are each H. [00400] Clause 225. The compound of clause 223 or 224, wherein the compound is selected from:
  • Clause 226 The compound of clause 201, wherein the compound of Formula (I) is a compound of Formula (IIIr) Formula (IIIr), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: R 30r is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and C 3 -C 9 heterocyclyl, wherein C 1 -C 6 alkyl and C 1 -C 6 alkoxy are each optionally substituted with one or more substituents selected from -OH and halogen, wherein C 3 -C 6 cycloalkyl is optionally substituted with one or more substituents selected from C 1 -C 6 alkyl and halogen, and wherein C 3 -C 9 heterocycyl is optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, C 3 -C 9 heterocy
  • Clause 230 The compound of clause 229, wherein at least one of (i)-(iv) applies: (i) R 30s is H; (ii) R 31s is selected from wherein M is N or CH and ; (iii) R 31s is wherein R 35s is selected from H, -CH 3 , isopropyl, phenyl, azetidinyl, and tetrahydropyranyl; (iv) R 32s , R 33s , and R 34s are each H. [00406] Clause 231. The compound of clause 229 or 230, wherein the compound is selected from:
  • Clause 232 The compound of any one of clauses 201-231, wherein the compound is an inhibitor of at least one of IRAK1, IRAK4, and FLT3.
  • Clause 233 The compound of any one of clauses 201-132, wherein the compound is an inhibitor of at least two of IRAK1, IRAK4, and FLT3.
  • Clause 234 The compound of any one of clauses 201-233, wherein the compound is an inhibitor of IRAK1 and IRAK4.
  • Clause 235 The compound of any one of clauses 201-234, wherein the compound is an inhibitor of IRAK1, IRAK4, and FLT3.
  • Clause 236 The compound of any one of clauses 201-231, wherein the compound is an inhibitor of at least one of IRAK1, IRAK4, and FLT3.
  • Clause 240 The composition of clause 239, wherein the composition is used in combination with a BCL2 inhibitor.
  • BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof.
  • Clause 242. A method of treating a disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of clauses 201-237 or a composition of any one of clauses 238-241.
  • Clause 243 Clause 243.
  • Clause 242 wherein the method comprises administering to the subject a composition comprising the therapeutically effective amount of the compound of clause 201 and a formulary ingredient, an adjuvant, or a carrier.
  • Clause 244 The method of clause 242 or 243, wherein the disease or disorder is responsive to at least one of interleukin-1 receptor-associated kinase (IRAK) inhibition and fms-like tyrosine kinase 3 (FLT3) inhibition.
  • IRAK interleukin-1 receptor-associated kinase
  • FLT3 fms-like tyrosine kinase 3
  • Clause 246 The method of any one of clauses 242-245, wherein the administration comprises parenteral administration, a mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration.
  • Clause 246 The method of any one of clauses 242-245, wherein the compound is administered to the subject in an amount of from about 0.005 mg/kg subject body weight to about 1,000 mg /kg subject body weight.
  • Clause 247 The method of any one of clauses 242-246, wherein the disease or disorder comprises a hematopoietic cancer.
  • Clause 248 Clause 248.
  • the disease or disorder comprises myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML).
  • MDS myelodysplastic syndrome
  • AML acute myeloid leukemia
  • Clause 249. The method of any one of clauses 242-246, wherein the disease or disorder comprises lymphoma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), bone marrow cancer, non- Hodgkin lymphoma, Waldenstrom’s macroglobulinemia, B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL with MYD88 mutation, follicular lymphoma, or marginal zone lymphoma.
  • CLL chronic lymphocytic leukemia
  • CML chronic myeloid leukemia
  • ALL acute lymphoblastic leukemia
  • bone marrow cancer non- Hodgkin lymphoma
  • Clause 250 The method of any one of clauses 242-246, wherein the disease or disorder comprises at least one cancer selected from glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblastoma, ovarian cancer, renal cell carcinoma, hepatocellular carcinoma, colon cancer, pancreatic cancer, rhabdomyosarcoma, meningioma, gastric cancer, Glioma, oral cancer, nasopharyngeal carcinoma, rectal cancer, stomach cancer, and uterine cancer, or one or more inflammatory diseases or autoimmune disease characterized by overactive IRAK1 and/or IRAK4, or combinations thereof.
  • the disease or disorder comprises at least one cancer selected from glioblastoma multiforme, endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma
  • Clause 251 The method of any one of clauses 242-246, wherein the disease or disorder comprises one or more inflammatory diseases or autoimmune disease selected from chronic inflammation, sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, or combinations thereof.
  • inflammatory diseases or autoimmune disease selected from chronic inflammation, sepsis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjögren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, or combinations thereof.
  • the disease or disorder comprises: (i) MDS, MDS with a splicing factor mutation, MDS with a mutation in isocitrate dehydrogenase 1, MDS with a mutation in isocitrate dehydrogenase 2; or (ii) AML with a splicing factor mutation, AML having enhanced IRAK4-Long expression and/or activity relative to IRAK4-Short, and/or wherein the AML is not driven by FLT3 mutations but expresses IRAK4-Long. [00428] Clause 253.
  • the MDS with a splicing factor mutation comprises MDS with a splicing factor mutation in U2AF1 or SF3B1 and the AML splicing factor mutation comprises AML with a splicing factor mutation in U2AF1 or SF3B1.
  • the disease or disorder comprises DLBCL
  • the DLBCL comprises a L265P MYD88 mutant (ABC) subtype of DLBCL or a S219C MYD88 mutant (GCB) subtype of DLBCL.
  • any one of clauses 242-254 further comprising administering to the subject one or more additional therapies selected from: a chemotherapy agent, a BCL2 inhibitor, an immune modulator, a BTK inhibitor, a DNA methyltransferase inhibitor/hypomethylating agent, an anthracycline, a histone deacetylase (HDAC) inhibitor, a purine nucleoside analogue (antimetabolite), an isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH2) inhibitor, an antibody-drug conjugate, an mAbs/immunotherapy, a Plk inhibitor, a MEK inhibitor, a CDK inhibitor, a CDK9 inhibitor, a CDK8 inhibitor, a retinoic acid receptor agonist, a TP53 activator, a CELMoD, a smoothened receptor antagonist, an ERK inhibitor including an ERK2/MAPK1 or ERK1/MAPK3 inhibitor, a PI3K inhibitor, an ERK inhibitor
  • Clause 256 The method of clause 255, wherein the additional therapy is a BCL2 inhibitor.
  • Clause 257 The method of clause 256, wherein the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof.
  • Clause 258 The method of any one of clauses 242-257, wherein the disease or disorder is a BCL2 inhibitor resistant disease or disorder.
  • Clause 259. The method of any one of clauses 242-257, wherein the disease or disorder is a venetoclax resistant disease or disorder.
  • Clause 260 The method of any one of clauses 242-257, wherein the disease or disorder is a FLT3 inhibitor resistant disease or disorder.
  • Clause 261 The method of any one of clauses 242-257, wherein the disease or disorder is BCL2 inhibitor resistant acute myeloid leukemia (AML). [00437] Clause 262. The method of any one of clauses 242-257, wherein the disease or disorder is venetoclax resistant acute myeloid leukemia (AML). [00438] Clause 263. The method of any one of clauses 242-257, wherein the disease or disorder is FLT3 inhibitor resistant acute myeloid leukemia (AML). [00439] Clause 264. The method of any one of clauses 242-257, wherein the disease or disorder is BCL2 inhibitor resistant refractory acute myeloid leukemia (AML). [00440] Clause 265.
  • Clause 266 The method of any one of clauses 242-257, wherein the disease or disorder is FLT3 inhibitor resistant refractory acute myeloid leukemia (AML).
  • Clause 267 The method of any one of clauses 242-257, wherein the disease or disorder is BCL2 inhibitor resistant relapsed acute myeloid leukemia (AML).
  • Clause 268 The method of any one of clauses 242-257, wherein the disease or disorder is venetoclax resistant relapsed acute myeloid leukemia (AML).
  • Clause 269. The method of any one of clauses 242-257, wherein the disease or disorder is FLT3 inhibitor resistant relapsed acute myeloid leukemia (AML).
  • AML FLT3 inhibitor resistant relapsed acute myeloid leukemia
  • Clause 270. The method of clause 255, wherein the compound of any one of clauses 201-237 or the composition of any one of clauses 238-241 and the one or more additional therapies are administered together in one administration or composition.
  • Clause 271. The method of clause 255, wherein the compound of any one of clauses 201-237 or the composition any one of clauses 238-241 and the one or more additional therapies are administered separately in more than one administration or more than one composition.
  • c-Bu cyclobutyl
  • c-Pr cyclopropyl
  • Cy cyclohexyl
  • DAST (diethylamino)sulfur trifluoride
  • dba dibenzylideneacetone
  • DCM dichloromethane
  • DIAD diisopropylazodicarboxylate
  • DIBAL, DIBAL-H diisobutylaluminum hydride
  • DIEA diisopropylethylamine
  • DME 1,2-dimethoxyethane
  • DMEM Dulbecco’s modified eagle medium
  • DMAP 4-dimethylaminopyridine
  • DMF N,N- dimethylformamide
  • DMSO dimethylsulfoxide; eq.
  • EDC N-[3- (dimethylamino)propyl]-N-ethylcarbodiimide
  • EDTA ethylenediaminetetraacetic acid
  • ESI electrospray ionization
  • Et ethyl
  • EtOAc ethyl acetate
  • EtOH ethanol
  • FBS Fetal Bovine Serum
  • h, hr hour
  • HATU N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1- ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide
  • HOAc acetic acid
  • HOAt 3H-[1,2,3]-triazolo[4,5-b]pyridin-3-ol
  • HOBt 1H-benzotriazol-1-ol
  • HPLC High pressure liquid chromatography
  • HTRF homogenous time resolved fluor
  • TBAF tetrabutylammonium fluoride
  • TBAI tetrabutylammonium iodide
  • t-Bu tert-butyl
  • TFA trifluoroacetic acid
  • THF tetrahydrofuran
  • TLC thin layer chromatography
  • prep TLC preparative thin layer chromatography
  • Tosyl toluenesulfonyl
  • OTf trifluoromethanesulfonate
  • triflic trifluoromethanesulfonic
  • Xantphos 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene
  • XPhos Pd G2 or XPhos-PD-G2 chloro(2- dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1’
  • the mobile phase was a mixture of acetonitrile (0.025% TFA) and H 2 O (0.05% TFA), with temperature maintained at 50 °C. Purity of final compounds was determined to be >95% using a 3 ⁇ L injection with quantitation by AUC at 220 and 254 nm (Agilent Diode Array Detector).
  • Example 1 Exemplary Synthetic Procedure #1 (Compounds 1 – 8) Compound 1, N-((3S,4S)-4-fluoropyrrolidin-3-yl)-6-(6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2- b]pyridazin-3-yl)pyridin-2-amine Step A.3-(6-bromo-2-pyridyl)-6-chloro-imidazo[1,2-b]pyridazine [00458] A mixture of 2,6-dibromopyridine (23.14 g, 97.68 mmol), 6- chloroimidazo[1,2-b]pyridazine (5.00 g, 32.6 mmol), potassium acetate (6.39 g, 65.1 mmol), and tetrakis(triphenylphosphine)palladium(0) (3.76 g, 3.26 mmol) in xylene (150 mL) was degassed and
  • reaction mixture was then cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (2 x 15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • Step C tert-butyl (3S,4S)-3-fluoro-4-[[6-[6-(1-methylpyrazol-4-yl)imidazo[1,2-b]pyridazin-3- yl]-2-pyridyl]amino]pyrrolidine-1-carboxylate
  • Example 2 Exemplary Synthetic Procedure #2 (Compounds 9 – 19) Compound 9, N-((3S,4S)-4-fluoropyrrolidin-3-yl)-6-(6-(pyrazolo[1,5-a]pyridin-3- yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-amine Step A.
  • reaction mixture was then cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (2 x 15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • Step B tert-butyl (3S,4S)-3-fluoro-4-[[6-(6-pyrazolo[1,5-a]pyridin-3-ylimidazo[1,2-b]pyridazin- 3-yl)-2-pyridyl]amino]pyrrolidine-1-carboxylate
  • a mixture of tert-butyl (3S,4S)-3-[[6-(6-chloroimidazo[1,2-b]pyridazin-3- yl)-2-pyridyl]amino]-4-fluoro-pyrrolidine-1-carboxylate (0.120 g, 0.277 mmol), 3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (0.074 g, 0.305 mmol), chloro(2- dicyclohexylphosphino-2',4',6'-trifluoro
  • a mixture of tert-butyl (3S,4S)-4-[[6-(6-chloroimidazo[1,2-b]pyridazin-3- yl)-2-pyridyl]amino]-3-fluoro-piperidine-1-carboxylate (0.100 g, 0.224 mmol), 3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (0.055 g, 0.224 mmol), chloro(2- dicyclohexylphosphino-2',4',6'-triisopropy
  • Example 4 Exemplary Synthetic Procedure #4 (Compounds 21 – 53) Compound 21, N-(4,4-difluoropyrrolidin-3-yl)-6-(6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2- b]pyridazin-3-yl)pyridin-2-amine Step A.3-(6-bromopyridin-2-yl)-6-chloroimidazo[1,2-b]pyridazine [00470] To a heavy-walled sealable flask equipped with a magnetic stir bar were added 6-chloroimidazo[1,2-b]pyridazine (1.00 g, 6.51 mmol), 2,6-dibromopyridine (2.31 g, 9.77 mmol), triphenylphosphine (0.171 g, 0.651 mmol), potassium carbonate (2.70 g, 19.54 mmol), palladium (II) acetate (0.073 g, 0.326
  • the vessel was sealed with a teflon screw cap and warmed to 100 oC. After 18 hours, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (2 x 10 mL), filtered through silica, and concentrated under reduced pressure.
  • tert-butyl 4-((6-(6-chloroimidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)amino)-3,3- difluoropyrrolidine-1-carboxylate [00471] To a heavy-walled sealable flask equipped with a magnetic stir bar were added 3-(6-bromopyridin-2-yl)-6-chloroimidazo[1,2-b]pyridazine (0.741 g, 2.39 mmol), tert-butyl 4-amino-3,3-difluoropyrrolidine-1-carboxylate (0.532 g, 2.39 mmol), RuPhos Pd G3 (0.200 g, 0.239 mmol), and cesium carbonate (2.34 g, 7.18 mmol), in that order.
  • the vessel was sealed with a rubber septum and flushed with nitrogen for 30 minutes. Tetrahydrofuran (15 mL, dried and stored over 4 ⁇ molecular sieves, deoxygenated via sparging with nitrogen for 30 minutes) was then added via syringe. The septum was removed, and the flask was quickly sealed with a teflon screwcap. The reaction mixture was warmed to 90 oC for 15 hours, then cooled to room temperature, diluted with ethyl acetate (2 x 25 mL), filtered through silica, and concentrated under reduced pressure.
  • tert-butyl 3,3-difluoro-4-((6-(6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3- yl)pyridin-2-yl)amino)pyrrolidine-1-carboxylate [00472] To a microwave vial equipped with a stir bar were added tert-butyl 4-((6- (6-chloroimidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)amino)-3,3-difluoropyrrolidine-1- carboxylate (0.088 g, 0.196 mmol)), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-pyrazole (0.081 g, 0.392 mmol), and XPhos Pd G2 (0.022 g, 0.029 mmol).
  • the vessel was sealed with a pressure release cap and purged with nitrogen for 30 minutes.
  • Aqueous potassium phosphate tribasic solution 1.0 M, 0.783 mL, 0.783 mmol, deoxygenated via sparging with nitrogen for 30 minutes
  • tetrahydrofuran 1.5 mL, dried and stored over 4 ⁇ molecular sieves, deoxygenated via sparging with nitrogen for 30 minutes
  • the reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure.
  • Step D N-(4,4-difluoropyrrolidin-3-yl)-6-(6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2- b]pyridazin-3-yl)pyridin-2-amine
  • tert-butyl 3,3-difluoro-4-((6-(6-(1-methyl- 1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)amino)pyrrolidine-1-carboxylate (0.166 g, 0.335 mmol), dichloromethane (2.0 mL), and trifluoroacetic acid (1.0 mL).
  • the vessel was sealed with a pressure release cap and flushed with nitrogen for 30 minutes.
  • Tetrahydrofuran (3 mL, dried and stored over 4 ⁇ molecular sieves, deoxygenated via sparging with nitrogen for 30 minutes) was added and the reaction warmed to 90 oC. After 18 hours the reaction was then cooled to room temperature, diluted with ethyl acetate (2 x 5 mL), filtered through silica, and concentrated under reduced pressure.
  • the vessel was sealed with a pressure release cap and flushed with nitrogen for 30 minutes.
  • Aqueous potassium phosphate tribasic solution 1.0 M, 0.790 milliliters, 0.790 mmol, deoxygenated via sparging with nitrogen for 30 minutes
  • tetrahydrofuran 1.0 mL, dried and stored over 4 ⁇ molecular sieves, deoxygenated via sparging with nitrogen for 30 minutes
  • the reaction mixture was then cooled to room temperature, diluted with ethyl acetate (5 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure.
  • Step C N-(4,4-difluoropyrrolidin-3-yl)-6-(6-(pyrazolo[1,5-b]pyridazin-3-yl)imidazo[1,2- b]pyridazin-3-yl)pyridin-2-amine
  • tert-butyl 4-((6-(6-chloroimidazo[1,2- b]pyridazin-3-yl)pyridin-2-yl)amino)-3,3-difluoropyrrolidine-1-carboxylate 0.049 g, 0.108 mmol
  • dichloromethane 2.0 mL
  • trifluoroacetic acid 1.0 mL
  • Example 7 Exemplary Synthetic Procedure #7 (Compounds 69 – 80) Compound 69, 6-(6-cyclopropylimidazo[1,2-b]pyridazin-3-yl)-N-((3S,4S)-4-fluoropyrrolidin-3- yl)pyridin-2-amine Step A.6-cyclopropylimidazo[1,2-b]pyridazine [00480] To a heavy-walled sealable flask equipped with a magnetic stir bar were added 6-cyclopropylpyridazin-3-amine (2.50 g, 18.5 mmol), sodium bicarbonate (3.88 g, 46.2 mmol), ethanol (75 mL), and 2-chloroacetaldehyde (7.20 mL, 48.4 mmol, 45% weight in H 2 O).
  • the vessel was sealed with a teflon screwcap and the reaction mixture warmed to 90 °C. After 8 hours the reaction mixture was cooled to room temperature, filtered through silica, poured into water (20 mL), and extracted with ethyl acetate (2 x 20 mL). The organic extracts were combined, washed with saturated aqueous sodium chloride solution (2 x 20 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure.
  • Step B.3-(6-bromopyridin-2-yl)-6-cyclopropylimidazo[1,2-b]pyridazine [00481] To a heavy-walled sealable flask equipped with a magnetic stir bar were added 6-cyclopropylimidazo[1,2-b]pyridazine (0.118 g, 0.739 mmol), 2,6-dibromopyridine (0.263 g, 1.11 mmol), triphenylphosphine (0.019 g, 0.074 mmol), potassium carbonate (0.307 g, 2.22 mmol), palladium (II) acetate (0.008 g, 0.037 mmol), 1,4-dioxane (2.0 mL), and ethanol (1.0 mL).
  • the flask was sealed with a teflon screwcap, and the reaction mixture warmed to 100 oC for 9 hours.
  • the reaction mixture was then cooled to room temperature, diluted with ethyl acetate (30 mL), filtered through silica, and concentrated under reduced pressure.
  • the vessel was sealed with a pressure relief cap and flushed with nitrogen for 30 minutes. Tetrahydrofuran (1.0 mL, dried and stored over 4 ⁇ molecular sieves, deoxygenated via sparging with nitrogen for 30 minutes) was added, and the resulting reaction mixture warmed to 90 oC. After 9 hours the reaction mixture was cooled to room temperature, diluted with ethyl acetate (2 x 5 mL), filtered through silica, and concentrated under reduced pressure.
  • Step D 6-(6-cyclopropylimidazo[1,2-b]pyridazin-3-yl)-N-((3S,4S)-4-fluoropyrrolidin-3- yl)pyridin-2-amine
  • tert-butyl (3S,4S)-3-((6-(6- cyclopropylimidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)amino)-4-fluoropyrrolidine-1-carboxylate 0.025 g, 0.058 mmol
  • dichloromethane 1.0 mL
  • trifluoroacetic acid 1.0 mL
  • Example 8 Exemplary Synthetic Procedure #8 (Compounds 81 – 86) Compound 81, (R)-6-(7-methoxy-6-(1-(trifluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazin-3- yl)-N-(pyrrolidin-3-yl)pyridin-2-amine Step A.6-chloro-4-methoxy-3-[1-(trifluoromethyl)vinyl]pyridazine [00485] A mixture of 3,6-dichloro-4-methoxy-pyridazine (8.47 g, 47.3 mmol), 4,4,6-trimethyl-2-[1-(trifluoromethyl)vinyl]-1,3,2-dioxaborinane (7.00 g, 31.5 mmol), cesium carbonate (25.68 g, 78.82 mmol), and [1,1- bis(diphenylphosphino)ferrocene]dich
  • reaction mixture was then cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (2 x 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • Step B.6-chloro-4-methoxy-3-[1-(trifluoromethyl)cyclopropyl]pyridazine [00486] To a cooled 0 °C solution of 6-chloro-4-methoxy-3-[1- (trifluoromethyl)vinyl]pyridazine (3.80 g, 15.9 mmol) and methyl(diphenyl)sulfonium tetrafluoroborate (5.51 g, 19.1 mmol) in tetrahydrofuran (100 mL) was added a solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (1 M, 31.85 mL, 31.85 mmol).
  • the resulting mixture was stirred at 0 °C for 30 minutes, and was then allowed to warm to 20 °C over 2 hours.
  • the reaction mixture was then cooled to 0 °C, quenched by addition of water (50 mL), and extracted with ethyl acetate (3 x 50 mL).
  • the combined organic layers were washed with saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • N-[5-methoxy-6-[1-(trifluoromethyl)cyclopropyl]pyridazin-3-yl]-1,1-diphenyl- methanimine [00487] A mixture of 6-chloro-4-methoxy-3-[1- (trifluoromethyl)cyclopropyl]pyridazine (2.50 g, 9.90 mmol), diphenylmethanimine (2.15 g, 11.9 mmol, 1.99 mL), cesium carbonate (9.67 g, 29.7 mmol), ( ⁇ )-2,2-bis(diphenylphosphino)-1,1'- binaphthalene (0.616 g, 0.990 mmol), and tris-(dibenzylideneacetone)dipalladium(0) (0.906 g, 0.990 mmol) in toluene (50 mL) was degassed and purged with nitrogen 3 times, and was then stirred at 100 °C for 16 hours
  • Step D 5-methoxy-6-[1-(trifluoromethyl)cyclopropyl]pyridazin-3-amine
  • N-[5-methoxy-6-[1- (trifluoromethyl)cyclopropyl]pyridazin-3-yl]-1,1-diphenyl-methanimine (3.00 g, 7.55 mmol) in tetrahydrofuran (30 mL) was added hydrochloric acid (6 M, 18.87 mL). The mixture was stirred at 20 °C for 3 hours, and was then washed with ethyl acetate (2 x 20 mL).
  • Step E.7-methoxy-6-[1-(trifluoromethyl)cyclopropyl]imidazo[1,2-b]pyridazine [00489] To a solution of 5-methoxy-6-[1-(trifluoromethyl)cyclopropyl]pyridazin-3- amine (1.00 g, 4.29 mmol) in ethanol (20 mL) were added sodium hydrogen carbonate (0.901 g, 10.72 mmol) and 2-chloroacetaldehyde (8.42 g, 42.9 mmol, 6.90 mL, 40% purity). The resulting mixture was stirred at 80 °C for 10 hours.
  • Step B N-((3S,4S)-4-fluoropyrrolidin-3-yl)-6-(6-methoxyimidazo[1,2-b]pyridazin-3-yl)pyridin- 2-amine [00496] To a solution of tert-butyl (3S,4S)-3-fluoro-4-[[6-(6-methoxyimidazo[1,2- b]pyridazin-3-yl)-2-pyridyl]amino]pyrrolidine-1-carboxylate (0.080 g, 0.187 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.770 g, 6.75 mmol, 0.500 mL).
  • Example 10 Exemplary Synthetic Procedure #10 (Compound 88) Compound 88, N-((3S,4S)-4-fluoropyrrolidin-3-yl)-6-(6-phenoxyimidazo[1,2-b]pyridazin-3- yl)pyridin-2-amine Step A.
  • Example 11 Exemplary Synthetic Procedure #11 (Compounds 89 – 90) Compound 89, 3-(6-(((3S,4S)-4-fluoropyrrolidin-3-yl)amino)pyridin-2-yl)-N- methylimidazo[1,2-b]pyridazin-6-amine Step A.
  • the reaction was then cooled to room temperature and concentrated under reduced pressure.
  • the resulting crude product was diluted with water (50 mL) and extracted with ethyl acetate (3 x 80 mL). The combined organic layers were then washed with saturated aqueous sodium chloride solution (60 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure.
  • Step B.6-cyclopropyl-5-methoxy-N-(4-methoxybenzyl)pyridazin-3-amine A mixture of 6-chloro-3-cyclopropyl-4-methoxy-pyridazine (4.00 g, 21.7 mmol), (4-methoxyphenyl)methanamine (8.92 g, 65.0 mmol, 8.41 mL), 4,5- bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (1.88 g, 3.25 mmol), palladuim(II)acetate (0.730 g, 3.25 mmol), and cesium carbonate (21.18 g, 65.00 mmol) in dioxane (50 mL) was degassed and purged with nitrogen three times, and was then stirred at 120 °C for 16 hours under nitrogen atmosphere.
  • Step C.6-cyclopropyl-5-methoxypyridazin-3-amine A solution of 6-cyclopropyl-5-methoxy-N-[(4- methoxyphenyl)methyl]pyridazin-3-amine (3.00 g, 10.5 mmol) in trifluoroacetic acid (30 mL) was stirred at 20 °C for 16 hours. Methanol was added, causing precipitation of a solid. The resulting mixture was filtered, and the mother liquor was concentrated under reduced pressure to provide the title compound: LCMS m/z 166.1 [M+H] + .
  • Step D.6-cyclopropyl-7-methoxyimidazo[1,2-b]pyridazine To a solution of 6-cyclopropyl-5-methoxy-pyridazin-3-amine (1.00 g, 6.05 mmol) and 2-chloroacetaldehyde (4.75 g, 60.5 mmol, 3.89 mL) in ethanol (2 mL) was added sodium bicarbonate (1.02 g, 12.1 mmol). The resulting reaction mixture was stirred at 80 °C for 4 hours, and was then cooled to room temperature and concentrated under reduced pressure. The resulting residue was diluted with water (10 mL) and extracted with ethyl acetate (3 x 10 mL).
  • Step E.3-(6-bromopyridin-2-yl)-6-cyclopropyl-7-methoxyimidazo[1,2-b]pyridazine A mixture of 6-cyclopropyl-7-methoxy-imidazo[1,2-b]pyridazine (0.600 g, 3.17 mmol), 2,6-dibromopyridine (2.25 g, 9.51 mmol), triphenylphosphine (0.125 g, 0.476 mmol), palladuim(II)acetate (0.071 g, 0.317 mmol), potassium carbonate (1.31 g, 9.51 mmol), and 2,2- dimethylpropanoic acid (0.097 g, 0.951 mmol, 109 uL) in toluene (20 mL) was degassed and purged with nitrogen three times, and was then stirred at 100 °C for 16 hours under nitrogen atmosphere.
  • Example 14 Exemplary Synthetic Procedure #14 (Compound 109) Compound 109, N-((3S,4S)-4-fluoropyrrolidin-3-yl)-6-(imidazo[1,2-b]pyridazin-3-yl)pyridin-2- amine Step A.3-(6-bromo-2-pyridyl)imidazo[1,2-b]pyridazine [00513] A mixture of imidazo[1,2-b]pyridazine (0.500 g, 4.20 mmol), 2,6- dibromopyridine (2.98 g, 12.6 mmol), potassium carbonate (1.74 g, 12.6 mmol), triphenylphosphine (0.220 g, 0.839 mmol), palladuim(II)acetate (0.094 g, 0.420 mmol), and 2,2- dimethylpropanoic acid (0.129 g, 1.26 mmol, 0.145 mL) in toluene (10 m
  • Example 15 Exemplary Synthetic Procedure #15 (Compound 110) Compound 110, 6-(7-chloroimidazo[1,2-b]pyridazin-3-yl)-N-((3S,4S)-4-fluoropyrrolidin-3- yl)pyridin-2-amine Step A.
  • tert-butyl (5-chloropyridazin-3-yl)carbamate [00516] A mixture of 3,5-dichloropyridazine (2.00 g, 13.4 mmol), tert-butyl carbamate (1.57 g, 13.4 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (1.10 g, 1.34 mmol), cesium carbonate (13.12 g, 40.27 mmol), and 4,5- bis(diphenylphosphino)-9,9-dimethyl-9 H-xanthene (0.777 g, 1.34 mmol) in toluene (20 mL) was degassed and purged with nitrogen three times, and was then stirred at 80 °C for 16 hours under nitrogen atmosphere.
  • reaction mixture was then cooled to room temperature, filtered, and concentrated under reduced pressure.
  • the resulting residue was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure.
  • Step B.5-chloropyridazin-3-amine A mixture of tert-butyl N-(5-chloropyridazin-3-yl)carbamate (1.70 g, 7.40 mmol) and trifluoroacetic acid (15.4 g, 135 mmol, 10.0 mL) in dichloromethane (20 mL) was stirred for 0.5 hour at 20 °C. The reaction mixture was then concentrated under reduced pressure to provide the title compound: LCMS m/z 259.0 [M+H] + .
  • Step C.7-chloroimidazo[1,2-b]pyridazine To a solution of 5-chloropyridazin-3-amine (1.30 g, 10.0 mmol) and sodium bicarbonate (1.69 g, 20.07 mmol) in ethanol (20 mL) was added 2-chloroacetaldehyde (14.07 g, 71.70 mmol, 11.53 mL, 40% purity). The resulting reaction mixture was stirred at 80 °C for 4 hours, and was then cooled to room temperature and concentrated under reduced pressure. The resulting residue was diluted with water (20 mL) and extracted with ethyl acetate (3 x 30 mL).
  • Step D.3-(6-bromopyridin-2-yl)-7-chloroimidazo[1,2-b]pyridazine A mixture of 7-chloroimidazo[1,2-b]pyridazine (0.900 g, 5.86 mmol), 2,6- dibromopyridine (4.16 g, 17.6 mmol), potassium carbonate (2.43 g, 17.6 mmol), triphenylphosphine (0.231 g, 0.879 mmol), 2,2-dimethylpropanoic acid (0.180 g, 1.76 mmol, 0.202 mL), and palladuim(II)acetate (0.132 g, 0.586 mmol) in toluene (20 mL) was degassed and purged with nitrogen three times, and was then stirred at 100 °C for 16 hours under nitrogen atmosphere.
  • Example 16 Exemplary Synthetic Procedure #16 (Compound 111) Compound 111, 6-(7-cyclopropylimidazo[1,2-b]pyridazin-3-yl)-N-((3S,4S)-4-fluoropyrrolidin- 3-yl)pyridin-2-amine Step A.
  • Step B 6-(7-cyclopropylimidazo[1,2-b]pyridazin-3-yl)-N-((3S,4S)-4-fluoropyrrolidin-3- yl)pyridin-2-amine
  • a mixture of tert-butyl (3S,4S)-3-[[6-(7-cyclopropylimidazo[1,2- b]pyridazin-3-yl)-2-pyridyl]amino]-4-fluoro-pyrrolidine-1-carboxylate (0.100 g, 0.228 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol, 1.00 mL).
  • Example 17 Exemplary Synthetic Procedure #17 (Compound 112) Compound 112, N-((3S,4S)-4-fluoropyrrolidin-3-yl)-6-(7-(1- (trifluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-amine Step A.7-(3,3,3-trifluoroprop-1-en-2-yl)imidazo[1,2-b]pyridazine [00524] A mixture of 7-chloroimidazo[1,2-b]pyridazine (0.291 g, 1.89 mmol), 4,4,6-trimethyl-2-[1-(trifluoromethyl)vinyl]-1,3,2-dioxaborinane (0.400 g, 1.80 mmol), [1,1- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.132 g, 0.180 mmol), and
  • Step B.7-(1-(trifluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazine [00525] To a cooled 0 °C solution of 7-[1-(trifluoromethyl)vinyl]imidazo[1,2- b]pyridazine (0.250 g, 1.17 mmol) and methyl(diphenyl)sulfonium tetrafluoroborate (0.405 g, 1.41 mmol) in tetrahydrofuran (3 mL) was added a solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (1 M, 2.35 mL, 2.35 mmol).
  • the resulting reaction was stirred at 0 °C for 0.5 hour, warmed to 20 °C, and stirred for an additional 2 hours.
  • the reaction mixture was then quenched by addition of water (5 mL) at 0 °C and extracted with ethyl acetate (3 x 5 mL).
  • the combined organic layers were washed with saturated aqueous sodium chloride solution (5 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure.
  • the resulting crude product was purified by flash chromatography on silica gel (0 – 30% ethyl acetate in petroleum ether) to provide the title compound: LCMS m/z 228.1 [M+H] + .
  • Step C.3-(6-bromopyridin-2-yl)-7-(1-(trifluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazine [00526] A mixture of 7-[1-(trifluoromethyl)cyclopropyl]imidazo[1,2-b]pyridazine (0.130 g, 0.572 mmol), 2,6-dibromopyridine (0.407 g, 1.72 mmol), palladuim(II)acetate (0.013 g, 0.057 mmol), triphenylphosphine (0.023 g, 0.086 mmol), 2,2-dimethylpropanoic acid (0.018 g, 0.172 mmol, 0.020 mL), and potassium carbonate (0.237 g, 1.72 mmol) in toluene (1 mL) was degassed and purged with nitrogen three times, and was then stirred at 100 °C for 16 hours under nitrogen
  • Example 18 Exemplary Synthetic Procedure #18 (Compound 113) Compound 113, 2-(3-(6-(((3S,4S)-4-fluoropyrrolidin-3-yl)amino)pyridin-2-yl)imidazo[1,2- b]pyridazin-7-yl)propan-2-ol Step A.
  • Step B 2-imidazo[1,2-b]pyridazin-7-ylpropan-2-ol
  • methyl imidazo[1,2-b]pyridazine-7- carboxylate (0.500 g, 2.82 mmol) in tetrahydrofuran (15 mL)
  • magnesium methyl bromide (3 M in diethyl ether, 5.64 mL).
  • the resulting reaction was stirred at 0 °C for 2 hours, and was then quenched by addition of water (15 mL) at 0 °C, and extracted with ethyl acetate (3 x 15 mL).
  • Example 19 Exemplary Synthetic Procedure #19 (Compounds 114 – 115) Compound 114, 6-(7-(2,2-difluoroethoxy)imidazo[1,2-b]pyridazin-3-yl)-N-((3S,4S)-4- fluoropyrrolidin-3-yl)pyridin-2-amine Step A.
  • Step B 6-(7-(2,2-difluoroethoxy)imidazo[1,2-b]pyridazin-3-yl)-N-((3S,4S)-4-fluoropyrrolidin-3- yl)pyridin-2-amine
  • a solution tert-butyl (3S,4S)-3-[[6-[7-(2,2-difluoroethoxy)imidazo[1,2- b]pyridazin-3-yl]-2-pyridyl]amino]-4-fluoro-pyrrolidine-1-carboxylate (0.080 g, 0.167 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1.23 g, 10.8 mmol, 0.80 mL).
  • tert-butyl (6-formyl-5-methoxypyridazin-3-yl)carbamate [00538] To a solution of tert-butyl N-(5-methoxy-6-vinyl-pyridazin-3-yl)carbamate (5.60 g, 22.3 mmol) in dioxane (45 mL) and water (15 mL) were added sodium periodate (7.15 g, 33.4 mmol, 1.85 mL), osmium tetroxide (0.453 g, 1.78 mmol), and 2,6-dimethylpyridine (4.78 g, 44.6 mmol, 5.19 mL), in that order.
  • tert-butyl (6-(difluoromethyl)-5-methoxypyridazin-3-yl)carbamate
  • dichloromethane 15 mL
  • diethylamino-sulfur trifluoride 1.91 g, 11.9 mmol, 1.57 mL
  • tert-butyl (6-(difluoromethyl)-5-methoxypyridazin-3-yl)carbamate
  • dichloromethane 10 mL
  • trifluoroacetic acid 4.62 g, 40.5 mmol, 3.00 mL
  • the resulting reaction was stirred at room temperature for 1 hour, and was then concentrated under reduced pressure to give the title compound: LCMS m/z 176.1 [M+H] + .
  • Step F.3-(6-bromopyridin-2-yl)-6-(difluoromethyl)-7-methoxyimidazo[1,2-b]pyridazine [00541] To a solution of 2-bromo-6-[(E)-2-ethoxyvinyl]pyridine (2.15 g, 9.42 mmol) in dioxane (15 mL) and water (5 mL) was added 1-bromopyrrolidine-2,5-dione (1.68 g, 9.42 mmol). The resulting reaction mixture was stirred at room temperature for 1 hour.
  • 6- (difluoromethyl)-5-methoxy-pyridazin-3-amine (1.10 g, 6.28 mmol) was then added, and the resulting mixture was heated at 80 °C for 15 hours.
  • the reaction was then cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (2 x 30 mL). The organic extracts were combined, washed with saturated aqueous sodium chloride solution (2 x 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • Example 21 Exemplary Synthetic Procedure #21 (Compounds 119 – 122) Compound 119, N-((3S,4S)-4-fluoropyrrolidin-3-yl)-6-(6-(1-methyl-1H-pyrazol-4- yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-amine Step A.6-chloro-4-methoxy-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl) pyridazine [00545] A mixture of 3,6-dichloro-4-methoxypyridazine (6.00 g, 33.5 mmol), 1- tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)
  • the reaction mixture was then cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (3 x 50 mL). The organic extracts were combined, washed with saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel (0 – 100% ethyl acetate in petroleum ether) to provide the title compound: LCMS m/z 396.2 [M+H] + .
  • Step C 5-methoxy-6-(1H-pyrazol-4-yl)pyridazin-3-amine
  • Step D.7-methoxy-6-(1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine [00548] To a solution of 5-methoxy-6-(1H-pyrazol-4-yl)pyridazin-3-amine (1.50 g, 4.91 mmol, TFA salt) and 2-chloroacetaldehyde (4.82 g, 24.57 mmol, 3.95 mL, 40% purity) in ethanol (20 mL) was added sodium bicarbonate (0.826 g, 9.83 mmol).
  • the resulting reaction was heated at 80 °C for 2 hours. The reaction was then cooled to room temperature, concentrated under reduced pressure, diluted with water (5 mL), and extracted with ethyl acetate (3 x 8 mL). The organic extracts were combined, washed with saturated aqueous sodium chloride solution (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel (0 – 15% methanol in dichloromethane) to provide the title compound: LCMS m/z 216.2 [M+H] + .
  • Step E.7-methoxy-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine [00549] To a solution of 7-methoxy-6-(1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine (0.600 g, 1.82 mmol, TFA salt) in tetrahydrofuran (20 mL) were added 3,4-dihydro-2H-pyran (0.920 g, 10.9 mmol) and 4-methylbenzenesulfonic acid pyridine (0.458 g, 1.82 mmol).
  • reaction mixture was then cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (3 x 60 mL). The organic extracts were combined, washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • Step B 2-(6-chloro-4-methoxypyridazin-3 -yl) propan-2-ol
  • Step D 2-(6-amino-4-methoxypyridazin-3-yl)propan-2-ol
  • 2-[4-methoxy-6-[(4- methoxyphenyl)methylamino]pyridazin-3-yl]propan-2-ol (1.30 g, 4.29 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (0.489 g, 4.29 mmol, 0.317 mL).
  • the resulting reaction was stirred at 50 °C for 12 hours, and was then cooled to room temperature and concentrated under reduced pressure.
  • Step E 2-(7-methoxyimidazo[1,2-b]pyridazin-6-yl)propan-2-ol
  • 2-(6-amino-4-methoxy-pyridazin-3-yl)propan-2-ol (0.800 mg, 4.37 mmol) and 2-chloroacetaldehyde (4.28 g, 21.8 mmol, 3.51 mL, 40% purity) in ethanol (10 mL) was added sodium bicarbonate (0.734 g, 8.73 mmol).
  • Step F 2-(3-(6-bromopyridin-2-yl)-7-methoxyimidazo[1,2-b]pyridazin-6-yl)propan-2-ol
  • 2-(7-methoxyimidazo[1,2-b]pyridazin-6-yl)propan-2-ol (0.240 g, 1.16 mmol) and 2,6-dibromopyridine (0.823 g, 3.47 mmol) in toluene (3 mL) were added triphenylphosphine (0.046 g, 0.174 mmol), 2,2-dimethylpropanoic acid (0.035 g, 0.347 mmol, 0.040 mL), potassium carbonate (0.480 g, 3.47 mmol), and palladuim(II)acetate (0.026 g, 0.116 mmol).
  • Example 23 Exemplary Synthetic Procedure #23 (Compounds 129 – 130) Compound 129, 6-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-7-methoxyimidazo[1,2-b]pyridazin- 3-yl)-N-((3S,4S)-4-fluoropiperidin-3-yl)pyridin-2-amine Step A.6-chloro-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-methoxypyridazine [00562] A mixture of 3,6-dichloro-4-methoxy-pyridazine (6.00 g, 33.5 mmol), 1- (difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (8.18 g
  • Step C.6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-5-methoxypyridazin-3-amine [00564] A mixture of 6-[1-(difluoromethyl)pyrazol-4-yl]-5-methoxy-N-[(4- methoxyphenyl)methyl]pyridazin-3-amine (0.500 g, 1.38 mmol) in trifluoroacetic acid (10 mL) was stirred at 50 °C for 16 hours under nitrogen atmosphere. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure.
  • Step D.3-(6-bromopyridin-2-yl)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-7-methoxyimidazo[1,2- b]pyridazine [00565] To a solution of 2-bromo-6-[(E)-2-ethoxyvinyl]pyridine (1.05 g, 4.61 mmol) in dioxane (15 mL) and water (5 mL) was added 1-bromopyrrolidine-2,5-dione (0.821 g, 4.61 mmol).
  • Step F 6-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-7-methoxyimidazo[1,2-b]pyridazin-3-yl)-N- ((3S,4S)-4-fluoropiperidin-3-yl)pyridin-2-amine [00567] To a solution of (3S,4S)-tert-butyl 3-((6-(6-(1-(difluoromethyl)-1H- pyrazol-4-yl)-7-methoxyimidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)amino)-4-fluoropiperidine-1- carboxylate (0.050 g, 0.090 mmol) in dichloromethane (3 mL) was added trifluor
  • reaction mixture was then cooled to room temperature. Hydrochloric acid (2 M, 210 mL) was added, and the resulting mixture was stirred at room temperature for 1 hour. The reaction was then quenched by addition of aqueous 20% potassium fluoride solution (100 mL), and extracted with ethyl acetate (3 x 100 mL). The organic extracts were combined, washed with saturated aqueous sodium chloride solution (3 x 50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure.
  • Step B 2-(6-chloro-4-methoxypyridazin-3-yl)-1,1,1-trifluoropropan-2-ol
  • 1-(6-chloro-4-methoxy-pyridazin-3-yl)ethanone (4.00 g, 21.4 mmol) in tetrahydrofuran (50 mL) were added cesium fluoride (3.26 g, 21.4 mmol) and trimethyl(trifluoromethyl)silane (6.10 g, 42.9 mmol).
  • cesium fluoride 3.26 g, 21.4 mmol
  • trimethyl(trifluoromethyl)silane 6.10 g, 42.9 mmol
  • Step C 1,1,1-trifluoro-2-(4-methoxy-6-((4-methoxybenzyl)amino)pyridazin-3-yl)propan-2-ol
  • Step D 2-(6-amino-4-methoxypyridazin-3-yl)-1,1,1-trifluoropropan-2-ol
  • the resulting reaction was stirred at room temperature for 16 hours, and was then concentrated under reduced pressure.
  • the resulting crude product was purified by HPLC (Phenomenex Luna C18 column, 5 micron, 150 x 30 mm; 1 – 37% acetonitrile in water containing 0.04% trifluoroacetic acid) to give a product that was further purified by SFC (Daicel Chiralpak IC column, 10 micron, 250 x 30 mm; mobile phase: [0.1% ammonium hydroxide IPA]; B%: 60%- 60%) to provide the title compounds as diastereomers of unknown absolute configuration.
  • 6-chloro-4-methoxy-pyridazin-3-amine (2.00 g, 12.5 mmol) in dichloromethane (20 mL) were added triethylamine (2.54 g, 25.1 mmol, 3.49 mL) and 4-bromobutanoyl chloride (4.65 g, 25.1 mmol, 2.91 mL).
  • the resulting mixture was stirred at room temperature for 1 hour.
  • Potassium carbonate (2.60 g, 18.8 mmol) was then added, and the mixture was stirred at room temperature for an additional 15 hours.
  • tert-butyl (5-methoxy-6-(2-oxopyrrolidin-1-yl)pyridazin-3-yl)carbamate
  • Step D.1-(6-amino-4-methoxypyridazin-3-yl)pyrrolidin-2-one [00580] To a solution of tert-butyl N-[5-methoxy-6-(2-oxopyrrolidin-1- yl)pyridazin-3-yl]carbamate (0.050 g, 0.162 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.770 g, 6.75 mmol, 0.50 mL). The resulting reaction was stirred at room temperature for 2 hours, and was then filtered and concentrated under reduced pressure to give the title compound: LCMS m/z 209.1 [M+H] + .
  • Step E.1-(6-amino-4-methoxypyridazin-3-yl)pyrrolidin-2-one To a solution of 2-bromo-6-[(E)-2-ethoxyvinyl]pyridine (0.082 g, 0.360 mmol) in dioxane (3 mL) and water (1 mL) was added 1-bromopyrrolidine-2,5-dione (0.064 g, 0.360 mmol).
  • Example 26 Biological Data for Exemplary Compounds
  • Kinase inhibitory data were obtained for various exemplary compounds prepared according to Examples 1-25 using the RBC HotSpot Kinase Assay Protocol (Anastassiadis T, et al. Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat Biotechnol.2011 Oct 30; 29(11):1039-45), as described below.
  • This assay uses the isolated kinase enzyme. This assay is very useful for determining competition of the inhibitor for ATP and/or substrates and for measuring the kinetics of enzyme inhibition. It also allows for measuring the relative affinity of binding to the isolated enzyme protein, and hence determines selectivity.
  • the HotSpot Kinase Assay is a functional assay that measures catalytic activity; as such it measures relative functional potency regardless of the mechanism of enzyme inhibition.
  • This assay uses the form of the various enzymes that are easiest to express, which may not necessarily be the form of the enzyme that exist in the cell.
  • the reagent used was as follows: Base Reaction buffer; 20 mM Hepes (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.01% Brij35, 0.02 mg/ml BSA, 0.1 mM Na3VO4, 2 mM DTT, 1% DMSO. Required cofactors were added individually to each kinase reaction. [00586] The reaction procedure was as follows: 1) Substrates were prepared in freshly prepared Reaction Buffer.
  • Example 27 Biological Data for Exemplary Compounds
  • Kinase binding data were obtained for various exemplary compounds prepared according to Examples 1-25 using the DiscoverX KINOMEscan ® active site-directed competition binding site-directed assay protocol described below. Unlike other kinase competitive binding site assays, KINOMEscan ® assays do not require ATP. As a result, the data report thermodynamic interaction affinities (K d values), rather than IC 50 values that are dependent on ATP concentrations. The assay uses a DNA-tagged version of the protein kinase, and an immobilized ligand bound to a solid support.
  • coli were grown to log-phase and infected with T7 phage and incubated with shaking at 32 °C until lysis. The lysates were centrifuged and filtered to remove cell debris. The remaining kinases were produced in HEK-293 cells and subsequently tagged with DNA for qPCR detection. Streptavidin-coated magnetic beads were treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase assays. The liganded beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and to reduce non- specific binding.
  • blocking buffer SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT
  • Binding reactions were assembled by combining kinases, liganded affinity beads, and test compounds in 1x binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT).
  • Test compounds were prepared as 111x stocks in 100% DMSO. Kds were determined using an 11-point 3-fold compound dilution series with three DMSO control points. All compounds for K d measurements are distributed by acoustic transfer (non-contact dispensing) in 100% DMSO. The compounds were then diluted directly into the assays such that the final concentration of DMSO was 0.9%. All reactions were performed in polypropylene 384-well plates. Each was a final volume of 0.02 mL.
  • Binding constants were calculated with a standard dose-response curve using the Hill equation. The Hill Slope was set to -1. Curves were fitted using a non-linear least square fit with the Levenberg-Marquardt algorithm. Table 17.
  • the NanoBRET assay measures kinase engagement in real time in the context of the intact cell. Unlike the previously described biochemical kinase assay methodologies in Examples 26-27, the NanoBRET assay measures the binding and activity characteristics under equilibrium conditions using full-length kinases in the presence of cellular concentrations of ATP in live, uncompromised cells.
  • the assay provides a more relevant assessment of kinase potency and selectivity that would be expected to be observed in the native cellular environment, where potency is often considerably lower than that observed in the isolated biochemical assays (Vasta, J.D. et al., (2016) Cell Chem. Biol. 25, 206-214).
  • the assay uses a Kinase-NanoLuc ® fusion vector expressing a kinase protein to which a luciferase tag has been added, a cell-permeant fluorescent NanoBRETTM tracer, a NanoLuc ® substrate, and an extracellular NanoLuc ® inhibitor.
  • HEK-293 cells Upon expression of the luciferase-tagged kinase, cells will produce a strong BRET signal only in the presence of the NanoBRETTM tracer.
  • the extracellular NanoLuc ® inhibitor ensures that the BRET signal observed emanates only from live cells. Because the BRET signal has tight distance constraints, addition of the test compound will decrease the BRET signal if the compound competes with the NanoBRETTM tracer for binding to the kinase domain. Under the appropriate tracer conditions established by the manufacturer, quantitative intracellular affinity and relative potency can then be determined using Mass Action model equations.
  • HEK-293 cells were purchased from ATCC.
  • FuGENEHD Transfection Reagent Kinase-NanoLucfusion plasmids, Transfection Carrier DNA, NanoBRETTracers and dilution buffer, NanoBRETNano-Glo Substrate, Extracellular NanoLucInhibitor were obtained from Promega.
  • Assays were conducted following Promega assay protocol with some modifications.
  • HEK-293 Cells were transiently transfected with Kinase-NanoLucFusion Vector DNA by FuGENEHD Transfection Reagent. Testing compounds were delivered into 384 well assay plate by Echo 550 (LabcyteInc, Sunnyvale, CA).
  • Transfected cells were harvested and mixed with NanoBRETTracer Reagent and dispensed into 384 well plates and incubated at 37 oC in 5% CO 2 cell culture incubator for 1 hour.
  • the NanoBRETNano-Glo Substrate plus Extracellular NanoLucInhibitor Solution were added into the wells of the assay plate and incubated for 2 - 3 minutes at room temperature.
  • the donor emission wavelength (460 nm) and acceptor emission wavelength (600 nm) were measured in the EnVisionplate reader.
  • the BRET Ratios were calculated.
  • BRET Ratio [(Acceptor sample ⁇ Donor sample) – (Acceptor no-tracer control ⁇ Donor no-tracer control)].
  • NanoBRETTM Target Engagement Assay Protocol 1. Transient Transfection of HEK-293 Cells NanoLuc® Fusion Vector DNA 1). Cultivate HEK-293 cells (70-80% confluence) appropriately prior to assay. Trypsinize and collect HEK-293 cells. 2).
  • NanoBRETTM Assay 1). Remove plate from incubator and equilibrate to room temperature for 15 minutes. 2). Prepare 3X Complete Substrate plus Inhibitor Solution in Assay Medium (Opti- MEMR I Reduced Serum Medium, no phenol red) just before measuring BRET. 3). Add 3X Complete Substrate plus Inhibitor Solution to each well of the 384-well plate. Incubate for 2–3 minutes at room temperature. 4). Measure donor emission wavelength (460 nm) and acceptor emission wavelength (600 nm) using the Envision 2104 plate reader. 5.
  • BRET Ratio To generate raw BRET ratio values, divide the acceptor emission value (600 nm) by the donor emission value (460 nm) for each sample. To correct for background, subtract the BRET ratio in the absence of tracer (average of no-tracer control samples) from the BRET ratio of each sample.
  • THP-1-Blue NF- ⁇ B cells (InvivoGen) carrying a stable integrated NF- ⁇ B- inducible secreted embryonic alkaline phosphatase (SEAP) reporter construct were plated at a concentration of 1 x 10 5 cells per well. The cells were stimulated with Pam3CSK4 (1ng/mL) or hIL1B (1ng/mL).
  • the cells were then treated with vehicle (DMSO) or serial dilutions of the test compounds (10 doses tested for each test compound, with a 1:10 dilution series starting at 1 ⁇ M or 3 ⁇ M) with a final volume of 200 ⁇ L for 24 hours at 37 °C. After 24 hours, the cells were centrifuged and 20 ⁇ L supernatant was incubated with 180 ⁇ L QUANTI-Blue reagent at 37 °C for 30 – 60 minutes. The levels of NF- ⁇ B-induced gene expression were measured in a microplate reader at 620 nm. Table 20. Biological data obtained in accordance with the protocol described in Example 29.
  • Example 30 Biological Data for Exemplary Compounds
  • Cellular potency data were obtained for various exemplary compounds prepared according to Examples 1-25, using the MOLM14 D835Y and MOLM14 F691L cell viability assay protocols described below. Both cell lines have activated FLT3 receptors, each of which carry additional resistance mutations in the kinase domain (D835Y and F691L, respectively). Leukemias from patients harboring these kinase domain resistance mutations are resistant to FLT3 inhibitors that do not inhibit the mutant kinase.
  • cells were seeded into 1536-well white polystyrene tissue culture-treated Greiner plates using a Multidrop Combi dispenser (ThermoFisher), in final volume 5 ⁇ L of growth media per well, at a density of 1000 cells per well. After cell addition, 23 nL of test compound were transferred into individual wells (22 doses tested for each test compound, with a 1:2 dilution series starting at 10 ⁇ M) via a 1536 pin-tool. Bortezomib (final concentration 2.3 ⁇ M) was used as a positive control for cell cytotoxicity.
  • ThermoFisher Multidrop Combi dispenser
  • MOLM14 (D835Y) cells were then added to compound-containing plates at a density of 500-cells/well in 5 ⁇ L of medium. A 10- point custom concentration range was used for all listed drugs. Plates were incubated for 48 hours at standard incubator conditions covered by a stainless steel gasketed lid to prevent evaporation. 48h post compound addition, 3 ⁇ L of Cell Titer Glo (Promega) were added to each well and plates were incubated at room temperature for 15 minutes with the stainless-steel lid in place. Luminescence readings were taken using a Viewlux imager (PerkinElmer) with a 2 second exposure time per plate. The results can be seen in Tables 22-23 and FIGS.1A-3B. Table 22.
  • Table 22 summarizes the combination results of Compounds 96, 99, 102, 106, and 108 with Venetoclax.
  • the large negative sum excess HSA score indicates profound synergism for each of these compounds with Venetoclax.
  • a combination analysis of Compound 106 and Venetoclax was obtained in a 10 x 10 dataset in the MOLM14 (FLT3 ITD, D835Y) cancer cell model.
  • cell viability % response
  • FOG.1A drug concentration
  • FIG 1B measures the degree of synergy as an excess HSA score, with the degree of synergy being highest for those drug combinations where the largest negative excess HSA values are observed.
  • a similar analysis of Compound 108 and Venetoclax was obtained in a 10 x 10 array in the MOLM14 (FLT3 ITD, D835Y) cancer cell model.
  • the excess HSA scores in FIG.2B illustrate that the synergy is highest when combining 15.6 nM Venetoclax with 0.8-1.6 nM Compound 108.
  • Table 23 Sum Excess HSA scores for a combination therapy of Compound 96 and an additional pharmaceutically active compound obtained in MOLM14 (D835Y) cells in a 10 x 10 dataset.
  • Table 23 summarizes the combination results of Compound 96 with 24 pharmaceutically active compounds obtained in MOLM14 (FLT3 ITD, D835Y) cells in a 10 x 10 dataset. Certain drug combinations are synergistic as reflected by negative sum excess HSA scores, whereas other drug combinations are antagonistic as reflected by positive sum excess HSA scores. [0002] The excess HSA scores for Compounds 96, 99, 102, 106, and 108 in Tables 22-23 are used herein to quantitate drug interactions for enhanced pharmacological effects. More information on excess HSA scores can be found in Vlot, Anna H. C. et al., Drug Discovery Today, 2019, 24(12):2286-2298.
  • excess HSA method is preferred because it does not require making assumptions about similarities in the mechanism of action of the drugs involved or the shape of the dose-response curves being compared and does not place arbitrary requirements on the computational algorithm that the two drugs produce similar efficacy in the given system.
  • different methodologies may yield different numerical scores, and different definitions of what constitutes a deviation from mere additivity vs true drug synergy.
  • a negative excess HSA score illustrates that the drug combination is better than either drug alone (at the concentrations being studied), and the excess HSA score is a measurement of the overall deviation from additivity that is observed across the entire matrix of concentrations studied.
  • the drug combinations that are noteworthy as having more profound synergistic effects are those with greater negative excess HSA scores.
  • the utility in certain drug combinations vs others should not be distinguished based on cutoffs between HSA scores, because the score itself is only a relative indicator that is completely dependent on experimental design and is not an absolute number.
  • the concept of what constitutes clinically meaningful drug synergy is something that is still being debated, not only between pharmacologists and physicians, but amongst pharmacologists themselves.
  • FIGS.3A-3B illustrate the relative potency of 36 compounds to synergize with Venetoclax in the Cell Titer Glo assay using a 10 x 10 array in the MOLM14 (FLT3 ITD, D835Y) cancer cell model.
  • the numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth, used to describe and claim certain embodiments of the application are to be understood as being modified in some instances by the term “about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the application are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable.

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WO2025029929A1 (en) * 2023-07-31 2025-02-06 Children's Hospital Medical Center Multi-cyclic irak1 and irak4 inhibiting compounds and uses thereof
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